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Propylene glycol dinitrate (PGDN, 1,2-propylene glycol dinitrate, or 1,2-propanediol dinitrate) is an organic chemical, an ester of nitric acid and propylene glycol. It is structurally similar to nitroglycerin, except that it has one fewer nitrate group. It is a characteristically and unpleasantly smelling colorless liquid, which decomposes at 121 °C, below its boiling point. It is flammable and explosive. It is shock-sensitive and burns with a clean flame producing water vapor, carbon monoxide, and nitrogen gas.
C3H6(ONO2)2 → 3 CO + 3 H2O + N2
The principal current use of propylene glycol dinitrate is as a propellant in Otto Fuel II, together with 2-nitrodiphenylamine and dibutyl sebacate. Otto Fuel II is used in some torpedoes as a propellant.
Nitrates of polyhydric alcohols, of which propylene glycol dinitrate is an example, have been used in medicine for the treatment of angina pectoris, and as explosives since the mid-nineteenth century.
PGDN affects blood pressure, causes respiratory toxicity, damages liver and kidneys, distorts vision, causes methoglobinuria, and can cause headache and lack of coordination. It may be absorbed through skin. Its primary toxicity mechanism is methemoglobinemia. It may cause permanent nerve damage.
For occupational exposures, the National Institute for Occupational Safety and Health has set a recommended exposure limit at 0.05 ppm (0.3 mg/m3) over an eight-hour workday, for dermal exposures.
== References ==
== Further reading ==
Schmidt, Eckart W. (2022). "1,2‑Propylene Glycol Dinitrate". Nitrate Esters. Encyclopedia of Oxidizers. De Gruyter. pp. 1936–1959. doi:10.1515/9783110750294-013. ISBN 978-3-11-075029-4. | Wikipedia/Propylene_glycol_dinitrate |
Berkelium(III) nitrate is the berkelium salt of nitric acid with the formula Bk(NO3)3. It commonly forms the tetrahydrate, Bk(NO3)3·4H2O, which is a light green solid. If heated to 450 °C, it decomposes to berkelium(IV) oxide and 22 milligrams of the solution of this compound is reported to cost one million dollars.
== Production and uses ==
Berkelium(III) nitrate is produced by the reaction of berkelium metal, the hydroxide, or chloride with nitric acid. This compound has no commercial uses, but was used to synthesize the element tennessine. The aqueous compound was painted onto a titanium foil and was bombarded with calcium-48 atoms to synthesize the element tennessine.
This compound is used as a pathway to pentavalent berkelium compounds by the collision-induced dissociation of this compound to produce BkO2(NO3)2– which contains berkelium in the +5 oxidation state.
== References == | Wikipedia/Berkelium(III)_nitrate |
Plutonium (IV) nitrate is an inorganic compound, a salt of plutonium and nitric acid with the chemical formula Pu(NO3)4. The compound dissolves in water and forms crystalline hydrates as dark green crystals.
== Synthesis ==
Crystals of dark green to black-green composition Pu(NO3)4•5H2O precipitate with a slow (months) evaporation of a solution of a plutonium (IV) compound in nitric acid.
== Physical properties ==
Plutonium (IV) nitrate forms a crystalline hydrate of the composition Pu(NO3)4•5H2O—dark green crystals of rhombic crystal structure, space group F dd2, cell parameters: a = 1.114 nm, b = 2.258 nm, c = 1.051 nm, Z = 8.
Crystalline hydrate melts in its own crystallization water at 95–100 °C.
It dissolves well in nitric acid (dark green solution) and water (brown solution). Also dissolves in acetone and ether.
== Chemical properties ==
When heated to 150–180 °C, it decomposes with autooxidation to plutonium (VI) with the formation of plutonyl nitrate (PuO2(NO3)2).
Upon evaporation of concentrated nitric acid solutions of plutonium nitrate and alkali metal nitrates, double nitrates of the composition M2[Pu(NO3)6] are formed, where M = Cs+, Rb+, K+, Tl+, NH4+, analogous to ceric ammonium nitrate.
== Toxicity ==
Plutonium nitrate is both radioactive and extremely toxic due to its high solubility in water.
== References == | Wikipedia/Plutonium(IV)_nitrate |
Zinc nitrate is an inorganic chemical compound with the formula Zn(NO3)2. This colorless, crystalline salt is highly deliquescent. It is typically encountered as a hexahydrate Zn(NO3)2·6H2O. It is soluble in both water and alcohol.
== Synthesis ==
Zinc nitrate is usually prepared by dissolving zinc metal, zinc oxide, or related materials in nitric acid:
Zn + 2 HNO3 → Zn(NO3)2 + H2
ZnO + 2 HNO3 → Zn(NO3)2 + H2O
These reactions are accompanied by the hydration of the zinc nitrate.
The anhydrous salt arises by the reaction of anhydrous zinc chloride with nitrogen dioxide:
ZnCl2 + 4 NO2 → Zn(NO3)2 + 2 NOCl
== Reactions ==
Treatment of zinc nitrate with acetic anhydride gives zinc acetate.
On heating, zinc nitrate undergoes thermal decomposition to form zinc oxide, nitrogen dioxide and oxygen:
2 Zn(NO3)2 → 2 ZnO + 4 NO2 + 1 O2
Aqueous zinc nitrate contains aquo complexes [Zn(H2O)6]2+ and [Zn(H2O)4]2+. and, thus, this reaction may be better written as the reaction of the aquated ion with hydroxide through donation of a proton, as follows.
== Applications ==
Zinc nitrate has no large scale application but is used on a laboratory scale for the synthesis of coordination polymers. Its controlled decomposition to zinc oxide has also been used for the generation of various ZnO based structures, including nanowires.
It is used as a corrosion inhibitor.
It can be used as a mordant in dyeing. An example reaction gives a precipitate of zinc carbonate:
Zn(NO3)2 + Na2CO3 → ZnCO3 + 2 NaNO3
== References == | Wikipedia/Zinc_nitrate |
Rhodium(III) nitrate is a inorganic compound, a salt of rhodium and nitric acid with the formula Rh(NO3)3. This anhydrous complex has been the subject of theoretical analysis but has not been isolated. However, a dihydrate and an aqueous solution are known with similar stoichiometry; they contain various hexacoordinated rhodium(III) aqua and nitrate complexes. A number of other rhodium nitrates have been characterized by X-ray crystallography: Rb4[trans-[Rh(H2O)2(NO3)4][Rh(NO3)6] and Cs2[-[Rh(NO3)5]. Rhodium nitrates are of interest because nuclear wastes, which contain rhodium, are recycled by dissolution in nitric acid.
== Uses ==
Rhodium(III) nitrate is used as a precursor to synthesize rhodium.
== References == | Wikipedia/Rhodium(III)_nitrate |
Ammonium nitrate is a chemical compound with the formula NH4NO3. It is a white crystalline salt consisting of ions of ammonium and nitrate. It is highly soluble in water and hygroscopic as a solid, but does not form hydrates. It is predominantly used in agriculture as a high-nitrogen fertilizer.
Its other major use is as a component of explosive mixtures used in mining, quarrying, and civil construction. It is the major constituent of ANFO, an industrial explosive which accounts for 80% of explosives used in North America; similar formulations have been used in improvised explosive devices.
Many countries are phasing out its use in consumer applications due to concerns over its potential for misuse. Accidental ammonium nitrate explosions have killed thousands of people since the early 20th century. Global production was estimated at 21.6 million tonnes in 2017. By 2021, global production of ammonium nitrate was down to 16.7 million tonnes.
== Occurrence ==
Ammonium nitrate is found as the natural mineral gwihabaite (formerly known as nitrammite) – the ammonium analogue of saltpetre (mineralogical name: niter) – in the driest regions of the Atacama Desert in Chile, often as a crust on the ground or in conjunction with other nitrate, iodate, and halide minerals. Ammonium nitrate was mined there until the Haber–Bosch process made it possible to synthesize nitrates from atmospheric nitrogen, rendering nitrate mining obsolete.
== Production, reactions and crystalline phases ==
The industrial production of ammonium nitrate entails the acid-base reaction of ammonia with nitric acid:
HNO3 + NH3 → NH4NO3
The ammonia required for this process is obtained by the Haber process from nitrogen and hydrogen. Ammonia produced by the Haber process can be oxidized to nitric acid by the Ostwald process. Ammonia is used in its anhydrous form (a gas) and the nitric acid is concentrated. The reaction is violent owing to its highly exothermic nature. After the solution is formed, typically at about 83% concentration, the excess water is evaporated off to leave an ammonium nitrate (AN) content of 95% to 99.9% concentration (AN melt), depending on grade. The AN melt is then made into "prills" or small beads in a spray tower, or into granules by spraying and tumbling in a rotating drum. The prills or granules may be further dried, cooled, and then coated to prevent caking. These prills or granules are the typical AN products in commerce.
Another production method is a variant of the nitrophosphate process:
Ca(NO3)2 + 2 NH3 + CO2 + H2O → 2 NH4NO3 + CaCO3
The products, calcium carbonate and ammonium nitrate, may be separately purified or sold combined as calcium ammonium nitrate.
Ammonium nitrate can also be made via metathesis reactions:
(NH4)2SO4 + Ba(NO3)2 → 2 NH4NO3 + BaSO4
(NH4)2SO4 + Ca(NO3)2 → 2 NH4NO3 + CaSO4
NH4Cl + AgNO3 → NH4NO3 + AgCl
=== Reactions ===
As ammonium nitrate is a salt, both the cation, NH+4, and the anion, NO−3, may take part in chemical reactions.
Solid ammonium nitrate decomposes on heating. At temperatures below around 300 °C, the decomposition mainly produces nitrous oxide and water:
NH4NO3 → N2O + 2 H2O
At higher temperatures, the following reaction predominates.
2 NH4NO3 → 2 N2 + O2 + 4 H2O
Both decomposition reactions are exothermic and their products are gases. Under certain conditions, this can lead to a runaway reaction, with the decomposition process becoming explosive. See § Disasters for details. Many ammonium nitrate disasters, with loss of lives, have occurred.
The red–orange colour in an explosion cloud is due to nitrogen dioxide, a secondary reaction product.
=== Crystalline phases ===
Several crystalline phases of ammonium nitrate have been observed. The following occur under atmospheric pressure.
The transition between β-rhombic to α-rhombic forms (at 32.3 °C) occurs at ambient temperature in many parts of the world. These forms have a 3.6% difference in density and hence transition between them causes a change in volume. One practical consequence of this is that ammonium nitrate cannot be used as a solid rocket motor propellant, as it develops cracks. Stabilized ammonium nitrate (PSAN) was developed as a solution to this and incorporates metal halides stabilisers, which prevent density fluctuations.
== Applications ==
=== Fertilizer ===
Ammonium nitrate is an important fertilizer with NPK rating 34-0-0 (34% nitrogen). It is less concentrated than urea (46-0-0), giving ammonium nitrate a slight transportation disadvantage. Ammonium nitrate's advantage over urea is that it is more stable and does not rapidly lose nitrogen to the atmosphere.
=== Explosives ===
Ammonium nitrate readily forms explosive mixtures with varying properties when combined with explosives such as TNT or with fuels like aluminium powder or fuel oil.
Examples of explosives containing ammonium nitrate include:
Amatex (ammonium nitrate, TNT and RDX)
Amatol (ammonium nitrate and TNT)
Ammonal (ammonium nitrate and aluminum powder)
ANFO (ammonium nitrate and fuel oil)
Astrolite (ammonium nitrate and hydrazine rocket fuel)
Goma-2 (ammonium nitrate, nitroglycol, nitrocellulose, dibutyl phthalate and fuel)
Minol (explosive) (ammonium nitrate, TNT and aluminum powder)
Nitrolite (ammonium nitrate, TNT and nitroglycerin +)
DBX (ammonium nitrate, RDX, TNT and aluminum powder)
Tovex (ammonium nitrate and methylammonium nitrate)
==== Mixture with fuel oil ====
ANFO is a mixture of 94% ammonium nitrate ("AN") and 6% fuel oil ("FO") widely used as a bulk industrial explosive.: 1 It is used in coal mining, quarrying, metal mining, and civil construction in undemanding applications where the advantages of ANFO's low cost, relative safety, and ease of use matter more than the benefits offered by conventional industrial explosives, such as water resistance, oxygen balance, high detonation velocity, and performance in small diameters.: 2
==== Terrorism ====
Ammonium nitrate-based explosives were used in the Sterling Hall bombing in Madison, Wisconsin, 1970, the Oklahoma City bombing in 1995, the 2011 Delhi bombings, the 2011 bombing in Oslo, the Myyrmanni bombing and the 2013 Hyderabad blasts.
In November 2009, the government of the KPK (previously termed as NWFP) of Pakistan imposed a ban on ammonium sulfate, ammonium nitrate, and calcium ammonium nitrate fertilizers in the former Malakand Division – comprising the Upper Dir, Lower Dir, Swat, Chitral, and Malakand districts of the NWFP – following reports that those chemicals were used by militants to make explosives. Due to these bans, "Potassium chlorate – the material which allows safety matches to catch fire – has surpassed fertilizer as the explosive of choice for insurgents."
=== Niche uses ===
Ammonium nitrate is used in some instant cold packs, as its dissolution in water is highly endothermic. In 2021, King Abdullah University of Science and Technology in Saudi Arabia conducted experiments to study the potential for dissolving ammonium nitrate in water for off-grid cooling systems and as a refrigerant. They suggested that the water could be distilled and reused using solar energy to avoid water wastage in severe environments.
It was once used, in combination with independently explosive "fuels" such as guanidine nitrate, as a cheaper (but less stable) alternative to 5-aminotetrazole in the inflators of airbags manufactured by Takata Corporation, which were recalled as unsafe after killing 14 people. The current USA death total is 27.
== Safety, handling, and storage ==
Numerous safety guidelines are available for storing and handling ammonium nitrate. Health and safety data are shown on the safety data sheets available from suppliers and from various governments.
Pure ammonium nitrate does not burn, but as a strong oxidizer, it supports and accelerates the combustion of organic (and some inorganic) material. It should not be stored near combustible substances.
While ammonium nitrate is stable at ambient temperature and pressure under many conditions, it may detonate from a strong initiation charge. It should not be stored near high explosives or blasting agents.
Molten ammonium nitrate is very sensitive to shock and detonation, particularly if it becomes contaminated with incompatible materials such as combustibles, flammable liquids, acids, chlorates, chlorides, sulfur, metals, charcoal and sawdust.
Contact with certain substances such as chlorates, mineral acids and metal sulfides, can lead to vigorous or even violent decomposition capable of igniting nearby combustible material or detonating.
Ammonium nitrate begins decomposition after melting, releasing NOx, HNO3, NH3 and H2O. It should not be heated in a confined space. The resulting heat and pressure from decomposition increases the sensitivity to detonation and increases the speed of decomposition. Detonation may occur at 80 atmospheres. Contamination can reduce this to 20 atmospheres.
Ammonium nitrate has a critical relative humidity of 59.4% at 30 °C. At higher humidity it will absorb moisture from the atmosphere. Therefore, it is important to store ammonium nitrate in a tightly sealed container. Otherwise, it can coalesce into a large, solid mass. Ammonium nitrate can absorb enough moisture to liquefy. Blending ammonium nitrate with certain other fertilizers can lower the critical relative humidity.
The potential for use of the material as an explosive has prompted regulatory measures. For example, in Australia, the Dangerous Goods Regulations came into effect in August 2005 to enforce licensing in dealing with such substances. Licenses are granted only to applicants (industry) with appropriate security measures in place to prevent any misuse. Additional uses such as education and research purposes may also be considered, but individual use will not. Employees of those with licenses to deal with the substance are still required to be supervised by authorized personnel and are required to pass a security and national police check before a license may be granted.
== Health hazards ==
Ammonium nitrate is not hazardous to health and is usually used in fertilizer products.
Ammonium nitrate has an LD50 of 2217 mg/kg, which for comparison is about two-thirds that of table salt.
== Disasters ==
Ammonium nitrate decomposes, non-explosively, into the gases nitrous oxide and water vapor when heated. However, it can be induced to decompose explosively by detonation. Large stockpiles of the material can also be a major fire risk due to their supporting oxidation, a situation which can easily escalate to detonation. Explosions are not uncommon: relatively minor incidents occur most years, and several large and devastating explosions have also occurred. Examples include the Oppau explosion of 1921 (one of the largest artificial non-nuclear explosions), the Texas City disaster of 1947, the 2015 Tianjin explosions in China, and the 2020 Beirut explosion.
Ammonium nitrate can explode through two mechanisms:
Shock induced detonation. An explosive charge within or in contact with a mass of ammonium nitrate causes the ammonium nitrate to detonate. Examples of such disasters are Kriewald, Morgan (present-day Sayreville, New Jersey), Oppau, and Tessenderlo.
Deflagration to detonation transition. The ammonium nitrate explosion results from a fire that spreads into the ammonium nitrate (Texas City, TX; Brest; West, TX; Tianjin; Beirut), or from ammonium nitrate mixing with a combustible material during the fire (Gibbstown, Cherokee, Nadadores). The fire must be confined at least to a degree for successful transition from a fire to an explosion.
== See also ==
Resource recovery
== References ==
=== Sources ===
== External links ==
International Chemical Safety Card 0216
"Storing and Handling Ammonium Nitrate", United Kingdom Health and Safety Executive publication INDG230 (1986)
Chemical Advisory: Safe Storage, Handling, and Management of Ammonium Nitrate United States Environmental Protection Agency
Calculators: surface tensions, and densities, molarities and molalities of aqueous ammonium nitrate | Wikipedia/Ammonium_nitrate |
Ethylene glycol dinitrate, abbreviated EGDN and NGC, also known as Nitroglycol, is a colorless, oily, explosive liquid obtained by nitrating ethylene glycol. It is similar to nitroglycerine in both manufacture and properties, though it is more volatile and less viscous. Unlike nitroglycerine, the chemical has a perfect oxygen balance, meaning that its ideal exothermic decomposition would completely convert it to low energy carbon dioxide, water, and nitrogen gas, with no excess unreacted substances, without needing to react with anything else.
== History and production ==
Pure EGDN was first produced by the Belgian chemist Louis Henry (1834–1913) in 1870 by dropping a small amount of ethylene glycol into a mixture of nitric and sulfuric acids cooled to 0 °C. The previous year, August Kekulé had produced EGDN by the nitration of ethylene, but this was actually contaminated with beta-nitroethyl nitrate.
Other investigators preparing NGC before publication in 1926 of Rinkenbach's work included: Champion (1871), Neff (1899) & Wieland & Sakellarios (1920), Dautriche, Hough & Oehme.
The American chemist William Henry Rinkenbach (1894–1965) prepared EGDN by nitrating purified glycol obtained by fractioning the commercial product under pressure of 40mm Hg, and at a temperature of 120°. For this 20g of middle fraction of purified glycol was gradually added to mixture of 70g nitric acid and 130g sulfuric acid, maintaining the temperature at 23°. The resulting 49g of crude product was washed with 300ml of water to obtain 39.6g of purified product. The low yield so obtained could be improved by maintaining a lower temperature and using a different nitrating acid mixture.
1) Direct Nitration of Glycol is carried out in exactly the same manner, with the same apparatus, and with the same mixed acids as nitration of glycerine.
In the test nitration of anhydrous glycol (100g) with 625g of mixed acid HNO3 40% & H2SO4 60% at 10-12°, the yield was 222g and it dropped to 218g when the temp was raised to 29-30°.
When 500g of mixed acid HNO3 50% & H2SO4 50% was used at 10-12°, the yield increased to 229g.
In commercial nitration, the yields obtained from 100 kg anhydrous glycol and 625 kg of mixed acid containing HNO3 41%, H2SO4 58% & water 1% were 222.2 kg of NGc at nitrating temp of 10-12° and only 218.3 kg at 29-30°. This means 90.6% of theory, as compared to 93.6% with NG.
C2H4(OH)2 + 2 HNO3 → C2H4(ONO2)2 + 2 H2O
or through the reaction of ethylene oxide and dinitrogen pentoxide:
C2H4O + N2O5 → C2H4(ONO2)2
2) Direct Production of NGc from Gaseous Ethylene.
3) Preparation of NGc from Ethylene Oxide.
4) Preparation of NGc by method of Messing from ethylene through chlorohydrin & ethylene oxide.
5) Preparation of NGc by duPont method.
== Properties ==
=== Physical properties ===
Ethylene glycol dinitrate is a colorless volatile liquid when in pure state, but is yellowish when impure.
Molar weight 152.07, N 18.42%, OB to CO2 0%, OB to CO +21%; colorless volatile liquid when in pure state; yellowish liquid in crude state; sp gr 1.488 at 20/4° or 1.480 at 25°; n_D 1.4452 at 25° or 1.4472 at 20°; freezing point -22.75° (versus +13.1° for NG); frozen point given in is -22.3°; boiling point 199° at 760mm Hg (with decomposition).
Brisance by lead block compression (Hess crusher test) is 30.0 mm, versus 18.5 mm for NG and 16 mm for TNT (misleading, needs to give exact density and mass of explosive (25 or 50 g). Brisance by sand test, determined in mixtures with 40% kieselguhr, gave for NGc mixtures slightly higher results then with those containing NG.
=== Chemical properties ===
When ethylene glycol dinitrate is rapidly heated to 215 °C, it explodes; this is preceded by partial decomposition similar to that of nitroglycerin. EGDN has a slightly higher brisance than nitroglycerin.
Ethylene glycol dinitrate reacts violently with potassium hydroxide, yielding ethylene glycol and potassium nitrate:
C2H2(ONO2)2 + 2 KOH → C2H2(OH)2 + 2 KNO3
== Other ==
EGDN was used in manufacturing explosives to lower the freezing point of nitroglycerin, in order to produce dynamite for use in colder weather. Due to its volatility it was used as a detection taggant in some plastic explosives, e.g. Semtex, to allow more reliable explosive detection, until 1995 when it was replaced by dimethyldinitrobutane. It is considerably more stable than glyceryl trinitrate owing to the lack of secondary hydroxyl groups in the precursor polyol.
Like other organic nitrates, ethylene glycol dinitrate is a vasodilator.
== See also ==
Methyl nitrate
Erythritol tetranitrate
Xylitol pentanitrate
Mannitol hexanitrate
RE factor
== References ==
== External links ==
WebBook page for ethylene glycol dinitrate
CDC - NIOSH Pocket Guide to Chemical Hazards | Wikipedia/Ethylene_glycol_dinitrate |
Gallium nitrate (brand name Ganite) is the gallium salt of nitric acid with the chemical formula Ga(NO3)3. It is a drug used to treat symptomatic hypercalcemia secondary to cancer. It works by preventing the breakdown of bone through the inhibition of osteoclast activity, thus lowering the amount of free calcium in the blood. Gallium nitrate is also used to synthesize other gallium compounds.
== History ==
Gallium (Ga) was discovered in 1875 by P.É. Lecoq de Boisbaudran. In most of its compounds, gallium is found with an oxidation number of 3+. Gallium chemically behaves similarly to iron 3+ when forming a coordination complex. That means gallium(III) and iron(III) are similar in similar coordination number, electrical charge, ion diameter and electron configuration.
=== Biological activity ===
Gallium atoms are bound to the phosphates of DNA at low gallium concentrations, forming a stable complex. Gallium competes with magnesium in DNA binding, since its DNA affinity is 100 times higher than that of magnesium. No interactions have been found between the metal and DNA bases. According to Hedley et al., gallium inhibits replicative DNA synthesis, the major gallium-specific target probably being ribonucleotide reductase. In addition to that, it was reported by Chitambar that gallium binds to transferrin more strongly than iron. The transferrin gallium complex inhibits DNA synthesis by acting on the M2 subunit of ribonucleotide reductase.
Gallium(III) seems to act as an antagonist to the actions of several ions (Ca2+, Mg2+, Fe2+ and Zn2+) in processes of cellular metabolism. The action of gallium on bone metabolism decreases hypercalcemia associated with cancer. However, gallium is mostly found within the cell as a salt in lysosomes.
== Preparation ==
Gallium nitrate is commercially available as the hydrate. The nonahydrate may also be prepared by dissolving gallium in nitric acid, followed by recrystallization. The structure of gallium nitrate nonahydrate has been determined by X-ray crystallography.
== Use and manufacturing ==
=== Preparation of gallium nitride from gallium nitrate ===
GaN powder was synthesized using a direct current (DC) non-transferred arc plasma.
=== Medication Information ===
Gallium nitrate injection (Ganite) is a clear, colorless, odorless, solution of the nonahydrate (Ga(NO3)3·9H2O) which is readily soluble in water. Each mL of Ganite contains 25 mg of Ga(NO3)3 (anhydrous basis) and sodium citrate dihydrate 28.75 mg. The solution may contain sodium hydroxide or hydrochloric acid for pH adjustment to 6.0-7.0.
=== Overdose ===
Use of higher doses of gallium nitrate than recommended may cause nausea, vomiting and increases risk of chronic kidney disease. In the case of overdose, serum calcium should be monitored, patients should receive vigorous hydration for 2–3 days and any further drug administrations should be discontinued.
== Treatment ==
The action of gallium in gallium nitrate on bone metabolism decreases the hypercalcemia associated with cancer. Gallium inhibits osteoclastic activity and therefore decreases hydroxyapatite crystal formation, with adsorption of gallium onto the surfaces of hydroxyapatite crystals. Also, the increased concentration of gallium in the bone leads to increasing the synthesis of collagen as well as the formation of the bone tissue inside the cell. It has been reported that a protracted infusion was effective against cancer-associated hypercalcemia. Preliminary studies in bladder carcinoma, carcinoma of the urothelium and lymphomas are also promising. Another interesting schedule of subcutaneous injection with low doses of gallium nitrate has been proposed, especially for the treatment of bone metastases, but the definitive results have not yet been published.
== Chemical reactivity ==
Gallium nitrate can react with reducing agents to generate heat and products that may be gaseous. The products may themselves be capable of further reactions (such as combustion in the air). The chemical reduction of materials in this group can be rapid, but do not necessarily proceed without addition of heat, catalyst or addition of a solvent. Explosive mixtures of gallium nitrate with reducing agents often remain unchanged for long periods if the reaction is not initiated. It is soluble in water; dissolution weakens but does not nullify its oxidizing capability. Generally, inorganic oxidizing agents can react violently with active metals, cyanides, esters, and thiocyanates.
== Adverse reactions ==
=== Kidney ===
Adverse renal effects have been reported in about 12.5% of patients treated with gallium nitrate. Two patients receiving gallium nitrate and one patient receiving calcitonin developed acute renal failure in a controlled trial of patients with cancer-related hypercalcemia. Also, it was reported that gallium nitrate should not be administered to patients with serum creatinine >2.5 mg/dL.
=== Blood pressure ===
In a controlled trial of patients, it was noticed a decrease in mean systolic and diastolic blood pressure after the treatment with gallium nitrate. The decrease in blood pressure was asymptomatic and did not require specific treatment.
=== Hematologic ===
High doses of gallium nitrate were associated with anemia when used in treating patients for advanced cancer. As a result, several patients have received red blood cell transfusions.
== See also ==
Bone resorption
== References ==
== External links ==
Ganite, brand website | Wikipedia/Gallium_nitrate |
Calcium nitrate are inorganic compounds with the formula Ca(NO3)2(H2O)x. The anhydrous compound, which is rarely encountered, absorbs moisture from the air to give the tetrahydrate. Both anhydrous and hydrated forms are colourless salts. Hydrated calcium nitrate, also called Norgessalpeter (Norwegian salpeter), is mainly used as a component in fertilizers, but it has other applications. Nitrocalcite is the name for a mineral which is a hydrated calcium nitrate that forms as an efflorescence where manure contacts concrete or limestone in a dry environment as in stables or caverns. A variety of related salts are known including calcium ammonium nitrate decahydrate and calcium potassium nitrate decahydrate.
== Production and reactivity ==
Norgessalpeter was synthesized at Notodden, Norway in 1905 by the Birkeland–Eyde process. Most of the world's calcium nitrate is now made in Porsgrunn. It is produced by treating limestone with nitric acid, followed by neutralization with ammonia:
CaCO3 + 2 HNO3 → Ca(NO3)2 + CO2 + H2O
It is also an intermediate product of the Odda Process:
Ca5(PO4)3OH + 10 HNO3 → 3 H3PO4 + 5 Ca(NO3)2 + H2O
It can also be prepared from an aqueous solution of ammonium nitrate, and calcium hydroxide:
2 NH4NO3 + Ca(OH)2 → Ca(NO3)2 + 2 NH4OH
Like related alkaline earth metal nitrates, calcium nitrate decomposes upon heating (starting at 500 °C) to release nitrogen dioxide:
2 Ca(NO3)2 → 2 CaO + 4 NO2 + O2 ΔH = 369 kJ/mol
== Applications ==
=== Use in agriculture ===
The fertilizer grade (15.5-0-0 + 19% Ca) is popular in the greenhouse and hydroponics trades; it contains ammonium nitrate and water, as the "double salt" 5Ca(NO3)2·NH4NO3·10H2O. This is called calcium ammonium nitrate and often the name calcium nitrate prill is used as it always comes in a prilled (granular) form. Formulations lacking ammonia are also known: Ca(NO3)2·4H2O (11.9-0-0 + 16.9 Ca) and the water-free 17-0-0 + 23.6 Ca. A liquid formulation (9-0-0 + 11 Ca) is also offered. An anhydrous, air-stable derivative is the urea complex Ca(NO3)2·4[OC(NH2)2], which has been sold as Cal-Urea.
Calcium nitrate is also used to control certain plant diseases. For example, dilute calcium nitrate (and calcium chloride) sprays are used to control bitter pit and cork spot in apple trees.
=== Waste water treatment ===
Calcium nitrate is used in waste water pre-conditioning for odour emission prevention. The waste water pre-conditioning is based on establishing an anoxic biology in the waste water system. In the presence of nitrate, the metabolism for sulfates stops, thus preventing formation of hydrogen sulfide. Additionally, easily degradable organic matter is consumed, which otherwise can cause anaerobic conditions downstream as well as odour emissions itself. The concept is also applicable for surplus sludge treatment.
=== Concrete ===
Calcium nitrate is used in set accelerating concrete admixtures. This use with concrete and mortar is based on two effects. The calcium ion accelerates formation of calcium hydroxide and thus precipitation and setting. This effect is used also in cold weather concreting agents as well as some combined plasticizers. The nitrate ion leads to formation of iron hydroxide, whose protective layer reduces corrosion of the concrete reinforcement.
=== Latex coagulant ===
Calcium nitrate is a very common coagulant in latex production, especially in dipping processes. Dissolved calcium nitrate is a part of the dipping bath solution. The warm former is dipped into the coagulation liquid and a thin film of the dipping liquid remains on the former. When now dipping the former into the latex the calcium nitrate will break up the stabilization of the latex solution and the latex will coagulate on the former.
=== Cold packs ===
The dissolution of calcium nitrate tetrahydrate is highly endothermic (cooling). For this reason, calcium nitrate tetrahydrate is sometimes used for regenerable cold packs.
=== Molten salts for heat transfer and storage ===
Calcium nitrate can be used as a part of molten salt mixtures. Typical are binary mixtures of calcium nitrate and potassium nitrate or ternary mixtures including also sodium nitrate. Those molten salts can be used to replace thermo oil in concentrated solar power plants for the heat transfer, but mostly those are used in heat storage.
== References == | Wikipedia/Calcium_nitrate |
In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukaryotes.
Typically, the signaling process involves three components: the signal, the receptor, and the effector.
In biology, signals are mostly chemical in nature, but can also be physical cues such as pressure, voltage, temperature, or light. Chemical signals are molecules with the ability to bind and activate a specific receptor. These molecules, also referred to as ligands, are chemically diverse, including ions (e.g. Na+, K+, Ca2+, etc.), lipids (e.g. steroid, prostaglandin), peptides (e.g. insulin, ACTH), carbohydrates, glycosylated proteins (proteoglycans), nucleic acids, etc. Peptide and lipid ligands are particularly important, as most hormones belong to these classes of chemicals. Peptides are usually polar, hydrophilic molecules. As such they are unable to diffuse freely across the bi-lipid layer of the plasma membrane, so their action is mediated by a cell membrane bound receptor. On the other hand, liposoluble chemicals such as steroid hormones, can diffuse passively across the plasma membrane and interact with intracellular receptors.
Cell signaling can occur over short or long distances, and can be further classified as autocrine, intracrine, juxtacrine, paracrine, or endocrine. Autocrine signaling occurs when the chemical signal acts on the same cell that produced the signaling chemical. Intracrine signaling occurs when the chemical signal produced by a cell acts on receptors located in the cytoplasm or nucleus of the same cell. Juxtacrine signaling occurs between physically adjacent cells. Paracrine signaling occurs between nearby cells. Endocrine interaction occurs between distant cells, with the chemical signal usually carried by the blood.
Receptors are complex proteins or tightly bound multimer of proteins, located in the plasma membrane or within the interior of the cell such as in the cytoplasm, organelles, and nucleus. Receptors have the ability to detect a signal either by binding to a specific chemical or by undergoing a conformational change when interacting with physical agents. It is the specificity of the chemical interaction between a given ligand and its receptor that confers the ability to trigger a specific cellular response. Receptors can be broadly classified into cell membrane receptors and intracellular receptors.
Cell membrane receptors can be further classified into ion channel linked receptors, G-Protein coupled receptors and enzyme linked receptors.
Ion channels receptors are large transmembrane proteins with a ligand activated gate function. When these receptors are activated, they may allow or block passage of specific ions across the cell membrane. Most receptors activated by physical stimuli such as pressure or temperature belongs to this category.
G-protein receptors are multimeric proteins embedded within the plasma membrane. These receptors have extracellular, trans-membrane and intracellular domains. The extracellular domain is responsible for the interaction with a specific ligand. The intracellular domain is responsible for the initiation of a cascade of chemical reactions which ultimately triggers the specific cellular function controlled by the receptor.
Enzyme-linked receptors are transmembrane proteins with an extracellular domain responsible for binding a specific ligand and an intracellular domain with enzymatic or catalytic activity. Upon activation the enzymatic portion is responsible for promoting specific intracellular chemical reactions.
Intracellular receptors have a different mechanism of action. They usually bind to lipid soluble ligands that diffuse passively through the plasma membrane such as steroid hormones. These ligands bind to specific cytoplasmic transporters that shuttle the hormone-transporter complex inside the nucleus where specific genes are activated and the synthesis of specific proteins is promoted.
The effector component of the signaling pathway begins with signal transduction. In this process, the signal, by interacting with the receptor, starts a series of molecular events within the cell leading to the final effect of the signaling process. Typically the final effect consists in the activation of an ion channel (ligand-gated ion channel) or the initiation of a second messenger system cascade that propagates the signal through the cell. Second messenger systems can amplify or modulate a signal, in which activation of a few receptors results in multiple secondary messengers being activated, thereby amplifying the initial signal (the first messenger). The downstream effects of these signaling pathways may include additional enzymatic activities such as proteolytic cleavage, phosphorylation, methylation, and ubiquitinylation.
Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.
Each cell is programmed to respond to specific extracellular signal molecules, and is the basis of development, tissue repair, immunity, and homeostasis. Errors in signaling interactions may cause diseases such as cancer, autoimmunity, and diabetes.
== Taxonomic range ==
In many small organisms such as bacteria, quorum sensing enables individuals to begin an activity only when the population is sufficiently large. This signaling between cells was first observed in the marine bacterium Aliivibrio fischeri, which produces light when the population is dense enough. The mechanism involves the production and detection of a signaling molecule, and the regulation of gene transcription in response. Quorum sensing operates in both gram-positive and gram-negative bacteria, and both within and between species.
In slime molds, individual cells aggregate together to form fruiting bodies and eventually spores, under the influence of a chemical signal, known as an acrasin. The individuals move by chemotaxis, i.e. they are attracted by the chemical gradient. Some species use cyclic AMP as the signal; others such as Polysphondylium violaceum use a dipeptide known as glorin.
In plants and animals, signaling between cells occurs either through release into the extracellular space, divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling such as notch signaling. Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells.
== Extracellular signal ==
=== Synthesis and release ===
Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, Vasopressin, Acetylcholine), while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic acid), but important exceptions to both are numerous, and the same molecule can act both via surface receptors or in an intracrine manner to different effects. In animal cells, specialized cells release these hormones and send them through the circulatory system to other parts of the body. They then reach target cells, which can recognize and respond to the hormones and produce a result. This is also known as endocrine signaling. Plant growth regulators, or plant hormones, move through cells or by diffusing through the air as a gas to reach their targets. Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon monoxide.
==== Exocytosis ====
Exocytosis is the process by which a cell transports molecules such as neurotransmitters and proteins out of the cell. As an active transport mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, endocytosis, the process that brings substances into the cell, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive transport. Exocytosis is the process by which a large amount of molecules are released; thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.
In the context of neurotransmission, neurotransmitters are typically released from synaptic vesicles into the synaptic cleft via exocytosis; however, neurotransmitters can also be released via reverse transport through membrane transport proteins.
=== Forms of Cell Signaling ===
==== Autocrine ====
Autocrine signaling involves a cell secreting a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell itself. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.
==== Intracrine ====
In intracrine signaling, the signaling chemicals are produced inside the cell and bind to cytosolic or nuclear receptors without being secreted from the cell. The intracrine signals not being secreted outside of the cell is what sets apart intracrine signaling from the other cell signaling mechanisms such as autocrine signaling. In both autocrine and intracrine signaling, the signal has an effect on the cell that produced it.
==== Juxtacrine ====
Juxtacrine signaling is a type of cell–cell or cell–extracellular matrix signaling in multicellular organisms that requires close contact. There are three types:
A membrane ligand (protein, oligosaccharide, lipid) and a membrane protein of two adjacent cells interact.
A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
An extracellular matrix glycoprotein and a membrane protein interact.
Additionally, in unicellular organisms such as bacteria, juxtacrine signaling means interactions by membrane contact. Juxtacrine signaling has been observed for some growth factors, cytokine and chemokine cellular signals, playing an important role in the immune response. Juxtacrine signalling via direct membrane contacts is also present between neuronal cell bodies and motile processes of microglia both during development, and in the adult brain.
==== Paracrine ====
In paracrine signaling, a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action), as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. Neurotransmitters represent another example of a paracrine signal.
Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.
Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set of receptors and pathways. In fact, different organs in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development. The highly conserved receptors and pathways can be organized into four major families based on similar structures: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.
==== Endocrine ====
Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Endocrine signaling involves the release of hormones by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland and the adrenal glands. The study of the endocrine system and its disorders is known as endocrinology.
== Receptors ==
Cells receive information from their neighbors through a class of proteins known as receptors. Receptors may bind with some molecules (ligands) or may interact with physical agents like light, mechanical temperature, pressure, etc. Reception occurs when the target cell (any cell with a receptor protein specific to the signal molecule) detects a signal, usually in the form of a small, water-soluble molecule, via binding to a receptor protein on the cell surface, or once inside the cell, the signaling molecule can bind to intracellular receptors, other elements, or stimulate enzyme activity (e.g. gasses), as in intracrine signaling.
Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects. In many mammals, early embryo cells exchange signals with cells of the uterus. In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) into their environment. The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.
=== Cell surface receptors ===
Cell surface receptors play an essential role in the biological systems of single- and multi-cellular organisms and malfunction or damage to these proteins is associated with cancer, heart disease, and asthma. These trans-membrane receptors are able to transmit information from outside the cell to the inside because they change conformation when a specific ligand binds to it. There are three major types: Ion channel linked receptors, G protein–coupled receptors, and enzyme-linked receptors.
==== Ion channel linked receptors ====
Ion channel linked receptors are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.
When a presynaptic neuron is excited, it releases a neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these receptors are ligand-gated ion channels (LICs), a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response.
These receptor proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.
==== G protein–coupled receptors ====
G protein-coupled receptors are a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. The G-protein acts as a "middle man" transferring the signal from its activated receptor to its target and therefore indirectly regulates that target protein. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.
G protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates, and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases.
There are two principal signal transduction pathways involving the G protein-coupled receptors: cAMP signal pathway and phosphatidylinositol signal pathway. When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).: 1160
G protein-coupled receptors are an important drug target and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018. It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of pharmaceutical research.
==== Enzyme-linked receptors ====
Enzyme-linked receptors (or catalytic receptors) are transmembrane receptors that, upon activation by an extracellular ligand, causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protein possessing both enzymatic, catalytic, and receptor functions.
They have two important domains, an extra-cellular ligand binding domain and an intracellular domain, which has a catalytic function; and a single transmembrane helix. The signaling molecule binds to the receptor on the outside of the cell and causes a conformational change on the catalytic function located on the receptor inside the cell. Examples of the enzymatic activity include:
Receptor tyrosine kinase, as in fibroblast growth factor receptor. Most enzyme-linked receptors are of this type.
Receptor protein serine/threonine kinase, as in bone morphogenetic protein
Guanylate cyclase, as in atrial natriuretic factor receptor
=== Intracellular receptors ===
Intracellular receptors exist freely in the cytoplasm, nucleus, or can be bound to organelles or membranes. For example, the presence of nuclear and mitochondrial receptors is well documented. The binding of a ligand to the intracellular receptor typically induces a response in the cell. Intracellular receptors often have a level of specificity, this allows the receptors to initiate certain responses when bound to a corresponding ligand. Intracellular receptors typically act on lipid soluble molecules. The receptors bind to a group of DNA binding proteins. Upon binding, the receptor-ligand complex translocates to the nucleus where they can alter patterns of gene expression.
Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C). In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.
== Mechanisms of Receptor Down-Regulation ==
Receptor mediated endocytosis is common way of turning receptors "off". Endocytic down regulation is regarded as a means for reducing receptor signaling. The process involves the binding of a ligand to the receptor, which then triggers the formation of coated pits, the coated pits transform to coated vesicles and are transported to the endosome.
Receptor Phosphorylation is another type of receptor down-regulation. Biochemical changes can reduce receptor affinity for a ligand.
Reducing the sensitivity of the receptor is a result of receptors being occupied for a long time. This results in a receptor adaptation in which the receptor no longer responds to the signaling molecule. Many receptors have the ability to change in response to ligand concentration.
== Signal transduction pathways ==
When binding to the signaling molecule, the receptor protein changes in some way and starts the process of transduction, which can occur in a single step or as a series of changes in a sequence of different molecules (called a signal transduction pathway). The molecules that compose these pathways are known as relay molecules. The multistep process of the transduction stage is often composed of the activation of proteins by addition or removal of phosphate groups or even the release of other small molecules or ions that can act as messengers. The amplifying of a signal is one of the benefits to this multiple step sequence. Other benefits include more opportunities for regulation than simpler systems do and the fine-tuning of the response, in both unicellular and multicellular organism.
In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For example, the neurotransmitter GABA can activate a cell surface receptor that is part of an ion channel. GABA binding to a GABAA receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABAA receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate physiological effect of the ligand on the cell's behavior is produced. Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway.
A more complex signal transduction pathway is the MAPK/ERK pathway, which involves changes of protein–protein interactions inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. Several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. This phosphorylation can generate a binding site for a different protein and thus induce protein–protein interaction. In this case, the ligand (called epidermal growth factor, or EGF) binds to the receptor (called EGFR). This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an adaptor protein (GRB2), which couples the signal to further downstream signaling processes. For example, one of the signal transduction pathways that are activated is called the mitogen-activated protein kinase (MAPK) pathway. The signal transduction component labeled as "MAPK" in the pathway was originally called "ERK," so the pathway is called the MAPK/ERK pathway. The MAPK protein is an enzyme, a protein kinase that can attach phosphate to target proteins such as the transcription factor MYC and, thus, alter gene transcription and, ultimately, cell cycle progression. Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal transduction pathway.
Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance, the hedgehog protein activates different genes, depending on the amount of hedgehog protein present.
Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways.
A specific cellular response is the result of the transduced signal in the final stage of cell signaling. This response can essentially be any cellular activity that is present in a body. It can spur the rearrangement of the cytoskeleton, or even as catalysis by an enzyme. These three steps of cell signaling all ensure that the right cells are behaving as told, at the right time, and in synchronization with other cells and their own functions within the organism. At the end, the end of a signal pathway leads to the regulation of a cellular activity. This response can take place in the nucleus or in the cytoplasm of the cell. A majority of signaling pathways control protein synthesis by turning certain genes on and off in the nucleus.
In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc. In quorum sensing, which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response. In this context, the signaling molecules are called autoinducers. This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. Bacteria also use contact-dependent signaling, notably to limit their growth.
Signaling molecules used by multicellular organisms are often called pheromones. They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction.
=== Short-term cellular responses ===
=== Regulating gene activity ===
==== Notch signaling pathway ====
Notch is a cell surface protein that functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. Ligand receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication. Notch acts as a receptor for ligands that are expressed on adjacent cells. While some receptors are cell-surface proteins, others are found inside cells. For example, estrogen is a hydrophobic molecule that can pass through the lipid bilayer of the membranes. As part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be activated by estrogen produced in the ovaries.
In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. As shown in Figure 2, the activation of Notch can cause the Notch protein to be altered by a protease. Part of the Notch protein is released from the cell surface membrane and takes part in gene regulation. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types. Emerging methods for single-cell mass-spectrometry analysis promise to enable studying signal transduction with single-cell resolution.
In notch signaling, direct contact between cells allows for precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell.
== See also ==
== References ==
== Further reading ==
== External links ==
NCI-Nature Pathway Interaction Database: authoritative information about signaling pathways in human cells.
Intercellular+Signaling+Peptides+and+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Cell+Communication at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Signaling Pathways Project: cell signaling hypothesis generation knowledgebase constructed using biocurated archived transcriptomic and ChIP-Seq datasets | Wikipedia/Signaling_molecule |
A cyanotic heart defect is any congenital heart defect (CHD) that occurs due to deoxygenated blood bypassing the lungs and entering the systemic circulation, or a mixture of oxygenated and unoxygenated blood entering the systemic circulation. It is caused by structural defects of the heart such as right-to-left or bidirectional shunting, malposition of the great arteries, or any condition which increases pulmonary vascular resistance. The result may be the development of collateral circulation.
== Types ==
Tetralogy of Fallot (ToF)
Total anomalous pulmonary venous connection
Hypoplastic left heart syndrome (HLHS)
Transposition of the great arteries (d-TGA)
Truncus arteriosus (Persistent)
Tricuspid atresia
Interrupted aortic arch
Pulmonary atresia (PA)
Pulmonary stenosis (critical)
Eisenmenger syndrome (reversal of shunt due to pulmonary hypertension).
== Signs and symptoms ==
Presentation includes the following:
Clubbing
The patient assuming a crouching position
Cyanosis - bluish face, particularly the lips; and bluish fingers and toes
Crying
Crabbiness/irritability
Tachycardia
Tachypnea
A history of inadequate feeding
Unusually large toe and fingernails
Delayed development (both biological and physiological)
== Diagnosis ==
== Management ==
Morphine during Tet spells to decrease associated infundibular spasm.
Prophylactic: Propranolol/Inderall
Prostaglandin E (to keep the ductus arteriosus patent)
Prophylactic antibiotic to prevent endocarditis
Surgery: Variable. Superior Cavopulmonary Bypass (Bidirectional Glenn or Hemi-Fontan Procedure), Total Cavopulmonary Bypass (Fontan Completion Procedure). The purpose of these operations is to redirect the blood flow of the deoxygenated blood to the lungs by attaching the Vena Cava directly to the Pulmonary Artery causing the blood that flows into the lungs to be oxygenated before entering the chambers on the right side of the heart. Mathematical models are used to address the issue of pressure level alterations of circulation after the procedures. The pulmonary pressure resistance in the cavopulmonary connection is increased, and these models permit clear analyses of the pressure increase allowing doctors to avoid possible venous circulation congestion.
== See also ==
what is cyanotic heart disease?
Acyanotic heart defect
== References ==
== External links == | Wikipedia/Cyanotic_heart_disease |
Gadolinium(III) nitrate is an inorganic compound of gadolinium. This salt is used as a water-soluble neutron poison in nuclear reactors. Gadolinium nitrate, like all nitrate salts, is an oxidizing agent.
The most common form of this substance is hexahydrate Gd(NO3)3•6H2O with molecular weight 451.36 g/mol and CAS Number: 19598-90-4.[1]
== Use ==
Gadolinium nitrate was used at the Savannah River Site heavy water nuclear reactors and had to be separated from the heavy water for storage or reuse.
The Canadian CANDU reactor, a pressurized heavy water reactor, also uses gadolinium nitrate as a water-soluble neutron poison in heavy water.
Gadolinium nitrate is also used as a raw material in the production of other gadolinium compounds, for production of specialty glasses and ceramics and as a phosphor.
== References == | Wikipedia/Gadolinium(III)_nitrate |
Mannitol hexanitrate is a powerful explosive. Physically, it is a powdery solid at normal temperature ranges, with density of 1.73 g/cm3. The chemical name is hexanitromannitol and it is also known as nitromannite, MHN, and nitromannitol, and by the trademarks Nitranitol and Mannitrin. It is more stable than nitroglycerin, and it is used in detonators.
Mannitol hexanitrate is a secondary explosive formed by the nitration of mannitol, a sugar alcohol. The product is used in medicine as a vasodilator and as an explosive in blasting caps. Its sensitivity is high, particularly at high temperatures (> 75 °C) where it is slightly more sensitive than nitroglycerine. Nitromannite is a class B explosive.
The production of pure MHN is not a trivial task, since most preparations will yield a mixture of MHN and lower esters (pentanitrate and lower).
== See also ==
Pentaerythritol tetranitrate (PETN)
Xylitol pentanitrate
Erythritol tetranitrate (ETN)
Ethylene glycol dinitrate
Methyl nitrate
== References ==
The Chemistry of Powder and Explosives, Tenney L. Davis
== External links ==
Powerlabs.org | Wikipedia/Mannitol_hexanitrate |
Yttrium(III) nitrate is an inorganic compound, a salt with the formula Y(NO3)3. The hexahydrate is the most common form commercially available.
== Preparation ==
Yttrium(III) nitrate can be prepared by dissolving corresponding metal oxide in 6 mol/L nitric acid:
Y2O3 + 6 HNO3 → 2 Y(NO3)3 + 3 H2O
== Properties ==
Yttrium(III) nitrate hexahydrate loses crystallized water at relatively low temperature. Upon further heating, basic salt YONO3 is formed. At 600 C, the thermal decomposition is complete. Y2O3 is the final product.
Y(NO3)3·3TBP is formed when tributyl phosphate is used as the extracting solvent.
== Uses ==
Yttrium(III) nitrate is mainly used as a source of Y3+ cations. It is a precursor of some yttrium-containing materials, such as Y4Al2O9, YBa2Cu3O6.5+x and yttrium-based metal-organic frameworks.
It can also be used as a catalyst in organic synthesis.
== References == | Wikipedia/Yttrium(III)_nitrate |
Scandium(III) nitrate, Sc(NO3)3, is an ionic compound. It is an oxidizer, as all nitrates are. The salt is applied in optical coatings, catalysts, electronic ceramics and the laser industry.
== Preparation ==
Scandium nitrate can be prepared by the reaction between scandium metal with dinitrogen tetroxide.
Sc + 3 N2O4 → Sc(NO3)3 + 3 NO
The anhydrous form can also be obtained by the reaction between scandium chloride and dinitrogen pentoxide. The tetrahydrate can be obtained from the reaction between scandium hydroxide and nitric acid.
== Properties ==
Scandium nitrate is a white solid which dissolves in water and ethanol. It has multiple hydrated forms, including the dihydrate, trihydrate, and tetrahydrate. The tri- and tetrahydrate exist in the monoclinic crystal system. Upon heating in air to 50 °C, the tetrahydrate transforms into the dihydrate, which at 60 °C further converts to Sc4O3(NO3)3·6.5H2O. At 140–220 °C, Sc4O5(NO3)3 is formed.
Scandium nitrate has been found to form clusters when in an aqueous solution which can affect its behavior and properties in various ways. Small Angle neutron scattering has been used in experiments to show the clusters can contain as many as 10 scandium ions. This number depends on the concentration of the original scandium nitrate in the solution.
== Applications ==
Scandium nitrate has been found to be a successful catalyst in chemical reactions such as Beckmann rearrangement of ketoximes to amides and the isomerization of allylic alcohols to aldehydes. The catalytic success of scandium nitrate can be increased by modifying its structure in ways such as adding a co catalyst. Scandium nitrate is also the precursor for the synthesis of other scandium based compounds such as scandium oxide or scandium hydroxide. Scandium nitrate has also been investigated for its potential in luminescent materials due to its ability to strongly emit in the blue region of the spectrum.
== References == | Wikipedia/Scandium_nitrate |
Fluorine nitrate is an unstable derivative of nitric acid with the formula FNO3. It is shock-sensitive. Due to its instability, it is often produced from chlorine nitrate as needed. Fluorine nitrate is an inert molecule thought to play a significant role in atmospheric chemistry.
== History ==
In 1935, professor George H. Cady was first to synthesize fluorine nitrate and has since maintained a long and controversial history. In 1937, American chemist and biochemist Linus Pauling and one of his first graduate students, Lawrence O. Brockway, utilized electron diffraction intensities to determine the structure of the oxygen and fluorine bond perpendicular to the NO2 plane to be a non-planar structure. This would later be confirmed in 1963 and 1966 utilizing infrared spectra.
In a 1995 study performed by Universität Tubingen in Germany, found through electron diffraction that the nitrogen–oxygen bond is surprisingly long at about a length of 150.7 ppm. This length is likely the result of the presence of electronegative atoms compared to other similar structures such as nitric acid.
== Synthesis and properties ==
Whilst not fully understood, it is thought that FNO3 forms as a result of termolecular recombination of FO and NO2 radicals. Fluorine Nitrate is prepared through the agitation of fluorine in its gaseous form, which will bubble through nitric acid or solid KNO3. Due to the shock sensitive nature of the compound, it is necessary to handle it with extreme caution:
F2 + HNO3 → FNO3 + HF
F2 + KNO3 → FNO3 + KF
It decomposes in water to form oxygen gas, oxygen difluoride, hydrofluoric acid, and nitric acid.
In fluorine nitrate, the oxygen atom bridging nitrogen and fluorine is in a rare oxidation state of 0 due to its electronegativity being lower than that of fluorine but higher than that of nitrogen. The role of electronegativity also is significant in the structure of fluorine nitrate. Through electron diffraction analysis, FNO3 was determined to have a planar structure with a particularly long nitrogen-oxygen bond length.
Fluorine nitrate has been linked to higher ionization potential due to the centrality of fluorine. This higher ionization potential is indicative of electron ionization of deeper shell orbitals.
== Applications ==
Since the 1990s, fluorine nitrate has been studied as a critical factor of atmospheric chemistry. It was in this period that fluorine nitrate began to be labeled as a reservoir species in the atmosphere.
The relationship between the ionization potential and the highest occupied molecular orbital (HOMO) in fluorine nitrate was determined to be large. In a 1996 study, researchers asserted that the ionization potential of the HOMO in a molecule is a reflection of the electron-donating capacities of a molecule and as the ionization potential of the HOMO is lowered, subsequently the electron donating capacities of the molecule increase and become stronger.
Despite the molecule’s inert nature, it is asserted by the 1996 study that fluorine nitrate may be the best possible reservoir species in the process of ozone depletion.
== References ==
Greenwood, Norman N.; Earnshaw, Alan (1997). Chemistry of the Elements (2nd ed.). Butterworth-Heinemann. ISBN 978-0-08-037941-8. | Wikipedia/Fluorine_nitrate |
In chemistry, the ball-and-stick model is a molecular model of a chemical substance which displays both the three-dimensional position of the atoms and the bonds between them. The atoms are typically represented by spheres, connected by rods which represent the bonds. Double and triple bonds are usually represented by two or three curved rods, respectively, or alternately by correctly positioned sticks for the sigma and pi bonds. In a good model, the angles between the rods should be the same as the angles between the bonds, and the distances between the centers of the spheres should be proportional to the distances between the corresponding atomic nuclei. The chemical element of each atom is often indicated by the sphere's color.
In a ball-and-stick model, the radius of the spheres is usually much smaller than the rod lengths, in order to provide a clearer view of the atoms and bonds throughout the model. As a consequence, the model does not provide a clear insight about the space occupied by the model. In this aspect, ball-and-stick models are distinct from space-filling (calotte) models, where the sphere radii are proportional to the Van der Waals atomic radii in the same scale as the atom distances, and therefore show the occupied space but not the bonds.
Ball-and-stick models can be physical artifacts or computer models as molecular graphics. The former are usually built from molecular modeling kits, consisting of a number of coil springs or plastic or wood sticks, and a number of plastic balls with pre-drilled holes. The sphere colors commonly follow the CPK coloring. Some university courses on chemistry require students to buy such models as learning material.
== History ==
In 1865, German chemist August Wilhelm von Hofmann was the first to make ball-and-stick molecular models. He used such models in lecture at the Royal Institution of Great Britain.
Specialist companies manufacture kits and models to order. One of the earlier companies was Woosters at Bottisham, Cambridgeshire, UK. Besides tetrahedral, trigonal and octahedral holes, there were all-purpose balls with 24 holes. These models allowed rotation about the single rod bonds, which could be both an advantage (showing molecular flexibility) and a disadvantage (models are floppy). The approximate scale was 5 cm per ångström (0.5 m/nm or 500,000,000:1), but was not consistent over all elements.
The Beeverses Miniature Models company in Edinburgh (now operating as Miramodus) produced small models beginning in 1961 using PMMA balls and stainless steel rods. In these models, the use of individually drilled balls with precise bond angles and bond lengths enabled large crystal structures to be accurately created in a light and rigid form.
== See also ==
structural formula – Graphic representation of a molecular structure
== References == | Wikipedia/Ball-and-stick_model |
Dysprosium(III) nitrate is an inorganic compound, a salt of dysprosium and nitric acid with the chemical formula Dy(NO3)3. The compound forms yellowish crystals, dissolves in water, forms a crystalline hydrate.
== Synthesis ==
Anhydrous salt is obtained by the action of nitrogen dioxide on dysprosium(III) oxide:
2
D
y
2
O
3
+
9
N
2
O
4
→
150
o
C
4
D
y
(
N
O
3
)
3
+
6
N
O
{\displaystyle {\mathsf {2Dy_{2}O_{3}+9N_{2}O_{4}\ {\xrightarrow {150^{o}C}}\ 4Dy(NO_{3})_{3}+6NO}}}
The action of nitrogen dioxide on metallic dysprosium:
D
y
+
3
N
2
O
4
→
200
o
C
D
y
(
N
O
3
)
3
+
3
N
O
{\displaystyle {\mathsf {Dy+3N_{2}O_{4}\ {\xrightarrow {200^{o}C}}\ Dy(NO_{3})_{3}+3NO}}}
== Physical properties ==
Dysprosium(III) nitrate forms yellowish crystals.
The anhydrous nitrate forms a crystalline hydrate in wet air with the ideal composition of Dy(NO3)3·5H2O, which melts in its own crystallization water at 88.6 °C.
All hydrates (anhydrous, pentahydrate, and hexahydrate) are soluble in water and ethanol, hygroscopic.
== Chemical properties ==
Hydrated dysprosium nitrate thermally decomposes to form DyONO3, and further heating produces dysprosium oxide.
== Application ==
Dysprosium(III) nitrate is used as a catalyst.
== References == | Wikipedia/Dysprosium(III)_nitrate |
Thallium(I) nitrate, also known as thallous nitrate, is a thallium compound with the formula TlNO3. It is a colorless and highly toxic salt.
== Preparation ==
Thallium(I) nitrate can be produced by reacting thallium(I) iodide with nitric acid.
However, the production is simpler starting from the metal, its hydroxide or the carbonate:
TlOH + HNO3 → TlNO3 + H2O
Tl2CO3 + 2 HNO3 → 2 TlNO3 + CO2 + H2O
== Toxicity ==
Thallium(I) nitrate is extremely toxic, like many other thallium compounds. It is highly toxic by ingestion but can also be absorbed through skin due to its solubility in water.
== See also ==
Thallium(III) nitrate
== References == | Wikipedia/Thallium(I)_nitrate |
Cobalt(III) nitrate is an inorganic compound with the chemical formula Co(NO3)3. It is a green, diamagnetic solid that sublimes at ambient temperature.
== Structure ==
The compound is a molecular coordination complex. The three bidentate nitrate ligands give a distorted octahedral arrangement. The nitrate ligands are planar. With D3 symmetry, the molecule is chiral. The Co-O bond lengths are about 190 pm long. The O-Co-O angles for the chelating oxygen atoms in the same nitrate anion is about 68 degrees. The same geometry seems to persist in carbon tetrachloride solution.
== Preparation and reactions ==
Cobalt(III) nitrate can be prepared by the reaction of dinitrogen pentoxide N2O5 with cobalt(III) fluoride CoF3. It can be purified by vacuum sublimation at 40 °C.
Cobalt(III) nitrate oxidizes water, the initial green solution rapidly turns pink, with formation of cobalt(II) ions and release of oxygen. Cobalt(III) nitrate can be intercalated in graphite, in the ratio of 1 molecule for each 12 carbon atoms.
== See also ==
Cobalt(III) fluoride
Cobalt(III) chloride
Cobalt(III) hydroxide
Iron(III) nitrate
Iron(III) oxalate
== References == | Wikipedia/Cobalt(III)_nitrate |
Denitrifying bacteria are a diverse group of bacteria that encompass many different phyla. This group of bacteria, together with denitrifying fungi and archaea, is capable of performing denitrification as part of the nitrogen cycle. Denitrification is performed by a variety of denitrifying bacteria that are widely distributed in soils and sediments and that use oxidized nitrogen compounds such as nitrate and nitrite in the absence of oxygen as a terminal electron acceptor. They metabolize nitrogenous compounds using various enzymes, including nitrate reductase (NAR), nitrite reductase (NIR), nitric oxide reductase (NOR) and nitrous oxide reductase (NOS), turning nitrogen oxides back to nitrogen gas (N2) or nitrous oxide (N2O).
The reducing power can be supplied by organic carbon compounds (termed "heterotrophic denitrification") or inorganic substances such as hydrogen, reduced iron, or sulfur species (termed "autotrophic denitrification"). Some microbes can use either organic or inorganic sources of reducing power (termed "mixotrophs").
== Diversity of denitrifying bacteria ==
There is a great diversity in biological traits. Denitrifying bacteria have been identified in over 50 genera with over 125 different species and are estimated to represent 10-15% of bacteria population in water, soil and sediment.
Denitrifying include for example several species of Pseudomonas, Alcaligenes , Bacillus and others.
The majority of denitrifying bacteria are facultative aerobic heterotrophs that switch from aerobic respiration to denitrification when oxygen as an available terminal electron acceptor (TEA) runs out. This forces the organism to use nitrate to be used as a TEA. Because the diversity of denitrifying bacteria is so large, this group can thrive in a wide range of habitats including some extreme environments such as environments that are highly saline and high in temperature. Aerobic denitrifiers can conduct an aerobic respiratory process in which nitrate is converted gradually to N2 (NO3− → NO2− → NO → N2O → N2 ), using nitrate reductase (Nar or Nap), nitrite reductase (Nir), nitric oxide reductase (Nor), and nitrous oxide reductase (Nos). Phylogenetic analysis revealed that aerobic denitrifiers mainly belong to α-, β- and γ-Proteobacteria.
== Denitrification mechanism ==
Denitrifying bacteria use denitrification to generate ATP.
The most common denitrification process is outlined below, with the nitrogen oxides being converted back to gaseous nitrogen:
2 NO3− + 10 e− + 12 H+ → N2 + 6 H2O
The result is one molecule of nitrogen and six molecules of water. Denitrifying bacteria are a part of the N cycle, and consists of sending the N back into the atmosphere. The reaction above is the overall half reaction of the process of denitrification. The reaction can be further divided into different half reactions each requiring a specific enzyme. The transformation from nitrate to nitrite is performed by nitrate reductase (Nar)
NO3− + 2 H+ + 2 e− → NO2− + H2O
Nitrite reductase (Nir) then converts nitrite into nitric oxide
2 NO2− + 4 H+ + 2 e− → 2 NO + 2 H2O
Nitric oxide reductase (Nor) then converts nitric oxide into nitrous oxide
2 NO + 2 H+ + 2 e− → N2O + H2O
Nitrous oxide reductase (Nos) terminates the reaction by converting nitrous oxide into dinitrogen
N2O + 2 H+ + 2 e− → N2 + H2O
It is important to note that any of the products produced at any step can be exchanged with the soil environment.
== Oxidation of methane and denitrification ==
=== Anaerobic oxidation of methane coupled to denitrification ===
Anaerobic denitrification coupled to methane oxidation was first observed in 2008, with the isolation of a methane-oxidizing bacterial strain found to oxidize methane independently. This process uses the excess electrons from methane oxidation to reduce nitrates, effectively removing both fixed nitrogen and methane from aquatic systems in habitats ranging from sediment to peat bogs to stratified water columns.
The process of anaerobic denitrification may contribute significantly to the global methane and nitrogen cycles, especially in light of the recent influx of both due to anthropogenic changes. The extent to which anthropogenic methane affects the atmosphere is known to be a significant driver of climate change, and considering it is multiple times more potent than carbon dioxide. Removing methane is widely considered to be beneficial to the environment, although the extent of the role that denitrification plays in the global flux of methane is not well understood. Anaerobic denitrification as a mechanism has been shown to be capable of removing the excess nitrate caused by fertilizer runoff, even in hypoxic conditions.
Additionally, microorganisms which employ this type of metabolism may be employed in bioremediation, as shown by a 2006 study of hydrocarbon contamination in the Antarctic, as well as a 2016 study which successfully increased the rates of denitrification by altering the environment housing the bacteria. Denitrifying bacteria are said to be high quality bioremediators because of their adaptability to a variety of different environments, as well as the lacking any toxic or undesirable leftovers, as are left by other metabolisms.
=== Role of denitrifying bacteria as a methane sink ===
Denitrifying bacteria have been found to play a significant role in the oxidation of methane (CH4) (where methane is converted to CO2, water, and energy) in deep freshwater bodies of water. This is important because methane is the second most significant anthropogenic greenhouse gas, with a global warming potential 25 times more potent than that of carbon dioxide, and freshwaters are a major contributor of global methane emissions.
A study conducted on Europe's Lake Constance found that anaerobic methane oxidation coupled to denitrification – also referred to as nitrate/nitrite-dependent anaerobic methane oxidation (n-damo) – is a dominant sink of methane in deep lakes. For a long time, it was considered that the mitigation of methane emissions was only due to aerobic methanotrophic bacteria. However, methane oxidation also takes place in anoxic, or oxygen depleted zones, of freshwater bodies. In the case of Lake Constance, this is carried out by M. oxyfera-like bacteria. M. oxyfera-like bacteria are bacteria similar to Candidatus Methylomirabilis oxyfera, which is a species of bacteria that acts as a denitrifying methanotroph.
The results from the study on Lake Constance found that nitrate was depleted in the water at the same depth as methane, which suggests that methane oxidation was coupled to denitrification. It could be inferred that it was M. oxyfera-like bacteria carrying out the methane oxidation because their abundance peaked at the same depth where the methane and nitrate profiles met. This n-damo process is significant because it aids in decreasing methane emissions from deep freshwater bodies and it aids in turning nitrates into nitrogen gas, reducing excess nitrates.
== Denitrifying bacteria and the environment ==
=== Denitrification effects on limiting plant productivity and producing by-products ===
The process of denitrification can lower the fertility of soil as nitrogen, a growth-limiting factor, is removed from the soil and lost to the atmosphere. This loss of nitrogen to the atmosphere can eventually be regained via introduced nutrients, as part of the nitrogen cycle. Some nitrogen may also be fixated by species of nitrifying bacteria and the cyanobacteria. Another important environmental issue concerning denitrification is the fact that the process tends to produce large amounts of by-products. Examples of by-products are nitric oxide (NO) and nitrous oxide (N2O). NO is an ozone depleting species and N2O is a potent greenhouse gas which can contribute to global warming.
=== Denitrifying bacteria use in wastewater treatment ===
Denitrifying bacteria are an essential component in treating wastewater. Wastewater often contains large amounts of nitrogen (in the form of ammonium or nitrate), which could be damaging to ecological processes if left untreated. Many physical, chemical, and biological methods have been used to remove the nitrogenous compounds and purify wastewaters. The process and methods vary, but it generally involves converting ammonium to nitrate via the nitrification process with ammonium oxidizing bacteria (AOB, NH4+ → NO2–) and nitrite oxidizing bacteria (NOB, NO2– → NO3–), and finally to nitrogen gas via denitrification. One example of this is ammonia-oxidizing bacteria which have a metabolic feature that, in combination with other nitrogen-cycling metabolic activities, such as nitrite oxidation and denitrification, remove nitrogen from wastewater in activated sludge. Since denitrifying bacteria are heterotrophic, an organic carbon source is supplied to the bacteria in an anoxic basin. With no available oxygen, denitrifying bacteria use the redox of nitrate to oxidize the carbon. This leads to the creation of nitrogen gas from nitrate, which then bubbles up out of the wastewater.
== See also ==
Nitrifying bacteria
Nitrogen Cycle
== References == | Wikipedia/Nitrate_reducing_bacteria |
Thulium(III) nitrate is an inorganic compound, a salt of thulium and nitric acid with the chemical formula Tm(NO3)3. The compound forms dark-green crystals, readily soluble in water, also forms crystalline hydrates.
== Synthesis ==
Reaction of thulium and nitric acid:
Tm + 6 HNO3 → Tm(NO3)3 + 3 NO2 + 3 H2O
Reaction of thulium hydroxide and nitric acid:
Tm(OH)3 + 3 HNO3 → Tm(NO3)3 + 3 H2O
== Physical properties ==
Thulium(III) nitrate forms dark-green hygroscopic crystals.
Forms crystalline hydrates of the composition Tm(NO3)3·5H2O.
Soluble in water and ethanol.
== Chemical properties ==
Both the compound and its crystalline hydrate decompose on moderate heating.
Hydrated thulium nitrate thermally decomposes to form TmONO3 and decomposes to thulium oxide upon further heating.
== Applications ==
Thulium(III) nitrate hydrate is used as a reagent. Also used in optical glasses, ceramics, catalysts, electrical components, and photo-optical materials.
== References == | Wikipedia/Thulium(III)_nitrate |
In oceanic biogeochemistry, the f-ratio is the fraction of total primary production fuelled by nitrate (as opposed to that fuelled by other nitrogen compounds such as ammonium). The ratio was originally defined by Richard Eppley and Bruce Peterson in one of the first papers estimating global oceanic production. This fraction was originally believed significant because it appeared to directly relate to the sinking (export) flux of organic marine snow from the surface ocean by the biological pump. However, this interpretation relied on the assumption of a strong depth-partitioning of a parallel process, nitrification, that more recent measurements has questioned.
== Overview ==
Gravitational sinking of organisms (or the remains of organisms) transfers particulate organic carbon from the surface waters of the ocean to its deep interior. This process is known as the biological pump, and quantifying it is of interest to scientists because it is an important aspect of the Earth's carbon cycle. Essentially, this is because carbon transported to the deep ocean is isolated from the atmosphere, allowing the ocean to act as a reservoir of carbon. This biological mechanism is accompanied by a physico-chemical mechanism known as the solubility pump which also acts to transfer carbon to the ocean's deep interior.
Measuring the flux of sinking material (so-called marine snow) is usually done by deploying sediment traps which intercept and store material as it sinks down the water column. However, this is a relatively difficult process, since traps can be awkward to deploy or recover, and they must be left in situ over a long period to integrate the sinking flux. Furthermore, they are known to experience biases and to integrate horizontal as well as vertical fluxes because of water currents. For this reason, scientists are interested in ocean properties that can be more easily measured, and that act as a proxy for the sinking flux. The f-ratio is one such proxy.
== "New" and "regenerated" production ==
Bio-available nitrogen occurs in the ocean in several forms, including simple ionic forms such as nitrate (NO3−), nitrite (NO2−) and ammonium (NH4+), and more complex organic forms such as urea ((NH2)2CO). These forms are used by autotrophic phytoplankton to synthesise organic molecules such as amino acids (the building blocks of proteins). Grazing of phytoplankton by zooplankton and larger organisms transfers this organic nitrogen up the food chain and throughout the marine food-web.
When nitrogenous organic molecules are ultimately metabolised by organisms, they are returned to the water column as ammonium (or more complex molecules that are then metabolised to ammonium). This is known as regeneration, since the ammonium can be used by phytoplankton, and again enter the food-web. Primary production fuelled by ammonium in this way is thus referred to as regenerated production.
However, ammonium can also be oxidised to nitrate (via nitrite), by the process of nitrification. This is performed by different bacteria in two stages :
NH3 + O2 → NO2− + 3H+ + 2e−
NO2− + H2O → NO3− + 2H+ + 2e−
Crucially, this process is believed to only occur in the absence of light (or as some other function of depth). In the ocean, this leads to a vertical separation of nitrification from primary production, and confines it to the aphotic zone. This leads to the situation whereby any nitrate in the water column must be from the aphotic zone, and must have originated from organic material transported there by sinking. Primary production fuelled by nitrate is, therefore, making use of a "fresh" nutrient source rather than a regenerated one. Production by nitrate is thus referred to as new production.
The figure at the head of this section illustrates this. Nitrate and ammonium are taken up by primary producers, processed through the food-web, and then regenerated as ammonium. Some of this return flux is released into the surface ocean (where it is available again for uptake), while some is returned at depth. The ammonium returned at depth is nitrified to nitrate, and ultimately mixed or upwelled into the surface ocean to repeat the cycle.
Consequently, the significance of new production lies in its connection to sinking material. At equilibrium, the export flux of organic material sinking into the aphotic zone is balanced by the upward flux of nitrate. By measuring how much nitrate is consumed by primary production, relative to that of regenerated ammonium, one should be able to estimate the export flux indirectly.
As an aside, the f-ratio can also reveal important aspects of local ecosystem function. High f-ratio values are typically associated with productive ecosystems dominated by large, eukaryotic phytoplankton (such as diatoms) that are grazed by large zooplankton (and, in turn, by larger organisms such as fish). By contrast, low f-ratio values are generally associated with low biomass, oligotrophic food webs consisting of small, prokaryotic phytoplankton (such as Prochlorococcus) which are kept in check by microzooplankton.
== Assumptions ==
A fundamental assumption in this interpretation of the f-ratio is the spatial separation of primary production and nitrification. Indeed, in their original paper, Eppley & Peterson noted that: "To relate new production to export requires that nitrification in the euphotic zone be negligible." However, subsequent observational work on the distribution of nitrification has found that nitrification can occur at shallower depths, and even within the photic zone.
As the adjacent diagram shows, if ammonium is indeed nitrified to nitrate in the ocean's surface waters it essentially "short circuits" the deep pathway of nitrate. In practice, this would lead to an overestimation of new production and a higher f-ratio, since some of the ostensibly new production would actually be fuelled by recently nitrified nitrate that had never left the surface ocean. After including nitrification measurements in its parameterisation, an ecosystem model of the oligotrophic subtropical gyre region (specifically the BATS site) found that, on an annual basis, around 40% of surface nitrate was recently nitrified (rising to almost 90% during summer). A further study synthesising geographically diverse nitrification measurements found high variability but no relationship with depth, and applied this in a global-scale model to estimate that up to a half of surface nitrate is supplied by surface nitrification rather than upwelling.
Although measurements of the rate of nitrification are still relatively rare, they do suggest that the f-ratio is not as straightforward a proxy for the biological pump as was once thought. For this reason, some workers have proposed distinguishing between the f-ratio and the ratio of particulate export to primary production, which they term the pe-ratio. While quantitatively different from the f-ratio, the pe-ratio shows similar qualitative variation between high productivity/high biomass/high export regimes and low productivity/low biomass/low export regimes.
In addition, a further process that potentially complicates the use of the f-ratio to estimate "new" and "regenerated" production is dissimilatory nitrate reduction to ammonium (DNRA). In low oxygen environments, such as oxygen minimum zones and seafloor sediments, chemoorganoheterotrophic microbes use nitrate as an electron acceptor for respiration, reducing it to nitrite, then to ammonium. Since, like nitrification, DNRA alters the balance in the availability of nitrate and ammonium, it has the potential to introduce inaccuracy to the calculated f-ratio. However, as DNRA's occurrence is limited to anaerobic situations, its importance is less widespread than nitrification, although it can occur in association with primary producers.
== See also ==
Marine snow
Biological pump
== References == | Wikipedia/F-ratio_(oceanography) |
Erythritol tetranitrate (ETN) is an explosive compound chemically similar to PETN, though it is thought to be slightly more sensitive to friction and impact.
Like many nitrate esters, ETN acts as a vasodilator, and was the active ingredient in the original "sustained release" tablets, made under a process patent in the early 1950s, called "nitroglyn". Ingesting ETN or prolonged skin contact can lead to absorption and what is known as a "nitro headache".
== History ==
ETN was discovered by John Stenhouse in 1849 by nitrating erythritol he recently discovered. He described its explosive properties but suggested an incorrect formula due to atomic weights not yet being accurately determined.
Its vasodilator properties have been researched since 1895.
DuPont researched the explosive after the war, getting a patent in 1928, but it was never commercialized due to the difficulty of erythritol synthesis. Only due to genetically-engineered yeasts in the 1990s did it become possible for the carbohydrate to become widely available.
== Properties ==
ETN has a relatively high velocity of detonation of 8,206 m/s at a density of 1.7219 (±0.0025) g/cm3. It is white in color and odorless. ETN is commonly cast into mixtures with other high explosives. It is somewhat sensitive to shock and friction, so care must be taken while handling. ETN dissolves readily in acetone and other ketone solvents. The impact and friction sensitivity is slightly higher than the sensitivity of pentaerythritol tetranitrate
(PETN). The sensitivity of melt cast and pressed ETN is comparable. Lower nitrates of erythritol, such as erythritol trinitrate, are soluble in water, so they do not contaminate most ETN samples.
Much like PETN, ETN is known for having a very long shelf life. Studies that directly observed the crystalline structure saw no signs of decomposition after four years of storage at room temperature. ETN has a melting point of 61 °C, compared to PETN which has a melting point of 141.3 °C. Recent studies of ETN decomposition suggested a unimolecular rate-limiting step in which the O−NO2 bond is cleaved and begins the decomposition sequence.
ETN can and should be recrystallized, as to remove the trapped acids from synthesis. Warm ethanol or methanol is a viable solvent (close to 10 g of ETN/100 ml EtOH). ETN will precipitate as big platelets with bulk density of about 0.3 g/cm3 (fluffy material) when the ETN/ethanol solution is quickly poured into several liters of cold water. Smaller, fine crystals are produced by slow addition of water in said ETN/ethanol solution with intense mixing. Very fine crystals can be prepared by shock cooling of warm ETN/ethanol solution in a below −20 °C cooling bath. ETN can be easily hand pressed to about 1.2 g/cm3 (with a slight risk of accidental detonation).
Even small samples of ETN on the order of 20 mg can cause relatively powerful explosions verging on detonation when heated without confinement, e.g. when placed on a layer of aluminium foil and heated with flame from below.
ETN can be melt-cast in warm (about 65 °C) water. Slight decomposition is possible (often displayed by change in color from white to very light yellow). No reports of runaway reactions leading to explosion have been confirmed (when melt-casting using only a bucket of warm water and recrystallized ETN). However, the handling sensitivity in molten state is extremely poor (e. g., much worse than acetone peroxide) and it makes melt-casting it impractical for commercial applications.
Melt-cast ETN, if cooled down slowly over a period of 10–30 minutes, has a density of 1.70 g/cm3, detonation velocity of 8,040 m/s, and Pcj detonation pressure of about 300 kbar. Its brisance is far higher than that of Semtex (about 220 kbar, depending on brand).
Mixtures of melt-cast ETN with PETN (about 50:50% by weight) are about the most brisant explosives that can be produced by moderately equipped amateurs. These mixtures have Pcj slightly above 300 kbar and detonation velocity above 8 km/s. This is close to the maximum of fielded military explosives like LX-10 or EDC-29 (about 370 kbar and close to 9 km/s).
ETN is often plasticized using PIB/synthethic oil binders (very comparable to the binder system in C4) or using liquid nitric esters. The PIB-based plastic explosives are nontoxic and completely comparable to C4 or Semtex with Pcj of 200–250 kbar, depending on density (influenced by crystal size, binder amount, and amount of final rolling). EGDN/ETN/NC systems are toxic to touch, quite sensitive to friction and impact, but generally slightly more powerful than C4 (Pcj of about 250 kbar and Edet of 5.3 MJ/kg) and more powerful than Semtex (Pcj of about 220 kbar and Edet below 5 MJ/kg) with Pcj of about 250–270 kbar and Edet of about 6 MJ/kg. Note that explosion modeling software and experimental tests will yield absolute detonation pressures that can vary by 5% or more with the relative proportions being maintained.
Melt-cast ETN gives invalid results in the Hess test, i.e. the deformation is greater than 26 mm, with the lead cylinder being completely destroyed. Semtex 1A gives only 21 mm in the same test, i.e. melt-cast ETN is at least 20% more brisant than Semtex 1A.
Melt-cast ETN or high density/low inert content ETN plastic explosives are one of the materials on "watch-lists" for terrorism.
== Oxygen balance ==
One positive characteristic of ETN that PETN does not possess is a positive oxygen balance, which means that ETN possesses more than enough oxygen in its structure to fully oxidize all of its carbon and hydrogen upon detonation. This can be seen in the schematic chemical equation below.
2 C4H6N4O12 → 8 CO2 + 6 H2O + 4 N2 + 1 O2
Whereas PETN decomposes to:
2 C5H8N4O12 → 6 CO2 + 8 H2O + 4 N2 + 4 CO
The carbon monoxide (CO) still requires oxygen to complete oxidation to carbon dioxide (CO2). A detailed study of the decomposition chemistry of ETN has been recently elucidated.
Thus, for every two moles of ETN that decompose, one free mole of O2 is released. This oxygen could be used to oxidize an added metal dust, or an oxygen-deficient explosive, such as TNT or PETN. A chemical equation of how the oxygen from ETN with oxidizes PETN is shown below. The extra oxygen from the ETN oxidizes the carbon monoxide (CO) to carbon dioxide (CO2).
2 C4H6N4O12 + 1 C5H8N4O12 → 13 CO2 + 10 H2O + 6 N2
== Manufacture ==
Like other nitrated polyols, ETN is made by nitrating erythritol either through the mixing of concentrated sulfuric acid and a nitrate salt, or by using a mixture of sulfuric and nitric acid.
== See also ==
Mannitol hexanitrate
Xylitol pentanitrate
== References == | Wikipedia/Erythritol_tetranitrate |
Tetranitratoborate is an anion composed of boron with four nitrate groups. It has formula [B(NO3)4]−. It can form salts with large cations such as tetramethylammonium nitratoborate, or tetraethylammonium tetranitratoborate. The ion was first discovered by C. R. Guibert and M. D. Marshall in 1966 after failed attempts to make neutral (non-ionic) boron nitrate, B(NO3)3, which has resisted attempts to make it; if it exists, it is unstable above −78 °C.
Other related ions are the slightly more stable tetraperchloratoborates, with perchlorate groups instead of nitrate, and tetranitratoaluminate with the next atom down the periodic table, aluminium instead of boron ([Al(NO3)4]−).
== Formation ==
Tetramethylammonium chloride reacts with BCl3 to make [N(CH3)4]+[BCl4]−. Then the tetrachloroborate is reacted with N2O4 at around −20 °C to form tetramethylammonium nitratoborate, and other gases such as NO2Cl and Cl2.
Another mechanism to make tetranitratoborate salts is to shake a metal nitrate with BCl3 in chloroform at 20 °C for several days. Trichloronitratoborate [BCl3(NO3)]− is an unstable intermediate.
M+NO−3 + BCl3 → M+[BCl3(NO3)]−
4 M+[BCl3(NO3)]− → 3 M+[BCl4]− + M+[B(NO3)4]−
== Properties ==
The infrared spectrum of tetramethylammonium nitratoborate includes a prominent line at 1,612 cm−1 with shoulders at 1582 and 1,626 cm−1 attributed to v4. Also prominent is 1,297 and 1,311 cm−1 attributed to v1, with these vibrations due to the nitrate bonded via one oxygen.
The density of tetramethylammonium nitratoborate is 1.555 g·cm−3. It is colourless and crystalline. As tetramethylammonium nitratoborate is heated it has some sort of transition between 51 and 62 °C. It decomposes above 75 °C producing gas. Above 112 °C it is exothermic, and a solid is left if it is heated to 160 °C.
Tetramethylammonium nitratoborate is insoluble in cold water but slightly soluble in hot water. It does not react with water. It also dissolves in liquid ammonia, acetonitrile, methanol, and dimethylformamide. It reacts with liquid sulfur dioxide.
At room temperature tetramethylammonium nitratoborate is stable for months. It does not explode with impact.
Alkali metal tetranitratoborates are unstable at room temperature and decompose.
1-Ethyl-3-methyl-imidazolimium tetranitratoborate was discovered in 2002. It is an ionic liquid that turns solid at −25 °C.
== References == | Wikipedia/Tetranitratoborate |
Bismuth(III) nitrate is a salt composed of bismuth in its cationic +3 oxidation state and nitrate anions. The most common solid form is the pentahydrate. It is used in the synthesis of other bismuth compounds. It is available commercially. It is the only nitrate salt formed by a group 15 element, indicative of bismuth's metallic nature.
== Preparation and reactions ==
Bismuth nitrate can be prepared by the reaction of bismuth metal and concentrated nitric acid.
Bi + 4HNO3 → Bi(NO3)3 + 2H2O + NO
It dissolves in nitric acid but is readily hydrolysed to form a range of oxynitrates when the pH increases above 0.
It is also soluble in acetone, acetic acid and glycerol but practically insoluble in ethanol and ethyl acetate.
Some uses in organic synthesis have been reported for example the nitration of aromatic compounds and selective oxidation of sulfides to sulfoxides.
Bismuth nitrate forms insoluble complexes with pyrogallol and cupferron and these have been the basis of gravimetric methods of determining bismuth content.
On heating bismuth nitrate can decompose forming nitrogen dioxide, NO2.
== Structure ==
The crystal form is triclinic, and contains 10 coordinate Bi3+, (three bidentate nitrate ions and four water molecules).
== References == | Wikipedia/Bismuth(III)_nitrate |
Titanium nitrate is the inorganic compound with formula Ti(NO3)4. It is a colorless, diamagnetic solid that sublimes readily. It is an unusual example of a volatile binary transition metal nitrate. Ill defined species called titanium nitrate are produced upon dissolution of titanium or its oxides in nitric acid.
== Preparation ==
Similarly to its original method, Ti(NO3)4 is prepared by the nitration of titanium tetrachloride using dinitrogen pentoxide or chlorine nitrate:
TiCl4 + 4 N2O5 → Ti(NO3)4 + 4 ClNO2
Hydrated titanium nitrate, the nitrate salt of the aquo complex [Ti(H2O)6]3+, is produced upon dissolution of titanium compounds in nitric acid.
== Structure ==
The complex has D2d symmetry, with four bidentate nitrate ligands. The N-O distances are 1·29 Å and 1·185 Å (noncoordinated).
== Physical properties ==
In the infrared spectrum, it absorbs strongly at 1635 cm−1, assigned to a N-O vibrational mode.
It is soluble in nonpolar solvents silicon tetrachloride and carbon tetrachloride.
== Reactions ==
Titanium nitrate is hygroscopic, converting to ill-defined hydrates. The anhydrous material is highly reactive, even toward hydrocarbons. Titanium nitrate also reacts with n-dodecane, p-dichlorobenzene, anisole, biphenyl,
It decomposes thermally to titanium dioxide.
== References ==
== Other reading ==
Partington, J. R.; A. L. Whynes (1949). "660. Reactions of nitrosyl chloride. Part II". Journal of the Chemical Society (Resumed): 3135. doi:10.1039/JR9490003135. ISSN 0368-1769.
Dauerman, L.; G.E. Salser (1973). "Mass spectra of covalent inorganic nitrates: copper(II) nitrate and titanium(IV) nitrate". Journal of Inorganic and Nuclear Chemistry. 35 (1): 304–306. doi:10.1016/0022-1902(73)80643-8. ISSN 0022-1902. | Wikipedia/Titanium(IV)_nitrate |
Copper(II) nitrate describes any member of the family of inorganic compounds with the formula Cu(NO3)2(H2O)x. The hydrates are hygroscopic blue solids. Anhydrous copper nitrate forms blue-green crystals and sublimes in a vacuum at 150-200 °C. Common hydrates are the hemipentahydrate and trihydrate.
== Synthesis and reactions ==
=== Hydrated copper(II) nitrate ===
Hydrated copper nitrate is prepared by treating copper metal or its oxide with nitric acid:
Cu + 4 HNO3 → Cu(NO3)2 + 2 H2O + 2 NO2
The same salts can be prepared treating copper metal with an aqueous solution of silver nitrate. That reaction illustrates the ability of copper metal to reduce silver ions.
In aqueous solution, the hydrates exist as the aqua complex [Cu(H2O)6]2+. Such complexes are highly labile and subject to rapid ligand exchange due to the d9 electronic configuration of copper(II).
Attempted dehydration of any of the hydrated copper(II) nitrates by heating affords the oxides, not Cu(NO3)2. At 80 °C the hydrates convert to "basic copper nitrate", Cu2(NO3)(OH)3, which converts to CuO at 180 °C. Exploiting this reactivity, copper nitrate can be used to generate nitric acid by heating it until decomposition and passing the fumes directly into water. This method is similar to the last step in the Ostwald process. The equations are as follows:
2 Cu(NO3)2 → 2 CuO + 4 NO2 + O2
3 NO2 + H2O → 2 HNO3 + NO
Treatment of copper(II) nitrate solutions with triphenylphosphine, triphenylarsine, and triphenylstibine gives the corresponding copper(I) complexes [Cu(EPh3)3]NO3 (E = P, As, Sb; Ph = C6H5). The group V ligand is oxidized to the oxide.
=== Anhydrous copper(II) nitrate ===
Anhydrous Cu(NO3)2 is one of the few anhydrous transition metal nitrates. It cannot be prepared by reactions containing or producing water. Instead, anhydrous Cu(NO3)2 forms when copper metal is treated with dinitrogen tetroxide:
Cu + 2 N2O4 → Cu(NO3)2 + 2 NO
== Structure ==
=== Anhydrous copper(II) nitrate ===
Two polymorphs of anhydrous copper(II) nitrate, α and β, are known. Both polymorphs are three-dimensional coordination polymer networks with infinite chains of copper(II) centers and nitrate groups. The α form has only one Cu environment, with [4+1] coordination, but the β form has two different copper centers, one with [4+1] and one that is square planar.
The nitromethane solvate also features "[4+1] coordination", with four short Cu-O bonds of approximately 200 pm and one longer bond at 240 pm.
Heating solid anhydrous copper(II) nitrate under a vacuum to 150-200 °C leads to sublimation and "cracking" to give a vapour of monomeric copper(II) nitrate molecules. In the vapour phase, the molecule features two bidentate nitrate ligands.
=== Hydrated copper(II) nitrate ===
Five hydrates have been reported: the monohydrate (Cu(NO3)2·2H2O), the sesquihydrate (Cu(NO3)2·1.5H2O), the hemipentahydrate (Cu(NO3)2·2.5H2O), a trihydrate (Cu(NO3)2·3H2O), and a hexahydrate ([Cu(OH2)6](NO3)2. The crystal structure of the hexahydrate appeared to show six almost equal Cu–O distances, not revealing the usual effect of a Jahn-Teller distortion that is otherwise characteristic of octahedral Cu(II) complexes. This non-effect was attributed to the strong hydrogen bonding that limits the elasticity of the Cu-O bonds but it is probably due to nickel being misidentified as copper in the refinement.
== Applications ==
Copper(II) nitrate finds a variety of applications, the main one being its conversion to copper(II) oxide, which is used as catalyst for a variety of processes in organic chemistry. Its solutions are used in textiles and polishing agents for other metals. Copper nitrates are found in some pyrotechnics. It is often used in school laboratories to demonstrate chemical voltaic cell reactions. It is a component in some ceramic glazes and metal patinas.
=== Organic synthesis ===
Copper nitrate, in combination with acetic anhydride, is an effective reagent for nitration of aromatic compounds, known as the Menke nitration.
Hydrated copper nitrate adsorbed onto clay affords a reagent called "Claycop". The resulting blue-colored clay is used as a slurry, for example for the oxidation of thiols to disulfides. Claycop is also used to convert dithioacetals to carbonyls. A related reagent based on montmorillonite has proven useful for the nitration of aromatic compounds.
=== Electrowinning ===
Copper(II) nitrate may also be used for copper electrowinning on small scale with a ammonia (NH3) as a byproduct.
== Naturally occurring copper nitrates ==
No mineral of the ideal Cu(NO3) formula, or the hydrates, are known. Likasite, Cu3(NO3)(OH)5·2H2O and buttgenbachite, Cu19(NO3)2(OH)32Cl4·2H2O are related minerals.
Natural basic copper nitrates include the rare minerals gerhardtite and rouaite, both being polymorphs of Cu2(NO3)(OH)3. A much more complex, basic, hydrated and chloride-bearing natural salt is buttgenbachite.
== References ==
== External links ==
National Pollutant Inventory – Copper and compounds fact sheet
ICSC Copper and compounds fact sheet | Wikipedia/Copper(II)_nitrate |
Pentaerythritol tetranitrate (PETN), also known as PENT, pentyl, PENTA (ПЕНТА, primarily in Russian), TEN (tetraeritrit nitrate), corpent, or penthrite (or, rarely and primarily in German, as nitropenta), is an explosive material. It is the nitrate ester of pentaerythritol, and is structurally very similar to nitroglycerin. Penta refers to the five carbon atoms of the neopentane skeleton. PETN is a very powerful explosive material with a relative effectiveness factor of 1.66. When mixed with a plasticizer, PETN forms a plastic explosive. Along with RDX it is the main ingredient of Semtex.
PETN is also used as a vasodilator drug to treat certain heart conditions, such as for management of angina.
== History ==
Pentaerythritol tetranitrate was first prepared and patented in 1894 by the explosives manufacturer Rheinisch-Westfälische Sprengstoff A.G. of Cologne, Germany. The production of PETN started in 1912, when the improved method of production was patented by the German government. PETN was used by the German Military in World War I. It was also used in the MG FF/M autocannons and many other weapon systems of the Luftwaffe in World War II.
== Properties ==
PETN is practically insoluble in water (0.01 g/100 mL at 50 °C), weakly soluble in common nonpolar solvents such as aliphatic hydrocarbons (like gasoline) or tetrachloromethane, but soluble in some other organic solvents, particularly in acetone (about 15 g/100 g of the solution at 20 °C, 55 g/100 g at 60 °C) and dimethylformamide (40 g/100 g of the solution at 40 °C, 70 g/100 g at 70 °C). It is a non-planar molecule that crystallizes in the space group P421c. PETN forms eutectic mixtures with some liquid or molten aromatic nitro compounds, e.g. trinitrotoluene (TNT) or tetryl. Due to the steric hindrance of the adjacent neopentyl-like moiety, PETN is resistant to attack by many chemical reagents; it does not hydrolyze in water at room temperature or in weaker alkaline aqueous solutions. Water at 100 °C or above causes hydrolysis to dinitrate; the presence of 0.1% nitric acid accelerates the reaction.
The chemical stability of PETN is of interest, because of the presence of PETN in aging weapons. Neutron radiation degrades PETN, producing carbon dioxide and some pentaerythritol dinitrate and trinitrate. Gamma radiation increases the thermal decomposition sensitivity of PETN, lowers melting point by few degrees Celsius, and causes swelling of the samples. Like other nitrate esters, the primary degradation mechanism is the loss of nitrogen dioxide; this reaction is autocatalytic. Studies were performed on thermal decomposition of PETN.
In the environment, PETN undergoes biodegradation. Some bacteria denitrate PETN to trinitrate and then dinitrate, which is then further degraded. PETN has low volatility and low solubility in water, and therefore has low bioavailability for most organisms. Its toxicity is relatively low, and its transdermal absorption also seems to be low. It poses a threat for aquatic organisms. It can be degraded to pentaerythritol by iron.
== Production ==
Production is by the reaction of pentaerythritol with concentrated nitric acid to form a precipitate which can be recrystallized from acetone to give processable crystals.
Variations of a method first published in US Patent 2,370,437 by Acken and Vyverberg (1945 to Du Pont) form the basis of all current commercial production.
PETN is manufactured by numerous manufacturers as a powder, or together with nitrocellulose and plasticizer as thin plasticized sheets (e.g. Primasheet 1000 or Detasheet). PETN residues are easily detectable in hair of people handling it. The highest residue retention is on black hair; some residues remain even after washing.
== Explosive use ==
The most common use of PETN is as an explosive with high brisance. It is a secondary explosive, meaning it is more difficult to detonate than primary explosives, so dropping or igniting it will typically not cause an explosion (at standard atmospheric pressure it is difficult to ignite and burns vigorously), but is more sensitive to shock and friction than other secondary explosives such as TNT or tetryl. Under certain conditions a deflagration to detonation transition can occur, just like that of ammonium nitrate.
It is rarely used alone in military operations due to its lower stability, but is primarily used in the main charges of plastic explosives (such as C4) along with other explosives (especially RDX), booster and bursting charges of small caliber ammunition, in upper charges of detonators in some land mines and shells, as the explosive core of detonation cord. PETN is the least stable of the common military explosives, but can be stored without significant deterioration for longer than nitroglycerin or nitrocellulose.
During World War II, PETN was most importantly used in exploding-bridgewire detonators for the atomic bombs. These exploding-bridgewire detonators gave more precise detonation compared to primacord. PETN was used for these detonators because it was safer than primary explosives like lead azide: while it was sensitive, it would not detonate below a threshold amount of energy. Exploding bridgewires containing PETN remain used in current nuclear weapons. In spark detonators, PETN is used to avoid the need for primary explosives; the energy needed for a successful direct initiation of PETN by an electric spark ranges between 10–60 mJ.
Its basic explosion characteristics are:
Explosion energy: 5810 kJ/kg (1390 kcal/kg), so 1 kg of PETN has the energy of 1.24 kg TNT.
Detonation velocity: 8350 m/s (1.73 g/cm3), 7910 m/s (1.62 g/cm3), 7420 m/s (1.5 g/cm3), 8500 m/s (pressed in a steel tube)
Volume of gases produced: 790 dm3/kg (other value: 768 dm3/kg)
Explosion temperature: 4230 °C
Oxygen balance: −6.31 atom -g/kg
Melting point: 141.3 °C (pure), 140–141 °C (technical)
Trauzl lead block test: 523 cm3 (other values: 500 cm3 when sealed with sand, or 560 cm3 when sealed with water)
Critical diameter (minimal diameter of a rod that can sustain detonation propagation): 0.9 mm for PETN at 1 g/cm3, smaller for higher densities (other value: 1.5 mm)
=== In mixtures ===
PETN is used in a number of compositions. It is a major ingredient of the Semtex plastic explosive. It is also used as a component of pentolite, a castable mixture with TNT (usually 50/50 but may contain more TNT), which is, along with pure PETN, a common explosive for boosters for the blasting work (as in mining). The XTX8003 extrudable explosive, used in the W68 and W76 nuclear warheads, is a mixture of 80% PETN and 20% of Sylgard 182, a silicone rubber. It is often phlegmatized by addition of 5–40% of wax, or by polymers (producing polymer-bonded explosives); in this form it is used in some cannon shells up to 30 mm caliber, though it is unsuitable for higher calibers. It is also used as a component of some gun propellants and solid rocket propellants. Nonphlegmatized PETN is stored and handled with approximately 10% water content. PETN alone cannot be cast as it explosively decomposes slightly above its melting point, but it can be mixed with other explosives to form castable mixtures.
PETN can be initiated by a laser. A pulse with duration of 25 nanoseconds and 0.5–4.2 joules of energy from a Q-switched ruby laser can initiate detonation of a PETN surface coated with a 100 nm thick aluminium layer in less than half of a microsecond.
PETN has been replaced in many applications by RDX, which is thermally more stable and has a longer shelf life. PETN can be used in some ram accelerator types. Replacement of the central carbon atom with silicon produces Si-PETN, which is extremely sensitive.
=== Terrorist and Military use ===
Ten kilograms of PETN was used in the 1980 Paris synagogue bombing.
In 1983, 307 people were killed after a truck bomb filled with PETN was detonated at the Beirut barracks.
In 1983, the "Maison de France" house in Berlin was brought to a near-total collapse by the detonation of 24 kilograms (53 lb) of PETN by terrorist Johannes Weinrich.
In 1999, Alfred Heinz Reumayr used PETN as the main charge for his fourteen improvised explosive devices that he constructed in a thwarted attempt to damage the Trans-Alaska Pipeline System.
In 2001, al-Qaeda member Richard Reid, the "Shoe Bomber", used PETN in the sole of his shoe in his unsuccessful attempt to blow up American Airlines Flight 63 from Paris to Miami. He had intended to use the solid triacetone triperoxide (TATP) as a detonator.
In 2009, PETN was used in an attempt by al-Qaeda in the Arabian Peninsula to assassinate the Saudi Arabian Deputy Minister of Interior Prince Muhammad bin Nayef, by Saudi suicide bomber Abdullah Hassan al Asiri. The target survived and the bomber died in the blast. The PETN was hidden in the bomber's rectum, which security experts described as a novel technique.
On 25 December 2009, PETN was found in the underwear of Umar Farouk Abdulmutallab, the "Underwear bomber", a Nigerian with links to al-Qaeda in the Arabian Peninsula. According to US law enforcement officials, he had attempted to blow up Northwest Airlines Flight 253 while approaching Detroit from Amsterdam. Abdulmutallab had tried, unsuccessfully, to detonate approximately 80 grams (2.8 oz) of PETN sewn into his underwear by adding liquid from a syringe; however, only a small fire resulted.
In the al-Qaeda in the Arabian Peninsula October 2010 cargo plane bomb plot, two PETN-filled printer cartridges were found at East Midlands Airport and in Dubai on flights bound for the US on an intelligence tip. Both packages contained sophisticated bombs concealed in computer printer cartridges filled with PETN. The bomb found in England contained 400 grams (14 oz) of PETN, and the one found in Dubai contained 300 grams (11 oz) of PETN. Hans Michels, professor of safety engineering at University College London, told a newspaper that 6 grams (0.21 oz) of PETN—"around 50 times less than was used—would be enough to blast a hole in a metal plate twice the thickness of an aircraft's skin". In contrast, according to an experiment conducted by a BBC documentary team designed to simulate Abdulmutallab's Christmas Day bombing, using a Boeing 747 plane, even 80 grams of PETN was not sufficient to materially damage the fuselage.
On 12 July 2017, 150 grams of PETN was found in the Assembly of Uttar Pradesh, India's most populous state.
PETN was used by Israel in the manufacturing of pagers provided to Hezbollah. On September 17, 2024, the pagers detonated, killing 12 people and injuring thousands.
=== Detection ===
In the wake of terrorist PETN bomb plots, an article in Scientific American noted PETN is difficult to detect because it does not readily vaporize into the surrounding air. The Los Angeles Times noted in November 2010 that PETN's low vapor pressure makes it difficult for bomb-sniffing dogs to detect.
Many technologies can be used to detect PETN, including chemical sensors, X-rays, infrared, microwaves and terahertz, some of which have been implemented in public screening applications, primarily for air travel. PETN is one of the explosive chemicals typically of interest in that area, and it belongs to a family of common nitrate-based explosive chemicals which can often be detected by the same tests.
One detection system in use at airports involves analysis of swab samples obtained from passengers and their baggage. Whole-body imaging scanners that use radio-frequency electromagnetic waves, low-intensity X-rays, or T-rays of terahertz frequency that can detect objects hidden under clothing are not widely used because of cost, concerns about the resulting traveler delays, and privacy concerns.
Both parcels in the 2010 cargo plane bomb plot were x-rayed without the bombs being spotted. Qatar Airways said the PETN bomb "could not be detected by x-ray screening or trained sniffer dogs". The Bundeskriminalamt received copies of the Dubai x-rays, and an investigator said German staff would not have identified the bomb either. New airport security procedures followed in the U.S., largely to protect against PETN.
== Medical use ==
Like nitroglycerin (glyceryl trinitrate) and other nitrates, PETN is also used medically as a vasodilator in the treatment of heart conditions. These drugs work by releasing the signaling gas nitric oxide in the body. The heart medicine Lentonitrat is nearly pure PETN.
Monitoring of oral usage of the drug by patients has been performed by determination of plasma levels of several of its hydrolysis products, pentaerythritol dinitrate, pentaerythritol mononitrate and pentaerythritol, in plasma using gas chromatography-mass spectrometry.
== See also ==
Erythritol tetranitrate
RE factor
== References ==
== Further reading ==
Cooper, Paul (1997). Explosives Engineering. Weinheim: Wiley-VCH. ISBN 978-0-471-18636-6. | Wikipedia/Pentaerithrityl_tetranitrate |
Nickel (II) nitrate is the inorganic compound Ni(NO3)2 or any hydrate thereof. In the hexahydrate, the nitrate anions are not bonded to nickel. Other hydrates have also been reported: Ni(NO3)2.9H2O, Ni(NO3)2.4H2O, and Ni(NO3)2.2H2O.
It is prepared by the reaction of nickel oxide with nitric acid:
NiO + 2 HNO3 + 5 H2O → Ni(NO3)2.6H2O
The anhydrous nickel nitrate is typically not prepared by heating the hydrates. Rather it is generated by the reaction of hydrates with dinitrogen pentoxide or of nickel carbonyl with dinitrogen tetroxide:
Ni(CO)4 + 2 N2O4 → Ni(NO3)2 + 2 NO + 4 CO
The hydrated nitrate is often used as a precursor to supported nickel catalysts.
== Structure ==
Nickel(II) compounds with oxygenated ligands often feature octahedral coordination geometry. Two polymorphs of the tetrahydrate Ni(NO3)2.4H2O have been crystallized. In one the monodentate nitrate ligands are trans while in the other they are cis.
== Reactions and uses ==
Nickel(II) nitrate is primarily used in electrotyping and electroplating of metallic nickel.
In heterogeneous catalysis, nickel(II) nitrate is used to impregnate alumina. Pyrolysis of the resulting material gives forms of Raney nickel and Urushibara nickel. In homogeneous catalysis, the hexahydrate is a precatalyst for cross coupling reactions.
== References == | Wikipedia/Nickel(II)_nitrate |
Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that a reduction of blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%. It can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers or antagonists (ARBs), and beta blockers.
Which type of medication to use initially for hypertension has been the subject of several large studies and resulting national guidelines. The fundamental goal of treatment should be the prevention of the important endpoints of hypertension, such as heart attack, stroke and heart failure. Patient age, associated clinical conditions and end-organ damage also play a part in determining dosage and type of medication administered. The several classes of antihypertensives differ in side effect profiles, ability to prevent endpoints, and cost. The choice of more expensive agents, where cheaper ones would be equally effective, may have negative impacts on national healthcare budgets. As of 2018, the best available evidence favors low-dose thiazide diuretics as the first-line treatment of choice for high blood pressure when drugs are necessary. Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most people (from both efficacy and cost points of view), an ACEi is recommended by NICE in the UK for those under 55 years old.
== Diuretics ==
Diuretics help the kidneys eliminate excess salt and water from the body's tissues and blood.
Loop diuretics:
bumetanide
ethacrynic acid
furosemide
torsemide
Thiazide diuretics:
epitizide
hydrochlorothiazide and chlorothiazide
bendroflumethiazide
methyclothiazide
polythiazide
Thiazide-like diuretics:
indapamide
chlorthalidone
metolazone
xipamide
clopamide
Potassium-sparing diuretics:
amiloride
triamterene
spironolactone
eplerenone
In the United States, the JNC8 (Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) recommends thiazide-type diuretics to be one of the first-line drug treatments for hypertension, either as monotherapy or in combination with calcium channel blockers, ACEis, or ARBs. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. Despite thiazides being cheap and effective, they are not prescribed as often as some newer drugs. This is because they have been associated with increased risk of new-onset diabetes and as such are recommended for use in patients over 65, for whom the risk of new-onset diabetes is outweighed by the benefits of controlling systolic blood pressure. Another theory is that they are off-patent and thus rarely promoted by the drug industry.
Medications that are classified as potassium-sparing diuretics which block the epithelial sodium channel (ENaC), such as amiloride and triamterene, are seldom prescribed as monotherapy. ENaC blocker medications need stronger public evidence for their blood pressure reducing effect.
== Calcium channel blockers ==
Calcium channel blockers block the entry of calcium into muscle cells in artery walls, resulting in the relaxation of muscle cells and vasodilation.
dihydropyridines:
amlodipine
barnidipine
cilnidipine
clevidipine
felodipine
isradipine
lercanidipine
levamlodipine
nicardipine
nifedipine
nimodipine
nisoldipine
nitrendipine
non-dihydropyridines:
diltiazem
verapamil
The 8th Joint National Committee (JNC-8) recommends calcium channel blockers to be a first-line treatment either as monotherapy or in combination with thiazide-type diuretics, ACEis, or ARBs for all patients regardless of age or race.
The ratio of CCBs' anti-proteinuria effect, non-dihydropyridine to dihydropyridine was 30 to −2. The anti-proteinuria effect of non-dihydropyridine is due to better selectivity during glomerular filtration and/or a lower perfusion rate through the renal system.
Notable side effects of CCBs include edema, flushing in the face, headache, drowsiness, and dizziness.
== ACEis ==
ACEis inhibit the activity of angiotensin-converting enzyme (ACE), an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor.
captopril
enalapril
fosinopril
lisinopril
moexipril
perindopril
quinapril
ramipril
trandolapril
benazepril
A systematic review of 63 trials with over 35,000 participants indicated ACEis significantly reduced doubling of serum creatinine levels compared to other drugs (ARBs, α blockers, β blockers, etc.), and the authors suggested this as a first line of defense. The AASK trial showed that ACEis are more effective at slowing down the decline of kidney function compared to calcium channel blockers and beta blockers. As such, ACEis should be the drug treatment of choice for patients with chronic kidney disease regardless of race or diabetic status.
However, ACEis (and ARBs) should not be a first-line treatment for black hypertensives without chronic kidney disease. Results from the ALLHAT trial showed that thiazide-type diuretics and calcium channel blockers were both more effective as monotherapy in improving cardiovascular outcomes compared to ACEis for this subgroup. Furthermore, ACEis were less effective in reducing blood pressure and had a 51% higher risk of stroke in black hypertensives when used as initial therapy compared to a calcium channel blocker. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations.
Notable side effects of ACEis include dry cough, high blood levels of potassium, fatigue, dizziness, headaches, loss of taste and a risk for angioedema.
== ARBs ==
ARBs work by antagonizing the activation of angiotensin receptors.
azilsartan
candesartan
eprosartan
irbesartan
losartan
olmesartan
telmisartan
valsartan
fimasartan
In 2004, an article in the BMJ examined the evidence for and against the suggestion that ARBs may increase the risk of myocardial infarction (heart attack). The matter was debated in 2006 in the medical journal of the American Heart Association. There is no consensus on whether ARBs have a tendency to increase MI, but there is also no substantive evidence to indicate that ARBs are able to reduce MI.
In the VALUE trial, the ARB valsartan produced a statistically significant 19% (p=0.02) relative increase in the prespecified secondary end point of myocardial infarction (fatal and non-fatal) compared with amlodipine.
The CHARM-alternative trial showed a significant +52% (p=0.025) increase in myocardial infarction with candesartan (versus placebo) despite a reduction in blood pressure.
As a consequence of AT1 blockade, ARBs increase angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy, as well as proatherogenic and proinflammatory effects.
An ARB happens to be the favorable alternative to an ACEi if a hypertensive patient with the heart-failure type of reduced ejection fraction treated with an ACEi (or ACEis) was intolerant of cough, angioedema other than hyperkalemia or chronic kidney disease.
== Adrenergic receptor antagonists ==
Beta-blockers can block beta-1 adrenergic receptors and/or beta-2 adrenergic receptors. Those that block beta-1-adrenergic receptors prevent the binding of endogenous catecholamines (such as epinephrine and norepinephrine), which ultimately reduces blood pressure through decreasing renin and cardiac output release. Those that block beta-2-adrenergic receptors reduce blood pressure through increased relaxation of smooth muscle.
Alpha-blockers can block alpha-1 adrenergic receptors and/or alpha-2 adrenergic receptors. Those that block alpha-1-adrenergic receptors on vascular smooth muscle cells prevent vasoconstriction. Blockade of alpha-2-adrenergic receptors prevents the negative feedback mechanism of norepinephrine (NE). Non-selective alpha-blockers generate a balance whereby alpha-2-blockers release NE to reduce the vasodilation effects induced by alpha-1-blockers.
Beta blockers
acebutolol
atenolol
bisoprolol
betaxolol
carteolol
carvedilol
labetalol
metoprolol
nadolol
nebivolol
oxprenolol
penbutolol
pindolol
propranolol
timolol
Alpha blockers:
doxazosin
chlorpromazine
phentolamine
indoramin
phenoxybenzamine
prazosin
terazosin
tolazoline
urapidil
Mixed Alpha + Beta blockers:
bucindolol
carvedilol
labetalol
clonidine (indirectly)
Although beta blockers lower blood pressure, they do not have a positive benefit on endpoints as some other antihypertensives do. In particular, beta-blockers are no longer recommended as first-line treatment due to relative adverse risk of stroke and new-onset of type 2 diabetes when compared to other medications, while certain specific beta-blockers such as atenolol appear to be less useful in overall treatment of hypertension than several other agents. A systematic review of 63 trials with over 35,000 participants indicated β-blockers increased the risk of mortality, compared to other antihypertensive therapies. They do, however, have an important role in the prevention of heart attacks in people who have already had a heart attack. In the United Kingdom, the June 2006 "Hypertension: Management of Hypertension in Adults in Primary Care" guideline of the National Institute for Health and Clinical Excellence, downgraded the role of beta-blockers due to their risk of provoking type 2 diabetes.
Despite lowering blood pressure, alpha blockers have significantly poorer endpoint outcomes than other antihypertensives, and are no longer recommended as a first-line choice in the treatment of hypertension.
However, they may be useful for some men with symptoms of prostate disease.
== Vasodilators ==
Vasodilators act directly on the smooth muscle of arteries to relax their walls so blood can move more easily through them; they are only used in hypertensive emergencies or when other drugs have failed, and even so are rarely given alone.
Sodium nitroprusside, a very potent, short-acting vasodilator, is most commonly used for the quick, temporary reduction of blood pressure in emergencies (such as malignant hypertension or aortic dissection). Hydralazine and its derivatives are also used in the treatment of severe hypertension, although they should be avoided in emergencies. They are no longer indicated as first-line therapy for high blood pressure due to side effects and safety concerns, but hydralazine remains a drug of choice in gestational hypertension.
== Renin inhibitors ==
Renin comes one level higher than ACE in the renin–angiotensin system. Renin inhibitors can therefore effectively reduce hypertension. Aliskiren (developed by Novartis) is a renin inhibitor which has been approved by the U.S. FDA for the treatment of hypertension.
== Aldosterone receptor antagonist ==
Aldosterone receptor antagonists, also known as mineralocorticoid receptor antagonist (MRA) can lower blood pressure by blocking the binding of aldosterone to the mineralocorticoid receptor. Spironolactone and eplerenone are MRAs that causes a block in the reabsorption of sodium, resulting in a decrease in blood pressure.
eplerenone
spironolactone
Aldosterone receptor antagonists are not recommended as first-line agents for blood pressure, but spironolactone and eplerenone are both used in the treatment of heart failure and resistant hypertension.
== Alpha-2 adrenergic receptor agonists ==
Central alpha agonists lower blood pressure by stimulating alpha-receptors in the brain which open peripheral arteries easing blood flow. These alpha 2 receptors are known as autoreceptors which provide negative feedback in neurotransmission (in this case, the vasoconstriction effects of adrenaline).
Central alpha agonists, such as clonidine, are usually prescribed when all other anti-hypertensive medications have failed. For treating hypertension, these drugs are usually administered in combination with a diuretic.
clonidine
guanabenz
guanfacine
methyldopa
moxonidine
Adverse effects of this class of drugs include sedation, drying of the nasal mucosa and rebound hypertension upon discontinuation.
Some indirect anti-adrenergics are rarely used in treatment-resistant hypertension:
guanethidine – replaces norepinephrine in vesicles, decreasing its tonic release
mecamylamine – antinicotinic and ganglion blocker
reserpine – indirect via irreversible VMAT inhibition
== Endothelium receptor blockers ==
Bosentan belongs to a new class of drugs and works by blocking endothelin receptors. It is specifically indicated only for the treatment of pulmonary artery hypertension in patients with moderate to severe heart failure.
== Choice of initial medication ==
For mild blood pressure elevation, consensus guidelines call for medically supervised lifestyle changes and observation before recommending initiation of drug therapy. However, according to the American Hypertension Association, evidence of sustained damage to the body may be present even prior to observed elevation of blood pressure. Therefore, the use of hypertensive medications may be started in individuals with apparent normal blood pressures but who show evidence of hypertension-related nephropathy, proteinuria, atherosclerotic vascular disease, as well as other evidence of hypertension-related organ damage.
If lifestyle changes are ineffective, then drug therapy is initiated, often requiring more than one agent to effectively lower hypertension.
Which type of many medications should be used initially for hypertension has been the subject of several large studies and various national guidelines. Considerations include factors such as age, race, and other medical conditions. In the United States, JNC8 (2014) recommends any drug from one of the four following classes to be a good choice as either initial therapy or as an add-on treatment: thiazide-type diuretics, calcium channel blockers, ACEis, or ARBs.
The first large study to show a mortality benefit from antihypertensive treatment was the VA-NHLBI study, which found that chlorthalidone was effective. The largest study, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in 2002, concluded that chlorthalidone (a thiazide-like diuretic) was as effective as lisinopril (an ACEi) or amlodipine (a calcium channel blocker). (ALLHAT showed that doxazosin, an alpha-adrenergic receptor blocker, had a higher incidence of heart failure events, and the doxazosin arm of the study was stopped.)
A subsequent smaller study (ANBP2) did not show the slight advantages in thiazide diuretic outcomes observed in the ALLHAT study, and actually showed slightly better outcomes for ACEis in older white male patients.
Thiazide diuretics are effective, recommended as the best first-line drug for hypertension, and are much more affordable than other therapies, yet they are not prescribed as often as some newer drugs. Chlorthalidone is the thiazide drug that is most strongly supported by the evidence as providing a mortality benefit; in the ALLHAT study, a chlorthalidone dose of 12.5 mg was used, with titration up to 25 mg for those subjects who did not achieve blood pressure control at 12.5 mg. Chlorthalidone has repeatedly been found to have a stronger effect on lowering blood pressure than hydrochlorothiazide, and hydrochlorothiazide and chlorthalidone have a similar risk of hypokalemia and other adverse effects at the usual doses prescribed in routine clinical practice. Patients with an exaggerated hypokalemic response to a low dose of a thiazide diuretic should be suspected to have hyperaldosteronism, a common cause of secondary hypertension.
Other medications have a role in treating hypertension. Adverse effects of thiazide diuretics include hypercholesterolemia, and impaired glucose tolerance with increased risk of developing diabetes mellitus type 2. The thiazide diuretics also deplete circulating potassium unless combined with a potassium-sparing diuretic or supplemental potassium. Some authors have challenged thiazides as first line treatment. However, as the Merck Manual of Geriatrics notes, "thiazide-type diuretics are especially safe and effective in the elderly."
Current UK guidelines suggest starting patients over the age of 55 years and all those of African/Afrocaribbean ethnicity firstly on calcium channel blockers or thiazide diuretics, whilst younger patients of other ethnic groups should be started on ACEis. Subsequently, if dual therapy is required to use an ACEi in combination with either a calcium channel blocker or a (thiazide) diuretic. Triple therapy is then of all three groups and should the need arise then to add in a fourth agent, to consider either a further diuretic (e.g. spironolactone or furosemide), an alpha-blocker or a beta-blocker. Prior to the demotion of beta-blockers as first line agents, the UK sequence of combination therapy used the first letter of the drug classes and was known as the "ABCD rule".
=== Patient factors ===
The choice between the drugs is to a large degree determined by the characteristics of the patient being prescribed for, the drugs' side effects, and cost. Most drugs have other uses; sometimes the presence of other symptoms can warrant the use of one particular antihypertensive. Examples include:
Age can affect the choice of medications. Current UK guidelines suggest starting patients over the age of 55 years first on calcium channel blockers or thiazide diuretics.
Age and multi-morbidity can affect the choice of medication, the target blood pressure and even whether to treat or not.
Anxiety may be improved with the use of beta blockers.
Asthmatics have been reported to have worsening symptoms when using beta blockers.
Beta blockers can trigger or worsen psoriasis, psoriatic arthritis, and rheumatoid arthritis.
Benign prostatic hyperplasia may be improved with the use of an alpha blocker.
Chronic kidney disease. ACEis or ARBs should be included in the treatment plan to improve kidney outcomes regardless of race or diabetic status.
Late-stage dementia should consider deprescribing antihypertensives, according to the Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D).
Diabetes mellitus. The ACEis and ARBs have been shown to prevent the kidney and retinal complications of diabetes mellitus.
Gout may be worsened by thiazide diuretics, while losartan reduces serum urate.
Kidney stones may be improved with the use of thiazide-type diuretics
Heart block. β-blockers and nondihydropyridine calcium channel blockers should not be used in patients with heart block greater than first degree. JNC8 does not recommend β-blockers as initial therapy for hypertension.
Heart failure may be worsened with nondihydropyridine calcium channel blockers, the alpha blocker doxazosin, and the alpha-2 agonists moxonidine and clonidine. On the other hand, β-blockers, diuretics, ACEis, ARBs, and aldosterone receptor antagonists have been shown to improve outcome.
Pregnancy. Although α-methyldopa is generally regarded as a first-line agent, labetalol and metoprolol are also acceptable. Atenolol has been associated with intrauterine growth retardation, as well as decreased placental growth and weight when prescribed during pregnancy. ACEis and ARBs are contraindicated in women who are or who intend to become pregnant.
Periodontal disease could mitigate the efficacy of antihypertensive drugs.
Race. JNC8 guidelines particularly point out that when used as monotherapy, thiazide diuretics, and calcium channel blockers have been found to be more effective in reducing blood pressure in black hypertensives than β-blockers, ACEis, or ARBs.
Tremor may warrant the use of beta blockers.
The JNC8 guidelines indicate reasons to choose one drug over the others for certain individual patients.
== Antihypertensive Medication during the First Trimester of Pregnancy ==
Hypertensive disorders during pregnancy constitute a significant risk factor for maternal and fetal outcomes, necessitating antihypertensive treatment. However, current data concerning the safety of in utero exposure to antihypertensive medication are controversial. While some studies recommend the administration of certain agents, others underline the possible adverse effects on fetal development. In general, a-methyldopa, β-blockers and calcium channel blockers are the first or second treatment line for hypertension during pregnancy. However, ACEis, ARBs and diuretics are mostly contraindicated, as the potential risk outweighs the benefits of their administration. Additionally, several drugs should be avoided, due to the lack of data regarding their safety. Women are often concerned about the safety of antihypertensives and as a result, many do not take their treatment as prescribed. Shared decision-making aids have been shown to reduce women's uncertainty about taking antihypertensives and increase the number of women taking them as prescribed.
== History ==
History of Thiazides
Chlorothiazide was discovered in 1957, but the first known instance of an effective antihypertensive treatment was in 1947 using primaquine, an antimalarial.
History of Calcium Channel Blockers
In 1883, Ringer discovered the involvement of calcium for cellular activity on isolated heart. Later in 1901, Stiles reported the same activity in muscle contraction. In the early 1940s, Kamada (from Japan) and Heilbrunn (from the United States) noted how calcium was involved with muscle contractions. In 1964, calcium channel blockers were discovered in Godfraind's laboratory through the screening of coronary dilators, which showed how calcium was blocked from entering artery cells, resulting in vasorelaxation.
== Research ==
=== Blood pressure vaccines ===
Vaccinations are being trialed and may become a treatment option for high blood pressure in the future. CYT006-AngQb was only moderately successful in studies, but similar vaccines are being investigated.
Anti-hypertensive drugs in older people
The latest evidence does not have evidence of an effect due to discontinuing vs continuing medications used for treating elevated blood pressure or prevention of heart disease in older adults on all-case mortality and incidence of heart attack. The findings are based on low quality evidence suggesting it may be safe to stop anti-hypertensive medications. However, older adults should not stop any of their medications without talking to a healthcare professional.
== References == | Wikipedia/Antihypertensive_drug |
In quantum chemistry, the electron localization function (ELF) is a measure of the likelihood of finding an electron in the neighborhood space of a reference electron located at a given point and with the same spin. Physically, this measures the extent of spatial localization of the reference electron and provides a method for the mapping of electron pair probability in multielectronic systems.
ELF's usefulness stems from the observation that it allows electron localization to be analyzed in a chemically intuitive way. For example, the shell structure of heavy atoms is obvious when plotting ELF against the radial distance from the nucleus; the ELF for radon has six clear maxima, whereas the electronic density decreases monotonically and the radially weighted density fails to show all shells. When applied to molecules, an analysis of the ELF shows a clear separation between the core and valence electron, and also shows covalent bonds and lone pairs, in what has been called "a faithful visualization of VSEPR theory in action". Another feature of the ELF is that it is invariant concerning the transformation of the molecular orbitals.
The ELF was originally defined by Becke and Edgecombe in 1990. They first argued that a measure of the electron localization is provided by
D
σ
(
r
)
=
τ
σ
(
r
)
−
1
4
(
∇
ρ
σ
(
r
)
)
2
ρ
σ
(
r
)
,
{\displaystyle D_{\sigma }(\mathbf {r} )=\tau _{\sigma }(\mathbf {r} )-{\tfrac {1}{4}}{\frac {(\nabla \rho _{\sigma }(\mathbf {r} ))^{2}}{\rho _{\sigma }(\mathbf {r} )}},}
where ρ is the electron spin density and τ the kinetic energy density. The second term (negative term) is the bosonic kinetic energy density, so D is the contribution due to fermions. D is expected to be small in those regions of space where localized electrons are to be found. Given the arbitrariness of the magnitude of the localization measure provided by D, it is compared to the corresponding value for a uniform electron gas with spin density equal to ρ(r), which is given by
D
σ
0
(
r
)
=
3
5
(
6
π
2
)
2
/
3
ρ
σ
5
/
3
(
r
)
.
{\displaystyle D_{\sigma }^{0}(\mathbf {r} )={\tfrac {3}{5}}(6\pi ^{2})^{2/3}\rho _{\sigma }^{5/3}(\mathbf {r} ).}
The ratio,
χ
σ
(
r
)
=
D
σ
(
r
)
D
σ
0
(
r
)
,
{\displaystyle \chi _{\sigma }(\mathbf {r} )={\frac {D_{\sigma }(\mathbf {r} )}{D_{\sigma }^{0}(\mathbf {r} )}},}
is a dimensionless localization index that expresses electron localization for the uniform electron gas. In the final step, the ELF is defined in terms of χ by mapping its values on to the range 0 ≤ ELF ≤ 1 by defining the electron localization function as
E
L
F
(
r
)
=
1
1
+
χ
σ
2
(
r
)
.
{\displaystyle \mathrm {ELF} (\mathbf {r} )={\frac {1}{1+\chi _{\sigma }^{2}(\mathbf {r} )}}.}
ELF = 1 corresponding to perfect localization and ELF = 1/2 corresponding to the electron gas.
The original derivation was based on Hartree–Fock theory. For density functional theory, the approach was generalized by Andreas Savin in 1992, who also have applied the formulation to examining various chemical and materials systems. In 1994, Bernard Silvi and Andreas Savin developed a method for explaining ELFs using differential topology.
The approach of electron localization, in the form of atoms in molecules (AIM), was pioneered by Richard Bader. Bader's analysis partitions the charge density in a molecule to "atoms" according to zero-flux surfaces (surfaces across which no electron flow is taking place). Bader's analysis allows many properties such as multipole moments, energies and forces, to be partitioned in a defensible and consistent manner to individual atoms within molecules.
Both the Bader approach and the ELF approach to partitioning of molecular properties have gained popularity in recent years because the fastest, accurate ab-initio calculations of molecular properties are now mostly made using density functional theory (DFT), which directly calculates the electron density. This electron density is then analyzed using the Bader charge analysis of Electron Localization Functions. One of the most popular functionals in DFT was first proposed by Becke, who also originated Electron Localization Functions.
== References ==
== External links ==
Frank R. Wagner (ed.) Electron localizability: chemical bonding analysis in direct and momentum space. Max-Planck-Institut für Chemische Physik fester Stoffe, 2002. (accessed 2008-09-02). | Wikipedia/Electron_localization_function |
A perchlorate is a chemical compound containing the perchlorate ion, ClO−4, the conjugate base of perchloric acid (ionic perchlorate). As counterions, there can be metal cations, quaternary ammonium cations or other ions, for example, nitronium cation (NO+2).
The term perchlorate can also describe perchlorate esters or covalent perchlorates. These are organic compounds that are alkyl or aryl esters of perchloric acid. They are characterized by a covalent bond between an oxygen atom of the ClO4 moiety and an organyl group.
In most ionic perchlorates, the cation is non-coordinating. The majority of ionic perchlorates are commercially produced salts commonly used as oxidizers for pyrotechnic devices and for their ability to control static electricity in food packaging. Additionally, they have been used in rocket propellants, fertilizers, and as bleaching agents in the paper and textile industries.
Perchlorate contamination of food and water endangers human health, primarily affecting the thyroid gland.
Ionic perchlorates are typically colorless solids that exhibit good solubility in water. The perchlorate ion forms when they dissolve in water, dissociating into ions. Many perchlorate salts also exhibit good solubility in non-aqueous solvents. Four perchlorates are of primary commercial interest: ammonium perchlorate (NH4)ClO4, perchloric acid HClO4, potassium perchlorate KClO4 and sodium perchlorate NaClO4.
== Production ==
Very few chemical oxidants are strong enough to convert chlorate to perchlorate. Persulfate, ozone, or lead dioxide are all known to do so, but the reactions are too delicate and low-yielding for commercial viability.
Perchlorate salts are typically manufactured through the process of electrolysis, which involves oxidizing aqueous solutions of corresponding chlorates. This technique is commonly employed in the production of sodium perchlorate, which finds widespread use as a key ingredient in rocket fuel. Perchlorate salts are also commonly produced by reacting perchloric acid with bases, such as ammonium hydroxide or sodium hydroxide. Ammonium perchlorate, which is highly valued, can also be produced via an electrochemical process.
Perchlorate esters are formed in the presence of a nucleophilic catalyst via a perchlorate salt's nucleophilic substitution onto an alkylating agent.
== Uses ==
The dominant use of perchlorates is as oxidizers in propellants for rockets, fireworks and highway flares. Of particular value is ammonium perchlorate composite propellant as a component of solid rocket fuel. In a related but smaller application, perchlorates are used extensively within the pyrotechnics industry and in certain munitions and for the manufacture of matches. Martian perchlorates might also be used to produce fuel on that planet.
Perchlorate is used to control static electricity in food packaging. Sprayed onto containers it stops statically charged food from clinging to plastic or paper/cardboard surface.
Niche uses include lithium perchlorate, which decomposes exothermically to produce oxygen, useful in oxygen "candles" on spacecraft, submarines, and in other situations where a reliable backup oxygen supply is needed.
Potassium perchlorate has, in the past, been used therapeutically to help manage Graves' disease. It impedes production of the thyroid hormones that contain iodine.
As perchlorate is generally a non-complexing anion and that its sodium salts is particularly soluble, it is commonly used as a background, or supporting, electrolyte in solution chemistry, electrophoresis, and electrochemistry. Although used as a powerful oxidizer in propulsive powders and explosives, quite surprisingly, the perchlorate anion is a weak oxidant in aqueous solution because of kinetics limitations severely hindering the electron transfer.
== Chemical properties ==
The perchlorate ion is the least redox reactive of the generalized chlorates. Perchlorate contains chlorine in its highest oxidation number (+7). A table of reduction potentials of the four chlorates shows that, contrary to expectation, perchlorate in aqueous solution is the weakest oxidant among the four.
These data show that the perchlorate and chlorate are stronger oxidizers in acidic conditions than in basic conditions.
Gas phase measurements of heats of reaction (which allow computation of ΔfH°) of various chlorine oxides do follow the expected trend wherein Cl2O7 exhibits the largest endothermic value of ΔfH° (238.1 kJ/mol) while Cl2O exhibits the lowest endothermic value of ΔfH° (80.3 kJ/mol).
=== Weak base and weak coordinating anion ===
As perchloric acid is one of the strongest mineral acids, perchlorate is a very weak base in the sense of Brønsted–Lowry acid–base theory.
As it is also generally a weakly coordinating anion, perchlorate is commonly used as a background, or supporting, electrolyte.
=== Weak oxidant in aqueous solution due to kinetic limitations ===
Perchlorate compounds oxidize organic compounds, especially when the mixture is heated. The explosive decomposition of ammonium perchlorate is catalyzed by metals and heat.
As perchlorate is a weak Lewis base (i.e., a weak electron pair donor) and a weak nucleophilic anion, it is also a very weakly coordinating anion. This is why it is often used as a supporting electrolyte to study the complexation and the chemical speciation of many cations in aqueous solution or in electroanalytical methods (voltammetry, electrophoresis…). Although the perchlorate reduction is thermodynamically favorable (∆G < 0; E° > 0), and that ClO−4 is expected to be a strong oxidant, most often in aqueous solution, it is practically an inert species behaving as an extremely slow oxidant because of severe kinetics limitations. The metastable character of perchlorate in the presence of reducing cations such as Fe2+ in solution is due to the difficulty to form an activated complex facilitating the electron transfer and the exchange of oxo groups in the opposite direction. These strongly hydrated cations cannot form a sufficiently stable coordination bridge with one of the four oxo groups of the perchlorate anion. Although thermodynamically a mild reductant, Fe2+ ion exhibits a stronger trend to remain coordinated by water molecules to form the corresponding hexa-aquo complex in solution. The high activation energy of the cation binding with perchlorate to form a transient inner sphere complex more favourable to electron transfer considerably hinders the redox reaction. The redox reaction rate is limited by the formation of a favorable activated complex involving an oxo-bridge between the perchlorate anion and the metallic cation. It depends on the molecular orbital rearrangement (HOMO and LUMO orbitals) necessary for a fast oxygen atom transfer (OAT) and the associated electron transfer as studied experimentally by Henry Taube (1983 Nobel Prize in Chemistry) and theoretically by Rudolph A. Marcus (1992 Nobel Prize in Chemistry), both awarded for their respective works on the mechanisms of electron-transfer reactions with metal complexes and in chemical systems.
In contrast to the Fe2+ cations which remain unoxidized in deaerated perchlorate aqueous solutions free of dissolved oxygen, other cations such as Ru(II) and Ti(III) can form a more stable bridge between the metal centre and one of the oxo groups of ClO−4. In the inner sphere electron transfer mechanism to observe the perchlorate reduction, the ClO−4 anion must quickly transfer an oxygen atom to the reducing cation. When it is the case, metallic cations can readily reduce perchlorate in solution. Ru(II) can reduce ClO−4 to ClO−3, while V(II), V(III), Mo(III), Cr(II) and Ti(III) can reduce ClO−4 to Cl−.
Some metal complexes, especially those of rhenium, and some metalloenzymes can catalyze the reduction of perchlorate under mild conditions. Perchlorate reductase (see below), a molybdoenzyme, also catalyzes the reduction of perchlorate. Both the Re- and Mo-based catalysts operate via metal-oxo intermediates.
=== Microbiology ===
Over 40 phylogenetically and metabolically diverse microorganisms capable of growth using perchlorate as an electron acceptor have been isolated since 1996. Most originate from the Pseudomonadota, but others include the Bacillota, Moorella perchloratireducens and Sporomusa sp., and the archaeon Archaeoglobus fulgidus. With the exception of A. fulgidus, microbes that grow via perchlorate reduction utilize the enzymes perchlorate reductase and chlorite dismutase, which collectively take perchlorate to chloride. In the process, free oxygen (O2) is generated.
== Natural abundance ==
=== Terrestrial abundance ===
Perchlorate is created by lightning discharges in the presence of chloride. Perchlorate has been detected in rain and snow samples from Florida and Lubbock, Texas. It is also present in Martian soil.
Naturally occurring perchlorate at its most abundant can be found commingled with deposits of sodium nitrate in the Atacama Desert of northern Chile. These deposits have been heavily mined as sources for nitrate-based fertilizers. Chilean nitrate is in fact estimated to be the source of around 81,000 tonnes (89,000 tons) of perchlorate imported to the U.S. (1909–1997). Results from surveys of ground water, ice, and relatively unperturbed deserts have been used to estimate a 100,000 to 3,000,000 tonnes (110,000 to 3,310,000 tons) "global inventory" of natural perchlorate presently on Earth.
=== On Mars ===
Perchlorate was detected in Martian soil at the level of ~0.6% by weight. It was shown that at the Phoenix landing site it was present as a mixture of 60% Ca(ClO4)2 and 40% Mg(ClO4)2. These salts, formed from perchlorates, act as antifreeze and substantially lower the freezing point of water. Based on the temperature and pressure conditions on present-day Mars at the Phoenix lander site, conditions would allow a perchlorate salt solution to be stable in liquid form for a few hours each day during the summer.
The possibility that the perchlorate was a contaminant brought from Earth was eliminated by several lines of evidence. The Phoenix retro-rockets used ultra pure hydrazine and launch propellants consisting of ammonium perchlorate or ammonium nitrate. Sensors on board Phoenix found no traces of ammonium nitrate, and thus the nitrate in the quantities present in all three soil samples is indigenous to the Martian soil. Perchlorate is widespread in Martian soils at concentrations between 0.5 and 1%. At such concentrations, perchlorate could be an important source of oxygen, but it could also become a critical chemical hazard to astronauts.
In 2006, a mechanism was proposed for the formation of perchlorates that is particularly relevant to the discovery of perchlorate at the Phoenix lander site. It was shown that soils with high concentrations of chloride converted to perchlorate in the presence of titanium dioxide and sunlight/ultraviolet light. The conversion was reproduced in the lab using chloride-rich soils from Death Valley. Other experiments have demonstrated that the formation of perchlorate is associated with wide band gap semiconducting oxides. In 2014, it was shown that perchlorate and chlorate can be produced from chloride minerals under Martian conditions via UV using only NaCl and silicate.
Further findings of perchlorate and chlorate in the Martian meteorite EETA79001 and by the Mars Curiosity rover in 2012-2013 support the notion that perchlorates are globally distributed throughout the Martian surface. With concentrations approaching 0.5% and exceeding toxic levels on Martian soil, Martian perchlorates would present a serious challenge to human settlement, as well as microorganisms. On the other hand, the perchlorate would provide a convenient source of oxygen for the settlements.
On September 28, 2015, NASA announced that analyses of spectral data from the Compact Reconnaissance Imaging Spectrometer for Mars instrument (CRISM) on board the Mars Reconnaissance Orbiter from four different locations where recurring slope lineae (RSL) are present found evidence for hydrated salts. The hydrated salts most consistent with the spectral absorption features are magnesium perchlorate, magnesium chlorate and sodium perchlorate. The findings strongly support the hypothesis that RSL form as a result of contemporary water activity on Mars.
== Contamination in environment ==
Perchlorates are of concern because of uncertainties about toxicity and health effects at low levels in drinking water, impact on ecosystems, and indirect exposure pathways for humans due to accumulation in vegetables. They are water-soluble, exceedingly mobile in aqueous systems, and can persist for many decades under typical groundwater and surface water conditions.
=== Industrial origin ===
Perchlorates are used mostly in rocket propellants but also in disinfectants, bleaching agents, and herbicides. Perchlorate contamination is caused during both the manufacture and ignition of rockets and fireworks. Fireworks are also a source of perchlorate in lakes. Removal and recovery methods of these compounds from explosives and rocket propellants include high-pressure water washout, which generates aqueous ammonium perchlorate.
=== In U.S. drinking water ===
In 2000, perchlorate contamination beneath the former flare manufacturing plant Olin Corporation Flare Facility, Morgan Hill, California was first discovered several years after the plant had closed. The plant had used potassium perchlorate as one of the ingredients during its 40 years of operation. By late 2003, the State of California and the Santa Clara Valley Water District had confirmed a groundwater plume currently extending over nine miles through residential and agricultural communities.
The California Regional Water Quality Control Board and the Santa Clara Valley Water District have engaged in a major outreach effort, a water well testing program has been underway for about 1,200 residential, municipal, and agricultural wells. Large ion exchange treatment units are operating in three public water supply systems which include seven municipal wells with perchlorate detection. The potentially responsible parties, Olin Corporation and Standard Fuse Incorporated, have been supplying bottled water to nearly 800 households with private wells, and the Regional Water Quality Control Board has been overseeing cleanup efforts.
The source of perchlorate in California was mainly attributed to two manufacturers in the southeast portion of the Las Vegas Valley in Nevada, where perchlorate has been produced for industrial use. This led to perchlorate release into Lake Mead in Nevada and the Colorado River which affected regions of Nevada, California and Arizona, where water from this reservoir is used for consumption, irrigation and recreation for approximately half the population of these states. Lake Mead has been attributed as the source of 90% of the perchlorate in Southern Nevada's drinking water. Based on sampling, perchlorate has been affecting 20 million people, with highest detection in Texas, southern California, New Jersey, and Massachusetts, but intensive sampling of the Great Plains and other middle state regions may lead to revised estimates with additional affected regions. An action level of 18 μg/L has been adopted by several affected states.
In 2001, the chemical was detected at levels as high as 5 μg/L at Joint Base Cape Cod (formerly Massachusetts Military Reservation), over the Massachusetts then state regulation of 2 μg/L.
As of 2009, low levels of perchlorate had been detected in both drinking water and groundwater in 26 states in the U.S., according to the Environmental Protection Agency (EPA).
=== In food ===
In 2004, the chemical was found in cow's milk in California at an average level of 1.3 parts per billion (ppb, or μg/L), which may have entered the cows through feeding on crops exposed to water containing perchlorates.
A 2005 study suggested human breast milk had an average of 10.5 μg/L of perchlorate.
=== From minerals and other natural occurrences ===
In some places, there is no clear source of perchlorate, and it may be naturally occurring. Natural perchlorate on Earth was first identified in terrestrial nitrate deposits /fertilizers of the Atacama Desert in Chile as early as the 1880s and for a long time considered a unique perchlorate source. The perchlorate released from historic use of Chilean nitrate based fertilizer which the U.S.imported by the hundreds of tons in the early 19th century can still be found in some groundwater sources of the United States, for example Long Island, New York. Recent improvements in analytical sensitivity using ion chromatography based techniques have revealed a more widespread presence of natural perchlorate, particularly in subsoils of Southwest USA, salt evaporites in California and Nevada, Pleistocene groundwater in New Mexico, and even present in extremely remote places such as Antarctica. The data from these studies and others indicate that natural perchlorate is globally deposited on Earth with the subsequent accumulation and transport governed by the local hydrologic conditions.
Despite its importance to environmental contamination, the specific source and processes involved in natural perchlorate production remain poorly understood. Laboratory experiments in conjunction with isotopic studies have implied that perchlorate may be produced on earth by oxidation of chlorine species through pathways involving ozone or its photochemical products. Other studies have suggested that perchlorate can also be formed by lightning activated oxidation of chloride aerosols (e.g., chloride in sea salt sprays), and ultraviolet or thermal oxidation of chlorine (e.g., bleach solutions used in swimming pools) in water.
=== From nitrate fertilizers ===
Although perchlorate as an environmental contaminant is usually associated with the manufacture, storage, and testing of solid rocket motors, contamination of perchlorate has been focused as a side effect of the use of natural nitrate fertilizer and its release into ground water. The use of naturally contaminated nitrate fertilizer contributes to the infiltration of perchlorate anions into the ground water and threaten the water supplies of many regions in the US.
One of the main sources of perchlorate contamination from natural nitrate fertilizer use was found to come from the fertilizer derived from Chilean caliche (calcium carbonate), because Chile has rich source of naturally occurring perchlorate anion. Perchlorate concentration was the highest in Chilean nitrate, ranging from 3.3 to 3.98%. Perchlorate in the solid fertilizer ranged from 0.7 to 2.0 mg g−1, variation of less than a factor of 3 and it is estimated that sodium nitrate fertilizers derived from Chilean caliche contain approximately 0.5–2 mg g−1 of perchlorate anion. The direct ecological effect of perchlorate is not well known; its impact can be influenced by factors including rainfall and irrigation, dilution, natural attenuation, soil adsorption, and bioavailability. Quantification of perchlorate concentrations in nitrate fertilizer components via ion chromatography revealed that in horticultural fertilizer components contained perchlorate ranging between 0.1 and 0.46%.
== Environmental cleanup ==
There have been many attempts to eliminate perchlorate contamination. Current remediation technologies for perchlorate have downsides of high costs and difficulty in operation. Thus, there have been interests in developing systems that would offer economic and green alternatives.
=== Treatment ex situ and in situ ===
Several technologies can remove perchlorate, via treatments ex situ (away from the location) and in situ (at the location).
Ex situ treatments include ion exchange using perchlorate-selective or nitrite-specific resins, bioremediation using packed-bed or fluidized-bed bioreactors, and membrane technologies via electrodialysis and reverse osmosis. In ex situ treatment via ion exchange, contaminants are attracted and adhere to the ion exchange resin because such resins and ions of contaminants have opposite charge. As the ion of the contaminant adheres to the resin, another charged ion is expelled into the water being treated, in which then ion is exchanged for the contaminant. Ion exchange technology has advantages of being well-suitable for perchlorate treatment and high volume throughput but has a downside that it does not treat chlorinated solvents. In addition, ex situ technology of liquid phase carbon adsorption is employed, where granular activated carbon (GAC) is used to eliminate low levels of perchlorate and pretreatment may be required in arranging GAC for perchlorate elimination.
In situ treatments, such as bioremediation via perchlorate-selective microbes and permeable reactive barrier, are also being used to treat perchlorate. In situ bioremediation has advantages of minimal above-ground infrastructure and its ability to treat chlorinated solvents, perchlorate, nitrate, and RDX simultaneously. However, it has a downside that it may negatively affect secondary water quality. In situ technology of phytoremediation could also be utilized, even though perchlorate phytoremediation mechanism is not fully founded yet.
Bioremediation using perchlorate-reducing bacteria, which reduce perchlorate ions to harmless chloride, has also been proposed.
== Health effects ==
=== Thyroid inhibition ===
Perchlorate is a potent competitive inhibitor of the thyroid sodium-iodide symporter. Thus, it has been used to treat hyperthyroidism since the 1950s. At very high doses (70,000–300,000 ppb) the administration of potassium perchlorate was considered the standard of care in the United States, and remains the approved pharmacologic intervention for many countries.
In large amounts perchlorate interferes with iodine uptake into the thyroid gland. In adults, the thyroid gland helps regulate the metabolism by releasing hormones, while in children, the thyroid helps in proper development. The NAS, in its 2005 report, Health Implications of Perchlorate Ingestion, emphasized that this effect, also known as Iodide Uptake Inhibition (IUI) is not an adverse health effect. However, in January 2008, California's Department of Toxic Substances Control stated that perchlorate is becoming a serious threat to human health and water resources. In 2010, the EPA's Office of the Inspector General determined that the agency's own perchlorate reference dose (RfD) of 24.5 parts per billion protects against all human biological effects from exposure, as the federal government is responsible for all US military base groundwater contamination. This finding was due to a significant shift in policy at the EPA in basing its risk assessment on non-adverse effects such as IUI instead of adverse effects. The Office of the Inspector General also found that because the EPA's perchlorate reference dose is conservative and protective of human health further reducing perchlorate exposure below the reference dose does not effectively lower risk.
Because of ammonium perchlorate's adverse effects upon children, Massachusetts set its maximum allowed limit of ammonium perchlorate in drinking water at 2 parts per billion (2 ppb = 2 micrograms per liter).
Perchlorate affects only thyroid hormone. Because it is neither stored nor metabolized, effects of perchlorate on the thyroid gland are reversible, though effects on brain development from lack of thyroid hormone in fetuses, newborns, and children are not.
Toxic effects of perchlorate have been studied in a survey of industrial plant workers who had been exposed to perchlorate, compared to a control group of other industrial plant workers who had no known exposure to perchlorate. After undergoing multiple tests, workers exposed to perchlorate were found to have a significant systolic blood pressure rise compared to the workers who were not exposed to perchlorate, as well as a significant decreased thyroid function compared to the control workers.
A study involving healthy adult volunteers determined that at levels above 0.007 milligrams per kilogram per day (mg/(kg·d)), perchlorate can temporarily inhibit the thyroid gland's ability to absorb iodine from the bloodstream ("iodide uptake inhibition", thus perchlorate is a known goitrogen). The EPA converted this dose into a reference dose of 0.0007 mg/(kg·d) by dividing this level by the standard intraspecies uncertainty factor of 10. The agency then calculated a "drinking water equivalent level" of 24.5 ppb by assuming a person weighs 70 kg (150 lb) and consumes 2 L (0.44 imp gal; 0.53 US gal) of drinking water per day over a lifetime.
In 2006, a study reported a statistical association between environmental levels of perchlorate and changes in thyroid hormones of women with low iodine. The study authors were careful to point out that hormone levels in all the study subjects remained within normal ranges. The authors also indicated that they did not originally normalize their findings for creatinine, which would have essentially accounted for fluctuations in the concentrations of one-time urine samples like those used in this study. When the Blount research was re-analyzed with the creatinine adjustment made, the study population limited to women of reproductive age, and results not shown in the original analysis, any remaining association between the results and perchlorate intake disappeared. Soon after the revised Blount Study was released, Robert Utiger, a doctor with the Harvard Institute of Medicine, testified before the US Congress and stated: "I continue to believe that that reference dose, 0.007 milligrams per kilo (24.5 ppb), which includes a factor of 10 to protect those who might be more vulnerable, is quite adequate."
In 2014, a study was published, showing that environmental exposure to perchlorate in pregnant women with hypothyroidism is associated with a significant risk of low IQ in their children.
=== Lung toxicity ===
Some studies suggest that perchlorate has pulmonary toxic effects as well. Studies have been performed on rabbits where perchlorate has been injected into the trachea. The lung tissue was removed and analyzed, and it was found that perchlorate injected lung tissue showed several adverse effects when compared to the control group that had been intratracheally injected with saline. Adverse effects included inflammatory infiltrates, alveolar collapse, subpleural thickening, and lymphocyte proliferation.
=== Aplastic anemia ===
In the early 1960s, potassium perchlorate used to treat Graves' disease was implicated in the development of aplastic anemia—a condition where the bone marrow fails to produce new blood cells in sufficient quantity—in thirteen patients, seven of whom died. Subsequent investigations have indicated the connection between administration of potassium perchlorate and development of aplastic anemia to be "equivocable at best", which means that the benefit of treatment, if it is the only known treatment, outweighs the risk, and it appeared a contaminant poisoned the 13.
== Regulation in the U.S. ==
=== Water ===
In 1998, perchlorate was included in the U.S. EPA Contaminant Candidate List, primarily due to its detection in California drinking water.
In 2002, the EPA completed its draft toxicological review of perchlorate and proposed an reference dose of 0.00003 milligrams per kilogram per day (mg/kg/day) based primarily on studies that identified neurodevelopmental deficits in rat pups. These deficits were linked to maternal exposure to perchlorate.
In 2003, a federal district court in California found that the Comprehensive Environmental Response, Compensation and Liability Act applied, because perchlorate is ignitable, and therefore was a "characteristic" hazardous waste.
Subsequently, the U.S. National Research Council of the National Academy of Sciences (NAS) reviewed the health implications of perchlorate, and in 2005 proposed a much higher reference dose of 0.0007 mg/kg/day based primarily on a 2002 study by Greer et al. During that study, 37 adult human subjects were split into four exposure groups exposed to 0.007 (7 subjects), 0.02 (10 subjects), 0.1 (10 subjects), and 0.5 (10 subjects) mg/kg/day. Significant decreases in iodide uptake were found in the three highest exposure groups. Iodide uptake was not significantly reduced in the lowest exposed group, but four of the seven subjects in this group experienced inhibited iodide uptake. In 2005, the RfD proposed by NAS was accepted by EPA and added to its integrated risk information system (IRIS).
The NAS report described the level of lowest exposure from Greer et al. as a "no-observed-effect level" (NOEL). However, there was actually an effect at that level although not statistically significant largely due to small size of study population (four of seven subjects showed a slight decrease in iodide uptake).
Reduced iodide uptake was not considered to be an adverse effect, even though it is a precursor to an adverse effect, hypothyroidism. Therefore, additional safety factors, would be necessary when extrapolating from the point of departure to the RfD.
Consideration of data uncertainty was insufficient because the Greer, et al. study reflected only a 14-day exposure (=acute) to healthy adults and no additional safety factors were considered to protect sensitive subpopulations like for example, breastfeeding newborns.
Although there has generally been consensus with the Greer et al. study, there has been no consensus with regard to developing a perchlorate RfD. One of the key differences results from how the point of departure is viewed (i.e., NOEL or "lowest-observed-adverse-effect level", LOAEL), or whether a benchmark dose should be used to derive the RfD. Defining the point of departure as a NOEL or LOAEL has implications when it comes to applying appropriate safety factors to the point of departure to derive the RfD.
In early 2006, EPA issued a "Cleanup Guidance" and recommended a Drinking Water Equivalent Level (DWEL) for perchlorate of 24.5 μg/L. Both DWEL and Cleanup Guidance were based on a 2005 review of the existing research by the National Academy of Sciences (NAS).
Lacking a federal drinking water standard, several states subsequently published their own standards for perchlorate including Massachusetts in 2006 and California in 2007. Other states, including Arizona, Maryland, Nevada, New Mexico, New York, and Texas have established non-enforceable, advisory levels for perchlorate.
In 2008, EPA issued an interim drinking water health advisory for perchlorate and with it a guidance and analysis concerning the impacts on the environment and drinking water. California also issued guidance regarding perchlorate use. Both the Department of Defense and some environmental groups voiced questions about the NAS report, but no credible science has emerged to challenge the NAS findings.
In February 2008, the U.S. Food and Drug Administration (FDA) reported that U.S. toddlers on average were being exposed to more than half of EPA's safe dose from food alone. In March 2009, a Centers for Disease Control study found 15 brands of infant formula contaminated with perchlorate and that combined with existing perchlorate drinking water contamination, infants could be at risk for perchlorate exposure above the levels considered safe by EPA.
In 2010, the Massachusetts Department of Environmental Protection set a 10 fold lower RfD (0.07 μg/kg/day) than the NAS RfD using a much higher uncertainty factor of 100. They also calculated an Infant drinking water value, which neither US EPA nor CalEPA had done.
On February 11, 2011, EPA determined that perchlorate meets the Safe Drinking Water Act criteria for regulation as a contaminant. The agency found that perchlorate may have an adverse effect on the health of persons and is known to occur in public water systems with a frequency and at levels that it presents a public health concern. Since then EPA has continued to determine what level of contamination is appropriate. EPA prepared extensive responses to submitted public comments.
In 2016, the Natural Resources Defense Council (NRDC) filed a lawsuit to accelerate EPA's regulation of perchlorate.
In 2019, EPA proposed a Maximum Contaminant Level of 0.056 mg/L for public water systems.
On June 18, 2020, EPA announced that it was withdrawing its 2011 regulatory determination and its 2019 proposal, stating that it had taken "proactive steps" with state and local governments to address perchlorate contamination. In September 2020 NRDC filed suit against EPA for its failure to regulate perchlorate, and stated that 26 million people may be affected by perchlorate in their drinking water. On March 31, 2022, the EPA announced that a review confirmed its 2020 decision. Following the NRDC lawsuit, in 2023 the US Court of Appeals for the DC Circuit ordered EPA to develop a perchlorate standard for public water systems. EPA stated that it will publish a proposed standard for perchlorate in 2025, and issue a final rule in 2027.
== Covalent perchlorates ==
Although typically found as a non-coordinating anion, a few metal complexes are known. Hexaperchloratoaluminate and tetraperchloratoaluminate are strong oxidising agents.
Several perchlorate esters are known. For example, methyl perchlorate is a high energy material that is a strong alkylating agent. Chlorine perchlorate is a covalent inorganic analog.
== Safety ==
As discussed above, iodide is competitor in the thyroid glands. In the presence of reductants, perchlorate forms potentially explosive mixtures. The PEPCON disaster destroyed a production plant for ammonium perchlorate when a fire caused the ammonium perchlorate stored on site to react with the aluminum that the storage tanks were constructed with and explode.
== References ==
== External links ==
NAS Report: The Health Effects of Perchlorate Ingestion
NRDC's criticism of NAS report
Environment California report Archived 2010-06-09 at the Wayback Machine (Executive Summary with link to full text)
Macho Moms: Perchlorate pollutant masculinizes fish: Science News Online, August 12, 2006 Archived February 20, 2008, at the Wayback Machine
New Scientist Space Blog: Phoenix discovery may be bad for Mars life
State Threatening to Sue Military over Water Pollution Archived 2005-11-09 at the Wayback Machine, Associated Press, May 19, 2003.
Health Effects of Perchlorate from Spent Rocket, SpaceDaily.com, July 11, 2002.
Dept of Defense, Dept of Energy, and US Environmental Protection Agency's Strategic Environmental Research and Development Program, Elimination of Perchlorate Oxidizers from Pyrotechnic Flare Compositions, 2009 Archived 2007-08-06 at the Wayback Machine | Wikipedia/Perchlorate |
In quantum chemistry, the quantum theory of atoms in molecules (QTAIM), sometimes referred to as atoms in molecules (AIM), is a model of molecular and condensed matter electronic systems (such as crystals) in which the principal objects of molecular structure - atoms and bonds - are natural expressions of a system's observable electron density distribution function. An electron density distribution of a molecule is a probability distribution that describes the average manner in which the electronic charge is distributed throughout real space in the attractive field exerted by the nuclei. According to QTAIM, molecular structure is revealed by the stationary points of the electron density together with the gradient paths of the electron density that originate and terminate at these points.
QTAIM was primarily developed by Professor Richard Bader and his research group at McMaster University over the course of decades, beginning with analyses of theoretically calculated electron densities of simple molecules in the early 1960s and culminating with analyses of both theoretically and experimentally measured electron densities of crystals in the 90s. The development of QTAIM was driven by the assumption that, since the concepts of atoms and bonds have been and continue to be so ubiquitously useful in interpreting, classifying, predicting and communicating chemistry, they should have a well-defined physical basis.
QTAIM recovers the central operational concepts of the molecular structure hypothesis, that of a functional grouping of atoms with an additive and characteristic set of properties, together with a definition of the bonds that link the atoms and impart the structure. QTAIM defines chemical bonding and structure of a chemical system based on the topology of the electron density. In addition to bonding, QTAIM allows the calculation of certain physical properties on a per-atom basis, by dividing space up into atomic volumes containing exactly one nucleus, which acts as a local attractor of the electron density. In QTAIM an atom is defined as a proper open system, i.e. a system that can share energy and electron density which is localized in the 3D space. The mathematical study of these features is usually referred to in the literature as charge density topology.
QTAIM rests on the fact that the dominant topological property of the vast majority of electron density distributions is the presence of strong maxima that occur exclusively at the nuclei, certain pairs of which are linked together by ridges of electron density. In terms of an electron density distribution's gradient vector field, this corresponds to a complete, non-overlapping partitioning of a molecule into three-dimensional basins (atoms) that are linked together by shared two-dimensional separatrices (interatomic surfaces). Within each interatomic surface, the electron density is a maximum at the corresponding internuclear saddle point, which also lies at the minimum of the ridge between corresponding pair of nuclei, the ridge being defined by the pair of gradient trajectories (bond path) originating at the saddle point and terminating at the nuclei. Because QTAIM atoms are always bounded by surfaces having zero flux in the gradient vector field of the electron density, they have some unique quantum mechanical properties compared to other subsystem definitions. These include unique electronic kinetic energy, the satisfaction of an electronic virial theorem analogous to the molecular electronic virial theorem, and some interesting variational properties. QTAIM has gradually become a method for addressing possible questions regarding chemical systems, in a variety of situations hardly handled before by any other model or theory in chemistry.
== Applications ==
QTAIM is applied to the description of certain organic crystals with unusually short distances between neighboring molecules as observed by X-ray diffraction. For example in the crystal structure of molecular chlorine, the experimental Cl...Cl distance between two molecules is 327 picometres, which is less than the sum of the van der Waals radii of 350 picometres. In one QTAIM result, 12 bond paths start from each chlorine atom to other chlorine atoms including the other chlorine atom in the molecule. The theory also aims to explain the metallic properties of metallic hydrogen in much the same way.
The theory is also applied to so-called hydrogen–hydrogen bonds as they occur in molecules such as phenanthrene and chrysene. In these compounds, the distance between two ortho hydrogen atoms again is shorter than their van der Waals radii, and according to in silico experiments based on this theory, a bond path is identified between them. Both hydrogen atoms have identical electron density and are closed shell and therefore they are very different from the so-called dihydrogen bonds that are postulated for compounds such as H3NBH3, and also different from so-called agostic interactions.
In mainstream chemistry descriptions, close proximity of two nonbonding atoms leads to destabilizing steric repulsion but in QTAIM the observed hydrogen-hydrogen interactions are in fact stabilizing. It is well known that both kinked phenanthrene and chrysene are around 6 kcal/mol (25 kJ/mol) more stable than their linear isomers anthracene and tetracene. One traditional explanation is given by Clar's rule. QTAIM shows that a calculated stabilization of 8 kcal/mol (33 kJ/mol) for phenanthrene is the result of destabilization of the compound by 8 kcal/mol (33 kJ/mol) originating from electron transfer from carbon to hydrogen, offset by 12.1 kcal (51 kJ/mol) of stabilization due to a H...H bond path. The electron density at the critical point between the two hydrogen atoms is low (0.012 e) for phenanthrene. Another property of the bond path is its curvature.
Another molecule analyzed by QTAIM is biphenyl. Its two phenyl ring planes are oriented at a 38° angle with respect to each other, with the planar molecular geometry (resulting from a rotation around the central C-C bond) destabilized by 2.1 kcal/mol (8.8 kJ/mol) and the perpendicular one destabilized by 2.5 kcal/mol (10.5 kJ/mol). The classic explanations for this rotational barrier are steric repulsion between the ortho-hydrogen atoms (planar) and breaking of delocalization of pi density over both rings (perpendicular).
In QTAIM, the energy increase on decreasing the dihedral angle from 38° to 0° is a summation of several factors. Destabilizing factors are the increase in bond length between the connecting carbon atoms (because they have to accommodate the approaching hydrogen atoms) and transfer of electronic charge from carbon to hydrogen. Stabilizing factors are increased delocalization of pi-electrons from one ring to the other and (the one that tips the balance) is a hydrogen–hydrogen bond between the ortho hydrogens.
QTAIM has also been applied to study the electron topology of solvated post-translational modifications to proteins. For example, covalent–bond force constants in a set of lysine-arginine advanced glycation end-products were derived using electronic structure calculations, and then bond paths were used to illustrate differences in each of the applied computational chemistry functionals. Furthermore, QTAIM had been used to identify a bond-path network of hydrogen bonds between glucosepane and nearby water molecules.
The hydrogen-hydrogen bond is not without its critics. According to one, the relative stability of phenanthrene compared to its isomers can be adequately explained by comparing resonance stabilizations. Another critic argues that the stability of phenanthrene can be attributed to more effective pi-pi overlap in the central double bond; the existence of bond paths is not questioned but the stabilizing energy derived from them is.
== See also ==
Quantum chemistry
== References ==
== External links ==
atoms and molecules
Atoms in Molecules page at McMaster University
Popelier Group Home Page
Multiwfn Home Page
AIM2000 Home Page
AIMAll Home Page
XD Home Page | Wikipedia/Atoms_in_molecules |
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms. Study of structure determines their structural formula. Study of properties includes physical and chemical properties, and evaluation of chemical reactivity to understand their behavior. The study of organic reactions includes the chemical synthesis of natural products, drugs, and polymers, and study of individual organic molecules in the laboratory and via theoretical (in silico) study.
The range of chemicals studied in organic chemistry includes hydrocarbons (compounds containing only carbon and hydrogen) as well as compounds based on carbon, but also containing other elements, especially oxygen, nitrogen, sulfur, phosphorus (included in many biochemicals) and the halogens. Organometallic chemistry is the study of compounds containing carbon–metal bonds.
Organic compounds form the basis of all earthly life and constitute the majority of known chemicals. The bonding patterns of carbon, with its valence of four—formal single, double, and triple bonds, plus structures with delocalized electrons—make the array of organic compounds structurally diverse, and their range of applications enormous. They form the basis of, or are constituents of, many commercial products including pharmaceuticals; petrochemicals and agrichemicals, and products made from them including lubricants, solvents; plastics; fuels and explosives. The study of organic chemistry overlaps organometallic chemistry and biochemistry, but also with medicinal chemistry, polymer chemistry, and materials science.
== Educational aspects ==
Organic chemistry is typically taught at the college or university level. It is considered a very challenging course but has also been made accessible to students.
== History ==
Before the 18th century, chemists generally believed that compounds obtained from living organisms were endowed with a vital force that distinguished them from inorganic compounds. According to the concept of vitalism (vital force theory), organic matter was endowed with a "vital force". During the first half of the nineteenth century, some of the first systematic studies of organic compounds were reported. Around 1816 Michel Chevreul started a study of soaps made from various fats and alkalis. He separated the acids that, in combination with the alkali, produced the soap. Since these were all individual compounds, he demonstrated that it was possible to make a chemical change in various fats (which traditionally come from organic sources), producing new compounds, without "vital force". In 1828 Friedrich Wöhler produced the organic chemical urea (carbamide), a constituent of urine, from inorganic starting materials (the salts potassium cyanate and ammonium sulfate), in what is now called the Wöhler synthesis. Although Wöhler himself was cautious about claiming he had disproved vitalism, this was the first time a substance thought to be organic was synthesized in the laboratory without biological (organic) starting materials. The event is now generally accepted as indeed disproving the doctrine of vitalism.
After Wöhler, Justus von Liebig worked on the organization of organic chemistry, being considered one of its principal founders.
In 1856, William Henry Perkin, while trying to manufacture quinine, accidentally produced the organic dye now known as Perkin's mauve. His discovery, made widely known through its financial success, greatly increased interest in organic chemistry.
A crucial breakthrough for organic chemistry was the concept of chemical structure, developed independently in 1858 by both Friedrich August Kekulé and Archibald Scott Couper. Both researchers suggested that tetravalent carbon atoms could link to each other to form a carbon lattice, and that the detailed patterns of atomic bonding could be discerned by skillful interpretations of appropriate chemical reactions.
The era of the pharmaceutical industry began in the last decade of the 19th century when the German company, Bayer, first manufactured acetylsalicylic acid—more commonly known as aspirin. By 1910 Paul Ehrlich and his laboratory group began developing arsenic-based arsphenamine (Salvarsan) as the first effective medicinal treatment of syphilis, and thereby initiated the medical practice of chemotherapy. Ehrlich popularized the concepts of "magic bullet" drugs and of systematically improving drug therapies. His laboratory made decisive contributions to developing antiserum for diphtheria and standardizing therapeutic serums.
Early examples of organic reactions and applications were often found because of a combination of luck and preparation for unexpected observations. The latter half of the 19th century however witnessed systematic studies of organic compounds. The development of synthetic indigo is illustrative. The production of indigo from plant sources dropped from 19,000 tons in 1897 to 1,000 tons by 1914 thanks to the synthetic methods developed by Adolf von Baeyer. In 2002, 17,000 tons of synthetic indigo were produced from petrochemicals.
In the early part of the 20th century, polymers and enzymes were shown to be large organic molecules, and petroleum was shown to be of biological origin.
The multiple-step synthesis of complex organic compounds is called total synthesis. Total synthesis of complex natural compounds increased in complexity to glucose and terpineol. For example, cholesterol-related compounds have opened ways to synthesize complex human hormones and their modified derivatives. Since the start of the 20th century, complexity of total syntheses has been increased to include molecules of high complexity such as lysergic acid and vitamin B12.
The discovery of petroleum and the development of the petrochemical industry spurred the development of organic chemistry. Converting individual petroleum compounds into types of compounds by various chemical processes led to organic reactions enabling a broad range of industrial and commercial products including, among (many) others: plastics, synthetic rubber, organic adhesives, and various property-modifying petroleum additives and catalysts.
The majority of chemical compounds occurring in biological organisms are carbon compounds, so the association between organic chemistry and biochemistry is so close that biochemistry might be regarded as in essence a branch of organic chemistry. Although the history of biochemistry might be taken to span some four centuries, fundamental understanding of the field only began to develop in the late 19th century and the actual term biochemistry was coined around the start of 20th century. Research in the field increased throughout the twentieth century, without any indication of slackening in the rate of increase, as may be verified by inspection of abstraction and indexing services such as BIOSIS Previews and Biological Abstracts, which began in the 1920s as a single annual volume, but has grown so drastically that by the end of the 20th century it was only available to the everyday user as an online electronic database.
== Characterization ==
Since organic compounds often exist as mixtures, a variety of techniques have also been developed to assess purity; chromatography techniques are especially important for this application, and include HPLC and gas chromatography. Traditional methods of separation include distillation, crystallization, evaporation, magnetic separation and solvent extraction.
Organic compounds were traditionally characterized by a variety of chemical tests, called "wet methods", but such tests have been largely displaced by spectroscopic or other computer-intensive methods of analysis. Listed in approximate order of utility, the chief analytical methods are:
Nuclear magnetic resonance (NMR) spectroscopy is the most commonly used technique, often permitting the complete assignment of atom connectivity and even stereochemistry using correlation spectroscopy. The principal constituent atoms of organic chemistry – hydrogen and carbon – exist naturally with NMR-responsive isotopes, respectively 1H and 13C.
Elemental analysis: A destructive method used to determine the elemental composition of a molecule. See also mass spectrometry, below.
Mass spectrometry indicates the molecular weight of a compound and, from the fragmentation patterns, its structure. High-resolution mass spectrometry can usually identify the exact formula of a compound and is used in place of elemental analysis. In former times, mass spectrometry was restricted to neutral molecules exhibiting some volatility, but advanced ionization techniques allow one to obtain the "mass spec" of virtually any organic compound.
Crystallography can be useful for determining molecular geometry when a single crystal of the material is available. Highly efficient hardware and software allows a structure to be determined within hours of obtaining a suitable crystal.
Traditional spectroscopic methods such as infrared spectroscopy, optical rotation, and UV/VIS spectroscopy provide relatively nonspecific structural information but remain in use for specific applications. Refractive index and density can also be important for substance identification.
== Properties ==
The physical properties of organic compounds typically of interest include both quantitative and qualitative features. Quantitative information includes a melting point, boiling point, solubility, and index of refraction. Qualitative properties include odor, consistency, and color.
== Melting and boiling properties ==
Organic compounds typically melt and many boil. In contrast, while inorganic materials generally can be melted, many do not boil, and instead tend to degrade. In earlier times, the melting point (m.p.) and boiling point (b.p.) provided crucial information on the purity and identity of organic compounds. The melting and boiling points correlate with the polarity of the molecules and their molecular weight. Some organic compounds, especially symmetrical ones, sublime. A well-known example of a sublimable organic compound is para-dichlorobenzene, the odiferous constituent of modern mothballs. Organic compounds are usually not very stable at temperatures above 300 °C, although some exceptions exist.
=== Solubility ===
Neutral organic compounds tend to be hydrophobic; that is, they are less soluble in water than in organic solvents. Exceptions include organic compounds that contain ionizable groups as well as low molecular weight alcohols, amines, and carboxylic acids where hydrogen bonding occurs. Otherwise, organic compounds tend to dissolve in organic solvents. Solubility varies widely with the organic solute and with the organic solvent.
=== Solid state properties ===
Various specialized properties of molecular crystals and organic polymers with conjugated systems are of interest depending on applications, e.g. thermo-mechanical and electro-mechanical such as piezoelectricity, electrical conductivity (see conductive polymers and organic semiconductors), and electro-optical (e.g. non-linear optics) properties. For historical reasons, such properties are mainly the subjects of the areas of polymer science and materials science.
== Nomenclature ==
The names of organic compounds are either systematic, following logically from a set of rules, or nonsystematic, following various traditions. Systematic nomenclature is stipulated by specifications from IUPAC (International Union of Pure and Applied Chemistry). Systematic nomenclature starts with the name for a parent structure within the molecule of interest. This parent name is then modified by prefixes, suffixes, and numbers to unambiguously convey the structure. Given that millions of organic compounds are known, rigorous use of systematic names can be cumbersome. Thus, IUPAC recommendations are more closely followed for simple compounds, but not complex molecules. To use the systematic naming, one must know the structures and names of the parent structures. Parent structures include unsubstituted hydrocarbons, heterocycles, and mono functionalized derivatives thereof.
Nonsystematic nomenclature is simpler and unambiguous, at least to organic chemists. Nonsystematic names do not indicate the structure of the compound. They are common for complex molecules, which include most natural products. Thus, the informally named lysergic acid diethylamide is systematically named
(6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo-[4,3-fg] quinoline-9-carboxamide.
With the increased use of computing, other naming methods have evolved that are intended to be interpreted by machines. Two popular formats are SMILES and InChI.
=== Structural drawings ===
Organic molecules are described more commonly by drawings or structural formulas, combinations of drawings and chemical symbols. The line-angle formula is simple and unambiguous. In this system, the endpoints and intersections of each line represent one carbon, and hydrogen atoms can either be notated explicitly or assumed to be present as implied by tetravalent carbon.
=== History ===
By 1880 an explosion in the number of chemical compounds being discovered occurred assisted by new synthetic and analytical techniques. Grignard described the situation as "chaos le plus complet" (complete chaos) due to the lack of convention it was possible to have multiple names for the same compound. This led to the creation of the Geneva rules in 1892.
== Classification of organic compounds ==
=== Functional groups ===
The concept of functional groups is central in organic chemistry, both as a means to classify structures and for predicting properties. A functional group is a molecular module, and the reactivity of that functional group is assumed, within limits, to be the same in a variety of molecules. Functional groups can have a decisive influence on the chemical and physical properties of organic compounds. Molecules are classified based on their functional groups. Alcohols, for example, all have the subunit C-O-H. All alcohols tend to be somewhat hydrophilic, usually form esters, and usually can be converted to the corresponding halides. Most functional groups feature heteroatoms (atoms other than C and H). Organic compounds are classified according to functional groups, alcohols, carboxylic acids, amines, etc. Functional groups make the molecule more acidic or basic due to their electronic influence on surrounding parts of the molecule.
As the pKa (aka basicity) of the molecular addition/functional group increases, there is a corresponding dipole, when measured, increases in strength. A dipole directed towards the functional group (higher pKa therefore basic nature of group) points towards it and decreases in strength with increasing distance. Dipole distance (measured in Angstroms) and steric hindrance towards the functional group have an intermolecular and intramolecular effect on the surrounding environment and pH level.
Different functional groups have different pKa values and bond strengths (single, double, triple) leading to increased electrophilicity with lower pKa and increased nucleophile strength with higher pKa. More basic/nucleophilic functional groups desire to attack an electrophilic functional group with a lower pKa on another molecule (intermolecular) or within the same molecule (intramolecular). Any group with a net acidic pKa that gets within range, such as an acyl or carbonyl group is fair game. Since the likelihood of being attacked decreases with an increase in pKa, acyl chloride components with the lowest measured pKa values are most likely to be attacked, followed by carboxylic acids (pKa = 4), thiols (13), malonates (13), alcohols (17), aldehydes (20), nitriles (25), esters (25), then amines (35). Amines are very basic, and are great nucleophiles/attackers.
=== Aliphatic compounds ===
The aliphatic hydrocarbons are subdivided into three groups of homologous series according to their state of saturation:
alkanes (paraffins): aliphatic hydrocarbons without any double or triple bonds, i.e. just C-C, C-H single bonds
alkenes (olefins): aliphatic hydrocarbons that contain one or more double bonds, i.e. di-olefins (dienes) or poly-olefins.
alkynes (acetylenes): aliphatic hydrocarbons which have one or more triple bonds.
The rest of the group is classified according to the functional groups present. Such compounds can be "straight-chain", branched-chain or cyclic. The degree of branching affects characteristics, such as the octane number or cetane number in petroleum chemistry.
Both saturated (alicyclic) compounds and unsaturated compounds exist as cyclic derivatives. The most stable rings contain five or six carbon atoms, but large rings (macrocycles) and smaller rings are common. The smallest cycloalkane family is the three-membered cyclopropane ((CH2)3). Saturated cyclic compounds contain single bonds only, whereas aromatic rings have an alternating (or conjugated) double bond. Cycloalkanes do not contain multiple bonds, whereas the cycloalkenes and the cycloalkynes do.
=== Aromatic compounds ===
Aromatic hydrocarbons contain conjugated double bonds. This means that every carbon atom in the ring is sp2 hybridized, allowing for added stability. The most important example is benzene, the structure of which was formulated by Kekulé who first proposed the delocalization or resonance principle for explaining its structure. For "conventional" cyclic compounds, aromaticity is conferred by the presence of 4n + 2 delocalized pi electrons, where n is an integer. Particular instability (antiaromaticity) is conferred by the presence of 4n conjugated pi electrons.
=== Heterocyclic compounds ===
The characteristics of the cyclic hydrocarbons are again altered if heteroatoms are present, which can exist as either substituents attached externally to the ring (exocyclic) or as a member of the ring itself (endocyclic). In the case of the latter, the ring is termed a heterocycle. Pyridine and furan are examples of aromatic heterocycles while piperidine and tetrahydrofuran are the corresponding alicyclic heterocycles. The heteroatom of heterocyclic molecules is generally oxygen, sulfur, or nitrogen, with the latter being particularly common in biochemical systems.
Heterocycles are commonly found in a wide range of products including aniline dyes and medicines. Additionally, they are prevalent in a wide range of biochemical compounds such as alkaloids, vitamins, steroids, and nucleic acids (e.g. DNA, RNA).
Rings can fuse with other rings on an edge to give polycyclic compounds. The purine nucleoside bases are notable polycyclic aromatic heterocycles. Rings can also fuse on a "corner" such that one atom (almost always carbon) has two bonds going to one ring and two to another. Such compounds are termed spiro and are important in several natural products.
=== Polymers ===
One important property of carbon is that it readily forms chains, or networks, that are linked by carbon-carbon (carbon-to-carbon) bonds. The linking process is called polymerization, while the chains, or networks, are called polymers. The source compound is called a monomer.
Two main groups of polymers exist: synthetic polymers and biopolymers. Synthetic polymers are artificially manufactured, and are commonly referred to as industrial polymers. Biopolymers occur within a respectfully natural environment, or without human intervention.
=== Biomolecules ===
Biomolecular chemistry is a major category within organic chemistry which is frequently studied by biochemists. Many complex multi-functional group molecules are important in living organisms. Some are long-chain biopolymers, and these include peptides, DNA, RNA and the polysaccharides such as starches in animals and celluloses in plants. The other main classes are amino acids (monomer building blocks of peptides and proteins), carbohydrates (which includes the polysaccharides), the nucleic acids (which include DNA and RNA as polymers), and the lipids. Besides, animal biochemistry contains many small molecule intermediates which assist in energy production through the Krebs cycle, and produces isoprene, the most common hydrocarbon in animals. Isoprenes in animals form the important steroid structural (cholesterol) and steroid hormone compounds; and in plants form terpenes, terpenoids, some alkaloids, and a class of hydrocarbons called biopolymer polyisoprenoids present in the latex of various species of plants, which is the basis for making rubber. Biologists usually classify the above-mentioned biomolecules into four main groups, i.e., proteins, lipids, carbohydrates, and nucleic acids. Petroleum and its derivatives are considered organic molecules, which is consistent with the fact that this oil comes from the fossilization of living beings, i.e., biomolecules.
See also: peptide synthesis, oligonucleotide synthesis and carbohydrate synthesis.
=== Small molecules ===
In pharmacology, an important group of organic compounds is small molecules, also referred to as 'small organic compounds'. In this context, a small molecule is a small organic compound that is biologically active but is not a polymer. In practice, small molecules have a molar mass less than approximately 1000 g/mol.
=== Fullerenes ===
Fullerenes and carbon nanotubes, carbon compounds with spheroidal and tubular structures, have stimulated much research into the related field of materials science. The first fullerene was discovered in 1985 by Sir Harold W. Kroto of the United Kingdom and by Richard E. Smalley and Robert F. Curl Jr., of the United States. Using a laser to vaporize graphite rods in an atmosphere of helium gas, these chemists and their assistants obtained cagelike molecules composed of 60 carbon atoms (C60) joined by single and double bonds to form a hollow sphere with 12 pentagonal and 20 hexagonal faces—a design that resembles a football, or soccer ball. In 1996 the trio was awarded the Nobel Prize for their pioneering efforts. The C60 molecule was named buckminsterfullerene (or, more simply, the buckyball) after the American architect R. Buckminster Fuller, whose geodesic dome is constructed on the same structural principles.
=== Others ===
Organic compounds containing bonds of carbon to nitrogen, oxygen and the halogens are not normally grouped separately. Others are sometimes put into major groups within organic chemistry and discussed under titles such as organosulfur chemistry, organometallic chemistry, organophosphorus chemistry and organosilicon chemistry.
== Organic reactions ==
Organic reactions are chemical reactions involving organic compounds. Many of these reactions are associated with functional groups. The general theory of these reactions involves careful analysis of such properties as the electron affinity of key atoms, bond strengths and steric hindrance. These factors can determine the relative stability of short-lived reactive intermediates, which usually directly determine the path of the reaction.
The basic reaction types are: addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions and redox reactions. An example of a common reaction is a substitution reaction written as:
Nu− + C−X → C−Nu + X−
where X is some functional group and Nu is a nucleophile.
The number of possible organic reactions is infinite. However, certain general patterns are observed that can be used to describe many common or useful reactions. Each reaction has a stepwise reaction mechanism that explains how it happens in sequence—although the detailed description of steps is not always clear from a list of reactants alone.
The stepwise course of any given reaction mechanism can be represented using arrow pushing techniques in which curved arrows are used to track the movement of electrons as starting materials transition through intermediates to final products.
== Organic synthesis ==
Synthetic organic chemistry is an applied science as it borders engineering, the "design, analysis, and/or construction of works for practical purposes". Organic synthesis of a novel compound is a problem-solving task, where a synthesis is designed for a target molecule by selecting optimal reactions from optimal starting materials. Complex compounds can have tens of reaction steps that sequentially build the desired molecule. The synthesis proceeds by utilizing the reactivity of the functional groups in the molecule. For example, a carbonyl compound can be used as a nucleophile by converting it into an enolate, or as an electrophile; the combination of the two is called the aldol reaction. Designing practically useful syntheses always requires conducting the actual synthesis in the laboratory. The scientific practice of creating novel synthetic routes for complex molecules is called total synthesis.
Strategies to design a synthesis include retrosynthesis, popularized by E.J. Corey, which starts with the target molecule and splices it to pieces according to known reactions. The pieces, or the proposed precursors, receive the same treatment, until available and ideally inexpensive starting materials are reached. Then, the retrosynthesis is written in the opposite direction to give the synthesis. A "synthetic tree" can be constructed because each compound and also each precursor has multiple syntheses.
== See also ==
Important publications in organic chemistry
List of organic reactions
Molecular modelling
== References ==
== External links ==
MIT.edu, OpenCourseWare: Organic Chemistry I
HaverFord.edu, Organic Chemistry Lectures, Videos and Text
Organic-Chemistry.org, Organic Chemistry Portal – Recent Abstracts and (Name)Reactions
Orgsyn.org, Organic Chemistry synthesis journal
Pearson Channels, Organic Chemistry Video Lectures and Practice Problems
Khanacademy.org, Khan Academy - Organic Chemistry
Organic Chemistry: Structure, Function, and Practice by William Tucker | Wikipedia/organic_chemistry |
Carbohydrate synthesis is a sub-field of organic chemistry concerned with generating complex carbohydrate structures from simple units (monosaccharides). The generation of carbohydrate structures usually involves linking monosaccharides or oligosaccharides through glycosidic bonds, a process called glycosylation. Therefore, it is important to construct glycosidic linkages that have optimum molecular geometry (stereoselectivity) and the stable bond (regioselectivity) at the reaction site (anomeric centre).
== Background ==
Carbohydrates can generally be classified into one of two groups, monosacharides, and complex carbohydrates. Monosacharides (also called "simple sugars") are the simplest single units of any carbohydrate; the most common monosaccharides are five and six carbon compounds such as glucose, fructose, and galactose. Complex carbohydrates are combinations of monosaccarides linked together through connections called glycosidic bonds, the product of these linkages can be further categorized according to their size. Two monosaccharides linked together produce a disaccharide such as lactose. Three to ten monosaccharide units linked together are referred to as oligosaccharides. Anything larger than ten monosacharide units is called a polysaccharide, this broad category includes very large molecules such as starch, a plant glucose polymer which can contain millions of glucose residues.
The synthesis of carbohydrates is very important to the study of biochemistry and certain kinds of synthetic chemistry since carbohydrates play important roles in many biological systems. In nature, monosaccharides are synthesized biologically from raw materials through the processes of photosynthesis in plants and certain prokaryotes, or by gluconeogenesis in animals.Laboratory processes also exist for the artificial synthesis of monosaccharides, such as the Kiliani-Fischer synthesis which can sequentially build large simple sugars from smaller monomers.
So far, there has not been a unified synthetic strategy of consistent oligosaccharide production because of the nuances in the anomeric effects of monomers and the complexity in the carbohydrate structures. The facile procedures such as the one-pot and solid phase synthesis which ensures atom economy are used. However, further developments in those synthetic approaches are needed since still not fully controlled and automated.
== Significance ==
The glycoconjugate is the product formed by oligosaccharides covalently bonding to other biomolecules such as proteins and lipids. They play indispensable roles in the biological activities of mammalian cells from energy generation to cell signalling. These glycoconjugates with short oligosaccharide structures are important for the characterization and purification in the course glycoconjucate vaccine developments. Therefore, research in the engineering of the glycosyl precursors that create oligosaccharides with controlled size is important in carbohydrate synthesis.
== Biological Synthesis ==
Mammals begin carbohydrate synthesis with monosaccharides, which come from either gluconeogenesis or the breakdown of complex carbohydrates. Gluconeogenesis begins with pyruvate, which comes from alanine and α-ketoglutarate amino acids. This process only begins when glycogen storages are near depletion due to the higher ATP cost of metabolising proteins into amino acids.
Conversely, plants undergo the Calvin Cycle to photosynthesize glucose-3-phosphate from CO2 and H2O in the presence of light; the phosphate is quickly hydrolyzed into glucose.
Digestion of complex carbohydrates allows glucose molecules to be re-polymerized into a form that is recognized by enzymes. In mammals, glucose molecules polymerize into glycogen stores or glycogenin. The reformation of carbohydrates is essential for converting them into forms that can be more easily transported to cells with higher glucose requirements.
Both mammals and plants use the same mechanisms to convert glucose into complex carbohydrates; the only difference is the enzymes used to catalyze the mechanisms. Mammals require glycogen synthase and glycogenin to synthesize glycogen. Plants synthesize amylose with starch synthase and amylopectin with starch-branching enzymes.
== Oligosaccharide synthesis ==
Oligosaccharides have diverse structures. The number of monosaccharides, ring size, the different anomeric stereochemistry, and the existence of the branched-chain sugars all contribute to the amazing complexity of the oligosaccharide structures. The essence of the reducing oligosaccharide synthesis is connecting the anomeric hydroxyl of the glycosyl donors to the alcoholic hydroxyl groups of the glycosyl acceptors. Protection of the hydroxyl groups of the acceptor with the target alcoholic hydroxyl group unprotected can assure regiochemical control. Additionally, factors such as the different protecting groups, the solvent, and the glycosylation methods can influence which anomer is formed.
=== Building blocks ===
Common donors in oligosaccharide synthesis are glycosyl halides, glycosyl acetates, thioglycosides, trichloroacetimidates, pentenyl glycosides, and glycals. Of all these donors, glycosyl halides are classic donors, which played a historical role in the development of glycosylation reactions. Thioglycoside and trichloroacetimidate donors are used more than others in contemporary glycosylation methods. When it comes to the trichloroacetimidate method, one of the advantages is that there is no need to introduce heavy metal reagents in the activation process. Moreover, using different bases can selectively lead to different anomeric configurations. (Scheme 2) As to the thioglycosides, the greatest strength is that they can offer temporary protection to the anomeric centre because they can survive after most of the activation processes. Additionally, a variety of activation methods can be employed, such as NIS/ AgOTf, NIS/ TfOH, IDCP (Iodine Dicollidine Perchlorate), iodine, and Ph2SO/ Tf2O. Furthermore, in the preparation of 1, 2-trans glycosidic linkage, using thioglycosides and imidates can promote the rearrangement of the orthoester byproducts, since the reaction mixtures are acidic enough.
=== Stereoselectivity ===
The structures of acceptors play a critical role in the rate and stereoselectivity of glycosylations. Generally, the unprotected hydroxyl groups are less reactive when they are between bulky protecting groups. That is the reason why the hydroxyl group at OH-4 in pyranosides is unreactive. Hyperconjugation is involved when OH-4 is anti-periplanar to the ring oxygen, which can also reduce its reactivity. (Scheme 3) Furthermore, acyl protecting groups can reduce the reactivity of the acceptors compared with alkyl protecting groups because of their electron-withdrawing ability. Hydroxyl group at OH-4 of N-acetylglucosamine derivatives is particularly unreactive.
The glycosidic bond is formed from a glycosyl donor and a glycosyl acceptor. There are four types of glycosidic linkages: 1, 2-trans-α, 1, 2-trans-beta, 1, 2-cis-α, and 1, 2-cis-beta linkages. 1, 2-trans glycosidic linkages can be easily achieved by using 2-O-acylated glycosyl donors (neighboring group participation). To prevent the accumulation of the orthoester intermediates, the glycosylation condition should be slightly acidic.
=== Challenging linkages ===
When connecting the monosaccharides, the oligosaccharides need to be reducing in order to sequentially connect the glycosyl units. The monosaccharides, in nature prefer ɑ-linkages due to anomeric effect, but the disaccharides with ɑ-linkages are non-reducing thus deactivating the consequent connection of the monosaccharides. In order to make the process of glycosylation continuous and automated, the glycosidic linkages must maintain beta so to keep the structure open to coupling with more glycosyl groups.
It is somewhat more difficult to prepare 1, 2-cis-β-glycosidic linkages stereoselectively. Typically, when non-participating groups on O-2 position, 1, 2-cis-β-linkage can be achieved either by using the historically important halide ion methods, or by using 2-O-alkylated glycosyl donors, commonly thioglycosides or trichloroacetimidates, in nonpolar solvents.
In the early 1990s, it was still the case that the beta mannoside linkage was too challenging to be attempted by amateurs. However, the method introduced by David Crich (Scheme 4), with 4,6-benzylidene protection a prerequisite and anomeric alpha triflate a key intermediate leaves this problem essentially solved. The concurrently developed but rather more protracted intramolecular aglycon delivery (IAD) approach is a little-used but nevertheless stereospecific alternative.
== See also ==
Carbohydrate chemistry
Chemical glycosylation
Crich beta-mannosylation
== References ==
== External links ==
Media related to Carbohydrate synthesis at Wikimedia Commons | Wikipedia/Carbohydrate_synthesis |
A saturated compound is a chemical compound (or ion) that resists addition reactions, such as hydrogenation, oxidative addition, and binding of a Lewis base. The term is used in many contexts and classes of chemical compounds. Overall, saturated compounds are less reactive than unsaturated compounds. Saturation is derived from the Latin word saturare, meaning 'to fill'.
== Organic chemistry ==
Generally distinct types of unsaturated organic compounds are recognized.
For hydrocarbons:
alkene (unsaturated) vs alkane (saturated)
alkyne (unsaturated) vs alkane (saturated)
arene (unsaturated) vs cycloalkane (saturated)
For organic compounds containing heteroatoms (other than C and H), the list of unsaturated groups is long but some common types are:
carbonyl, e.g. ketones, aldehydes, esters, carboxylic acids (unsaturated) vs alcohol or ether (saturated)
nitrile (unsaturated) vs amine (saturated)
nitro (unsaturated) vs amine (saturated)
Unsaturated compounds generally carry out typical addition reactions that are not possible with saturated compounds such as alkanes. A saturated organic compound has only single bond between carbon atoms. An important class of saturated compounds are the alkanes. Many saturated compounds have functional groups, e.g., alcohols.
=== Unsaturated organic compounds ===
The concept of saturation can be described using various naming systems, formulas, and analytical tests. For instance, IUPAC nomenclature is a system of naming conventions used to describe the type and location of unsaturation within organic compounds. The "degree of unsaturation" is a formula used to summarize and diagram the amount of hydrogen that a compound can bind. Unsaturation can be determined by NMR, mass spectrometry, and IR spectroscopy, or by determining a compound's bromine number or iodine number.
=== Fatty acids and fats ===
The terms saturated vs unsaturated are often applied to the fatty acid constituents of fats. The triglycerides (fats) that comprise tallow are derived from the saturated stearic and monounsaturated oleic acids. Many vegetable oils contain fatty acids with one (monounsaturated) or more (polyunsaturated) double bonds in them.
== Saturated and unsaturated compounds beyond organic chemistry ==
=== Organometallic chemistry ===
In organometallic chemistry, a coordinatively unsaturated complex has fewer than 18 valence electrons and thus is susceptible to oxidative addition or coordination of an additional ligand. Unsaturation is the characteristic of many catalysts. The opposite of coordinatively unsaturated is coordinatively saturated. Complexes that are coordinatively saturated rarely exhibit catalytic properties.
=== Surfaces ===
In physical chemistry, when referring to surface processes, saturation denotes the degree at which a binding site is fully occupied. For example, base saturation refers to the fraction of exchangeable cations that are base cations.
== References == | Wikipedia/Saturated_and_unsaturated_compounds |
Laser ablation synthesis in solution (LASiS) is a commonly used method for obtaining colloidal solution of nanoparticles in a variety of solvents. Nanoparticles (NPs,), are useful in chemistry, engineering and biochemistry due to their large surface-to-volume ratio that causes them to have unique physical properties. LASiS is considered a "green" method due to its lack of use for toxic chemical precursors to synthesize nanoparticles.
In the LASiS method, nanoparticles are produced by a laser beam hitting a solid target in a liquid and during the condensation of the plasma plume, the nanoparticles are formed. Since the ablation is occurring in a liquid, versus air/vacuum/gas/, the environment allows for plume expansion, cooling and condensation with a higher temperature, pressure and density to create a plume with stronger confinement. These environmental conditions allow for more refined and smaller nanoparticles LASiS is usually considered a top-down physical approach. LASiS emerged as a reliable alternative to traditional chemical reduction methods for obtaining noble metal nanoparticles (NMNp). LASiS is also used for synthesis of silver nanoparticles AgNPs, which are known for their antimicrobial effects. Production of AgNPs via LASiS causes nanoparticles with varying antimicrobial characteristics due to different properties achieved via the fine tuning of NPs size in liquid ablation.
== Pros and Cons ==
LASiS has some limitations in the size control of NMNp, which can be overcome by laser treatments of NMNp. Other cons of LASiS include: the slow rate of NPs production, high consumption of energy, laser equipment cost, and decreased ablation efficiency with longer usage of the laser within a session. Other pros of LASiS include: minimal waste production, minimal manual operation, and refined size control of nanoparticles.
== References == | Wikipedia/Laser_ablation_synthesis_in_solution |
Nucleic acid thermodynamics is the study of how temperature affects the nucleic acid structure of double-stranded DNA (dsDNA). The melting temperature (Tm) is defined as the temperature at which half of the DNA strands are in the random coil or single-stranded (ssDNA) state. Tm depends on the length of the DNA molecule and its specific nucleotide sequence. DNA, when in a state where its two strands are dissociated (i.e., the dsDNA molecule exists as two independent strands), is referred to as having been denatured by the high temperature.
== Concepts ==
=== Hybridization ===
Hybridization is the process of establishing a non-covalent, sequence-specific interaction between two or more complementary strands of nucleic acids into a single complex, which in the case of two strands is referred to as a duplex. Oligonucleotides, DNA, or RNA will bind to their complement under normal conditions, so two perfectly complementary strands will bind to each other readily. In order to reduce the diversity and obtain the most energetically preferred complexes, a technique called annealing is used in laboratory practice. However, due to the different molecular geometries of the nucleotides, a single inconsistency between the two strands will make binding between them less energetically favorable. Measuring the effects of base incompatibility by quantifying the temperature at which two strands anneal can provide information as to the similarity in base sequence between the two strands being annealed. The complexes may be dissociated by thermal denaturation, also referred to as melting. In the absence of external negative factors, the processes of hybridization and melting may be repeated in succession indefinitely, which lays the ground for polymerase chain reaction. Most commonly, the pairs of nucleic bases A=T and G≡C are formed, of which the latter is more stable.
=== Denaturation ===
DNA denaturation, also called DNA melting, is the process by which double-stranded deoxyribonucleic acid unwinds and separates into single-stranded strands through the breaking of hydrophobic stacking attractions between the bases. See Hydrophobic effect. Both terms are used to refer to the process as it occurs when a mixture is heated, although "denaturation" can also refer to the separation of DNA strands induced by chemicals like formamide or urea.
The process of DNA denaturation can be used to analyze some aspects of DNA. Because cytosine / guanine base-pairing is generally stronger than adenine / thymine base-pairing, the amount of cytosine and guanine in a genome is called its GC-content and can be estimated by measuring the temperature at which the genomic DNA melts. Higher temperatures are associated with high GC content.
DNA denaturation can also be used to detect sequence differences between two different DNA sequences. DNA is heated and denatured into single-stranded state, and the mixture is cooled to allow strands to rehybridize. Hybrid molecules are formed between similar sequences and any differences between those sequences will result in a disruption of the base-pairing. On a genomic scale, the method has been used by researchers to estimate the genetic distance between two species, a process known as DNA-DNA hybridization. In the context of a single isolated region of DNA, denaturing gradient gels and temperature gradient gels can be used to detect the presence of small mismatches between two sequences, a process known as temperature gradient gel electrophoresis.
Methods of DNA analysis based on melting temperature have the disadvantage of being proxies for studying the underlying sequence; DNA sequencing is generally considered a more accurate method.
The process of DNA melting is also used in molecular biology techniques, notably in the polymerase chain reaction. Although the temperature of DNA melting is not diagnostic in the technique, methods for estimating Tm are important for determining the appropriate temperatures to use in a protocol. DNA melting temperatures can also be used as a proxy for equalizing the hybridization strengths of a set of molecules, e.g. the oligonucleotide probes of DNA microarrays.
=== Annealing ===
Annealing, in genetics, means for complementary sequences of single-stranded DNA or RNA to pair by hydrogen bonds to form a double-stranded polynucleotide. Before annealing can occur, one of the strands may need to be phosphorylated by an enzyme such as kinase to allow proper hydrogen bonding to occur. The term annealing is often used to describe the binding of a DNA probe, or the binding of a primer to a DNA strand during a polymerase chain reaction. The term is also often used to describe the reformation (renaturation) of reverse-complementary strands that were separated by heat (thermally denatured). Proteins such as RAD52 can help DNA anneal. DNA strand annealing is a key step in pathways of homologous recombination. In particular, during meiosis, synthesis-dependent strand annealing is a major pathway of homologous recombination.
=== Stacking ===
Stacking is the stabilizing interaction between the flat surfaces of adjacent bases. Stacking can happen with any face of the base, that is 5'-5', 3'-3', and vice versa.
Stacking in "free" nucleic acid molecules is mainly contributed by intermolecular force, specifically electrostatic attraction among aromatic rings, a process also known as pi stacking. For biological systems with water as a solvent, hydrophobic effect contributes and helps in formation of a helix. Stacking is the main stabilizing factor in the DNA double helix.
Contribution of stacking to the free energy of the molecule can be experimentally estimated by observing the bent-stacked equilibrium in nicked DNA. Such stabilization is dependent on the sequence. The extent of the stabilization varies with salt concentrations and temperature.
== Thermodynamics of the two-state model ==
Several formulas are used to calculate Tm values. Some formulas are more accurate in predicting melting temperatures of DNA duplexes. For DNA oligonucleotides, i.e. short sequences of DNA, the thermodynamics of hybridization can be accurately described as a two-state process. In this approximation one neglects the possibility of intermediate partial binding states in the formation of a double strand state from two single stranded oligonucleotides. Under this assumption one can elegantly describe the thermodynamic parameters for forming double-stranded nucleic acid AB from single-stranded nucleic acids A and B.
AB ↔ A + B
The equilibrium constant for this reaction is
K
=
[
A
]
[
B
]
[
A
B
]
{\displaystyle K={\frac {[A][B]}{[AB]}}}
. According to the Van´t Hoff equation, the relation between free energy, ΔG, and K is ΔG° = -RTln K, where R is the ideal gas law constant, and T is the kelvin temperature of the reaction. This gives, for the nucleic acid system,
Δ
G
∘
=
−
R
T
ln
[
A
]
[
B
]
[
A
B
]
{\displaystyle \Delta G^{\circ }=-RT\ln {\frac {[A][B]}{[AB]}}}
.
The melting temperature, Tm, occurs when half of the double-stranded nucleic acid has dissociated. If no additional nucleic acids are present, then [A], [B], and [AB] will be equal, and equal to half the initial concentration of double-stranded nucleic acid, [AB]initial. This gives an expression for the melting point of a nucleic acid duplex of
T
m
=
−
Δ
G
∘
R
ln
[
A
B
]
i
n
i
t
i
a
l
2
{\displaystyle T_{m}=-{\frac {\Delta G^{\circ }}{R\ln {\frac {[AB]_{initial}}{2}}}}}
.
Because ΔG° = ΔH° -TΔS°, Tm is also given by
T
m
=
Δ
H
∘
Δ
S
∘
−
R
ln
[
A
B
]
i
n
i
t
i
a
l
2
{\displaystyle T_{m}={\frac {\Delta H^{\circ }}{\Delta S^{\circ }-R\ln {\frac {[AB]_{initial}}{2}}}}}
.
The terms ΔH° and ΔS° are usually given for the association and not the dissociation reaction (see the nearest-neighbor method for example). This formula then turns into:
T
m
=
Δ
H
∘
Δ
S
∘
+
R
ln
(
[
A
]
t
o
t
a
l
−
[
B
]
t
o
t
a
l
/
2
)
{\displaystyle T_{m}={\frac {\Delta H^{\circ }}{\Delta S^{\circ }+R\ln([A]_{total}-[B]_{total}/2)}}}
, where [B]total ≤ [A]total.
As mentioned, this equation is based on the assumption that only two states are involved in melting: the double stranded state and the random-coil state. However, nucleic acids may melt via several intermediate states. To account for such complicated behavior, the methods of statistical mechanics must be used, which is especially relevant for long sequences.
== Estimating thermodynamic properties from nucleic acid sequence ==
The previous paragraph shows how melting temperature and thermodynamic parameters (ΔG° or ΔH° & ΔS°) are related to each other. From the observation of melting temperatures one can experimentally determine the thermodynamic parameters. Vice versa, and important for applications, when the thermodynamic parameters of a given nucleic acid sequence are known, the melting temperature can be predicted. It turns out that for oligonucleotides, these parameters can be well approximated by the nearest-neighbor model.
=== Nearest-neighbor method ===
The interaction between bases on different strands depends somewhat on the neighboring bases. Instead of treating a DNA helix as a string of interactions between base pairs, the nearest-neighbor model treats a DNA helix as a string of interactions between 'neighboring' base pairs. So, for example, the DNA shown below has nearest-neighbor interactions indicated by the arrows.
↓ ↓ ↓ ↓ ↓
5' C-G-T-T-G-A 3'
3' G-C-A-A-C-T 5'
The free energy of forming this DNA from the individual strands, ΔG°, is represented (at 37 °C) as
ΔG°37(predicted) = ΔG°37(C/G initiation) + ΔG°37(CG/GC) + ΔG°37(GT/CA) + ΔG°37(TT/AA) + ΔG°37(TG/AC) + ΔG°37(GA/CT) + ΔG°37(A/T initiation)
Except for the C/G initiation term, the first term represents the free energy of the first base pair, CG, in the absence of a nearest neighbor. The second term includes both the free energy of formation of the second base pair, GC, and stacking interaction between this base pair and the previous base pair. The remaining terms are similarly defined. In general, the free energy of forming a nucleic acid duplex is
Δ
G
37
∘
(
t
o
t
a
l
)
=
Δ
G
37
∘
(
i
n
i
t
i
a
t
i
o
n
s
)
+
∑
i
=
1
10
n
i
Δ
G
37
∘
(
i
)
{\displaystyle \Delta G_{37}^{\circ }(\mathrm {total} )=\Delta G_{37}^{\circ }(\mathrm {initiations} )+\sum _{i=1}^{10}n_{i}\Delta G_{37}^{\circ }(i)}
,
where
Δ
G
37
∘
(
i
)
{\displaystyle \Delta G_{37}^{\circ }(i)}
represents the free energy associated with one of the ten possible the nearest-neighbor nucleotide pairs, and
n
i
{\displaystyle n_{i}}
represents its count in the sequence.
Each ΔG° term has enthalpic, ΔH°, and entropic, ΔS°, parameters, so the change in free energy is also given by
Δ
G
∘
(
t
o
t
a
l
)
=
Δ
H
t
o
t
a
l
∘
−
T
Δ
S
t
o
t
a
l
∘
{\displaystyle \Delta G^{\circ }(\mathrm {total} )=\Delta H_{\mathrm {total} }^{\circ }-T\Delta S_{\mathrm {total} }^{\circ }}
.
Values of ΔH° and ΔS° have been determined for the ten possible pairs of interactions. These are given in Table 1, along with the value of ΔG° calculated at 37 °C. Using these values, the value of ΔG37° for the DNA duplex shown above is calculated to be −22.4 kJ/mol. The experimental value is −21.8 kJ/mol.
The parameters associated with the ten groups of neighbors shown in table 1 are determined from melting points of short oligonucleotide duplexes. It works out that only eight of the ten groups are independent.
The nearest-neighbor model can be extended beyond the Watson-Crick pairs to include parameters for interactions between mismatches and neighboring base pairs. This allows the estimation of the thermodynamic parameters of sequences containing isolated mismatches, like e.g. (arrows indicating mismatch)
↓↓↓
5' G-G-A-C-T-G-A-C-G 3'
3' C-C-T-G-G-C-T-G-C 5'
These parameters have been fitted from melting experiments and an extension of Table 1 which includes mismatches can be found in literature.
A more realistic way of modeling the behavior of nucleic acids would seem to be to have parameters that depend on the neighboring groups on both sides of a nucleotide, giving a table with entries like "TCG/AGC". However, this would involve around 32 groups for Watson-Crick pairing and even more for sequences containing mismatches; the number of DNA melting experiments needed to get reliable data for so many groups would be inconveniently high. However, other means exist to access thermodynamic parameters of nucleic acids: microarray technology allows hybridization monitoring of tens of thousands sequences in parallel. This data, in combination with molecular adsorption theory allows the determination of many thermodynamic parameters in a single experiment and to go beyond the nearest neighbor model. In general the predictions from the nearest neighbor method agree reasonably well with experimental results, but some unexpected outlying sequences, calling for further insights, do exist. Finally, we should also mention the increased accuracy provided by single molecule unzipping assays which provide a wealth of new insight into the thermodynamics of DNA hybridization and the validity of the nearest-neighbour model as well.
== See also ==
Melting point
Primer (molecular biology) for calculations of Tm
Base pair
Complementary DNA
Western blot
== References ==
== External links ==
Tm calculations in OligoAnalyzer – Integrated DNA Technologies
DNA thermodynamics calculations – Tm, melting profile, mismatches, free energy calculations
Tm calculation – by bioPHP.org.
https://web.archive.org/web/20080516194508/http://www.promega.com/biomath/calc11.htm#disc
Invitrogen Tm calculation
AnnHyb Open Source software for Tm calculation using the Nearest-neighbour method
Sigma-aldrich technical notes
Primer3 calculation
"Discovery of the Hybrid Helix and the First DNA-RNA Hybridization" by Alexander Rich
uMelt: Melting Curve Prediction
Tm Tool
Nearest Neighbor Database: Provides a description of RNA-RNA interaction nearest neighbor parameters and examples of their use. | Wikipedia/Nucleic_acid_thermodynamics |
Evolution is the change in the heritable characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, resulting in certain characteristics becoming more or less common within a population over successive generations. The process of evolution has given rise to biodiversity at every level of biological organisation.
The scientific theory of evolution by natural selection was conceived independently by two British naturalists, Charles Darwin and Alfred Russel Wallace, in the mid-19th century as an explanation for why organisms are adapted to their physical and biological environments. The theory was first set out in detail in Darwin's book On the Origin of Species. Evolution by natural selection is established by observable facts about living organisms: (1) more offspring are often produced than can possibly survive; (2) traits vary among individuals with respect to their morphology, physiology, and behaviour; (3) different traits confer different rates of survival and reproduction (differential fitness); and (4) traits can be passed from generation to generation (heritability of fitness). In successive generations, members of a population are therefore more likely to be replaced by the offspring of parents with favourable characteristics for that environment.
In the early 20th century, competing ideas of evolution were refuted and evolution was combined with Mendelian inheritance and population genetics to give rise to modern evolutionary theory. In this synthesis the basis for heredity is in DNA molecules that pass information from generation to generation. The processes that change DNA in a population include natural selection, genetic drift, mutation, and gene flow.
All life on Earth—including humanity—shares a last universal common ancestor (LUCA), which lived approximately 3.5–3.8 billion years ago. The fossil record includes a progression from early biogenic graphite to microbial mat fossils to fossilised multicellular organisms. Existing patterns of biodiversity have been shaped by repeated formations of new species (speciation), changes within species (anagenesis), and loss of species (extinction) throughout the evolutionary history of life on Earth. Morphological and biochemical traits tend to be more similar among species that share a more recent common ancestor, which historically was used to reconstruct phylogenetic trees, although direct comparison of genetic sequences is a more common method today.
Evolutionary biologists have continued to study various aspects of evolution by forming and testing hypotheses as well as constructing theories based on evidence from the field or laboratory and on data generated by the methods of mathematical and theoretical biology. Their discoveries have influenced not just the development of biology but also other fields including agriculture, medicine, and computer science.
== Heredity ==
Evolution in organisms occurs through changes in heritable characteristics—the inherited characteristics of an organism. In humans, for example, eye colour is an inherited characteristic and an individual might inherit the "brown-eye trait" from one of their parents. Inherited traits are controlled by genes and the complete set of genes within an organism's genome (genetic material) is called its genotype.
The complete set of observable traits that make up the structure and behaviour of an organism is called its phenotype. Some of these traits come from the interaction of its genotype with the environment while others are neutral. Some observable characteristics are not inherited. For example, suntanned skin comes from the interaction between a person's genotype and sunlight; thus, suntans are not passed on to people's children. The phenotype is the ability of the skin to tan when exposed to sunlight. However, some people tan more easily than others, due to differences in genotypic variation; a striking example are people with the inherited trait of albinism, who do not tan at all and are very sensitive to sunburn.
Heritable characteristics are passed from one generation to the next via DNA, a molecule that encodes genetic information. DNA is a long biopolymer composed of four types of bases. The sequence of bases along a particular DNA molecule specifies the genetic information, in a manner similar to a sequence of letters spelling out a sentence. Before a cell divides, the DNA is copied, so that each of the resulting two cells will inherit the DNA sequence. Portions of a DNA molecule that specify a single functional unit are called genes; different genes have different sequences of bases. Within cells, each long strand of DNA is called a chromosome. The specific location of a DNA sequence within a chromosome is known as a locus. If the DNA sequence at a locus varies between individuals, the different forms of this sequence are called alleles. DNA sequences can change through mutations, producing new alleles. If a mutation occurs within a gene, the new allele may affect the trait that the gene controls, altering the phenotype of the organism. However, while this simple correspondence between an allele and a trait works in some cases, most traits are influenced by multiple genes in a quantitative or epistatic manner.
== Sources of variation ==
Evolution can occur if there is genetic variation within a population. Variation comes from mutations in the genome, reshuffling of genes through sexual reproduction and migration between populations (gene flow). Despite the constant introduction of new variation through mutation and gene flow, most of the genome of a species is very similar among all individuals of that species. However, discoveries in the field of evolutionary developmental biology have demonstrated that even relatively small differences in genotype can lead to dramatic differences in phenotype both within and between species.
An individual organism's phenotype results from both its genotype and the influence of the environment it has lived in. The modern evolutionary synthesis defines evolution as the change over time in this genetic variation. The frequency of one particular allele will become more or less prevalent relative to other forms of that gene. Variation disappears when a new allele reaches the point of fixation—when it either disappears from the population or replaces the ancestral allele entirely.
=== Mutation ===
Mutations are changes in the DNA sequence of a cell's genome and are the ultimate source of genetic variation in all organisms. When mutations occur, they may alter the product of a gene, or prevent the gene from functioning, or have no effect.
About half of the mutations in the coding regions of protein-coding genes are deleterious — the other half are neutral. A small percentage of the total mutations in this region confer a fitness benefit. Some of the mutations in other parts of the genome are deleterious but the vast majority are neutral. A few are beneficial.
Mutations can involve large sections of a chromosome becoming duplicated (usually by genetic recombination), which can introduce extra copies of a gene into a genome. Extra copies of genes are a major source of the raw material needed for new genes to evolve. This is important because most new genes evolve within gene families from pre-existing genes that share common ancestors. For example, the human eye uses four genes to make structures that sense light: three for colour vision and one for night vision; all four are descended from a single ancestral gene.
New genes can be generated from an ancestral gene when a duplicate copy mutates and acquires a new function. This process is easier once a gene has been duplicated because it increases the redundancy of the system; one gene in the pair can acquire a new function while the other copy continues to perform its original function. Other types of mutations can even generate entirely new genes from previously noncoding DNA, a phenomenon termed de novo gene birth.
The generation of new genes can also involve small parts of several genes being duplicated, with these fragments then recombining to form new combinations with new functions (exon shuffling). When new genes are assembled from shuffling pre-existing parts, domains act as modules with simple independent functions, which can be mixed together to produce new combinations with new and complex functions. For example, polyketide synthases are large enzymes that make antibiotics; they contain up to 100 independent domains that each catalyse one step in the overall process, like a step in an assembly line.
One example of mutation is wild boar piglets. They are camouflage coloured and show a characteristic pattern of dark and light longitudinal stripes. However, mutations in the melanocortin 1 receptor (MC1R) disrupt the pattern. The majority of pig breeds carry MC1R mutations disrupting wild-type colour and different mutations causing dominant black colouring.
=== Sex and recombination ===
In asexual organisms, genes are inherited together, or linked, as they cannot mix with genes of other organisms during reproduction. In contrast, the offspring of sexual organisms contain random mixtures of their parents' chromosomes that are produced through independent assortment. In a related process called homologous recombination, sexual organisms exchange DNA between two matching chromosomes. Recombination and reassortment do not alter allele frequencies, but instead change which alleles are associated with each other, producing offspring with new combinations of alleles. Sex usually increases genetic variation and may increase the rate of evolution.
The two-fold cost of sex was first described by John Maynard Smith. The first cost is that in sexually dimorphic species only one of the two sexes can bear young. This cost does not apply to hermaphroditic species, like most plants and many invertebrates. The second cost is that any individual who reproduces sexually can only pass on 50% of its genes to any individual offspring, with even less passed on as each new generation passes. Yet sexual reproduction is the more common means of reproduction among eukaryotes and multicellular organisms. The Red Queen hypothesis has been used to explain the significance of sexual reproduction as a means to enable continual evolution and adaptation in response to coevolution with other species in an ever-changing environment. Another hypothesis is that sexual reproduction is primarily an adaptation for promoting accurate recombinational repair of damage in germline DNA, and that increased diversity is a byproduct of this process that may sometimes be adaptively beneficial.
=== Gene flow ===
Gene flow is the exchange of genes between populations and between species. It can therefore be a source of variation that is new to a population or to a species. Gene flow can be caused by the movement of individuals between separate populations of organisms, as might be caused by the movement of mice between inland and coastal populations, or the movement of pollen between heavy-metal-tolerant and heavy-metal-sensitive populations of grasses.
Gene transfer between species includes the formation of hybrid organisms and horizontal gene transfer. Horizontal gene transfer is the transfer of genetic material from one organism to another organism that is not its offspring; this is most common among bacteria. In medicine, this contributes to the spread of antibiotic resistance, as when one bacteria acquires resistance genes it can rapidly transfer them to other species. Horizontal transfer of genes from bacteria to eukaryotes such as the yeast Saccharomyces cerevisiae and the adzuki bean weevil Callosobruchus chinensis has occurred. An example of larger-scale transfers are the eukaryotic bdelloid rotifers, which have received a range of genes from bacteria, fungi and plants. Viruses can also carry DNA between organisms, allowing transfer of genes even across biological domains.
Large-scale gene transfer has also occurred between the ancestors of eukaryotic cells and bacteria, during the acquisition of chloroplasts and mitochondria. It is possible that eukaryotes themselves originated from horizontal gene transfers between bacteria and archaea.
=== Epigenetics ===
Some heritable changes cannot be explained by changes to the sequence of nucleotides in the DNA. These phenomena are classed as epigenetic inheritance systems. DNA methylation marking chromatin, self-sustaining metabolic loops, gene silencing by RNA interference and the three-dimensional conformation of proteins (such as prions) are areas where epigenetic inheritance systems have been discovered at the organismic level. Developmental biologists suggest that complex interactions in genetic networks and communication among cells can lead to heritable variations that may underlay some of the mechanics in developmental plasticity and canalisation. Heritability may also occur at even larger scales. For example, ecological inheritance through the process of niche construction is defined by the regular and repeated activities of organisms in their environment. This generates a legacy of effects that modify and feed back into the selection regime of subsequent generations. Other examples of heritability in evolution that are not under the direct control of genes include the inheritance of cultural traits and symbiogenesis.
== Evolutionary forces ==
From a neo-Darwinian perspective, evolution occurs when there are changes in the frequencies of alleles within a population of interbreeding organisms, for example, the allele for black colour in a population of moths becoming more common. Mechanisms that can lead to changes in allele frequencies include natural selection, genetic drift, and mutation bias.
=== Natural selection ===
Evolution by natural selection is the process by which traits that enhance survival and reproduction become more common in successive generations of a population. It embodies three principles:
Variation exists within populations of organisms with respect to morphology, physiology and behaviour (phenotypic variation).
Different traits confer different rates of survival and reproduction (differential fitness).
These traits can be passed from generation to generation (heritability of fitness).
More offspring are produced than can possibly survive, and these conditions produce competition between organisms for survival and reproduction. Consequently, organisms with traits that give them an advantage over their competitors are more likely to pass on their traits to the next generation than those with traits that do not confer an advantage. This teleonomy is the quality whereby the process of natural selection creates and preserves traits that are seemingly fitted for the functional roles they perform. Consequences of selection include nonrandom mating and genetic hitchhiking.
The central concept of natural selection is the evolutionary fitness of an organism. Fitness is measured by an organism's ability to survive and reproduce, which determines the size of its genetic contribution to the next generation. However, fitness is not the same as the total number of offspring: instead fitness is indicated by the proportion of subsequent generations that carry an organism's genes. For example, if an organism could survive well and reproduce rapidly, but its offspring were all too small and weak to survive, this organism would make little genetic contribution to future generations and would thus have low fitness.
If an allele increases fitness more than the other alleles of that gene, then with each generation this allele has a higher probability of becoming common within the population. These traits are said to be selected for. Examples of traits that can increase fitness are enhanced survival and increased fecundity. Conversely, the lower fitness caused by having a less beneficial or deleterious allele results in this allele likely becoming rarer—they are selected against.
Importantly, the fitness of an allele is not a fixed characteristic; if the environment changes, previously neutral or harmful traits may become beneficial and previously beneficial traits become harmful. However, even if the direction of selection does reverse in this way, traits that were lost in the past may not re-evolve in an identical form. However, a re-activation of dormant genes, as long as they have not been eliminated from the genome and were only suppressed perhaps for hundreds of generations, can lead to the re-occurrence of traits thought to be lost like hindlegs in dolphins, teeth in chickens, wings in wingless stick insects, tails and additional nipples in humans etc. "Throwbacks" such as these are known as atavisms.
Natural selection within a population for a trait that can vary across a range of values, such as height, can be categorised into three different types. The first is directional selection, which is a shift in the average value of a trait over time—for example, organisms slowly getting taller. Secondly, disruptive selection is selection for extreme trait values and often results in two different values becoming most common, with selection against the average value. This would be when either short or tall organisms had an advantage, but not those of medium height. Finally, in stabilising selection there is selection against extreme trait values on both ends, which causes a decrease in variance around the average value and less diversity. This would, for example, cause organisms to eventually have a similar height.
Natural selection most generally makes nature the measure against which individuals and individual traits, are more or less likely to survive. "Nature" in this sense refers to an ecosystem, that is, a system in which organisms interact with every other element, physical as well as biological, in their local environment. Eugene Odum, a founder of ecology, defined an ecosystem as: "Any unit that includes all of the organisms...in a given area interacting with the physical environment so that a flow of energy leads to clearly defined trophic structure, biotic diversity, and material cycles (i.e., exchange of materials between living and nonliving parts) within the system...." Each population within an ecosystem occupies a distinct niche, or position, with distinct relationships to other parts of the system. These relationships involve the life history of the organism, its position in the food chain and its geographic range. This broad understanding of nature enables scientists to delineate specific forces which, together, comprise natural selection.
Natural selection can act at different levels of organisation, such as genes, cells, individual organisms, groups of organisms and species. Selection can act at multiple levels simultaneously. An example of selection occurring below the level of the individual organism are genes called transposons, which can replicate and spread throughout a genome. Selection at a level above the individual, such as group selection, may allow the evolution of cooperation.
=== Genetic drift ===
Genetic drift is the random fluctuation of allele frequencies within a population from one generation to the next. When selective forces are absent or relatively weak, allele frequencies are equally likely to drift upward or downward in each successive generation because the alleles are subject to sampling error. This drift halts when an allele eventually becomes fixed, either by disappearing from the population or by replacing the other alleles entirely. Genetic drift may therefore eliminate some alleles from a population due to chance alone. Even in the absence of selective forces, genetic drift can cause two separate populations that begin with the same genetic structure to drift apart into two divergent populations with different sets of alleles.
According to the neutral theory of molecular evolution most evolutionary changes are the result of the fixation of neutral mutations by genetic drift. In this model, most genetic changes in a population are thus the result of constant mutation pressure and genetic drift. This form of the neutral theory has been debated since it does not seem to fit some genetic variation seen in nature. A better-supported version of this model is the nearly neutral theory, according to which a mutation that would be effectively neutral in a small population is not necessarily neutral in a large population. Other theories propose that genetic drift is dwarfed by other stochastic forces in evolution, such as genetic hitchhiking, also known as genetic draft. Another concept is constructive neutral evolution (CNE), which explains that complex systems can emerge and spread into a population through neutral transitions due to the principles of excess capacity, presuppression, and ratcheting, and it has been applied in areas ranging from the origins of the spliceosome to the complex interdependence of microbial communities.
The time it takes a neutral allele to become fixed by genetic drift depends on population size; fixation is more rapid in smaller populations. The number of individuals in a population is not critical, but instead a measure known as the effective population size. The effective population is usually smaller than the total population since it takes into account factors such as the level of inbreeding and the stage of the lifecycle in which the population is the smallest. The effective population size may not be the same for every gene in the same population.
It is usually difficult to measure the relative importance of selection and neutral processes, including drift. The comparative importance of adaptive and non-adaptive forces in driving evolutionary change is an area of current research.
=== Mutation bias ===
Mutation bias is usually conceived as a difference in expected rates for two different kinds of mutation, e.g., transition-transversion bias, GC-AT bias, deletion-insertion bias. This is related to the idea of developmental bias. J. B. S. Haldane and Ronald Fisher argued that, because mutation is a weak pressure easily overcome by selection, tendencies of mutation would be ineffectual except under conditions of neutral evolution or extraordinarily high mutation rates. This opposing-pressures argument was long used to dismiss the possibility of internal tendencies in evolution, until the molecular era prompted renewed interest in neutral evolution.
Noboru Sueoka and Ernst Freese proposed that systematic biases in mutation might be responsible for systematic differences in genomic GC composition between species. The identification of a GC-biased E. coli mutator strain in 1967, along with the proposal of the neutral theory, established the plausibility of mutational explanations for molecular patterns, which are now common in the molecular evolution literature.
For instance, mutation biases are frequently invoked in models of codon usage. Such models also include effects of selection, following the mutation-selection-drift model, which allows both for mutation biases and differential selection based on effects on translation. Hypotheses of mutation bias have played an important role in the development of thinking about the evolution of genome composition, including isochores. Different insertion vs. deletion biases in different taxa can lead to the evolution of different genome sizes. The hypothesis of Lynch regarding genome size relies on mutational biases toward increase or decrease in genome size.
However, mutational hypotheses for the evolution of composition suffered a reduction in scope when it was discovered that (1) GC-biased gene conversion makes an important contribution to composition in diploid organisms such as mammals and (2) bacterial genomes frequently have AT-biased mutation.
Contemporary thinking about the role of mutation biases reflects a different theory from that of Haldane and Fisher. More recent work showed that the original "pressures" theory assumes that evolution is based on standing variation: when evolution depends on events of mutation that introduce new alleles, mutational and developmental biases in the introduction of variation (arrival biases) can impose biases on evolution without requiring neutral evolution or high mutation rates.
Several studies report that the mutations implicated in adaptation reflect common mutation biases though others dispute this interpretation.
==== Genetic hitchhiking ====
Recombination allows alleles on the same strand of DNA to become separated. However, the rate of recombination is low (approximately two events per chromosome per generation). As a result, genes close together on a chromosome may not always be shuffled away from each other and genes that are close together tend to be inherited together, a phenomenon known as linkage. This tendency is measured by finding how often two alleles occur together on a single chromosome compared to expectations, which is called their linkage disequilibrium. A set of alleles that is usually inherited in a group is called a haplotype. This can be important when one allele in a particular haplotype is strongly beneficial: natural selection can drive a selective sweep that will also cause the other alleles in the haplotype to become more common in the population; this effect is called genetic hitchhiking or genetic draft. Genetic draft caused by the fact that some neutral genes are genetically linked to others that are under selection can be partially captured by an appropriate effective population size.
==== Sexual selection ====
A special case of natural selection is sexual selection, which is selection for any trait that increases mating success by increasing the attractiveness of an organism to potential mates. Traits that evolved through sexual selection are particularly prominent among males of several animal species. Although sexually favoured, traits such as cumbersome antlers, mating calls, large body size and bright colours often attract predation, which compromises the survival of individual males. This survival disadvantage is balanced by higher reproductive success in males that show these hard-to-fake, sexually selected traits.
== Natural outcomes ==
Evolution influences every aspect of the form and behaviour of organisms. Most prominent are the specific behavioural and physical adaptations that are the outcome of natural selection. These adaptations increase fitness by aiding activities such as finding food, avoiding predators or attracting mates. Organisms can also respond to selection by cooperating with each other, usually by aiding their relatives or engaging in mutually beneficial symbiosis. In the longer term, evolution produces new species through splitting ancestral populations of organisms into new groups that cannot or will not interbreed. These outcomes of evolution are distinguished based on time scale as macroevolution versus microevolution. Macroevolution refers to evolution that occurs at or above the level of species, in particular speciation and extinction, whereas microevolution refers to smaller evolutionary changes within a species or population, in particular shifts in allele frequency and adaptation. Macroevolution is the outcome of long periods of microevolution. Thus, the distinction between micro- and macroevolution is not a fundamental one—the difference is simply the time involved. However, in macroevolution, the traits of the entire species may be important. For instance, a large amount of variation among individuals allows a species to rapidly adapt to new habitats, lessening the chance of it going extinct, while a wide geographic range increases the chance of speciation, by making it more likely that part of the population will become isolated. In this sense, microevolution and macroevolution might involve selection at different levels—with microevolution acting on genes and organisms, versus macroevolutionary processes such as species selection acting on entire species and affecting their rates of speciation and extinction.
A common misconception is that evolution has goals, long-term plans, or an innate tendency for "progress", as expressed in beliefs such as orthogenesis and evolutionism; realistically, however, evolution has no long-term goal and does not necessarily produce greater complexity. Although complex species have evolved, they occur as a side effect of the overall number of organisms increasing, and simple forms of life still remain more common in the biosphere. For example, the overwhelming majority of species are microscopic prokaryotes, which form about half the world's biomass despite their small size and constitute the vast majority of Earth's biodiversity. Simple organisms have therefore been the dominant form of life on Earth throughout its history and continue to be the main form of life up to the present day, with complex life only appearing more diverse because it is more noticeable. Indeed, the evolution of microorganisms is particularly important to evolutionary research since their rapid reproduction allows the study of experimental evolution and the observation of evolution and adaptation in real time.
=== Adaptation ===
Adaptation is the process that makes organisms better suited to their habitat. Also, the term adaptation may refer to a trait that is important for an organism's survival. For example, the adaptation of horses' teeth to the grinding of grass. By using the term adaptation for the evolutionary process and adaptive trait for the product (the bodily part or function), the two senses of the word may be distinguished. Adaptations are produced by natural selection. The following definitions are due to Theodosius Dobzhansky:
Adaptation is the evolutionary process whereby an organism becomes better able to live in its habitat or habitats.
Adaptedness is the state of being adapted: the degree to which an organism is able to live and reproduce in a given set of habitats.
An adaptive trait is an aspect of the developmental pattern of the organism which enables or enhances the probability of that organism surviving and reproducing.
Adaptation may cause either the gain of a new feature, or the loss of an ancestral feature. An example that shows both types of change is bacterial adaptation to antibiotic selection, with genetic changes causing antibiotic resistance by both modifying the target of the drug, or increasing the activity of transporters that pump the drug out of the cell. Other striking examples are the bacteria Escherichia coli evolving the ability to use citric acid as a nutrient in a long-term laboratory experiment, Flavobacterium evolving a novel enzyme that allows these bacteria to grow on the by-products of nylon manufacturing, and the soil bacterium Sphingobium evolving an entirely new metabolic pathway that degrades the synthetic pesticide pentachlorophenol. An interesting but still controversial idea is that some adaptations might increase the ability of organisms to generate genetic diversity and adapt by natural selection (increasing organisms' evolvability).
Adaptation occurs through the gradual modification of existing structures. Consequently, structures with similar internal organisation may have different functions in related organisms. This is the result of a single ancestral structure being adapted to function in different ways. The bones within bat wings, for example, are very similar to those in mice feet and primate hands, due to the descent of all these structures from a common mammalian ancestor. However, since all living organisms are related to some extent, even organs that appear to have little or no structural similarity, such as arthropod, squid and vertebrate eyes, or the limbs and wings of arthropods and vertebrates, can depend on a common set of homologous genes that control their assembly and function; this is called deep homology.
During evolution, some structures may lose their original function and become vestigial structures. Such structures may have little or no function in a current species, yet have a clear function in ancestral species, or other closely related species. Examples include pseudogenes, the non-functional remains of eyes in blind cave-dwelling fish, wings in flightless birds, the presence of hip bones in whales and snakes, and sexual traits in organisms that reproduce via asexual reproduction. Examples of vestigial structures in humans include wisdom teeth, the coccyx, the vermiform appendix, and other behavioural vestiges such as goose bumps and primitive reflexes.
However, many traits that appear to be simple adaptations are in fact exaptations: structures originally adapted for one function, but which coincidentally became somewhat useful for some other function in the process. One example is the African lizard Holaspis guentheri, which developed an extremely flat head for hiding in crevices, as can be seen by looking at its near relatives. However, in this species, the head has become so flattened that it assists in gliding from tree to tree—an exaptation. Within cells, molecular machines such as the bacterial flagella and protein sorting machinery evolved by the recruitment of several pre-existing proteins that previously had different functions. Another example is the recruitment of enzymes from glycolysis and xenobiotic metabolism to serve as structural proteins called crystallins within the lenses of organisms' eyes.
An area of current investigation in evolutionary developmental biology is the developmental basis of adaptations and exaptations. This research addresses the origin and evolution of embryonic development and how modifications of development and developmental processes produce novel features. These studies have shown that evolution can alter development to produce new structures, such as embryonic bone structures that develop into the jaw in other animals instead forming part of the middle ear in mammals. It is also possible for structures that have been lost in evolution to reappear due to changes in developmental genes, such as a mutation in chickens causing embryos to grow teeth similar to those of crocodiles. It is now becoming clear that most alterations in the form of organisms are due to changes in a small set of conserved genes.
=== Coevolution ===
Interactions between organisms can produce both conflict and cooperation. When the interaction is between pairs of species, such as a pathogen and a host, or a predator and its prey, these species can develop matched sets of adaptations. Here, the evolution of one species causes adaptations in a second species. These changes in the second species then, in turn, cause new adaptations in the first species. This cycle of selection and response is called coevolution. An example is the production of tetrodotoxin in the rough-skinned newt and the evolution of tetrodotoxin resistance in its predator, the common garter snake. In this predator-prey pair, an evolutionary arms race has produced high levels of toxin in the newt and correspondingly high levels of toxin resistance in the snake.
=== Cooperation ===
Not all co-evolved interactions between species involve conflict. Many cases of mutually beneficial interactions have evolved. For instance, an extreme cooperation exists between plants and the mycorrhizal fungi that grow on their roots and aid the plant in absorbing nutrients from the soil. This is a reciprocal relationship as the plants provide the fungi with sugars from photosynthesis. Here, the fungi actually grow inside plant cells, allowing them to exchange nutrients with their hosts, while sending signals that suppress the plant immune system.
Coalitions between organisms of the same species have also evolved. An extreme case is the eusociality found in social insects, such as bees, termites and ants, where sterile insects feed and guard the small number of organisms in a colony that are able to reproduce. On an even smaller scale, the somatic cells that make up the body of an animal limit their reproduction so they can maintain a stable organism, which then supports a small number of the animal's germ cells to produce offspring. Here, somatic cells respond to specific signals that instruct them whether to grow, remain as they are, or die. If cells ignore these signals and multiply inappropriately, their uncontrolled growth causes cancer.
Such cooperation within species may have evolved through the process of kin selection, which is where one organism acts to help raise a relative's offspring. This activity is selected for because if the helping individual contains alleles which promote the helping activity, it is likely that its kin will also contain these alleles and thus those alleles will be passed on. Other processes that may promote cooperation include group selection, where cooperation provides benefits to a group of organisms.
=== Speciation ===
Speciation is the process where a species diverges into two or more descendant species.
There are multiple ways to define the concept of "species". The choice of definition is dependent on the particularities of the species concerned. For example, some species concepts apply more readily toward sexually reproducing organisms while others lend themselves better toward asexual organisms. Despite the diversity of various species concepts, these various concepts can be placed into one of three broad philosophical approaches: interbreeding, ecological and phylogenetic. The Biological Species Concept (BSC) is a classic example of the interbreeding approach. Defined by evolutionary biologist Ernst Mayr in 1942, the BSC states that "species are groups of actually or potentially interbreeding natural populations, which are reproductively isolated from other such groups." Despite its wide and long-term use, the BSC like other species concepts is not without controversy, for example, because genetic recombination among prokaryotes is not an intrinsic aspect of reproduction; this is called the species problem. Some researchers have attempted a unifying monistic definition of species, while others adopt a pluralistic approach and suggest that there may be different ways to logically interpret the definition of a species.
Barriers to reproduction between two diverging sexual populations are required for the populations to become new species. Gene flow may slow this process by spreading the new genetic variants also to the other populations. Depending on how far two species have diverged since their most recent common ancestor, it may still be possible for them to produce offspring, as with horses and donkeys mating to produce mules. Such hybrids are generally infertile. In this case, closely related species may regularly interbreed, but hybrids will be selected against and the species will remain distinct. However, viable hybrids are occasionally formed and these new species can either have properties intermediate between their parent species, or possess a totally new phenotype. The importance of hybridisation in producing new species of animals is unclear, although cases have been seen in many types of animals, with the grey tree frog being a particularly well-studied example.
Speciation has been observed multiple times under both controlled laboratory conditions and in nature. In sexually reproducing organisms, speciation results from reproductive isolation followed by genealogical divergence. There are four primary geographic modes of speciation. The most common in animals is allopatric speciation, which occurs in populations initially isolated geographically, such as by habitat fragmentation or migration. Selection under these conditions can produce very rapid changes in the appearance and behaviour of organisms. As selection and drift act independently on populations isolated from the rest of their species, separation may eventually produce organisms that cannot interbreed.
The second mode of speciation is peripatric speciation, which occurs when small populations of organisms become isolated in a new environment. This differs from allopatric speciation in that the isolated populations are numerically much smaller than the parental population. Here, the founder effect causes rapid speciation after an increase in inbreeding increases selection on homozygotes, leading to rapid genetic change.
The third mode is parapatric speciation. This is similar to peripatric speciation in that a small population enters a new habitat, but differs in that there is no physical separation between these two populations. Instead, speciation results from the evolution of mechanisms that reduce gene flow between the two populations. Generally this occurs when there has been a drastic change in the environment within the parental species' habitat. One example is the grass Anthoxanthum odoratum, which can undergo parapatric speciation in response to localised metal pollution from mines. Here, plants evolve that have resistance to high levels of metals in the soil. Selection against interbreeding with the metal-sensitive parental population produced a gradual change in the flowering time of the metal-resistant plants, which eventually produced complete reproductive isolation. Selection against hybrids between the two populations may cause reinforcement, which is the evolution of traits that promote mating within a species, as well as character displacement, which is when two species become more distinct in appearance.
Finally, in sympatric speciation species diverge without geographic isolation or changes in habitat. This form is rare since even a small amount of gene flow may remove genetic differences between parts of a population. Generally, sympatric speciation in animals requires the evolution of both genetic differences and nonrandom mating, to allow reproductive isolation to evolve.
One type of sympatric speciation involves crossbreeding of two related species to produce a new hybrid species. This is not common in animals as animal hybrids are usually sterile. This is because during meiosis the homologous chromosomes from each parent are from different species and cannot successfully pair. However, it is more common in plants because plants often double their number of chromosomes, to form polyploids. This allows the chromosomes from each parental species to form matching pairs during meiosis, since each parent's chromosomes are represented by a pair already. An example of such a speciation event is when the plant species Arabidopsis thaliana and Arabidopsis arenosa crossbred to give the new species Arabidopsis suecica. This happened about 20,000 years ago, and the speciation process has been repeated in the laboratory, which allows the study of the genetic mechanisms involved in this process. Indeed, chromosome doubling within a species may be a common cause of reproductive isolation, as half the doubled chromosomes will be unmatched when breeding with undoubled organisms.
Speciation events are important in the theory of punctuated equilibrium, which accounts for the pattern in the fossil record of short "bursts" of evolution interspersed with relatively long periods of stasis, where species remain relatively unchanged. In this theory, speciation and rapid evolution are linked, with natural selection and genetic drift acting most strongly on organisms undergoing speciation in novel habitats or small populations. As a result, the periods of stasis in the fossil record correspond to the parental population and the organisms undergoing speciation and rapid evolution are found in small populations or geographically restricted habitats and therefore rarely being preserved as fossils.
=== Extinction ===
Extinction is the disappearance of an entire species. Extinction is not an unusual event, as species regularly appear through speciation and disappear through extinction. Nearly all animal and plant species that have lived on Earth are now extinct, and extinction appears to be the ultimate fate of all species. These extinctions have happened continuously throughout the history of life, although the rate of extinction spikes in occasional mass extinction events. The Cretaceous–Paleogene extinction event, during which the non-avian dinosaurs became extinct, is the most well-known, but the earlier Permian–Triassic extinction event was even more severe, with approximately 96% of all marine species driven to extinction. The Holocene extinction event is an ongoing mass extinction associated with humanity's expansion across the globe over the past few thousand years. Present-day extinction rates are 100–1000 times greater than the background rate and up to 30% of current species may be extinct by the mid 21st century. Human activities are now the primary cause of the ongoing extinction event; global warming may further accelerate it in the future. Despite the estimated extinction of more than 99% of all species that ever lived on Earth, about 1 trillion species are estimated to be on Earth currently with only one-thousandth of 1% described.
The role of extinction in evolution is not very well understood and may depend on which type of extinction is considered. The causes of the continuous "low-level" extinction events, which form the majority of extinctions, may be the result of competition between species for limited resources (the competitive exclusion principle). If one species can out-compete another, this could produce species selection, with the fitter species surviving and the other species being driven to extinction. The intermittent mass extinctions are also important, but instead of acting as a selective force, they drastically reduce diversity in a nonspecific manner and promote bursts of rapid evolution and speciation in survivors.
== Applications ==
Concepts and models used in evolutionary biology, such as natural selection, have many applications.
Artificial selection is the intentional selection of traits in a population of organisms. This has been used for thousands of years in the domestication of plants and animals. More recently, such selection has become a vital part of genetic engineering, with selectable markers such as antibiotic resistance genes being used to manipulate DNA. Proteins with valuable properties have evolved by repeated rounds of mutation and selection (for example modified enzymes and new antibodies) in a process called directed evolution.
Understanding the changes that have occurred during an organism's evolution can reveal the genes needed to construct parts of the body, genes which may be involved in human genetic disorders. For example, the Mexican tetra is an albino cavefish that lost its eyesight during evolution. Breeding together different populations of this blind fish produced some offspring with functional eyes, since different mutations had occurred in the isolated populations that had evolved in different caves. This helped identify genes required for vision and pigmentation.
Evolutionary theory has many applications in medicine. Many human diseases are not static phenomena, but capable of evolution. Viruses, bacteria, fungi and cancers evolve to be resistant to host immune defences, as well as to pharmaceutical drugs. These same problems occur in agriculture with pesticide and herbicide resistance. It is possible that we are facing the end of the effective life of most of available antibiotics and predicting the evolution and evolvability of our pathogens and devising strategies to slow or circumvent it is requiring deeper knowledge of the complex forces driving evolution at the molecular level.
In computer science, simulations of evolution using evolutionary algorithms and artificial life started in the 1960s and were extended with simulation of artificial selection. Artificial evolution became a widely recognised optimisation method as a result of the work of Ingo Rechenberg in the 1960s. He used evolution strategies to solve complex engineering problems. Genetic algorithms in particular became popular through the writing of John Henry Holland. Practical applications also include automatic evolution of computer programmes. Evolutionary algorithms are now used to solve multi-dimensional problems more efficiently than software produced by human designers and also to optimise the design of systems.
== Evolutionary history of life ==
=== Origin of life ===
The Earth is about 4.54 billion years old. The earliest undisputed evidence of life on Earth dates from at least 3.5 billion years ago, during the Eoarchean Era after a geological crust started to solidify following the earlier molten Hadean Eon. Microbial mat fossils have been found in 3.48 billion-year-old sandstone in Western Australia. Other early physical evidence of a biogenic substance is graphite in 3.7 billion-year-old metasedimentary rocks discovered in Western Greenland as well as "remains of biotic life" found in 4.1 billion-year-old rocks in Western Australia. Commenting on the Australian findings, Stephen Blair Hedges wrote: "If life arose relatively quickly on Earth, then it could be common in the universe." In July 2016, scientists reported identifying a set of 355 genes from the last universal common ancestor (LUCA) of all organisms living on Earth.
More than 99% of all species, amounting to over five billion species, that ever lived on Earth are estimated to be extinct. Estimates on the number of Earth's current species range from 10 million to 14 million, of which about 1.9 million are estimated to have been named and 1.6 million documented in a central database to date, leaving at least 80% not yet described.
Highly energetic chemistry is thought to have produced a self-replicating molecule around 4 billion years ago, and half a billion years later the last common ancestor of all life existed. The current scientific consensus is that the complex biochemistry that makes up life came from simpler chemical reactions. The beginning of life may have included self-replicating molecules such as RNA and the assembly of simple cells.
=== Common descent ===
All organisms on Earth are descended from a common ancestor or ancestral gene pool. Current species are a stage in the process of evolution, with their diversity the product of a long series of speciation and extinction events. The common descent of organisms was first deduced from four simple facts about organisms: First, they have geographic distributions that cannot be explained by local adaptation. Second, the diversity of life is not a set of completely unique organisms, but organisms that share morphological similarities. Third, vestigial traits with no clear purpose resemble functional ancestral traits. Fourth, organisms can be classified using these similarities into a hierarchy of nested groups, similar to a family tree.
Due to horizontal gene transfer, this "tree of life" may be more complicated than a simple branching tree, since some genes have spread independently between distantly related species. To solve this problem and others, some authors prefer to use the "Coral of life" as a metaphor or a mathematical model to illustrate the evolution of life. This view dates back to an idea briefly mentioned by Darwin but later abandoned.
Past species have also left records of their evolutionary history. Fossils, along with the comparative anatomy of present-day organisms, constitute the morphological, or anatomical, record. By comparing the anatomies of both modern and extinct species, palaeontologists can infer the lineages of those species. However, this approach is most successful for organisms that had hard body parts, such as shells, bones or teeth. Further, as prokaryotes such as bacteria and archaea share a limited set of common morphologies, their fossils do not provide information on their ancestry.
More recently, evidence for common descent has come from the study of biochemical similarities between organisms. For example, all living cells use the same basic set of nucleotides and amino acids. The development of molecular genetics has revealed the record of evolution left in organisms' genomes: dating when species diverged through the molecular clock produced by mutations. For example, these DNA sequence comparisons have revealed that humans and chimpanzees share 98% of their genomes and analysing the few areas where they differ helps shed light on when the common ancestor of these species existed.
=== Evolution of life ===
Prokaryotes inhabited the Earth from approximately 3–4 billion years ago. No obvious changes in morphology or cellular organisation occurred in these organisms over the next few billion years. The eukaryotic cells emerged between 1.6 and 2.7 billion years ago. The next major change in cell structure came when bacteria were engulfed by eukaryotic cells, in a cooperative association called endosymbiosis. The engulfed bacteria and the host cell then underwent coevolution, with the bacteria evolving into either mitochondria or hydrogenosomes. Another engulfment of cyanobacterial-like organisms led to the formation of chloroplasts in algae and plants.
The history of life was that of the unicellular eukaryotes, prokaryotes and archaea until around 1.7 billion years ago, when multicellular organisms began to appear, with differentiated cells performing specialised functions. The evolution of multicellularity occurred in multiple independent events, in organisms as diverse as sponges, brown algae, cyanobacteria, slime moulds and myxobacteria. In January 2016, scientists reported that, about 800 million years ago, a minor genetic change in a single molecule called GK-PID may have allowed organisms to go from a single cell organism to one of many cells.
Approximately 538.8 million years ago, a remarkable amount of biological diversity appeared over a span of around 10 million years in what is called the Cambrian explosion. Here, the majority of types of modern animals appeared in the fossil record, as well as unique lineages that subsequently became extinct. Various triggers for the Cambrian explosion have been proposed, including the accumulation of oxygen in the atmosphere from photosynthesis.
About 500 million years ago, plants and fungi colonised the land and were soon followed by arthropods and other animals. Insects were particularly successful and even today make up the majority of animal species. Amphibians first appeared around 364 million years ago, followed by early amniotes and birds around 155 million years ago (both from "reptile"-like lineages), mammals around 129 million years ago, Homininae around 10 million years ago and modern humans around 250,000 years ago. However, despite the evolution of these large animals, smaller organisms similar to the types that evolved early in this process continue to be highly successful and dominate the Earth, with the majority of both biomass and species being prokaryotes.
== History of evolutionary thought ==
=== Classical antiquity ===
The proposal that one type of organism could descend from another type goes back to some of the first pre-Socratic Greek philosophers, such as Anaximander and Empedocles. Such proposals survived into Roman times. The poet and philosopher Lucretius followed Empedocles in his masterwork De rerum natura (lit. 'On the Nature of Things').
=== Middle Ages ===
In contrast to these materialistic views, Aristotelianism had considered all natural things as actualisations of fixed natural possibilities, known as forms. This became part of a medieval teleological understanding of nature in which all things have an intended role to play in a divine cosmic order. Variations of this idea became the standard understanding of the Middle Ages and were integrated into Christian learning, but Aristotle did not demand that real types of organisms always correspond one-for-one with exact metaphysical forms and specifically gave examples of how new types of living things could come to be.
A number of Arab Muslim scholars wrote about evolution, most notably Ibn Khaldun, who wrote the book Muqaddimah in 1377, in which he asserted that humans developed from "the world of the monkeys", in a process by which "species become more numerous".
=== Pre-Darwinian ===
The "New Science" of the 17th century rejected the Aristotelian approach. It sought to explain natural phenomena in terms of physical laws that were the same for all visible things and that did not require the existence of any fixed natural categories or divine cosmic order. However, this new approach was slow to take root in the biological sciences: the last bastion of the concept of fixed natural types. John Ray applied one of the previously more general terms for fixed natural types, "species", to plant and animal types, but he strictly identified each type of living thing as a species and proposed that each species could be defined by the features that perpetuated themselves generation after generation. The biological classification introduced by Carl Linnaeus in 1735 explicitly recognised the hierarchical nature of species relationships, but still viewed species as fixed according to a divine plan.
Other naturalists of this time speculated on the evolutionary change of species over time according to natural laws. In 1751, Pierre Louis Maupertuis wrote of natural modifications occurring during reproduction and accumulating over many generations to produce new species. Georges-Louis Leclerc, Comte de Buffon, suggested that species could degenerate into different organisms, and Erasmus Darwin proposed that all warm-blooded animals could have descended from a single microorganism (or "filament"). The first full-fledged evolutionary scheme was Jean-Baptiste Lamarck's "transmutation" theory of 1809, which envisaged spontaneous generation continually producing simple forms of life that developed greater complexity in parallel lineages with an inherent progressive tendency, and postulated that on a local level, these lineages adapted to the environment by inheriting changes caused by their use or disuse in parents. (The latter process was later called Lamarckism.) These ideas were condemned by established naturalists as speculation lacking empirical support. In particular, Georges Cuvier insisted that species were unrelated and fixed, their similarities reflecting divine design for functional needs. In the meantime, Ray's ideas of benevolent design had been developed by William Paley into the Natural Theology or Evidences of the Existence and Attributes of the Deity (1802), which proposed complex adaptations as evidence of divine design and which was admired by Charles Darwin.
=== Darwinian revolution ===
The crucial break from the concept of constant typological classes or types in biology came with the theory of evolution through natural selection, which was formulated by Charles Darwin and Alfred Wallace in terms of variable populations. Darwin used the expression descent with modification rather than evolution. Partly influenced by An Essay on the Principle of Population (1798) by Thomas Robert Malthus, Darwin noted that population growth would lead to a "struggle for existence" in which favourable variations prevailed as others perished. In each generation, many offspring fail to survive to an age of reproduction because of limited resources. This could explain the diversity of plants and animals from a common ancestry through the working of natural laws in the same way for all types of organism. Darwin developed his theory of "natural selection" from 1838 onwards and was writing up his "big book" on the subject when Alfred Russel Wallace sent him a version of virtually the same theory in 1858. Their separate papers were presented together at an 1858 meeting of the Linnean Society of London. At the end of 1859, Darwin's publication of his "abstract" as On the Origin of Species explained natural selection in detail and in a way that led to an increasingly wide acceptance of Darwin's concepts of evolution at the expense of alternative theories. Thomas Henry Huxley applied Darwin's ideas to humans, using palaeontology and comparative anatomy to provide strong evidence that humans and apes shared a common ancestry. Some were disturbed by this since it implied that humans did not have a special place in the universe.
Othniel C. Marsh, America's first palaeontologist, was the first to provide solid fossil evidence to support Darwin's theory of evolution by unearthing the ancestors of the modern horse. In 1877, Marsh delivered a very influential speech before the annual meeting of the American Association for the Advancement of Science, providing a demonstrative argument for evolution. For the first time, Marsh traced the evolution of vertebrates from fish all the way through humans. Sparing no detail, he listed a wealth of fossil examples of past life forms. The significance of this speech was immediately recognised by the scientific community, and it was printed in its entirety in several scientific journals.
In 1880, Marsh caught the attention of the scientific world with the publication of Odontornithes: a Monograph on Extinct Birds of North America, which included his discoveries of birds with teeth. These skeletons helped bridge the gap between dinosaurs and birds, and provided invaluable support for Darwin's theory of evolution. Darwin wrote to Marsh saying, "Your work on these old birds & on the many fossil animals of N. America has afforded the best support to the theory of evolution, which has appeared within the last 20 years" (since Darwin's publication of Origin of Species).
=== Pangenesis and heredity ===
The mechanisms of reproductive heritability and the origin of new traits remained a mystery. Towards this end, Darwin developed his provisional theory of pangenesis. In 1865, Gregor Mendel reported that traits were inherited in a predictable manner through the independent assortment and segregation of elements (later known as genes). Mendel's laws of inheritance eventually supplanted most of Darwin's pangenesis theory. August Weismann made the important distinction between germ cells that give rise to gametes (such as sperm and egg cells) and the somatic cells of the body, demonstrating that heredity passes through the germ line only. Hugo de Vries connected Darwin's pangenesis theory to Weismann's germ/soma cell distinction and proposed that Darwin's pangenes were concentrated in the cell nucleus and when expressed they could move into the cytoplasm to change the cell's structure. De Vries was also one of the researchers who made Mendel's work well known, believing that Mendelian traits corresponded to the transfer of heritable variations along the germline. To explain how new variants originate, de Vries developed a mutation theory that led to a temporary rift between those who accepted Darwinian evolution and biometricians who allied with de Vries. In the 1930s, pioneers in the field of population genetics, such as Ronald Fisher, Sewall Wright and J. B. S. Haldane set the foundations of evolution onto a robust statistical philosophy. The false contradiction between Darwin's theory, genetic mutations, and Mendelian inheritance was thus reconciled.
=== The 'modern synthesis' ===
In the 1920s and 1930s, the modern synthesis connected natural selection and population genetics, based on Mendelian inheritance, into a unified theory that included random genetic drift, mutation, and gene flow. This new version of evolutionary theory focused on changes in allele frequencies in population. It explained patterns observed across species in populations, through fossil transitions in palaeontology.
=== Further syntheses ===
Since then, further syntheses have extended evolution's explanatory power in the light of numerous discoveries, to cover biological phenomena across the whole of the biological hierarchy from genes to populations.
The publication of the structure of DNA by James Watson and Francis Crick with contribution of Rosalind Franklin in 1953 demonstrated a physical mechanism for inheritance. Molecular biology improved understanding of the relationship between genotype and phenotype. Advances were also made in phylogenetic systematics, mapping the transition of traits into a comparative and testable framework through the publication and use of evolutionary trees. In 1973, evolutionary biologist Theodosius Dobzhansky penned that "nothing in biology makes sense except in the light of evolution", because it has brought to light the relations of what first seemed disjointed facts in natural history into a coherent explanatory body of knowledge that describes and predicts many observable facts about life on this planet.
One extension, known as evolutionary developmental biology and informally called "evo-devo", emphasises how changes between generations (evolution) act on patterns of change within individual organisms (development). Since the beginning of the 21st century, some biologists have argued for an extended evolutionary synthesis, which would account for the effects of non-genetic inheritance modes, such as epigenetics, parental effects, ecological inheritance and cultural inheritance, and evolvability.
== Social and cultural responses ==
In the 19th century, particularly after the publication of On the Origin of Species in 1859, the idea that life had evolved was an active source of academic debate centred on the philosophical, social and religious implications of evolution. Today, the modern evolutionary synthesis is accepted by a vast majority of scientists. However, evolution remains a contentious concept for some theists.
While various religions and denominations have reconciled their beliefs with evolution through concepts such as theistic evolution, there are creationists who believe that evolution is contradicted by the creation myths found in their religions and who raise various objections to evolution. As had been demonstrated by responses to the publication of Vestiges of the Natural History of Creation in 1844, the most controversial aspect of evolutionary biology is the implication of human evolution that humans share common ancestry with apes and that the mental and moral faculties of humanity have the same types of natural causes as other inherited traits in animals. In some countries, notably the United States, these tensions between science and religion have fuelled the current creation–evolution controversy, a religious conflict focusing on politics and public education. While other scientific fields such as cosmology and Earth science also conflict with literal interpretations of many religious texts, evolutionary biology experiences significantly more opposition from religious literalists.
The teaching of evolution in American secondary school biology classes was uncommon in most of the first half of the 20th century. The Scopes Trial decision of 1925 caused the subject to become very rare in American secondary biology textbooks for a generation, but it was gradually re-introduced later and became legally protected with the 1968 Epperson v. Arkansas decision. Since then, the competing religious belief of creationism was legally disallowed in secondary school curricula in various decisions in the 1970s and 1980s, but it returned in pseudoscientific form as intelligent design (ID), to be excluded once again in the 2005 Kitzmiller v. Dover Area School District case. The debate over Darwin's ideas did not generate significant controversy in China.
== See also ==
Devolution (biology) – Notion that species can revert to primitive forms
Chronospecies
== References ==
== Bibliography ==
== Further reading ==
== External links ==
General information
"Evolution" on In Our Time at the BBC
"Evolution Resources from the National Academies". Washington, D.C.: National Academy of Sciences. Retrieved 30 May 2011.
"Understanding Evolution: your one-stop resource for information on evolution". Berkeley, California: University of California, Berkeley. Retrieved 30 May 2011.
"Evolution of Evolution – 150 Years of Darwin's 'On the Origin of Species'". Arlington County, Virginia: National Science Foundation. Archived from the original on 19 May 2011. Retrieved 30 May 2011.
"Human Evolution Timeline Interactive". Smithsonian Institution, National Museum of Natural History. 28 January 2010. Retrieved 14 July 2018. Adobe Flash required.
"History of Evolution in the United States". Salon. Retrieved 2021-08-24.
Video (1980; Cosmos animation; 8:01): "Evolution" – Carl Sagan on YouTube
Experiments
Lenski, Richard E. "Experimental Evolution". East Lansing, Michigan: Michigan State University. Retrieved 31 July 2013.
Chastain, Erick; Livnat, Adi; Papadimitriou, Christos; Vazirani, Umesh (22 July 2014). "Algorithms, games, and evolution". PNAS. 111 (29): 10620–10623. Bibcode:2014PNAS..11110620C. doi:10.1073/pnas.1406556111. ISSN 0027-8424. PMC 4115542. PMID 24979793.
Online lectures
"Evolution Matters Lecture Series". Harvard Online Learning. Cambridge, Massachusetts: Harvard University. Archived from the original on 18 December 2017. Retrieved 15 July 2018.
Stearns, Stephen C. "EEB 122: Principles of Evolution, Ecology and Behavior". Open Yale Courses. New Haven, Connecticut: Yale University. Archived from the original on 1 December 2017. Retrieved 14 July 2018. | Wikipedia/Evolution_theory |
Protein engineering is the process of developing useful or valuable proteins through the design and production of unnatural polypeptides, often by altering amino acid sequences found in nature. It is a young discipline, with much research taking place into the understanding of protein folding and recognition for protein design principles. It has been used to improve the function of many enzymes for industrial catalysis. It is also a product and services market, with an estimated value of $168 billion by 2017.
There are two general strategies for protein engineering: rational protein design and directed evolution. These methods are not mutually exclusive; researchers will often apply both. In the future, more detailed knowledge of protein structure and function, and advances in high-throughput screening, may greatly expand the abilities of protein engineering. Eventually, even unnatural amino acids may be included, via newer methods, such as expanded genetic code, that allow encoding novel amino acids in genetic code.
The applications in numerous fields, including medicine and industrial bioprocessing, are vast and numerous.
== Approaches ==
=== Rational design ===
In rational protein design, a scientist uses detailed knowledge of the structure and function of a protein to make desired changes. In general, this has the advantage of being inexpensive and technically easy, since site-directed mutagenesis methods are well-developed. However, its major drawback is that detailed structural knowledge of a protein is often unavailable, and, even when available, it can be very difficult to predict the effects of various mutations since structural information most often provide a static picture of a protein structure. However, programs such as Folding@home and Foldit have utilized crowdsourcing techniques in order to gain insight into the folding motifs of proteins.
Computational protein design algorithms seek to identify novel amino acid sequences that are low in energy when folded to the pre-specified target structure. While the sequence-conformation space that needs to be searched is large, the most challenging requirement for computational protein design is a fast, yet accurate, energy function that can distinguish optimal sequences from similar suboptimal ones.
=== Multiple sequence alignment ===
Without structural information about a protein, sequence analysis is often useful in elucidating information about the protein. These techniques involve alignment of target protein sequences with other related protein sequences. This alignment can show which amino acids are conserved between species and are important for the function of the protein. These analyses can help to identify hot spot amino acids that can serve as the target sites for mutations. Multiple sequence alignment utilizes data bases such as PREFAB, SABMARK, OXBENCH, IRMBASE, and BALIBASE in order to cross reference target protein sequences with known sequences. Multiple sequence alignment techniques are listed below.
This method begins by performing pair wise alignment of sequences using k-tuple or Needleman–Wunsch methods. These methods calculate a matrix that depicts the pair wise similarity among the sequence pairs. Similarity scores are then transformed into distance scores that are used to produce a guide tree using the neighbor joining method. This guide tree is then employed to yield a multiple sequence alignment.
==== Clustal omega ====
This method is capable of aligning up to 190,000 sequences by utilizing the k-tuple method. Next sequences are clustered using the mBed and k-means methods. A guide tree is then constructed using the UPGMA method that is used by the HH align package. This guide tree is used to generate multiple sequence alignments.
==== MAFFT ====
This method utilizes fast Fourier transform (FFT) that converts amino acid sequences into a sequence composed of volume and polarity values for each amino acid residue. This new sequence is used to find homologous regions.
==== K-Align ====
This method utilizes the Wu-Manber approximate string matching algorithm to generate multiple sequence alignments.
==== Multiple sequence comparison by log expectation (MUSCLE) ====
This method utilizes Kmer and Kimura distances to generate multiple sequence alignments.
==== T-Coffee ====
This method utilizes tree based consistency objective functions for alignment evolution. This method has been shown to be 5–10% more accurate than Clustal W.
=== Coevolutionary analysis ===
Coevolutionary analysis is also known as correlated mutation, covariation, or co-substitution. This type of rational design involves reciprocal evolutionary changes at evolutionarily interacting loci. Generally this method begins with the generation of a curated multiple sequence alignments for the target sequence. This alignment is then subjected to manual refinement that involves removal of highly gapped sequences, as well as sequences with low sequence identity. This step increases the quality of the alignment. Next, the manually processed alignment is utilized for further coevolutionary measurements using distinct correlated mutation algorithms. These algorithms result in a coevolution scoring matrix. This matrix is filtered by applying various significance tests to extract significant coevolution values and wipe out background noise. Coevolutionary measurements are further evaluated to assess their performance and stringency. Finally, the results from this coevolutionary analysis are validated experimentally.
=== Structural prediction ===
De novo generation of protein benefits from knowledge of existing protein structures. This knowledge of existing protein structure assists with the prediction of new protein structures. Methods for protein structure prediction fall under one of the four following classes: ab initio, fragment based methods, homology modeling, and protein threading.
==== Ab initio ====
These methods involve free modeling without using any structural information about the template. Ab initio methods are aimed at prediction of the native structures of proteins corresponding to the global minimum of its free energy. some examples of ab initio methods are AMBER, GROMOS, GROMACS, CHARMM, OPLS, and ENCEPP12. General steps for ab initio methods begin with the geometric representation of the protein of interest. Next, a potential energy function model for the protein is developed. This model can be created using either molecular mechanics potentials or protein structure derived potential functions. Following the development of a potential model, energy search techniques including molecular dynamic simulations, Monte Carlo simulations and genetic algorithms are applied to the protein.
==== Fragment based ====
These methods use database information regarding structures to match homologous structures to the created protein sequences. These homologous structures are assembled to give compact structures using scoring and optimization procedures, with the goal of achieving the lowest potential energy score. Webservers for fragment information are I-TASSER, ROSETTA, ROSETTA @ home, FRAGFOLD, CABS fold, PROFESY, CREF, QUARK, UNDERTAKER, HMM, and ANGLOR.: 72
==== Homology modeling ====
These methods are based upon the homology of proteins. These methods are also known as comparative modeling. The first step in homology modeling is generally the identification of template sequences of known structure which are homologous to the query sequence. Next the query sequence is aligned to the template sequence. Following the alignment, the structurally conserved regions are modeled using the template structure. This is followed by the modeling of side chains and loops that are distinct from the template. Finally the modeled structure undergoes refinement and assessment of quality. Servers that are available for homology modeling data are listed here: SWISS MODEL, MODELLER, ReformAlign, PyMOD, TIP-STRUCTFAST, COMPASS, 3d-PSSM, SAMT02, SAMT99, HHPRED, FAGUE, 3D-JIGSAW, META-PP, ROSETTA, and I-TASSER.
==== Protein threading ====
Protein threading can be used when a reliable homologue for the query sequence cannot be found. This method begins by obtaining a query sequence and a library of template structures. Next, the query sequence is threaded over known template structures. These candidate models are scored using scoring functions. These are scored based upon potential energy models of both query and template sequence. The match with the lowest potential energy model is then selected. Methods and servers for retrieving threading data and performing calculations are listed here: GenTHREADER, pGenTHREADER, pDomTHREADER, ORFEUS, PROSPECT, BioShell-Threading, FFASO3, RaptorX, HHPred, LOOPP server, Sparks-X, SEGMER, THREADER2, ESYPRED3D, LIBRA, TOPITS, RAPTOR, COTH, MUSTER.
For more information on rational design see site-directed mutagenesis.
=== Multivalent binding ===
Multivalent binding can be used to increase the binding specificity and affinity through avidity effects. Having multiple binding domains in a single biomolecule or complex increases the likelihood of other interactions to occur via individual binding events. Avidity or effective affinity can be much higher than the sum of the individual affinities providing a cost and time-effective tool for targeted binding.
==== Multivalent proteins ====
Multivalent proteins are relatively easy to produce by post-translational modifications or multiplying the protein-coding DNA sequence. The main advantage of multivalent and multispecific proteins is that they can increase the effective affinity for a target of a known protein. In the case of an inhomogeneous target using a combination of proteins resulting in multispecific binding can increase specificity, which has high applicability in protein therapeutics.
The most common example for multivalent binding are the antibodies, and there is extensive research for bispecific antibodies. Applications of bispecific antibodies cover a broad spectrum that includes diagnosis, imaging, prophylaxis, and therapy.
=== Directed evolution ===
In directed evolution, random mutagenesis, e.g. by error-prone PCR or sequence saturation mutagenesis, is applied to a protein, and a selection regime is used to select variants having desired traits. Further rounds of mutation and selection are then applied. This method mimics natural evolution and, in general, produces superior results to rational design. An added process, termed DNA shuffling, mixes and matches pieces of successful variants to produce better results. Such processes mimic the recombination that occurs naturally during sexual reproduction. Advantages of directed evolution are that it requires no prior structural knowledge of a protein, nor is it necessary to be able to predict what effect a given mutation will have. Indeed, the results of directed evolution experiments are often surprising in that desired changes are often caused by mutations that were not expected to have some effect. The drawback is that they require high-throughput screening, which is not feasible for all proteins. Large amounts of recombinant DNA must be mutated and the products screened for desired traits. The large number of variants often requires expensive robotic equipment to automate the process. Further, not all desired activities can be screened for easily.
Natural Darwinian evolution can be effectively imitated in the lab toward tailoring protein properties for diverse applications, including catalysis. Many experimental technologies exist to produce large and diverse protein libraries and for screening or selecting folded, functional variants. Folded proteins arise surprisingly frequently in random sequence space, an occurrence exploitable in evolving selective binders and catalysts. While more conservative than direct selection from deep sequence space, redesign of existing proteins by random mutagenesis and selection/screening is a particularly robust method for optimizing or altering extant properties. It also represents an excellent starting point for achieving more ambitious engineering goals. Allying experimental evolution with modern computational methods is likely the broadest, most fruitful strategy for generating functional macromolecules unknown to nature.
The main challenges of designing high quality mutant libraries have shown significant progress in the recent past. This progress has been in the form of better descriptions of the effects of mutational loads on protein traits. Also computational approaches have shown large advances in the innumerably large sequence space to more manageable screenable sizes, thus creating smart libraries of mutants. Library size has also been reduced to more screenable sizes by the identification of key beneficial residues using algorithms for systematic recombination. Finally a significant step forward toward efficient reengineering of enzymes has been made with the development of more accurate statistical models and algorithms quantifying and predicting coupled mutational effects on protein functions.
Generally, directed evolution may be summarized as an iterative two step process which involves generation of protein mutant libraries, and high throughput screening processes to select for variants with improved traits. This technique does not require prior knowledge of the protein structure and function relationship. Directed evolution utilizes random or focused mutagenesis to generate libraries of mutant proteins. Random mutations can be introduced using either error prone PCR, or site saturation mutagenesis. Mutants may also be generated using recombination of multiple homologous genes. Nature has evolved a limited number of beneficial sequences. Directed evolution makes it possible to identify undiscovered protein sequences which have novel functions. This ability is contingent on the proteins ability to tolerant amino acid residue substitutions without compromising folding or stability.
Directed evolution methods can be broadly categorized into two strategies, asexual and sexual methods.
=== Asexual methods ===
Asexual methods do not generate any cross links between parental genes. Single genes are used to create mutant libraries using various mutagenic techniques. These asexual methods can produce either random or focused mutagenesis.
==== Random mutagenesis ====
Random mutagenic methods produce mutations at random throughout the gene of interest. Random mutagenesis can introduce the following types of mutations: transitions, transversions, insertions, deletions, inversion, missense, and nonsense. Examples of methods for producing random mutagenesis are below.
==== Error prone PCR ====
Error prone PCR utilizes the fact that Taq DNA polymerase lacks 3' to 5' exonuclease activity. This results in an error rate of 0.001–0.002% per nucleotide per replication. This method begins with choosing the gene, or the area within a gene, one wishes to mutate. Next, the extent of error required is calculated based upon the type and extent of activity one wishes to generate. This extent of error determines the error prone PCR strategy to be employed. Following PCR, the genes are cloned into a plasmid and introduced to competent cell systems. These cells are then screened for desired traits. Plasmids are then isolated for colonies which show improved traits, and are then used as templates the next round of mutagenesis. Error prone PCR shows biases for certain mutations relative to others. Such as biases for transitions over transversions.
Rates of error in PCR can be increased in the following ways:
Increase concentration of magnesium chloride, which stabilizes non complementary base pairing.
Add manganese chloride to reduce base pair specificity.
Increased and unbalanced addition of dNTPs.
Addition of base analogs like dITP, 8 oxo-dGTP, and dPTP.
Increase concentration of Taq polymerase.
Increase extension time.
Increase cycle time.
Use less accurate Taq polymerase.
Also see polymerase chain reaction for more information.
==== Rolling circle error-prone PCR ====
This PCR method is based upon rolling circle amplification, which is modeled from the method that bacteria use to amplify circular DNA. This method results in linear DNA duplexes. These fragments contain tandem repeats of circular DNA called concatamers, which can be transformed into bacterial strains. Mutations are introduced by first cloning the target sequence into an appropriate plasmid. Next, the amplification process begins using random hexamer primers and Φ29 DNA polymerase under error prone rolling circle amplification conditions. Additional conditions to produce error prone rolling circle amplification are 1.5 pM of template DNA, 1.5 mM MnCl2 and a 24 hour reaction time. MnCl2 is added into the reaction mixture to promote random point mutations in the DNA strands. Mutation rates can be increased by increasing the concentration of MnCl2, or by decreasing concentration of the template DNA. Error prone rolling circle amplification is advantageous relative to error prone PCR because of its use of universal random hexamer primers, rather than specific primers. Also the reaction products of this amplification do not need to be treated with ligases or endonucleases. This reaction is isothermal.
==== Chemical mutagenesis ====
Chemical mutagenesis involves the use of chemical agents to introduce mutations into genetic sequences. Examples of chemical mutagens follow.
Sodium bisulfate is effective at mutating G/C rich genomic sequences. This is because sodium bisulfate catalyses deamination of unmethylated cytosine to uracil.
Ethyl methane sulfonate alkylates guanidine residues. This alteration causes errors during DNA replication.
Nitrous acid causes transversion by de-amination of adenine and cytosine.
The dual approach to random chemical mutagenesis is an iterative two step process. First it involves the in vivo chemical mutagenesis of the gene of interest via EMS. Next, the treated gene is isolated and cloning into an untreated expression vector in order to prevent mutations in the plasmid backbone. This technique preserves the plasmids genetic properties.
==== Targeting glycosylases to embedded arrays for mutagenesis (TaGTEAM) ====
This method has been used to create targeted in vivo mutagenesis in yeast. This method involves the fusion of a 3-methyladenine DNA glycosylase to tetR DNA-binding domain. This has been shown to increase mutation rates by over 800 time in regions of the genome containing tetO sites.
==== Mutagenesis by random insertion and deletion ====
This method involves alteration in length of the sequence via simultaneous deletion and insertion of chunks of bases of arbitrary length. This method has been shown to produce proteins with new functionalities via introduction of new restriction sites, specific codons, four base codons for non-natural amino acids.
==== Transposon based random mutagenesis ====
Recently many methods for transposon based random mutagenesis have been reported. This methods include, but are not limited to the following: PERMUTE-random circular permutation, random protein truncation, random nucleotide triplet substitution, random domain/tag/multiple amino acid insertion, codon scanning mutagenesis, and multicodon scanning mutagenesis. These aforementioned techniques all require the design of mini-Mu transposons. Thermo scientific manufactures kits for the design of these transposons.
==== Random mutagenesis methods altering the target DNA length ====
These methods involve altering gene length via insertion and deletion mutations. An example is the tandem repeat insertion (TRINS) method. This technique results in the generation of tandem repeats of random fragments of the target gene via rolling circle amplification and concurrent incorporation of these repeats into the target gene.
==== Mutator strains ====
Mutator strains are bacterial cell lines which are deficient in one or more DNA repair mechanisms. An example of a mutator strand is the E. coli XL1-RED. This subordinate strain of E. coli is deficient in the MutS, MutD, MutT DNA repair pathways. Use of mutator strains is useful at introducing many types of mutation; however, these strains show progressive sickness of culture because of the accumulation of mutations in the strains own genome.
==== Focused mutagenesis ====
Focused mutagenic methods produce mutations at predetermined amino acid residues. These techniques require and understanding of the sequence-function relationship for the protein of interest. Understanding of this relationship allows for the identification of residues which are important in stability, stereoselectivity, and catalytic efficiency. Examples of methods that produce focused mutagenesis are below.
==== Site saturation mutagenesis ====
Site saturation mutagenesis is a PCR based method used to target amino acids with significant roles in protein function. The two most common techniques for performing this are whole plasmid single PCR, and overlap extension PCR.
Whole plasmid single PCR is also referred to as site directed mutagenesis (SDM). SDM products are subjected to Dpn endonuclease digestion. This digestion results in cleavage of only the parental strand, because the parental strand contains a GmATC which is methylated at N6 of adenine. SDM does not work well for large plasmids of over ten kilobases. Also, this method is only capable of replacing two nucleotides at a time.
Overlap extension PCR requires the use of two pairs of primers. One primer in each set contains a mutation. A first round of PCR using these primer sets is performed and two double stranded DNA duplexes are formed. A second round of PCR is then performed in which these duplexes are denatured and annealed with the primer sets again to produce heteroduplexes, in which each strand has a mutation. Any gaps in these newly formed heteroduplexes are filled with DNA polymerases and further amplified.
==== Sequence saturation mutagenesis (SeSaM) ====
Sequence saturation mutagenesis results in the randomization of the target sequence at every nucleotide position. This method begins with the generation of variable length DNA fragments tailed with universal bases via the use of template transferases at the 3' termini. Next, these fragments are extended to full length using a single stranded template. The universal bases are replaced with a random standard base, causing mutations. There are several modified versions of this method such as SeSAM-Tv-II, SeSAM-Tv+, and SeSAM-III.
==== Single primer reactions in parallel (SPRINP) ====
This site saturation mutagenesis method involves two separate PCR reaction. The first of which uses only forward primers, while the second reaction uses only reverse primers. This avoids the formation of primer dimer formation.
==== Mega primed and ligase free focused mutagenesis ====
This site saturation mutagenic technique begins with one mutagenic oligonucleotide and one universal flanking primer. These two reactants are used for an initial PCR cycle. Products from this first PCR cycle are used as mega primers for the next PCR.
==== Ω-PCR ====
This site saturation mutagenic method is based on overlap extension PCR. It is used to introduce mutations at any site in a circular plasmid.
==== PFunkel-ominchange-OSCARR ====
This method utilizes user defined site directed mutagenesis at single or multiple sites simultaneously. OSCARR is an acronym for one pot simple methodology for cassette randomization and recombination. This randomization and recombination results in randomization of desired fragments of a protein. Omnichange is a sequence independent, multisite saturation mutagenesis which can saturate up to five independent codons on a gene.
==== Trimer-dimer mutagenesis ====
This method removes redundant codons and stop codons.
==== Cassette mutagenesis ====
This is a PCR based method. Cassette mutagenesis begins with the synthesis of a DNA cassette containing the gene of interest, which is flanked on either side by restriction sites. The endonuclease which cleaves these restriction sites also cleaves sites in the target plasmid. The DNA cassette and the target plasmid are both treated with endonucleases to cleave these restriction sites and create sticky ends. Next the products from this cleavage are ligated together, resulting in the insertion of the gene into the target plasmid. An alternative form of cassette mutagenesis called combinatorial cassette mutagenesis is used to identify the functions of individual amino acid residues in the protein of interest. Recursive ensemble mutagenesis then utilizes information from previous combinatorial cassette mutagenesis. Codon cassette mutagenesis allows you to insert or replace a single codon at a particular site in double stranded DNA.
=== Sexual methods ===
Sexual methods of directed evolution involve in vitro recombination which mimic natural in vivo recombination. Generally these techniques require high sequence homology between parental sequences. These techniques are often used to recombine two different parental genes, and these methods do create cross overs between these genes.
==== In vitro homologous recombination ====
Homologous recombination can be categorized as either in vivo or in vitro. In vitro homologous recombination mimics natural in vivo recombination. These in vitro recombination methods require high sequence homology between parental sequences. These techniques exploit the natural diversity in parental genes by recombining them to yield chimeric genes. The resulting chimera show a blend of parental characteristics.
==== DNA shuffling ====
This in vitro technique was one of the first techniques in the era of recombination. It begins with the digestion of homologous parental genes into small fragments by DNase1. These small fragments are then purified from undigested parental genes. Purified fragments are then reassembled using primer-less PCR. This PCR involves homologous fragments from different parental genes priming for each other, resulting in chimeric DNA. The chimeric DNA of parental size is then amplified using end terminal primers in regular PCR.
==== Random priming in vitro recombination (RPR) ====
This in vitro homologous recombination method begins with the synthesis of many short gene fragments exhibiting point mutations using random sequence primers. These fragments are reassembled to full length parental genes using primer-less PCR. These reassembled sequences are then amplified using PCR and subjected to further selection processes. This method is advantageous relative to DNA shuffling because there is no use of DNase1, thus there is no bias for recombination next to a pyrimidine nucleotide. This method is also advantageous due to its use of synthetic random primers which are uniform in length, and lack biases. Finally this method is independent of the length of DNA template sequence, and requires a small amount of parental DNA.
==== Truncated metagenomic gene-specific PCR ====
This method generates chimeric genes directly from metagenomic samples. It begins with isolation of the desired gene by functional screening from metagenomic DNA sample. Next, specific primers are designed and used to amplify the homologous genes from different environmental samples. Finally, chimeric libraries are generated to retrieve the desired functional clones by shuffling these amplified homologous genes.
==== Staggered extension process (StEP) ====
This in vitro method is based on template switching to generate chimeric genes. This PCR based method begins with an initial denaturation of the template, followed by annealing of primers and a short extension time. All subsequent cycle generate annealing between the short fragments generated in previous cycles and different parts of the template. These short fragments and the templates anneal together based on sequence complementarity. This process of fragments annealing template DNA is known as template switching. These annealed fragments will then serve as primers for further extension. This method is carried out until the parental length chimeric gene sequence is obtained. Execution of this method only requires flanking primers to begin. There is also no need for Dnase1 enzyme.
==== Random chimeragenesis on transient templates (RACHITT) ====
This method has been shown to generate chimeric gene libraries with an average of 14 crossovers per chimeric gene. It begins by aligning fragments from a parental top strand onto the bottom strand of a uracil containing template from a homologous gene. 5' and 3' overhang flaps are cleaved and gaps are filled by the exonuclease and endonuclease activities of Pfu and taq DNA polymerases. The uracil containing template is then removed from the heteroduplex by treatment with a uracil DNA glcosylase, followed by further amplification using PCR. This method is advantageous because it generates chimeras with relatively high crossover frequency. However it is somewhat limited due to the complexity and the need for generation of single stranded DNA and uracil containing single stranded template DNA.
==== Synthetic shuffling ====
Shuffling of synthetic degenerate oligonucleotides adds flexibility to shuffling methods, since oligonucleotides containing optimal codons and beneficial mutations can be included.
==== In vivo Homologous Recombination ====
Cloning performed in yeast involves PCR dependent reassembly of fragmented expression vectors. These reassembled vectors are then introduced to, and cloned in yeast. Using yeast to clone the vector avoids toxicity and counter-selection that would be introduced by ligation and propagation in E. coli.
==== Mutagenic organized recombination process by homologous in vivo grouping (MORPHING) ====
This method introduces mutations into specific regions of genes while leaving other parts intact by utilizing the high frequency of homologous recombination in yeast.
==== Phage-assisted continuous evolution (PACE) ====
This method utilizes a bacteriophage with a modified life cycle to transfer evolving genes from host to host. The phage's life cycle is designed in such a way that the transfer is correlated with the activity of interest from the enzyme. This method is advantageous because it requires minimal human intervention for the continuous evolution of the gene.
=== In vitro non-homologous recombination methods ===
These methods are based upon the fact that proteins can exhibit similar structural identity while lacking sequence homology.
=== Exon shuffling ===
Exon shuffling is the combination of exons from different proteins by recombination events occurring at introns. Orthologous exon shuffling involves combining exons from orthologous genes from different species. Orthologous domain shuffling involves shuffling of entire protein domains from orthologous genes from different species. Paralogous exon shuffling involves shuffling of exon from different genes from the same species. Paralogous domain shuffling involves shuffling of entire protein domains from paralogous proteins from the same species. Functional homolog shuffling involves shuffling of non-homologous domains which are functional related. All of these processes being with amplification of the desired exons from different genes using chimeric synthetic oligonucleotides. This amplification products are then reassembled into full length genes using primer-less PCR. During these PCR cycles the fragments act as templates and primers. This results in chimeric full length genes, which are then subjected to screening.
==== Incremental truncation for the creation of hybrid enzymes (ITCHY) ====
Fragments of parental genes are created using controlled digestion by exonuclease III. These fragments are blunted using endonuclease, and are ligated to produce hybrid genes. THIOITCHY is a modified ITCHY technique which utilized nucleotide triphosphate analogs such as α-phosphothioate dNTPs. Incorporation of these nucleotides blocks digestion by exonuclease III. This inhibition of digestion by exonuclease III is called spiking. Spiking can be accomplished by first truncating genes with exonuclease to create fragments with short single stranded overhangs. These fragments then serve as templates for amplification by DNA polymerase in the presence of small amounts of phosphothioate dNTPs. These resulting fragments are then ligated together to form full length genes. Alternatively the intact parental genes can be amplified by PCR in the presence of normal dNTPs and phosphothioate dNTPs. These full length amplification products are then subjected to digestion by an exonuclease. Digestion will continue until the exonuclease encounters an α-pdNTP, resulting in fragments of different length. These fragments are then ligated together to generate chimeric genes.
==== SCRATCHY ====
This method generates libraries of hybrid genes inhibiting multiple crossovers by combining DNA shuffling and ITCHY. This method begins with the construction of two independent ITCHY libraries. The first with gene A on the N-terminus. And the other having gene B on the N-terminus. These hybrid gene fragments are separated using either restriction enzyme digestion or PCR with terminus primers via agarose gel electrophoresis. These isolated fragments are then mixed together and further digested using DNase1. Digested fragments are then reassembled by primerless PCR with template switching.
==== Recombined extension on truncated templates (RETT) ====
This method generates libraries of hybrid genes by template switching of uni-directionally growing polynucleotides in the presence of single stranded DNA fragments as templates for chimeras. This method begins with the preparation of single stranded DNA fragments by reverse transcription from target mRNA. Gene specific primers are then annealed to the single stranded DNA. These genes are then extended during a PCR cycle. This cycle is followed by template switching and annealing of the short fragments obtained from the earlier primer extension to other single stranded DNA fragments. This process is repeated until full length single stranded DNA is obtained.
==== Sequence homology-independent protein recombination (SHIPREC) ====
This method generates recombination between genes with little to no sequence homology. These chimeras are fused via a linker sequence containing several restriction sites. This construct is then digested using DNase1. Fragments are made are made blunt ended using S1 nuclease. These blunt end fragments are put together into a circular sequence by ligation. This circular construct is then linearized using restriction enzymes for which the restriction sites are present in the linker region. This results in a library of chimeric genes in which contribution of genes to 5' and 3' end will be reversed as compared to the starting construct.
==== Sequence independent site directed chimeragenesis (SISDC) ====
This method results in a library of genes with multiple crossovers from several parental genes. This method does not require sequence identity among the parental genes. This does require one or two conserved amino acids at every crossover position. It begins with alignment of parental sequences and identification of consensus regions which serve as crossover sites. This is followed by the incorporation of specific tags containing restriction sites followed by the removal of the tags by digestion with Bac1, resulting in genes with cohesive ends. These gene fragments are mixed and ligated in an appropriate order to form chimeric libraries.
==== Degenerate homo-duplex recombination (DHR) ====
This method begins with alignment of homologous genes, followed by identification of regions of polymorphism. Next the top strand of the gene is divided into small degenerate oligonucleotides. The bottom strand is also digested into oligonucleotides to serve as scaffolds. These fragments are combined in solution are top strand oligonucleotides are assembled onto bottom strand oligonucleotides. Gaps between these fragments are filled with polymerase and ligated.
==== Random multi-recombinant PCR (RM-PCR) ====
This method involves the shuffling of plural DNA fragments without homology, in a single PCR. This results in the reconstruction of complete proteins by assembly of modules encoding different structural units.
==== User friendly DNA recombination (USERec) ====
This method begins with the amplification of gene fragments which need to be recombined, using uracil dNTPs. This amplification solution also contains primers, PfuTurbo, and Cx Hotstart DNA polymerase. Amplified products are next incubated with USER enzyme. This enzyme catalyzes the removal of uracil residues from DNA creating single base pair gaps. The USER enzyme treated fragments are mixed and ligated using T4 DNA ligase and subjected to Dpn1 digestion to remove the template DNA. These resulting dingle stranded fragments are subjected to amplification using PCR, and are transformed into E. coli.
==== Golden Gate shuffling (GGS) recombination ====
This method allows you to recombine at least 9 different fragments in an acceptor vector by using type 2 restriction enzyme which cuts outside of the restriction sites. It begins with sub cloning of fragments in separate vectors to create Bsa1 flanking sequences on both sides. These vectors are then cleaved using type II restriction enzyme Bsa1, which generates four nucleotide single strand overhangs. Fragments with complementary overhangs are hybridized and ligated using T4 DNA ligase. Finally these constructs are then transformed into E. coli cells, which are screened for expression levels.
==== Phosphoro thioate-based DNA recombination method (PRTec) ====
This method can be used to recombine structural elements or entire protein domains. This method is based on phosphorothioate chemistry which allows the specific cleavage of phosphorothiodiester bonds. The first step in the process begins with amplification of fragments that need to be recombined along with the vector backbone. This amplification is accomplished using primers with phosphorothiolated nucleotides at 5' ends. Amplified PCR products are cleaved in an ethanol-iodine solution at high temperatures. Next these fragments are hybridized at room temperature and transformed into E. coli which repair any nicks.
==== Integron ====
This system is based upon a natural site specific recombination system in E. coli. This system is called the integron system, and produces natural gene shuffling. This method was used to construct and optimize a functional tryptophan biosynthetic operon in trp-deficient E. coli by delivering individual recombination cassettes or trpA-E genes along with regulatory elements with the integron system.
==== Y-Ligation based shuffling (YLBS) ====
This method generates single stranded DNA strands, which encompass a single block sequence either at the 5' or 3' end, complementary sequences in a stem loop region, and a D branch region serving as a primer binding site for PCR. Equivalent amounts of both 5' and 3' half strands are mixed and formed a hybrid due to the complementarity in the stem region. Hybrids with free phosphorylated 5' end in 3' half strands are then ligated with free 3' ends in 5' half strands using T4 DNA ligase in the presence of 0.1 mM ATP. Ligated products are then amplified by two types of PCR to generate pre 5' half and pre 3' half PCR products. These PCR product are converted to single strands via avidin-biotin binding to the 5' end of the primes containing stem sequences that were biotin labeled. Next, biotinylated 5' half strands and non-biotinylated 3' half strands are used as 5' and 3' half strands for the next Y-ligation cycle.
== Semi-rational design ==
Semi-rational design uses information about a proteins sequence, structure and function, in tandem with predictive algorithms. Together these are used to identify target amino acid residues which are most likely to influence protein function. Mutations of these key amino acid residues create libraries of mutant proteins that are more likely to have enhanced properties.
Advances in semi-rational enzyme engineering and de novo enzyme design provide researchers with powerful and effective new strategies to manipulate biocatalysts. Integration of sequence and structure based approaches in library design has proven to be a great guide for enzyme redesign. Generally, current computational de novo and redesign methods do not compare to evolved variants in catalytic performance. Although experimental optimization may be produced using directed evolution, further improvements in the accuracy of structure predictions and greater catalytic ability will be achieved with improvements in design algorithms. Further functional enhancements may be included in future simulations by integrating protein dynamics.
Biochemical and biophysical studies, along with fine-tuning of predictive frameworks will be useful to experimentally evaluate the functional significance of individual design features. Better understanding of these functional contributions will then give feedback for the improvement of future designs.
Directed evolution will likely not be replaced as the method of choice for protein engineering, although computational protein design has fundamentally changed the way protein engineering can manipulate bio-macromolecules. Smaller, more focused and functionally-rich libraries may be generated by using in methods which incorporate predictive frameworks for hypothesis-driven protein engineering. New design strategies and technical advances have begun a departure from traditional protocols, such as directed evolution, which represents the most effective strategy for identifying top-performing candidates in focused libraries. Whole-gene library synthesis is replacing shuffling and mutagenesis protocols for library preparation. Also highly specific low throughput screening assays are increasingly applied in place of monumental screening and selection efforts of millions of candidates. Together, these developments are poised to take protein engineering beyond directed evolution and towards practical, more efficient strategies for tailoring biocatalysts.
== Screening and selection techniques ==
Once a protein has undergone directed evolution, ration design or semi-ration design, the libraries of mutant proteins must be screened to determine which mutants show enhanced properties. Phage display methods are one option for screening proteins. This method involves the fusion of genes encoding the variant polypeptides with phage coat protein genes. Protein variants expressed on phage surfaces are selected by binding with immobilized targets in vitro. Phages with selected protein variants are then amplified in bacteria, followed by the identification of positive clones by enzyme linked immunosorbent assay. These selected phages are then subjected to DNA sequencing.
Cell surface display systems can also be utilized to screen mutant polypeptide libraries. The library mutant genes are incorporated into expression vectors which are then transformed into appropriate host cells. These host cells are subjected to further high throughput screening methods to identify the cells with desired phenotypes.
Cell free display systems have been developed to exploit in vitro protein translation or cell free translation. These methods include mRNA display, ribosome display, covalent and non covalent DNA display, and in vitro compartmentalization.: 53
=== Enzyme engineering ===
Enzyme engineering is the application of modifying an enzyme's structure (and, thus, its function) or modifying the catalytic activity of isolated enzymes to produce new metabolites, to allow new (catalyzed) pathways for reactions to occur, or to convert from certain compounds into others (biotransformation). These products are useful as chemicals, pharmaceuticals, fuel, food, or agricultural additives.
An enzyme reactor consists of a vessel containing a reactional medium that is used to perform a desired conversion by enzymatic means. Enzymes used in this process are free in the solution. Also Microorganisms are one of important origin for genuine enzymes .
== Examples of engineered proteins ==
Computing methods have been used to design a protein with a novel fold, such as Top7, and sensors for unnatural molecules. The engineering of fusion proteins has yielded rilonacept, a pharmaceutical that has secured Food and Drug Administration (FDA) approval for treating cryopyrin-associated periodic syndrome.
Another computing method, IPRO, successfully engineered the switching of cofactor specificity of Candida boidinii xylose reductase. Iterative Protein Redesign and Optimization (IPRO) redesigns proteins to increase or give specificity to native or novel substrates and cofactors. This is done by repeatedly randomly perturbing the structure of the proteins around specified design positions, identifying the lowest energy combination of rotamers, and determining whether the new design has a lower binding energy than prior ones. The iterative nature of this process allows IPRO to make additive mutations to a protein sequence that collectively improve the specificity toward desired substrates and/or cofactors.
Computation-aided design has also been used to engineer complex properties of a highly ordered nano-protein assembly. A protein cage, E. coli bacterioferritin (EcBfr), which naturally shows structural instability and an incomplete self-assembly behavior by populating two oligomerization states, is the model protein in this study. Through computational analysis and comparison to its homologs, it has been found that this protein has a smaller-than-average dimeric interface on its two-fold symmetry axis due mainly to the existence of an interfacial water pocket centered on two water-bridged asparagine residues. To investigate the possibility of engineering EcBfr for modified structural stability, a semi-empirical computational method is used to virtually explore the energy differences of the 480 possible mutants at the dimeric interface relative to the wild type EcBfr. This computational study also converges on the water-bridged asparagines. Replacing these two asparagines with hydrophobic amino acids results in proteins that fold into alpha-helical monomers and assemble into cages as evidenced by circular dichroism and transmission electron microscopy. Both thermal and chemical denaturation confirm that, all redesigned proteins, in agreement with the calculations, possess increased stability. One of the three mutations shifts the population in favor of the higher order oligomerization state in solution as shown by both size exclusion chromatography and native gel electrophoresis.
A in silico method, PoreDesigner, was developed to redesign bacterial channel protein (OmpF) to reduce its 1 nm pore size to any desired sub-nm dimension. Transport experiments on the narrowest designed pores revealed complete salt rejection when assembled in biomimetic block-polymer matrices.
== See also ==
== References ==
== External links ==
servers for protein engineering and related topics based on the WHAT IF software
Enzymes Built from Scratch – Researchers engineer never-before-seen catalysts using a new computational technique, Technology Review, March 10, 2008 | Wikipedia/Protein_engineering |
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesis is most commonly performed by ribosomes in cells. Peptides can also be synthesized in the laboratory. Protein primary structures can be directly sequenced, or inferred from DNA sequences.
== Formation ==
=== Biological ===
Amino acids are polymerised via peptide bonds to form a long backbone, with the different amino acid side chains protruding along it. In biological systems, proteins are produced during translation by a cell's ribosomes. Some organisms can also make short peptides by non-ribosomal peptide synthesis, which often use amino acids other than the encoded 22, and may be cyclised, modified and cross-linked.
=== Chemical ===
Peptides can be synthesised chemically via a range of laboratory methods. Chemical methods typically synthesise peptides in the opposite order (starting at the C-terminus) to biological protein synthesis (starting at the N-terminus).
== Notation ==
Protein sequence is typically notated as a string of letters, listing the amino acids starting at the amino-terminal end through to the carboxyl-terminal end. Either a three letter code or single letter code can be used to represent the 22 naturally encoded amino acids, as well as mixtures or ambiguous amino acids (similar to nucleic acid notation).
Peptides can be directly sequenced, or inferred from DNA sequences. Large sequence databases now exist that collate known protein sequences.
== Modification ==
In general, polypeptides are unbranched polymers, so their primary structure can often be specified by the sequence of amino acids along their backbone. However, proteins can become cross-linked, most commonly by disulfide bonds, and the primary structure also requires specifying the cross-linking atoms, e.g., specifying the cysteines involved in the protein's disulfide bonds. Other crosslinks include desmosine.
=== Isomerisation ===
The chiral centers of a polypeptide chain can undergo racemization. Although it does not change the sequence, it does affect the chemical properties of the sequence. In particular, the L-amino acids normally found in proteins can spontaneously isomerize at the
C
α
{\displaystyle \mathrm {C^{\alpha }} }
atom to form D-amino acids, which cannot be cleaved by most proteases. Additionally, proline can form stable trans-isomers at the peptide bond.
=== Post-translational modification ===
Additionally, the protein can undergo a variety of post-translational modifications, which are briefly summarized here.
The N-terminal amino group of a polypeptide can be modified covalently, e.g.,
acetylation
−
C
(
=
O
)
−
C
H
3
{\displaystyle \mathrm {-C(=O)-CH_{3}} }
The positive charge on the N-terminal amino group may be eliminated by changing it to an acetyl group (N-terminal blocking).
formylation
−
C
(
=
O
)
H
{\displaystyle \mathrm {-C(=O)H} }
The N-terminal methionine usually found after translation has an N-terminus blocked with a formyl group. This formyl group (and sometimes the methionine residue itself, if followed by Gly or Ser) is removed by the enzyme deformylase.
pyroglutamate
An N-terminal glutamine can attack itself, forming a cyclic pyroglutamate group.
myristoylation
−
C
(
=
O
)
−
(
C
H
2
)
12
−
C
H
3
{\displaystyle \mathrm {-C(=O)-\left(CH_{2}\right)_{12}-CH_{3}} }
Similar to acetylation. Instead of a simple methyl group, the myristoyl group has a tail of 14 hydrophobic carbons, which make it ideal for anchoring proteins to cellular membranes.
The C-terminal carboxylate group of a polypeptide can also be modified, e.g.,
amination (see Figure)
The C-terminus can also be blocked (thus, neutralizing its negative charge) by amination.
glycosyl phosphatidylinositol (GPI) attachment
Glycosyl phosphatidylinositol(GPI) is a large, hydrophobic phospholipid prosthetic group that anchors proteins to cellular membranes. It is attached to the polypeptide C-terminus through an amide linkage that then connects to ethanolamine, thence to sundry sugars and finally to the phosphatidylinositol lipid moiety.
Finally, the peptide side chains can also be modified covalently, e.g.,
phosphorylation
Aside from cleavage, phosphorylation is perhaps the most important chemical modification of proteins. A phosphate group can be attached to the sidechain hydroxyl group of serine, threonine and tyrosine residues, adding a negative charge at that site and producing an unnatural amino acid. Such reactions are catalyzed by kinases and the reverse reaction is catalyzed by phosphatases. The phosphorylated tyrosines are often used as "handles" by which proteins can bind to one another, whereas phosphorylation of Ser/Thr often induces conformational changes, presumably because of the introduced negative charge. The effects of phosphorylating Ser/Thr can sometimes be simulated by mutating the Ser/Thr residue to glutamate.
glycosylation
A catch-all name for a set of very common and very heterogeneous chemical modifications. Sugar moieties can be attached to the sidechain hydroxyl groups of Ser/Thr or to the sidechain amide groups of Asn. Such attachments can serve many functions, ranging from increasing solubility to complex recognition. All glycosylation can be blocked with certain inhibitors, such as tunicamycin.
deamidation (succinimide formation)
In this modification, an asparagine or aspartate side chain attacks the following peptide bond, forming a symmetrical succinimide intermediate. Hydrolysis of the intermediate produces either aspartate or the β-amino acid, iso(Asp). For asparagine, either product results in the loss of the amide group, hence "deamidation".
hydroxylation
Proline residues may be hydroxylated at either of two atoms, as can lysine (at one atom). Hydroxyproline is a critical component of collagen, which becomes unstable upon its loss. The hydroxylation reaction is catalyzed by an enzyme that requires ascorbic acid (vitamin C), deficiencies in which lead to many connective-tissue diseases such as scurvy.
methylation
Several protein residues can be methylated, most notably the positive groups of lysine and arginine. Arginine residues interact with the nucleic acid phosphate backbone and commonly form hydrogen bonds with the base residues, particularly guanine, in protein–DNA complexes. Lysine residues can be singly, doubly and even triply methylated. Methylation does not alter the positive charge on the side chain, however.
acetylation
Acetylation of the lysine amino groups is chemically analogous to the acetylation of the N-terminus. Functionally, however, the acetylation of lysine residues is used to regulate the binding of proteins to nucleic acids. The cancellation of the positive charge on the lysine weakens the electrostatic attraction for the (negatively charged) nucleic acids.
sulfation
Tyrosines may become sulfated on their
O
η
{\displaystyle \mathrm {O^{\eta }} }
atom. Somewhat unusually, this modification occurs in the Golgi apparatus, not in the endoplasmic reticulum. Similar to phosphorylated tyrosines, sulfated tyrosines are used for specific recognition, e.g., in chemokine receptors on the cell surface. As with phosphorylation, sulfation adds a negative charge to a previously neutral site.
prenylation and palmitoylation
−
C
(
=
O
)
−
(
C
H
2
)
14
−
C
H
3
{\displaystyle \mathrm {-C(=O)-\left(CH_{2}\right)_{14}-CH_{3}} }
The hydrophobic isoprene (e.g., farnesyl, geranyl, and geranylgeranyl groups) and palmitoyl groups may be added to the
S
γ
{\displaystyle \mathrm {S^{\gamma }} }
atom of cysteine residues to anchor proteins to cellular membranes. Unlike the GPI and myritoyl anchors, these groups are not necessarily added at the termini.
carboxylation
A relatively rare modification that adds an extra carboxylate group (and, hence, a double negative charge) to a glutamate side chain, producing a Gla residue. This is used to strengthen the binding to "hard" metal ions such as calcium.
ADP-ribosylation
The large ADP-ribosyl group can be transferred to several types of side chains within proteins, with heterogeneous effects. This modification is a target for the powerful toxins of disparate bacteria, e.g., Vibrio cholerae, Corynebacterium diphtheriae and Bordetella pertussis.
ubiquitination and SUMOylation
Various full-length, folded proteins can be attached at their C-termini to the sidechain ammonium groups of lysines of other proteins. Ubiquitin is the most common of these, and usually signals that the ubiquitin-tagged protein should be degraded.
Most of the polypeptide modifications listed above occur post-translationally, i.e., after the protein has been synthesized on the ribosome, typically occurring in the endoplasmic reticulum, a subcellular organelle of the eukaryotic cell.
Many other chemical reactions (e.g., cyanylation) have been applied to proteins by chemists, although they are not found in biological systems.
=== Cleavage and ligation ===
In addition to those listed above, the most important modification of primary structure is peptide cleavage (by chemical hydrolysis or by proteases). Proteins are often synthesized in an inactive precursor form; typically, an N-terminal or C-terminal segment blocks the active site of the protein, inhibiting its function. The protein is activated by cleaving off the inhibitory peptide.
Some proteins even have the power to cleave themselves. Typically, the hydroxyl group of a serine (rarely, threonine) or the thiol group of a cysteine residue will attack the carbonyl carbon of the preceding peptide bond, forming a tetrahedrally bonded intermediate [classified as a hydroxyoxazolidine (Ser/Thr) or hydroxythiazolidine (Cys) intermediate]. This intermediate tends to revert to the amide form, expelling the attacking group, since the amide form is usually favored by free energy, (presumably due to the strong resonance stabilization of the peptide group). However, additional molecular interactions may render the amide form less stable; the amino group is expelled instead, resulting in an ester (Ser/Thr) or thioester (Cys) bond in place of the peptide bond. This chemical reaction is called an N-O acyl shift.
The ester/thioester bond can be resolved in several ways:
Simple hydrolysis will split the polypeptide chain, where the displaced amino group becomes the new N-terminus. This is seen in the maturation of glycosylasparaginase.
A β-elimination reaction also splits the chain, but results in a pyruvoyl group at the new N-terminus. This pyruvoyl group may be used as a covalently attached catalytic cofactor in some enzymes, especially decarboxylases such as S-adenosylmethionine decarboxylase (SAMDC) that exploit the electron-withdrawing power of the pyruvoyl group.
Intramolecular transesterification, resulting in a branched polypeptide. In inteins, the new ester bond is broken by an intramolecular attack by the soon-to-be C-terminal asparagine.
Intermolecular transesterification can transfer a whole segment from one polypeptide to another, as is seen in the Hedgehog protein autoprocessing.
== Sequence compression ==
The compression of amino acid sequences is a comparatively challenging task. The existing specialized amino acid sequence compressors are low compared with that of DNA sequence compressors, mainly because of the characteristics of the data. For example, modeling inversions is harder because of the reverse information loss (from amino acids to DNA sequence). The current lossless data compressor that provides higher compression is AC2. AC2 mixes various context models using Neural Networks and encodes the data using arithmetic encoding.
== History ==
The proposal that proteins were linear chains of α-amino acids was made nearly simultaneously by two scientists at the same conference in 1902, the 74th meeting of the Society of German Scientists and Physicians, held in Karlsbad. Franz Hofmeister made the proposal in the morning, based on his observations of the biuret reaction in proteins. Hofmeister was followed a few hours later by Emil Fischer, who had amassed a wealth of chemical details supporting the peptide-bond model. For completeness, the proposal that proteins contained amide linkages was made as early as 1882 by the French chemist E. Grimaux.
Despite these data and later evidence that proteolytically digested proteins yielded only oligopeptides, the idea that proteins were linear, unbranched polymers of amino acids was not accepted immediately. Some scientists such as William Astbury doubted that covalent bonds were strong enough to hold such long molecules together; they feared that thermal agitations would shake such long molecules asunder. Hermann Staudinger faced similar prejudices in the 1920s when he argued that rubber was composed of macromolecules.
Thus, several alternative hypotheses arose. The colloidal protein hypothesis stated that proteins were colloidal assemblies of smaller molecules. This hypothesis was disproved in the 1920s by ultracentrifugation measurements by Theodor Svedberg that showed that proteins had a well-defined, reproducible molecular weight and by electrophoretic measurements by Arne Tiselius that indicated that proteins were single molecules. A second hypothesis, the cyclol hypothesis advanced by Dorothy Wrinch, proposed that the linear polypeptide underwent a chemical cyclol rearrangement C=O + HN
→
{\displaystyle \rightarrow }
C(OH)-N that crosslinked its backbone amide groups, forming a two-dimensional fabric. Other primary structures of proteins were proposed by various researchers, such as the diketopiperazine model of Emil Abderhalden and the pyrrol/piperidine model of Troensegaard in 1942. Although never given much credence, these alternative models were finally disproved when Frederick Sanger successfully sequenced insulin and by the crystallographic determination of myoglobin and hemoglobin by Max Perutz and John Kendrew.
== Primary structure in other molecules ==
Any linear-chain heteropolymer can be said to have a "primary structure" by analogy to the usage of the term for proteins, but this usage is rare compared to the extremely common usage in reference to proteins. In RNA, which also has extensive secondary structure, the linear chain of bases is generally just referred to as the "sequence" as it is in DNA (which usually forms a linear double helix with little secondary structure). Other biological polymers such as polysaccharides can also be considered to have a primary structure, although the usage is not standard.
== Relation to secondary and tertiary structure ==
The primary structure of a biological polymer to a large extent determines the three-dimensional shape (tertiary structure). Protein sequence can be used to predict local features, such as segments of secondary structure, or trans-membrane regions. However, the complexity of protein folding currently prohibits predicting the tertiary structure of a protein from its sequence alone. Knowing the structure of a similar homologous sequence (for example a member of the same protein family) allows highly accurate prediction of the tertiary structure by homology modeling. If the full-length protein sequence is available, it is possible to estimate its general biophysical properties, such as its isoelectric point.
Sequence families are often determined by sequence clustering, and structural genomics projects aim to produce a set of representative structures to cover the sequence space of possible non-redundant sequences.
== See also ==
Protein sequencing
Nucleic acid primary structure
Translation
Pseudo amino acid composition
== Notes and references == | Wikipedia/Protein_primary_structure |
A saturated fat is a type of fat in which the fatty acid chains have all single bonds between the carbon atoms. A fat known as a glyceride is made of two kinds of smaller molecules: a short glycerol backbone, and fatty acids that each contain a long linear or branched chain of carbon (C) atoms. Along the chain, some carbon atoms are linked by single bonds (-C-C-) and others are linked by double bonds (-C=C-). A double bond along the carbon chain can react with a pair of hydrogen atoms to change into a single -C-C- bond, with each H atom now bonded to one of the two C atoms. Glyceride fats without any carbon chain double bonds are called saturated because they are "saturated with" hydrogen atoms, having no double bonds available to react with more hydrogen. Saturated fats are generally solid. All fats, both saturated and unsaturated, contain 9kcal per gram making them more energy dense than both proteins and carbohydrates.
Most animal fats are saturated. The fats of plants and fish are generally unsaturated. Various foods contain different proportions of saturated and unsaturated. Many processed foods, like foods deep-fried in hydrogenated oil and sausages, are high in saturated fat content. Some store-bought baked goods are as well, especially those containing partially hydrogenated oils. Other examples of foods containing a high proportion of saturated fat and dietary cholesterol include animal fat products such as lard or schmaltz, fatty meats and dairy products made with whole or reduced fat milk like yogurt, ice cream, cheese and butter. Certain vegetable products have high saturated fat content, such as coconut oil and palm kernel oil.
Guidelines released by many medical organizations, including the World Health Organization, have advocated for reduction in the intake of saturated fat to promote health and reduce the risk from cardiovascular diseases.
== Fat profiles ==
While nutrition labels regularly combine them, the saturated fatty acids appear in different proportions among food groups. Lauric and myristic acids are most commonly found in "tropical" oils (e.g., palm kernel, coconut) and dairy products. The saturated fat in meat, eggs, cacao, and nuts is primarily the triglycerides of palmitic and stearic acids.
== Examples of saturated fatty acids ==
Some common examples of saturated fatty acids:
Lauric acid with 12 carbon atoms (contained in coconut oil, palm kernel oil, cow's milk, and breast milk)
Myristic acid with 14 carbon atoms (contained in cow's milk and dairy products)
Palmitic acid with 16 carbon atoms (contained in palm oil and meat)
Stearic acid with 18 carbon atoms (also contained in meat and cocoa butter)
== Association with diseases ==
=== Cardiovascular disease ===
The effect of saturated fat on heart disease has been extensively studied. Saturated fat intake increases low-density lipoprotein cholesterol (LDL-C) concentrations. The American Heart Association have stated that "the scientific rationale for decreasing saturated fat in the diet has been and remains based on well-established effects of saturated fat to raise low-density lipoprotein (LDL) cholesterol, a leading cause of atherosclerosis".
Many health authorities, such as the American Heart Association, the Academy of Nutrition and Dietetics, the British Dietetic Association, the World Heart Federation, the British National Health Service, among others, advise that saturated fat is a risk factor for cardiovascular diseases. In 2020, the World Health Organization recommended lowering dietary intake of saturated fats to less than 10% of total energy consumption, and increasing intake of unsaturated fats. There is moderate-quality evidence that reducing the proportion of saturated fat in the diet and replacing it with unsaturated fats or carbohydrates for a period of at least two years leads to a reduction in the risk of cardiovascular disease.
A 2017 review by the Sax Institute for the National Heart Foundation of Australia found that saturated fat consumption is associated with higher mortality and that replacement of saturated fat with polyunsaturated fat decreases risk of cardiovascular disease events and mortality. In 2019, the UK Scientific Advisory Committee on Nutrition concluded that higher saturated fat consumption is associated with raised blood cholesterol and increased risk of cardiovascular disease.
A 2021 review found that diets high in saturated fat were associated with higher mortality from all causes, as well as from cardiovascular disease.
A 2023 review by the World Health Organization found convincing evidence that higher saturated fat consumption is associated with higher coronary heart disease incidence and mortality.
A 2023 review by the Academy of Nutrition and Dietetics found moderate certainty evidence to support reducing saturated fat intake for reduced risk of CVD and CVD events.
A scoping review for Nordic Nutrition Recommendations 2023 found that partial replacement of saturated fatty acid with omega-6 fatty acid decreases the risk of cardiovascular disease and improves the blood lipid profile.
A 2024 meta-analysis found that odd-chain and longer-chain saturated fatty acids were negatively associated with the risk of cardiovascular disease, including stroke.
=== Dyslipidemia ===
The consumption of saturated fat is generally considered a risk factor for dyslipidemia, which in turn is a risk factor for some types of cardiovascular disease.
Abnormal blood lipid levels – high total cholesterol, high levels of triglycerides, high levels of low-density lipoprotein (LDL) or low levels of high-density lipoprotein (HDL) cholesterol – are associated with increased risk of heart disease and stroke.
Meta-analyses have found a significant relationship between saturated fat and serum cholesterol levels. High total cholesterol levels, which may be caused by many factors, are associated with an increased risk of cardiovascular disease.
There are other pathways involving obesity, triglyceride levels, insulin sensitivity, endothelial function, and thrombogenicity, among others, that play a role in cardiovascular disease. Different saturated fatty acids have differing effects on various lipid levels. There is strong evidence that lauric, myristic, and palmitic acids raise LDL-C, while stearic acid is more neutral.
=== Type 2 diabetes ===
A 2022 review of cohort studies found that the risk of type 2 diabetes was not associated with dietary intake of total saturated fats, palmitic acid, and stearic acid. Dietary lauric acid and myristic acid, present in plant oils and also in dairy fat, were associated with reduced risk of diabetes.
=== Cancer ===
Several reviews of case–control studies have found that saturated fat intake is associated with breast cancer risk and mortality. Observational studies have shown that a diet high in saturated fat is associated with increased prostate cancer risk.
A 2024 systematic review found that higher levels of myristic acid, palmitic acid and stearic acid are associated with increased cancer risk.
== Dietary sources ==
== Dietary recommendations ==
Recommendations to reduce, limit or replace dietary intake of trans fats and saturated fats, in favor of unsaturated fats, are made by the World Health Organization, American Heart Association, Health Canada, the US Department of Health and Human Services, the UK National Health Service, the UK Scientific Advisory Committee on Nutrition, the Australian Department of Health and Aging, the Singapore Ministry of Health, the Indian Ministry of Health and Family Welfare, the New Zealand Ministry of Health, and Hong Kong's Department of Health.
In 2003, the World Health Organization (WHO) and Food and Agriculture Organization (FAO) expert consultation report concluded:
The evidence shows that intake of saturated fatty acids is directly related to cardiovascular risk. The traditional target is to restrict the intake of saturated fatty acids to less than 10% of daily energy intake and less than 7% for high-risk groups. If populations are consuming less than 10%, they should not increase that level of intake. Within these limits, the intake of foods rich in myristic and palmitic acids should be replaced by fats with a lower content of these particular fatty acids. In developing countries, however, where energy intake for some population groups may be inadequate, energy expenditure is high and body fat stores are low (BMI <18.5 kg/m2). The amount and quality of fat supply have to be considered keeping in mind the need to meet energy requirements. Specific sources of saturated fat, such as coconut and palm oil, provide low-cost energy and may be an important source of energy for the poor.
A 2004 statement released by the Centers for Disease Control (CDC) determined that "Americans need to continue working to reduce saturated fat intake…" In addition, reviews by the American Heart Association led the Association to recommend reducing saturated fat intake to less than 7% of total calories according to its 2006 recommendations. This concurs with similar conclusions made by the US Department of Health and Human Services, which determined that reduction in saturated fat consumption would positively affect health and reduce the prevalence of heart disease.
The United Kingdom, National Health Service claims the majority of British people eat too much saturated fat. The British Heart Foundation also advises people to cut down on saturated fat, and to read labels on the food they buy. The British Nutrition Foundation have said that based on the totality of available evidence the saturated fatty acids should make up no more than 10% of total dietary energy.
A 2004 review stated that "no lower safe limit of specific saturated fatty acid intakes has been identified" and recommended that the influence of varying saturated fatty acid intakes against a background of different individual lifestyles and genetic backgrounds should be the focus in future studies.
Blanket recommendations to lower saturated fat were criticized at a 2010 conference debate of the American Dietetic Association for focusing too narrowly on reducing saturated fats rather than emphasizing increased consumption of healthy fats and unrefined carbohydrates. Concern was expressed over the health risks of replacing saturated fats in the diet with refined carbohydrates, which carry a high risk of obesity and heart disease, particularly at the expense of polyunsaturated fats which may have health benefits. None of the panelists recommended heavy consumption of saturated fats, emphasizing instead the importance of overall dietary quality to cardiovascular health.
In a 2017 comprehensive review of the literature and clinical trials, the American Heart Association published a recommendation that saturated fat intake be reduced or replaced by products containing monounsaturated and polyunsaturated fats, a dietary adjustment that could reduce the risk of cardiovascular diseases by 30%.
== Molecular description ==
The two-dimensional illustration has implicit hydrogen atoms bonded to each of the carbon atoms in the polycarbon tail of the myristic acid molecule (there are 13 carbon atoms in the tail; 14 carbon atoms in the entire molecule).
Carbon atoms are also implicitly drawn, as they are portrayed as intersections between two straight lines. "Saturated," in general, refers to a maximum number of hydrogen atoms bonded to each carbon of the polycarbon tail as allowed by the Octet Rule. This also means that only single bonds (sigma bonds) will be present between adjacent carbon atoms of the tail.
== See also ==
== Notes ==
== References == | Wikipedia/Saturated_fat |
In biochemistry, equilibrium unfolding is the process of unfolding a protein or RNA molecule by gradually changing its environment, such as by changing the temperature or pressure, pH, adding chemical denaturants, or applying force as with an atomic force microscope tip. If the equilibrium was maintained at all steps, the process theoretically should be reversible during equilibrium folding. Equilibrium unfolding can be used to determine the thermodynamic stability of the protein or RNA structure, i.e. free energy difference between the folded and unfolded states.
== Theoretical background ==
In its simplest form, equilibrium unfolding assumes that the molecule may belong to only two thermodynamic states, the folded state (typically denoted N for "native" state) and the unfolded state (typically denoted U). This "all-or-none" model of protein folding was first proposed by Tim Anson in 1945, but is believed to hold only for small, single structural domains of proteins (Jackson, 1998); larger domains and multi-domain proteins often exhibit intermediate states. As usual in statistical mechanics, these states correspond to ensembles of molecular conformations, not just one conformation.
The molecule may transition between the native and unfolded states according to a simple kinetic model
N ⇌ U
with rate constants
k
f
{\displaystyle k_{f}}
and
k
u
{\displaystyle k_{u}}
for the folding (
U
⟶
N
{\displaystyle {\ce {U -> N}}}
) and unfolding (
N
⟶
U
{\displaystyle {\ce {N -> U}}}
) reactions, respectively. The dimensionless equilibrium constant
K
e
q
=
d
e
f
k
u
k
f
=
[
U
]
e
q
[
N
]
e
q
{\displaystyle K_{eq}\ {\stackrel {\mathrm {def} }{=}}\ {\frac {k_{u}}{k_{f}}}={\frac {\left[{\ce {U}}\right]_{eq}}{\left[{\ce {N}}\right]_{eq}}}}
can be used to determine the conformational stability
Δ
G
o
{\displaystyle \Delta G^{o}}
by the equation
Δ
G
o
=
−
R
T
ln
K
e
q
{\displaystyle \Delta G^{o}=-RT\ln K_{eq}}
where
R
{\displaystyle R}
is the gas constant and
T
{\displaystyle T}
is the absolute temperature in kelvin. Thus,
Δ
G
o
{\displaystyle \Delta G^{o}}
is positive if the unfolded state is less stable (i.e., disfavored) relative to the native state.
The most direct way to measure the conformational stability
Δ
G
o
{\displaystyle \Delta G^{o}}
of a molecule with two-state folding is to measure its kinetic rate constants
k
f
{\displaystyle k_{f}}
and
k
u
{\displaystyle k_{u}}
under the solution conditions of interest. However, since protein folding is typically completed in milliseconds, such measurements can be difficult to perform, usually requiring expensive stopped flow or (more recently) continuous-flow mixers to provoke folding with a high time resolution. Dual polarisation interferometry is an emerging technique to directly measure conformational change and
Δ
G
o
{\displaystyle \Delta G^{o}}
.
== Chemical denaturation ==
In the less extensive technique of equilibrium unfolding, the fractions of folded and unfolded molecules (denoted as
p
N
{\displaystyle p_{N}}
and
p
U
{\displaystyle p_{U}}
, respectively) are measured as the solution conditions are gradually changed from those favoring the native state to those favoring the unfolded state, e.g., by adding a denaturant such as guanidinium hydrochloride or urea. (In equilibrium folding, the reverse process is carried out.) Given that the fractions must sum to one and their ratio must be given by the Boltzmann factor, we have
p
N
=
1
1
+
e
−
Δ
G
/
R
T
{\displaystyle p_{N}={\frac {1}{1+e^{-\Delta G/RT}}}}
p
U
=
1
−
p
N
=
e
−
Δ
G
/
R
T
1
+
e
−
Δ
G
/
R
T
=
1
1
+
e
Δ
G
/
R
T
{\displaystyle p_{U}=1-p_{N}={\frac {e^{-\Delta G/RT}}{1+e^{-\Delta G/RT}}}={\frac {1}{1+e^{\Delta G/RT}}}}
Protein stabilities are typically found to vary linearly with the denaturant concentration. A number of models have been proposed to explain this observation prominent among them being the denaturant binding model, solvent-exchange model (both by John Schellman) and the Linear Extrapolation Model (LEM; by Nick Pace). All of the models assume that only two thermodynamic states are populated/de-populated upon denaturation. They could be extended to interpret more complicated reaction schemes.
The denaturant binding model assumes that there are specific but independent sites on the protein molecule (folded or unfolded) to which the denaturant binds with an effective (average) binding constant k. The equilibrium shifts towards the unfolded state at high denaturant concentrations as it has more binding sites for the denaturant relative to the folded state (
Δ
n
{\displaystyle \Delta n}
). In other words, the increased number of potential sites exposed in the unfolded state is seen as the reason for denaturation transitions. An elementary treatment results in the following functional form:
Δ
G
=
Δ
G
w
−
R
T
Δ
n
ln
(
1
+
k
[
D
]
)
{\displaystyle \Delta G=\Delta G_{w}-RT\Delta n\ln \left(1+k[D]\right)}
where
Δ
G
w
{\displaystyle \Delta G_{w}}
is the stability of the protein in water and [D] is the denaturant concentration. Thus the analysis of denaturation data with this model requires 7 parameters:
Δ
G
w
{\displaystyle \Delta G_{w}}
,
Δ
n
{\displaystyle \Delta n}
, k, and the slopes and intercepts of the folded and unfolded state baselines.
The solvent exchange model (also called the ‘weak binding model’ or ‘selective solvation’) of Schellman invokes the idea of an equilibrium between the water molecules bound to independent sites on protein and the denaturant molecules in solution. It has the form:
Δ
G
=
Δ
G
w
−
R
T
Δ
n
ln
(
1
+
(
K
−
1
)
X
D
)
{\displaystyle \Delta G=\Delta G_{w}-RT\Delta n\ln \left(1+(K-1)X_{D}\right)}
where
K
{\displaystyle K}
is the equilibrium constant for the exchange reaction and
X
d
{\displaystyle X_{d}}
is the mole-fraction of the denaturant in solution. This model tries to answer the question of whether the denaturant molecules actually bind to the protein or they seem to be bound just because denaturants occupy about 20-30% of the total solution volume at high concentrations used in experiments, i.e. non-specific effects – and hence the term ‘weak binding’. As in the denaturant-binding model, fitting to this model also requires 7 parameters. One common theme obtained from both these models is that the binding constants (in the molar scale) for urea and guanidinium hydrochloride are small: ~ 0.2
M
−
1
{\displaystyle M^{-1}}
for urea and 0.6
M
−
1
{\displaystyle M^{-1}}
for GuHCl.
Intuitively, the difference in the number of binding sites between the folded and unfolded states is directly proportional to the differences in the accessible surface area. This forms the basis for the LEM which assumes a simple linear dependence of stability on the denaturant concentration. The resulting slope of the plot of stability versus the denaturant concentration is called the m-value. In pure mathematical terms, m-value is the derivative of the change in stabilization free energy upon the addition of denaturant. However, a strong correlation between the accessible surface area (ASA) exposed upon unfolding, i.e. difference in the ASA between the unfolded and folded state of the studied protein (dASA), and the m-value has been documented by Pace and co-workers. In view of this observation, the m-values are typically interpreted as being proportional to the dASA. There is no physical basis for the LEM and it is purely empirical, though it is widely used in interpreting solvent-denaturation data. It has the general form:
Δ
G
=
m
(
[
D
]
1
/
2
−
[
D
]
)
{\displaystyle \Delta G=m\left([D]_{1/2}-[D]\right)}
where the slope
m
{\displaystyle m}
is called the "m-value"(> 0 for the above definition) and
[
D
]
1
/
2
{\displaystyle \left[D\right]_{1/2}}
(also called Cm) represents the denaturant concentration at which 50% of the molecules are folded (the denaturation midpoint of the transition, where
p
N
=
p
U
=
1
/
2
{\displaystyle p_{N}=p_{U}=1/2}
).
In practice, the observed experimental data at different denaturant concentrations are fit to a two-state model with this functional form for
Δ
G
{\displaystyle \Delta G}
, together with linear baselines for the folded and unfolded states. The
m
{\displaystyle m}
and
[
D
]
1
/
2
{\displaystyle \left[D\right]_{1/2}}
are two fitting parameters, along with four others for the linear baselines (slope and intercept for each line); in some cases, the slopes are assumed to be zero, giving four fitting parameters in total. The conformational stability
Δ
G
{\displaystyle \Delta G}
can be calculated for any denaturant concentration (including the stability at zero denaturant) from the fitted parameters
m
{\displaystyle m}
and
[
D
]
1
/
2
{\displaystyle \left[D\right]_{1/2}}
. When combined with kinetic data on folding, the m-value can be used to roughly estimate the amount of buried hydrophobic surface in the folding transition state.
=== Structural probes ===
Unfortunately, the probabilities
p
N
{\displaystyle p_{N}}
and
p
U
{\displaystyle p_{U}}
cannot be measured directly. Instead, we assay the relative population of folded molecules using various structural probes, e.g., absorbance at 287 nm (which reports on the solvent exposure of tryptophan and tyrosine), far-ultraviolet circular dichroism (180-250 nm, which reports on the secondary structure of the protein backbone), dual polarisation interferometry (which reports the molecular size and fold density) and near-ultraviolet fluorescence (which reports on changes in the environment of tryptophan and tyrosine). However, nearly any probe of folded structure will work; since the measurement is taken at equilibrium, there is no need for high time resolution. Thus, measurements can be made of NMR chemical shifts, intrinsic viscosity, solvent exposure (chemical reactivity) of side chains such as cysteine, backbone exposure to proteases, and various hydrodynamic measurements.
To convert these observations into the probabilities
p
N
{\displaystyle p_{N}}
and
p
U
{\displaystyle p_{U}}
, one generally assumes that the observable
A
{\displaystyle A}
adopts one of two values,
A
N
{\displaystyle A_{N}}
or
A
U
{\displaystyle A_{U}}
, corresponding to the native or unfolded state, respectively. Hence, the observed value equals the linear sum
A
=
A
N
p
N
+
A
U
p
U
{\displaystyle A=A_{N}p_{N}+A_{U}p_{U}}
By fitting the observations of
A
{\displaystyle A}
under various solution conditions to this functional form, one can estimate
A
N
{\displaystyle A_{N}}
and
A
U
{\displaystyle A_{U}}
, as well as the parameters of
Δ
G
{\displaystyle \Delta G}
. The fitting variables
A
N
{\displaystyle A_{N}}
and
A
U
{\displaystyle A_{U}}
are sometimes allowed to vary linearly with the solution conditions, e.g., temperature or denaturant concentration, when the asymptotes of
A
{\displaystyle A}
are observed to vary linearly under strongly folding or strongly unfolding conditions.
== Thermal denaturation ==
Assuming a two state denaturation as stated above, one can derive the fundamental thermodynamic parameters namely,
Δ
H
{\displaystyle \Delta H}
,
Δ
S
{\displaystyle \Delta S}
and
Δ
G
{\displaystyle \Delta G}
provided one has knowledge on the
Δ
C
p
{\displaystyle \Delta C_{p}}
of the system under investigation.
The thermodynamic observables of denaturation can be described by the following equations:
Δ
H
(
T
)
=
Δ
H
(
T
d
)
+
∫
T
d
T
Δ
C
p
d
T
=
Δ
H
(
T
d
)
+
Δ
C
p
[
T
−
T
d
]
Δ
S
(
T
)
=
Δ
H
(
T
d
)
T
d
+
∫
T
d
T
Δ
C
p
d
ln
T
=
Δ
H
(
T
d
)
T
d
+
Δ
C
p
ln
T
T
d
Δ
G
(
T
)
=
Δ
H
−
T
Δ
S
=
Δ
H
(
T
d
)
T
d
−
T
T
d
+
∫
T
d
T
Δ
C
p
d
T
−
T
∫
T
d
T
Δ
C
p
d
ln
T
=
Δ
H
(
T
d
)
(
1
−
T
T
d
)
−
Δ
C
p
[
T
d
−
T
+
T
ln
(
T
T
d
)
]
{\displaystyle {\begin{aligned}\Delta H(T)&=\Delta H(T_{d})+\int _{T_{d}}^{T}\Delta C_{p}dT\\&=\Delta H(T_{d})+\Delta C_{p}[T-T_{d}]\\\Delta S(T)&={\frac {\Delta H(T_{d})}{T_{d}}}+\int _{T_{d}}^{T}\Delta C_{p}d\ln T\\&={\frac {\Delta H(T_{d})}{T_{d}}}+\Delta C_{p}\ln {\frac {T}{T_{d}}}\\\Delta G(T)&=\Delta H-T\Delta S\\&=\Delta H(T_{d}){\frac {T_{d}-T}{T_{d}}}+\int _{T_{d}}^{T}\Delta C_{p}dT-T\int _{T_{d}}^{T}\Delta C_{p}d\ln T\\&=\Delta H(T_{d})\left(1-{\frac {T}{T_{d}}}\right)-\Delta C_{p}\left[T_{d}-T+T\ln \left({\frac {T}{T_{d}}}\right)\right]\end{aligned}}}
where
Δ
H
{\displaystyle \ \Delta H}
,
Δ
S
{\displaystyle \ \Delta S}
and
Δ
G
{\displaystyle \ \Delta G}
indicate the enthalpy, entropy and Gibbs free energy of unfolding under a constant pH and pressure. The temperature,
T
{\displaystyle \ T}
is varied to probe the thermal stability of the system and
T
d
{\displaystyle \ T_{d}}
is the temperature at which half of the molecules in the system are unfolded. The last equation is known as the Gibbs–Helmholtz equation.
=== Determining the heat capacity of proteins ===
In principle one can calculate all the above thermodynamic observables from a single differential scanning calorimetry thermogram of the system assuming that the
Δ
C
p
{\displaystyle {\ce {\Delta C_p}}}
is independent of the temperature. However, it is difficult to obtain accurate values for
Δ
C
p
{\displaystyle {\ce {\Delta C_p}}}
this way. More accurately, the
Δ
C
p
{\displaystyle {\ce {\Delta C_p}}}
can be derived from the variations in
Δ
H
(
T
d
)
{\displaystyle {\ce {\Delta H(T_d)}}}
vs.
T
d
{\displaystyle {\ce {T_d}}}
which can be achieved from measurements with slight variations in pH or protein concentration. The slope of the linear fit is equal to the
Δ
C
p
{\displaystyle {\ce {\Delta C_p}}}
. Note that any non-linearity of the datapoints indicates that
Δ
C
p
{\displaystyle \Delta C_{p}}
is probably not independent of the temperature.
Alternatively, the
Δ
C
p
{\displaystyle {\ce {\Delta C_p}}}
can also be estimated from the calculation of the accessible surface area (ASA) of a protein prior and after thermal denaturation as follows:
Δ
ASA
=
ASA
unfolded
−
ASA
native
{\displaystyle {\ce {\Delta ASA}}={\ce {ASA_{unfolded}}}-{\ce {ASA_{native}}}}
For proteins that have a known 3d structure, the
ASA
native
{\displaystyle {\ce {ASA_{native}}}}
can be calculated through computer programs such as Deepview (also known as swiss PDB viewer). The
ASA
unfolded
{\displaystyle {\ce {ASA_{unfolded}}}}
can be calculated from tabulated values of each amino acid through the semi-empirical equation:
ASA
unfolded
=
(
a
polar
×
ASA
polar
)
+
(
a
aromatic
×
ASA
aromatic
)
+
(
a
nonpolar
×
ASA
nonpolar
)
{\displaystyle {\ce {ASA_{unfolded}}}=\left(a_{{\ce {polar}}}\times {\ce {ASA_{polar}}}\right)+\left(a_{{\ce {aromatic}}}\times {\ce {ASA_{aromatic}}}\right)+\left(a_{{\ce {nonpolar}}}\times {\ce {ASA_{nonpolar}}}\right)}
where the subscripts polar, non-polar and aromatic indicate the parts of the 20 naturally occurring amino acids.
Finally for proteins, there is a linear correlation between
Δ
ASA
{\displaystyle {\ce {\Delta ASA}}}
and
Δ
C
p
{\displaystyle {\ce {\Delta C_p}}}
through the following equation:
Δ
C
p
=
0.61
×
Δ
ASA
{\displaystyle {\ce {\Delta C_p}}=0.61\times {\ce {\Delta ASA}}}
=== Assessing two-state unfolding ===
Furthermore, one can assess whether the folding proceeds according to a two-state unfolding as described above. This can be done with differential scanning calorimetry by comparing the calorimetric enthalpy of denaturation i.e. the area under the peak,
A
peak
{\displaystyle A_{\text{peak}}}
to the van 't Hoff enthalpy described as follows:
Δ
H
v
H
(
T
)
=
−
R
d
ln
K
d
T
−
1
{\displaystyle \Delta H_{vH}(T)=-R{\frac {d\ln K}{dT^{-1}}}}
at
T
=
T
d
{\displaystyle T=T_{d}}
the
Δ
H
v
H
(
T
d
)
{\displaystyle \Delta H_{vH}(T_{d})}
can be described as:
Δ
H
v
H
(
T
d
)
=
R
T
d
2
Δ
C
p
max
A
peak
{\displaystyle \Delta H_{vH}(T_{d})={\frac {RT_{d}^{2}\Delta C_{p}^{\max }}{A_{\text{peak}}}}}
When a two-state unfolding is observed the
A
peak
=
Δ
H
v
H
(
T
d
)
{\displaystyle A_{\text{peak}}=\Delta H_{vH}(T_{d})}
. The
Δ
C
p
max
{\displaystyle \Delta C_{p}^{\max }}
is the height of the heat capacity peak.
== Generalization to protein complexes and multi-domain proteins ==
Using the above principles, equations that relate a global protein signal, corresponding to the folding states in equilibrium, and the variable value of a denaturing agent, either temperature or a chemical molecule, have been derived for homomeric and heteromeric proteins, from monomers to trimers and potentially tetramers. These equations provide a robust theoretical basis for measuring the stability of complex proteins, and for comparing the stabilities of wild type and mutant proteins. Such equations cannot be derived for pentamers of higher oligomers because of mathematical limitations (Abel–Ruffini theorem).
== References ==
== Further reading ==
Pace CN. (1975) "The Stability of Globular Proteins", CRC Critical Reviews in Biochemistry, 1-43.
Santoro MM and Bolen DW. (1988) "Unfolding Free Energy Changes Determined by the Linear Extrapolation Method. 1. Unfolding of Phenylmethanesulfonyl α-Chymotrypsin Using Different Denaturants", Biochemistry, 27, 8063–8068.
Privalov PL. (1992) "Physical Basis for the Stability of the Folded Conformations of Proteins", in Protein Folding, TE Creighton, ed., W. H. Freeman, pp. 83–126.
Yao M and Bolen DW. (1995) "How Valid Are Denaturant-Induced Unfolding Free Energy Measurements? Level of Conformance to Common Assumptions over an Extended Range of Ribonuclease A Stability", Biochemistry, 34, 3771–3781.
Jackson SE. (1998) "How do small single-domain proteins fold?", Folding & Design, 3, R81-R91.
Schwehm JM and Stites WE. (1998) "Application of Automated Methods for Determination of Protein Conformational Stability", Methods in Enzymology, 295, 150–170. | Wikipedia/Protein_thermodynamics |
Multi-state modeling of biomolecules refers to a series of techniques used to represent and compute the behaviour of biological molecules or complexes that can adopt a large number of possible functional states.
Biological signaling systems often rely on complexes of biological macromolecules that can undergo several functionally significant modifications that are mutually compatible. Thus, they can exist in a very large number of functionally different states. Modeling such multi-state systems poses two problems: The problem of how to describe and specify a multi-state system (the "specification problem") and the problem of how to use a computer to simulate the progress of the system over time (the "computation problem"). To address the specification problem, modelers have in recent years moved away from explicit specification of all possible states, and towards rule-based modeling that allow for implicit model specification, including the κ-calculus, BioNetGen, the Allosteric Network Compiler and others. To tackle the computation problem, they have turned to particle-based methods that have in many cases proved more computationally efficient than population-based methods based on ordinary differential equations, partial differential equations, or the Gillespie stochastic simulation algorithm. Given current computing technology, particle-based methods are sometimes the only possible option. Particle-based simulators further fall into two categories: Non-spatial simulators such as StochSim, DYNSTOC, RuleMonkey, and NFSim
and spatial simulators, including Meredys, SRSim and MCell. Modelers can thus choose from a variety of tools; the best choice depending on the particular problem. Development of faster and more powerful methods is ongoing, promising the ability to simulate ever more complex signaling processes in the future.
== Introduction ==
=== Multi-state biomolecules in signal transduction ===
In living cells, signals are processed by networks of proteins that can act as complex computational devices. These networks rely on the ability of single proteins to exist in a variety of functionally different states achieved through multiple mechanisms, including post-translational modifications, ligand binding, conformational change, or formation of new complexes. Similarly, nucleic acids can undergo a variety of transformations, including protein binding, binding of other nucleic acids, conformational change and DNA methylation.
In addition, several types of modifications can co-exist, exerting a combined influence on a biological macromolecule at any given time. Thus, a biomolecule or complex of biomolecules can often adopt a very large number of functionally distinct states. The number of states scales exponentially with the number of possible modifications, a phenomenon known as "combinatorial explosion". This is of concern for computational biologists who model or simulate such biomolecules, because it raises questions about how such large numbers of states can be represented and simulated.
=== Examples of combinatorial explosion ===
Biological signaling networks incorporate a wide array of reversible interactions, post-translational modifications and conformational changes. Furthermore, it is common for a protein to be composed of several - identical or nonidentical - subunits, and for several proteins and/or nucleic acid species to assemble into larger complexes. A molecular species with several of those features can therefore exist in a large number of possible states.
For instance, it has been estimated that the yeast scaffold protein Ste5 can be a part of 25666 unique protein complexes. In E. coli, chemotaxis receptors of four different kinds interact in groups of three, and each individual receptor can exist in at least two possible conformations and has up to eight methylation sites, resulting in billions of potential states. The protein kinase CaMKII is a dodecamer of twelve catalytic subunits, arranged in two hexameric rings. Each subunit can exist in at least two distinct conformations, and each subunit features various phosphorylation and ligand binding sites. A recent model incorporated conformational states, two phosphorylation sites and two modes of binding calcium/calmodulin, for a total of around one billion possible states per hexameric ring. A model of coupling of the EGF receptor to a MAP kinase cascade presented by Danos and colleagues accounts for
∼
10
23
{\displaystyle \sim 10^{23}}
distinct molecular species, yet the authors note several points at which the model could be further extended. A more recent model of ErbB receptor signalling even accounts for more than one googol (
10
100
{\displaystyle 10^{100}}
) distinct molecular species. The problem of combinatorial explosion is also relevant to synthetic biology, with a recent model of a relatively simple synthetic eukaryotic gene circuit featuring 187 species and 1165 reactions.
Of course, not all of the possible states of a multi-state molecule or complex will necessarily be populated. Indeed, in systems where the number of possible states is far greater than that of molecules in the compartment (e.g. the cell), they cannot be. In some cases, empirical information can be used to rule out certain states if, for instance, some combinations of features are incompatible. In the absence of such information, however, all possible states need to be considered a priori. In such cases, computational modeling can be used to uncover to what extent the different states are populated.
The existence (or potential existence) of such large numbers of molecular species is a combinatorial phenomenon: It arises from a relatively small set of features or modifications (such as post-translational modification or complex formation) that combine to dictate the state of the entire molecule or complex, in the same way that the existence of just a few choices in a coffee shop (small, medium or large, with or without milk, decaf or not, extra shot of espresso) quickly leads to a large number of possible beverages (24 in this case; each additional binary choice will double that number). Although it is difficult for us to grasp the total numbers of possible combinations, it is usually not conceptually difficult to understand the (much smaller) set of features or modifications and the effect each of them has on the function of the biomolecule. The rate at which a molecule undergoes a particular reaction will usually depend mainly on a single feature or a small subset of features. It is the presence or absence of those features that dictates the reaction rate. The reaction rate is the same for two molecules that differ only in features which do not affect this reaction. Thus, the number of parameters will be much smaller than the number of reactions. (In the coffee shop example, adding an extra shot of espresso will cost 40 cent, no matter what size the beverage is and whether or not it has milk in it). It is such "local rules" that are usually discovered in laboratory experiments. Thus, a multi-state model can be conceptualised in terms of combinations of modular features and local rules. This means that even a model that can account for a vast number of molecular species and reactions is not necessarily conceptually complex.
=== Specification vs computation ===
The combinatorial complexity of signaling systems involving multi-state proteins poses two kinds of problems. The first problem is concerned with how such a system can be specified; i.e. how a modeler can specify all complexes, all changes those complexes undergo and all parameters and conditions governing those changes in a robust and efficient way. This problem is called the "specification problem". The second problem concerns computation. It asks questions about whether a combinatorially complex model, once specified, is computationally tractable, given the large number of states and the even larger number of possible transitions between states, whether it can be stored electronically, and whether it can be evaluated in a reasonable amount of computing time. This problem is called the "computation problem". Among the approaches that have been proposed to tackle combinatorial complexity in multi-state modeling, some are mainly concerned with addressing the specification problem, some are focused on finding effective methods of computation. Some tools address both specification and computation. The sections below discuss rule-based approaches to the specification problem and particle-based approaches to solving the computation problem. A wide range of computational tools exist for multi-state modeling.
== The specification problem ==
=== Explicit specification ===
The most naïve way of specifying, e.g., a protein in a biological model is to specify each of its states explicitly and use each of them as a molecular species in a simulation framework that allows transitions from state to state. For instance, if a protein can be ligand-bound or not, exist in two conformational states (e.g. open or closed) and be located in two possible subcellular areas (e.g. cytosolic or membrane-bound), then the eight possible resulting states can be explicitly enumerated as:
bound, open, cytosol
bound, open, membrane
bound, closed, cytosol
bound, closed, membrane
unbound, open, cytosol
unbound, open, membrane
unbound, closed, cytosol
unbound, closed, membrane
Enumerating all possible states is a lengthy and potentially error-prone process. For macromolecular complexes that can adopt multiple states, enumerating each state quickly becomes tedious, if not impossible. Moreover, the addition of a single additional modification or feature to the model of the complex under investigation will double the number of possible states (if the modification is binary), and it will more than double the number of transitions that need to be specified.
=== Rule-based model specification ===
It is clear that an explicit description, which lists all possible molecular species (including all their possible states), all possible reactions or transitions these species can undergo, and all parameters governing these reactions, very quickly becomes unwieldy as the complexity of the biological system increases. Modelers have therefore looked for implicit, rather than explicit, ways of specifying a biological signaling system. An implicit description is one that groups reactions and parameters that apply to many types of molecular species into one reaction template. It might also add a set of conditions that govern reaction parameters, i.e. the likelihood or rate at which a reaction occurs, or whether it occurs at all. Only properties of the molecule or complex that matter to a given reaction (either affecting the reaction or being affected by it) are explicitly mentioned, and all other properties are ignored in the specification of the reaction.
For instance, the rate of ligand dissociation from a protein might depend on the conformational state of the protein, but not on its subcellular localization. An implicit description would therefore list two dissociation processes (with different rates, depending on conformational state), but would ignore attributes referring to subcellular localization, because they do not affect the rate of ligand dissociation, nor are they affected by it. This specification rule has been summarized as "Don't care, don't write".
Since it is not written in terms of reactions, but in terms of more general "reaction rules" encompassing sets of reactions, this kind of specification is often called "rule-based". This description of the system in terms of modular rules relies on the assumption that only a subset of features or attributes are relevant for a particular reaction rule. Where this assumption holds, a set of reactions can be coarse-grained into one reaction rule. This coarse-graining preserves the important properties of the underlying reactions. For instance, if the reactions are based on chemical kinetics, so are the rules derived from them.
Many rule-based specification methods exist. In general, the specification of a model is a separate task from the execution of the simulation. Therefore, among the existing rule-based model specification systems, some concentrate on model specification only, allowing the user to then export the specified model into a dedicated simulation engine. However, many solutions to the specification problem also contain a method of interpreting the specified model. This is done by providing a method to simulate the model or a method to convert it into a form that can be used for simulations in other programs.
An early rule-based specification method is the κ-calculus, a process algebra that can be used to encode macromolecules with internal states and binding sites and to specify rules by which they interact. The κ-calculus is merely concerned with providing a language to encode multi-state models, not with interpreting the models themselves. A simulator compatible with Kappa is KaSim.
BioNetGen is a software suite that provides both specification and simulation capacities. Rule-based models can be written down using a specified syntax, the BioNetGen language (BNGL). The underlying concept is to represent biochemical systems as graphs, where molecules are represented as nodes (or collections of nodes) and chemical bonds as edges. A reaction rule, then, corresponds to a graph rewriting rule. BNGL provides a syntax for specifying these graphs and the associated rules as structured strings. BioNetGen can then use these rules to generate ordinary differential equations (ODEs) to describe each biochemical reaction. Alternatively, it can generate a list of all possible species and reactions in SBML, which can then be exported to simulation software packages that can read SBML. One can also make use of BioNetGen's own ODE-based simulation software and its capability to generate reactions on-the-fly during a stochastic simulation. In addition, a model specified in BNGL can be read by other simulation software, such as DYNSTOC, RuleMonkey, and NFSim.
Another tool that generates full reaction networks from a set of rules is the Allosteric Network Compiler (ANC). Conceptually, ANC sees molecules as allosteric devices with a Monod-Wyman-Changeux (MWC) type regulation mechanism, whose interactions are governed by their internal state, as well as by external modifications. A very useful feature of ANC is that it automatically computes dependent parameters, thereby imposing thermodynamic correctness.
An extension of the κ-calculus is provided by React(C). The authors of React C show that it can express the stochastic π calculus. They also provide a stochastic simulation algorithm based on the Gillespie stochastic algorithm for models specified in React(C).
ML-Rules is similar to React(C), but provides the added possibility of nesting: A component species of the model, with all its attributes, can be part of a higher-order component species. This enables ML-Rules to capture multi-level models that can bridge the gap between, for instance, a series of biochemical processes and the macroscopic behaviour of a whole cell or group of cells. For instance, a proof-of-concept model of cell division in fission yeast includes cyclin/cdc2 binding and activation, pheromone secretion and diffusion, cell division and movement of cells. Models specified in ML-Rules can be simulated using the James II simulation framework. A similar nested language to represent multi-level biological systems has been proposed by Oury and Plotkin. A specification formalism based on molecular finite automata (MFA) framework can then be used to generate and simulate a system of ODEs or for stochastic simulation using a kinetic Monte Carlo algorithm.
Some rule-based specification systems and their associated network generation and simulation tools have been designed to accommodate spatial heterogeneity, in order to allow for the realistic simulation of interactions within biological compartments. For instance, the Simmune project includes a spatial component: Users can specify their multi-state biomolecules and interactions within membranes or compartments of arbitrary shape. The reaction volume is then divided into interfacing voxels, and a separate reaction network generated for each of these subvolumes.
The Stochastic Simulator Compiler (SSC) allows for rule-based, modular specification of interacting biomolecules in regions of arbitrarily complex geometries. Again, the system is represented using graphs, with chemical interactions or diffusion events formalised as graph-rewriting rules. The compiler then generates the entire reaction network before launching a stochastic reaction-diffusion algorithm.
A different approach is taken by PySB, where model specification is embedded in the programming language Python. A model (or part of a model) is represented as a Python programme. This allows users to store higher-order biochemical processes such as catalysis or polymerisation as macros and re-use them as needed. The models can be simulated and analysed using Python libraries, but PySB models can also be exported into BNGL, kappa, and SBML.
Models involving multi-state and multi-component species can also be specified in Level 3 of the Systems Biology Markup Language (SBML) using the multi package. A draft specification is available.
Thus, by only considering states and features important for a particular reaction, rule-based model specification eliminates the need to explicitly enumerate every possible molecular state that can undergo a similar reaction, and thereby allows for efficient specification.
== The computation problem ==
When running simulations on a biological model, any simulation software evaluates a set of rules, starting from a specified set of initial conditions, and usually iterating through a series of time steps until a specified end time. One way to classify simulation algorithms is by looking at the level of analysis at which the rules are applied: they can be population-based, single-particle-based or hybrid.
=== Population-based rule evaluation ===
In Population-based rule evaluation, rules are applied to populations. All molecules of the same species in the same state are pooled together. Application of a specific rule reduces or increases the size of one of the pools, possibly at the expense of another.
Some of the best-known classes of simulation approaches in computational biology belong to the population-based family, including those based on the numerical integration of ordinary and partial differential equations and the Gillespie stochastic simulation algorithm.
Differential equations describe changes in molecular concentrations over time in a deterministic manner. Simulations based on differential equations usually do not attempt to solve those equations analytically, but employ a suitable numerical solver.
The stochastic Gillespie algorithm changes the composition of pools of molecules through a progression of randomness reaction events, the probability of which is computed from reaction rates and from the numbers of molecules, in accordance with the stochastic master equation.
In population-based approaches, one can think of the system being modeled as being in a given state at any given time point, where a state is defined according to the nature and size of the populated pools of molecules. This means that the space of all possible states can become very large. With some simulation methods implementing numerical integration of ordinary and partial differential equations or the Gillespie stochastic algorithm, all possible pools of molecules and the reactions they undergo are defined at the start of the simulation, even if they are empty. Such "generate-first" methods scale poorly with increasing numbers of molecular states. For instance, it has recently been estimated that even for a simple model of CaMKII with just 6 states per subunits and 10 subunits, it would take 290 years to generate the entire reaction network on a 2.54 GHz Intel Xeon processor. In addition, the model generation step in generate-first methods does not necessarily terminate, for instance when the model includes assembly of proteins into complexes of arbitrarily large size, such as actin filaments. In these cases, a termination condition needs to be specified by the user.
Even if a large reaction system can be successfully generated, its simulation using population-based rule evaluation can run into computational limits. In a recent study, a powerful computer was shown to be unable to simulate a protein with more than 8 phosphorylation sites (
2
8
=
256
{\displaystyle 2^{8}=256}
phosphorylation states) using ordinary differential equations.
Methods have been proposed to reduce the size of the state space. One is to consider only the states adjacent to the present state (i.e. the states that can be reached within the next iteration) at each time point. This eliminates the need for enumerating all possible states at the beginning. Instead, reactions are generated "on-the-fly" at each iteration. These methods are available both for stochastic and deterministic algorithms. These methods still rely on the definition of an (albeit reduced) reaction network - in contrast to the "network-free" methods discussed below.
Even with "on-the-fly" network generation, networks generated for population-based rule evaluation can become quite large, and thus difficult - if not impossible - to handle computationally. An alternative approach is provided by particle-based rule evaluation.
=== Particle-based rule evaluation ===
In particle-based (sometimes called "agent-based") simulations, proteins, nucleic acids, macromolecular complexes or small molecules are represented as individual software objects, and their progress is tracked through the course of the entire simulation. Because particle-based rule evaluation keeps track of individual particles rather than populations, it comes at a higher computational cost when modeling systems with a high total number of particles, but a small number of kinds (or pools) of particles. In cases of combinatorial complexity, however, the modeling of individual particles is an advantage because, at any given point in the simulation, only existing molecules, their states and the reactions they can undergo need to be considered. Particle-based rule evaluation does not require the generation of complete or partial reaction networks at the start of the simulation or at any other point in the simulation and is therefore called "network-free".
This method reduces the complexity of the model at the simulation stage, and thereby saves time and computational power. The simulation follows each particle, and at each simulation step, a particle only "sees" the reactions (or rules) that apply to it. This depends on the state of the particle and, in some implementation, on the states of its neighbours in a holoenzyme or complex. As the simulation proceeds, the states of particles are updated according to the rules that are fired.
Some particle-based simulation packages use an ad-hoc formalism for specification of reactants, parameters and rules. Others can read files in a recognised rule-based specification format such as BNGL.
=== Non-spatial particle-based methods ===
StochSim is a particle-based stochastic simulator used mainly to model chemical reactions and other molecular transitions. The algorithm used in StochSim is different from the more widely known Gillespie stochastic algorithm in that it operates on individual entities, not entity pools, making it particle-based rather than population-based.
In StochSim, each molecular species can be equipped with a number of binary state flags representing a particular modification. Reactions can be made dependent on a set of state flags set to particular values. In addition, the outcome of a reaction can include a state flag being changed. Moreover, entities can be arranged in geometric arrays (for instance, for holoenzymes consisting of several subunits), and reactions can be "neighbor-sensitive", i.e. the probability of a reaction for a given entity is affected by the value of a state flag on a neighboring entity. These properties make StochSim ideally suited to modeling multi-state molecules arranged in holoenzymes or complexes of specified size. Indeed, StochSim has been used to model clusters of bacterial chemotactic receptors, and CaMKII holoenzymes.
An extension to StochSim includes a particle-based simulator DYNSTOC, which uses a StochSim-like algorithm to simulate models specified in the BioNetGen language (BNGL), and improves the handling of molecules within macromolecular complexes.
Another particle-based stochastic simulator that can read BNGL input files is RuleMonkey. Its simulation algorithm differs from the algorithms underlying both StochSim and DYNSTOC in that the simulation time step is variable.
The Network-Free Stochastic Simulator (NFSim) differs from those described above by allowing for the definition of reaction rates as arbitrary mathematical or conditional expressions and thereby facilitates selective coarse-graining of models. RuleMonkey and NFsim implement distinct but related simulation algorithms. A detailed review and comparison of both tools is given by Yang and Hlavacek.
It is easy to imagine a biological system where some components are complex multi-state molecules, whereas others have few possible states (or even just one) and exist in large numbers. A hybrid approach has been proposed to model such systems: Within the Hybrid Particle/Population (HPP) framework, the user can specify a rule-based model, but can designate some species to be treated as populations (rather than particles) in the subsequent simulation. This method combines the computational advantages of particle-based modeling for multi-state systems with relatively low molecule numbers and of population-based modeling for systems with high molecule numbers and a small number of possible states. Specification of HPP models is supported by BioNetGen, and simulations can be performed with NFSim.
=== Spatial particle-based methods ===
Spatial particle-based methods differ from the methods described above by their explicit representation of space.
One example of a particle-based simulator that allows for a representation of cellular compartments is SRSim. SRSim is integrated in the LAMMPS molecular dynamics simulator and allows the user to specify the model in BNGL. SRSim allows users to specify the geometry of the particles in the simulation, as well as interaction sites. It is therefore especially good at simulating the assembly and structure of complex biomolecular complexes, as evidenced by a recent model of the inner kinetochore.
MCell allows individual molecules to be traced in arbitrarily complex geometric environments which are defined by the user. This allows for simulations of biomolecules in realistic reconstructions of living cells, including cells with complex geometries like those of neurons. The reaction compartment is a reconstruction of a dendritic spine.
MCell uses an ad-hoc formalism within MCell itself to specify a multi-state model: In MCell, it is possible to assign "slots" to any molecular species. Each slot stands for a particular modification, and any number of slots can be assigned to a molecule. Each slot can be occupied by a particular state. The states are not necessarily binary. For instance, a slot describing binding of a particular ligand to a protein of interest could take the states "unbound", "partially bound", and "fully bound".
The slot-and-state syntax in MCell can also be used to model multimeric proteins or macromolecular complexes. When used in this way, a slot is a placeholder for a subunit or a molecular component of a complex, and the state of the slot will indicate whether a specific protein component is absent or present in the complex. A way to think about this is that MCell macromolecules can have several dimensions: A "state dimension" and one or more "spatial dimensions". The "state dimension" is used to describe the multiple possible states making up a multi-state protein, while the spatial dimension(s) describe topological relationships between neighboring subunits or members of a macromolecular complex. One drawback of this method for representing protein complexes, compared to Meredys, is that MCell does not allow for the diffusion of complexes, and hence, of multi-state molecules. This can in some cases be circumvented by adjusting the diffusion constants of ligands that interact with the complex, by using checkpointing functions or by combining simulations at different levels.
== Examples of multi-state models in biology ==
A (by no means exhaustive) selection of models of biological systems involving multi-state molecules and using some of the tools discussed here is give in the table below.
== See also ==
Multiscale modeling
Rule-based modeling
== References ==
This article was adapted from the following source under a CC BY 4.0 license (2014) (reviewer reports):
Melanie I Stefan; Thomas M Bartol; Terrence J Sejnowski; Mary B Kennedy (September 2014). "Multi-state modeling of biomolecules". PLOS Computational Biology. 10 (9): e1003844. doi:10.1371/JOURNAL.PCBI.1003844. ISSN 1553-734X. PMC 4201162. PMID 25254957. Wikidata Q18145441. | Wikipedia/Multi-state_modeling_of_biomolecules |
Protein quaternary structure is the fourth (and highest) classification level of protein structure. Protein quaternary structure refers to the structure of proteins which are themselves composed of two or more smaller protein chains (also referred to as subunits). Protein quaternary structure describes the number and arrangement of multiple folded protein subunits in a multi-subunit complex. It includes organizations from simple dimers to large homooligomers and complexes with defined or variable numbers of subunits. In contrast to the first three levels of protein structure, not all proteins will have a quaternary structure since some proteins function as single units. Protein quaternary structure can also refer to biomolecular complexes of proteins with nucleic acids and other cofactors.
== Description and examples ==
Many proteins are actually assemblies of multiple polypeptide chains. The quaternary structure refers to the number and arrangement of the protein subunits with respect to one another. Examples of proteins with quaternary structure include hemoglobin, DNA polymerase, ribosomes, antibodies, and ion channels.
Enzymes composed of subunits with diverse functions are sometimes called holoenzymes, in which some parts may be known as regulatory subunits and the functional core is known as the catalytic subunit. Other assemblies referred to instead as multiprotein complexes also possess quaternary structure. Examples include nucleosomes and microtubules. Changes in quaternary structure can occur through conformational changes within individual subunits or through reorientation of the subunits relative to each other. It is through such changes, which underlie cooperativity and allostery in "multimeric" enzymes, that many proteins undergo regulation and perform their physiological function.
The above definition follows a classical approach to biochemistry, established at times when the distinction between a protein and a functional, proteinaceous unit was difficult to elucidate. More recently, people refer to protein–protein interaction when discussing quaternary structure of proteins and consider all assemblies of proteins as protein complexes.
== Nomenclature ==
The number of subunits in an oligomeric complex is described using names that end in -mer (Greek for "part, subunit"). Formal and Greco-Latinate names are generally used for the first ten types and can be used for up to twenty subunits, whereas higher order complexes are usually described by the number of subunits, followed by -meric.
*No known examples
The smallest unit forming a homo-oligomer, i.e. one protein chain or subunit, is designated as a monomer, subunit or protomer. The latter term was originally devised to specify the smallest unit of hetero-oligomeric proteins, but is also applied to homo-oligomeric proteins in current literature. The subunits usually arrange in cyclic symmetry to form closed point group symmetries.
Although complexes higher than octamers are rarely observed for most proteins, there are some important exceptions. Viral capsids are often composed of multiples of 60 proteins. Several molecular machines are also found in the cell, such as the proteasome (four heptameric rings = 28 subunits), the transcription complex and the spliceosome. The ribosome is probably the largest molecular machine, and is composed of many RNA and protein molecules.
In some cases, proteins form complexes that then assemble into even larger complexes. In such cases, one uses the nomenclature, e.g., "dimer of dimers" or "trimer of dimers". This may suggest that the complex might dissociate into smaller sub-complexes before dissociating into monomers. This usually implies that the complex consists of different oligomerisation interfaces. For example, a tetrameric protein may have one four-fold rotation axis, i.e. point group symmetry 4 or C4. In this case the four interfaces between the subunits are identical. It may also have point group symmetry 222 or D2. This tetramer has different interfaces and the tetramer can dissociate into two identical homodimers. Tetramers of 222 symmetry are "dimer of dimers". Hexamers of 32 point group symmetry are "trimer of dimers" or "dimer of trimers". Thus, the nomenclature "dimer of dimers" is used to specify the point group symmetry or arrangement of the oligomer, independent of information relating to its dissociation properties.
Another distinction often made when referring to oligomers is whether they are homomeric or heteromeric, referring to whether the smaller protein subunits that come together to make the protein complex are the same (homomeric) or different (heteromeric) from each other. For example, two identical protein monomers would come together to form a homo-dimer, whereas two different protein monomers would create a hetero-dimer.
== Structure Determination ==
Protein quaternary structure can be determined using a variety of experimental techniques that require a sample of protein in a variety of experimental conditions. The experiments often provide an estimate of the mass of the native protein and, together with knowledge of the masses and/or stoichiometry of the subunits, allow the quaternary structure to be predicted with a given accuracy. It is not always possible to obtain a precise determination of the subunit composition for a variety of reasons.
The number of subunits in a protein complex can often be determined by measuring the hydrodynamic molecular volume or mass of the intact complex, which requires native solution conditions. For folded proteins, the mass can be inferred from its volume using the partial specific volume of 0.73 ml/g. However, volume measurements are less certain than mass measurements, since unfolded proteins appear to have a much larger volume than folded proteins; additional experiments are required to determine whether a protein is unfolded or has formed an oligomer.
=== Common techniques used to study protein quaternary structure ===
Ultracentrifugation
Surface-induced dissociation mass spectrometry
Coimmunoprecipation
FRET
Nuclear Magnetic Resonance (NMR)
=== Direct mass measurement of intact complexes ===
Sedimentation-equilibrium analytical ultracentrifugation
Electrospray mass spectrometry
Mass Spectrometric Immunoassay MSIA
=== Direct size measurement of intact complexes ===
Static light scattering
Size exclusion chromatography (requires calibration)
Dual polarisation interferometry
=== Indirect size measurement of intact complexes ===
Sedimentation-velocity analytical ultracentrifugation (measures the translational diffusion constant)
Dynamic light scattering (measures the translational diffusion constant)
Pulsed-gradient protein nuclear magnetic resonance (measures the translational diffusion constant)
Fluorescence polarization (measures the rotational diffusion constant)
Dielectric relaxation (measures the rotational diffusion constant)
Dual polarisation interferometry (measures the size and the density of the complex)
Methods that measure the mass or volume under unfolding conditions (such as
MALDI-TOF mass spectrometry and SDS-PAGE) are generally not useful, since non-native conditions usually cause the complex to dissociate into monomers. However, these may sometimes be applicable; for example, the experimenter may apply SDS-PAGE after first treating the intact complex with chemical cross-link reagents.
== Structure Prediction ==
Some bioinformatics methods have been developed for predicting the quaternary structural attributes of proteins based on their sequence information by using various modes of pseudo amino acid composition.
Protein folding prediction programs used to predict protein tertiary structure have also been expanding to better predict protein quaternary structure. One such development is AlphaFold-Multimer built upon the AlphaFold model for predicting protein tertiary structure.
== Role in Cell Signaling ==
Protein quaternary structure also plays an important role in certain cell signaling pathways. The G-protein coupled receptor pathway involves a heterotrimeric protein known as a G-protein. G-proteins contain three distinct subunits known as the G-alpha, G-beta, and G-gamma subunits. When the G-protein is activated, it binds to the G-protein coupled receptor protein and the cell signaling pathway is initiated. Another example is the receptor tyrosine kinase (RTK) pathway, which is initiated by the dimerization of two receptor tyrosine kinase monomers. When the dimer is formed, the two kinases can phosphorylate each other and initiate a cell signaling pathway.
== Protein–protein interactions ==
Proteins are capable of forming very tight but also only transient complexes. For example, ribonuclease inhibitor binds to ribonuclease A with a roughly 20 fM dissociation constant. Other proteins have evolved to bind specifically to unusual moieties on another protein, e.g., biotin groups (avidin), phosphorylated tyrosines (SH2 domains) or proline-rich segments (SH3 domains). Protein–protein interactions can be engineered to favor certain oligomerization states.
== Intragenic complementation ==
When multiple copies of a polypeptide encoded by a gene form a quaternary complex, this protein structure is referred to as a multimer. When a multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. In such a case, the phenomenon is referred to as intragenic complementation (also called inter-allelic complementation). Intragenic complementation appears to be common and has been studied in many different genes in a variety of organisms including the fungi Neurospora crassa, Saccharomyces cerevisiae and Schizosaccharomyces pombe; the bacterium Salmonella typhimurium; the virus bacteriophage T4, an RNA virus, and humans. The intermolecular forces likely responsible for self-recognition and multimer formation were discussed by Jehle.
== Assembly ==
Direct interaction of two nascent proteins emerging from nearby ribosomes appears to be a general mechanism for oligomer formation. Hundreds of protein oligomers were identified that assemble in human cells by such an interaction. The most prevalent form of interaction was between the N-terminal regions of the interacting proteins. Dimer formation appears to be able to occur independently of dedicated assembly machines.
== See also ==
Structural biology
Nucleic acid quaternary structure
Multiprotein complex
Biomolecular complex
Oligomers
== Notes ==
== References ==
== External links ==
The Macromolecular Structure Database (MSD) at the European Bioinformatics Institute (EBI) – Serves a list of the Probable Quaternary Structure (PQS) for every protein in the Protein Data Bank (PDB).
PQS server – PQS has not been updated since August 2009
PISA – The Protein Interfaces, Surfaces and Assemblies server at the MSD.
EPPIC – Evolutionary Protein–Protein Interface Classification: evolutionary assessment of interfaces in crystal structures
3D complex – Structural classification of protein complexes
Proteopedia – Proteopedia Home Page The collaborative, 3D encyclopedia of proteins and other molecules.
PDBWiki – PDBWiki Home Page – a website for community annotation of PDB structures.
ProtCID – ProtCID—a database of similar protein–protein interfaces in crystal structures of homologous proteins. | Wikipedia/Protein_quaternary_structure |
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.
In proteins that have segments extending extracellularly, the extracellular segments are also often glycosylated. Glycoproteins are also often important integral membrane proteins, where they play a role in cell–cell interactions. It is important to distinguish endoplasmic reticulum-based glycosylation of the secretory system from reversible cytosolic-nuclear glycosylation. Glycoproteins of the cytosol and nucleus can be modified through the reversible addition of a single GlcNAc residue that is considered reciprocal to phosphorylation and the functions of these are likely to be an additional regulatory mechanism that controls phosphorylation-based signalling. In contrast, classical secretory glycosylation can be structurally essential. For example, inhibition of asparagine-linked, i.e. N-linked, glycosylation can prevent proper glycoprotein folding and full inhibition can be toxic to an individual cell. In contrast, perturbation of glycan processing (enzymatic removal/addition of carbohydrate residues to the glycan), which occurs in both the endoplasmic reticulum and Golgi apparatus, is dispensable for isolated cells (as evidenced by survival with glycosides inhibitors) but can lead to human disease (congenital disorders of glycosylation) and can be lethal in animal models. It is therefore likely that the fine processing of glycans is important for endogenous functionality, such as cell trafficking, but that this is likely to have been secondary to its role in host-pathogen interactions. A famous example of this latter effect is the ABO blood group system.
Though there are different types of glycoproteins, the most common are N-linked and O-linked glycoproteins. These two types of glycoproteins are distinguished by structural differences that give them their names. Glycoproteins vary greatly in composition, making many different compounds such as antibodies or hormones. Due to the wide array of functions within the body, interest in glycoprotein synthesis for medical use has increased. There are now several methods to synthesize glycoproteins, including recombination and glycosylation of proteins.
Glycosylation is also known to occur on nucleo cytoplasmic proteins in the form of O-GlcNAc.
== Types of glycosylation ==
There are several types of glycosylation, although the first two are the most common.
In N-glycosylation, sugars are attached to nitrogen, typically on the amide side-chain of asparagine.
In O-glycosylation, sugars are attached to oxygen, typically on serine or threonine, but also on tyrosine or non-canonical amino acids such as hydroxylysine and hydroxyproline.
In P-glycosylation, sugars are attached to phosphorus on a phosphoserine.
In C-glycosylation, sugars are attached directly to carbon, such as in the addition of mannose to tryptophan.
In S-glycosylation, a beta-GlcNAc is attached to the sulfur atom of a cysteine residue.
In glypiation, a GPI glycolipid is attached to the C-terminus of a polypeptide, serving as a membrane anchor.
In glycation, also known as non-enzymatic glycosylation, sugars are covalently bonded to a protein or lipid molecule, without the controlling action of an enzyme, but through a Maillard reaction.
== Monosaccharides ==
Monosaccharides commonly found in eukaryotic glycoproteins include:: 526
The sugar group(s) can assist in protein folding, improve proteins' stability and are involved in cell signalling.
== Structure ==
The critical structural element of all glycoproteins is having oligosaccharides bonded covalently to a protein. There are 10 common monosaccharides in mammalian glycans including: glucose (Glc), fucose (Fuc), xylose (Xyl), mannose (Man), galactose (Gal), N-acetylglucosamine (GlcNAc), glucuronic acid (GlcA), iduronic acid (IdoA), N-acetylgalactosamine (GalNAc), sialic acid, and 5-N-acetylneuraminic acid (Neu5Ac). These glycans link themselves to specific areas of the protein amino acid chain.
The two most common linkages in glycoproteins are N-linked and O-linked glycoproteins. An N-linked glycoprotein has glycan bonds to the nitrogen containing an asparagine amino acid within the protein sequence. An O-linked glycoprotein has the sugar is bonded to an oxygen atom of a serine or threonine amino acid in the protein.
Glycoprotein size and composition can vary largely, with carbohydrate composition ranges from 1% to 70% of the total mass of the glycoprotein. Within the cell, they appear in the blood, the extracellular matrix, or on the outer surface of the plasma membrane, and make up a large portion of the proteins secreted by eukaryotic cells. They are very broad in their applications and can function as a variety of chemicals from antibodies to hormones.
=== Glycomics ===
Glycomics is the study of the carbohydrate components of cells. Though not exclusive to glycoproteins, it can reveal more information about different glycoproteins and their structure. One of the purposes of this field of study is to determine which proteins are glycosylated and where in the amino acid sequence the glycosylation occurs. Historically, mass spectrometry has been used to identify the structure of glycoproteins and characterize the carbohydrate chains attached.
== Examples ==
The unique interaction between the oligosaccharide chains have different applications. First, it aids in quality control by identifying misfolded proteins. The oligosaccharide chains also change the solubility and polarity of the proteins that they are bonded to. For example, if the oligosaccharide chains are negatively charged, with enough density around the protein, they can repulse proteolytic enzymes away from the bonded protein. The diversity in interactions lends itself to different types of glycoproteins with different structures and functions.
One example of glycoproteins found in the body is mucins, which are secreted in the mucus of the respiratory and digestive tracts. The sugars when attached to mucins give them considerable water-holding capacity and also make them resistant to proteolysis by digestive enzymes.
Glycoproteins are important for white blood cell recognition. Examples of glycoproteins in the immune system are:
molecules such as antibodies (immunoglobulins), which interact directly with antigens.
molecules of the major histocompatibility complex (or MHC), which are expressed on the surface of cells and interact with T cells as part of the adaptive immune response.
sialyl Lewis X antigen on the surface of leukocytes.
H antigen of the ABO blood compatibility antigens.
Other examples of glycoproteins include:
gonadotropins (luteinizing hormone and follicle-stimulating hormone)
glycoprotein IIb/IIIa, an integrin found on platelets that is required for normal platelet aggregation and adherence to the endothelium.
components of the zona pellucida, which surrounds the oocyte, and is important for sperm-egg interaction.
structural glycoproteins, which occur in connective tissue. These help bind together the fibers, cells, and ground substance of connective tissue. They may also help components of the tissue bind to inorganic substances, such as calcium in bone.
Glycoprotein-41 (gp41) and glycoprotein-120 (gp120) are HIV viral coat proteins.
Soluble glycoproteins often show a high viscosity, for example, in egg white and blood plasma.
Miraculin, is a glycoprotein extracted from Synsepalum dulcificum a berry which alters human tongue receptors to recognize sour foods as sweet.
Variable surface glycoproteins allow the sleeping sickness Trypanosoma parasite to escape the immune response of the host.
The viral spike of the human immunodeficiency virus is heavily glycosylated. Approximately half the mass of the spike is glycosylation and the glycans act to limit antibody recognition as the glycans are assembled by the host cell and so are largely 'self'. Over time, some patients can evolve antibodies to recognise the HIV glycans and almost all so-called 'broadly neutralising antibodies (bnAbs) recognise some glycans. This is possible mainly because the unusually high density of glycans hinders normal glycan maturation and they are therefore trapped in the premature, high-mannose, state. This provides a window for immune recognition. In addition, as these glycans are much less variable than the underlying protein, they have emerged as promising targets for vaccine design.
P-glycoproteins are critical for antitumor research due to its ability block the effects of antitumor drugs. P-glycoprotein, or multidrug transporter (MDR1), is a type of ABC transporter that transports compounds out of cells. This transportation of compounds out of cells includes drugs made to be delivered to the cell, causing a decrease in drug effectiveness. Therefore, being able to inhibit this behavior would decrease P-glycoprotein interference in drug delivery, making this an important topic in drug discovery. For example, P-Glycoprotein causes a decrease in anti-cancer drug accumulation within tumor cells, limiting the effectiveness of chemotherapies used to treat cancer.
== Hormones ==
Hormones that are glycoproteins include:
Follicle-stimulating hormone
Luteinizing hormone
Thyroid-stimulating hormone
Human chorionic gonadotropin
Alpha-fetoprotein
Erythropoietin (EPO)
== Distinction between glycoproteins and proteoglycans ==
== Functions ==
== Analysis ==
A variety of methods used in detection, purification, and structural analysis of glycoproteins are: 525
== Synthesis ==
The glycosylation of proteins has an array of different applications from influencing cell to cell communication to changing the thermal stability and the folding of proteins. Due to the unique abilities of glycoproteins, they can be used in many therapies. By understanding glycoproteins and their synthesis, they can be made to treat cancer, Crohn's Disease, high cholesterol, and more.
The process of glycosylation (binding a carbohydrate to a protein) is a post-translational modification, meaning it happens after the production of the protein. Glycosylation is a process that roughly half of all human proteins undergo and heavily influences the properties and functions of the protein. Within the cell, glycosylation occurs in the endoplasmic reticulum.
=== Recombination ===
There are several techniques for the assembly of glycoproteins. One technique utilizes recombination. The first consideration for this method is the choice of host, as there are many different factors that can influence the success of glycoprotein recombination such as cost, the host environment, the efficacy of the process, and other considerations. Some examples of host cells include E. coli, yeast, plant cells, insect cells, and mammalian cells. Of these options, mammalian cells are the most common because their use does not face the same challenges that other host cells do such as different glycan structures, shorter half life, and potential unwanted immune responses in humans. Of mammalian cells, the most common cell line used for recombinant glycoprotein production is the Chinese hamster ovary line. However, as technologies develop, the most promising cell lines for recombinant glycoprotein production are human cell lines.
=== Glycosylation ===
The formation of the link between the glycan and the protein is key element of the synthesis of glycoproteins. The most common method of glycosylation of N-linked glycoproteins is through the reaction between a protected glycan and a protected Asparagine. Similarly, an O-linked glycoprotein can be formed through the addition of a glycosyl donor with a protected Serine or Threonine. These two methods are examples of natural linkage. However, there are also methods of unnatural linkages. Some methods include ligation and a reaction between a serine-derived sulfamidate and thiohexoses in water. Once this linkage is complete, the amino acid sequence can be expanded upon using solid-phase peptide synthesis.
== See also ==
== Notes and references ==
== Further reading ==
== External links ==
Glycoproteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
"Biological Importance of the glycosylation of a protein". BiochemPages. 15 August 2015. Archived from the original on 30 November 2020. Retrieved 18 August 2015.
"Carbohydrate Chemistry and Glycobiology: A Web Tour". Science. 291 (5512): 2263–2502. 23 March 2001. Archived from the original on 9 January 2008. Special Web Supplement
"Glycan Recognizing Proteins". bioWORLD.
"Structure of Glycoprotein and Carbohydrate Chain". Home Page for Learning Environmental Chemistry. | Wikipedia/Glycoproteins |
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of several domains, and a domain may appear in a variety of different proteins. Molecular evolution uses domains as building blocks and these may be recombined in different arrangements to create proteins with different functions. In general, domains vary in length from between about 50 amino acids up to 250 amino acids in length. The shortest domains, such as zinc fingers, are stabilized by metal ions or disulfide bridges. Domains often form functional units, such as the calcium-binding EF hand domain of calmodulin. Because they are independently stable, domains can be "swapped" by genetic engineering between one protein and another to make chimeric proteins.
== Background ==
The concept of the domain was first proposed in 1973 by Wetlaufer after X-ray
crystallographic studies of hen lysozyme and papain
and by limited proteolysis studies of immunoglobulins. Wetlaufer defined domains as stable units of protein structure that could fold autonomously. In the past domains have been described as units of:
compact structure
function and evolution
folding.
Each definition is valid and will often overlap, i.e. a compact structural domain that is found amongst diverse proteins is likely to fold independently within its structural environment. Nature often brings several domains together to form multidomain and multifunctional proteins with a vast number of possibilities. In a multidomain protein, each domain may fulfill its own function independently, or in a concerted manner with its neighbours. Domains can either serve as modules for building up large assemblies such as virus particles or muscle fibres, or can provide specific catalytic or binding sites as found in enzymes or regulatory proteins.
== Example: Pyruvate kinase ==
An appropriate example is pyruvate kinase (see first figure), a glycolytic enzyme that plays an important role in regulating the flux from fructose-1,6-biphosphate to pyruvate. It contains an all-β nucleotide-binding domain (in blue), an α/β-substrate binding domain (in grey) and an α/β-regulatory domain (in olive green), connected by several polypeptide linkers. Each domain in this protein occurs in diverse sets of protein families.
The central α/β-barrel substrate binding domain is one of the most common enzyme folds. It is seen in many different enzyme families catalysing completely unrelated reactions. The α/β-barrel is commonly called the TIM barrel named after triose phosphate isomerase, which was the first such structure to be solved. It is currently classified into 26 homologous families in the CATH domain database. The TIM barrel is formed from a sequence of β-α-β motifs closed by the first and last strand hydrogen bonding together, forming an eight stranded barrel. There is debate about the evolutionary origin of this domain. One study has suggested
that a single ancestral enzyme could have diverged into several families, while another suggests that a stable TIM-barrel structure has evolved
through convergent evolution.
The TIM-barrel in pyruvate kinase is 'discontinuous', meaning that more than one segment of the polypeptide is required to form the domain. This is likely to be the result of the insertion of one domain into another during the protein's evolution. It has been shown from known structures that about a quarter of structural domains are discontinuous. The inserted β-barrel regulatory domain is 'continuous', made up of a single stretch of polypeptide.
== Units of protein structure ==
The primary structure (string of amino acids) of a protein ultimately encodes its uniquely folded three-dimensional (3D) conformation. The most important factor governing the folding of a protein into 3D structure is the distribution of polar and non-polar side chains. Folding is driven by the burial of hydrophobic side chains into the interior of the molecule so to avoid contact with the aqueous environment. Generally proteins have a core of hydrophobic residues surrounded by a shell of hydrophilic residues. Since the peptide bonds themselves are polar they are neutralised by hydrogen bonding with each other when in the hydrophobic environment. This gives rise to regions of the polypeptide that form regular 3D structural patterns called secondary structure. There are two main types of secondary structure: α-helices and β-sheets.
Some simple combinations of secondary structure elements have been found to frequently occur in protein structure and are referred to as supersecondary structure or motifs. For example, the β-hairpin motif consists of two adjacent antiparallel β-strands joined by a small loop. It is present in most antiparallel β structures both as an isolated ribbon and as part of more complex β-sheets. Another common super-secondary structure is the β-α-β motif, which is frequently used to connect two parallel β-strands. The central α-helix connects the C-termini of the first strand to the N-termini of the second strand, packing its side chains against the β-sheet and therefore shielding the hydrophobic residues of the β-strands from the surface.
Covalent association of two domains represents a functional and structural advantage since there is an increase in stability when compared with the same structures non-covalently associated. Other, advantages are the protection of intermediates within inter-domain enzymatic clefts that may
otherwise be unstable in aqueous environments, and a fixed stoichiometric ratio of the enzymatic activity necessary for a sequential set of reactions.
Structural alignment is an important tool for determining domains.
=== Tertiary structure ===
Several motifs pack together to form compact, local, semi-independent units called domains.
The overall 3D structure of the polypeptide chain is referred to as the protein's tertiary structure. Domains are the fundamental units of tertiary structure, each domain containing an individual hydrophobic core built from secondary structural units connected by loop regions. The packing of the polypeptide is usually much tighter in the interior than the exterior of the domain producing a solid-like core and a fluid-like surface. Core residues are often conserved in a protein family, whereas the residues in loops are less conserved, unless they are involved in the protein's function. Protein tertiary structure can be divided into four main classes based on the secondary structural content of the domain.
All-α domains have a domain core built exclusively from α-helices. This class is dominated by small folds, many of which form a simple bundle with helices running up and down.
All-β domains have a core composed of antiparallel β-sheets, usually two sheets packed against each other. Various patterns can be identified in the arrangement of the strands, often giving rise to the identification of recurring motifs, for example the Greek key motif.
α+β domains are a mixture of all-α and all-β motifs. Classification of proteins into this class is difficult because of overlaps to the other three classes and therefore is not used in the CATH domain database.
α/β domains are made from a combination of β-α-β motifs that predominantly form a parallel β-sheet surrounded by amphipathic α-helices. The secondary structures are arranged in layers or barrels.
=== Limits on size ===
Domains have limits on size. The size of individual structural domains varies from 36 residues in E-selectin to 692 residues in lipoxygenase-1, but the majority, 90%, have fewer than 200 residues with an average of approximately 100 residues. Very short domains, less than 40 residues, are often stabilised by metal ions or disulfide bonds. Larger domains, greater than 300 residues, are likely to consist of multiple hydrophobic cores.
=== Quaternary structure ===
Many proteins have a quaternary structure, which consists of several polypeptide chains that associate into an oligomeric molecule. Each polypeptide chain in such a protein is called a subunit. Hemoglobin, for example, consists of two α and two β subunits. Each of the four chains has an all-α globin fold with a heme pocket.
==== Domain swapping ====
Domain swapping is a mechanism for forming oligomeric assemblies. In domain swapping, a secondary or tertiary element of a monomeric protein is replaced by the same element of another protein. Domain swapping can range from secondary structure elements to whole structural domains. It also represents a model of evolution for functional adaptation by oligomerisation, e.g. oligomeric enzymes that have their active site at subunit interfaces.
== Domains as evolutionary modules ==
Nature is a tinkerer and not an inventor, new sequences are adapted from pre-existing sequences rather than invented. Domains are the common material used by nature to generate new sequences; they can be thought of as genetically mobile units, referred to as 'modules'. Often, the C and N termini of domains are close together in space, allowing them to easily be "slotted into" parent structures during the process of evolution. Many domain families are found in all three forms of life, Archaea, Bacteria and Eukarya. Protein modules are a subset of protein domains which are found across a range of different proteins with a particularly versatile structure. Examples can be found among extracellular proteins associated with clotting, fibrinolysis, complement, the extracellular matrix, cell surface adhesion molecules and cytokine receptors. Four concrete examples of widespread protein modules are the following domains: SH2, immunoglobulin, fibronectin type 3 and the kringle.
Molecular evolution gives rise to families of related proteins with similar sequence and structure. However, sequence similarities can be extremely low between proteins that share the same structure. Protein structures may be similar because proteins have diverged from a common ancestor. Alternatively, some folds may be more favored than others as they represent stable arrangements of secondary structures and some proteins may converge towards these folds over the course of evolution. There are currently about 110,000 experimentally determined protein 3D structures deposited within the Protein Data Bank (PDB). However, this set contains many identical or very similar structures. All proteins should be classified to structural families to understand their evolutionary relationships. Structural comparisons are best achieved at the domain level. For this reason many algorithms have been developed to automatically assign domains in proteins with known 3D structure (see § Domain definition from structural co-ordinates).
The CATH domain database classifies domains into approximately 800 fold families; ten of these folds are highly populated and are referred to as 'super-folds'. Super-folds are defined as folds for which there are at least three structures without significant sequence similarity. The most populated is the α/β-barrel super-fold, as described previously.
== Multidomain proteins ==
The majority of proteins, two-thirds in unicellular organisms and more than 80% in metazoa, are multidomain proteins. However, other studies concluded that 40% of prokaryotic proteins consist of multiple domains while eukaryotes have approximately 65% multi-domain proteins.
Many domains in eukaryotic multidomain proteins can be found as independent proteins in prokaryotes, suggesting that domains in multidomain proteins have once existed as independent proteins. For example, vertebrates have a multi-enzyme polypeptide containing the GAR synthetase, AIR synthetase and GAR transformylase domains (GARs-AIRs-GARt; GAR: glycinamide ribonucleotide synthetase/transferase; AIR: aminoimidazole ribonucleotide synthetase). In insects, the polypeptide appears as GARs-(AIRs)2-GARt, in yeast GARs-AIRs is encoded separately from GARt, and in bacteria each domain is encoded separately.
=== Origin ===
Multidomain proteins are likely to have emerged from selective pressure during evolution to create new functions. Various proteins have diverged from common ancestors by different combinations and associations of domains. Modular units frequently move about, within and between biological systems through mechanisms of genetic shuffling:
transposition of mobile elements including horizontal transfers (between species);
gross rearrangements such as inversions, translocations, deletions and duplications;
homologous recombination;
slippage of DNA polymerase during replication.
=== Types of organization ===
The simplest multidomain organization seen in proteins is that of a single domain repeated in tandem. The domains may interact with each other (domain-domain interaction) or remain isolated, like beads on string. The giant 30,000 residue muscle protein titin comprises about 120 fibronectin-III-type and Ig-type domains. In the serine proteases, a gene duplication event has led to the formation of a two β-barrel domain enzyme. The repeats have diverged so widely that there is no obvious sequence similarity between them. The active site is located at a cleft between the two β-barrel domains, in which functionally important residues are contributed from each domain. Genetically engineered mutants of the chymotrypsin serine protease were shown to have some proteinase activity even though their active site residues were abolished and it has therefore been postulated that the duplication event enhanced the enzyme's activity.
Modules frequently display different connectivity relationships, as illustrated by the kinesins and ABC transporters. The kinesin motor domain can be at either end of a polypeptide chain that includes a coiled-coil region and a cargo domain. ABC transporters are built with up to four domains consisting of two unrelated modules, ATP-binding cassette and an integral membrane module, arranged in various combinations.
Not only do domains recombine, but there are many examples of a domain having been inserted into another. Sequence or structural similarities to other
domains demonstrate that homologues of inserted and parent domains can exist independently. An example is that of the 'fingers' inserted into the 'palm' domain within the polymerases of the Pol I family. Since a domain can be inserted into another, there should always be at least one continuous domain in a multidomain protein. This is the main difference between definitions of structural domains and evolutionary/functional domains. An evolutionary domain will be limited to one or two connections between domains, whereas structural domains can have unlimited connections, within a given criterion of the existence of a common core. Several structural domains could be assigned to an evolutionary domain.
A superdomain consists of two or more conserved domains of nominally independent origin, but subsequently inherited as a single structural/functional unit. This combined superdomain can occur in diverse proteins that are not related by gene duplication alone. An example of a superdomain is the protein tyrosine phosphatase–C2 domain pair in PTEN, tensin, auxilin and the membrane protein TPTE2. This superdomain is found in proteins in animals, plants and fungi. A key feature of the PTP-C2 superdomain is amino acid residue conservation in the domain interface.
== Domains are autonomous folding units ==
=== Folding ===
Protein folding - the unsolved problem : Since the seminal work of Anfinsen in the early 1960s, the goal to completely understand the mechanism by which a polypeptide rapidly folds into its stable native conformation remains elusive. Many experimental folding studies have contributed much to our understanding, but the principles that govern protein folding are still based on those discovered in the very first studies of folding. Anfinsen showed that the native state of a protein is thermodynamically stable, the conformation being at a global minimum of its free energy.
Folding is a directed search of conformational space allowing the protein to fold on a biologically feasible time scale. The Levinthal paradox states that if an averaged sized protein would sample all possible conformations before finding the one with the lowest energy, the whole process would take billions of years. Proteins typically fold within 0.1 and 1000 seconds. Therefore, the protein folding process must be directed some way through a specific folding pathway. The forces
that direct this search are likely to be a combination of local and global influences whose effects are felt at various stages of the reaction.
Advances in experimental and theoretical studies have shown that folding can be viewed in terms of energy landscapes, where folding kinetics is considered as a progressive organisation of an ensemble of partially folded structures through which a protein passes on its way to the folded structure. This has been described in terms of a folding funnel, in which an unfolded protein has a large number of conformational states available and there are fewer states available to the folded protein. A funnel implies that for protein folding there is a decrease in energy and loss of entropy with increasing tertiary structure formation. The local roughness of the funnel reflects kinetic traps, corresponding to the accumulation of misfolded intermediates. A folding chain progresses toward lower intra-chain free-energies by increasing its compactness. The chain's conformational options become increasingly narrowed ultimately toward one native structure.
=== Advantage of domains in protein folding ===
The organisation of large proteins by structural domains represents an advantage for protein folding, with each domain being able to individually fold, accelerating the folding process and reducing a potentially large combination of residue interactions. Furthermore, given the observed random distribution of hydrophobic residues in proteins, domain formation appears to be the optimal solution for a large protein to bury its hydrophobic residues while keeping the hydrophilic residues at the surface.
However, the role of inter-domain interactions in protein folding and in energetics of stabilisation of the native structure, probably differs for each protein. In T4 lysozyme, the influence of one domain on the other is so strong that the entire molecule is resistant to proteolytic cleavage. In this case, folding is a sequential process where the C-terminal domain is required to fold independently in an early step, and the other domain requires the presence of the folded C-terminal domain for folding and stabilisation.
It has been found that the folding of an isolated domain can take place at the same rate or sometimes faster than that of the integrated domain, suggesting that unfavourable interactions with the rest of the protein can occur during folding. Several arguments suggest that the slowest step in the folding of large proteins is the pairing of the folded domains. This is either because the domains are not folded entirely correctly or because the small adjustments required for their interaction are energetically unfavourable, such as the removal of water from the domain interface.
== Domains and protein flexibility ==
Protein domain dynamics play a key role in a multitude of molecular recognition and signaling processes.
Protein domains, connected by intrinsically disordered flexible linker domains, induce long-range allostery via protein domain dynamics.
The resultant dynamic modes cannot be generally predicted from static structures of either the entire protein or individual domains. They can however be inferred by comparing different structures of a protein (as in Database of Molecular Motions). They can also be suggested by sampling in extensive molecular dynamics trajectories and principal component analysis, or they can be directly observed using spectra
measured by neutron spin echo spectroscopy.
== Domain definition from structural co-ordinates ==
The importance of domains as structural building blocks and elements of evolution has brought about many automated methods for their identification and classification in proteins of known structure. Automatic procedures for reliable domain assignment is essential for the generation of the domain databases, especially as the number of known protein structures is increasing. Although the boundaries of a domain can be determined by visual inspection, construction of an automated method is not straightforward. Problems occur when faced with domains that are discontinuous or highly associated. The fact that there is no standard definition of what a domain really is has meant that domain assignments have varied enormously, with each researcher using a unique set of criteria.
A structural domain is a compact, globular sub-structure with more interactions within it than with the rest of the protein.
Therefore, a structural domain can be determined by two visual characteristics: its compactness and its extent of isolation. Measures of local compactness in proteins have been used in many of the early methods of domain assignment and in several of the more recent methods.
=== Methods ===
One of the first algorithms used a Cα-Cα distance map together with a hierarchical clustering routine that considered proteins as several small segments, 10 residues in length. The initial segments were clustered one after another based on inter-segment distances; segments with the shortest distances were clustered and considered as single segments thereafter. The stepwise clustering finally included the full protein. Go also exploited the fact that inter-domain distances are normally larger than intra-domain distances; all possible Cα-Cα distances were represented as diagonal plots in which there were distinct patterns for helices, extended strands and combinations of secondary structures.
The method by Sowdhamini and Blundell clusters secondary structures in a protein based on their Cα-Cα distances and identifies domains from the pattern in
their dendrograms. As the procedure does not consider the protein as a continuous chain of amino acids there are no problems in treating discontinuous domains. Specific nodes in these dendrograms are identified as tertiary structural clusters of the protein, these include both super-secondary structures and domains. The DOMAK algorithm is used to create the 3Dee domain database. It calculates a 'split value' from the number of each type of contact when the protein is divided arbitrarily into two parts. This split value is
large when the two parts of the structure are distinct.
The method of Wodak and Janin was based on the calculated interface areas between two chain segments repeatedly cleaved at various residue positions. Interface areas were calculated by comparing surface areas of the cleaved segments with that of the native structure. Potential domain boundaries can be identified at a site where the interface area was at a minimum. Other methods have used measures of solvent accessibility to calculate compactness.
The PUU algorithm incorporates a harmonic model used to approximate inter-domain dynamics. The underlying physical concept is that many rigid interactions will occur within each domain and loose interactions will occur between domains. This algorithm is used to define domains in the FSSP domain database.
Swindells (1995) developed a method, DETECTIVE, for identification of domains in protein structures based on the idea that domains have a hydrophobic
interior. Deficiencies were found to occur when hydrophobic cores from different domains continue through the interface region.
RigidFinder is a novel method for identification of protein rigid blocks (domains and loops) from two different conformations. Rigid blocks are defined as blocks where all inter residue distances are conserved across conformations.
The method RIBFIND developed by Pandurangan and Topf identifies rigid bodies in protein structures by performing spacial clustering of secondary structural elements in proteins. The RIBFIND rigid bodies have been used to flexibly fit protein structures into cryo electron microscopy density maps.
A general method to identify dynamical domains, that is protein
regions that behave approximately as rigid units in the course of
structural fluctuations, has been introduced by Potestio et al. and, among other applications was also used
to compare the consistency of the dynamics-based domain
subdivisions with standard structure-based ones. The method,
termed PiSQRD, is publicly available in the form of a webserver. The latter allows users to optimally subdivide single-chain
or multimeric proteins into quasi-rigid domains based on the collective modes of fluctuation of the system. By default the
latter are calculated through an elastic network model;
alternatively pre-calculated essential dynamical spaces can be
uploaded by the user.
=== Example domains ===
Armadillo repeats: named after the β-catenin-like Armadillo protein of the fruit fly Drosophila melanogaster.
Basic leucine zipper domain (bZIP domain): found in many DNA-binding eukaryotic proteins. One part of the domain contains a region that mediates sequence-specific DNA-binding properties and the Leucine zipper that is required for the dimerization of two DNA-binding regions. The DNA-binding region comprises a number of basic aminoacids such as arginine and lysine.
Cadherin repeats: Cadherins function as Ca2+-dependent cell–cell adhesion proteins. Cadherin domains are extracellular regions which mediate cell-to-cell homophilic binding between cadherins on the surface of adjacent cells.
Death effector domain (DED): allows protein–protein binding by homotypic interactions (DED-DED). Caspase proteases trigger apoptosis via proteolytic cascades. Pro-caspase-8 and pro-caspase-9 bind to specific adaptor molecules via DED domains, which leads to autoactivation of caspases.
EF hand: a helix-turn-helix structural motif found in each structural domain of the signaling protein calmodulin and in the muscle protein troponin-C.
Foldon domain: A small protein domain from fibritin in T4 bacteriophage that can cause proteins to trimerize.
Immunoglobulin-like domains: found in proteins of the immunoglobulin superfamily (IgSF). They contain about 70-110 amino acids and are classified into different categories (IgV, IgC1, IgC2 and IgI) according to their size and function. They possess a characteristic fold in which two beta sheets form a "sandwich" that is stabilized by interactions between conserved cysteines and other charged amino acids. They are important for protein–protein interactions in processes of cell adhesion, cell activation, and molecular recognition. These domains are commonly found in molecules with roles in the immune system.
Phosphotyrosine-binding domain (PTB): PTB domains usually bind to phosphorylated tyrosine residues. They are often found in signal transduction proteins. PTB-domain binding specificity is determined by residues to the amino-terminal side of the phosphotyrosine. Examples: the PTB domains of both SHC and IRS-1 bind to a NPXpY sequence. PTB-containing proteins such as SHC and IRS-1 are important for insulin responses of human cells.
Pleckstrin homology domain (PH): PH domains bind phosphoinositides with high affinity. Specificity for PtdIns(3)P, PtdIns(4)P, PtdIns(3,4)P2, PtdIns(4,5)P2, and PtdIns(3,4,5)P3 have all been observed. Given the fact that phosphoinositides are sequestered to various cell membranes (due to their long lipophilic tail) the PH domains usually causes recruitment of the protein in question to a membrane where the protein can exert a certain function in cell signalling, cytoskeletal reorganization or membrane trafficking.
Src homology 2 domain (SH2): SH2 domains are often found in signal transduction proteins. SH2 domains confer binding to phosphorylated tyrosine (pTyr). Named after the phosphotyrosine binding domain of the src viral oncogene, which is itself a tyrosine kinase. See also: SH3 domain.
Zinc finger DNA-binding domain (ZnF_GATA): ZnF_GATA domain-containing proteins are typically transcription factors that usually bind to the DNA sequence [AT]GATA[AG] of promoters.
== Domains of unknown function ==
A large fraction of domains are of unknown function. A domain of unknown function (DUF) is a protein domain that has no characterized function. These families have been collected together in the Pfam database using the prefix DUF followed by a number, with examples being DUF2992 and DUF1220. There are now over 3,000 DUF families within the Pfam database representing over 20% of known families. Surprisingly, the number of DUFs in Pfam has increased from 20% (in 2010) to 22% (in 2019), mostly due to an increasing number of new genome sequences. Pfam release 32.0 (2019) contained 3,961 DUFs.
== See also ==
Binding domain
Cofactor transferase family
PANDIT, a biological database covering protein domains
Pfam: database of protein domains
Protein
Protein structure
Protein structure prediction
Protein structure prediction software
Protein superfamily
Protein tandem repeats
Protein family
Protein subfamily
Short linear motif
Structural biology
Structural Classification of Proteins (SCOP)
CATH Protein Structure Classification database
Sequence motif
Structural motif
== References ==
George, R. A. (2002) "Predicting Structural Domains in Proteins" Thesis, University College London (contributed by its author).
== Key papers ==
== External links ==
=== Structural domain databases ===
Conserved Domains at the National Center for Biotechnology website
3Dee
CATH
DALI
Definition and assignment of structural domains in proteins at the Wayback Machine (archived 2006-09-11)
PFAM clan browser
=== Sequence domain databases ===
InterPro
Pfam at the Library of Congress Web Archives (archived 2011-05-06)
PROSITE
ProDom
SMART
NCBI Conserved Domain Database
SUPERFAMILY Library of HMMs representing superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
=== Functional domain databases ===
dcGO A comprehensive database of domain-centric ontologies on functions, phenotypes and diseases. | Wikipedia/Protein_domain |
In chemistry, polarity is a separation of electric charge leading to a molecule or its chemical groups having an electric dipole moment, with a negatively charged end and a positively charged end.
Polar molecules must contain one or more polar bonds due to a difference in electronegativity between the bonded atoms. Molecules containing polar bonds have no molecular polarity if the bond dipoles cancel each other out by symmetry.
Polar molecules interact through dipole-dipole intermolecular forces and hydrogen bonds. Polarity underlies a number of physical properties including surface tension, solubility, and melting and boiling points.
== Polarity of bonds ==
Not all atoms attract electrons with the same force. The amount of "pull" an atom exerts on its electrons is called its electronegativity. Atoms with high electronegativities – such as fluorine, oxygen, and nitrogen – exert a greater pull on electrons than atoms with lower electronegativities such as alkali metals and alkaline earth metals. In a bond, this leads to unequal sharing of electrons between the atoms, as electrons will be drawn closer to the atom with the higher electronegativity.
Because electrons have a negative charge, the unequal sharing of electrons within a bond leads to the formation of an electric dipole: a separation of positive and negative electric charge. Because the amount of charge separated in such dipoles is usually smaller than a fundamental charge, they are called partial charges, denoted as δ+ (delta plus) and δ− (delta minus). These symbols were introduced by Sir Christopher Ingold and Edith Hilda (Usherwood) Ingold in 1926. The bond dipole moment is calculated by multiplying the amount of charge separated and the distance between the charges.
These dipoles within molecules can interact with dipoles in other molecules, creating dipole-dipole intermolecular forces.
=== Classification ===
Bonds can fall between one of two extremes – completely nonpolar or completely polar. A completely nonpolar bond occurs when the electronegativities are identical and therefore possess a difference of zero. A completely polar bond is more correctly called an ionic bond, and occurs when the difference between electronegativities is large enough that one atom actually takes an electron from the other. The terms "polar" and "nonpolar" are usually applied to covalent bonds, that is, bonds where the polarity is not complete. To determine the polarity of a covalent bond using numerical means, the difference between the electronegativity of the atoms is used.
Bond polarity is typically divided into three groups that are loosely based on the difference in electronegativity between the two bonded atoms. According to the Pauling scale:
Nonpolar bonds generally occur when the difference in electronegativity between the two atoms is less than 0.5
Polar bonds generally occur when the difference in electronegativity between the two atoms is roughly between 0.5 and 2.0
Ionic bonds generally occur when the difference in electronegativity between the two atoms is greater than 2.0
Pauling based this classification scheme on the partial ionic character of a bond, which is an approximate function of the difference in electronegativity between the two bonded atoms. He estimated that a difference of 1.7 corresponds to 50% ionic character, so that a greater difference corresponds to a bond which is predominantly ionic.
As a quantum-mechanical description, Pauling proposed that the wave function for a polar molecule AB is a linear combination of wave functions for covalent and ionic molecules: ψ = aψ(A:B) + bψ(A+B−). The amount of covalent and ionic character depends on the values of the squared coefficients a2 and b2.
=== Bond dipole moments ===
The bond dipole moment uses the idea of electric dipole moment to measure the polarity of a chemical bond within a molecule. It occurs whenever there is a separation of positive and negative charges.
The bond dipole μ is given by:
μ
=
δ
d
{\displaystyle \mu =\delta \,d}
.
The bond dipole is modeled as δ+ — δ– with a distance d between the partial charges δ+ and δ–. It is a vector, parallel to the bond axis, pointing from minus to plus, as is conventional for electric dipole moment vectors.
Chemists often draw the vector pointing from plus to minus. This vector can be physically interpreted as the movement undergone by electrons when the two atoms are placed a distance d apart and allowed to interact, the electrons will move from their free state positions to be localised more around the more electronegative atom.
The SI unit for electric dipole moment is the coulomb–meter. This is too large to be practical on the molecular scale.
Bond dipole moments are commonly measured in debyes, represented by the symbol D, which is obtained by measuring the charge
δ
{\displaystyle \delta }
in units of 10−10 statcoulomb and the distance d in Angstroms. Based on the conversion factor of
10−10 statcoulomb being 0.208 units of elementary charge, so 1.0 debye results from an electron and a proton separated by 0.208 Å. A useful conversion factor is 1 D = 3.335 64×10−30 C m.
For diatomic molecules there is only one (single or multiple) bond so the bond dipole moment is the molecular dipole moment, with typical values in the range of 0 to 11 D. At one extreme, a symmetrical molecule such as bromine, Br2, has zero dipole moment, while near the other extreme, gas phase potassium bromide, KBr, which is highly ionic, has a dipole moment of 10.41 D.
For polyatomic molecules, there is more than one bond. The total molecular dipole moment may be approximated as the vector sum of the individual bond dipole moments. Often bond dipoles are obtained by the reverse process: a known total dipole of a molecule can be decomposed into bond dipoles. This is done to transfer bond dipole moments to molecules that have the same bonds, but for which the total dipole moment is not yet known. The vector sum of the transferred bond dipoles gives an estimate for the total (unknown) dipole of the molecule.
== Polarity of molecules ==
A molecule is composed of one or more chemical bonds between molecular orbitals of different atoms. A molecule may be polar either as a result of polar bonds due to differences in electronegativity as described above, or as a result of an asymmetric arrangement of nonpolar covalent bonds and non-bonding pairs of electrons known as a full molecular orbital.
While the molecules can be described as "polar covalent", "nonpolar covalent", or "ionic", this is often a relative term, with one molecule simply being more polar or more nonpolar than another. However, the following properties are typical of such molecules.
=== Boiling point ===
When comparing a polar and nonpolar molecule with similar molar masses, the polar molecule in general has a higher boiling point, because the dipole–dipole interaction between polar molecules results in stronger intermolecular attractions. One common form of polar interaction is the hydrogen bond, which is also known as the H-bond. For example, water forms H-bonds and has a molar mass M = 18 and a boiling point of +100 °C, compared to nonpolar methane with M = 16 and a boiling point of −161 °C.
=== Solubility ===
Due to the polar nature of the water molecule itself, other polar molecules are generally able to dissolve in water. Most nonpolar molecules are water-insoluble (hydrophobic) at room temperature. Many nonpolar organic solvents, such as turpentine, are able to dissolve nonpolar substances.
=== Surface tension ===
Polar compounds tend to have higher surface tension than nonpolar compounds.
=== Capillary action ===
Polar liquids have a tendency to rise against gravity in a small diameter tube.
=== Viscosity ===
Polar liquids have a tendency to be more viscous than nonpolar liquids. For example, nonpolar hexane is much less viscous than polar water. However, molecule size is a much stronger factor on viscosity than polarity, where compounds with larger molecules are more viscous than compounds with smaller molecules. Thus, water (small polar molecules) is less viscous than hexadecane (large nonpolar molecules).
== Examples ==
=== Polar molecules ===
A polar molecule has a net dipole as a result of the opposing charges (i.e. having partial positive and partial negative charges) from polar bonds arranged asymmetrically. Water (H2O) is an example of a polar molecule since it has a slight positive charge on one side and a slight negative charge on the other. The dipoles do not cancel out, resulting in a net dipole. The dipole moment of water depends on its state. In the gas phase the dipole moment is ≈ 1.86 debye (D), whereas liquid water (≈ 2.95 D) and ice (≈ 3.09 D) are higher due to differing hydrogen-bonded environments. Other examples include sugars (like sucrose), which have many polar oxygen–hydrogen (−OH) groups and are overall highly polar.
If the bond dipole moments of the molecule do not cancel, the molecule is polar. For example, the water molecule (H2O) contains two polar O−H bonds in a bent (nonlinear) geometry. The bond dipole moments do not cancel, so that the molecule forms a molecular dipole with its negative pole at the oxygen and its positive pole midway between the two hydrogen atoms. In the figure each bond joins the central O atom with a negative charge (red) to an H atom with a positive charge (blue).
The hydrogen fluoride, HF, molecule is polar by virtue of polar covalent bonds – in the covalent bond electrons are displaced toward the more electronegative fluorine atom.
Ammonia, NH3, is a molecule whose three N−H bonds have only a slight polarity (toward the more electronegative nitrogen atom). The molecule has two lone electrons in an orbital that points towards the fourth apex of an approximately regular tetrahedron, as predicted by the VSEPR theory. This orbital is not participating in covalent bonding; it is electron-rich, which results in a powerful dipole across the whole ammonia molecule.
In ozone (O3) molecules, the two O−O bonds are nonpolar (there is no electronegativity difference between atoms of the same element). However, the distribution of other electrons is uneven – since the central atom has to share electrons with two other atoms, but each of the outer atoms has to share electrons with only one other atom, the central atom is more deprived of electrons than the others (the central atom has a formal charge of +1, while the outer atoms each have a formal charge of −1⁄2). Since the molecule has a bent geometry, the result is a dipole across the whole ozone molecule.
=== Nonpolar molecules ===
A molecule may be nonpolar either when there is an equal sharing of electrons between the two atoms of a diatomic molecule or because of the symmetrical arrangement of polar bonds in a more complex molecule. For example, boron trifluoride (BF3) has a trigonal planar arrangement of three polar bonds at 120°. This results in no overall dipole in the molecule.
Carbon dioxide (CO2) has two polar C=O bonds, but the geometry of CO2 is linear so that the two bond dipole moments cancel and there is no net molecular dipole moment; the molecule is nonpolar.
Examples of household nonpolar compounds include fats, oil, and petrol/gasoline.
In the methane molecule (CH4) the four C−H bonds are arranged tetrahedrally around the carbon atom. Each bond has polarity (though not very strong). The bonds are arranged symmetrically so there is no overall dipole in the molecule. The diatomic oxygen molecule (O2) does not have polarity in the covalent bond because of equal electronegativity, hence there is no polarity in the molecule.
=== Amphiphilic molecules ===
Large molecules that have one end with polar groups attached and another end with nonpolar groups are described as amphiphiles or amphiphilic molecules. They are good surfactants and can aid in the formation of stable emulsions, or blends, of water and fats. Surfactants reduce the interfacial tension between oil and water by adsorbing at the liquid–liquid interface.
== Predicting molecule polarity ==
Determining the point group is a useful way to predict polarity of a molecule. In general, a molecule will not possess dipole moment if the individual bond dipole moments of the molecule cancel each other out. This is because dipole moments are euclidean vector quantities with magnitude and direction, and a two equal vectors that oppose each other will cancel out.
Any molecule with a centre of inversion ("i") or a horizontal mirror plane ("σh") will not possess dipole moments.
Likewise, a molecule with more than one Cn axis of rotation will not possess a dipole moment because dipole moments cannot lie in more than one dimension. As a consequence of that constraint, all molecules with dihedral symmetry (Dn) will not have a dipole moment because, by definition, D point groups have two or multiple Cn axes.
Since C1, Cs,C∞h Cn and Cnv point groups do not have a centre of inversion, horizontal mirror planes or multiple Cn axis, molecules in one of those point groups will have dipole moment.
== Electrical deflection of water ==
Contrary to popular misconception, the electrical deflection of a stream of water from a charged object is not based on polarity. The deflection occurs because of electrically charged droplets in the stream, which the charged object induces. A stream of water can also be deflected in a uniform electrical field, which cannot exert force on polar molecules. Additionally, after a stream of water is grounded, it can no longer be deflected. Weak deflection is even possible for nonpolar liquids.
== See also ==
Chemical properties
Colloid
Detergent
Electronegativities of the elements (data page)
Polar point group
== References ==
== External links ==
Chemical Bonding
Polarity of Bonds and Molecules (archived)
Molecule Polarity | Wikipedia/Polar_molecule |
Protein tertiary structure is the three-dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains and the backbone may interact and bond in a number of ways. The interactions and bonds of side chains within a particular protein determine its tertiary structure. The protein tertiary structure is defined by its atomic coordinates. These coordinates may refer either to a protein domain or to the entire tertiary structure. A number of these structures may bind to each other, forming a quaternary structure.
== History ==
The science of the tertiary structure of proteins has progressed from one of hypothesis to one of detailed definition. Although Emil Fischer had suggested proteins were made of polypeptide chains and amino acid side chains, it was Dorothy Maud Wrinch who incorporated geometry into the prediction of protein structures. Wrinch demonstrated this with the Cyclol model, the first prediction of the structure of a globular protein. Contemporary methods are able to determine, without prediction, tertiary structures to within 5 Å (0.5 nm) for small proteins (<120 residues) and, under favorable conditions, confident secondary structure predictions.
== Determinants ==
=== Stability of native states ===
==== Thermostability ====
A protein folded into its native state or native conformation typically has a lower Gibbs free energy (a combination of enthalpy and entropy) than the unfolded conformation. A protein will tend towards low-energy conformations, which will determine the protein's fold in the cellular environment. Because many similar conformations will have similar energies, protein structures are dynamic, fluctuating between these similar structures.
Globular proteins have a core of hydrophobic amino acid residues and a surface region of water-exposed, charged, hydrophilic residues. This arrangement may stabilize interactions within the tertiary structure. For example, in secreted proteins, which are not bathed in cytoplasm, disulfide bonds between cysteine residues help to maintain the tertiary structure. There is a commonality of stable tertiary structures seen in proteins of diverse function and diverse evolution. For example, the TIM barrel, named for the enzyme triosephosphateisomerase, is a common tertiary structure as is the highly stable, dimeric, coiled coil structure. Hence, proteins may be classified by the structures they hold. Databases of proteins which use such a classification include SCOP and CATH.
==== Kinetic traps ====
Folding kinetics may trap a protein in a high-energy conformation, i.e. a high-energy intermediate conformation blocks access to the lowest-energy conformation. The high-energy conformation may contribute to the function of the protein. For example, the influenza hemagglutinin protein is a single polypeptide chain which when activated, is proteolytically cleaved to form two polypeptide chains. The two chains are held in a high-energy conformation. When the local pH drops, the protein undergoes an energetically favorable conformational rearrangement that enables it to penetrate the host cell membrane.
==== Metastability ====
Some tertiary protein structures may exist in long-lived states that are not the expected most stable state. For example, many serpins (serine protease inhibitors) show this metastability. They undergo a conformational change when a loop of the protein is cut by a protease.
=== Chaperone proteins ===
It is commonly assumed that the native state of a protein is also the most thermodynamically stable and that a protein will reach its native state, given its chemical kinetics, before it is translated. Protein chaperones within the cytoplasm of a cell assist a newly synthesised polypeptide to attain its native state. Some chaperone proteins are highly specific in their function, for example, protein disulfide isomerase; others are general in their function and may assist most globular proteins, for example, the prokaryotic GroEL/GroES system of proteins and the homologous eukaryotic heat shock proteins (the Hsp60/Hsp10 system).
=== Cytoplasmic environment ===
Prediction of protein tertiary structure relies on knowing the protein's primary structure and comparing the possible predicted tertiary structure with known tertiary structures in protein data banks. This only takes into account the cytoplasmic environment present at the time of protein synthesis to the extent that a similar cytoplasmic environment may also have influenced the structure of the proteins recorded in the protein data bank.
=== Ligand binding ===
The structure of a protein, such as an enzyme, may change upon binding of its natural ligands, for example a cofactor. In this case, the structure of the protein bound to the ligand is known as holo structure, while the unbound protein has an apo structure.
Structure stabilized by the formation of weak bonds between amino acid side chains
- Determined by the folding of the polypeptide chain on itself (nonpolar residues are located
inside the protein, while polar residues are mainly located outside)
- Envelopment of the protein brings the protein closer and relates a-to located in distant regions of the sequence
- Acquisition of the tertiary structure leads to the formation of pockets and sites suitable for the recognition and
the binding of specific molecules (biospecificity).
== Determination ==
The knowledge of the tertiary structure of soluble globular proteins is more advanced than that of membrane proteins because the former are easier to study with available technology.
=== X-ray crystallography ===
X-ray crystallography is the most common tool used to determine protein structure. It provides high resolution of the structure but it does not give information about protein's conformational flexibility.
=== NMR ===
Protein NMR gives comparatively lower resolution of protein structure. It is limited to smaller proteins. However, it can provide information about conformational changes of a protein in solution.
=== Cryogenic electron microscopy ===
Cryogenic electron microscopy (cryo-EM) can give information about both a protein's tertiary and quaternary structure. It is particularly well-suited to large proteins and symmetrical complexes of protein subunits.
=== Dual polarisation interferometry ===
Dual polarisation interferometry provides complementary information about surface captured proteins. It assists in determining structure and conformation changes over time.
== Projects ==
=== Prediction algorithm ===
The Folding@home project at the University of Pennsylvania is a distributed computing research effort which uses approximately 5 petaFLOPS (≈10 x86 petaFLOPS) of available computing. It aims to find an algorithm which will consistently predict protein tertiary and quaternary structures given the protein's amino acid sequence and its cellular conditions.
A list of software for protein tertiary structure prediction can be found at
List of protein structure prediction software.
=== Protein aggregation diseases ===
Protein aggregation diseases such as Alzheimer's disease and Huntington's disease and prion diseases such as bovine spongiform encephalopathy can be better understood by constructing (and reconstructing) disease models. This is done by causing the disease in laboratory animals, for example, by administering a toxin, such as MPTP to cause Parkinson's disease, or through genetic manipulation.
Protein structure prediction is a new way to create disease models, which may avoid the use of animals.
=== Protein Tertiary Structure Retrieval Project (CoMOGrad) ===
Matching patterns in tertiary structure of a given protein to huge number of known protein tertiary structures and retrieve most similar ones in ranked order is in the heart of many research areas like function prediction of novel proteins, study of evolution, disease diagnosis, drug discovery, antibody design etc. The CoMOGrad project at BUET is a research effort to device an extremely fast and much precise method for protein tertiary structure retrieval and develop online tool based on research outcome.
== See also ==
== References ==
== External links ==
Protein Data Bank
Display, analyse and superimpose protein 3D structures
Alphabet of protein structures.
Display, analyse and superimpose protein 3D structures
WWW-based course teaching elementary protein bioinformatics
Critical Assessment of Structure Prediction (CASP)
Structural Classification of Proteins (SCOP)
CATH Protein Structure Classification
DALI/FSSP software and database of superposed protein structures
TOPOFIT-DB Invariant Structural Cores between proteins
PDBWiki — PDBWiki Home Page – a website for community annotation of PDB structures. | Wikipedia/Protein_tertiary_structure |
An unsaturated fat is a fat or fatty acid in which there is at least one double bond within the fatty acid chain. A fatty acid chain is monounsaturated if it contains one double bond, and polyunsaturated if it contains more than one double bond.
A saturated fat has no carbon-to-carbon double bonds, so the maximum possible number of hydrogen is bonded to carbon, and thus, is considered to be "saturated" with hydrogen atoms. To form carbon-to-carbon double bonds, hydrogen atoms are removed from the carbon chain. In cellular metabolism, unsaturated fat molecules contain less energy (i.e., fewer calories) than an equivalent amount of saturated fat. The greater the degree of unsaturation in a fatty acid (i.e., the more double bonds in the fatty acid) the more susceptible it becomes to lipid peroxidation (rancidity). Antioxidants can protect unsaturated fat from lipid peroxidation.
== Composition of common fats ==
In chemical analysis, fats are broken down to their constituent fatty acids, which can be analyzed in various ways. In one approach, fats undergo transesterification to give fatty acid methyl esters (FAMEs), which are amenable to separation and quantitation using gas chromatography. Classically, unsaturated isomers were separated and identified by argentation thin-layer chromatography.
The saturated fatty acid components are almost exclusively stearic (C18) and palmitic acids (C16). Monounsaturated fats are almost exclusively oleic acid. Linolenic acid comprises most of the triunsaturated fatty acid component.
== Chemistry and nutrition ==
Although polyunsaturated fats are protective against cardiac arrhythmias, a study of post-menopausal women with a relatively low fat intake showed that polyunsaturated fat is positively associated with progression of coronary atherosclerosis, whereas monounsaturated fat is not. This probably is an indication of the greater vulnerability of polyunsaturated fats to lipid peroxidation, against which vitamin E has been shown to be protective.
Examples of unsaturated fatty acids are palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, and arachidonic acid. Foods containing unsaturated fats include avocado, nuts, olive oils, and vegetable oils such as canola. Meat products contain both saturated and unsaturated fats.
Although unsaturated fats are conventionally regarded as 'healthier' than saturated fats, the United States Food and Drug Administration (FDA) recommendation stated that the amount of unsaturated fat consumed should not exceed 30% of one's daily caloric intake. Most foods contain both unsaturated and saturated fats. Marketers advertise only one or the other, depending on which one makes up the majority. Thus, various unsaturated fat vegetable oils, such as olive oils, also contain saturated fat.
== Membrane composition as a metabolic pacemaker ==
Studies on the cell membranes of mammals and reptiles discovered that mammalian cell membranes are composed of a higher proportion of polyunsaturated fatty acids (DHA, omega-3 fatty acid) than reptiles. Studies on bird fatty acid composition have noted similar proportions to mammals but with 1/3rd less omega-3 fatty acids as compared to omega-6 for a given body size. This fatty acid composition results in a more fluid cell membrane but also one that is permeable to various ions (H+ & Na+), resulting in cell membranes that are more costly to maintain. This maintenance cost has been argued to be one of the key causes for the high metabolic rates and concomitant warm-bloodedness of mammals and birds. However polyunsaturation of cell membranes may also occur in response to chronic cold temperatures as well. In fish increasingly cold environments lead to increasingly high cell membrane content of both monounsaturated and polyunsaturated fatty acids, to maintain greater membrane fluidity (and functionality) at the lower temperatures.
== See also ==
Iodine value – a chemical analysis method to determine the proportion of unsaturated fat.
List of unsaturated fatty acids
== References == | Wikipedia/Unsaturated_fat |
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesis is most commonly performed by ribosomes in cells. Peptides can also be synthesized in the laboratory. Protein primary structures can be directly sequenced, or inferred from DNA sequences.
== Formation ==
=== Biological ===
Amino acids are polymerised via peptide bonds to form a long backbone, with the different amino acid side chains protruding along it. In biological systems, proteins are produced during translation by a cell's ribosomes. Some organisms can also make short peptides by non-ribosomal peptide synthesis, which often use amino acids other than the encoded 22, and may be cyclised, modified and cross-linked.
=== Chemical ===
Peptides can be synthesised chemically via a range of laboratory methods. Chemical methods typically synthesise peptides in the opposite order (starting at the C-terminus) to biological protein synthesis (starting at the N-terminus).
== Notation ==
Protein sequence is typically notated as a string of letters, listing the amino acids starting at the amino-terminal end through to the carboxyl-terminal end. Either a three letter code or single letter code can be used to represent the 22 naturally encoded amino acids, as well as mixtures or ambiguous amino acids (similar to nucleic acid notation).
Peptides can be directly sequenced, or inferred from DNA sequences. Large sequence databases now exist that collate known protein sequences.
== Modification ==
In general, polypeptides are unbranched polymers, so their primary structure can often be specified by the sequence of amino acids along their backbone. However, proteins can become cross-linked, most commonly by disulfide bonds, and the primary structure also requires specifying the cross-linking atoms, e.g., specifying the cysteines involved in the protein's disulfide bonds. Other crosslinks include desmosine.
=== Isomerisation ===
The chiral centers of a polypeptide chain can undergo racemization. Although it does not change the sequence, it does affect the chemical properties of the sequence. In particular, the L-amino acids normally found in proteins can spontaneously isomerize at the
C
α
{\displaystyle \mathrm {C^{\alpha }} }
atom to form D-amino acids, which cannot be cleaved by most proteases. Additionally, proline can form stable trans-isomers at the peptide bond.
=== Post-translational modification ===
Additionally, the protein can undergo a variety of post-translational modifications, which are briefly summarized here.
The N-terminal amino group of a polypeptide can be modified covalently, e.g.,
acetylation
−
C
(
=
O
)
−
C
H
3
{\displaystyle \mathrm {-C(=O)-CH_{3}} }
The positive charge on the N-terminal amino group may be eliminated by changing it to an acetyl group (N-terminal blocking).
formylation
−
C
(
=
O
)
H
{\displaystyle \mathrm {-C(=O)H} }
The N-terminal methionine usually found after translation has an N-terminus blocked with a formyl group. This formyl group (and sometimes the methionine residue itself, if followed by Gly or Ser) is removed by the enzyme deformylase.
pyroglutamate
An N-terminal glutamine can attack itself, forming a cyclic pyroglutamate group.
myristoylation
−
C
(
=
O
)
−
(
C
H
2
)
12
−
C
H
3
{\displaystyle \mathrm {-C(=O)-\left(CH_{2}\right)_{12}-CH_{3}} }
Similar to acetylation. Instead of a simple methyl group, the myristoyl group has a tail of 14 hydrophobic carbons, which make it ideal for anchoring proteins to cellular membranes.
The C-terminal carboxylate group of a polypeptide can also be modified, e.g.,
amination (see Figure)
The C-terminus can also be blocked (thus, neutralizing its negative charge) by amination.
glycosyl phosphatidylinositol (GPI) attachment
Glycosyl phosphatidylinositol(GPI) is a large, hydrophobic phospholipid prosthetic group that anchors proteins to cellular membranes. It is attached to the polypeptide C-terminus through an amide linkage that then connects to ethanolamine, thence to sundry sugars and finally to the phosphatidylinositol lipid moiety.
Finally, the peptide side chains can also be modified covalently, e.g.,
phosphorylation
Aside from cleavage, phosphorylation is perhaps the most important chemical modification of proteins. A phosphate group can be attached to the sidechain hydroxyl group of serine, threonine and tyrosine residues, adding a negative charge at that site and producing an unnatural amino acid. Such reactions are catalyzed by kinases and the reverse reaction is catalyzed by phosphatases. The phosphorylated tyrosines are often used as "handles" by which proteins can bind to one another, whereas phosphorylation of Ser/Thr often induces conformational changes, presumably because of the introduced negative charge. The effects of phosphorylating Ser/Thr can sometimes be simulated by mutating the Ser/Thr residue to glutamate.
glycosylation
A catch-all name for a set of very common and very heterogeneous chemical modifications. Sugar moieties can be attached to the sidechain hydroxyl groups of Ser/Thr or to the sidechain amide groups of Asn. Such attachments can serve many functions, ranging from increasing solubility to complex recognition. All glycosylation can be blocked with certain inhibitors, such as tunicamycin.
deamidation (succinimide formation)
In this modification, an asparagine or aspartate side chain attacks the following peptide bond, forming a symmetrical succinimide intermediate. Hydrolysis of the intermediate produces either aspartate or the β-amino acid, iso(Asp). For asparagine, either product results in the loss of the amide group, hence "deamidation".
hydroxylation
Proline residues may be hydroxylated at either of two atoms, as can lysine (at one atom). Hydroxyproline is a critical component of collagen, which becomes unstable upon its loss. The hydroxylation reaction is catalyzed by an enzyme that requires ascorbic acid (vitamin C), deficiencies in which lead to many connective-tissue diseases such as scurvy.
methylation
Several protein residues can be methylated, most notably the positive groups of lysine and arginine. Arginine residues interact with the nucleic acid phosphate backbone and commonly form hydrogen bonds with the base residues, particularly guanine, in protein–DNA complexes. Lysine residues can be singly, doubly and even triply methylated. Methylation does not alter the positive charge on the side chain, however.
acetylation
Acetylation of the lysine amino groups is chemically analogous to the acetylation of the N-terminus. Functionally, however, the acetylation of lysine residues is used to regulate the binding of proteins to nucleic acids. The cancellation of the positive charge on the lysine weakens the electrostatic attraction for the (negatively charged) nucleic acids.
sulfation
Tyrosines may become sulfated on their
O
η
{\displaystyle \mathrm {O^{\eta }} }
atom. Somewhat unusually, this modification occurs in the Golgi apparatus, not in the endoplasmic reticulum. Similar to phosphorylated tyrosines, sulfated tyrosines are used for specific recognition, e.g., in chemokine receptors on the cell surface. As with phosphorylation, sulfation adds a negative charge to a previously neutral site.
prenylation and palmitoylation
−
C
(
=
O
)
−
(
C
H
2
)
14
−
C
H
3
{\displaystyle \mathrm {-C(=O)-\left(CH_{2}\right)_{14}-CH_{3}} }
The hydrophobic isoprene (e.g., farnesyl, geranyl, and geranylgeranyl groups) and palmitoyl groups may be added to the
S
γ
{\displaystyle \mathrm {S^{\gamma }} }
atom of cysteine residues to anchor proteins to cellular membranes. Unlike the GPI and myritoyl anchors, these groups are not necessarily added at the termini.
carboxylation
A relatively rare modification that adds an extra carboxylate group (and, hence, a double negative charge) to a glutamate side chain, producing a Gla residue. This is used to strengthen the binding to "hard" metal ions such as calcium.
ADP-ribosylation
The large ADP-ribosyl group can be transferred to several types of side chains within proteins, with heterogeneous effects. This modification is a target for the powerful toxins of disparate bacteria, e.g., Vibrio cholerae, Corynebacterium diphtheriae and Bordetella pertussis.
ubiquitination and SUMOylation
Various full-length, folded proteins can be attached at their C-termini to the sidechain ammonium groups of lysines of other proteins. Ubiquitin is the most common of these, and usually signals that the ubiquitin-tagged protein should be degraded.
Most of the polypeptide modifications listed above occur post-translationally, i.e., after the protein has been synthesized on the ribosome, typically occurring in the endoplasmic reticulum, a subcellular organelle of the eukaryotic cell.
Many other chemical reactions (e.g., cyanylation) have been applied to proteins by chemists, although they are not found in biological systems.
=== Cleavage and ligation ===
In addition to those listed above, the most important modification of primary structure is peptide cleavage (by chemical hydrolysis or by proteases). Proteins are often synthesized in an inactive precursor form; typically, an N-terminal or C-terminal segment blocks the active site of the protein, inhibiting its function. The protein is activated by cleaving off the inhibitory peptide.
Some proteins even have the power to cleave themselves. Typically, the hydroxyl group of a serine (rarely, threonine) or the thiol group of a cysteine residue will attack the carbonyl carbon of the preceding peptide bond, forming a tetrahedrally bonded intermediate [classified as a hydroxyoxazolidine (Ser/Thr) or hydroxythiazolidine (Cys) intermediate]. This intermediate tends to revert to the amide form, expelling the attacking group, since the amide form is usually favored by free energy, (presumably due to the strong resonance stabilization of the peptide group). However, additional molecular interactions may render the amide form less stable; the amino group is expelled instead, resulting in an ester (Ser/Thr) or thioester (Cys) bond in place of the peptide bond. This chemical reaction is called an N-O acyl shift.
The ester/thioester bond can be resolved in several ways:
Simple hydrolysis will split the polypeptide chain, where the displaced amino group becomes the new N-terminus. This is seen in the maturation of glycosylasparaginase.
A β-elimination reaction also splits the chain, but results in a pyruvoyl group at the new N-terminus. This pyruvoyl group may be used as a covalently attached catalytic cofactor in some enzymes, especially decarboxylases such as S-adenosylmethionine decarboxylase (SAMDC) that exploit the electron-withdrawing power of the pyruvoyl group.
Intramolecular transesterification, resulting in a branched polypeptide. In inteins, the new ester bond is broken by an intramolecular attack by the soon-to-be C-terminal asparagine.
Intermolecular transesterification can transfer a whole segment from one polypeptide to another, as is seen in the Hedgehog protein autoprocessing.
== Sequence compression ==
The compression of amino acid sequences is a comparatively challenging task. The existing specialized amino acid sequence compressors are low compared with that of DNA sequence compressors, mainly because of the characteristics of the data. For example, modeling inversions is harder because of the reverse information loss (from amino acids to DNA sequence). The current lossless data compressor that provides higher compression is AC2. AC2 mixes various context models using Neural Networks and encodes the data using arithmetic encoding.
== History ==
The proposal that proteins were linear chains of α-amino acids was made nearly simultaneously by two scientists at the same conference in 1902, the 74th meeting of the Society of German Scientists and Physicians, held in Karlsbad. Franz Hofmeister made the proposal in the morning, based on his observations of the biuret reaction in proteins. Hofmeister was followed a few hours later by Emil Fischer, who had amassed a wealth of chemical details supporting the peptide-bond model. For completeness, the proposal that proteins contained amide linkages was made as early as 1882 by the French chemist E. Grimaux.
Despite these data and later evidence that proteolytically digested proteins yielded only oligopeptides, the idea that proteins were linear, unbranched polymers of amino acids was not accepted immediately. Some scientists such as William Astbury doubted that covalent bonds were strong enough to hold such long molecules together; they feared that thermal agitations would shake such long molecules asunder. Hermann Staudinger faced similar prejudices in the 1920s when he argued that rubber was composed of macromolecules.
Thus, several alternative hypotheses arose. The colloidal protein hypothesis stated that proteins were colloidal assemblies of smaller molecules. This hypothesis was disproved in the 1920s by ultracentrifugation measurements by Theodor Svedberg that showed that proteins had a well-defined, reproducible molecular weight and by electrophoretic measurements by Arne Tiselius that indicated that proteins were single molecules. A second hypothesis, the cyclol hypothesis advanced by Dorothy Wrinch, proposed that the linear polypeptide underwent a chemical cyclol rearrangement C=O + HN
→
{\displaystyle \rightarrow }
C(OH)-N that crosslinked its backbone amide groups, forming a two-dimensional fabric. Other primary structures of proteins were proposed by various researchers, such as the diketopiperazine model of Emil Abderhalden and the pyrrol/piperidine model of Troensegaard in 1942. Although never given much credence, these alternative models were finally disproved when Frederick Sanger successfully sequenced insulin and by the crystallographic determination of myoglobin and hemoglobin by Max Perutz and John Kendrew.
== Primary structure in other molecules ==
Any linear-chain heteropolymer can be said to have a "primary structure" by analogy to the usage of the term for proteins, but this usage is rare compared to the extremely common usage in reference to proteins. In RNA, which also has extensive secondary structure, the linear chain of bases is generally just referred to as the "sequence" as it is in DNA (which usually forms a linear double helix with little secondary structure). Other biological polymers such as polysaccharides can also be considered to have a primary structure, although the usage is not standard.
== Relation to secondary and tertiary structure ==
The primary structure of a biological polymer to a large extent determines the three-dimensional shape (tertiary structure). Protein sequence can be used to predict local features, such as segments of secondary structure, or trans-membrane regions. However, the complexity of protein folding currently prohibits predicting the tertiary structure of a protein from its sequence alone. Knowing the structure of a similar homologous sequence (for example a member of the same protein family) allows highly accurate prediction of the tertiary structure by homology modeling. If the full-length protein sequence is available, it is possible to estimate its general biophysical properties, such as its isoelectric point.
Sequence families are often determined by sequence clustering, and structural genomics projects aim to produce a set of representative structures to cover the sequence space of possible non-redundant sequences.
== See also ==
Protein sequencing
Nucleic acid primary structure
Translation
Pseudo amino acid composition
== Notes and references == | Wikipedia/Protein_sequence |
Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occur as well. Secondary structure elements typically spontaneously form as an intermediate before the protein folds into its three dimensional tertiary structure.
Secondary structure is formally defined by the pattern of hydrogen bonds between the amino hydrogen and carboxyl oxygen atoms in the peptide backbone. Secondary structure may alternatively be defined based on the regular pattern of backbone dihedral angles in a particular region of the Ramachandran plot regardless of whether it has the correct hydrogen bonds.
The concept of secondary structure was first introduced by Kaj Ulrik Linderstrøm-Lang at Stanford in 1952. Other types of biopolymers such as nucleic acids also possess characteristic secondary structures.
== Types ==
The most common secondary structures are alpha helices and beta sheets. Other helices, such as the 310 helix and π helix, are calculated to have energetically favorable hydrogen-bonding patterns but are rarely observed in natural proteins except at the ends of α helices due to unfavorable backbone packing in the center of the helix. Other extended structures such as the polyproline helix and alpha sheet are rare in native state proteins but are often hypothesized as important protein folding intermediates. Tight turns and loose, flexible loops link the more "regular" secondary structure elements. The random coil is not a true secondary structure, but is the class of conformations that indicate an absence of regular secondary structure.
Amino acids vary in their ability to form the various secondary structure elements. Proline and glycine are sometimes known as "helix breakers" because they disrupt the regularity of the α helical backbone conformation; however, both have unusual conformational abilities and are commonly found in turns. Amino acids that prefer to adopt helical conformations in proteins include methionine, alanine, leucine, glutamate and lysine ("MALEK" in amino-acid 1-letter codes); by contrast, the large aromatic residues (tryptophan, tyrosine and phenylalanine) and Cβ-branched amino acids (isoleucine, valine, and threonine) prefer to adopt β-strand conformations. However, these preferences are not strong enough to produce a reliable method of predicting secondary structure from sequence alone.
Low frequency collective vibrations are thought to be sensitive to local rigidity within proteins, revealing beta structures to be generically more rigid than alpha or disordered proteins. Neutron scattering measurements have directly connected the spectral feature at ~1 THz to collective motions of the secondary structure of beta-barrel protein GFP.
Hydrogen bonding patterns in secondary structures may be significantly distorted, which makes automatic determination of secondary structure difficult. There are several methods for formally defining protein secondary structure (e.g., DSSP, DEFINE, STRIDE, ScrewFit, SST).
=== DSSP classification ===
The Dictionary of Protein Secondary Structure, in short DSSP, is commonly used to describe the protein secondary structure with single letter codes. The secondary structure is assigned based on hydrogen bonding patterns as those initially proposed by Pauling et al. in 1951 (before any protein structure had ever been experimentally determined). There are eight types of secondary structure that DSSP defines:
G = 3-turn helix (310 helix). Min length 3 residues.
H = 4-turn helix (α helix). Minimum length 4 residues.
I = 5-turn helix (π helix). Minimum length 5 residues.
T = hydrogen bonded turn (3, 4 or 5 turn)
E = extended strand in parallel and/or anti-parallel β-sheet conformation. Min length 2 residues.
B = residue in isolated β-bridge (single pair β-sheet hydrogen bond formation)
S = bend (the only non-hydrogen-bond based assignment).
C = coil (residues which are not in any of the above conformations).
'Coil' is often codified as ' ' (space), C (coil) or '–' (dash). The helices (G, H and I) and sheet conformations are all required to have a reasonable length. This means that 2 adjacent residues in the primary structure must form the same hydrogen bonding pattern. If the helix or sheet hydrogen bonding pattern is too short they are designated as T or B, respectively. Other protein secondary structure assignment categories exist (sharp turns, Omega loops, etc.), but they are less frequently used.
Secondary structure is defined by hydrogen bonding, so the exact definition of a hydrogen bond is critical. The standard hydrogen-bond definition for secondary structure is that of DSSP, which is a purely electrostatic model. It assigns charges of ±q1 ≈ 0.42e to the carbonyl carbon and oxygen, respectively, and charges of ±q2 ≈ 0.20e to the amide hydrogen and nitrogen, respectively. The electrostatic energy is
E
=
q
1
q
2
(
1
r
O
N
+
1
r
C
H
−
1
r
O
H
−
1
r
C
N
)
⋅
332
kcal/mol
.
{\displaystyle E=q_{1}q_{2}\left({\frac {1}{r_{\mathrm {ON} }}}+{\frac {1}{r_{\mathrm {CH} }}}-{\frac {1}{r_{\mathrm {OH} }}}-{\frac {1}{r_{\mathrm {CN} }}}\right)\cdot 332{\text{ kcal/mol}}.}
According to DSSP, a hydrogen-bond exists if and only if E is less than −0.5 kcal/mol (−2.1 kJ/mol). Although the DSSP formula is a relatively crude approximation of the physical hydrogen-bond energy, it is generally accepted as a tool for defining secondary structure.
=== SST classification ===
SST is a Bayesian method to assign secondary structure to protein coordinate data using the Shannon information criterion of Minimum Message Length (MML) inference. SST treats any assignment of secondary structure as a potential hypothesis that attempts to explain (compress) given protein coordinate data. The core idea is that the best secondary structural assignment is the one that can explain (compress) the coordinates of a given protein coordinates in the most economical way, thus linking the inference of secondary structure to lossless data compression. SST accurately delineates any protein chain into regions associated with the following assignment types:
E = (Extended) strand of a β-pleated sheet
G = Right-handed 310 helix
H = Right-handed α-helix
I = Right-handed π-helix
g = Left-handed 310 helix
h = Left-handed α-helix
i = Left-handed π-helix
3 = 310-like Turn
4 = α-like Turn
5 = π-like Turn
T = Unspecified Turn
C = Coil
- = Unassigned residue
SST detects π and 310 helical caps to standard α-helices, and automatically assembles the various extended strands into consistent β-pleated sheets. It provides a readable output of dissected secondary structural elements, and a corresponding PyMol-loadable script to visualize the assigned secondary structural elements individually.
== Experimental determination ==
The rough secondary-structure content of a biopolymer (e.g., "this protein is 40% α-helix and 20% β-sheet.") can be estimated spectroscopically. For proteins, a common method is far-ultraviolet (far-UV, 170–250 nm) circular dichroism. A pronounced double minimum at 208 and 222 nm indicate α-helical structure, whereas a single minimum at 204 nm or 217 nm reflects random-coil or β-sheet structure, respectively. A less common method is infrared spectroscopy, which detects differences in the bond oscillations of amide groups due to hydrogen-bonding. Finally, secondary-structure contents may be estimated accurately using the chemical shifts of an initially unassigned NMR spectrum.
== Prediction ==
Predicting protein tertiary structure from only its amino sequence is a very challenging problem (see protein structure prediction), but using the simpler secondary structure definitions is more tractable.
Early methods of secondary-structure prediction were restricted to predicting the three predominate states: helix, sheet, or random coil. These methods were based on the helix- or sheet-forming propensities of individual amino acids, sometimes coupled with rules for estimating the free energy of forming secondary structure elements. The first widely used techniques to predict protein secondary structure from the amino acid sequence were the Chou–Fasman method and the GOR method. Although such methods claimed to achieve ~60% accurate in predicting which of the three states (helix/sheet/coil) a residue adopts, blind computing assessments later showed that the actual accuracy was much lower.
A significant increase in accuracy (to nearly ~80%) was made by exploiting multiple sequence alignment; knowing the full distribution of amino acids that occur at a position (and in its vicinity, typically ~7 residues on either side) throughout evolution provides a much better picture of the structural tendencies near that position. For illustration, a given protein might have a glycine at a given position, which by itself might suggest a random coil there. However, multiple sequence alignment might reveal that helix-favoring amino acids occur at that position (and nearby positions) in 95% of homologous proteins spanning nearly a billion years of evolution. Moreover, by examining the average hydrophobicity at that and nearby positions, the same alignment might also suggest a pattern of residue solvent accessibility consistent with an α-helix. Taken together, these factors would suggest that the glycine of the original protein adopts α-helical structure, rather than random coil. Several types of methods are used to combine all the available data to form a 3-state prediction, including neural networks, hidden Markov models and support vector machines. Modern prediction methods also provide a confidence score for their predictions at every position.
Secondary-structure prediction methods were evaluated by the Critical Assessment of protein Structure Prediction (CASP) experiments and continuously benchmarked, e.g. by EVA (benchmark). Based on these tests, the most accurate methods were Psipred, SAM, PORTER, PROF, and SABLE. The chief area for improvement appears to be the prediction of β-strands; residues confidently predicted as β-strand are likely to be so, but the methods are apt to overlook some β-strand segments (false negatives). There is likely an upper limit of ~90% prediction accuracy overall, due to the idiosyncrasies of the standard method (DSSP) for assigning secondary-structure classes (helix/strand/coil) to PDB structures, against which the predictions are benchmarked.
Accurate secondary-structure prediction is a key element in the prediction of tertiary structure, in all but the simplest (homology modeling) cases. For example, a confidently predicted pattern of six secondary structure elements βαββαβ is the signature of a ferredoxin fold.
== Applications ==
Both protein and nucleic acid secondary structures can be used to aid in multiple sequence alignment. These alignments can be made more accurate by the inclusion of secondary structure information in addition to simple sequence information. This is sometimes less useful in RNA because base pairing is much more highly conserved than sequence. Distant relationships between proteins whose primary structures are unalignable can sometimes be found by secondary structure.
It has been shown that α-helices are more stable, robust to mutations, and designable than β-strands in natural proteins, thus designing functional all-α proteins is likely to be easier that designing proteins with both helices and strands; this has been recently confirmed experimentally.
== See also ==
== References ==
== Further reading ==
== External links ==
NetSurfP – Secondary Structure and Surface Accessibility predictor
PROF
ScrewFit
PSSpred A multiple neural network training program for protein secondary structure prediction
Genesilico metaserver Metaserver which allows to run over 20 different secondary structure predictors by one click
SST webserver: An information-theoretic (compression-based) secondary structural assignment. | Wikipedia/Protein_secondary_structure |
The Philadelphia chromosome or Philadelphia translocation (Ph) is an abnormal version of chromosome 22 where a part of the Abelson murine leukemia 1 (ABL1) gene on chromosome 9 breaks off and attaches to the breakpoint cluster region (BCR) gene in chromosome 22. The balanced reciprocal translocation between the long arms of 9 and 22 chromosomes [t (9; 22) (q34; q11)] results in the fusion gene BCR::ABL1. The oncogenic protein with persistently enhanced tyrosine kinase (TK) activity transcribed by the BCR::ABL1 fusion gene can lead to rapid, uncontrolled growth of immature white blood cells that accumulates in the blood and bone marrow.
The Philadelphia chromosome is present in the bone marrow cells of a vast majority chronic myelogenous leukemia (CML) patients. The expression patterns off different BCR-ABL1 transcripts vary during the progression of CML. Each variant is present in a distinct leukemia phenotype and can be used to predict response to therapy and clinical outcomes. The Ph is also observed in patients with acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), and mixed-phenotype acute leukemia.
== Molecular biology ==
The chromosomal abnormality in the Philadelphia chromosome from the reciprocal translocation t(9;22)(q34;q11), is the result of fragments from chromosomes 9 and 22 swapping places. The ABL proto-oncogene 1 on chromosome 9, from region q34, is juxtaposed with a portion of the BCR gene on chromosome 22, region q11.2. The derivative chromosome 22 produced by this translocation is known as the Philadelphia chromosome. This translocation creates a fusion gene, BCR::ABL1, which codes for a constitutively active ("always on") tyrosine kinase signaling protein, driving uncontrolled cell division.
The formation of the Philadelphia chromosome is due to the fusion of the BCR and ABL1 genes. ABL1 is derived from Abelson murine leukemia, a retrovirus that causes leukemia and lymphoma in mice. It is named after Herbert T. Abelson, who discovered it in 1970. BCR stands for breakpoint cluster region because of the relatively small genomic region where the DNA breaks occurs. The fusion can happen at different points in the BCR gene, where the gene will fuse with exon 2 of ABL (breakpoints in exon 3 of ABL1 have also been observed, but are less frequent). The BCR::ABL1 oncogene exists in three primary isoforms depending on the breakpoint site of the BCR gene and are named after the fuse region, and the molecular weight of the transcribed BCR-ABL1 fusion protein, and all encode for a tyrosine kinase protein. The e1a2 transcript is a fusion between exon 1 of BCR, also called the minor breakpoint region (m-BCR), and exon 2 of ABL1 and encodes an oncoprotein of 185-190kDa, referred to as P190. BCR::ABL1 is associated with around 20-30% of all Philadelphia chromosome positive B-cell ALL (ph+ B-ALL) and is the most genetic subgroup of B-ALL. The incident rate for ALL is age related, as the incident rate increases to 50% for ALL in patients aged 50 years and older. where P190 is associated with 60-80% of these. The e13a2 and e14a2 transcripts found in the major breakpoint region (M-BCR), which consists of exons 12 through 16. These transcripts encode for a oncoprotein of size 210kDa, and is referred to as P210. P210 is associated with over 95% of CML cases, with a 50/50 split between the e13a2 and e14a2 variants. Additionally, e13a2 and e14a2 has been found to be co-expressed in an estimated 5-10% of CML patients. P210 is also found to be present in 40% of adult and 10% of child B-ALL cases. CML has an incidence of 50 cases per million per year Lastly, the e19a2 transcript, located in the μ-BCR region, produces an oncoprotein of 230kDa which is referred to as P230. This variant is uncommon in comparison, and has been linked to the rare disease chronic neutrophilic leukemia (CNL), which falls under mixed-phenotype acute leukemias.
Detection of these variants is carried out using methods such as sanger sequencing, reverse transcription polymerase chain reaction (RT-PCR), qPCR, Flourescense In Situ Hybridization (FISH), and southern blotting. However, many laboratories are working on incorporating Next Generation Sequencing (NGS) into routine diagnostic analysis as NGS technology is rapidly improving, and will in the near future enable full clinical sequencing of the entire gene.
The normal BCR gene is ubiquitously expressed cytoplasmic protein with many known functionalities. ABL1 gene expresses a membrane-associated protein, a nonreceptor protein-tyrosine kinase. ABL1 is linked to multiple processes related to cell growth and survival, such as cytoskeleton and actin remodelling, and inhibition of cell cycle progression. ABL1 can also be found translocated in the nucleus and has DNA binding capabilities, as it is involved in DNA damage control and repair, and apoptosis. The BCR-ABL1 transcript is also translated into a tyrosine kinase containing domains from both the BCR and ABL1 genes. The activity of tyrosine kinases is typically regulated in an auto-inhibitory fashion, but the BCR-ABL1 fusion gene codes for a protein that is constitutively activated, leading to impaired DNA binding and unregulated cell division (i.e. cancer).
== Mechanisms ==
The formation of the BCR::ABL1 oncogene leads to a constitutively active Tyrosine kinase, which is important for transformation of hematopoietic cells. Kinases are enzymes that add phosphate groups to their substrates. In cell biology and cell signalling, phosphorylated substrates are mainly used as a "on" signal, usually setting in motion a cascade of downstream signalling pathways. The high activity of TK leads to a chronic activation of signalling pathways associated with all stages of cell transformation. Resulting in uncontrolled cell proliferation, blocked cell differentiation, and inhibited apoptosis. Meaning cells with the BCR::ABL1 fusion multiply uncontrollably, without differentiating into mature white blood cells that live longer due to a lack of apoptosis promoting signals. This leads to a buildup of these immature white blood cells in the bloodstream There are several signalling pathways associated with the BCR::ABL1 pathogenesis, such as: the Mitogen-activated protein kinase (MAPK/RAS) pathway, PI3K-AKT-mTOR (PAM) pathway, Janus kinase (JAK) - Signal transducers and activators of transcription (STAT) pathway and the Protein Phosphatase 2A (PP2A) tumour suppressor gene –β-catenin pathway.
=== MAPK Pathway ===
The MAPK pathway includes several key signalling components, and phosphorylation events known to play a crucial part in carcinogenesis. MAPK is composed of multiple signalling cascades, of which the RAS-RAF-MEK-ERK signalling pathway can be found. This pathway is known to play a vital role in cell development, proliferation and survival. Mutations in, and abnormal activation of this pathway will induce tumours, being present in 30% of all cancers. BCR::ABL1 fusions will create constitutively active tyrosine kinases. BCR::ABL1 contains a kinase domain containing Tyr 177, which is a binding site for growth factor receptor binding protein 2 (GRB2). GRB2 binds to a protein called son of sevenless (SOS), a guanine nucleotide exchange factor (GEF). SOS facilitates the conversion of inactive RAS-GDP to active RAS-GTP, which turns on the cascade of enzymes which the RAS-RAF-MEK-ERK pathway is composed of. All steps in this pathway are phosphorylation of enzyme downstream of the signalling pathway, which ends with ERK which in turn phosphorylates hundreds of substrates in the cytoplasm and nucleus which regulate many cellular processes including proliferation, survival, and growth. The RAS/RAF/MEK/ERK pathway is also implicated in overexpression of osteopontin (OPN), which is important for maintenance of the hematopoietic stem cell niche, which indirectly influences unchecked proliferation characteristic of leukemic cells. The RAS-MAPK pathway is associated with many types of cancers, including CML and ph+ ALL, being also linked to imatinib resistance in some cases.
=== PI3K-AKT-mTOR (PAM) pathway ===
Associated with cell survival, growth and cell cycle, the PAM signalling pathway plays a central role in both CML, ALL, other leukemias and solid tumours, being found in around 50% of all cancers. Normally the PAM signalling pathway maintains and controls growth factors in all higher eukaryotic cells in response to external stimuli. Hyperactivation of this pathway therefore promotes pro-survival intracellular signalling via the PAM pathway, inducing drug resistance. In cancer cells, the PAM pathway gets stimulated by receptors like G-protein-coupled receptors (GPCR), and receptor tyrosine kinases (RTKs), among others. It is especially through the RTKs that cells with the BCR::ABL1 fusion, the PAM pathway is activated. PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3). The phosphorylation of PIP2 to PIP3 activates AKT, which has numerous downstream signalling targets, related to cellular processes. Additionally, mTOR can act both upstream and downstream of AKT. Two multiprotein complexes of mTOR are involved in the PAM pathway, mTORC1 and mTORC2 which both regulate protein synthesis required for cell growth, angiogenesis, and proliferation. mTORC2 stimulates AKT activity, which in turn amplifies activity of mTORC1 by suppressing mTORC1 inhibitors. BCR::ABL1 activation of the PAM pathway may additionally also occur by binding of two proteins, Crkl and c-Cbl, to the ABL fragment of the fusion oncoprotein. The BCR::ABL1 kinase protein will phosphorylate c-Cbl which will activate PI3K.
=== JAK-STAT pathway ===
The JAK-STAT pathway is an evolutionary conserved signalling pathway involved over 50 cytokines and growth factors are associated with this pathway. Playing an important role in haematopoiesis, differentiation, immune modulation and apoptosis. In healthy cells, JAK proteins naturally phosphorylate each other, prompting a STAT protein to bind to the JAK tyrosine phosphorylated domain. The STAT protein is in turn itself phosphorylated by JAK. STAT is separated from JAK, followed by a translocation of STAT from the cytosol to the nucleus. In the nucleus STAT will induce transcriptional activation of specific genes and other downstream targets. JAK2, STAT1, STAT3 and STAT5 have been shown to be constitutively active in CML models. Where JAK2 and STAT5 being the main components, where BCR::ABL1 enhances the JAK2-STAT5 pathway to enable oncogenic transformation. JAK2 has been shown to phosphorylate the Y177 domain on the BCR::ABL1 oncoprotein, which increases protein stability. JAK2 induces expression of the oncogene c-MYC, which is overexpressed in BCR::ABL1 positive cells, and is a downstream target for activated JAK2 proteins in these cells. STAT 5 is crucial for development and survival of lymphoid leukemia cells, by regulating transcription of anti-apoptotic BCL proteins. c-MYC additionally enables the transactivation of the survivin promoter via JAK2-PI3K pathways, indicating a complex connection between these pathways. STAT5 is not essential for normal haematopoiesis, making it a good therapeutic target in ph+ leukemias.
=== PP2A tumour suppressor gene –β-catenin pathway ===
PP2A is a tumour-suppressor gene which constitutes 0,2% to 1% of total proteins found in mammalian cells, tasked with numerous processes, such as signal transduction, DNA replication, protein translation, regulating cell proliferation, cell cycle progression and differentiation. Studies have shown that in patients with the BCR::ABL1 translocation, BCR::ABL1 fusion protein promotes loss of PP2A function; effectively turning off the tumour suppressor gene. The mechanism for this pathway, involving BCR::ABL1, is complex, involving both the JAK/STAT pathway, and the Wnt/β-catenin pathway. The BCR::ABL1 tyrosine kinase will promote activation of JAK2, which in turn enhances β-catenin activity. β-catenin, a part of the Wnt/ β-catenin pathway associated with cancers unrelated directly to BCR::ABL1, induces inactivation of PP2A via a protein called SET (also known as Inhibitor-2 of PP2A). SET acts as a potent inhibitor of PP2A, turning off PP2A's tumour suppressive activity. Counterintuitively, inhibition of PP2A has been shown to sensitize TKI-resistant cancer cells, making PP2A a target for therapies.
=== Apoptosis ===
Programmed cell death, apoptosis, is controlled by several different mechanisms and pathways involving many enzymes and proteins. Disruption of these mechanisms can lead to loss of apoptotic function in a damaged cell, a hallmark characteristic of cancers. BCR::ABL1 encoded tyrosine kinase can impact both pro-apoptotic and anti-apoptotic proteins via different pathways. An important pro apoptotic is the p53 tumour suppressor, which reacts to DNA damage by inducing apoptosis. Related to p53 is p73, which encodes for multiple proteins through alternative splicing, and has a similar function to p53. Chemotherapeutic chemical cisplatin increases p73 levels in the cell, additionally cisplatin activates c-Abl tyrosine kinase, which enhances the pro-apoptotic ability of p73. c-Abl is activated by DNA damage, and regulates p73 through a c-Abl mechanism. BCR::ABL1 induces and MDM2 mRNA translation via a RNA binding protein. MDM2 negatively regulates p53 and p73 activity by targeting them for ubiquitination, a post translational process that recruits proteins to the proteasomes where they are degraded and recycled. Many chemotherapies are based on creating DNA damage to induce natural apoptosis, cancer cells with BCR::ABL1 are therefore more resistant to these chemotherapies. Other main pathway for apoptosis resistance in BCR::ABL1 positive cancer cells is through the Bcl2 family of apoptotic regulatory proteins. BAD is a pro-apoptotic member of said protein family, when BAD is nonphosphorylated, it binds to the anti-apoptotic Bcl-XL and Bcl-2, promoting cell death. AKT and PI3K can phosphorylate BAD, preventing it from inhibiting anti-apoptotic Bcl-XL and Bcl-2, preventing cell death. AKT can also increase NF-κB activity by accelerating degradation of its inhibitor IκBα. This causes elevated Bcl-XL expression. The STAT5 pathway can also be involved, STAT5 can bind to the Bcl-x promoter, which increases expression of Bcl-XL further reinforcing resistance to apoptosis. Another pro-apoptotic is BAX, which plays a central role in mitochondria dependent apoptosis, is usually regulated by p53. In BCR::ABL1 patients p53 is usually heavily downregulated, resulting in low to no activation of BAX. It is theorised that TKI activity can be enhanced by inhibition of Bcl-2, as Bcl-2 normally prevents apoptosis by binding and inhibiting BAD and BAX. All of these mechanisms attribute to the cell survival and drug resistance which is so characteristic for CML and ALL.
== Nomenclature ==
Table 1. Philadelphia chromosome nomenclature defined by the BCR-ABL1 fusion gene, from a translocation between chromosomes 9 and 22 t(9;22)(q34;q11).
Table 2. The size and disease association of the different BCR-ABL1 fusion proteins based on the breakpoints in the BCR and ABL1 genes.
== Therapy ==
The primary objective of Ph+ CML and ALL treatment is to improve survival rates to match the general population. A secondary objective, although achieved in fewer patients, is a deep molecular response (DMR), which can allow treatment discontinuation and lead to a treatment-free remission.
The main treatment options for Ph+ leukemias are Tyrosine kinase inhibitors (TKIs), chemotherapy, often in combination with TKIs, and allogeneic treatments such as stem cell transplantation (HSCT). Chemotherapy is often used before stem cell transplantation in high-risk patients. HSCT is used for younger or high-risk patients who don't respond well to TKIs.
=== Tyrosine kinase inhibitors (TKIs) ===
The BCR-ABL fusion gene produces an abnormal tyrosine kinase that drives Ph+ leukemia. TKIs target the BRC-ABL1 fusion protein and block the abnormal tyrosine kinase activity, preventing uncontrolled cell proliferation. The first TKI (imatinib) was approved in the US in 2001; since then, 5 additional BCR::ABL1 TKIs have been approved by the US food and drug administration (FDA). The TKIs are categorized in generations pertaining to potency, whereas each subsequent generation is effective to mutations with resistance to the previous generation.
Table 3. FDA approved BCR::ABL1 TKIs categorized by generation.
The introduction of TKIs was initially alongside chemotherapy. Prior to TKIs, chemotherapy had been the standard treatment for Ph-positive leukemia with limited success and low long-term survival rates. The combination improved survival rates resulted in more patients achieving hematologic remission, where leukemia cells can no longer be detected in the blood. However, this approach had significant side effects, with some patients dying from complications during early phases of treatment. Further research explored the use of TKIs with reduced-intensity chemotherapy and since 2004, clinical trials in Italy have used TKIs without chemotherapy during the first phase of treatment. This approach led to higher remission rates, fewer complications and eligibility for elderly patients unable to tolerate intense chemotherapy. Tyrosine kinase inhibitors are now a standard first line therapy for Ph positive ALL and CML. ALL was once the deadliest hematologic cancer, but since the introduction of TKIs in the early 2000s, long term survival is greater than 60% and TKIs are associated with 94-100% complete response rates and 30-40% molecular response rates. TKIs are usually used with a low dose of chemotherapy for induction therapy for Ph positive ALL, but clinical trials have shown that long term remission can be achieved with TKIs alone, sparing the person potentially toxic chemotherapy. Blinatumomab a CD19 monoclonal antibody (with CD19 present on B-lineage ALL cells) may be used in relapsed or refractory Ph positive ALL. Blinatumomab activates CD19 on T cells and activates them to attack leukemic B cells. When combined with TKIs it is associated with greater hematologic response and greater survival; an overall survival of 95% at 18 months and 88% disease free survival.
=== Allogeneic transplantation and immunotherapy ===
Based on the patient's condition and response to TKIs, other treatment options such as Allogeneic Stem Cell Transplantation (HSCT) or immunotherapy. HSCT is primarily considered for younger patients or high-risk patients that do not respond well to TKIs. The process involves transplanting bone marrow stem cells from a matched donor and is infrequently used to treat CML due to long-term complications and risk factors. Traditionally Allogeneic transplantation has been the standard curative treatment for Ph+ leukemia however, studies suggest it may not improve survival in patients without minimal residual disease (MRD). Immunotherapies are often considered in MRD cases or in instances of relapsed patients. Third generation, more potent TKIs and immunotherapies, may lead to fewer patients requiring transplantation as standard treatment. For patients with persistent MRD, TKI resistant mutations or multiple relapses, HSCT should be considered. Depending on the stage of CML, cure rates with HSCT range from 20% to 60%. Improved techniques have reduced relapse free mortality rates after transplant to ~12% after 5 years and has made HSCT feasible for older patients. Post-transplant, TKI maintenance therapy is recommended.
== Prognosis ==
The introduction of BCR::ABL1 targeting TKIs significantly improved Ph+ CML prognosis. TKIs have increased the 10-year overall survival rate from less than 20% to 80%-85%. This has resulted in a similar 10-year relative survival rate for patients with CML and age-matched CML negative controls.
== History ==
In 1960, the Philadelphia chromosome was co-discovered by cytogeneticists David Hungerford and Peter Nowell. The at the time junior faculty member at the university of Pennsylvania School of Medicine Peter Nowell, through an accident managed to clearly see metaphase spreads in leukemic cells. This led him to seek the assistance of graduate student David Hungerford. Together they described an unusual, small chromosome present in leukocytes from patients with CML. This finding provided strong evidence supporting Boveri's hypothesis that a single genetic alteration could drive cancer development. While no other consistent chromosomal abnormalities were initially found in leukemias, the discovery of the Philadelphia chromosome marked a breakthrough in understanding cancer genetics.
The mechanism for which the Philadelphia chromosome arises as a translocation, not a deletion was discovered by Janet Rowley in 1972, and subsequent paper was published in 1973. Rowley used Giemsa staining and quinacrine banding to show that the Ph chromosome resulted from a translocation between chromosomes 9 and 22. The presence of the t(9;22) translocation in nearly all bone marrow cells from CML patients implied that the abnormality was involved as a cause and not a result of the cancer.
In 1984, Nora Heisterkamp and John Groffen later mapped the breakpoints on chromosomes 9 and 22, identifying the BCR on chromosome 22 and its fusion with the ABL gene from chromosome 9. Owen Witte’s work demonstrated that the abnormal tyrosine kinase produced by BRC-ABL fusion gene had enhanced kinase activity. Experiments introducing the BCR-ABL gene in mice led to CML-like disease, proving its central role in leukemia development.
== Notes ==
Many of the sources used in this article refer to different statistics. For example, frequencies of the P190, P210 and P230 oncoproteins in CML and ph+ B-ALL. In this article, the % frequencies were set at an average value based on information from different sources. This discrepancy can probably be attributed to the fact that the review articles used here were based on different studies where frequencies were determined from populations used in the study. Random variations in detected frequency could therefore be to blame for this discrepancy.
Apart from the RAS-RAF, PI3K-AKT and JAK/STAT pathways, a certain source mentioned an additional pathway, the WNT/β-Catenin Pathway, that could also be involved in BCR::ABL1 related cancers. This was however excluded from this article, with exception to its part in the PP2A, due to a lack of good sources supporting this.
== See also ==
Chronic myelogenous leukemia
Acute lymphocytic leukemia
== References ==
== External links ==
Philadelphia+chromosome at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
bcr-abl+Fusion+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Bcr-abl_fusion_protein |
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally.
== Routes of administration ==
=== Ocular ===
Indicated when the fungal infection is located in the eye. There is currently only one ocular antifungal available: natamycin. However, various other antifungal agents could be compounded in this formulation.
=== Intrathecal ===
Used occasionally when there's an infection of the central nervous system and other systemic options cannot reach the concentration required in that region for therapeutic benefit. Example(s): amphotericin B.
=== Vaginal ===
This may be used to treat some fungal infections of the vaginal region. An example of a condition they are sometimes used for is candida vulvovaginitis which is treated with intravaginal Clotrimazole.
=== Topical ===
This is sometimes indicated when there's a fungal infection on the skin. An example is tinea pedis; this is sometimes treated with topical terbinafine.
=== Oral ===
If the antifungal has good bioavailability, this is a common route to handle a fungal infection. An example is the use of ketoconazole to treat coccidioidomycosis.
=== Intravenous ===
Like the oral route, this will reach the bloodstream and distribute throughout the body. However, it is faster and a good option if the drug has poor bioavailability. An example of this is IV amphotericin B for the treatment of coccidioidomycosis.
== Classes ==
The available classes of antifungal drugs are still limited but as of 2021 novel classes of antifungals are being developed and are undergoing various stages of clinical trials to assess performance.
=== Polyenes ===
A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic. The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol. This changes the transition temperature (Tg) of the cell membrane, thereby placing the membrane in a less fluid, more crystalline state. (In ordinary circumstances membrane sterols increase the packing of the phospholipid bilayer making the plasma membrane more dense.) As a result, the cell's contents including monovalent ions (K+, Na+, H+, and Cl−) and small organic molecules leak, which is regarded as one of the primary ways a cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. However, at therapeutic doses, some amphotericin B may bind to animal membrane cholesterol, increasing the risk of human toxicity. Amphotericin B is nephrotoxic when given intravenously. As a polyene's hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.
Amphotericin B
Candicidin
Filipin – 35 carbons, binds to cholesterol (toxic)
Hamycin
Natamycin – 33 carbons, binds well to ergosterol
Nystatin
Rimocidin
=== Azoles ===
Azole antifungals inhibit the conversion of lanosterol to ergosterol by inhibiting lanosterol 14α-demethylase. These compounds have a five-membered ring containing two or three nitrogen atoms. The imidazole antifungals contain a 1,3-diazole (imidazole) ring (two nitrogen atoms), whereas the triazole antifungals have a ring with three nitrogen atoms.
==== Imidazoles ====
==== Triazoles ====
==== Thiazoles ====
=== Allylamines ===
Allylamines inhibit squalene epoxidase, another enzyme required for ergosterol synthesis. Examples include butenafine, naftifine, and terbinafine.
=== Echinocandins ===
Echinocandins inhibit the creation of glucan in the fungal cell wall by inhibiting 1,3-Beta-glucan synthase:
Anidulafungin
Caspofungin
Micafungin
Echinocandins are administered intravenously, particularly for the treatment of resistant Candida species.
=== Triterpenoids ===
Ibrexafungerp
=== Others ===
Acrisorcin
Amorolfine – a morpholine derivative used topically in dermatophytosis
Aurones – possess antifungal properties
Benzoic acid – has antifungal properties, such as in Whitfield's ointment, Friar's Balsam, and Balsam of Peru
Carbol fuchsin (Castellani's paint)
Ciclopirox (ciclopirox olamine) – a hydroxypyridone antifungal that interferes with active membrane transport, cell membrane integrity, and fungal respiratory processes. It is most useful against tinea versicolour.
Clioquinol
Coal tar
Copper(II) sulfate
Crystal violet – a triarylmethane dye. It has antibacterial, antifungal, and anthelmintic properties and was formerly important as a topical antiseptic.
Chlorhexidine is a topical antibacterial and antifungal. It is commonly used in hospitals as an antiseptic. It is much more strongly antibacterial than antifungal, requiring at least a 10 times higher concentration to kill yeast compared to gram negative bacteria
Chlorophetanol
Diiodohydroxyquinoline (Iodoquinol)
Flucytosine (5-fluorocytosine) – an antimetabolite pyrimidine analog
Fumagillin
Griseofulvin – binds to microtubules and inhibits mitosis
Haloprogin – discontinued due to the emergence of antifungals with fewer side effects
Miltefosine works by damaging fungal cell membranes
Nikkomycin – blocks formation of chitin present in the cell wall of fungus.
Orotomide (F901318) – pyrimidine synthesis inhibitor
Piroctone olamine
Pentanenitrile
Potassium iodide – preferred treatment for lymphocutaneous sporotrichosis and subcutaneous zygomycosis (basidiobolomycosis). The mode of action is obscure.
Potassium permanganate - for use only on thicker, more insensitive skin such as the soles of the feet.
Selenium disulfide
Sodium thiosulfate
Sulfur
Tolnaftate – a thiocarbamate antifungal, which inhibits fungal squalene epoxidase (similar mechanism to allylamines like terbinafine)
Triacetin – hydrolysed to acetic acid by fungal esterases
Undecylenic acid – an unsaturated fatty acid derived from natural castor oil; fungistatic, antibacterial, antiviral, and inhibits Candida morphogenesis
Zinc pyrithione
== Side effects ==
Incidents of liver injury or failure among modern antifungal medicines are very low to non-existent. However, some can cause allergic reactions in people.
There are also many drug interactions. Patients must read in detail the enclosed data sheet(s) of any medicine. For example, the azole antifungals such as ketoconazole or itraconazole can be both substrates and inhibitors of the P-glycoprotein, which (among other functions) excretes toxins and drugs into the intestines. Azole antifungals are also both substrates and inhibitors of the cytochrome P450 family CYP3A4, causing increased concentration when administering, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, tricyclic antidepressants, macrolides and SSRIs.
Before oral antifungal therapies are used to treat nail disease, a confirmation of the fungal infection should be made. Approximately half of suspected cases of fungal infection in nails have a non-fungal cause. The side effects of oral treatment are significant and people without an infection should not take these drugs.
Azoles are the group of antifungals which act on the cell membrane of fungi. They inhibit the enzyme 14-alpha-sterol demethylase, a microsomal CYP, which is required for the biosynthesis of ergosterol for the cytoplasmic membrane. This leads to the accumulation of 14-alpha-methylsterols resulting in impairment of function of certain membrane-bound enzymes and disruption of close packing of acyl chains of phospholipids, thus inhibiting growth of the fungi. Some azoles directly increase permeability of the fungal cell membrane.
== Resistance ==
Antifungal resistance is a subset of antimicrobial resistance, that specifically applies to fungi that have become resistant to antifungals. Resistance to antifungals can arise naturally, for example by genetic mutation or through aneuploidy. Extended use of antifungals leads to the development of antifungal resistance through various mechanisms.
Some fungi (e.g. Candida krusei and fluconazole) exhibit intrinsic resistance to certain antifungal drugs or classes, whereas some species develop antifungal resistance to external pressures. Antifungal resistance is a One Health concern, driven by multiple extrinsic factors, including extensive fungicidal use, overuse of clinical antifungals, environmental change and host factors.
Like resistance to antibacterials, antifungal resistance can be driven by antifungal use in agriculture. Currently there is no regulation on the use of similar antifungal classes in agriculture and the clinic.
The emergence of Candida auris as a potential human pathogen that sometimes exhibits multi-class antifungal drug resistance is concerning and has been associated with several outbreaks globally. The WHO has released a priority fungal pathogen list, including pathogens with antifungal resistance.
== References ==
== External links ==
Antifungal Drugs – Detailed information on antifungals from the Fungal Guide written by R. Thomas and K. Barber
"Clotrimazole". Clotrimazole (Canesten). Bayer Philippines. | Wikipedia/Antifungal_drug |
Electrochemotherapy (ECT) is a type of chemotherapy that allows delivery of non-permeant drugs to the cell interior. It is based on the local application of short and intense electric pulses that transiently permeabilize the cell membrane, thus allowing transport of molecules otherwise not permitted by the membrane. Applications for treatment of cutaneous and subcutaneous tumors have reached clinical use by utilizing drugs such as bleomycin or cisplatin). Electrochemotherapy with bleomycin was used to treat a patient for the first time in 1991 at the Institute Gustave Roussy in France, while electrochemotherapy with cisplatin was used to treat for the first time in 1995 at the Institute of Oncology, Ljubljana, Slovenia. Since then, more than 4000 patients were treated with electrochemotherapy all over the world (Argentina, Australia, Austria, Belgium, Bulgaria, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Mexico, Nicaragua, Poland, Portugal, Slovenia, Spain, Sweden, UK, USA). Recently, new electrochemotherapy modalities have been developed for treatment of internal tumors using surgical procedures, endoscopic routes, or percutaneous approaches to gain access to the treatment area.
== Physical principle ==
When a biological cell is exposed to an electric field of sufficient strength, an increase in the transmembrane voltage is generated, which leads to rearrangements of the cell membrane structure. These changes result in an increase of the cell membrane permeability, which allows nonpermeant molecules to enter the cell. This phenomenon is called electroporation (or electropermeabilization) and is becoming widely used to improve anticancer drug delivery into cells, which is being referred to as electrochemotherapy.
All biomedical applications of cell electropermeabilization use direct currents (all unipolar) with short and intense pulses (even though in vitro, time-decayed pulses can be used). Amplitude of the pulses depends on the tissues and on the shape and position of the electrodes, but, in vivo, in the case of the tumors, the amplitude of the electric pulses has to be high enough to establish an electrical field of 400 V/cm in the area of tumor (8 pulses with duration of 100 microseconds). The duration of pulses is usually one hundred microseconds. In early experiments, pulses were delivered with period of 1 second (i.e. at a repetition frequency of 1 Hz); today, pulses are delivered in a much shorter time period, at a repetition frequency of 5000 Hz, resulting in a much less discomfort for the patient and in the shorter duration of treatment. For treatment of deep-seated tumors in relative vicinity of the heart, pulses are synchronized with absolute refractory period of each heartbeat to minimize the probability of interaction of pulses with the heart function.
== Treatment ==
The electrochemotherapeutic treatment consists of delivering, either systemically or locally, non-permeant cytotoxic drugs (e.g. bleomycin) or low-permeant drugs (e.g. cisplatin) and applying electric pulses to the area to be treated when the concentration of the drug in the tumor is at its peak. With the delivery of the electric pulses, cells are subjected to an electric field that causes the formation of nanoscale defects on the cell membrane, which alter the permeability of the membrane. At this stage and for some time after pulses are delivered, molecules of the cytotoxic agents can freely diffuse into the cytoplasm and exert their cytotoxic effect. Multiple positioning of the electrodes, and subsequent pulse delivery, can be performed during a session to treat the whole lesion, provided that drug concentration is sufficient. Treatment can be repeated over the course of weeks or months to achieve regression of large lesions.
== Application ==
Electrochemotherapy (ECT) is currently primarily used for the treatment of skin cancers, such as basal cell carcinoma, squamous cell carcinoma, melanoma, and Kaposi's sarcoma, an area in which its use is increasing. Additionally, ECT is uniquely employed by a clinic in Germany for the treatment of prostate cancer, often in combination with Irreversible Electroporation (IRE).
== Efficacy and clinical relevance ==
In a number of clinical studies (phase II and phase III), investigators have concluded that electrochemotherapy of cutaneous or subcutaneous metastasis or tumours with bleomycin and cisplatin have an objective response rate of more than 80%. Reduction of tumor size has been achieved with electrochemotherapy faster and more efficiently than in standard chemotherapy for both cutaneous and subcutaneous tumors. Patients with skin metastasis from melanoma, Kaposi sarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, or breast cancer have been successfully treated. First clinical results of electrochemotherapy of internal tumors (e.g. liver metastases) are also promising and encouraging.
The success rate for electrochemotherapy in "human malignancies" has been stated to be more than 80% provided that a proper patient selection criteria will be performed.
== Safety ==
Electrochemotherapy employs lower dosages of chemotherapeutic drugs than standard chemotherapy protocols; thus, the patient's burden usually associated to chemotherapy is not present. In the clinical use of electrochemotherapy, limited side effects related to bleomycin or cisplatin use are recorded. Provided that appropriate anesthesia is used for alleviation of the symptoms associated with application of electric pulses, the control of the pain level during the electrochemotherapy is acceptable for the patients. Other than pain, which is limited to the treated tumor and surrounding tissue, muscle contraction during electric pulse delivery is the only other discomfort. There is also induction of a vascular lock by the type of pulses used in electrochemotherapy: for a few minutes, blood flow is interrupted in the treated volume in the normal tissues. Its duration is too short to induce deleterious effects due to ischemia. In tumors however, vascular lock is of a longer duration and can contribute to the effectiveness of the electrochemotherapy.
== Veterinary use ==
Electrochemotherapy is also used in veterinary oncology for a variety of tumors in dogs, cats, horses, and rabbits. There are centers in Argentina, Brazil, Chile, Uruguay, Paraguay, Mexico, Peru, Bolivia, Colombia, Ecuador, Republica Dominicana, Spain, France, Italy, Ireland, Slovenia, United Arab Emirates, and the UK,. There are now multiple institutions in the US including Maine, New York, Rhode Island, Washington, Missouri, South Carolina, Hawaii, Las Vegas, Florida, Virginia, and the Bay Area of Northern California where this treatment is available.
The success rate for electrochemotherapy has been stated to be around 90%, with an average of 3-4 treatments in the case of rabbits.
== See also ==
Cancer
Chemotherapy
Electricity
== References == | Wikipedia/Electrochemotherapy |
Thrombolysis, also called fibrinolytic therapy, is the breakdown (lysis) of blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism (massive pulmonary embolism or extensive deep vein thrombosis).
The main complication is bleeding (which can be dangerous), and in some situations thrombolysis may therefore be unsuitable. Thrombolysis can also play an important part in reperfusion therapy that deals specifically with blocked arteries.
== Medical uses ==
Diseases where thrombolysis is used:
ST elevation myocardial infarction: Large trials have shown that mortality can be reduced using thrombolysis (particularly fibrinolysis) in treating heart attacks. It works by stimulating secondary fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator (tPA), the protein that normally activates plasmin.
Stroke: Thrombolysis reduces major disability or death when given within 3 hours (or perhaps even 6 hours) of ischaemic stroke onset when there are no contraindications to treatment.
Massive pulmonary embolism. For the treatment of a massive pulmonary embolism, catheter-directed therapy is a safer and more effective alternative to systemic thrombolysis. This involves the injecting of drugs directly into the clot.
Severe deep vein thrombosis (DVT), such as phlegmasia cerulea dolens, which threatens limb loss, or iliofemoral DVT, where clots involve at a minimum the common iliac vein
Acute limb ischaemia
Clotted hemothorax
Thrombolysis is usually intravenous. It may also be used directly into the affected blood vessel during an angiogram (intra-arterial thrombolysis), e.g. when patients present with stroke beyond three hours or in severe deep vein thrombosis (catheter-directed thrombolysis).
Thrombolysis is performed by many types of medical specialists, including interventional radiologists, vascular surgeons, cardiologists, interventional neuroradiologists, and neurosurgeons. In some countries such as the United States of America, emergency medical technicians may administer thrombolytics for heart attacks in prehospital settings, by on-line medical direction. In countries with more extensive and independent qualifications, prehospital thrombolysis (fibrinolysis) may be initiated by the emergency care practitioner (ECP). Other countries which employ ECP's include, South Africa, the United Kingdom, and New Zealand. Prehospital thrombolysis is always the result of a risk-benefit calculation of the heart attack, thrombolysis risks, and primary percutaneous coronary intervention (pPCI) availability.
== Contraindications ==
Thrombolysis is not without risks. Therefore, clinicians must select patients who are to be best suited for the procedure, and those who have the least risk of having a fatal complication. An absolute contraindication is in itself enough to avoid thrombolysis, while a relative contraindication needs to be considered in relation to the overall clinical situation.
=== Myocardial infarction ===
Absolute contraindications:
Any previous history of hemorrhagic stroke, ischemic stroke within 3 months.
History of stroke, dementia, or central nervous system damage within 1 year
Head trauma within 3 weeks or brain surgery within 6 months
Known intracranial neoplasm
Suspected aortic dissection
Internal bleeding within 6 weeks
Active bleeding or known bleeding disorder
Traumatic cardiopulmonary resuscitation within 3 weeks
Relative contraindications:
Oral anticoagulant therapy
Acute pancreatitis
Pregnancy or within 1 week postpartum
Active peptic ulceration
Transient ischemic attack within 6 months
Dementia
Infective endocarditis
Active cavitating pulmonary tuberculosis
Advanced liver disease
Intracardiac thrombi
Uncontrolled hypertension (systolic blood pressure >180 mm Hg, diastolic blood pressure >110 mm Hg)
Puncture of noncompressible blood vessel within 2 weeks
Previous streptokinase therapy
Major surgery, trauma, or bleeding within 2 weeks
=== Stroke ===
Absolute contraindications:
Uncertainty about time of stroke onset (e.g. patients awakening from sleep).
Coma or severe obtundation with fixed eye deviation and complete hemiplegia.
Hypertension: systolic blood pressure ≥ 185mmHg; or diastolic blood pressure >110mmHg on repeated measures prior to study (if reversed, patient can be treated).
Clinical presentation suggestive of subarachnoid haemorrhage even if the CT scan is normal.
Presumed septic embolus.
Patient having received a heparin medication within the last 48 hours and has an elevated Activated Prothrombin Time (APTT) or has a known hereditary or acquired haemorrhagic diathesis
INR >1.7
Known advanced liver disease, advanced right heart failure, or anticoagulation, and INR > 1.5 (no need to wait for INR result in the absence of the former three conditions).
Known platelet count <100,000 uL.
Serum glucose is < 2.8 mmol/L or >22.0 mmol/L.
Relative contraindications:
Severe neurological impairment with NIHSS score >22.
Age >80 years.
CT evidence of extensive middle cerebral artery (MCA) territory infarction (sulcal effacement or blurring of grey-white junction in greater than 1/3 of MCA territory).
Stroke or serious head trauma within the past three months where the risks of bleeding are considered to outweigh the benefits of therapy.
Major surgery within the last 14 days (consider intra-arterial thrombolysis).
Patient has a known history of intracranial haemorrhage, subarachnoid haemorrhage, known intracranial arteriovenous malformation or previously known intracranial neoplasm
Suspected recent (within 30 days) myocardial infarction.
Recent (within 30 days) biopsy of a parenchymal organ or surgery that, in the opinion of the responsible clinician, would increase the risk of unmanageable (e.g. uncontrolled by local pressure) bleeding.
Recent (within 30 days) trauma with internal injuries or ulcerative wounds.
Gastrointestinal or urinary tract haemorrhage within the last 30 days or any active or recent haemorrhage that, in the opinion of the responsible clinician, would increase the risk of unmanageable (e.g. by local pressure) bleeding.
Arterial puncture at non-compressible site within the last 7 days.
Concomitant serious, advanced or terminal illness or any other condition that, in the opinion of the responsible clinician would pose an unacceptable risk.
Minor or Rapidly improving deficit.
Seizure: If the presenting neurological deficit is deemed due to a seizure.
Pregnancy is not an absolute contraindication. Consider intra-arterial thrombolysis.
== Side-effects ==
Hemorrhagic stroke is a rare but serious complication of thrombolytic therapy. If a patient has had thrombolysis before, an allergy against the thrombolytic drug may have developed (especially after streptokinase). If the symptoms are mild, the infusion is stopped and the patient is commenced on an antihistamine before infusion is recommenced. Anaphylaxis generally requires immediate cessation of thrombolysis.
== Agents ==
Thrombolysis therapy uses thrombolytic drugs that dissolve blood clots. Most of these drugs target fibrin (one of the main constituent of blood clots) and are therefore called fibrinolytics. All currently approved thrombolytic drugs are biologics, either derived from Streptococcus species, or, more recently, using recombinant biotechnology whereby tPA is manufactured using cell culture, resulting in a recombinant tissue plasminogen activator or rtPA.
Some fibrinolytics are:
Streptokinase (Kabikinase)
Urokinase
Recombinant tissue plasminogen activators (rtPA)
Alteplase (Activase or Actilyse)
Reteplase (Retavase)
Tenecteplase
Anistreplase (Eminase)
== Catheter-directed thrombolysis ==
A 2023 meta-analysis of 44 studies compared treatments for pulmonary embolism including thrombolytic therapy delivered through a catheter. Catheter-directed thrombolysis (CDT) methods included fragmentation and ultrasound use. CDT was associated with better outcomes than anticoagulation alone or systemic thrombolysis, but the studies were mostly small and observational.
In people who receive CDT, there is a risk of hemorrhage as a side effect. Scientists have studied whether measuring fibrinogen in blood can be used as a biomarker to predict hemorrhage. As of 2017 it was not known if this works or not.
== Research ==
Researchers showed a 10-fold variation in the proportion of patients who received thrombolysis after stroke in England and Wales, ranging from 1 in 50 (2%) to 1 in 4 (24%). The team also showed that most of the variation was explained by hospital processes (such as how quickly people can have a brain scan) and in doctors’ decision-making (who they think should or should not receive thrombolysis) rather than knowledge of the time of stroke.
Prospective, randomized clinical trials to evaluate the utility of catheter-directed thrombolysis in pulmonary embolism include HI-PEITHO (Higher-Risk Pulmonary Embolism Thrombolysis).
== See also ==
TIMI – thrombolysis in myocardial infarction
== References == | Wikipedia/Thrombolytic_drug |
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
== Classification ==
Immunosuppressive drugs can be classified into five groups:
glucocorticoids
cytostatics
antibodies
drugs acting on immunophilins
other drugs
=== Glucocorticoids ===
In pharmacologic (supraphysiologic) doses, glucocorticoids, such as prednisone, dexamethasone, and hydrocortisone are used to suppress various allergic, inflammatory, and autoimmune disorders. They are also administered as posttransplantory immunosuppressants to prevent the acute transplant rejection and graft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes.
==== Immunosuppressive mechanism ====
Glucocorticoids suppress cell-mediated immunity. They act by inhibiting gene expression of cytokines including Interleukin 1 (IL-1), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-alpha by binding to corticosteroid response elements on DNA. This decrease in cytokine production reduces T cell proliferation. With decreased T cell proliferation there is decreased production of IL-2. This further decreases the proliferation of T cells.
Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis.
==== Anti-inflammatory effects ====
Glucocorticoids influence all types of inflammatory events, no matter their cause. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect.
Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes.
=== Cytostatics ===
Cytostatics inhibit cell division. In immunotherapy, they are used in smaller doses than in the treatment of malignant diseases. They affect the proliferation of both T cells and B cells. Due to their highest effectiveness, purine analogs are most frequently administered.
==== Alkylating agents ====
The alkylating agents used in immunotherapy are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others. Cyclophosphamide (Baxter's Cytoxan) is probably the most potent immunosuppressive compound. In small doses, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias, granulomatosis with polyangiitis, and other immune diseases. High doses cause pancytopenia and hemorrhagic cystitis.
==== Antimetabolites ====
Antimetabolites interfere with the synthesis of nucleic acids. These include:
folic acid analogues, such as methotrexate
purine analogues, such as azathioprine and mercaptopurine
pyrimidine analogues, such as fluorouracil
protein synthesis inhibitors.
===== Methotrexate =====
Methotrexate is a folic acid analogue. It binds dihydrofolate reductase and prevents synthesis of tetrahydrofolate. It is used in the treatment of autoimmune diseases (for example rheumatoid arthritis or Behcet's Disease) and in transplantations.
===== Azathioprine and mercaptopurine =====
Azathioprine (Prometheus' Imuran), is the main immunosuppressive cytotoxic substance. It is extensively used to control transplant rejection reactions. It is nonenzymatically cleaved to mercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis. Mercaptopurine itself can also be administered directly.
By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. It is also efficient in the treatment of autoimmune diseases.
===== Cytotoxic antibiotics =====
Among these, dactinomycin is the most important. It is used in kidney transplantations. Other cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, mithramycin.
=== Antibodies ===
Antibodies are sometimes used as a quick and potent immunosuppressive therapy to prevent the acute rejection reactions as well as a targeted treatment of lymphoproliferative or autoimmune disorders (e.g., anti-CD20 monoclonals).
==== Polyclonal antibodies ====
Heterologous polyclonal antibodies are obtained from the serum of animals (e.g., rabbit, horse), and injected with the patient's thymocytes or lymphocytes. The antilymphocyte (ALG) and antithymocyte antigens (ATG) are being used. They are part of the steroid-resistant acute rejection reaction and grave aplastic anemia treatment. However, they are added primarily to other immunosuppressives to diminish their dosage and toxicity. They also allow transition to cyclosporin therapy.
Polyclonal antibodies inhibit T lymphocytes and cause their lysis, which is both complement-mediated cytolysis and cell-mediated opsonization followed by removal of reticuloendothelial cells from the circulation in the spleen and liver. In this way, polyclonal antibodies inhibit cell-mediated immune reactions, including graft rejection, delayed hypersensitivity (i.e., tuberculin skin reaction), and the graft-versus-host disease (GVHD), but influence thymus-dependent antibody production.
As of March 2005, there are two preparations available to the market: Atgam, obtained from horse serum, and Thymoglobuline, obtained from rabbit serum. Polyclonal antibodies affect all lymphocytes and cause general immunosuppression, possibly leading to post-transplant lymphoproliferative disorders (PTLD) or serious infections, especially by cytomegalovirus. To reduce these risks, treatment is provided in a hospital, where adequate isolation from infection is available. They are usually administered for five days intravenously in the appropriate quantity. Patients stay in the hospital as long as three weeks to give the immune system time to recover to a point where there is no longer a risk of serum sickness.
Because of a high immunogenicity of polyclonal antibodies, almost all patients have an acute reaction to the treatment. It is characterized by fever, rigor episodes, and even anaphylaxis. Later during the treatment, some patients develop serum sickness or immune complex glomerulonephritis. Serum sickness arises seven to fourteen days after the therapy has begun. The patient has fever, joint pain, and erythema that can be soothed with the use of steroids and analgesics. Urticaria (hives) can also be present. It is possible to diminish their toxicity by using highly purified serum fractions and intravenous administration in the combination with other immunosuppressants, for example, calcineurin inhibitors, cytostatics, and corticosteroids. The most frequent combination is to use antibodies and ciclosporin simultaneously in order to prevent patients from gradually developing a strong immune response to these drugs, reducing or eliminating their effectiveness.
==== Monoclonal antibodies ====
Monoclonal antibodies are directed towards exactly defined antigens. Therefore, they cause fewer side-effects. Especially significant are the IL-2 receptor- (CD25-) and CD3-directed antibodies. They are used to prevent the rejection of transplanted organs, but also to track changes in the lymphocyte subpopulations. It is reasonable to expect similar new drugs in the future.
===== T-cell receptor directed antibodies =====
Muromonab-CD3 is a murine anti-CD3 monoclonal antibody of the IgG2a type that was previously used to prevent T-cell activation and proliferation by binding the T-cell receptor complex present on all differentiated T cells. As such it was one of the first potent immunosuppressive substances and was administered to control the steroid- and/or polyclonal antibodies-resistant acute rejection episodes. As it acts more specifically than polyclonal antibodies it was also used prophylactically in transplantations. However, muromonab-CD3 is no longer produced, and this mouse monoclonal antibody has been replaced in the clinic with chimeric, humanized, or human monoclonal antibodies.
The muromonab's mechanism of action is only partially understood. It is known that the molecule binds TCR/CD3 receptor complex. In the first few administrations this binding non-specifically activates T-cells, leading to a serious syndrome 30 to 60 minutes later. It is characterized by fever, myalgia, headache, and arthralgia. Sometimes it develops in a life-threatening reaction of the cardiovascular system and the central nervous system, requiring a lengthy therapy. Past this period CD3 blocks the TCR-antigen binding and causes conformational change or the removal of the entire TCR3/CD3 complex from the T-cell surface. This lowers the number of available T-cells, perhaps by sensitizing them for the uptake by the epithelial reticular cells. The cross-binding of CD3 molecules as well activates an intracellular signal causing the T cell anergy or apoptosis, unless the cells receive another signal through a co-stimulatory molecule. CD3 antibodies shift the balance from Th1 to Th2 cells as CD3 stimulates Th1 activation.
The patient may develop neutralizing antibodies reducing the effectiveness of muromonab-CD3.
Muromonab-CD3 can cause excessive immunosuppression. Although CD3 antibodies act more specifically than polyclonal antibodies, they lower the cell-mediated immunity significantly, predisposing the patient to opportunistic infections and malignancies.
===== IL-2 receptor directed antibodies =====
Interleukin-2 is an important immune system regulator necessary for the clone expansion and survival of activated lymphocytes T. Its effects are mediated by the trimer cell surface receptor IL-2a, consisting of the α, β, and γ chains. The IL-2a (CD25, T-cell activation antigen, TAC) is expressed only by the already-activated T lymphocytes. Therefore, it is of special significance to the selective immunosuppressive treatment, and research has been focused on the development of effective and safe anti-IL-2 antibodies. By the use of recombinant gene technology, the mouse anti-Tac antibodies have been modified, leading to the presentation of two chimeric mouse/human anti-Tac antibodies in the year 1998: basiliximab (Simulect) and daclizumab (Zenapax). These drugs act by binding the IL-2a receptor's α chain, preventing the IL-2 induced clonal expansion of activated lymphocytes and shortening their survival. They are used in the prophylaxis of the acute organ rejection after bilateral kidney transplantation, both being similarly effective and with only few side-effects.
=== Drugs acting on immunophilins ===
==== Ciclosporin ====
Like tacrolimus, ciclosporin (Novartis' Sandimmune) is a calcineurin inhibitor (CNI). It has been in use since 1983 and is one of the most widely used immunosuppressive drugs. It is a cyclic fungal peptide, composed of 11 amino acids.
Ciclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits the phosphatase calcineurin, which under normal circumstances induces the transcription of interleukin-2. The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.
Ciclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer, and less nephrotoxic, immunosuppressants.
Calcineurin inhibitors and azathioprine have been linked with post-transplant malignancies and skin cancers in organ transplant recipients. Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can result in significant morbidity and mortality. The results of several studies suggest that calcineurin inhibitors have oncogenic properties mainly linked to the production of cytokines that promote tumor growth, metastasis and angiogenesis.
This drug has been reported to reduce the frequency of regulatory T cells (T-Reg) and after converting from a CNI monotherapy to a mycophenolate monotherapy, patients were found to have increased graft success and T-Reg frequency.
==== Tacrolimus ====
Tacrolimus (trade names Prograf, Astagraf XL, Envarsus XR) is a product of the bacterium Streptomyces tsukubensis. It is a macrolide lactone and acts by inhibiting calcineurin.
The drug is used primarily in liver and kidney transplantations, although in some clinics it is used in heart, lung, and heart/lung transplantations. It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects.
==== Sirolimus ====
Sirolimus (rapamycin, trade name Rapamune) is a macrolide lactone, produced by the actinomycete bacterium Streptomyces hygroscopicus. It is used to prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side-effects.
Contrary to ciclosporin and tacrolimus, drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second phase, namely signal transduction and lymphocyte clonal proliferation. It binds to FKBP1A like tacrolimus, however the complex does not inhibit calcineurin but another protein, mTOR. Therefore, sirolimus acts synergistically with ciclosporin and, in combination with other immunosuppressants, has few side effects. Also, it indirectly inhibits several T lymphocyte-specific kinases and phosphatases, hence preventing their transition from G1 to S phase of the cell cycle. In a similar manner, Sirolimus prevents B cell differentiation into plasma cells, reducing production of IgM, IgG, and IgA antibodies.
It is also active against tumors that are PI3K/AKT/mTOR-dependent.
==== Everolimus ====
Everolimus is an analog of sirolimus and also is an mTOR inhibitor.
==== Zotarolimus ====
Zotarolimus is a semi-synthetic derivative of sirolimus used in drug-eluting stents.
=== Other drugs ===
==== Interferons ====
IFN-β suppresses the production of Th1 cytokines and the activation of monocytes. It is used to slow down the progression of multiple sclerosis. IFN-γ is able to trigger lymphocytic apoptosis.
==== Opioids ====
Prolonged use of opioids may cause immunosuppression of both innate and adaptive immunity. Decrease in proliferation as well as immune function has been observed in macrophages, as well as lymphocytes. It is thought that these effects are mediated by opioid receptors expressed on the surface of these immune cells.
==== TNF binding proteins ====
A TNF-α (tumor necrosis factor-alpha) binding protein is a monoclonal antibody or a circulating receptor such as infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira) that binds to TNF-α, preventing it from inducing the synthesis of IL-1 and IL-6 and the adhesion of lymphocyte-activating molecules. They are used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, and psoriasis.
These drugs may raise the risk of contracting tuberculosis or inducing a latent infection to become active. Infliximab and adalimumab have label warnings stating that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with them.
TNF or the effects of TNF are also suppressed by various natural compounds, including curcumin (an ingredient in turmeric) and catechins (in green tea).
==== Mycophenolate ====
Mycophenolic acid acts as a non-competitive, selective, and reversible inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novo guanosine nucleotide synthesis. In contrast to other human cell types, lymphocytes B and T are very dependent on this process. Mycophenolate mofetil is used in combination with ciclosporin or tacrolimus in transplant patients.
==== Small biological agents ====
Fingolimod is a synthetic immunosuppressant. It increases the expression or changes the function of certain adhesion molecules (α4/β7 integrin) in lymphocytes, so they accumulate in the lymphatic tissue (lymphatic nodes) and their number in the circulation is diminished. In this respect, it differs from all other known immunosuppressants.
Myriocin has been reported being 10 to 100 times more potent than Ciclosporin.
== Therapy ==
Immunosuppressive drugs are used in immunosuppressive therapy to:
Prevent the rejection of transplanted organs and tissues (e.g., bone marrow, heart, kidney, liver)
Treat autoimmune diseases or diseases that are most likely of autoimmune origin (e.g., rheumatoid arthritis, multiple sclerosis, myasthenia gravis, psoriasis and psoriatic arthritis, vitiligo, granulomatosis with polyangiitis, systemic lupus erythematosus, systemic sclerosis, scleroderma, sarcoidosis, focal segmental glomerulosclerosis, Crohn's disease, Behcet's Disease, pemphigus, ankylosing spondylitis, and ulcerative colitis).
Treat some other non-autoimmune inflammatory diseases (e.g., long term allergic asthma control).
== Side effects ==
A common side-effect of many immunosuppressive drugs is immunodeficiency, because the majority of them act non-selectively, resulting in increased susceptibility to infections, decreased cancer immunosurveillance and decreased ability to produce antibodies after vaccination.
However, the vaccination status of patients taking immunosuppressive drugs for chronic diseases such as Rheumatoid arthritis or Inflammatory bowel disease should be investigated before starting any treatment, and patients should eventually be vaccinated against Vaccine-preventable disease. Some studies showed a low vaccination rate against some Vaccine-preventable disease among patients taking immunosuppressive drugs, despite a generally positive attitude towards vaccinations.
There are also other side-effects, such as hypertension, dyslipidemia, hyperglycemia, peptic ulcers, lipodystrophy, moon face, liver injury and kidney injury. The immunosuppressive drugs also interact with other medicines and affect their metabolism and action. Actual or suspected immunosuppressive agents can be evaluated in terms of their effects on lymphocyte subpopulations in tissues using immunohistochemistry.
== See also ==
Immunosuppression
BK virus
Behcet's Disease
Discovery and development of mTOR inhibitors
Treatment methods for preventing organ rejection
== References ==
== Further reading ==
== External links ==
"Pancreas-Kidney Transplantation: Drugs". pancreas-kidney.com. Archived from the original on 29 October 2013. a brief history of immunosuppressive drugs. Retrieved 21 August 2005.
Papich M (2001). "Immunosuppressive drug therapy". World Small Animal Veterinary Association (WSAVA). Archived from the original on 30 November 2016. Retrieved 21 August 2005.
"Are Immunosuppressive Drugs a Useful Adjuvant to Treatment of HIV with Antiretrovirals?". Hivandhepatitis.com. Archived from the original on 28 February 2019. Retrieved 21 August 2005.
Induction of Tolerance at eMedicine
"Immunosuppressants". A to Z Health Guide. National Kidney Foundation. 24 December 2015.
"Immunosuppressants, Pharmacologic profile". Drugguide.com. Retrieved 15 March 2016.
Immunosuppressive+Agents at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Immunosuppressive_drug |
An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation where classical Vitamin K antagonist anticoagulants have minimal effect.
Antiplatelet drugs are widely used in primary and secondary prevention of thrombotic disease, especially myocardial infarction and ischemic stroke.
Antiplatelet therapy with one or more of these drugs decreases the ability of blood clots to form by interfering with the platelet activation process in primary hemostasis. Antiplatelet drugs can reversibly or irreversibly inhibit the process involved in platelet activation resulting in decreased tendency of platelets to adhere to one another and to damaged blood vessels' endothelium.
== Choice ==
Antiplatelet medications are one of the primary recommendations for treatment of both stable and unstable ischemic heart disease. Most commonly, aspirin is used as a single medication in cases of uncomplicated stable angina, and in some cases of unstable angina. If a patient does not tolerate aspirin, ADP/P2Y inhibitors may be used as single-drug therapy instead. More severe and complicated cases are treated with dual antiplatelet therapy, or in some cases triple therapy that includes direct oral anticoagulants. Clinicians must make a choice that balances patient risk with the increased risks of bleeding associated with combination therapy.
== Dual antiplatelet therapy ==
Often a combination of aspirin plus an ADP/P2Y inhibitor (such as clopidogrel, prasugrel, ticagrelor, or another) is used to obtain greater effectiveness than with either agent alone. This is known as "dual antiplatelet therapy" (or DAPT). DAPT is used in patients who have, or are at high risk of developing, unstable angina, NSTEMI myocardial infarctions, and other high-risk thrombotic conditions. Dual antiplatelet therapy has been found to significantly reduce rates of heart attacks, strokes, and overall cardiovascular death, but is not used in low-risk patients because it significantly increases the risks of major bleeding.
== Classification ==
Classes of antiplatelet drugs include:
Adenosine diphosphate (ADP) receptor inhibitors
Cangrelor (Kengreal)
Clopidogrel (Plavix)
Prasugrel (Effient)
Ticagrelor (Brilinta)
Ticlopidine (Ticlid)
Adenosine reuptake inhibitors
Dipyridamole (Persantine)
Glycoprotein IIB/IIIA inhibitors (intravenous use only)
Abciximab (ReoPro)
Eptifibatide (Integrilin)
Tirofiban (Aggrastat)
Irreversible cyclooxygenase inhibitors
Aspirin
Triflusal (Disgren)
Phosphodiesterase inhibitors
Cilostazol (Pletaal)
Protease-activated receptor-1 antagonists (which inhibit the protease-activated receptor 1 a.k.a. PAR-1)
Vorapaxar (Zontivity)
Thromboxane inhibitors
Thromboxane receptor antagonists
Terutroban
Thromboxane synthase inhibitors
== Usage ==
=== Prevention and treatment of arterial thrombosis ===
Prevention and treatment of arterial thrombosis is essential in patients with certain medical conditions whereby the risk of thrombosis or thromboembolism may result in disastrous consequences such as heart attack, pulmonary embolism or stroke. Patients who require the use of antiplatelet drugs are: stroke with or without atrial fibrillation, any heart surgery (especially prosthetic replacement heart valve), Coronary Heart Disease such as stable angina, unstable angina and heart attack, patients with coronary stent, Peripheral Vascular Disease/Peripheral Arterial Disease and apical/ventricular/mural thrombus.
Treatment of established arterial thrombosis includes the use of antiplatelet drugs and thrombolytic therapy. Antiplatelet drugs alter the platelet activation at the site of vascular damage crucial to the development of arterial thrombosis.
Aspirin and Triflusal irreversibly inhibits the enzyme COX, resulting in reduced platelet production of TXA2 (thromboxane – powerful vasoconstrictor that lowers cyclic AMP and initiates the platelet release reaction).
Clopidogrel affects the ADP-dependent activation of IIb/IIIa complex
Dipyridamole inhibits platelet phosphodiesterase, causing an increase in cyclic AMP with potentiation of the action of PGI2 – opposes actions of TXA2
Epoprostenol is a prostacyclin that is used to inhibit platelet aggregation during renal dialysis (with or without heparin) and is also used in primary pulmonary hypertension.
Glycoprotein IIb/IIIa receptor antagonists block a receptor on the platelet for fibrinogen and von Willebrand factor. 3 classes:
Murine-human chimeric antibodies (e.g., abciximab)
Synthetic non-peptides (e.g., tirofiban)
Synthetic peptides (e.g., eptifibatide)
== Management in the perioperative period ==
Antiplatelet therapy may increase the risk of a bleed during surgery, however, stopping therapy may increase the risk of other thrombotic problems including myocardial infarction. When considering these medications and the risk-benefit ratio in the perioperative period, one must consider the risk of stopping the medication and a clot forming versus the risk of bleeding during or after the surgery if medication is continued. A 2018 Cochrane Review that included five randomized controlled trials found low-certainty evidence to suggest that continuing or discontinuing antiplatelet therapy for a non-cardiac surgery does not make a difference in mortality, major bleeds that require surgery, or ischaemic events. The same review found moderate certainty evidence that continuing or discontinuing therapy also did not have a big difference on the incidence of bleeds requiring a blood transfusion.
Balloon angioplasty in the preoperative period – patients can proceed to surgery two weeks after the procedure.
Bare metal stents required at least one month of DAPT
CABG: Patients may proceed with surgery as soon as they are healed from the coronary artery bypass procedure and they do not need any specific amount of time on DAPT
In patients with truly time-sensitive disease (defined in the 2014 ACC/AHA guidelines as needing to proceed in 2–6 weeks), DAPT can be stopped 3 (three) months (90 days) after a coronary stent is placed if postponing surgery any longer would result in significant morbidity. Examples of these types of surgeries include some cancer surgery and possibly some orthopedic surgery (non-urgent/emergent fracture management). Preferably 6 to 12 months of DAPT should be continued in patients having elective surgery.
== Dental management of patients on antiplatelet drugs ==
Dentists should be aware of the risk of prolonged bleeding time in patients taking antiplatelet drugs when planning dental treatments that are likely to cause bleeding. Therefore, it is important for dentists to know how to assess patient's bleeding risk and how to manage them.
=== Assess bleeding risk ===
Identify the likelihood and risk of dental treatment causing bleeding complications.
== Drug toxicity ==
Antiplatelet drugs effect may be affected by patient's medications, current medical conditions, food and supplements taken. Antiplatelet drugs effect may be increased or decreased. An increase in antiplatelet effect would increase the risk of bleeding and could cause prolonged or excessive bleeding. A decrease in antiplatelet effect would reduce the risk of bleeding, but increase the thromboembolic risk. Drug toxicity may increase when multiple antiplatelet drugs are used. Gastrointestinal bleeding is a common adverse event seen in many patients.
=== Medications ===
Medications that may increase antiplatelet drug effect:
Cytotoxic drugs or drugs associated with bone marrow suppression (e.g.: leflunomide, hydroxychloroquine, adalimumab, infliximab, etanercept, sulfasalazine, penicillamine, gold, methotrexate, azathioprine, mycophenolate)
Drugs affecting the nervous system (e.g.: Selective serotonin reuptake inhibitors (SSRIs))
NSAIDS (e.g.: aspirin, ibuprofen, diclofenac, naproxen)
Other anticoagulants or antiplatelet drugs
Medications that may decrease antiplatelet drug effect:
Carbamazepine
Erythromycin
Fluconazole
Omeprazole
Use of NSAIDs as part of dental management of patients with vascular disease should be discouraged as NSAIDs have antiplatelet effect. Instead, simple analgesics such as paracetamol or co-codamol should be of first choice. If NSAIDs are required, the risk of bleeding increases with duration of dental treatment.
=== Medical conditions ===
Medical conditions that may increase antiplatelet drugs' effect include:
Chronic kidney failure, liver disease, haematological malignancy, recent or current chemotherapy, advanced heart failure, mild forms of inherited bleeding disorders (e.g. haemophilia, Von Willebrand's disease) and idiopathic thrombocytopenic purpura.
=== Food and supplements ===
Food and supplements that may increase antiplatelet drugs' effect:
St. John's wort, ginkgo biloba, garlic.
== Oral antiplatelet drugs available in the UK ==
== See also ==
Anticoagulant drug
Nitrophorin
Thrombolytic drug
== References == | Wikipedia/Antiplatelet_drug |
Post-chemotherapy cognitive impairment (PCCI) (also known in the scientific community as "CRCIs or Chemotherapy-Related Cognitive Impairments" and in lay terms as chemotherapy-induced cognitive dysfunction or impairment, chemo brain, or chemo fog) describes the cognitive impairment that can result from chemotherapy treatment. While there is no concrete statistic for the number of patients that experience some level of post-chemotherapy cognitive impairment, the estimated percentage is between 13 and 70 percent of patients. The phenomenon first came to light because of the large number of breast cancer survivors who complained of changes in memory, fluency, and other cognitive abilities that impeded their ability to function as they had pre-chemotherapy.
Although the causes and existence of post-chemotherapy cognitive impairment have been a subject of debate, recent studies have confirmed that post-chemotherapy cognitive impairment is a real, measurable side effect of chemotherapy that appears in some patients. While any cancer patient may experience temporary cognitive impairment while undergoing chemotherapy, patients with PCCI continue to experience these symptoms long after chemotherapy has been completed. Some patients may experience cognitive dysfunction up to 10 years after undergoing chemotherapy treatment. PCCI is often seen in patients treated for breast cancer, ovarian cancer, prostate cancer, and other reproductive cancers, as well as other types of cancers requiring aggressive treatment with chemotherapy.
The clinical relevance of PCCI is significant, considering the increasing number of long-term cancer survivors in the population, many of whom may have been treated with aggressive dosing of chemotherapeutic agents, or with chemotherapy as an adjuvant to other forms of treatment. In some patients, fear of PCCI can impact treatment decisions. The magnitude of chemotherapy-related cognitive changes and their impact on the activities of daily living are uncertain.
== Signs and symptoms ==
The systems of the body most affected by chemotherapy drugs include visual and semantic memory, attention and motor coordination and executive functioning. These effects can impair a chemotherapy patient's ability to understand and make decisions regarding treatment, perform in school or employment and can reduce quality of life. Survivors often report difficulty multitasking, comprehending what they have just read, following the thread of a conversation, and retrieving words.
Breast cancer survivors who were treated with chemotherapy may find it harder to perform tasks than survivors whose treatment was surgical. One study demonstrated that, a year after treatment, the brains of cancer survivors treated with chemotherapy (after surgery) had physically shrunk while those of people only treated surgically had not.
Post-chemotherapy cognitive impairment comes as a surprise to many cancer survivors. Often, survivors think their lives will return to normal when the cancer is gone, only to find that the lingering effects of post-chemotherapy cognitive impairment impede their efforts. Working, connecting with loved ones, carrying out day-to-day tasks—all can be very challenging for an impaired brain. Due to such challenges, patients have reported difficulty concentrating to be as significant a stressor as dealing with thoughts of mortality. Although post-chemotherapy cognitive impairment appears to be temporary, it can be quite long-lived, with some cases lasting 10 years or more.
== Proposed mechanisms ==
The details of PCCI's causes and boundaries are not well known. Two major theories have been advanced: the direct effect of chemotherapy drugs on the brain, and the role of hormones in nervous system health.
PCCI is complex and factors other than the chemotherapeutic agents may impact cognitive functioning. Menopause, the biological impact of a surgical procedure with anesthesia, medications prescribed in addition to the chemotherapy, genetic predisposition, hormone therapy, emotional states (including anxiety, depression and fatigue), comorbid conditions and paraneoplastic syndrome may all co-occur and act as confounding factors in the study or experience of PCCI.
Chemotherapy drugs thalidomide, the epothilones such as ixabepilone, the vinca alkaloids vincristine and vinblastine, the taxanes paclitaxel and docetaxel, the proteasome inhibitors such as bortezomib, and the platinum-based drugs cisplatin, oxaliplatin and carboplatin often cause chemotherapy-induced peripheral neuropathy, a progressive and enduring tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs. In most cases there is no known way of reducing the effects of chemotherapeutic agents related to taxanes, thalidomide and platinum-based compounds (oxaliplatin is a notable exception to the latter category—though it does cause PCCI its effects can be buffered by infusion of calcium and thought related to PCCI include the ability of the nerves to repair themselves, the ability of cells to excrete compounds, permeability of the blood–brain barrier, damage done to DNA including shortening of telomeres and cellular oxidative stress.
The importance of hormones, particularly estrogen, on cognitive function is underscored by the presence of cognitive impairment in breast cancer patients before chemotherapy is begun, the similarity of the cognitive impairments to several menopausal symptoms, the increased rate of PCCI in pre-menopausal women, and the fact that the symptoms can frequently be reversed by taking estrogen.
Other theories suggest vascular injury, inflammation, autoimmunity, anemia and the presence of the epsilon 4 version of the apolipoprotein E gene.
Fifty-six of the 132 chemotherapy agents approved by the FDA have been reported to induce oxidative stress.
The drug doxorubicin (adriamycin) has been investigated as a PCCI-causing agent due to its production of reactive oxygen species. It has been investigated in an animal model with mice.
Mice were treated with the chemotherapeutic agent mitomycin C. In the prefrontal cortex, this treatment resulted in an increase of the oxidative DNA damage 8-oxodG, a decrease in the enzyme OGG1 that ordinarily repairs such damage, and an increase in epigenetic alterations. These alterations, at the DNA level, may explain, at least in part, the impairments of cognitive function after chemotherapy.
Research has revealed that neural progenitor cells are particularly vulnerable to the cytotoxic effects of chemotherapy agents. 5-fluorouracil has been demonstrated to reduce the viability of neural progenitor cells by 55–70% at concentrations of 1 μM, whereas cancer cell lines exposed to 1 μM of 5-fluorouracil were unaffected. Other chemotherapy agents such as BCNU, cisplatin, and cytarabine also displayed toxicity to progenitor cells in vivo and in vitro. This is a concern because neural progenitor cells are the major dividing cell population in the brain, giving rise to neurons and glia.
Due to the critical role the hippocampus plays in memory, it has been the focus of various studies involving post-chemotherapy cognitive impairment. The hippocampus is one of the rare areas of the brain that exhibits neurogenesis. These new neurons created by the hippocampus are important for memory and learning and require a brain-derived neurotrophic factor (BDNF) to form. 5-fluorouracil, a commonly used chemotherapy agent, has been shown to significantly reduce the levels of BDNF in the hippocampus of the rat. Methotrexate, an agent widely used in the chemotherapy treatment of breast cancer, has also displayed a long-lasting dose dependent decrease in hippocampal cell proliferation in the rat following a single intravenous injection of the drug. This evidence suggests that chemotherapy agent toxicity to cells in the hippocampus may be partially responsible for the memory declines experienced by some patients.
Deficits in visuo-spatial, visual-motor, and visual memory functions are among the symptoms seen in post-chemotherapy patients. There is evidence that this may be due to damage to the visual system rather than caused by cognitive deficits. In one study, 5-flouracil caused ocular toxicity in 25–38% of patients treated with the drug. Methotrexate also caused ocular toxicity in 25% of patients within 2–7 days of initial chemotherapy regimen with the drug. This evidence suggests that some of the visual-based cognitive deficits experienced by cancer survivors may be due to damage at the ocular level rather than cognitive processing, but most likely it is due to a synergistic effect on both systems.
== Management ==
Hypothesized treatment options include the use of antioxidants, cognitive behavioral therapy, erythropoietin and stimulant drugs such as methylphenidate, though as the mechanism of PCCI is not well understood the potential treatment options are equally theoretical. Patients who engage in cognitive behavioral therapy to treat CRCI routinely report improved symptoms, and studies have shown self-reported improvement of depression, anxiety, fatigue and cognitive complaints. A specific form of CBT shown to have successful improvement of cognitive impairment is Memory and Attention Adaptation Training, which mostly focuses on working memory and has reported high satisfaction by patients and increase in quality of life. While these physical and mental forms of management for PCCI symptoms show subjective improvements, they are less supported in regards to objective assessment and still require further testing.
Modafinil, approved for narcolepsy, has been used off-label in trials with people with symptoms of PCCI. Modafinil is a wakefulness-promoting agent that can improve alertness and concentration, and studies have shown it to be effective at least among women treated for breast cancer.
While estrogen hormone supplementation may reverse the symptoms of PCCI in women treated for breast cancer, this carries health risks, including possibly promoting the proliferation of estrogen-responsive breast cancer cells.
There are other proposed forms of managing PCCI symptoms, one being physical activity. Studies have shown that when compared with control groups, breast cancer patients with a diagnosis within the last two years, who were a part of the exercise trial group, experienced improved processing speed and reduction in cognitive symptoms. Additionally, yoga and meditation have been seen to improve cognitive flexibility and attention, as well as decrease some of the other psychological stressors that contribute to cognitive complaints such as anxiety and depression.
== Objective and subjective measures ==
When measuring cancer related cognitive impairments, there are both objective and subjective measures. Objective measures of CRCI include neuropsychological tests of cognitive function, while subjective tests include self-reported data such as survey's and interviews. A controversy in PCCI that presents trouble for researchers is the significant difference between objectively assessed cognitive impairment and levels of self-reported cognitive impairment in patients. Data shows that as few as 12% of cancer survivors may objectively experience mild cognitive impairment while 80% of the same population subjectively reported impairments. An explanation for the differences between objective and subjective measures may be due to confounding factors that influence complaints and cognitive struggles in subjective reports, such as emotional distress, anxiety, depression and fatigue. These large discrepancies cause confusion as to how common PCCI is and which cognitive functions are actually being impaired, which can have harmful impacts on the future of research for treatments and implementation of interventions. Regardless of the lack of correlation between objective and subjective measures, there are statistically significant relationships between subjective measures of cognitive impairment and executive function, attention, processing speed, visuospatial performance, response inhibition, cognitive flexibility and total cognitive performance. Both objective and subjective measures of cognitive impairment help to assess quality of life and day to day concerns for cancer patients, and therefore is important to consider in the development of treatment plans and psychological assessments.
== Prognosis ==
While frustrating, the ultimate outcome is very good: symptoms typically disappear in about four years, e.g., for breast cancer patients.
== Incidence ==
PCCI affects a subset of cancer survivors, though the overall epidemiology and prevalence is not well known and may depend on many factors. As previously mentioned, PCCI affects between 13 and 70% of the general cancer patient population.
It generally affects about 10–40% of breast cancer patients, with higher rates among pre-menopausal women and patients who receive high-dose chemotherapy. Additionally, there are high complaints of cognitive impairment in glioblastoma patients; 60–85% of patients report cancer-related cognitive impairments following surgery and adjunctive treatment.
== Research ==
Research on PCCI is limited, and studies on the subject have often been conflicting in results, in part due to differing means of assessing and defining the phenomenon, which makes comparison and synthesis difficult. Most studies have involved small samples, making generalization difficult. There has been a focus on PCCI in younger cancer patients. This makes it difficult to draw conclusions about PCCI in the elderly.
Several recent studies have advanced the field using neuroimaging techniques. In 2005, Dr. Masatoshi Inagaki used magnetic resonance imaging (MRI) to measure differences in brain volume between breast cancer patients exposed to chemotherapy and subjects unexposed. Subjects were tested at two periods: one year after surgery, and again at three years post-surgery. Results from the first year study found smaller volumes of gray and white matter in patients exposed to chemotherapy. However, in the three-year study, both groups of breast cancer survivors were observed to have similar gray and white matter volumes. Altered brain structure in chemotherapy patients provides explanation for cognitive impairment.
Another study in 2007 investigated the differences in brain structure between two adult, monozygotic twin females. One underwent chemotherapy treatment for breast cancer, while the other did not have cancer and was not treated with chemotherapy. MRI scans were taken of both twins' brain while taking part in a working memory task. Results found that twin A (exposed to chemotherapy) experienced a broader spatial extent of activation in her brain than twin B (not exposed to chemotherapy). Twin A also reported a greater difficulty than twin B in completing the memory activity. The authors of this study declare that commonly chemotherapy patients will self-report cognitive complaints, although they perform within normal limits on neuropsychological tasks. MRI scans may provide evidence for this occurrence. Chemotherapy patients may require greater volume of neural circuitry to complete neuropsychological tasks compared to others.
Positron Emission Tomography (PET) is also used to study post-chemotherapy cognitive impairment. In one study in 2007, scans were taken of patients exposed to adjuvant chemotherapy. Significantly altered blood flow in the brain was found, most notably in the frontal cortex and cerebellum. The most significant difference of blood flow was found in the inferior frontal gyrus. Authors report resting metabolism in this area is associated with performance on short-term memory tasks.
While post-treatment studies suggest significant negative side effects of chemotherapy on cognition, other studies have indicated that there may be baseline vulnerability factors which could contribute to cognitive impairment development. Such factors may include menopausal status, surgery/anesthesia, stress, genetics and fatigue, among other suspected confounding variables.
== History ==
The symptoms of PCCI were recognized by researchers in the 1980s, who typically described it as mild cognitive impairment subsequent to successful cancer treatment. Some authors say that it was identified primarily in breast cancer survivor and support groups as affecting a subset of individuals treated with chemotherapy, who attributed it to the effects of the medication taken to treat their cancers.
The term chemobrain appears in publications at least as early as 1997.
== See also ==
Cancer-related fatigue
Menopause-related cognitive impairment
Radiation induced cognitive decline
== Footnotes ==
== External links ==
"Chemo Brain". American Cancer Society. April 15, 2014. Archived from the original on December 4, 2016. Retrieved November 27, 2015.
Mayo Clinic Staff (February 2, 2013). "Chemo Brain". Mayo Clinic. Retrieved November 27, 2015.
Brody J (August 3, 2009). "The Fog That Follows Chemotherapy". Personal Health (column). The New York Times. p. D7. Retrieved November 27, 2015. | Wikipedia/Post-chemotherapy_cognitive_impairment |
Drug delivery involves various methods and technologies designed to transport pharmaceutical compounds to their target sites helping therapeutic effect. It involves principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity all aimed to optimize efficacy and safety, while improving patient convenience and compliance. A key goal of drug delivery is to modify a drug's pharmacokinetics and specificity by combining it with different excipients, drug carriers, and medical devices designed to control its distribution and activity in the body. Enhancing bioavailability and prolonging duration of action are essential strategies for improving therapeutic outcomes, particularly in chronic disease management. Additionally, some research emphasizes on improving safety for the individuals administering the medication. For example, microneedle patches have been developed for vaccines and drug delivery to minimize the risk of needlestick injuries.
Drug delivery is closely linked with dosage form and route of administration, the latter of which is sometimes considered to be part of the definition. Although the terms are often used interchangeably, they represent distinct concepts. The route of administration refers specifically to the path by which a drug enters the body, such as oral, parenteral, or transdermal. In contrast, the dosage form refers to the physical form in which the drug is manufactured and delivered, such as tablets, capsules, patches, inhalers or injectable solutions. These are various dosage forms and technologies which include but not limited to nanoparticles, liposomes, microneedles, and hydrogels that can be used to enhance therapeutic efficacy and safety. The same route can accommodate multiple dosage forms; for example, the oral route may involve tablet, capsule, or liquid suspension. While the transdermal route may use a patch, gel, or cream. Drug delivery incorporates both of these concepts while encompassing a broader scope, including the design and engineering of systems that operate within or across these routes. Common routes of administration include oral, parenteral (injected), sublingual, topical, transdermal, nasal, ocular, rectal, and vaginal. However, modern drug delivery continue to expand the possibilities of these routes through novel and hybrid approaches.
Since the approval of the first controlled-release formulation in the 1950s, research into new delivery systems has been progressing, as opposed to new drug development which has been declining. Several factors may be contributing to this shift in focus. One of the driving factors is the high cost of developing new drugs. A 2013 review found the cost of developing a delivery system was only 10% of the cost of developing a new pharmaceutical. A more recent study found the median cost of bringing a new drug to market was $985 million in 2020, but did not look at the cost of developing drug delivery systems. Other factors that have potentially influenced the increase in drug delivery system development may include the increasing prevalence of both chronic and infectious diseases, as well as a general increased understanding of the pharmacology, pharmacokinetics, and pharmacodynamics of many drugs.
== Current efforts ==
Current efforts in drug delivery are vast and include topics such as controlled-release formulations, targeted delivery, nanomedicine, drug carriers, 3D printing, and the delivery of biologic drugs.
=== The relation between nanomaterial and drug delivery ===
Nanotechnology is a broad field of research and development that deals with the manipulation of matter at the atomic or subatomic level. It is used in fields such as medicine, energy, aerospace engineering, and more. One of the applications of nanotechnology is in drug delivery. This is a process by which nanoparticles are used to carry and deliver drugs to a specific area in the body. There are several advantages of using nanotechnology for drug delivery, including precise targeting of specific cells, increased drug potency, and lowered toxicity to the cells that are targeted. Nanoparticles can also carry vaccines to cells that might be hard to reach with traditional delivery methods. However, there are some concerns with the use of nanoparticles for drug delivery. Some studies have shown that nanoparticles may contribute to the development of tumors in other parts of the body. There is also growing concern that nanoparticles may have harmful effects on the environment. Despite these potential drawbacks, the use of nanotechnology in drug delivery is still a promising area for future research.
=== Targeted delivery ===
Targeted drug delivery is the delivery of a drug to its target site without having an effect on other tissues. Interest in targeted drug delivery has grown drastically due to its potential implications in the treatment of cancers and other chronic diseases. In order to achieve efficient targeted delivery, the designed system must avoid the host's defense mechanisms and circulate to its intended site of action. A number of drug carriers have been studied to effectively target specific tissues, including liposomes, nanogels, and other nanotechnologies.
=== Controlled-release formulations ===
Controlled or modified-release formulations are designed to deliver medications at a steady rate over time, helping maintain consistent drug levels in the bloodstream. This steady release reduced how often patients need to take their medication and minimizes the ups and downs in drug concentration that can cause side effects or lower effectiveness. These systems often take the form of matrix tablets, osmotic pumps, and reservoir-type devices, all of which use physical or chemical barriers to regulate how the drug is released. This approach is especially useful for chronic conditions such as high blood pressure, diabetes, or chronic pain, where maintaining stable therapeutic levels is key to keeping symptoms under control.
The concept of controlled-release medication dates back to the 1950s, when Dexedrine became the first such formulation on the market. This era saw the introduction of transdermal patches, which deliver drugs slowly through the skin. As technology progressed, new formulations were developed to match the specific properties of different drugs. Examples include long-acting depot injections for medication like antipsychotics and hormone therapies, which remain effective for weeks or even months after a single dose.
Since the late 1990s, research has increasingly turned to nanotechnology asa way to improve controlled-released drug delivery. Nanoparticles, tiny carriers engineered at a molecular level, can protect drugs from being broken down too quickly in the body, improve how well they're absorbed, and deliver them directly to the tissues where they're needed. This targeted delivery not only reduces side effects but also helps patients stay on track with their treatments. These advances in nanotechnology are transforming the landscape of drug delivery and are emphasizing the importance of developing the next generation of CR systems.
=== Nanoparticle-based Controlled-Release ===
The use of nanotechnology into drug delivery has opened the door to new possibilities, particularly with the development of nanoparticle-based controlled-release systems. These systems are designed to deliver drugs more precisely and over longer periods of time helping with targeted sites and therapeutic effects. Tiny carriers, such as liposomes, dendrimers, and polymeric nanoparticles, can hold medication and release them at controlled rates. Some are even engineered to respond to specific conditions in the body. For instance, acidic microenvironment commonly found in tumor tissues can be used to trigger drug release at the site needed. This targeted approach helps minimize side effects by limiting exposure to the rest the body. Thus, making treatment more effective.
Recent studies have shown the effectiveness of smart nanoparticles that respond to biological cues, such as pH or redox conditions, thereby delivering drugs more precisely to tumor sites. For instance, pH-sensitive nanoparticles take advantage of the lower pH in tumor cells to release the drugs, which boost effectiveness while protecting healthy cells. Additionally, the use of biocompatible materials and switching the nanoparticle surfaces have improved their accuracy and release of delivery systems.
Advances in design have also made it possible to create multi-functional nanoparticles that are capable of handling tough challenges like multi-drug resistance in cancer. These systems can carry more than one type of drug, targeting specific molecules, which helps to deliver a stronger punch to tumor tissues. Altogether, these breakthroughs point to a potential for nanoparticle-based controlled-release therapies in the fields of cancer therapy and personalized medicine.
=== Advancements in Smart Polymers and Hydrogels ===
In recent years, advances in smart polymers and hydrogels have brought major improvements to how drugs are delivered in controlled-released systems. These materials are unique in that they can respond to changes inside the body, like shifts in pH, temperature, and glucose levels, making it possible to fine-tune when and how much of a drug is released. For example, some hydrogels are designed to expand or contract based on these internal signals, which helps regulate the speed of drug release. This kind of precision helps improves therapeutic treatment and reduces side effects. These responsive materials are useful for managing chronic condition like diabetes, where glucose-responsive hydrogels can adjust insulin release based on blood sugar levels.
=== Modulated drug release and zero-order drug release ===
Many scientists worked to create oral formulations that could maintain a constant drug level because of the ability of drug release at a zero-order rate.blood's concentration. However, a few physiological restrictions made it challenging to create such oral formulations. First, because the lower parts of the intestine have a decreased capacity for absorption, the medication absorption typically declines as an oral formulation moves from the stomach to the intestine. The decreased drug amount released from the formulation over time frequently made this condition worse. Phenylpropanolamine HCl release from was the only instance of sustaining consistent blood concentration for roughly 16 hours.
=== Delivery of biologic drugs ===
Delivering biological drugs such as peptides, proteins, antibodies, and genetic material, comes with unique challenges. Because of their large size and electrical charges, these molecules are often poorly absorbed and easily broken down by enzymes in the body. To overcome these hurdles, scientists have been developing advanced delivery methods using tools like liposomes, nanoparticles, fusion proteins, and protein-based nanocages. Some strategies take inspiration from how toxins naturally enter cells by adapting those mechanisms for therapeutic use.
Among the macromolecules studied, RNA delivery has made progress, especially with the success of RNA-based COVID-19 vaccines. While protein and DNA delivery have shown progress, proteins in live animals and DNA in lab settings, delivering these large molecules, still remain a complex task. Although oral administration is generally preferred by patients for convenience, it's rarely effective for biologics due to poor absorption. That being said, innovative technologies such as enzyme inhibitors, permeation enhancers, lipid-based nanoparticles, and microneedles are being used to improve oral bioavailability for these drugs.
One of the recent developments that has been successful is the use of lipid nanoparticles (LNPs) to deliver messenger RNA (mRNA). LNPs protect fragile mRNA from degradation and escape from endosomes so it can reach the cytoplasm and produce proteins. This delivery method gained worldwide recognition during COVID-19 pandemic with the approval of mRNA vaccines from Pfizer-BioTech and Moderna. The rapid rollout of these vaccines proved that LNPs are not only effective but also scalable for mass production and global use.
Looking beyond vaccines, mRNA therapies are now being explored for a range of therapeutic applications including cancer immunotherapy, genetic disorders, and other infectious diseases. Researchers are also testing alternative delivery systems, like exosomes and new types of nanoparticles, to make mRNA therapies safer and more efficient. However, challenges remain, as mRNA is highly sensitive to environmental conditions. To address this, ongoing research is expanding into new administration routes including inhalable or oral mNRA formulations. This could reduce production costs and make these therapies more accessible to the world.
=== Nanoparticle drug delivery ===
Delivering medications to the brain has long been a significant challenge in treating neurological diseases. The main reason lies in the blood-brain barrier (BBB), a highly selective, protective layer that shields the brain from toxins and pathogens in the bloodstream. While the BBB is crucial for maintaining brain health, it also makes it difficult for most therapeutic drugs to reach their target, especially in conditions like Alzheimer's and Parkinson's disease. As a result, conventional drug delivery methods often fall short, either causing unwanted side effects or failing to deliver a high enough concentration to be effective.
To address this, researchers have turned to nanoparticles, tiny engineered carriers designed to sneak past the BBB and deliver drugs directly to the brain tissue These particles can be tailored to take advantage of the body's own transport systems. For example, by attaching certain molecules to their surfaces, nanoparticles can trigger receptor-mediated transcytosis, a natural process that allows them to pass through cells lining the BBB and enter the brain.This kind of targeted delivery helps reduce the drug's exposure to the rest of the body, lowering the risk of side effects and increasing concentration where it matters most. So far, this strategy has shown promise in delivering treatments to the brain for conditions like Alzheimer's and Parkinson's disease.
Several types of nanoparticles are being studied for this purpose. Liposomes, for instance, are small vesicles that can carry drugs and be modified to circulate longer or hone in on specific brain regions. Dendrimers, with their tree-like structure, can hold multiple drug molecules and targeting agents at once. Polymeric nanoparticles, made from biodegradable materials like polylactic acid (PLA) or polylactic-co-glycolic acid (PLGA), can be engineered to released drugs over time in a controlled way. Solid lipid nanoparticles offer another alternative, combining biocompatibility with the ability to cross barriers more efficiently. Altogether, these advances are paving the way for more effective and precise treatments for a range of neurological disorders.
== See also ==
== References ==
== External links ==
Article in Chemical and Engineering News | Wikipedia/Drug_delivery |
Anti-Cancer Drugs is an international medical journal, which aims to promote and encourage research on anti-cancer agents. It was first published in 1990 and it includes reports on clinical and experimental research results, from conventional cytotoxic chemotherapy to hormonal or biological response modalities. The journal has 10 issues per year and the current editor in chief is Mels Sluyser. According to the 2014 Journal Citation Reports, the journal has an impact factor of 1.784, ranking it 164th out of 211 in the category Oncology and 162nd out of 254 in the category Pharmacology & Pharmacy.
== References ==
== External links ==
Official website | Wikipedia/Anti-Cancer_Drugs |
A chemotherapy regimen is a regimen for chemotherapy, defining the drugs to be used, their dosage, the frequency and duration of treatments, and other considerations. In modern oncology, many regimens combine several chemotherapy drugs in combination chemotherapy. The majority of drugs used in cancer chemotherapy are cytostatic, many via cytotoxicity.
A fundamental philosophy of medical oncology, including combination chemotherapy, is that different drugs work through different mechanisms, and that the results of using multiple drugs will be synergistic to some extent. Because they have different dose-limiting adverse effects, they can be given together at full doses in chemotherapy regimens.
The first successful combination chemotherapy was MOPP, introduced in 1963 for lymphomas.
The term "induction regimen" refers to a chemotherapy regimen used for the initial treatment of a disease. A "maintenance regimen" refers to the ongoing use of chemotherapy to reduce the chances of a cancer recurring or to prevent an existing cancer from continuing to grow.
== Nomenclature ==
Chemotherapy regimens are often identified by acronyms, identifying the agents used in the drug combination. However, the letters used are not consistent across regimens, and in some cases - for example, "BEACOPP" - the same letter combination is used to represent two different treatments.
There is no widely accepted naming convention or standard for the nomenclature of chemotherapy regimens. For example, either generic or brand names may be used for acronyms. This page merely lists commonly used conventions.
== List of chemotherapy regimen acronyms ==
== See also ==
National Comprehensive Cancer Network Treatment Guidelines
Breast cancer chemotherapy
High-dose chemotherapy
Sequential high-dose chemotherapy
== References ==
== External links ==
Chemotherapy regimens and references
Chemotherapy side effects Archived 2012-08-15 at the Wayback Machine
Christie Hospital Chemotherapy Patient Information Sheets | Wikipedia/Chemotherapy_regimen |
Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the lymph nodes. The condition was named after the English physician Thomas Hodgkin, who first described it in 1832. Symptoms may include fever, night sweats, and weight loss. Often, non-painful enlarged lymph nodes occur in the neck, under the arm, or in the groin. Persons affected may feel tired or be itchy.
The two major types of Hodgkin lymphoma are classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. About half of cases of Hodgkin lymphoma are due to Epstein–Barr virus (EBV) and these are generally the classic form. Other risk factors include a family history of the condition and having HIV/AIDS. Diagnosis is conducted by confirming the presence of cancer and identifying Reed–Sternberg cells in lymph node biopsies. The virus-positive cases are classified as a form of the Epstein–Barr virus-associated lymphoproliferative diseases.
Hodgkin lymphoma may be treated with chemotherapy, radiation therapy, and stem-cell transplantation. The choice of treatment often depends on how advanced the cancer has become and whether or not it has favorable features. If the disease is detected early, a cure is often possible. In the United States, 88% of people diagnosed with Hodgkin lymphoma survive for five years or longer. For those under the age of 20, rates of survival are 97%. Radiation and some chemotherapy drugs, however, increase the risk of other cancers, heart disease, or lung disease over the subsequent decades.
In 2015, about 574,000 people globally had Hodgkin lymphoma, and 23,900 (4.2%) died. In the United States, 0.2% of people are affected at some point in their life. Most people are diagnosed with the disease between the ages of 20 and 40.
== Signs and symptoms ==
People with Hodgkin lymphoma may present with these symptoms:
Lymphadenopathy: The most common symptom of Hodgkin is the painless enlargement of one or more lymph nodes. The nodes may also feel rubbery and swollen when examined. The nodes of the neck, armpits and groin (cervical and supraclavicular) are most frequently involved (80–90% of the time, on average). The lymph nodes of the chest are often affected, and these may be noticed on a chest radiograph.
Systemic symptoms: About one-third of people with Hodgkin disease may also present with systemic symptoms, including:
Itchy skin
Night sweats
Unexplained weight loss of at least 10% of the person's total body mass in six months or less
Low-grade fever.
Fatigue (lassitude)
Systemic symptoms such as fever, night sweats, and weight loss are known as B symptoms; thus, presence of these indicate that the person's stage is, for example, 2B instead of 2A.
Splenomegaly: Enlargement of the spleen is often present in people with Hodgkin lymphoma. The enlargement is seldom massive, and the size of the spleen may fluctuate during the course of treatment.
Hepatomegaly: Enlargement of the liver, due to liver involvement, is infrequent in people with Hodgkin lymphoma.
Hepatosplenomegaly: The enlargement of both the liver and spleen can be caused by the same disease.
Pain following alcohol consumption: Classically, involved nodes are painful after alcohol consumption, though this phenomenon is very uncommon, occurring in only two to three percent of people with Hodgkin lymphoma, thus having a low sensitivity. On the other hand, its positive predictive value is high enough for it to be regarded as a pathognomonic sign of Hodgkin lymphoma. The pain typically has an onset within minutes after ingesting alcohol, and is usually felt as coming from the vicinity where there is an involved lymph node. The pain has been described as either sharp and stabbing or dull and aching.
Back pain: Nonspecific back pain (pain that cannot be localised or its cause determined by examination or scanning techniques) has been reported in some cases of Hodgkin lymphoma. The lower back is most often affected.
Cyclical fever: People may also present with a cyclical high-grade fever known as the Pel–Ebstein fever, or more simply "P-E fever". However, there is debate as to whether the P-E fever truly exists.
Nephrotic syndrome can occur in individuals with Hodgkin lymphoma and is most commonly caused by minimal change disease.
May present with airway obstruction, pleural/pericardial effusion, hepatocellular dysfunction, or bone-marrow infiltration.
== Diagnosis ==
Hodgkin lymphoma must be distinguished from noncancerous causes of lymph node swelling (such as various infections) and from other types of cancer. Definitive diagnosis is by lymph node biopsy (usually excisional biopsy with microscopic examination). Blood tests are also performed to assess function of major organs and safety for chemotherapy. Positron emission tomography (PET) is used to detect small deposits that do not show on CT scanning. PET scans are also useful in functional imaging (by using a radiolabeled glucose to image tissues of high metabolism). In some cases, a gallium scan may be used instead of a PET scan.
=== Types ===
The two main types of Hodgkin lymphoma are classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. The prevalence of classic Hodgkin lymphoma and nodular-lymphocyte Hodgkin lymphoma are about 90% and 10%, respectively. The morphology, phenotype, molecular features, and, therefore, the clinical behaviour and presentation of the two types differ.
==== Classic ====
Classic Hodgkin lymphoma (excluding nodular lymphocyte predominant Hodgkin lymphoma) can be subclassified into four pathologic subtypes based upon Reed–Sternberg cell morphology and the composition of the reactive cell infiltrate seen in the lymph node biopsy specimen (the cell composition around the Reed–Sternberg cell(s)). Presence of EBV in Reed-Sternberg cells is most commonly found in the subtypes lymphocyte depleted HL (>70%) and mixed cellularity HL (70%), whilst being less prevalent in lymphocyte-rich HL (40%) and relatively uncommon by comparison in nodular sclerosing HL.
For the other forms, although the traditional B-cell markers (such as CD20) are not expressed on all cells, Reed–Sternberg cells are usually of B cell origin. Although Hodgkin lymphoma is now frequently grouped with other B-cell malignancies, some T-cell markers (such as CD2 and CD4) are occasionally expressed.
Hodgkin cells produce interleukin-21 (IL-21), which was once thought to be exclusive to T-cells. This feature may explain the behavior of classic Hodgkin lymphoma, including clusters of other immune cells gathered around HL cells (infiltrate) in cultures.
==== Nodular lymphocyte predominant ====
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is another subtype of Hodgkin lymphoma distinct from classic Hodgkin lymphoma and is characterized by the presence of popcorn cells which express CD20. Due to these differences, among others, NLPHL is often treated differently from classic Hodgkin lymphoma, including using rituximab in combination with AVBD chemotherapy, though individual cases vary and clinical trials are ongoing.
=== Staging ===
The staging is the same for both Hodgkin and non-Hodgkin lymphomas.
After Hodgkin lymphoma is diagnosed, a person will be staged by undergoing a series of tests and procedures that will determine what areas of the body are affected. These procedures may include documentation of their histology, a physical examination, blood tests, chest X-ray radiographs, computed tomography (CT)/positron emission tomography (PET)/magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis, and usually a bone marrow biopsy. PET scan is now used instead of the gallium scan for staging. On the PET scan, sites involved with lymphoma light up very brightly enabling accurate and reproducible imaging. In the past, a lymphangiogram or surgical laparotomy (which involves opening the abdominal cavity and visually inspecting for tumors) were performed. Lymphangiograms or laparotomies are very rarely performed, having been supplanted by improvements in imaging with the CT scan and PET scan.
On the basis of this staging, the person will be classified according to a staging classification (the Ann Arbor staging classification scheme is a common one):
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie);
Stage II is involvement of two or more lymph node regions on the same side of the diaphragm (II) or of one lymph node region and a contiguous extralymphatic site (IIe);
Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) or limited contiguous extralymphatic organ or site (IIIe, IIIes);
Stage IV is disseminated involvement of one or more extralymphatic organs.
The absence of systemic symptoms is signified by adding "A" to the stage; the presence of systemic symptoms is signified by adding "B" to the stage. For localized extranodal extension from mass of nodes that does not advance the stage, subscript "E" is added. Splenic involvement is signified by adding "S" to the stage. The inclusion of "bulky disease" is signified by "X".
=== Pathology ===
==== Macroscopy ====
Affected lymph nodes (most often, laterocervical lymph nodes) are enlarged, but their shape is preserved because the capsule is not invaded. Usually, the cut surface is white-grey and uniform; in some histological subtypes (e.g. nodular sclerosis) a nodular aspect may appear.
A fibrin ring granuloma may be seen.
==== Microscopy ====
Microscopic examination of the lymph node biopsy reveals complete or partial effacement of the lymph node architecture by scattered large malignant cells known as Reed-Sternberg cells (RSC) (typical and variants) admixed within a reactive cell infiltrate composed of variable proportions of lymphocytes, histiocytes, eosinophils, and plasma cells. The Reed–Sternberg cells are identified as large often bi-nucleated cells with prominent nucleoli and an unusual CD45−, CD30+, CD15+/− immunophenotype. In approximately 50% of cases, the Reed–Sternberg cells are infected by the Epstein–Barr virus.
Characteristics of classic Reed–Sternberg cells include large size (20–50 micrometres), abundant, amphophilic, finely granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes) each with an eosinophilic nucleolus and a thick nuclear membrane (chromatin is distributed close to the nuclear membrane). Almost all of these cells have an increased copy number of chromosome 9p/9p24.1.
Variants:
Hodgkin cell (atypical mononuclear RSC) is a variant of RS cell, which has the same characteristics but is mononucleated.
Lacunar RSC is large, with a single hyperlobulated nucleus, multiple, small nucleoli and eosinophilic cytoplasm which is retracted around the nucleus, creating an empty space ("lacunae").
Pleomorphic RSC has multiple irregular nuclei.
"Popcorn" RSC (lympho-histiocytic variant) is a small cell, with a very lobulated nucleus, small nucleoli.
"Mummy" RSC has a compact nucleus with no nucleolus and basophilic cytoplasm.
Hodgkin lymphoma can be sub-classified by histological type. The cell histology in Hodgkin lymphoma is not as important as it is in non-Hodgkin lymphoma: the treatment and prognosis in classic Hodgkin lymphoma usually depends on the stage of disease rather than the histotype.
== Management ==
The approach for treatment aims to reduce the acute and long-term toxicities associated with Hodgkin lymphoma (e.g. cardiac damage and secondary cancers) and increase overall survival.
People with early stage disease (IA or IIA) can be treated effectively with radiation therapy or chemotherapy. The choice of treatment depends on the age, sex, bulk and the histological subtype of the disease.
Adding localised radiation therapy after the chemotherapy regimen may provide a longer progression-free survival compared with chemotherapy treatment alone. People with later disease (III, IVA, or IVB) are treated with combination chemotherapy alone. People of any stage with a large mass in the chest are usually treated with combined chemotherapy and radiation therapy.
The common non-Hodgkin treatment, rituximab (which is a monoclonal antibody against CD20) is not routinely used to treat Hodgkin lymphoma due to the lack of CD20 surface antigens in most cases. The use of rituximab in Hodgkin lymphoma, including the lymphocyte predominant subtype has been reviewed. The evidence is uncertain about the effect of nivolumab for people with a Hodgkin lymphoma e.g. on the overall survival.
Increased age is an adverse risk factor for Hodgkin lymphoma, but in general elderly people (≥ 60 years of age) without major comorbidities are sufficiently fit to tolerate therapy with curative intent. Despite this, treatment outcome in the elderly patient is not comparable to that of younger people and the disease is a different entity in older people where different considerations enter into treatment decisions.
Two novel targeted drugs have been developed for relapsing and refractory HL patients; brentuximab vedotin, a CD30 antibody conjugated with a cytotoxic component MMAE, and the checkpoint inhibitors, nivolumab and pembrolizumab. This has been an important step in the treatment for the few, but still existing refractory patients.
For Hodgkin lymphomas, radiation oncologists typically use external beam radiation therapy (sometimes shortened to EBRT or XRT). Radiation oncologists deliver external beam radiation therapy to the lymphoma from a machine called a linear accelerator which produces high energy X-rays and electrons. People usually describe treatments as painless and similar to getting an X-ray. Treatments last less than 30 minutes each.
For lymphomas, there are a few different ways radiation oncologists target the cancer cells. Involved site radiation is when the radiation oncologists give radiation only to those parts of the person's body known to have the cancer. Very often, this is combined with chemotherapy. Radiation therapy directed above the diaphragm to the neck, chest or underarms is called mantle field radiation. Radiation to below the diaphragm to the abdomen, spleen or pelvis is called inverted-Y field radiation. Total nodal irradiation is when the therapist gives radiation to all the lymph nodes in the body to destroy cells that may have spread.
=== Adverse effects ===
The high cure rates and long survival of many people with Hodgkin lymphoma has led to a high concern with late adverse effects of treatment, including cardiovascular disease and second malignancies such as acute leukemias, lymphomas, and solid tumors within the radiation therapy field. Most people with early-stage disease are now treated with abbreviated chemotherapy and involved site radiation therapy rather than with radiation therapy alone. Clinical research strategies are exploring reduction of the duration of chemotherapy and dose and volume of radiation therapy in an attempt to reduce late morbidity and mortality of treatment while maintaining high cure rates. Hospitals are also treating those who respond quickly to chemotherapy with no radiation.
In childhood cases of Hodgkin lymphoma, long-term endocrine adverse effects are a major concern, mainly gonadal dysfunction and growth retardation. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents or pelvic radiotherapy.
It is possible that patients undergoing a chemotherapy need a platelet transfusion. If a stem cell transplantation is necessary for the treatment of a relapse, graft-versus-host diseases might occur.
=== Supportive treatment ===
Adding physical exercises to the standard treatment for adult patients with haematological malignancies like Hodgkin lymphoma may result in little to no difference in the mortality, the quality of life and the physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect on anxiety and serious adverse events.
== Prognosis ==
Treatment of Hodgkin lymphoma has been improving. Types of chemotherapy have resulted in higher survival rates than have previously been seen. In a 2007 European trial, the five-year survival rate for those people with a favorable prognosis (FFP) was 98%, while that for people with worse outlooks was at least 85%.
In 1998, an international effort identified seven prognostic factors that accurately predict the success rate of conventional treatment in people with locally extensive or advanced-stage Hodgkin lymphoma. Freedom from progression (FFP) at five years was directly related to the number of factors present in a person. The five-year FFP for people with zero factors is 84%. Each additional factor lowers the five-year FFP rate by 7%, such that the five-year FFP for a person with five or more factors is 42%.
The adverse prognostic factors identified in the international study are:
Age ≥ 45 years
Stage IV disease
Hemoglobin < 10.5 g/dl
Lymphocyte count < 600/μL or < 8%
Male
Albumin < 4.0 g/dl
White blood count ≥ 15,000/μL
Other studies have reported the following to be the most important adverse prognostic factors: mixed-cellularity or lymphocyte-depleted histologies, male sex, large number of involved nodal sites, advanced stage, age of 40 years or more, the presence of B symptoms, high erythrocyte sedimentation rate, and bulky disease (widening of the mediastinum by more than one third, or the presence of a nodal mass measuring more than 10 cm in any dimension.)
The use of positron emission tomography (PET) early after commencing chemotherapy has demonstrated to have powerful prognostic ability. This enables assessment of an individual's response to chemotherapy as the PET activity switches off rapidly in people who are responding. In this study, after two cycles of ABVD chemotherapy, 83% of people were free of disease at 3 years if they had a negative PET versus only 28% in those with positive PET scans. This prognostic method improves on FFP estimates based on the seven conventional factors. Several trials are underway to see if PET-based risk adapted response can be used to improve a person's outcomes by changing chemotherapy early in people who are not responding.
The evidence is uncertain about the effect of negative (= good prognosis) or positive (= bad prognosis) interim PET scan results for people with a Hodgkin lymphoma on the progression-free survival. Negative interim PET scan results may result in an increase in progression-free survival compared if the adjusted result was measured. Negative interim PET scan results probably result in a large increase in the overall survival compared to those with a positive interim PET scan result,
== Epidemiology ==
Unlike some other lymphomas, whose number of new cases per year increases with age, Hodgkin lymphoma has a bimodal distribution curve for the number of cases; that is, it occurs most frequently in two separate age groups, the first being young adulthood (age 15–35) and the second being in those over 55 years of age although these peaks may vary slightly with nationality. Overall, it is more common in males, except for the nodular sclerosis variant, which is slightly more common in females. The annual number of cases of Hodgkin lymphoma is 2.7 per 100,000 per persons per year, and the disease accounts for slightly less than 1% of all cancers worldwide.
In 2010, globally it resulted in about 18,000 deaths down from 19,000 in 1990. In 2012, there were an estimated 65,950 cases and 25,469 deaths from Hodgkin lymphoma worldwide, with 28,852 and 37,098 cases occurring in developed and developing countries, respectively. However, the age-standardized rates were higher in developed regions, with the greatest rates in the Americas (1.5 per 100,000), East Mediterranean Region (1.5 per 100,000), and Europe (2.0 per 100,000). The East Mediterranean Region also has the highest age-standardized mortality rate of 1.0 per 100,000, which is mainly attributed to lifestyle and environmental risk factors associated with transitional economies such as smoking, obesity, physical inactivity, and reproductive behaviors, as well as availability of diagnostic practices and awareness of the disease.
The number of cases of Hodgkin lymphoma is increased in people with infected with HIV.
=== United Kingdom ===
Hodgkin lymphoma accounts for less than 1% of all cancer cases and deaths in the United Kingdom. Around 1,800 people were diagnosed with the disease in 2011, and around 330 people died in 2012.
=== United States ===
In 2016, there were 8,389 new cases and 1,000 mortalities attributed to Hodgkin lymphoma, a decrease from the 8,625 new cases and 1,120 mortalities in 2015. As of January 2016, the five-year limited duration prevalence of Hodgkin lymphoma was 37,513 representing 0.71% of all diagnosed cancers in the United States.
== History ==
Hodgkin lymphoma was first described in an 1832 report by Thomas Hodgkin, although Hodgkin noted that perhaps an earlier reference to the condition was provided by Marcello Malpighi in 1666. While occupied as museum curator at Guy's Hospital, London, Hodgkin studied seven people with painless lymph node enlargement. Of the seven cases, two were under the care of Richard Bright, one was of Thomas Addison, and one was of Robert Carswell. Carswell's report of the seventh case was accompanied by numerous illustrations that aided early descriptions of the disease.
Hodgkin's report on the seven cases, entitled "On some morbid appearances of the absorbent glands and spleen", was presented to the Medical and Chirurgical Society of London in January 1832 and was subsequently published in the society's journal, Medical-Chirurgical Society Transactions. Hodgkin's paper went largely unnoticed, however, even though Bright highlighted it in an 1838 publication. Indeed, Hodgkin himself did not view his contribution as particularly significant.
In 1856, Samuel Wilks independently reported on a series of patients with the same disease that Hodgkin had previously described. Wilks, a successor to Hodgkin at Guy's Hospital, was unaware of Hodgkin's prior work on the subject. Bright informed Wilks of Hodgkin's contribution and in 1865, Wilks published a second paper, entitled "Cases of enlargement of the lymphatic glands and spleen", in which he named the illness "Hodgkin's disease" in honor of his predecessor.
Theodor Langhans and WS Greenfield first described the microscopic characteristics of Hodgkin lymphoma in 1872 and 1878, respectively. In 1898 and 1902, respectively, Carl Sternberg and Dorothy Reed independently described the cytogenetic features of the malignant cells of Hodgkin lymphoma, now called Reed–Sternberg cells.
Tissue specimens from Hodgkin's seven cases were preserved at Guy's Hospital. Nearly 100 years after Hodgkin's initial publication, histopathologic reexamination confirmed Hodgkin lymphoma in only three of seven of these people. The remaining cases included non-Hodgkin lymphoma, tuberculosis, and syphilis.
== Notable cases ==
Paul Allen, co-founder of Microsoft was diagnosed with Hodgkin lymphoma in 1982. He later died from non-Hodgkin lymphoma, in October 2018.
Eric Berry, All-Pro strong safety for the Kansas City Chiefs of the National Football League, diagnosed in 2014.
David Brooks, Welsh professional footballer, diagnosed in 2021, while playing for AFC Bournemouth.
Dale Carnegie, public speaker and author of How to Win Friends and Influence People.
Howard Carter, Egyptologist and discoverer of the Tomb of Tutankhamun, died in 1939 from Hodgkin's disease.
Starchild Abraham Cherrix, a teenager whose refusal to undergo further conventional treatment after relapsing in 2006 resulted in a court battle and a change to Virginia laws about medical neglect.
James Conner, running back and 2014 ACC Player of the Year for the Arizona Cardinals.
Michael Cuccione, Canadian child actor, was diagnosed in 1994 at age 9. Treatments that rendered him cancer-free, including chemotherapy, a bone marrow transplant, and radiation, left him with permanent lung and respiratory problems and he died in 2001 just after turning 16.
Victoria Duval, American tennis player, was diagnosed in 2014.
Gerald Finzi, British composer, was diagnosed in 1951 and died in 1956.
Mist Edvardsdóttir, Icelandic football player and member of the Icelandic women's national team. Diagnosed in June 2014 at the age of 23. Continued to play until becoming too ill due to chemotherapy. Made recovery in early 2015.
Delta Goodrem, Australian singer, songwriter, and actress. She was diagnosed in July 2003 at the age of 18.
Hank Green, one of the cofounders of the Vlogbrothers, VidCon and production company Complexly, announced that he was diagnosed with Hodgkin lymphoma in a video he released on 19 May 2023. Green would announce his entrance into remission on 25 August 2023.
Jiří Grossmann, Czechoslovak theatre actor, poet, and composer
Michael C. Hall (born 1 February 1971), American actor, best known for his lead role as Dexter Morgan, in Showtime's crime series Dexter. In 2010, aged 38, Hall announced he was undergoing treatment for Hodgkin lymphoma; within two years, the disease was in full remission.
Richard Harris, Irish actor who portrayed Albus Dumbledore in the first two Harry Potter movies, died on 25 October 2002, after being diagnosed earlier that year.
Daniel Hauser, whose mother fled with him in 2009 in order to prevent him from undergoing chemotherapy.
Tessa James, Australian actress, was diagnosed in 2014.
Sean Kent, American stand up comedian and actor. Was diagnosed in 2002 while writing on The Best Damn Sports Show Period. After three months of chemotherapy and one month of radiation, the cancer went into remission.
Mario Lemieux, Hall of Fame NHL player, co-owner of the Pittsburgh Penguins and founder of the Mario Lemieux Foundation, diagnosed in 1993.
Dinu Lipatti (1917–1950), Romanian classical pianist and composer. Diagnosed in 1947, received cortisone treatment in 1949; died from a burst abscess on his one lung.
Jack Lisowski, English snooker player, diagnosed in 2008 at the age of 16.
Mamta Mohandas, Indian film actress and producer, diagnosed in 2010.
Nanni Moretti, Italian actor and director.
Laura Packard, health care activist diagnosed in 2017, spoke at the 2020 Democratic National Convention.
Nikola Pokrivač, Croatian soccer midfielder, diagnosed in 2015.
Anthony Rizzo, MLB All-Star first baseman for the New York Yankees, diagnosed in May 2008 while signed as a minor league player for the Boston Red Sox.
Dave Roberts, MLB outfielder and manager of the Los Angeles Dodgers. Diagnosed in March 2010 while he was a coach for the San Diego Padres.
Chip Roy, Texas congressman.
Flip Saunders, head coach of the NBA team Minnesota Timberwolves, announced in August 2015 that he was diagnosed with Hodgkin's disease. He died of the disease in October 2015.
Arlen Specter, United States Senator from Pennsylvania (1981–2011), diagnosed in 2005. He later died from non-Hodgkin lymphoma in 2012.
Brandon Tartikoff, American television executive, diagnosed around 1974, died in 1997.
Bernardo Tengarrinha, Portuguese professional footballer, diagnosed in 2017 Tengarrinha died on 30 October 2021, at the age of 32. Hours later, his former teams FC Porto and Boavista FC paid tribute to him before the local derby. playing for FC Porto.
Ethan Zohn, American professional soccer player and a winner of the Survivor reality television series. Zohn was diagnosed twice (in 2009 and 2011).
Richard Holliday, American professional wrestler, reported to be ill with diagnosis from June 2022, completed treatment 17 February 2023
== References ==
== Further reading ==
Jacobs CD (2010). Henry Kaplan and the Story of Hodgkin's Disease. Stanford University Press. ISBN 978-0-8047-7448-2. OCLC 648759629; combines a biography of the American radiation oncologist (1918–84) with a history of the lymphatic cancer whose treatment he helped to transform.
== External links ==
Hodgkin Lymphoma at American Cancer Society
Hodgkin Lymphoma at the American National Cancer Institute | Wikipedia/Hodgkin's_disease |
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials, a larger group which also includes antibiotic (also termed antibacterial), antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.
== Medical uses ==
Most of the antiviral drugs now available are designed to help deal with HIV, herpes viruses, the hepatitis B and C viruses, and influenza A and B viruses.
Viruses use the host's cells to replicate and this makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells. Moreover, the major difficulty in developing vaccines and antiviral drugs is due to viral variation.
The emergence of antivirals is the product of a greatly expanded knowledge of the genetic and molecular function of organisms, allowing biomedical researchers to understand the structure and function of viruses, major advances in the techniques for finding new drugs, and the pressure placed on the medical profession to deal with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS).
The first experimental antivirals were developed in the 1960s, mostly to deal with herpes viruses, and were found using traditional trial-and-error drug discovery methods. Researchers grew cultures of cells and infected them with the target virus. They then introduced into the cultures chemicals which they thought might inhibit viral activity and observed whether the level of virus in the cultures rose or fell. Chemicals that seemed to have an effect were selected for closer study.
This was a very time-consuming, hit-or-miss procedure, and in the absence of a good knowledge of how the target virus worked, it was not efficient in discovering effective antivirals which had few side effects. Only in the 1980s, when the full genetic sequences of viruses began to be unraveled, did researchers begin to learn how viruses worked in detail, and exactly what chemicals were needed to thwart their reproductive cycle.
== Antiviral drug design ==
=== Antiviral targeting ===
The general idea behind modern antiviral drug design is to identify viral proteins, or parts of proteins, that can be disabled. These "targets" should generally be as unlike any proteins or parts of proteins in humans as possible, to reduce the likelihood of side effects and toxicity. The targets should also be common across many strains of a virus, or even among different species of virus in the same family, so a single drug will have broad effectiveness. For example, a researcher might target a critical enzyme synthesized by the virus, but not by the patient, that is common across strains, and see what can be done to interfere with its operation.
Once targets are identified, candidate drugs can be selected, either from drugs already known to have appropriate effects or by actually designing the candidate at the molecular level with a computer-aided design program.
The target proteins can be manufactured in the lab for testing with candidate treatments by inserting the gene that synthesizes the target protein into bacteria or other kinds of cells. The cells are then cultured for mass production of the protein, which can then be exposed to various treatment candidates and evaluated with "rapid screening" technologies.
=== Approaches by virus life cycle stage ===
Viruses consist of a genome and sometimes a few enzymes stored in a capsule made of protein (called a capsid), and sometimes covered with a lipid layer (sometimes called an 'envelope'). Viruses cannot reproduce on their own and instead propagate by subjugating a host cell to produce copies of themselves, thus producing the next generation.
Researchers working on such "rational drug design" strategies for developing antivirals have tried to attack viruses at every stage of their life cycles. Some species of mushrooms have been found to contain multiple antiviral chemicals with similar synergistic effects.
Compounds isolated from fruiting bodies and filtrates of various mushrooms have broad-spectrum antiviral activities, but successful production and availability of such compounds as frontline antiviral is a long way away.
Viral life cycles vary in their precise details depending on the type of virus, but they all share a general pattern:
Attachment to a host cell.
Release of viral genes and possibly enzymes into the host cell.
Replication of viral components using host-cell machinery.
Assembly of viral components into complete viral particles.
Release of viral particles to infect new host cells.
==== Before cell entry ====
One antiviral strategy is to interfere with the ability of a virus to infiltrate a target cell. The virus must go through a sequence of steps to do this, beginning with binding to a specific "receptor" molecule on the surface of the host cell and ending with the virus "uncoating" inside the cell and releasing its contents. Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them into the cell before they can uncoat.
This stage of viral replication can be inhibited in two ways:
Using agents which mimic the virus-associated protein (VAP) and bind to the cellular receptors. This may include VAP anti-idiotypic antibodies, natural ligands of the receptor, and anti-receptor antibodies.
Using agents which mimic the cellular receptor and bind to the VAP. This includes anti-VAP antibodies, receptor anti-idiotypic antibodies, extraneous receptor and synthetic receptor mimics.
This strategy of designing drugs can be very expensive, and since the process of generating anti-idiotypic antibodies is partly trial and error, it can be a relatively slow process until an adequate molecule is produced.
===== Entry inhibitor =====
A very early stage of viral infection is viral entry, when the virus attaches to and enters the host cell. A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV. HIV most heavily targets a specific type of lymphocyte known as "helper T cells", and identifies these target cells through T-cell surface receptors designated "CD4" and "CCR5". Attempts to interfere with the binding of HIV with the CD4 receptor have failed to stop HIV from infecting helper T cells, but research continues on trying to interfere with the binding of HIV to the CCR5 receptor in hopes that it will be more effective.
HIV infects a cell through fusion with the cell membrane, which requires two different cellular molecular participants, CD4 and a chemokine receptor (differing depending on the cell type). Approaches to blocking this virus/cell fusion have shown some promise in preventing entry of the virus into a cell. At least one of these entry inhibitors—a biomimetic peptide called Enfuvirtide, or the brand name Fuzeon—has received FDA approval and has been in use for some time. Potentially, one of the benefits from the use of an effective entry-blocking or entry-inhibiting agent is that it potentially may not only prevent the spread of the virus within an infected individual but also the spread from an infected to an uninfected individual.
One possible advantage of the therapeutic approach of blocking viral entry (as opposed to the currently dominant approach of viral enzyme inhibition) is that it may prove more difficult for the virus to develop resistance to this therapy than for the virus to mutate or evolve its enzymatic protocols.
===== Uncoating inhibitors =====
Inhibitors of uncoating have also been investigated.
Amantadine and rimantadine have been introduced to combat influenza. These agents act on penetration and uncoating.
Pleconaril works against rhinoviruses, which cause the common cold, by blocking a pocket on the surface of the virus that controls the uncoating process. This pocket is similar in most strains of rhinoviruses and enteroviruses, which can cause diarrhea, meningitis, conjunctivitis, and encephalitis.
Some scientists are making the case that a vaccine against rhinoviruses, the predominant cause of the common cold, is achievable.
Vaccines that combine dozens of varieties of rhinovirus at once are effective in stimulating antiviral antibodies in mice and monkeys, researchers reported in Nature Communications in 2016.
Rhinoviruses are the most common cause of the common cold; other viruses such as respiratory syncytial virus, parainfluenza virus and adenoviruses can cause them too. Rhinoviruses also exacerbate asthma attacks. Although rhinoviruses come in many varieties, they do not drift to the same degree that influenza viruses do. A mixture of 50 inactivated rhinovirus types should be able to stimulate neutralizing antibodies against all of them to some degree.
==== During viral synthesis ====
A second approach is to target the processes that synthesize virus components after a virus invades a cell.
===== Reverse transcription =====
One way of doing this is to develop nucleotide or nucleoside analogues that look like the building blocks of RNA or DNA, but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated. This approach is more commonly associated with the inhibition of reverse transcriptase (RNA to DNA) than with "normal" transcriptase (DNA to RNA).
The first successful antiviral, aciclovir, is a nucleoside analogue, and is effective against herpesvirus infections. The first antiviral drug to be approved for treating HIV, zidovudine (AZT), is also a nucleoside analogue.
An improved knowledge of the action of reverse transcriptase has led to better nucleoside analogues to treat HIV infections. One of these drugs, lamivudine, has been approved to treat hepatitis B, which uses reverse transcriptase as part of its replication process. Researchers have gone further and developed inhibitors that do not look like nucleosides, but can still block reverse transcriptase.
Another target being considered for HIV antivirals include RNase H—which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA.
===== Integrase =====
Another target is integrase, which integrate the synthesized DNA into the host cell genome. Examples of integrase inhibitors include raltegravir, elvitegravir, and dolutegravir.
===== Transcription =====
Once a virus genome becomes operational in a host cell, it then generates messenger RNA (mRNA) molecules that direct the synthesis of viral proteins. Production of mRNA is initiated by proteins known as transcription factors. Several antivirals are now being designed to block attachment of transcription factors to viral DNA.
===== Translation/antisense =====
Genomics has not only helped find targets for many antivirals, it has provided the basis for an entirely new type of drug, based on "antisense" molecules. These are segments of DNA or RNA that are designed as complementary molecule to critical sections of viral genomes, and the binding of these antisense segments to these target sections blocks the operation of those genomes. A phosphorothioate antisense drug named fomivirsen has been introduced, used to treat opportunistic eye infections in AIDS patients caused by cytomegalovirus, and other antisense antivirals are in development. An antisense structural type that has proven especially valuable in research is morpholino antisense.
Morpholino oligos have been used to experimentally suppress many viral types:
caliciviruses
flaviviruses (including West Nile virus)
dengue
HCV
coronaviruses
===== Translation/ribozymes =====
Yet another antiviral technique inspired by genomics is a set of drugs based on ribozymes, which are enzymes that will cut apart viral RNA or DNA at selected sites. In their natural course, ribozymes are used as part of the viral manufacturing sequence, but these synthetic ribozymes are designed to cut RNA and DNA at sites that will disable them.
A ribozyme antiviral to deal with hepatitis C has been suggested, and ribozyme antivirals are being developed to deal with HIV. An interesting variation of this idea is the use of genetically modified cells that can produce custom-tailored ribozymes. This is part of a broader effort to create genetically modified cells that can be injected into a host to attack pathogens by generating specialized proteins that block viral replication at various phases of the viral life cycle.
===== Protein processing and targeting =====
Interference with post translational modifications or with targeting of viral proteins in the cell is also possible.
==== Protease inhibitors ====
Some viruses include an enzyme known as a protease that cuts viral protein chains apart so they can be assembled into their final configuration. HIV includes a protease, and so considerable research has been performed to find "protease inhibitors" to attack HIV at that phase of its life cycle. Protease inhibitors became available in the 1990s and have proven effective, though they can have unusual side effects, for example causing fat to build up in unusual places. Improved protease inhibitors are now in development.
Protease inhibitors have also been seen in nature. A protease inhibitor was isolated from the shiitake mushroom (Lentinus edodes). The presence of this may explain the Shiitake mushrooms' noted antiviral activity in vitro.
===== Long dsRNA helix targeting =====
Most viruses produce long dsRNA helices during transcription and replication. In contrast, uninfected mammalian cells generally produce dsRNA helices of fewer than 24 base pairs during transcription. DRACO (double-stranded RNA activated caspase oligomerizer) is a group of experimental antiviral drugs initially developed at the Massachusetts Institute of Technology. In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus, Amapari and Tacaribe arenavirus, Guama bunyavirus, H1N1 influenza and rhinovirus, and was additionally found effective against influenza in vivo in weanling mice. It was reported to induce rapid apoptosis selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed. DRACO effects cell death via one of the last steps in the apoptosis pathway in which complexes containing intracellular apoptosis signalling molecules simultaneously bind multiple procaspases. The procaspases transactivate via cleavage, activate additional caspases in the cascade, and cleave a variety of cellular proteins, thereby killing the cell.
==== Assembly ====
Rifampicin acts at the assembly phase.
==== Release phase ====
The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers. Two drugs named zanamivir (Relenza) and oseltamivir (Tamiflu) that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains.
=== Immune system stimulation ===
Rather than attacking viruses directly, a second category of tactics for fighting viruses involves encouraging the body's immune system to attack them. Some antivirals of this sort do not focus on a specific pathogen, instead stimulating the immune system to attack a range of pathogens.
One of the best-known of this class of drugs are interferons, which inhibit viral synthesis in infected cells. One form of human interferon named "interferon alpha" is well-established as part of the standard treatment for hepatitis B and C, and other interferons are also being investigated as treatments for various diseases.
A more specific approach is to synthesize antibodies, protein molecules that can bind to a pathogen and mark it for attack by other elements of the immune system. Once researchers identify a particular target on the pathogen, they can synthesize quantities of identical "monoclonal" antibodies to link up that target. A monoclonal drug is now being sold to help fight respiratory syncytial virus in babies, and antibodies purified from infected individuals are also used as a treatment for hepatitis B.
== Antiviral drug resistance ==
Antiviral resistance can be defined by a decreased susceptibility to a drug caused by changes in viral genotypes. In cases of antiviral resistance, drugs have either diminished or no effectiveness against their target virus. The issue inevitably remains a major obstacle to antiviral therapy as it has developed to almost all specific and effective antimicrobials, including antiviral agents.
The Centers for Disease Control and Prevention (CDC) inclusively recommends anyone six months and older to get a yearly vaccination to protect them from influenza A viruses (H1N1) and (H3N2) and up to two influenza B viruses (depending on the vaccination). Comprehensive protection starts by ensuring vaccinations are current and complete. However, vaccines are preventative and are not generally used once a patient has been infected with a virus. Additionally, the availability of these vaccines can be limited based on financial or locational reasons which can prevent the effectiveness of herd immunity, making effective antivirals a necessity.
The three FDA-approved neuraminidase antiviral flu drugs available in the United States, recommended by the CDC, include: oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab). Influenza antiviral resistance often results from changes occurring in neuraminidase and hemagglutinin proteins on the viral surface. Currently, neuraminidase inhibitors (NAIs) are the most frequently prescribed antivirals because they are effective against both influenza A and B. However, antiviral resistance is known to develop if mutations to the neuraminidase proteins prevent NAI binding. This was seen in the H257Y mutation, which was responsible for oseltamivir resistance to H1N1 strains in 2009. The inability of NA inhibitors to bind to the virus allowed this strain of virus with the resistance mutation to spread due to natural selection. Furthermore, a study published in 2009 in Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir stockpiles with additional antiviral drugs including zanamivir. This finding was based on a performance evaluation of these drugs supposing the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the oseltamivir-resistance (His274Tyr) mutation, which is currently widespread in seasonal H1N1 strains.
=== Origin of antiviral resistance ===
The genetic makeup of viruses is constantly changing, which can cause a virus to become resistant to currently available treatments. Viruses can become resistant through spontaneous or intermittent mechanisms throughout the course of an antiviral treatment. Immunocompromised patients, more often than immunocompetent patients, hospitalized with pneumonia are at the highest risk of developing oseltamivir resistance during treatment. Subsequent to exposure to someone else with the flu, those who received oseltamivir for "post-exposure prophylaxis" are also at higher risk of resistance.
The mechanisms for antiviral resistance development depend on the type of virus in question. RNA viruses such as hepatitis C and influenza A have high error rates during genome replication because RNA polymerases lack proofreading activity. RNA viruses also have small genome sizes that are typically less than 30 kb, which allow them to sustain a high frequency of mutations. DNA viruses, such as HPV and herpesvirus, hijack host cell replication machinery, which gives them proofreading capabilities during replication. DNA viruses are therefore less error prone, are generally less diverse, and are more slowly evolving than RNA viruses. In both cases, the likelihood of mutations is exacerbated by the speed with which viruses reproduce, which provides more opportunities for mutations to occur in successive replications. Billions of viruses are produced every day during the course of an infection, with each replication giving another chance for mutations that encode for resistance to occur.
Multiple strains of one virus can be present in the body at one time, and some of these strains may contain mutations that cause antiviral resistance. This effect, called the quasispecies model, results in immense variation in any given sample of virus, and gives the opportunity for natural selection to favor viral strains with the highest fitness every time the virus is spread to a new host. Recombination, the joining of two different viral variants, and reassortment, the swapping of viral gene segments among viruses in the same cell, also play a role in resistance, especially in influenza.
Antiviral resistance has been reported in antivirals for herpes, HIV, hepatitis B and C, and influenza, but antiviral resistance is a possibility for all viruses. Mechanisms of antiviral resistance vary between virus types.
=== Detection of antiviral resistance ===
National and international surveillance is performed by the CDC to determine effectiveness of the current FDA-approved antiviral flu drugs. Public health officials use this information to make current recommendations about the use of flu antiviral medications. WHO further recommends in-depth epidemiological investigations to control potential transmission of the resistant virus and prevent future progression. As novel treatments and detection techniques to antiviral resistance are enhanced so can the establishment of strategies to combat the inevitable emergence of antiviral resistance.
=== Treatment options for antiviral resistant pathogens ===
If a virus is not fully wiped out during a regimen of antivirals, treatment creates a bottleneck in the viral population that selects for resistance, and there is a chance that a resistant strain may repopulate the host. Viral treatment mechanisms must therefore account for the selection of resistant viruses.
The most commonly used method for treating resistant viruses is combination therapy, which uses multiple antivirals in one treatment regimen. This is thought to decrease the likelihood that one mutation could cause antiviral resistance, as the antivirals in the cocktail target different stages of the viral life cycle. This is frequently used in retroviruses like HIV, but a number of studies have demonstrated its effectiveness against influenza A, as well. Viruses can also be screened for resistance to drugs before treatment is started. This minimizes exposure to unnecessary antivirals and ensures that an effective medication is being used. This may improve patient outcomes and could help detect new resistance mutations during routine scanning for known mutants. However, this has not been consistently implemented in treatment facilities at this time.
== Direct-acting antivirals ==
The term Direct-acting antivirals (DAA) has long been associated with the combination of antiviral drugs used to treat hepatitis C infections. These are the more effective than older treatments such as ribavirin (partially indirectly acting) and interferon (indirect acting). The DAA drugs against hepatitis C are taken orally, as tablets, for 8 to 12 weeks. The treatment depends on the type or types (genotypes) of hepatitis C virus that are causing the infection. Both during and at the end of treatment, blood tests are used to monitor the effectiveness of the treatment and subsequent cure.
The DAA combination drugs used include:
Harvoni (sofosbuvir and ledipasvir)
Epclusa (sofosbuvir and velpatasvir)
Vosevi (sofosbuvir, velpatasvir, and voxilaprevir)
Zepatier (elbasvir and grazoprevir)
Mavyret (glecaprevir and pibrentasvir)
The United States Food and Drug Administration approved DAAs on the basis of a surrogate endpoint called sustained virological response (SVR). SVR is achieved in a patient when hepatitis C virus RNA remains undetectable 12–24 weeks after treatment ends. Whether through DAAs or older interferon-based regimens, SVR is associated with improved health outcomes and significantly decreased mortality. For those who already have advanced liver disease (including hepatocellular carcinoma), however, the benefits of achieving SVR may be less pronounced, though still substantial.
Despite its historical roots in hepatitis C research, the term "direct-acting antivirals" is becoming more broadly used to also include other anti-viral drugs with a direct viral target such as aciclovir (against herpes simplex virus), letermovir (against cytomegalovirus), or AZT (against human immunodeficiency virus). In this context it serves to distinguish these drugs from those with an indirect mechanism of action such as immune modulators like interferon alfa. This difference is of particular relevance for potential drug resistance mutation development.
== Public policy ==
=== Use and distribution ===
Guidelines regarding viral diagnoses and treatments change frequently and limit quality care. Even when physicians diagnose older patients with influenza, use of antiviral treatment can be low. Provider knowledge of antiviral therapies can improve patient care, especially in geriatric medicine. Furthermore, in local health departments (LHDs) with access to antivirals, guidelines may be unclear, causing delays in treatment. With time-sensitive therapies, delays could lead to lack of treatment.
Overall, national guidelines, regarding infection control and management, standardize care and improve healthcare worker and patient safety. Guidelines, such as those provided by the Centers for Disease Control and Prevention (CDC) during the 2009 flu pandemic caused by the H1N1 virus, recommend, among other things, antiviral treatment regimens, clinical assessment algorithms for coordination of care, and antiviral chemoprophylaxis guidelines for exposed persons. Roles of pharmacists and pharmacies have also expanded to meet the needs of public during public health emergencies.
=== Stockpiling ===
Public Health Emergency Preparedness initiatives are managed by the CDC via the Office of Public Health Preparedness and Response. Funds aim to support communities in preparing for public health emergencies, including pandemic influenza. Also managed by the CDC, the Strategic National Stockpile (SNS) consists of bulk quantities of medicines and supplies for use during such emergencies. Antiviral stockpiles prepare for shortages of antiviral medications in cases of public health emergencies. During the H1N1 pandemic in 2009–2010, guidelines for SNS use by local health departments was unclear, revealing gaps in antiviral planning. For example, local health departments that received antivirals from the SNS did not have transparent guidance on the use of the treatments. The gap made it difficult to create plans and policies for their use and future availabilities, causing delays in treatment.
== See also ==
Antiretroviral drug (especially HAART for HIV)
CRISPR-Cas13
Discovery and development of CCR5 receptor antagonists (for HIV)
Monoclonal antibody
List of antiviral drugs
Antiprion drugs and Astemizole
Discovery and development of NS5A inhibitors
COVID-19 drug repurposing research
== References == | Wikipedia/Antiviral_drug |
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells (e.g. with traditional chemotherapy). Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy (and thus distinguished from chemotherapy, that is, cytotoxic therapy). However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
Another form of targeted therapy involves the use of nanoengineered enzymes to bind to a tumor cell such that the body's natural cell degradation process can digest the cell, effectively eliminating it from the body.
Targeted cancer therapies are expected to be more effective than older forms of treatments and less harmful to normal cells. Many targeted therapies are examples of immunotherapy (using immune mechanisms for therapeutic goals) developed by the field of cancer immunology. Thus, as immunomodulators, they are one type of biological response modifiers.
The most successful targeted therapies are chemical entities that target or preferentially target a protein or enzyme that carries a mutation or other genetic alteration that is specific to cancer cells and not found in normal host tissue. One of the most successful molecular targeted therapeutics is imatinib, marketed as Gleevec, which is a kinase inhibitor with exceptional affinity for the oncofusion protein BCR-Abl which is a strong driver of tumorigenesis in chronic myelogenous leukemia. Although employed in other indications, imatinib is most effective targeting BCR-Abl. Other examples of molecular targeted therapeutics targeting mutated oncogenes, include PLX27892 which targets mutant B-raf in melanoma.
There are targeted therapies for lung cancer, colorectal cancer, head and neck cancer, breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers.
Biomarkers are usually required to aid the selection of patients who will likely respond to a given targeted therapy.
Co-targeted therapy involves the use of one or more therapeutics aimed at multiple targets, for example PI3K and MEK, in an attempt to generate a synergistic response and prevent the development of drug resistance.
The definitive experiments that showed that targeted therapy would reverse the malignant phenotype of tumor cells involved treating Her2/neu transformed cells with monoclonal antibodies in vitro and in vivo by Mark Greene's laboratory and reported from 1985.
Some have challenged the use of the term, stating that drugs usually associated with the term are insufficiently selective. The phrase occasionally appears in scare quotes: "targeted therapy". Targeted therapies may also be described as "chemotherapy" or "non-cytotoxic chemotherapy", as "chemotherapy" strictly means only "treatment by chemicals". But in typical medical and general usage "chemotherapy" is now mostly used specifically for "traditional" cytotoxic chemotherapy.
== Types ==
The main categories of targeted therapy are currently small molecules and monoclonal antibodies.
=== Small molecules ===
Many are tyrosine-kinase inhibitors.
Imatinib (Gleevec, also known as STI–571) is approved for chronic myelogenous leukemia, gastrointestinal stromal tumor and some other types of cancer. Early clinical trials indicate that imatinib may be effective in treatment of dermatofibrosarcoma protuberans.
Gefitinib (Iressa, also known as ZD1839), targets the epidermal growth factor receptor (EGFR) tyrosine kinase and is approved in the U.S. for non small cell lung cancer.
Erlotinib (marketed as Tarceva). Erlotinib inhibits epidermal growth factor receptor, and works through a similar mechanism as gefitinib. Erlotinib has been shown to increase survival in metastatic non small cell lung cancer when used as second line therapy. Because of this finding, erlotinib has replaced gefitinib in this setting.
Sorafenib (Nexavar)
Sunitinib (Sutent)
Dasatinib (Sprycel)
Lapatinib (Tykerb)
Nilotinib (Tasigna)
Bosutinib (Bosulif)
Ponatinib (Iclusig)
Asciminib (Scemblix)
Bortezomib (Velcade) is an apoptosis-inducing proteasome inhibitor drug that causes cancer cells to undergo cell death by interfering with proteins. It is approved in the U.S. to treat multiple myeloma that has not responded to other treatments.
The selective estrogen receptor modulator tamoxifen has been described as the foundation of targeted therapy.
Janus kinase inhibitors, e.g. FDA approved tofacitinib
ALK inhibitors, e.g. crizotinib
Bcl-2 inhibitors (e.g. FDA approved venetoclax, obatoclax in clinical trials, navitoclax, and gossypol.
PARP inhibitors (e.g. FDA approved olaparib, rucaparib, niraparib and talazoparib)
PI3K inhibitors (e.g. perifosine in a phase III trial)
Apatinib is a selective VEGF Receptor 2 inhibitor which has shown encouraging anti-tumor activity in a broad range of malignancies in clinical trials. Apatinib is currently in clinical development for metastatic gastric carcinoma, metastatic breast cancer and advanced hepatocellular carcinoma.
Zoptarelin doxorubicin (AN-152), doxorubicin linked to [D-Lys(6)]- LHRH, Phase II results for ovarian cancer.
Braf inhibitors (vemurafenib, dabrafenib, LGX818) used to treat metastatic melanoma that harbors BRAF V600E mutation
MEK inhibitors (trametinib, MEK162) are used in experiments, often in combination with BRAF inhibitors to treat melanoma
CDK inhibitors, e.g. PD-0332991, LEE011 in clinical trials
Hsp90 inhibitors, some in clinical trials
Hedgehog pathway inhibitors (e.g. FDA approved vismodegib and sonidegib).
Salinomycin has demonstrated potency in killing cancer stem cells in both laboratory-created and naturally occurring breast tumors in mice.
VAL-083 (dianhydrogalactitol), a “first-in-class” DNA-targeting agent with a unique bi-functional DNA cross-linking mechanism. NCI-sponsored clinical trials have demonstrated clinical activity against a number of different cancers including glioblastoma, ovarian cancer, and lung cancer. VAL-083 is currently undergoing Phase 2 and Phase 3 clinical trials as a potential treatment for glioblastoma (GBM) and ovarian cancer. As of July 2017, four different trials of VAL-083 are registered.
Ibrutinib blocks Bruton's tyrosine kinase (BTK) and is used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia.
=== Small molecule drug conjugates ===
Vintafolide is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor. It is currently in clinical trials for platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study (TARGET trial) in non-small-cell lung carcinoma (NSCLC).
=== Serine/threonine kinase inhibitors (small molecules) ===
Temsirolimus (Torisel)
Everolimus (Afinitor)
Vemurafenib (Zelboraf)
Trametinib (Mekinist)
Dabrafenib (Tafinlar)
=== Monoclonal antibodies ===
Several are in development and a few have been licensed by the FDA and the European Commission. Examples of licensed monoclonal antibodies include:
Pembrolizumab (Keytruda) binds to PD-1 proteins found on T cells. Pembrolizumab blocks PD-1 and help the immune system kill cancer cells. It is used to treat melanoma, Hodgkin's lymphoma, non-small cell lung carcinoma and several other types of cancer.
Rituximab targets CD20 found on B cells. It is used in non Hodgkin lymphoma
Trastuzumab targets the Her2/neu (also known as ErbB2) receptor expressed in some types of breast cancer
Alemtuzumab
Cetuximab target the epidermal growth factor receptor (EGFR). It is approved for use in the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck.
Panitumumab also targets the EGFR. It is approved for the use in the treatment of metastatic colorectal cancer.
Bevacizumab targets circulating VEGF ligand. It is approved for use in the treatment of colon cancer, breast cancer, non-small cell lung cancer, and is investigational in the treatment of sarcoma. Its use for the treatment of brain tumors has been recommended.
Ipilimumab (Yervoy)
Brentuximab targets CD30 and is useful in some types of lymphoma.
Many antibody-drug conjugates (ADCs) are being developed. See also antibody-directed enzyme prodrug therapy (ADEPT).
== Progress and future ==
In the U.S., the National Cancer Institute's Molecular Targets Development Program (MTDP) aims to identify and evaluate molecular targets that may be candidates for drug development. A systematic review published in Cochrane database found that targeted therapies significantly improve progression-free survival by 35 to 40% in metastatic or relapsed cancer. While the research points to promising clinical outcomes, there is still limited evidence on the long-term effects of targeted therapies in terms of overall survival, quality of life, and severe adverse events.
== See also ==
== References ==
== External links ==
Targeted Therapy Database (TTD) [1] from the Melanoma Molecular Map Project [2]
Targeted therapy Fact sheet from the U.S. National Cancer Institute
Molecular Oncology: Receptor-Based Therapy Special issue of Journal of Clinical Oncology (April 10, 2005) dedicated to targeted therapies in cancer treatment
Targeting Targeted Therapy New England Journal of Medicine (2004)
Targeting tumors with medicinal cannabis oil – publication list from Spain | Wikipedia/Targeted_cancer_therapy |
The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.
== Beginnings ==
The beginnings of the modern era of cancer chemotherapy can be traced directly to the German introduction of chemical warfare during World War I. Among the chemical agents used, mustard gas was particularly devastating. Although banned by the Geneva Protocol in 1925, the advent of World War II caused concerns over the possible re-introduction of chemical warfare. Such concerns led to the discovery of nitrogen mustard, a chemical warfare agent, as an effective treatment for some types of cancer. Two pharmacologists from the Yale School of Medicine, Louis S. Goodman and Alfred Gilman, were recruited by the US Department of Defense to investigate potential therapeutic applications of chemical warfare agents. Goodman and Gilman observed that mustard gas was too volatile an agent to be suitable for laboratory experiments. They exchanged a sulfur molecule for nitrogen and had a more stable compound in nitrogen mustard.
Goodman and Gilman hypothetized that this agent could be used to treat lymphoma, a tumor of lymphoid cells. They first set up an animal model by establishing lymphomas in mice and demonstrated they could treat them with mustard agents. Next, in collaboration with a thoracic surgeon, Gustaf Lindskog, they injected a related agent, mustine (the prototype nitrogen mustard anticancer chemotherapeutic), into a patient with non-Hodgkin's lymphoma. The patient, a Polish immigrant to Connecticut known in literature only as JD, received his first injections on August 27, 1942 at 10 a.m. The doctors observed a dramatic reduction in the patient's tumor masses. Although the effect lasted only a few weeks, and the patient had to return for another set of treatment, that was the first step to the realization that cancer could be treated by pharmacological agents. The patient ultimately died of cancer on December 1, 1942, 96 days after his first dose. Publication of the first clinical trials was reported in 1946 in The New York Times.
A year into the start of their research, in December 1943, a German air raid in Bari, Italy led to the exposure of more than 1000 people to the SS John Harvey's secret cargo composed of mustard gas bombs. Dr. Stewart Francis Alexander, a lieutenant colonel who was an expert in chemical warfare, was subsequently deployed to investigate the aftermath. Autopsies of the victims suggested that profound lymphoid and myeloid suppression had occurred after exposure. In his report, Dr. Alexander theorized that since mustard gas all but ceased the division of certain types of somatic cells whose nature was to divide fast, it could also potentially be put to use in helping to suppress the division of certain types of cancerous cells.
After World War II was over, the Yale group's studies and the Bari incident eventually converged prompting a search for other similar compounds.
== Antifolates ==
Shortly after World War II, a second approach to drug therapy of cancer began. Sidney Farber, a pathologist at Harvard Medical School, studied the effects of folic acid on leukemia patients. Folic acid, a vitamin crucial for DNA metabolism (the significance of DNA was not known at that time), had been discovered by Lucy Wills, when she was working in India, in 1937. It seemed to stimulate the proliferation of acute lymphoblastic leukemia (ALL) cells when administered to children with this cancer. In one of the first examples of rational drug design (rather than accidental discovery), Farber used folate analogues synthesized by Harriett Kiltie and Yellapragada Subbarow of Lederle Laboratories. These analogues — first aminopterin and then amethopterin (now methotrexate) were antagonistic to folic acid, and blocked the function of folate-requiring enzymes. When administered to children with ALL in 1948, these agents became the first drugs to induce remission in children with ALL. Remissions were brief, but the principle was clear — antifolates could suppress proliferation of malignant cells, and could thereby re-establish normal bone-marrow function. Farber met resistance to conducting his studies at a time when the commonly held medical belief was that leukemia was incurable, and that the children should be allowed to die in peace. Afterwards, Farber's 1948 report in the New England Journal of Medicine was met with incredulity and ridicule.
In 1947, Major League Baseball Hall of Famer Babe Ruth, who was battling nasopharyngeal cancer, became one of the first human subjects of pteroyl triglutamate (also known by its brand name Teropterin, and similar to aminopterin) treatment. Dr. Richard Lewisohn of Mount Sinai Hospital in New York administered the drug, and over the course of several months, Ruth's condition began to improve. However, Ruth died the following year.
In 1951, Jane C. Wright demonstrated the use of methotrexate in solid tumors, showing remission in breast cancer. Wright's group was the first to demonstrate use of the drug in solid tumors, as opposed to leukemias, which are cancers of the marrow. Several years later at the National Cancer Institute, Roy Hertz and Min Chiu Li then demonstrated complete remission in women with choriocarcinoma and chorioadenoma in 1956, discovering that methotrexate alone could cure choriocarcinoma (1958), a germ-cell malignancy that originates in trophoblastic cells of the placenta. In 1960 Wright et al. produced remissions in mycosis fungoides.
== 6-MP ==
Joseph Burchenal, at Memorial Sloan-Kettering Cancer Center in New York, with Farber's help, started his own methotrexate study and found the same effects. He then decided to try to develop anti-metabolites in the same way as Farber, by making small changes in a metabolite needed by a cell to divide. With the help of George Hitchings and Gertrude Elion, two pharmaceutical chemists who were working at the Burroughs Wellcome Co. in Tuckahoe, many purine analogues were tested, culminating in the discovery of 6-mercaptopurine (6-MP), which was subsequently shown to be a highly active antileukemic drug.
== Vinca Alkaloids ==
The Eli Lilly natural products group found that alkaloids of the Madagascar periwinkle (Vinca rosea), originally discovered in a screen for anti-diabetic drugs, blocked proliferation of tumour cells. The antitumour effect of the vinca alkaloids (e.g. vincristine) was later shown to be due to their ability to inhibit microtubule polymerization alkaloys, and therefore cell division.
== Cancer Chemotherapy National Service Center ==
The NCI, headed by Dr. John R. Heller Jr., lobbied the United States Congress for financial support for second-generation chemotherapy research. In response, Congress created a Cancer Chemotherapy National Service Center (CCNSC) at the NCI in 1955. This was the first federal programme to promote drug discovery for cancer – unlike now, most pharmaceutical companies were not yet interested in developing anticancer drugs. The CCNSC developed the methodologies and crucial tools (like cell lines and animal models) for chemotherapeutic development.
== Combination chemotherapy ==
In 1965, a major breakthrough in cancer therapy occurred. James F. Holland, Emil Freireich, and Emil Frei hypothesized that cancer chemotherapy should follow the strategy of antibiotic therapy for tuberculosis with combinations of drugs, each with a different mechanism of action. Cancer cells could conceivably mutate to become resistant to a single agent, but by using different drugs concurrently it would be more difficult for the tumor to develop resistance to the combination. Holland, Freireich, and Frei simultaneously administered methotrexate (an antifolate), vincristine (a Vinca alkaloid), 6-mercaptopurine (6-MP) and prednisone — together referred to as the POMP regimen — and induced long-term remissions in children with acute lymphoblastic leukaemia (ALL). With incremental refinements of original regimens, using randomized clinical studies by St. Jude Children's Research Hospital, the Medical Research Council in the UK (UKALL protocols) and German Berlin-Frankfurt-Münster clinical trials group (ALL-BFM protocols), ALL in children has become a largely curable disease.
This approach was extended to the lymphomas in 1963 by Vincent T. DeVita and George Canellos at the NCI, who ultimately proved in the late 1960s that nitrogen mustard, vincristine, procarbazine and prednisone — known as the MOPP regimen — could cure patients with Hodgkin's and non-Hodgkin's lymphoma.
Currently, nearly all successful cancer chemotherapy regimens use this paradigm of multiple drugs given simultaneously, called combination chemotherapy or polychemotherapy.
== Adjuvant therapy ==
As predicted by studies in animal models, drugs were most effective when used in patients with tumours of smaller volume. Another important strategy developed from this — if the tumour burden could be reduced first by surgery, then chemotherapy may be able to clear away any remaining malignant cells, even if it would not have been potent enough to destroy the tumor in its entirety. This approach was termed "adjuvant therapy".
Emil Frei first demonstrated this effect — high doses of methotrexate prevented recurrence of osteosarcoma following surgical removal of the primary tumour. 5-fluorouracil, which inhibits thymidylate synthase, was later shown to improve survival when used as an adjuvant to surgery in treating patients with colon cancer. Similarly, the landmark trials of Bernard Fisher, chair of the National Surgical Adjuvant Breast and Bowel Project, and of Gianni Bonadonna, working in the Istituto Nazionale Tumori di Milano, Italy, proved that adjuvant chemotherapy after complete surgical resection of breast tumours significantly extended survival — particularly in more advanced cancer.
== Drug discovery at the NCI and elsewhere ==
=== Zubrod's initiatives ===
In 1956, C. Gordon Zubrod, who had formerly led the development of antimalarial agents for the United States Army, took over the Division of Cancer Treatment of the NCI and guided development of new drugs. In the two decades that followed the establishment of the NCCSC, a large network of cooperative clinical trial groups evolved under the auspices of the NCI to test anticancer agents. Zubrod had a particular interest in natural products, and established a broad programme for collecting and testing plant and marine sources, a controversial programme that led to the discovery of taxanes (in 1964) and camptothecins (in 1966). Both classes of drug were isolated and characterized by the laboratory of Monroe Wall at the Research Triangle Institute.
=== Taxanes ===
Paclitaxel (Taxol) was a novel antimitotic agent that promoted microtubule assembly. This agent proved difficult to synthesize and could only be obtained from the bark of the Pacific Yew tree, which forced the NCI into the costly business of harvesting substantial quantities of yew trees from public lands. After 4 years of clinical testing in solid tumours, it was found in 1987 (23 years after its initial discovery) to be effective in ovarian cancer therapy. Notably, this agent, although developed by the NCI in partnership with Bristol-Myers Squibb, was exclusively marketed by BMS (who had utilized the synthetic methodology developed by Robert Holton at Florida State University) who went on to make over a billion dollars profit from Taxol.
=== Camptothecins ===
Another drug class originating from the NCI was the camptothecins. Camptothecin, derived from a Chinese ornamental tree, inhibits topoisomerase I, an enzyme that allows DNA unwinding. Despite showing promise in preclinical studies, the agent had little antitumour activity in early clinical trials, and dosing was limited by kidney toxicity: its lactone ring is unstable at neutral pH, so while in the acidic environment of the kidneys it becomes active, damaging the renal tubules. In 1996 a more stable analogue, irinotecan, won Food and Drug Administration (FDA) approval for the treatment of colon cancer. Later, this agent would also be used to treat lung and ovarian cancers.
=== Platinum-based agents ===
Cisplatin, a platinum-based compound, was discovered by a Michigan State University researcher, Barnett Rosenberg, working under an NCI contract. This was yet another serendipitous discovery: Rosenberg had initially wanted to explore the possible effects of an electric field on the growth of bacteria. He observed that the bacteria unexpectedly ceased to divide when placed in an electric field. Excited, he spent months of testing to try to explain this phenomenon. He was disappointed to find that the cause was an experimental artifact — the inhibition of bacterial division was pinpointed to an electrolysis product of the platinum electrode rather than the electrical field. This accidental discovery, however, soon initiated a series of investigations and studies into the effects of platinum compounds on cell division, culminating in the synthesis of cisplatin. This drug was pivotal in the cure of testicular cancer. Subsequently, Eve Wiltshaw and others at the Institute of Cancer Research in the United Kingdom extended the clinical usefulness of the platinum compounds with their development of carboplatin, a cisplatin derivative with broad antitumour activity and comparatively less nephrotoxicity.
=== Nitrosoureas ===
A second group with an NCI contract, led by John Montgomery at the Southern Research Institute, synthesized nitrosoureas, an alkylating agent which cross-links DNA. Fludarabine phosphate, a purine analogue which has become a mainstay in treatment of patients with chronic lymphocytic leukaemia, was another similar development by Montgomery.
=== Anthracyclines and epipodophyllotoxins ===
Other effective molecules also came from industry during the period of 1970 to 1990, including anthracyclines and epipodophyllotoxins — both of which inhibited the action of topoisomerase II, an enzyme crucial for DNA synthesis.
== Supportive care during chemotherapy ==
As is obvious from their origins, the above cancer chemotherapies are essentially poisons. Patients receiving these agents experienced severe side-effects that limited the doses which could be administered, and hence limited the beneficial effects. Clinical investigators realized that the ability to manage these toxicities was crucial to the success of cancer chemotherapy.
Several examples are noteworthy. Many chemotherapeutic agents cause profound suppression of the bone marrow. This is reversible, but takes time to recover. Support with platelet and red-cell transfusions as well as broad-spectrum antibiotics in case of infection during this period is crucial to allow the patient to recover.
Several practical factors are also worth mentioning. Most of these agents caused very severe nausea (termed chemotherapy-induced nausea and vomiting (CINV) in the literature) which, while not directly causing patient deaths, was unbearable at higher doses. The development of new drugs to prevent nausea (the prototype of which was ondansetron) was of great practical use, as was the design of indwelling intravenous catheters (e.g. Hickman lines and PICC lines) which allowed safe administration of chemotherapy as well as supportive therapy.
== Bone marrow transplantation ==
One important contribution during this period was the discovery of a means that allowed the administration of previously lethal doses of chemotherapy. The patient's bone marrow was first harvested, the chemotherapy administered, and the harvested marrow then returned to patient a few days later. This approach, termed autologous bone marrow transplantation, was initially thought to be of benefit to a wide group of patients, including those with advanced breast cancer. However, rigorous studies have failed to confirm this benefit, and autologous transplantation is no longer widely used for solid tumors. The proven curative benefits of high doses of chemotherapy afforded by autologous bone marrow rescue are limited to both Hodgkin's and selected non-Hodgkin's lymphoma patients who have failed therapy with conventional combination chemotherapy. Autologous transplantation continues to be used as a component of therapy for a number of other hematologic malignancies.
== Antihormone therapy ==
The hormonal contribution to several categories of breast cancer subtypes was recognized during this time, leading to the development of pharmacological modulators (e.g. of oestrogen) such as tamoxifen.
== Targeted therapy ==
Molecular genetics has uncovered signalling networks that regulate cellular activities such as proliferation and survival. In a particular cancer, such a network may be radically altered, due to a chance somatic mutation. Targeted therapy inhibits the metabolic pathway that underlies that type of cancer's cell division.
=== Tyrosine kinase inhibitors ===
The classic example of targeted development is imatinib mesylate (Gleevec), a small molecule which inhibits a signaling molecule kinase. The genetic abnormality causing chronic myelogenous leukemia (CML) has been known for a long time to be a chromosomal translocation creating an abnormal fusion protein, kinase BCR-ABL, which signals aberrantly, leading to uncontrolled proliferation of the leukemia cells. Imatinib precisely inhibits this kinase. Unlike so many other anti-cancer agents, this pharmaceutical was no accident. Brian Druker, working in Oregon Health & Science University, had extensively researched the abnormal enzyme kinase in CML. He reasoned that precisely inhibiting this kinase with a drug would control the disease and have little effect on normal cells. Druker collaborated with Novartis chemist Nicholas Lydon, who developed several candidate inhibitors. From these, imatinib was found to have the most promise in laboratory experiments. First Druker and then other groups worldwide demonstrated that when this small molecule is used to treat patients with chronic-phase CML, 90% achieve complete haematological remission. It is hoped that molecular targeting of similar defects in other cancers will have the same effect.
=== Monoclonal antibodies ===
Another branch in targeted therapy is the increasing use of monoclonal antibodies in cancer therapy. Although monoclonal antibodies (immune proteins which can be selected to precisely bind to almost any target) have been around for decades, they were derived from mice and did not function particularly well when administered to humans, causing allergic reactions and being rapidly removed from circulation. "Humanization" of these antibodies (genetically transforming them to be as similar to a human antibody as possible) has allowed the creation of a new family of highly effective humanized monoclonal antibodies. Trastuzumab, a drug used to treat breast cancer, is a prime example.
== Effectiveness ==
The discovery that certain toxic chemicals administered in combination can cure certain cancers ranks as one of the greatest in modern medicine. Childhood ALL (Acute Lymphoblastic Leukemia), testicular cancer, and Hodgkins disease, previously universally fatal, are now generally curable diseases. They have also proved effective in the adjuvant setting, in reducing the risk of recurrence after surgery for high-risk breast cancer, colon cancer, and lung cancer, among others.
The overall impact of chemotherapy on cancer survival can be difficult to estimate, since improved cancer screening, prevention (e.g. anti-smoking campaigns), and detection all influence statistics on cancer incidence and mortality. In the United States, overall cancer incidence rates were stable from 1995 through 1999, while cancer death rates decreased steadily from 1993 through 1999. Again, this likely reflects the combined impact of improved screening, prevention, and treatment. Nonetheless, cancer remains a major cause of illness and death, and conventional cytotoxic chemotherapy has proved unable to cure most cancers after they have metastasized.
== See also ==
Cancer (2015 PBS film)
== References ==
== Further reading ==
DeVita VT, Jr; Chu, E (1 November 2008). "A history of cancer chemotherapy". Cancer Research. 68 (21): 8643–53. doi:10.1158/0008-5472.CAN-07-6611. PMID 18974103.
Mukherjee, Siddhartha (2010). The Emperor of All Maladies: A Biography of Cancer. Scribner. ISBN 978-1-4391-0795-9.
== External links ==
Time line for cancer chemotherapy A time line of milestones in cancer chemotherapy from the National Cancer Institute that includes recollections of people involved with the NCI effort. This was put together on the occasion of the 50th anniversary of the Cancer Chemotherapy National Service Center (CCNSC). | Wikipedia/Combination_chemotherapy |
In biochemistry, intercalation is the insertion of molecules between the planar bases of deoxyribonucleic acid (DNA). This process is used as a method for analyzing DNA and it is also the basis of certain kinds of poisoning.
There are several ways molecules (in this case, also known as ligands) can interact with DNA. Ligands may interact with DNA by covalently binding, electrostatically binding, or intercalating. Intercalation occurs when ligands of an appropriate size and chemical nature fit themselves in between base pairs of DNA. These ligands are mostly polycyclic, aromatic, and planar, and therefore often make good nucleic acid stains. Intensively studied DNA intercalators include berberine, ethidium bromide, proflavine, daunomycin, doxorubicin, and thalidomide. DNA intercalators are used in chemotherapeutic treatment to inhibit DNA replication in rapidly growing cancer cells. Examples include doxorubicin (adriamycin) and daunorubicin (both of which are used in treatment of Hodgkin's lymphoma), and dactinomycin (used in Wilm's tumour, Ewing's Sarcoma, rhabdomyosarcoma).
Metallointercalators are complexes of a metal cation with polycyclic aromatic ligands. The most commonly used metal ion is ruthenium(II), because its complexes are very slow to decompose in the biological environment. Other metallic cations that have been used include rhodium(III) and iridium(III). Typical ligands attached to the metal ion are dipyridine and terpyridine whose planar structure is ideal for intercalation.
Base pairs in DNA must separate to admit the intercalator. The separation is achieved by unwinding. For example, ethidium unwinds DNA by about 26°, whereas proflavine unwinds it by about 17°. This unwinding causes the base pairs to separate, or "rise", creating an opening of about 0.34 nm (3.4 Å). Similarly, in the case of the intercalation of thiazole orange derivatives, the distance between the base pairs increased significantly, from ca. 4.7 Å to ca, 6.9. This unwinding induces local structural changes to the DNA strand, such as lengthening of the DNA strand or twisting of the base pairs. These structural modifications can lead to functional changes, often to the inhibition of transcription and replication and DNA repair processes, which makes intercalators potent mutagens. For this reason, DNA intercalators are often carcinogenic, such as the exo (but not the endo) 8,9 epoxide of aflatoxin B1 and acridines such as proflavine or quinacrine.
Intercalation as a mechanism of interaction between cationic, planar, polycyclic aromatic systems of the correct size (on the order of a base pair) was first proposed by Leonard Lerman in 1961. One proposed mechanism of intercalation is as follows: In aqueous isotonic solution, the cationic intercalator is attracted electrostatically to the surface of the polyanionic DNA. The ligand displaces a sodium and/or magnesium cation present in the "condensation cloud" of such cations that surrounds DNA (to partially balance the sum of the negative charges carried by each phosphate oxygen), thus forming a weak electrostatic association with the outer surface of DNA. From this position, the ligand diffuses along the surface of the DNA and may slide into the hydrophobic environment found between two base pairs that may transiently "open" to form an intercalation site, allowing the ethidium to move away from the hydrophilic (aqueous) environment surrounding the DNA and into the intercalation site. The base pairs transiently form such openings due to energy absorbed during collisions with solvent molecules.
== See also ==
Anthracycline
Intercalation (chemistry)
Molecular tweezers
Twisted intercalating nucleic acid
== References == | Wikipedia/DNA_intercalation |
Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
MAP2K is classified as EC 2.7.12.2.
There are seven genes:
MAP2K1 (a.k.a. MEK1)
MAP2K2 (a.k.a. MEK2)
MAP2K3 (a.k.a. MKK3)
MAP2K4 (a.k.a. MKK4)
MAP2K5 (a.k.a. MKK5)
MAP2K6 (a.k.a. MKK6)
MAP2K7 (a.k.a. MKK7)
The activators of p38 (MKK3 and MKK6), JNK (MKK4 and MKK7), and ERK (MEK1 and MEK2) define independent MAP kinase signal transduction pathways. The acronym MEK derives from MAPK/ERK Kinase.
== Role in melanoma ==
MEK is a member of the MAPK signaling cascade that is activated in melanoma. When MEK is inhibited, cell proliferation is blocked and apoptosis (controlled cell death) is induced.
== See also ==
Signal transduction
MAP kinase
MAP kinase kinase kinase
MAP kinase kinase kinase kinase
== References ==
== External links ==
Mitogen-Activated+Protein+Kinase+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Mitogen-activated_protein_kinase_kinase |
Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells (e.g. macrophages). As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.
== Classification ==
Anemia of chronic disease is usually mild but can be severe. It is usually normocytic, but can be microcytic. The presence of both anemia of chronic disease and dietary iron deficiency results in a more severe anemia.
== Pathophysiology ==
Anemia is defined by hemoglobin (Hb) concentration
< 13.0 g/dL (130 g/L) in males
< 11.5 g/dL (115 g/L) in females
In response to inflammatory cytokines, increasingly IL-6, the liver produces increased amounts of hepcidin. Hepcidin in turn causes increased internalisation of ferroportin molecules on cell membranes which prevents release from iron stores. Inflammatory cytokines also appear to affect other important elements of iron metabolism, including decreasing ferroportin expression, and probably directly blunting erythropoiesis by decreasing the ability of the bone marrow to respond to erythropoietin.
Before the recent discovery of hepcidin and its function in iron metabolism, anemia of chronic disease was seen as the result of a complex web of inflammatory changes. Over the last few years, however, many investigators have come to feel that hepcidin is the central actor in producing anemia of chronic inflammation. Hepcidin provides a unifying explanation for the condition, and more recent descriptions of human iron metabolism and hepcidin function reflect this view.
In addition to effects of iron sequestration, inflammatory cytokines promote the production of white blood cells. Bone marrow produces both white blood cells and red blood cells from the same precursor stem cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This effect may be an important additional cause for the decreased erythropoiesis and red blood cell production seen in anemia of inflammation, even when erythropoietin levels are normal, and even aside from the effects of hepcidin. Nonetheless, there are other mechanisms that also contribute to the lowering of hemoglobin levels during inflammation: (i) Inflammatory cytokines suppress the proliferation of erythroid precursors in the bone marrow.; (ii) inflammatory cytokines inhibit the release of erythropoietin (EPO) from the kidney; and (iii) the survival time of circulating red cells is shortened.
In the short term, the overall effect of these changes is likely positive: it allows the body to keep more iron away from bacterial pathogens in the body, while producing more immune cells to fight off infection. Almost all bacteria depend on iron to live and multiply. However, if inflammation continues, the effect of locking up iron stores is to reduce the ability of the bone marrow to produce red blood cells. These cells require iron for their massive amounts of hemoglobin which allow them to transport oxygen.
Because anemia of chronic disease can be the result of non-infective causes of inflammation, future research is likely to investigate whether hepcidin antagonists might be able to treat this problem.
Anemia of chronic disease may also be due to neoplastic disorders and non-infectious inflammatory diseases. Neoplastic disorders include Hodgkin disease and lung and breast carcinoma, while non-infectious inflammatory diseases include celiac disease, rheumatoid arthritis, systemic lupus erythematosus, scleroderma and dermatomyositis.
Anemia of chronic disease, as it is now understood, is to at least some degree separate from the anemia seen in kidney failure in which anemia results from reduced production of erythropoietin, or the anemia caused by some drugs (like AZT, used to treat HIV infection) that have the side effect of inhibiting erythropoiesis. In other words, not all anemia seen in people with chronic disease should be diagnosed as anemia of chronic disease. On the other hand, both of these examples show the complexity of this diagnosis: HIV infection itself can produce anemia of chronic disease, and kidney failure can lead to inflammatory changes that also can produce anemia of chronic disease.
== Diagnosis ==
While no single test is reliable to distinguish iron deficiency anemia from the anemia of chronic inflammation, there are sometimes some suggestive data:
In anemia of chronic inflammation without iron deficiency, ferritin is normal or high, reflecting the fact that iron is sequestered within cells, and ferritin is being produced as an acute phase reactant. In iron deficiency anemia (IDA) ferritin is low.
Total iron-binding capacity (TIBC) is high in iron deficiency, reflecting production of more transferrin to increase iron binding; TIBC is low or normal in anemia of chronic inflammation.
== Treatment ==
The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully, but this is rarely possible.
Parenteral iron is increasingly used for anemia in chronic renal disease and inflammatory bowel disease (IBD). There is low-certainty evidence that people receiving treatment for IBD-related anemia with Intravenous (IV) iron infusion may be 17% more likely to benefit than those given oral iron therapy, and could be 61% less likely to stop treatment early due to adverse effects. However, the type of IV iron preparation may influence the degree of both benefit and harm: Moderate-certainty evidence suggests that IV ferric carboxymaltose treatment may be 25% more likely to improve anemia than IV iron sucrose preparation. The risk of serious side effects such as bleeding, electrolyte depletion and cardiac arrest could be greater with ferric carboxymaltose therapy, however the certainty of this evidence is low.
Erythropoietin treatment, which stimulates the production of red blood cell production, is sometimes used to treat severe or persistent anemia, both as a monotherapy and a combination therapy alongside IV iron, but is costly and the benefit is unclear. Very low-certainty evidence suggests that erythropoietin as a monotherapy may improve anemia more than a placebo. Any additional benefit of treating someone with erythropoietin in combination with IV iron sucrose treatment is not clear.
Limiting some microbes' access to iron can reduce their virulence, thereby potentially reducing the severity of infection. Blood transfusion to patients with anemia of chronic disease is associated with a higher mortality, supporting the concept.
== See also ==
List of circulatory system conditions
List of hematologic conditions
== References ==
== External links ==
National Anemia Action Council | Wikipedia/Anemia_of_chronic_disease |
Experimental cancer treatments are mainstream medical therapies intended to treat cancer by improving on, supplementing or replacing conventional methods (surgery, chemotherapy, radiation, and immunotherapy). However, researchers are still trying to determine whether these treatments are safe and effective treatments. Experimental cancer treatments are normally available only to people who participate in formal research programs, which are called clinical trials. Occasionally, a seriously ill person may be able to access an experimental drug through an expanded access program. Some of the treatments have regulatory approval for treating other conditions. Health insurance and publicly funded health care programs normally refuse to pay for experimental cancer treatments.
The entries listed below vary between theoretical therapies to unproven controversial therapies. Many of these treatments are alleged to help against only specific forms of cancer. It is not a list of treatments widely available at hospitals.
== Studying cancer treatments ==
The twin goals of research are to determine whether the treatment actually works (called efficacy) and whether it is sufficiently safe. Regulatory processes attempt to balance the potential benefits with the potential harms, so that people given the treatment are more likely to benefit from it than to be harmed by it.
Medical research for cancer begins much like research for any disease. In organized studies of new treatments for cancer, the pre-clinical development of drugs, devices, and techniques begins in laboratories, either with isolated cells or in small animals, most commonly rats or mice. In other cases, the proposed treatment for cancer is already in use for some other medical condition, in which case more is known about its safety and potential efficacy.
Clinical trials are the study of treatments in humans. The first-in-human tests of a potential treatment are called Phase I studies. Early clinical trials typically enroll a very small number of patients, and the purpose is to identify major safety issues and the maximum tolerated dose, which is the highest dose that does not produce serious or fatal adverse effects. The dose given in these trials may be far too small to produce any useful effect. In most research, these early trials may involve healthy people, but cancer studies normally enroll only people with relatively severe forms of the disease in this stage of testing. On average, 95% of the participants in these early trials receive no benefit, but all are exposed to the risk of adverse effects. Most participants show signs of optimism bias (the irrational belief that they will beat the odds).
Later studies, called Phase II and Phase III studies, enroll more people, and the goal is to determine whether the treatment actually works. Phase III studies are frequently randomized controlled trials, with the experimental treatment being compared to the current best available treatment rather than to a placebo. In some cases, the Phase III trial provides the best available treatment to all participants, in addition to some of the patients receiving the experimental treatment.
== Bacterial treatments ==
Chemotherapeutic drugs have a hard time penetrating tumors to kill them at their core because these cells may lack a good blood supply. Researchers have been using anaerobic bacteria, such as Clostridium novyi, to consume the interior of oxygen-poor tumours. These should then die when they come in contact with the tumor's oxygenated sides, meaning they would be harmless to the rest of the body. A major problem has been that bacteria do not consume all parts of the malignant tissue. However, combining the therapy with chemotherapeutic treatments can help to solve this problem.
Another strategy is to use anaerobic bacteria that have been transformed with an enzyme that can convert a non-toxic prodrug into a toxic drug. With the proliferation of the bacteria in the necrotic and hypoxic areas of the tumor, the enzyme is expressed solely in the tumor. Thus, a systemically applied prodrug is metabolised to the toxic drug only in the tumor. This has been demonstrated to be effective with the nonpathogenic anaerobe Clostridium sporogenes.
== Drug therapies ==
=== HAMLET (human alpha-lactalbumin made lethal to tumor cells) ===
HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human breast milk that kills tumor cells by a process resembling programmed cell death (apoptosis). As of 2008, it had been tested in humans with skin papillomas and bladder cancer.
=== p53 activation therapy ===
Several drug therapies are being developed based on p53, the tumour suppressor gene that protects the cell in response to damage and stress. It is analogous to deciding what to do with a damaged car: p53 brings everything to a halt, and then decides whether to fix the cell or, if the cell is beyond repair, to destroy the cell. This protective function of p53 is disabled in most cancer cells, allowing them to multiply without check. Restoration of p53 activity in tumours (where possible) has been shown to inhibit tumour growth and can even shrink the tumour.
As p53 protein levels are usually kept low, one could block its degradation and allow large amounts of p53 to accumulate, thus stimulating p53 activity and its antitumour effects. Drugs that utilize this mechanism include nutlin and MI-219, which are both in phase I clinical trials. As of 2009, there are also other drugs that are still in the preclinical stage of testing, such as RITA and MITA.
=== BI811283 ===
BI811283 is a small molecule inhibitor of the aurora B kinase protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. As of 2010, BI 811283 is currently in the early stages of clinical development and is undergoing first-in-human trials in patients with solid tumors and Acute Myeloid Leukaemia.
=== Itraconazole ===
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. Recent research works suggest itraconazole (ITZ) could also be used in the treatment of cancer by inhibiting the hedgehog pathway in a similar way to Sonidegib.
=== Selective androgen receptor modulators ===
The majority of breast cancers are androgen receptor (AR) positive and SARMs may help treat these cancers, although promising results have only been obtained with cancers that are both estrogen receptor (ER) positive and AR positive. Anabolic androgenic steroids (AAS) were historically used successfully to treat AR positive breast cancer, but were phased out after the development of anti-estrogen therapies, due to androgenic side effects and concerns about aromatization to estrogen. SARMs have some of the same therapeutic effects as AAS, but fewer side effects, and they cannot be aromatized. Although a trial on AR positive triple negative breast cancer was ended early due to lack of efficacy, ostarine showed benefits in some patients with ER+, AR+ metastatic breast cancer in a phase II study. In patients with more than 40 percent AR positivity as determined by immunohistochemistry, the clinical benefit rate (CBR) was 80 percent and the objective response rate (ORR) was 48 percent—which was considered promising given that the patients had advanced disease and had been heavily pretreated. In 2022, the FDA granted fast track designation to ostarine for AR+, ER+, HER2- metastatic breast cancer. SARMs have also shown antitumor effects in prostate cancer.
== Gene therapy ==
Introduction of tumor suppressor genes into rapidly dividing cells has been thought to slow down or arrest tumor growth. Adenoviruses are a commonly utilized vector for this purpose. Much research has focused on the use of adenoviruses that cannot reproduce, or reproduce only to a limited extent, within the patient to ensure safety via the avoidance of cytolytic destruction of noncancerous cells infected with the vector. However, new studies focus on adenoviruses that can be permitted to reproduce, and destroy cancerous cells in the process, since the adenoviruses' ability to infect normal cells is substantially impaired, potentially resulting in a far more effective treatment.
Another use of gene therapy is the introduction of enzymes into these cells that make them susceptible to particular chemotherapy agents; studies with introducing thymidine kinase in gliomas, making them susceptible to aciclovir, are in their experimental stage.
== Epigenetic options ==
Epigenetics is the study of heritable changes in gene activity that are not caused by changes in the DNA sequence, often a result of environmental or dietary damage to the histone receptors within the cell. Current research has shown that epigenetic pharmaceuticals could be a putative replacement or adjuvant therapy for currently accepted treatment methods such as radiation and chemotherapy, or could enhance the effects of these current treatments. It has been shown that the epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones directly affects the formation and progression of cancer. Epigenetics also has the factor of reversibility, a characteristic that other cancer treatments do not offer.
Some investigators, like Randy Jirtle, PhD, of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.
== Telomerase deactivation therapy ==
Because most malignant cells rely on the activity of the protein telomerase for their immortality, it has been proposed that a drug that inactivates telomerase might be effective against a broad spectrum of malignancies. At the same time, most healthy tissues in the body express little if any telomerase, and would function normally in its absence. Currently, inositol hexaphosphate, which is available over-the-counter, is undergoing testing in cancer research due to its telomerase-inhibiting abilities.
A number of research groups have experimented with the use of telomerase inhibitors in animal models, and as of 2005 and 2006 phase I and II human clinical trials are underway. Geron Corporation is currently conducting two clinical trials involving telomerase inhibitors. One uses a vaccine (GRNVAC1) and the other uses a lipidated oligonucleotide (GRN163L).
== Radiation therapies ==
=== Photodynamic therapy ===
Photodynamic therapy (PDT) is generally a non-invasive treatment using a combination of light and a photosensitive drug, such as 5-ALA, Foscan, Metvix, padeliporfin (Tookad, WST09, WST11), Photofrin, or Visudyne. The drug is triggered by light of a specific wavelength.
=== Hyperthermiatic therapy ===
Localized and whole-body application of heat has been proposed as a technique for the treatment of malignant tumours. Intense heating will cause denaturation and coagulation of cellular proteins, rapidly killing cells within a tumour.
More prolonged moderate heating to temperatures just a few degrees above normal (39.5 °C) can cause more subtle changes. A mild heat treatment combined with other stresses can cause cell death by apoptosis. There are many biochemical consequences to the heat shock response within the cell, including slowed cell division and increased sensitivity to ionizing radiation therapy. The purpose of overheating the tumor cells is to create a lack of oxygen so that the heated cells become overacidified, which leads to a lack of nutrients in the tumor. This in turn disrupts the metabolism of the cells so that cell death (apoptosis) can set in. In certain cases chemotherapy or radiation that has previously not had any effect can be made effective. Hyperthermia alters the cell walls by means of so-called heat shock proteins. The cancer cells then react very much more effectively to the cytostatics and radiation. If hyperthermia is used conscientiously it has no serious side effects.
There are many techniques by which heat may be delivered. Some of the most common involve the use of focused ultrasound (FUS or HIFU), microwave heating, induction heating, magnetic hyperthermia, and direct application of heat through the use of heated saline pumped through catheters. Experiments with carbon nanotubes that selectively bind to cancer cells have been performed. Lasers are then used that pass harmlessly through the body, but heat the nanotubes, causing the death of the cancer cells. Similar results have also been achieved with other types of nanoparticles, including gold-coated nanoshells and nanorods that exhibit certain degrees of 'tunability' of the absorption properties of the nanoparticles to the wavelength of light for irradiation. The success of this approach to cancer treatment rests on the existence of an 'optical window' in which biological tissue (i.e., healthy cells) are completely transparent at the wavelength of the laser light, while nanoparticles are highly absorbing at the same wavelength. Such a 'window' exists in the so-called near-infrared region of the electromagnetic spectrum. In this way, the laser light can pass through the system without harming healthy tissue, and only diseased cells, where the nanoparticles reside, get hot and are killed.
Magnetic Hyperthermia makes use of magnetic nanoparticles, which can be injected into tumours and then generate heat when subjected to an alternating magnetic field.
One of the challenges in thermal therapy is delivering the appropriate amount of heat to the correct part of the patient's body. A great deal of current research focuses on precisely positioning heat delivery devices (catheters, microwave, and ultrasound applicators, etc.) using ultrasound or magnetic resonance imaging, as well as of developing new types of nanoparticles that make them particularly efficient absorbers while offering little or no concerns about toxicity to the circulation system. Clinicians also hope to use advanced imaging techniques to monitor heat treatments in real time—heat-induced changes in tissue are sometimes perceptible using these imaging instruments. In magnetic hyperthermia or magnetic fluid hyperthermia method, it will be easier to control temperature distribution by controlling the velocity of ferrofluid injection and size of magnetic nanoparticles.
=== Noninvasive cancer heat treatment ===
Heat treatment involves using radio waves to heat up tiny metals that are implanted in cancerous tissue. Gold nanoparticles or carbon nanotubes are the most likely candidate. Promising preclinical trials have been conducted, although clinical trials may not be held for another few years.
Another method that is entirely non-invasive referred to as Tumor Treating Fields has already reached clinical trial stage in many countries. The concept applies an electric field through a tumour region using electrodes external to the body. Successful trials have shown the process effectiveness to be greater than chemotherapy and there are no side-effects and only negligible time spent away from normal daily activities. This treatment is still in very early development stages for many types of cancer.
High-intensity focused ultrasound (HIFU) is still in investigatory phases in many places around the world. In China it has CFDA approval and over 180 treatment centres have been established in China, Hong Kong, and Korea. HIFU has been successfully used to treat cancer to destroy tumours of the bone, brain, breast, liver, pancreas, rectum, kidney, testes, and prostate. Several thousand patients have been treated with various types of tumours. HIFU has CE approval for palliative care for bone metastasis. Experimentally, palliative care has been provided for cases of advanced pancreatic cancer. High-energy therapeutic ultrasound could increase higher-density anti-cancer drug load and nanomedicines to target tumor sites by 20x fold higher than traditional target cancer therapy.
== Cold atmospheric plasma treatment ==
Cold atmospheric plasma or CAP for has been proposed for the treatment of solid tumors.
== Electromagnetic treatments ==
Tumor Treating Fields is a novel FDA-approved cancer treatment therapy that uses alternating electric field to disturb the rapid cell division exhibited by cancer cells.
== Complementary and alternative treatments ==
Complementary and alternative medicine (CAM) treatments are the diverse group of medical and healthcare systems, practices, and products that are not part of conventional medicine and have not been proven to be effective. Complementary medicine usually refers to methods and substances used along with conventional medicine, while alternative medicine refers to compounds used instead of conventional medicine. CAM use is common among people with cancer.
Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments that have been proven ineffective continue to be marketed and promoted.
== References ==
== External links ==
"Questionable Cancer Therapies"
clinicaltrials.gov | Wikipedia/Experimental_cancer_treatments |
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.
The development of antibiotic resistance in particular stems from the drugs targeting only specific bacterial molecules (almost always proteins). Because the drug is so specific, any mutation in these molecules will interfere with or negate its destructive effect, resulting in antibiotic resistance. Furthermore, there is mounting concern over the abuse of antibiotics in the farming of livestock, which in the European Union alone accounts for three times the volume dispensed to humans – leading to development of super-resistant bacteria.
Bacteria are capable of not only altering the enzyme targeted by antibiotics, but also by the use of enzymes to modify the antibiotic itself and thus neutralize it. Examples of target-altering pathogens are Staphylococcus aureus, vancomycin-resistant enterococci and macrolide-resistant Streptococcus, while examples of antibiotic-modifying microbes are Pseudomonas aeruginosa and aminoglycoside-resistant Acinetobacter baumannii.
In short, the lack of concerted effort by governments and the pharmaceutical industry, together with the innate capacity of microbes to develop resistance at a rate that outpaces development of new drugs, suggests that existing strategies for developing viable, long-term anti-microbial therapies are ultimately doomed to failure. Without alternative strategies, the acquisition of drug resistance by pathogenic microorganisms looms as possibly one of the most significant public health threats facing humanity in the 21st century. Some of the best alternative sources to reduce the chance of antibiotic resistance are probiotics, prebiotics, dietary fibers, enzymes, organic acids, phytogenics.
Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and P aeruginosa were the six main causes (73%) of AMR-associated mortality in 2019, according to the 2022 Global Burden of Disease research.
AMR not only causes death and disability, but it also has high financial expenses. AMR may lead to US$ 1 trillion in higher healthcare expenses by 2050 and US$ 1 trillion to US$ 3.4 trillion in annual GDP losses by 2030, according to World Bank estimations.
== Types ==
Drug, toxin, or chemical resistance is a consequence of evolution and is a response to pressures imposed on any living organism. Individual organisms vary in their sensitivity to the drug used and some with greater fitness may be capable of surviving drug treatment. Drug-resistant traits are accordingly inherited by subsequent offspring, resulting in a population that is more drug-resistant. Unless the drug used makes sexual reproduction or cell-division or horizontal gene transfer impossible in the entire target population, resistance to the drug will inevitably follow. This can be seen in cancerous tumors where some cells may develop resistance to the drugs used in chemotherapy. Chemotherapy causes fibroblasts near tumors to produce large amounts of the protein WNT16B. This protein stimulates the growth of cancer cells which are drug-resistant. MicroRNAs have also been shown to affect acquired drug resistance in cancer cells and this can be used for therapeutic purposes. Malaria in 2012 has become a resurgent threat in South East Asia and sub-Saharan Africa, and drug-resistant strains of Plasmodium falciparum are posing massive problems for health authorities. Leprosy has shown an increasing resistance to dapsone.
A rapid process of sharing resistance exists among single-celled organisms, and is termed horizontal gene transfer in which there is a direct exchange of genes, particularly in the biofilm state. A similar asexual method is used by fungi and is called "parasexuality". Examples of drug-resistant strains are to be found in microorganisms such as bacteria and viruses, parasites both endo- and ecto-, plants, fungi, arthropods, mammals, birds, reptiles, fish, and amphibians.
In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of bleach, tooth-brushing and mouthwashing, the use of antibiotics, disinfectants and detergents, shampoos, and soaps, particularly antibacterial soaps, hand-washing, surface sprays, application of deodorants, sunblocks and any cosmetic or health-care product, insecticides, and dips. The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance.
== Mechanisms ==
The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:
Drug inactivation or modification: e.g., enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases.
Alteration of target site: e.g., alteration of PBP — the binding target site of penicillins — in MRSA and other penicillin-resistant bacteria.
Alteration of metabolic pathway: e.g., some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid.
Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.
=== Mechanisms of Acquired Drug Resistance ===
== Metabolic cost ==
Biological cost is a measure of the increased energy metabolism required to achieve a function.
Drug resistance has a high metabolic price in pathogens for which this concept is relevant (bacteria, endoparasites, and tumor cells.) In viruses, an equivalent "cost" is genomic complexity. The high metabolic cost means that, in the absence of antibiotics, a resistant pathogen will have decreased evolutionary fitness as compared to susceptible pathogens. This is one of the reasons drug resistance adaptations are rarely seen in environments where antibiotics are absent. However, in the presence of antibiotics, the survival advantage conferred off-sets the high metabolic cost and allows resistant strains to proliferate.
== Treatment ==
In humans, the gene ABCB1 encodes MDR1(p-glycoprotein) which is a key transporter of medications on the cellular level. If MDR1 is overexpressed, drug resistance increases. Therefore, ABCB1 levels can be monitored. In patients with high levels of ABCB1 expression, the use of secondary treatments, like metformin, have been used in conjunction with the primary drug treatment with some success.
For antibiotic resistance, which represents a widespread problem nowadays, drugs designed to block the mechanisms of bacterial antibiotic resistance are used. For example, bacterial resistance against beta-lactam antibiotics (such as penicillin and cephalosporins) can be circumvented by using antibiotics such as nafcillin that are not susceptible to destruction by certain beta-lactamases (the group of enzymes responsible for breaking down beta-lactams). Beta-lactam bacterial resistance can also be dealt with by administering beta-lactam antibiotics with drugs that block beta-lactamases such as clavulanic acid so that the antibiotics can work without getting destroyed by the bacteria first. Researchers have recognized the need for new drugs that inhibit bacterial efflux pumps, which cause resistance to multiple antibiotics such as beta-lactams, quinolones, chloramphenicol, and trimethoprim by sending molecules of those antibiotics out of the bacterial cell. Sometimes a combination of different classes of antibiotics may be used synergistically; that is, they work together to effectively fight bacteria that may be resistant to one of the antibiotics alone.
Destruction of the resistant bacteria can also be achieved by phage therapy, in which a specific bacteriophage (virus that kills bacteria) is used.
== See also ==
Antibiotic resistance
Fecal bacteriotherapy
Mass drug administration
Multidrug resistance
Pharmacoepidemiology
Physical factors affecting microbial life
Small multidrug resistance protein
Eleftheria terrae
== References ==
== External links ==
BURDEN of Resistance and Disease in European Nations—An EU project to estimate the financial burden of antibiotic resistance in European hospitals
Merck - Tolerance and Resistance
Cosmetics Database
HCMV drug resistance mutations tool
Combating Drug Resistance - An informative article on multidrug resistance
Battle of the Bugs: Fighting Antibiotic Resistance
MDRIpred : A web server for predicting inhibitors against drug tolerant M. Tuberculosis, published in Chemistry Central Journal
CancerDR: Cancer Drug Resistance Database. Scientific Reports 3, 1445 | Wikipedia/Drug_resistance |
Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic hallucinogens or serotonergic hallucinogens, the term psychedelic is sometimes used more broadly to include various other types of hallucinogens as well, such as those which are atypical or adjacent to psychedelia like salvia and MDMA, respectively.
Classic psychedelics generally cause specific psychological, visual, and auditory changes, and oftentimes a substantially altered state of consciousness. They have had the largest influence on science and culture, and include mescaline, LSD, psilocybin, and DMT. There are a large number of both naturally occurring and synthetic serotonergic psychedelics.
Most psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides. They produce their psychedelic effects by binding to and activating a receptor in the brain called the serotonin 5-HT2A receptor. By activating serotonin 5-HT2A receptors, they modulate the activity of key circuits in the brain involved with sensory perception and cognition. However, the exact nature of how psychedelics induce changes in perception and cognition via the serotonin 5-HT2A receptor is still unknown. The psychedelic experience is often compared to non-ordinary forms of consciousness such as those experienced in meditation, mystical experiences, and near-death experiences, which also appear to be partially underpinned by altered default mode network activity. The phenomenon of ego death is often described as a key feature of the psychedelic experience.
Many psychedelic drugs are illegal to possess without lawful authorisation, exemption or license worldwide under the UN conventions, with occasional exceptions for religious use or research contexts. Despite these controls, recreational use of psychedelics is common. There is also a long history of use of naturally occurring psychedelics as entheogens dating back thousands of years. Legal barriers have made the scientific study of psychedelics more difficult. Research has been conducted, however, and studies show that psychedelics are physiologically safe and rarely lead to addiction. Studies conducted using psilocybin in a psychotherapeutic setting reveal that psychedelic drugs may assist with treating depression, anxiety, alcohol addiction, and nicotine addiction. Although further research is needed, existing results suggest that psychedelics could be effective treatments for certain mental health conditions. A 2022 survey by YouGov found that 28% of Americans had used a psychedelic at some point in their life.
== Examples ==
LSD (lysergic acid diethylamide) is a derivative of lysergic acid, which is obtained from the hydrolysis of ergotamine. Ergotamine is an alkaloid found in the fungus Claviceps purpurea (ergot), which primarily infects rye. LSD is both the prototypical psychedelic and the prototypical lysergamide. As a lysergamide, LSD contains both a tryptamine and phenethylamine group within its structure. Uniquely among psychedelics, LSD agonises dopamine receptors as well as serotonin receptors.
Psilocin (4-HO-DMT) is the dephosphorylated active metabolite of the indole alkaloid psilocybin and a substituted tryptamine, which is produced by hundreds of species of psilocybin-containing mushrooms. Of the classical psychedelics, psilocybin has attracted the greatest academic interest regarding its ability to manifest mystical experiences, although all psychedelics are capable of doing so to variable degrees. 4-AcO-DMT (O-acetylpsilocin or psilacetin) is a synthetic acetylated analogue of psilocin and is a prodrug of psilocin similarly to psilocybin.
Mescaline (3,4,5-trimethoxyphenethylamine) is a phenethylamine alkaloid found in various species of cacti, the best-known of these being peyote (Lophophora williamsii) and the San Pedro cactus (Trichocereus macrogonus var. pachanoi, syn. Echinopsis pachanoi). Mescaline has effects comparable to those of LSD and psilocybin. Ceremonial San Pedro use seems to be characterized by relatively strong spiritual experiences, and low incidence of challenging experiences.
DMT (N,N-dimethyltryptamine) is an indole alkaloid found in various species of plants. Traditionally, it is consumed by tribes in South America in the form of ayahuasca. A brew is used that consists of DMT-containing plants as well as plants containing MAOIs, specifically harmaline, which allows DMT to be consumed orally without being rendered inactive by monoamine oxidase enzymes in the digestive system. A pharmaceutical version of ayahuasca is called pharmahuasca. In the Western world, DMT is more commonly consumed via the vaporisation of freebase DMT. Whereas ayahuasca typically lasts for several hours, inhalation has an onset measured in seconds and has effects measured in minutes, being much more intense. Particularly in vaporised form, DMT has the ability to cause users to enter a hallucinatory realm fully detached from reality, being typically characterised by hyperbolic geometry, and described as defying visual or verbal description. Users have also reported encountering and communicating with entities within this hallucinatory state. DMT is the archetypal substituted tryptamine, being the structural scaffold of psilocybin and, to a lesser extent, the lysergamides.
2C-B (2,5-dimethoxy-4-bromophenethylamine) is a substituted phenethylamine first synthesized in 1974 by Alexander Shulgin. 2C-B is both a psychedelic and a mild entactogen, with its psychedelic effects increasing and its entactogenic effects decreasing with dosage. 2C-B is the most well-known compound in the 2C family, their general structure being discovered as a result of modifying the structure of mescaline. It is also the most widely used synthetic phenethylamine psychedelic.
MDMA ("ecstasy") is sometimes said to also have weak psychedelic effects, but it acts and is classified mainly as an entactogen rather than as a hallucinogen. Certain related drugs like MDA and MMDA have greater psychedelic effects however.
== Uses ==
=== Recreational ===
Recreational use of psychedelics has been common since the psychedelic era of the mid-1960s and continues to play a role in various festivals and events, including Burning Man. A survey published in 2013 found that 13.4% of American adults had used a psychedelic.
A June 2024 report by the RAND Corporation suggests psilocybin mushrooms may be the most prevalent psychedelic drug among adults in the United States. The RAND national survey indicated that 3.1% of U.S. adults reported using psilocybin in the past year. Roughly 12% of respondents acknowledged lifetime use of psilocybin, while a similar percentage reported having used LSD at some point in their lives. MDMA, also known as ecstasy, showed a lower prevalence of use at 7.6%. Notably, less than 1% of U.S. adults reported using any psychedelic drugs within the past month.
=== Traditional ===
A number of frequently mentioned or traditional psychedelics such as Ayahuasca (which contains DMT), San Pedro, Peyote, and Peruvian torch (which all contain mescaline), Psilocybe mushrooms (which contain psilocin/psilocybin) and Tabernanthe iboga (which contains the unique psychedelic ibogaine) all have a long and extensive history of spiritual, shamanic and traditional usage by indigenous peoples in various world regions, particularly in Latin America, but also Gabon, Africa in the case of iboga. Different countries and/or regions have come to be associated with traditional or spiritual use of particular psychedelics, such as the ancient and entheogenic use of psilocybe mushrooms by the native Mazatec people of Oaxaca, Mexico or the use of the ayahuasca brew in the Amazon basin, particularly in Peru for spiritual and physical healing as well as for religious festivals. Peyote has also been used for several thousand years in the Rio Grande Valley in North America by native tribes as an entheogen. In the Andean region of South America, the San Pedro cactus (Trichocereus macrogonus var. pachanoi, syn. Echinopsis pachanoi) has a long history of use, possibly as a traditional medicine. Archaeological studies have found evidence of use going back two thousand years, to Moche culture, Nazca culture, and Chavín culture. Although authorities of the Roman Catholic church attempted to suppress its use after the Spanish conquest, this failed, as shown by the Christian element in the common name "San Pedro cactus" – Saint Peter cactus. The name has its origin in the belief that just as St Peter holds the keys to heaven, the effects of the cactus allow users "to reach heaven while still on earth." In 2022, the Peruvian Ministry of Culture declared the traditional use of San Pedro cactus in northern Peru as cultural heritage.
Although people of Western culture have tended to use psychedelics for either psychotherapeutic or recreational reasons, most indigenous cultures, particularly in South America, have seemingly tended to use psychedelics for more supernatural reasons such as divination. This can often be related to "healing" or health as well but typically in the context of finding out what is wrong with the individual, such as using psychedelic states to "identify" a disease and/or its cause, locate lost objects, and identify a victim or even perpetrator of sorcery. In some cultures and regions, even psychedelics themselves, such as ayahuasca and the psychedelic lichen of eastern Ecuador (Dictyonema huaorani) that supposedly contains both 5-MeO-DMT and psilocybin, have also been used by witches and sorcerers to conduct their malicious magic, similarly to nightshade deliriants like brugmansia and latua.
=== Medical ===
Psychedelic therapy (or psychedelic-assisted therapy) is the proposed use of psychedelic drugs to treat mental disorders. As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials, with some exceptions.
The procedure for psychedelic therapy differs from that of therapies using conventional psychiatric medications. While conventional medications are usually taken without supervision at least once daily, in contemporary psychedelic therapy the drug is administered in a single session (or sometimes up to three sessions) in a therapeutic context. The therapeutic team prepares the patient for the experience beforehand and helps them integrate insights from the drug experience afterwards. After ingesting the drug, the patient normally wears eyeshades and listens to music to facilitate focus on the psychedelic experience, with the therapeutic team interrupting only to provide reassurance if adverse effects such as anxiety or disorientation arise.
As of 2022, the body of high-quality evidence on psychedelic therapy remains relatively small and more, larger studies are needed to reliably show the effectiveness and safety of psychedelic therapy's various forms and applications. On the basis of favorable early results, ongoing research is examining proposed psychedelic therapies for conditions including major depressive disorder, and anxiety and depression linked to terminal illness. The United States Food and Drug Administration has granted breakthrough therapy status, which expedites the assessment of promising drug therapies for potential approval, to psilocybin therapy for treatment-resistant depression and major depressive disorder.
It has been proposed that psychedelics used for therapeutic purposes may act as active "super placebos".
=== Microdosing ===
Psychedelic microdosing is the practice of using sub-threshold doses (microdoses) of psychedelics in an attempt to improve creativity, boost physical energy level, emotional balance, increase performance on problems-solving tasks and to treat anxiety, depression and addiction. The practice of microdosing has become more widespread in the 21st century with more people claiming long-term benefits from the practice.
A 2022 study recognized signatures of psilocybin microdosing in natural language and concluded that low amount of psychedelics have potential for application, and ecological observation of microdosing schedules.
=== Dosage ===
The table below provides doses of major serotonergic psychedelics as well as the entactogen and mild psychedelic MDMA ("ecstasy") that have been determined on the basis of clinical studies. Other dosage schemes have also been reported.
In the case of dried psilocybin-containing mushrooms, microdoses are 0.1 g to 0.3 g and psychedelic doses are 1.0 g to 3.5–5.0 g. The preceding 1.0 to 5.0 g range corresponds to psilocybin doses of about 10 to 50 mg. Psilocybin-containing mushrooms vary in their psilocybin and psilocin content, but are typically around 1% of the dried weight of the mushrooms (in terms of total or combined psilocybin and psilocin content). Psilocybin and psilocin are similar in potency and dose but psilocin is about 1.4-fold more active, this being related to the difference in molecular weight between the two compounds.
Some psychedelics, such as 2C-B, 2C-E, and 4-HO-DiPT, have been said to have steep dose–response curves, meaning that the difference in dose between a light experience and an overwhelming disconnection from reality can be small.: 506, 518 : 467
== Effects ==
=== Psychedelic effects ===
Although several attempts have been made, starting in the 19th and 20th centuries, to define common phenomenological structures of the effects produced by classic psychedelics, a universally accepted taxonomy does not yet exist. At lower doses, features of psychedelic experiences include sensory alterations, such as the warping of surfaces, shape suggestibility, pareidolia, and color variations. Users often report intense colors that they have not previously experienced, and repetitive geometric shapes or form constants are common as well. Higher doses often cause intense and fundamental alterations of sensory (notably visual) perception, such as synesthesia or the experience of additional spatial or temporal dimensions. Tryptamines are well documented to cause classic psychedelic states, such as increased empathy, visual distortions (drifting, morphing, breathing, melting of various surfaces and objects), auditory hallucinations, ego dissolution or ego death with high enough dose, mystical, transpersonal and spiritual experiences, autonomous "entity" encounters, time distortion, closed eye hallucinations and complete detachment from reality with a high enough dose. Luis Luna describes psychedelic experiences as having a distinctly gnosis-like quality, and says that they offer "learning experiences that elevate consciousness and can make a profound contribution to personal development." Czech psychiatrist Stanislav Grof studied the effects of psychedelics like LSD early in his career and said of the experience, that it commonly includes "complex revelatory insights into the nature of existence… typically accompanied by a sense of certainty that this knowledge is ultimately more relevant and 'real' than the perceptions and beliefs we share in everyday life." Traditionally, the standard model for the subjective phenomenological effects of psychedelics has typically been based on LSD, with anything that is considered "psychedelic" evidently being compared to it and its specific effects.
Good trips are reportedly deeply pleasurable, and typically involve intense joy or euphoria, a greater appreciation for life, reduced anxiety, a sense of spiritual enlightenment, and a sense of belonging or interconnectedness with the universe. Negative experiences, colloquially known as "bad trips," evoke an array of dark emotions, such as irrational fear, anxiety, panic, paranoia, dread, distrustfulness, hopelessness, and even suicidal ideation. While it is impossible to predict when a bad trip will occur, one's mood, surroundings, sleep, hydration, social setting, and other factors can be controlled (colloquially referred to as "set and setting") to minimize the risk of a bad trip. The concept of "set and setting" also generally appears to be more applicable to psychedelics than to other types of hallucinogens such as deliriants, hypnotics and dissociative anesthetics.
Psychedelics include naturally occurring tryptamines like psilocybin and DMT, the naturally occurring phenethylamine mescaline, and naturally occurring lysergamides like ergine (lysergic acid amide; LSA), as well as synthetic analogues and derivatives like LSD and 2C-B. Many of these psychedelics cause remarkably similar effects, despite their different chemical structures. However, many users anecdotally report that the three major families have subjectively different qualities in the "feel" of the experience, which are difficult to describe. There can also be very substantial differences between the drugs; for instance, 5-MeO-DMT rarely produces the visual effects typical of other psychedelics. As additional examples, DiPT is said to primarily affect the auditory sense, 2C-T-17 and ASR-3001 (5-MeO-iPALT) are said to produce psychedelic effects on thinkng or "head space" with few or no visuals, and N-methyltryptamine (NMT) has been said to be a primarily spatial psychedelic.
The visuals of psychedelics have been reproduced in video and image form using artificial intelligence.
Some rare individuals do not experience hallucinogenic effects with serotonergic psychedelics.
=== Other psychoactive effects ===
Some psychedelics have been associated with other psychoactive effects in addition to their hallucinogenic effects. For example, psychedelics like LSD and DOM have been described as having mild stimulant and/or "psychic-energizing" (i.e., acute antidepressant) effects. Some psychedelics and related drugs, like DOET (low doses), Ariadne, and ASR-2001 (2CB-5PrO), have been investigated specifically for such effects. 2C-B has been said to have mild entactogenic effects at low doses.
Some drugs, such as MDxx compounds like MDMA and MDA as well as α-alkyltryptamines like α-methyltryptamine (AMT), are entactogens and/or stimulants acting at monoamine transporters in addition to having varying degrees of psychedelic effects.
=== Psychedelic afterglows ===
Psychedelics are associated with an afterglow, also known as positive subacute or post-experience effects, which may last days or even weeks after the psychedelic experience. These effects include reduction in psychopathology and increased well-being, mood, mindfulness, social functioning, spirituality, and executive functioning, and positive behavioral changes. They also include mixed changes in personality, values, attitudes, creativity, and flexibility, as well as adverse effects like headaches, sleep disturbances, and sometimes increased psychological distress. The afterglow period has been associated with changes in brain function, neuroplasticity, and immune system function. Both psychological and pharmacological effects may be involved in the afterglow phenomenon.
In 1898, the English writer and intellectual Havelock Ellis reported a heightened perceptual sensitivity to "the more delicate phenomena of light and shade and color" for a prolonged period of time after his exposure to mescaline. The term "psychedelic afterglow" was first formally coined in the 1960s. Albert Hofmann, the discoverer of LSD, said the following about the aftermath of his first full LSD experience in his 1980 book LSD: My Problem Child:
Exhausted, I then slept, to awake next morning refreshed, with a clear head, though still somewhat tired physically. A sensation of well-being and renewed life flowed through me. Breakfast tasted delicious and gave me extraordinary pleasure. When I later walked out into the garden, in which the sun shone now after a spring rain, everything glistened and sparkled in a fresh light. The world was as if newly created. All my senses vibrated in a condition of highest sensitivity, which persisted for the entire day.
During a speech on his 100th birthday in 2006, Hofmann additionally said of LSD:
It gave me an inner joy, an open mindedness, a gratefulness, open eyes and an internal sensitivity for the miracles of creation... I think that in human evolution it has never been as necessary to have this substance LSD. It is just a tool to turn us into what we are supposed to be.
== Adverse effects ==
Despite the contrary perception of much of the public, psychedelic drugs are not addictive and are physiologically safe.
Risks do exist during an unsupervised psychedelic experience, however; Ira Byock wrote in 2018 in the Journal of Palliative Medicine that psilocybin is safe when administered to a properly screened patient and supervised by a qualified professional with appropriate set and setting. However, he called for an "abundance of caution" because in the absence of these conditions a range of negative reactions is possible, including "fear, a prolonged sense of dread, or full panic." He notes that driving or even walking in public can be dangerous during a psychedelic experience because of impaired hand-eye coordination and fine motor control. In some cases, individuals taking psychedelics have performed dangerous or fatal acts because they believed they possessed superhuman powers.
Psilocybin-induced states of mind share features with states experienced in psychosis, and while a causal relationship between psilocybin and the onset of psychosis has not been established as of 2011, researchers have called for investigation of the relationship. Many of the persistent negative perceptions of psychological risks are unsupported by the currently available scientific evidence, with the majority of reported adverse effects not being observed in a regulated and/or medical context. A population study on associations between psychedelic use and mental illness published in 2013 found no evidence that psychedelic use was associated with increased prevalence of any mental illness. In any case, induction of psychosis has been associated with psychedelics in small percentages of individuals, and the rates appear to be higher in people with schizophrenia.
Using psychedelics poses certain risks of re-experiencing of the drug's effects, including flashbacks and hallucinogen persisting perception disorder (HPPD). These non-psychotic effects are poorly studied, but the permanent symptoms (also called "endless trip") are considered to be rare.
Serotonergic psychedelics are agonists not only of the serotonin 5-HT2A receptor but also of the serotonin 5-HT2B receptor and other serotonin receptors. A potential risk of frequent repeated use of serotonergic psychedelics is cardiac fibrosis and valvulopathy caused by serotonin 5-HT2B receptor activation. However, single high doses or widely spaced doses (e.g., months) are widely thought to be safe and concerns about cardiac toxicity apply more to chronic psychedelic microdosing or very frequent use (e.g., weekly). Selective serotonin 5-HT2A receptor agonists that do not activate the serotonin 5-HT2B receptor or other serotonin receptors, such as 25CN-NBOH, DMBMPP, and LPH-5, have been developed and are being studied. Selective serotonin 5-HT2A receptor agonists are expected to avoid the cardiac risks of serotonin 5-HT2B receptor activation.
== Overdose ==
There have been a handful of cases of fatal overdose with LSD, psilocybin, and mescaline. There have also been cases of death with dimethyltryptamine (DMT), 5-MeO-DMT, 2C-B, Bromo-DragonFLY, NBOMes like 25I-NBOMe, and other psychedelics. LSD and psilocybin appear to have very wide margins of safety with overdose, whereas mescaline and 2C-B have much narrower margins, and NBOMes appear to be especially toxic and uniquely linked to serotonin syndrome-type symptoms. In terms of extrapolated human lethal doses based on animal studies and human case reports, lethal doses of psychedelics relative to typical recreational doses are estimated to be 1,000-fold for LSD, 200-fold for psilocybin, 50-fold for oral DMT (as ayahuasca), and 24-fold for mescaline. Estimates for other psychedelics, like 5-MeO-DMT and 2C-B, could not be made.
== Interactions ==
Serotonin 5-HT2A receptor antagonists can block the hallucinogenic effects of serotonergic psychedelics. Numerous drugs act as serotonin 5-HT2A receptor antagonists, for instance antidepressants like trazodone and mirtazapine, antipsychotics like quetiapine, olanzapine, and risperidone, and other agents like ketanserin, pimavanserin, cyproheptadine, and pizotifen. Such drugs are sometimes referred to as "trip killers" due to their ability to prevent or abort the hallucinogenic effects of psychedelics. Besides serotonin 5-HT2A receptor antagonists, non-hallucinogenic serotonin 5-HT2A receptor partial agonists, such as lisuride, may also block the hallucinogenic effects of serotonergic psychedelics.
The serotonin 5-HT1A receptor partial agonist buspirone has been found to markedly reduce the hallucinogenic effects of psilocybin in humans. Conversely, the serotonin 5-HT1A receptor antagonist pindolol has been found to potentiate the hallucinogenic effects of DMT by 2- to 3-fold in humans. Serotonin 5-HT1A receptor agonism may modify and self-inhibit the effects of psychedelics that possess this property. A particularly notable example is 5-methoxytryptamine derivatives such as 5-MeO-DMT, which are more potent serotonin 5-HT1A receptor agonists than other psychedelics and have qualitatively unique and differing hallucinogenic effects.
Benzodiazepines, for example diazepam, alprazolam, clonazepam, and lorazepam, as well as alcohol, which act as GABAA receptor positive allosteric modulators, have been limitedly studied in combination with psychedelics and are not currently known to directly interact with them. However, these GABAergic drugs produce effects such as anxiolysis, sedation, and amnesia, and in relation to this, may diminish or otherwise oppose the effects of psychedelics. As a result of this, benzodiazepines and alcohol are often used by recreational users as "trip killers" to manage difficult hallucinogenic experiences with psychedelics, for instance experiences with prominent anxiety. The safety of this strategy is not entirely clear and might have risks. However, benzodiazepines have been used clinically to manage the adverse psychological effects of psychedelics, for instance in clinical studies and in the emergency department. A clinical trial of psilocybin and midazolam coadministration found that midazolam clouded the effects of psilocybin and impaired memory of the experience. Benzodiazepines might interfere with the therapeutic effects of psychedelics, such as sustained antidepressant effects.
Some serotonergic psychedelics, for instance dimethyltryptamine (DMT) and 5-MeO-DMT, are highly susceptible substrates for monoamine oxidase (MAO), specifically MAO-A, and hence can be greatly potentiated by monoamine oxidase inhibitors (MAOIs). An example of this is ayahuasca, in which plants containing both DMT and harmala alkaloids acting as MAOIs such as harmine and harmaline are combined. This allows DMT to become orally active and to have a much longer duration of action than usual. The 2C psychedelics, such as 2C-B, 2C-I, and 2C-E, are also substrates of both MAO-A and MAO-B, and may likewise be greatly potentiated by MAOIs. Examples of MAOIs that may potentiate psychedelics behaving as MAO-A and/or MAO-B substrates include phenelzine, tranylcypromine, isocarboxazid, moclobemide, and selegiline. Combination of MAO-substrate psychedelics with MAOIs can result in overdose and serious toxicity, including death. Other psychedelics, such as LSD, are not substrates of MAO and are not potentiated by MAOIs. The extent to which psilocin (and by extension psilocybin) is metabolized by MAO, specifically MAO-A, is not fully clear, but has ranged from 4% to 33% in different studies based on metabolite excretion. However, circulating levels of the deaminated metabolite of psilocin are far higher than those of free unmetabolized psilocin with psilocybin administration. An early clinical study of psilocybin in combination with short-term tranylcypromine pretreatment found that tranylcypromine marginally potentiated the peripheral effects of psilocybin, including pressor effects and mydriasis, but overall did not significantly modify the psychoactive and hallucinogenic effects of the psilocybin, although some of its emotional effects were said to be reduced and some of its perceptual effects were said to be amplified.
Some psychedelics are substrates of cytochrome P450 (CYP450) enzymes, for instance LSD being a substrate of CYP2D6 as well as of several other CYP450 enzymes. As such, CYP450 inhibitors may increase exposure to CYP450-substrate psychedelics such as LSD and thereby potentiate their effects as well as risks. A clinical study found that administration of LSD to people taking paroxetine, a selective serotonin reuptake inhibitor (SSRI) and strong CYP2D6 inhibitor, increased LSD exposure by about 1.5-fold. The combination was well-tolerated and did not modify the pleasant subjective effects or physiological effects of LSD, whereas negative effects of LSD, including "bad drug effect", anxiety, and nausea, were reduced. Similarly to the findings with a strong CYP2D6 inhibitor, a pharmacogenomic clinical study with LSD found that LSD levels were 75% higher in people with non-functional CYP2D6 (poor metabolizers) compared to those with functional CYP2D6.
Serotonin syndrome can be caused by combining psychedelics with other serotonergic drugs, including certain antidepressants, opioids, psychostimulants (e.g. MDMA), serotonin 5-HT1 agonists (e.g. triptans), herbs or supplements, and others.
A high rate of seizures has been reported when people on lithium have taken serotonergic psychedelics. In an analysis of online reports, 47% of 62 accounts reported seizures when a psychedelic was taken while on lithium. The mechanism underlying this apparent interaction is unclear.
== Pharmacology ==
=== Mechanism of action ===
Most serotonergic psychedelics act as non-selective agonists of serotonin receptors, including of the serotonin 5-HT2 receptors, but often also of other serotonin receptors, such as the serotonin 5-HT1 receptors. They are thought to mediate their hallucinogenic effects specifically by activation of serotonin 5-HT2A receptors. Psychedelics (including tryptamines like psilocin, DMT, and 5-MeO-DMT; phenethylamines like mescaline, DOM, and 2C-B; and ergolines and lysergamides like LSD) all act as agonists of the serotonin 5-HT2A receptors. Some psychedelics, such as phenethylamines like DOM and 2C-B, show high selectivity for the serotonin 5-HT2 receptors over other serotonin receptors. There is a very strong correlation between 5-HT2A receptor affinity and human hallucinogenic potency. In addition, the intensity of hallucinogenic effects in humans is directly correlated with the level of serotonin 5-HT2A receptor occupancy as measured with positron emission tomography (PET) imaging. Serotonin 5-HT2A receptor blockade with drugs like the semi-selective ketanserin and the non-selective risperidone can abolish the hallucinogenic effects of psychedelics in humans. However, studies with more selective serotonin 5-HT2A receptor antagonists, like pimavanserin, are still needed.
In animals, potency for stimulus generalization to the psychedelic DOM in drug discrimination tests is strongly correlated with serotonin 5-HT2A receptor affinity. Non-selective serotonin 5-HT2A receptor antagonists, like ketanserin and pirenperone, and selective serotonin 5-HT2A receptor antagonists, like volinanserin (MDL-100907), abolish the stimulus generalization of psychedelics in drug discrimination tests. Conversely, serotonin 5-HT2B and 5-HT2C receptor antagonists are ineffective. The potencies of serotonin 5-HT2 receptor antagonists in blocking psychedelic substitution are strongly correlated with their serotonin 5-HT2A receptor affinities. Highly selective serotonin 5-HT2A receptor agonists have recently been developed and show stimulus generalization to psychedelics, whereas selective serotonin 5-HT2C receptor agonists do not do so. The head-twitch response (HTR) is induced by serotonergic psychedelics and is a behavioral proxy of psychedelic-like effects in animals. The HTR is invariably induced by serotonergic psychedelics, is blocked by selective serotonin 5-HT2A receptor antagonists, and is abolished in serotonin 5-HT2A receptor knockout mice. In addition, there is a strong correlation between hallucinogenic potency in humans and potency in the HTR assay. Moreover, the HTR paradigm is one of the only animal tests that can distinguish between hallucinogenic serotonin 5-HT2A receptor agonists and non-hallucinogenic serotonin 5-HT2A receptor agonists, such as lisuride. In accordance with the preceding animal and human findings, it has been said that the evidence that the serotonin 5-HT2A receptor mediates the hallucinogenic effects of serotonergic psychedelics is overwhelming.
The serotonin 5-HT2A receptor activates several downstream signaling pathways. These include the Gq, β-arrestin2, and other pathways. Activation of both the Gq and β-arrestin2 pathways have been implicated in mediating the hallucinogenic effects of serotonergic psychedelics. However, subsequently, activation of the Gq pathway and not β-arrestin2 has been implicated. Interestingly, Gq signaling appeared to mediate hallucinogenic-like effects, whereas β-arrestin2 mediated receptor downregulation and tachyphylaxis. The lack of psychedelic effects with non-hallucinogenic serotonin 5-HT2A receptor agonists may be due to partial agonism of the serotonin 5-HT2A receptor with efficacy insufficient to produce psychedelic effects or may be due to biased agonism of the serotonin 5-HT2A receptor. There appears to be a threshold level of Gq activation (in terms of intrinsic activity, with EmaxTooltip maximal efficacy >70%) required for production of hallucinogenic effects. Full agonists and partial agonists above this threshold are psychedelic 5-HT2A receptor agonists, whereas partial agonists below this threshold, such as lisuride, 2-bromo-LSD, 6-fluoro-DET, 6-MeO-DMT, and Ariadne, are non-hallucinogenic 5-HT2A receptor agonists. In addition, biased agonists that activate β-arrestin2 signaling but not Gq signaling, such as ITI-1549, IHCH-7086, and 25N-N1-Nap, are non-hallucinogenic serotonin 5-HT2A receptor agonists.
The hallucinogenic effects of serotonergic psychedelics may be critically mediated by serotonin 5-HT2A receptor activation in the medial prefrontal cortex (mPFC). Layer V pyramidal neurons in this area are especially discussed. Activation of serotonin 5-HT2A receptors in the mPFC results in marked excitatory and inhibitory effects as well as increased release of glutamate and GABA. Direct injection of serotonin 5-HT2A receptor agonists into the mPFC produces the HTR. Drugs that suppress glutamatergic activity in the mPFC, including AMPA receptor antagonists, metabotropic glutamate mGlu2/3 receptor agonists, μ-opioid receptor agonists, and adenosine A1 receptor agonists, block or suppress many of the neurochemical and behavioral effects of serotonergic psychedelics, including the HTR. Metabotropic glutamate mGlu2 receptors are primarily expressed as presynaptic autoreceptors and have inhibitory effects on glutamate release. Serotonergic psychedelics have been found to produce frontal cortex hyperactivity in humans in PET and single-photon emission computed tomography (SPECT) imaging studies. The PFC projects to many other cortical and subcortical brain areas, such as the locus coeruleus, nucleus accumbens, and amygdala, among others, and activation of the PFC by serotonergic psychedelics may thereby indirectly modulate these areas. In addition to the PFC, there is moderate to high expression of serotonin 5-HT2A receptors in the primary visual cortex (V1), as well as expression of the serotonin 5-HT2A receptor in other visual areas, and activation of these receptors may contribute to or mediate the visual effects of serotonergic psychedelics. Serotonergic psychedelics also directly or indirectly modulate a variety of other brain areas, like the claustrum, and this may be involved in their effects as well.
Serotonin, as well as drugs that increase serotonin levels, like the serotonin precursor 5-hydroxytryptophan (5-HTP), serotonin reuptake inhibitors, and serotonin releasing agents, are non-hallucinogenic in humans despite increasing activation of serotonin 5-HT2A receptors. Serotonin is a hydrophilic molecule which cannot easily cross biological membranes without active transport, and the serotonin 5-HT2A receptor is usually expressed as a cell surface receptor that is readily accessible to extracellular serotonin. The HTR, a behavioral proxy of psychedelic-like effects, appears to be mediated by activation of intracellularly expressed serotonin 5-HT2A receptors in a population of mPFC neurons that do not also express the serotonin transporter (SERT) and hence cannot be activated by serotonin. In contrast to serotonin, serotonergic psychedelics are more lipophilic than serotonin and are able to readily enter these neurons and activate the serotonin 5-HT2A receptors within them. Artificial expression of the SERT in this population of neurons in animals resulted in a serotonin releasing agent that doesn't normally produce the HTR being able to do so. Although serotonin itself is non-hallucinogenic, at very high concentrations achieved pharmacologically (e.g., injected into the brain or with massive doses of 5-HTP) it can produce psychedelic-like effects in animals by being metabolized by indolethylamine N-methyltransferase (INMT) into more lipophilic N-methylated tryptamines like N-methylserotonin and bufotenin (N,N-dimethylserotonin).
In addition to their hallucinogenic effects, serotonergic psychedelics may also produce a variety of other effects, including psychoplastogenic (i.e., neuroplasticity-enhancing), antidepressant, anxiolytic, empathy-enhancing or prosocial effects, anti-obsessional, anti-addictive, anti-inflammatory and immunomodulatory effects, analgesic effects, and/or antimigraine effects. While psychedelics themselves are also being clinically evaluated for these potential therapeutic benefits, non-hallucinogenic serotonin 5-HT2A receptor agonists, which are often analogues of serotonergic psychedelics, have been developed and are being studied for potential use in medicine in an attempt to provide some such benefits without hallucinogenic effects.
Although the hallucinogenic effects of serotonergic psychedelics are thought to be mediated by serotonin 5-HT2A receptor activation, interactions with other receptors, such as the serotonin 5-HT1A, 5-HT1B, 5-HT2B, and 5-HT2C receptors among many others, may additionally contribute to and modulate their effects. Interestingly, some psychedelics, such as LSD and psilocybin, have been claimed to act as positive allosteric modulators of the tropomyosin receptor kinase B (TrkB), one of the signaling receptors of brain-derived neurotrophic factor (BDNF). However, this finding has yet to be replicated. Moreover, despite the apparent TrkB potentiation, the psychoplastogenic effects of serotonergic psychedelics, including dendritogenesis, spinogenesis, and synaptogenesis, appear to be mediated by activation of serotonin 5-HT2A receptors, whereas psychedelics do not generally stimulate neurogenesis.
== Chemistry ==
The three major chemical groups of serotonergic psychedelics include the tryptamines, phenethylamines, and lysergamides, which each have different profiles of pharmacological activity.
=== Tryptamines ===
Tryptamines are derivatives of tryptamine and are structurally related to the monoamine neurotransmitter serotonin (also known as 5-hydroxytryptamine or 5-HT). Many tryptamines act as non-selective serotonin receptor agonists, including of the serotonin 5-HT2A receptor. Some tryptamines also act as monoamine releasing agents, including of serotonin, norepinephrine, and/or dopamine. Examples of psychedelic tryptamines include psilocin and psilocybin, dimethyltryptamine (DMT), 5-MeO-DMT, bufotenin, α-methyltryptamine (αMT), 4-AcO-DMT (psilacetin), 4-HO-MET, 5-MeO-MiPT, and 5-MeO-DiPT, among others. Harmala alkaloids like harmaline and iboga-type alkaloids like ibogaine are cyclized tryptamines and may also be considered hallucinogenic tryptamines.
=== Phenethylamines ===
Phenethylamines, as well as amphetamines (α-methylphenethylamines), are derivatives of β-phenethylamine and are structurally related to the monoamine neurotransmitters dopamine, norepinephrine, and epinephrine. Some phenethylamines and amphetamines, particularly those with methoxy and other substitions on the phenyl ring, are potent serotonin 5-HT2 receptor agonists, including of the serotonin 5-HT2A receptor, and can produce psychedelic effects. In contrast to phenethylamines and amphetamines generally, most psychedelic phenethylamines are not monoamine releasing agents. Examples of psychedelic phenethylamines and amphetamines include mescaline and other scalines like trimethoxyamphetamine (TMA) and escaline, the 2C drugs like 2C-B, 2C-E, and 2C-I, the DOx drugs like DOB, DOI, and DOM, certain MDxx drugs like MDA and MDMA (weak psychedelics), and the NBOMe (25x-NBx) drugs like 25I-NBOMe, among others.
=== Lysergamides ===
Lysergamides are ergoline derivatives related to the ergot alkaloids. They are notable in containing both tryptamine and phenethylamine within their chemical structures. As such, ergolines and lysergamides may be considered structurally related to the monoamine neurotransmitters. Many ergolines and lysergamides act as highly promiscuous ligands of monoamine receptors, including of serotonin, dopamine, and adrenergic receptors. Some lysergamides are efficacious serotonin 5-HT2A receptor agonists and thereby produce psychedelic effects. Examples of psychedelic lysergamides include lysergic acid diethylamide (LSD), ergine (lysergic acid amide; LSA), isoergine (isolysergic acid amide; iso-LSA), ETH-LAD, AL-LAD, 1P-LSD, 1S-LSD, ALD-52 (1A-LSD), LA-SS-Az (LSZ), ergonovine (ergometrine; lysergic acid propanolamide), methylergometrine (methylergonovine), and methysergide (methylmethylergonovine), among others. Ergine, isoergine, and ergonovine occur naturally in morning glories and certain fungi like ergot and Periglandula species, while others like LSD are synthetic. LSD is among the most potent psychedelics, as well as psychoactive drugs in general, that are known.
=== Others ===
Other psychedelics not belonging to any of the above three structural families have been discovered, for instance certain arylpiperazine derivatives like quipazine, the antiretroviral drug efavirenz, and simplified or partial lysergamides (which are also rigid tryptamines and/or phenethylamines) like NDTDI and DEMPDHPCA.
== History ==
=== Early history ===
Psychedelics occurring in plants, fungi, and animals have been used by indigenous peoples throughout the world for thousands of years. These psychedelics and their sources include psilocybin and psilocin in psilocybin-containing mushrooms (teonanacatl), dimethyltryptamine (DMT) in ayahuasca (a combination typically of Psychotria viridis and Banisteriopsis caapi), bufotenin in Anadenanthera trees, 5-MeO-DMT in the Colorado River Toad, mescaline in peyote (peyotl) and San Pedro cacti, and ergine and isoergine in morning glories (ololiuqui, tlitliltzin) and ergot, among others. The kykeon of the Eleusinian Mysteries in Ancient Greece might have been a psychedelic, for instance ergot or psilocybin-containing mushrooms. The earliest archeological evidence of the use of psychedelic plants and fungi by humans dates back roughly 10,000 years.
=== Western characterization ===
Psychedelics were discovered by the Western world and the scientific community relatively late. The use of hallucinogenic snuffs by indigenous South American people was first observed by Western explorers like Christopher Columbus as early as 1496. The first written description of an observed psychedelic experience, with cohoba, was published by Ramon Pane in 1511. Spanish explorers observed the use of psilocybin-containing mushrooms (teonanacatl) in Mexico as early as 1519 with the arrival of Hernán Cortés. Spanish ethnographer Bernardino de Sahagún traveled to Mexico in 1529 and described the use of these mushrooms in his books. The botanists Richard Spruce and Alfred Russel Wallace observed and described the use of ayahuasca in the Amazon in the 1850s.
==== The phenethylamine psychedelic mescaline ====
Mescaline is sometimes described as the "first psychedelic", as it was the first to be discovered and characterized by the Western world. American physician John Raleigh Briggs, living in Texas, learned of peyote from Native Americans and Mexicans, who told him that it produced "beautiful visions" and made them journey into the "spirit world". He obtained mescal buttons from Mexico and published a journal article about trying a very low dose of them in May 1887. This article is said to have brought peyote into North American pharmacology. Briggs described the physiological effects of his experience, such as increased heart rate, and of experiencing "intoxication". The article was read by George Davis, of Parke, Davis and Company, who then obtained the buttons from Briggs in June 1887. Parke-Davis attempted to market peyote as a cardiac stimulant and for other uses, but met with little success. The German pharmacologist Louis Lewin obtained mescal buttons from Parke-Davis during a trip to the United States in 1887 and began studying them and sharing his findings.
The first known published description of a hallucinogenic peyote experience was by American neurologist Silas Weir Mitchell in December 1896. After reading Mitchell's article, others, including psychologist and sexologist Havelock Ellis, American psychologist William James, and German pharmacologist, chemist, and Lewin rival Arthur Heffter, among others, tried peyote and described their experiences. Heffter isolated and ingested mescaline from peyote, experiencing psychedelic effects with the pure compound, in 1897, and published his findings in 1898.
Austrian chemist Ernst Späth synthesized mescaline for the first time in 1919. The German pharmaceutical company Merck then began distributing pharmaceutical mescaline in 1920. The German psychiatrist Kurt Beringer, a student of Lewin and an acquaintance of Hermann Hesse and Carl Jung, became the father of psychedelic psychiatry and conducted experiments with mescaline in more than 60 people starting in 1921. He published his monograph on the subject, Der Meskalinrausch (Mescaline Intoxication), in 1927. German–American psychologist Heinrich Klüver published his monograph, Mescal: The Divine Plant and Its Psychological Effects, in English in 1928. He is said to have been the first to attempt to provide a phenomenological description of the psychedelic experience.
==== Tryptamine and lysergamide psychedelics ====
Austrian anthropologist and ethnobotanist Blas Pablo Reko, traveling through Central and South America, wrote of the use of teonanacatl by native Mexican people in Oaxaca in 1919. Reko subsequently sent samples of teonanacatl (Psilocybe mexicana) as well as Ipomoea violacea (morning glory) seeds to Swedish anthropologist Henry Wassén in 1937. Reko had obtained the mushroom sample from Austrian engineer Robert Weitlaner who was working in Mexico. Eventually, Wassén forwarded Reko and Weitlaner's mushroom sample to Harvard University, where the mushrooms came to the attention of American ethnobotanist Richard Evans Schultes. However, they had decomposed so badly that they could not be identified. Prior to Wassén obtaining specimens around 1936, the existence of teonanacatl was very controversial and was debated and even denied by some. In 1938, a small group of Westerners, which included Weitlaner's daughter and American anthropologist Jean Basset Johnson, attended a mushroom ceremony. They were the first Westerners known to do so and described the event. Schultes published reviews of teonanacatl being a hallucinogenic mushroom in the late 1930s. Schultes obtained specimens of three of the hallucinogenic mushrooms used in ceremonies, including Psilocybe caerulescens, Panaeolus campanulatus, and Stropharia cubensis, but further investigations of the mushrooms were interrupted by World War II.
Ergine (lysergic acid amide; LSA) and isoergine (isolysergic acid amide; iso-LSA) were first identified from hydrolysis of ergot alkaloids in 1932 and 1936, respectively. In 1938, Swiss chemist Albert Hofmann, working at Sandoz Laboratories, synthesized lysergic acid diethylamide (LSD), a synthetic derivative of ergine, while developing new oxytocic drugs derived from ergot. LSD was not further investigated and was placed in storage for 5 years. In 1943 however, Hofmann worked with LSD again and accidentally discovered its hallucinogenic effects when minute amounts of the potent psychedelic absorbed through his skin. His subsequent self-experiment with LSD three days later on April 19 is the psychedelic holiday Bicycle Day. Hofmann and his colleague, psychiatrist Werner Stoll, first described LSD in 1943 and first described its psychedelic effects in 1947. LSD began being distributed by Sandoz Laboratories for research purposes under the brand name Delysid in 1949.
Schultes described the indigenous and shamanic use of dimethyltryptamine (DMT)-containing psychedelic plants in 1954 and also described the use of hallucinogenic morning glories in the 1950s. The psychedelic effects of synthesized DMT were described by Hungarian chemist and psychiatrist Stephen Szára in 1956. Osmond described the hallucinogenic and other effects of morning glory seeds in clinical studies in 1955. Hofmann identified and described ergine and isoergine as the active constituents of morning glory seeds in 1960. Their hallucinogenic effects were first described by Hofmann in 1963.
In 1952, couple and amateur ethnomycologists R. Gordon Wasson and Valentina Wasson learned of the ritual use of hallucinogenic mushrooms in the 16th century in Mexico from the published work of Schultes. They made several trips to Mexico in search of the mushrooms. In mid-1955, the Wassons participated in a mushroom ceremony with Mazatec curandera Maria Sabina in Huautla de Jiménez, Oaxaca, Mexico. Gordon Wasson published his experience in an article for Life magazine titled "Seeking the Magic Mushroom" in 1957, while Valentina Wasson published her experience as "I Ate the Sacred Mushroom" in This Week magazine the same year. Later in 1957, a second expedition was made by the Wassons to Mexico with French mycologist Roger Heim. Heim identified several of the mushrooms as belonging to the genus Psilocybe. They collected samples of the mushrooms and Heim sent a sample to Hofmann. Hofmann identified psilocybin as the active constituent in 1958 and developed a chemical synthesis for it. Sandoz Pharmaceuticals began distributing tablets of psilocybin under the brand name Indocybin in 1960.
French scientists Césaire Phisalix and Gabriel Bertrand isolated bufotenin from Bufo toads in 1893 and named it. The compound was first isolated to purity by Austrian chemist Hans Handovsky in 1920. Clinical studies assessed the effects of bufotenin and were published starting in 1956. However, the findings of these studies were conflicting, and bufotenin developed a long-standing reputation of being inactive and toxic. American ethnobotanist Jonathan Ott and colleagues subsequently showed in 2001 that bufotenin is in fact a psychedelic and does not necessarily produce major adverse effects, although marked nausea and vomiting are prominent. The related psychedelic 5-MeO-DMT was first synthesized by Japanese chemists Toshio Hoshino and Kenya Shimodaira in 1935. It was later isolated from Dictyoloma incanescens in 1959. Subsequently, 5-MeO-DMT was isolated from numerous other plants and fungi. The compound was isolated from the skin of toads, specifically the Colorado River toad (Incilius alvarius, formerly Bufo alvarius), by Italian chemist and pharmacologist Vittorio Erspamer in 1967. A 1984 pamphlet by Albert Most (real name Ken Nelson), titled Bufo Alvarius: the Psychedelic Toad of the Sonoran Desert, described how to obtain and use Colorado River toad secretions as a psychedelic drug, and this started its recreational use.
==== Mid-20th-century research, popularization, and prohibition ====
Extensive clinical research on almost exclusively LSD, mescaline, and psilocybin was conducted in the 1950s and 1960s. However, the amount of research done on psilocybin was nowhere near that of LSD. Psychedelics like LSD started to become more visible in the mainstream sphere in the 1950s. English writer Aldous Huxley tried mescaline, which he had obtained from English psychiatrist Humphry Osmond, in 1953, and described its effects in his 1954 book The Doors of Perception. British politician Christopher Mayhew tried mescaline in 1955 and this was reported on in the media. Osmond, in correspondence with Huxley, coined the term "psychedelic", meaning "mind-manifesting", in 1956.
Psychedelics became widely recreationally used by the public, for instance by the hippies, during the counterculture of the 1960s. Harvard psychologists Timothy Leary and Richard Alpert began studying LSD and psilocybin in the early 1960s and ended up being fired from the university in 1963. Sandoz Laboratories ceased distribution of Delysid in 1965. Psychedelics became controlled substances in the United States and internationally in the 1960s and 1970s. By the end of the 1960s, psychedelic clinical research throughout the world had largely ceased.
Besides public research, it was eventually learned that the United States government had also conducted research into psychedelics, as possible mind-control and truth-serum drugs, in the 1940s through the 1970s, for instance Project MKUltra by the Central Intelligence Agency (CIA) and the Edgewood Arsenal research by the U.S. Army.
==== Creation of other synthetic psychedelics ====
The psychedelic effects of 3,4-methylenedioxyamphetamine (MDA), a synthetic analogue of mescaline that had been derived from amphetamine in 1910, were discovered by American chemist and pharmacologist Gordon Alles in 1930, but weren't subsequently described by him until 1959. 3,4,5-Trimethoxyamphetamine (TMA), another synthetic mescaline analogue, was first described in 1947 and its psychedelic effects were described in 1955. 2,4,5-Trimethoxyphenethylamine (2C-O), a synthetic positional isomer of mescaline, was synthesized and claimed to be psychedelic similarly to mescaline in 1931, but later trials found it to be inactive. Various synthetic tryptamine psychedelics, such as diethyltryptamine (DET), 4-PO-DET (CEY-19), and 4-HO-DET (CZ-74), were developed in the late 1950s. In addition, the synthetic α-alkyltryptamine analogues α-methyltryptamine (AMT; Indopan) and α-ethyltryptamine (AET; Monase), which are psychedelics and/or entactogens, were marketed and clinically used at non-hallucinogenic doses as antidepressants in the early 1960s, but were quickly withdrawn due to physical toxicity.
Alexander Shulgin, an American chemist working at Dow Chemical Company, tried mescaline by 1960. This experience has been described as "the most consequential mescaline trip of the sixties", as it caused Shulgin to redirect his focus and life's work to psychedelic chemistry. Starting in the 1960s, Shulgin synthesized and gradually described hundreds of novel synthetic psychedelics as well as entactogens in scientific publications and published books such as PiHKAL (1991) and TiHKAL (1997). Notable major examples of these drugs have included the DOx psychedelic DOM, the 2C psychedelic 2C-B, and the MDxx entactogen MDMA, among others. However, MDMA was not an original creation of Shulgin's but had previously been first synthesized in 1912 and had surfaced as a recreational drug related to MDA by the mid- to late-1960s. Instead, Shulgin had merely served to help popularize and spread awareness about MDMA and its unique effects.
MDMA became outlawed in the mid-1980s. In response to this, the Multidisciplinary Association for Psychedelic Studies (MAPS) was founded by Rick Doblin in 1986 and began efforts to develop MDMA and other psychedelics as medicines. American chemist David E. Nichols has developed numerous novel psychedelics and entactogens from the 1970s to present. Swiss chemist Daniel Trachsel, sometimes referred to as the "German Shulgin", has also developed and published numerous novel psychedelics as well as entactogens since the 1990s.
NBOMe psychedelics such as 25I-NBOMe, derived from structural modification of 2C psychedelics, were first described by Ralf Heim and colleagues by 2000. The NBOMe drugs were subsequently encountered as novel recreational drugs by 2010, and by 2012 had eclipsed other psychedelics like LSD and psilocybin-containing mushrooms in popularity, at least for a time.
==== Psychedelics, serotonin, and their actions ====
Serotonin, also known as 5-hydroxytryptamine (5-HT) and originally called enteramine, was discovered by Vittorio Erspamer in the 1930s and its structural identity was fully characterized in the late 1940s and early 1950s. Serotonin was discovered in the brain by Betty Twarog and Irvine Page in 1953. It was quickly noticed that LSD contains the serotonin-like tryptamine scaffold within its chemical structure. Shortly thereafter, it was found that LSD showed serotonin-like effects and could antagonize serotonin in certain assays. Studies in the 1960s and 1970s showed that various serotonin antagonists could block the behavioral effects of psychedelics in animals. The serotonin receptors, including the serotonin 5-HT2 receptors, were elucidated by the late 1970s. Mediation of the hallucinogenic effects of psychedelics by serotonin 5-HT2 receptor agonism was proposed by Richard Glennon and other researchers by the early 1980s. The human serotonin 5-HT2A receptor was first cloned in 1990. The hallucinogenic effects of psilocybin in humans were shown to be blocked by the selective serotonin 5-HT2A receptor antagonist ketanserin by Franz Vollenweider and colleagues in 1998, solidifying theoretical notions that agonism of the serotonin 5-HT2A receptor mediates the hallucinogenic effects of serotonergic psychedelics.
=== Psychedelic renaissance ===
Since the prohibition of the 1960s and 1970s, clinical research into psychedelics started to resume by the 1990s, for instance the studies of DMT by Rick Strassman, and they have once again started to be developed as pharmaceutical drugs for potential medical use. A so-called "psychedelic renaissance", in which interest in psychedelics has resurged, began in the late 2010s and early 2020s. Michael Pollan's 2018 book How to Change Your Mind, which was also adapted into a Netflix series in 2022, was especially impactful in terms of increasing mainstream awareness and interest in psychedelics. More than 100 clinical trials of four major psychedelics, including psilocybin, LSD, ayahuasca, and MDMA, were identified as being underway in 2024.
== Society and culture ==
=== Etymology and nomenclature ===
The term psychedelic was coined by the psychiatrist Humphrey Osmond during written correspondence with author Aldous Huxley (written in a rhyme: “To fathom Hell or soar angelic/Just take a pinch of psychedelic.”) and presented to the New York Academy of Sciences by Osmond in 1957. It is irregularly derived from the Greek words ψυχή (psychḗ, meaning 'mind, soul') and δηλείν (dēleín, meaning 'to manifest'), with the intended meaning "mind manifesting" or alternatively "soul manifesting", and the implication that psychedelics can reveal unused potentials of the human mind. The term was loathed by American ethnobotanist Richard Schultes but championed by American psychologist Timothy Leary.
Aldous Huxley had suggested his own coinage phanerothyme (Greek phaneroein- "to make manifest or visible" and Greek thymos "soul", thus "to reveal the soul") to Osmond in 1956. Recently, the term entheogen (meaning "that which produces the divine within") has come into use to denote the use of psychedelic drugs, as well as various other types of psychoactive substances, in a religious, spiritual, and mystical context.
In 2004, David E. Nichols wrote the following about the nomenclature used for psychedelic drugs:
Many different names have been proposed over the years for this drug class. The famous German toxicologist Louis Lewin used the name phantastica earlier in this century, and as we shall see later, such a descriptor is not so farfetched. The most popular names—hallucinogen, psychotomimetic, and psychedelic ("mind manifesting")—have often been used interchangeably. Hallucinogen is now, however, the most common designation in the scientific literature, although it is an inaccurate descriptor of the actual effects of these drugs. In the lay press, the term psychedelic is still the most popular and has held sway for nearly four decades. Most recently, there has been a movement in nonscientific circles to recognize the ability of these substances to provoke mystical experiences and evoke feelings of spiritual significance. Thus, the term entheogen, derived from the Greek word entheos, which means "god within", was introduced by Ruck et al. and has seen increasing use. This term suggests that these substances reveal or allow a connection to the "divine within". Although it seems unlikely that this name will ever be accepted in formal scientific circles, its use has dramatically increased in the popular media and on internet sites. Indeed, in much of the counterculture that uses these substances, entheogen has replaced psychedelic as the name of choice and we may expect to see this trend continue.
Robin Carhart-Harris and Guy Goodwin write that the term psychedelic is preferable to hallucinogen for describing classical psychedelics because of the term hallucinogen's "arguably misleading emphasis on these compounds' hallucinogenic properties."
While the term psychedelic is most commonly used to refer only to serotonergic hallucinogens, it is sometimes used for a much broader range of drugs, including empathogen–entactogens, dissociatives, and atypical hallucinogens/psychoactives such as Amanita muscaria, Cannabis sativa, Nymphaea nouchali and Salvia divinorum. Thus, the term serotonergic psychedelic is sometimes used for the narrower class. It is important to check the definition of a given source. This article uses the more common, narrower definition of psychedelic.
=== Surrounding culture ===
Psychedelic culture includes manifestations such as psychedelic music, psychedelic art, psychedelic literature, psychedelic film, and psychedelic festivals. Examples of psychedelic music are found in the work of 1960s rock bands like the Grateful Dead, Jefferson Airplane, The 13th Floor Elevators, and Syd Barrett-era Pink Floyd. Many psychedelic bands and elements of the psychedelic subculture originated in San Francisco during the mid to late 1960s.
=== Legal status ===
Many psychedelics are classified under Schedule I of the United Nations Convention on Psychotropic Substances of 1971 as drugs with the greatest potential to cause harm and no acceptable medical uses. In addition, many countries have analogue laws; for example, in the United States, the Federal Analogue Act of 1986 automatically forbids any drugs sharing similar chemical structures or chemical formulas to prohibited substances if sold for human consumption.
In July 2022, though, under the United States Food and Drug Administration, the drug psilocybin was on track to be approved of as a treatment for depression, and MDMA as a treatment for post-traumatic stress disorder.
U.S. states such as Oregon and Colorado have also instituted decriminalization and legalization measures for accessing psychedelics and states like New Hampshire are attempting to do the same. J.D. Tuccille argues that increasing rates of use of psychedelics in defiance of the law are likely to result in more widespread legalization and decriminalization of access to the substances in the United States (as has happened with alcohol and cannabis).
== Research ==
=== Therapeutic effects ===
Psychedelic substances which may have therapeutic uses include psilocybin, LSD, and mescaline. During the 1950s and 1960s, lack of informed consent in some scientific trials on psychedelics led to significant, long-lasting harm to some participants. Since then, research regarding the effectiveness of psychedelic therapy has been conducted under strict ethical guidelines, with fully informed consent and a pre-screening to avoid people with psychosis taking part. Although the history behind these substances has hindered research into their potential medicinal value, scientists are now able to conduct studies and renew research that was halted in the 1970s. Some research has shown that these substances have helped people with such mental disorders as obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), alcoholism, depression, and cluster headaches.
It has long been known that psychedelics promote neurite growth and neuroplasticity and are potent psychoplastogens. There is evidence that psychedelics induce molecular and cellular adaptations related to neuroplasticity and that these could potentially underlie therapeutic benefits. Psychedelics have also been shown to have potent anti-inflammatory activity and therapeutic effects in animal models of inflammatory diseases including asthma, cardiovascular disease, and diabetes. They might also be useful for the treatment of neuroinflammation as well as post-COVID-19 syndrome (long COVID).
== See also ==
== References ==
== Further reading ==
Dyck E, Elcock C (2023). Expanding Mindscapes: A Global History of Psychedelics. MIT Press. ISBN 9780262376891.
Halberstadt AL, Franz X. Vollenweider, David E. Nichols, eds. (2018). Behavioral Neurobiology of Psychedelic Drugs. Vol. 36. Berlin, Heidelberg: Springer. ISBN 978-3-662-55878-2.
Jay M (2019). Mescaline: A Global History of the First Psychedelic. New Haven, CT: Yale University Press. doi:10.2307/j.ctvgc61q9. ISBN 978-0-300-25750-2. S2CID 241952235.
Letheby C (2021). Philosophy of Psychedelics. Oxford: Oxford University Press. doi:10.1093/med/9780198843122.001.0001. ISBN 978-0-19-884312-2.
Richards WA (2016). Sacred Knowledge: Psychedelics and Religious Experiences. New York: Columbia University Press. ISBN 978-0-231-54091-9.
Siff S (2015). Acid Hype: American News Media and the Psychedelic Experience. Champaign, Illinois: University of Illinois Press. ISBN 978-0-252-09723-2.
Winstock, Ar; Timmerman, C; Davies, E; Maier, Lj; Zhuparris, A; Ferris, Ja; Barratt, Mj; Kuypers, Kpc (2021). Global Drug Survey (GDS) 2020 Psychedelics Key Findings Report.
== External links ==
Psychedelic Timeline - Tom Frame - Psychedelic Times
Psychedelic drugs - Massviews Analysis - Wikipedia | Wikipedia/Psychedelic_drug |
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.
Cell-based immunotherapies are effective for some cancers. Immune effector cells such as lymphocytes, macrophages, dendritic cells, natural killer cells, and cytotoxic T lymphocytes work together to defend the body against cancer by targeting abnormal antigens expressed on the surface of tumor cells. Vaccine-induced immunity to COVID-19 relies mostly on an immunomodulatory T-cell response.
Therapies such as granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacteria are licensed for medical use. Others including IL-2, IL-7, IL-12, various chemokines, synthetic cytosine phosphate-guanosine (CpG) oligodeoxynucleotides and glucans are involved in clinical and preclinical studies.
== Immunomodulators ==
Immunomodulators are the active agents of immunotherapy. They are a diverse array of recombinant, synthetic, and natural preparations.
== Activation immunotherapies ==
=== Cancer ===
Cancer treatment used to be focused on killing or removing cancer cells and tumours, with chemotherapy or surgery or radiation. In 2018 the Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation." Cancer immunotherapy attempts to stimulate the immune system to destroy tumours. A variety of strategies are in use or are undergoing research and testing. Randomized controlled studies in different cancers resulting in significant increase in survival and disease free period have been reported and its efficacy is enhanced by 20–30% when cell-based immunotherapy is combined with conventional treatment methods.
One of the oldest forms of cancer immunotherapy is the use of BCG vaccine, which was originally to vaccinate against tuberculosis and later was found to be useful in the treatment of bladder cancer. BCG immunotherapy induces both local and systemic immune responses. The mechanisms by which BCG immunotherapy mediates tumor immunity have been widely studied, but they are still not completely understood.
The use of monoclonal antibodies in cancer therapy was first introduced in 1997 with rituximab, an anti-CD20 antibody for treatment of B cell lymphoma. Since then several monoclonal antibodies have been approved for treatment of various haematological malignancies as well as for solid tumours.
The extraction of G-CSF lymphocytes from the blood and expanding in vitro against a tumour antigen before reinjecting the cells with appropriate stimulatory cytokines. The cells then destroy the tumour cells that express the antigen. Topical immunotherapy utilizes an immune enhancement cream (imiquimod) which produces interferon, causing the recipient's killer T cells to destroy warts, actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia, squamous cell cancer, cutaneous lymphoma, and superficial malignant melanoma. Injection immunotherapy ("intralesional" or "intratumoural") uses mumps, candida, the HPV vaccine or trichophytin antigen injections to treat warts (HPV induced tumours).
Adoptive cell transfer has been tested on lung and other cancers, with greatest success achieved in melanoma.
==== Dendritic cell-based pump-priming or vaccination ====
Dendritic cells (DC) can be stimulated to activate a cytotoxic response towards an antigen. Dendritic cells, a type of antigen-presenting cell, are harvested from the person needing the immunotherapy. These cells are then either pulsed with an antigen or tumour lysate or transfected with a viral vector, causing them to display the antigen. Upon transfusion into the person, these activated cells present the antigen to the effector lymphocytes (CD4+ helper T cells, cytotoxic CD8+ T cells and B cells). This initiates a cytotoxic response against tumour cells expressing the antigen (against which the adaptive response has now been primed). The first FDA-approved cell-based immunotherapy, the cancer vaccine Sipuleucel-T is one example of this approach. The Immune Response Corporation (IRC) developed this immunotherapy and licensed the technology to Dendreon, which obtained FDA clearance.
The current approaches for DC-based vaccination are mainly based on antigen loading on in vitro-generated DCs from monocytes or CD34+ cells, activating them with different TLR ligands, cytokine combinations, and injecting them back to the patients. The in vivo targeting approaches comprise administering specific cytokines (e.g., Flt3L, GM-CSF) and targeting the DCs with antibodies to C-type lectin receptors or agonistic antibodies (e.g., anti-CD40) that are conjugated with antigen of interest. Multiple, next-generation anti-CD40 platforms are being actively developed. Future approach may target DC subsets based on their specifically expressed C-type lectin receptors or chemokine receptors. Another potential approach is the generation of genetically engineered DCs from induced pluripotent stem cells and use of neoantigen-loaded DCs for inducing better clinical outcome.
==== T-cell adoptive transfer ====
Adoptive cell transfer in vitro cultivates autologous, extracted T cells for later transfusion.
Alternatively, Genetically engineered T cells are created by harvesting T cells and then infecting the T cells with a retrovirus that contains a copy of a T cell receptor (TCR) gene that is specialised to recognise tumour antigens. The virus integrates the receptor into the T cells' genome. The cells are expanded non-specifically and/or stimulated. The cells are then reinfused and produce an immune response against the tumour cells. The technique has been tested on refractory stage IV metastatic melanomas and advanced skin cancer. The first FDA-approved CAR-T drug, Kymriah, used this approach. To obtain the clinical and commercial supply of this CAR-T, Novartis purchased the manufacturing plant, the distribution system and hired the production team that produced Sipuleucel-T developed by Dendreon and the Immune Response Corporation.
Whether T cells are genetically engineered or not, before re-infusion, lympho-depletion of the recipient is required to eliminate regulatory T cells as well as unmodified, endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines. Lymphodepletion may be achieved by myeloablative chemotherapy, to which total body irradiation may be added for greater effect. Transferred cells multiplied in vivo and persisted in peripheral blood in many people, sometimes representing levels of 75% of all CD8+ T cells at 6–12 months after infusion. As of 2012, clinical trials for metastatic melanoma were ongoing at multiple sites. Clinical responses to adoptive transfer of T cells were observed in patients with metastatic melanoma resistant to multiple immunotherapies.
==== Checkpoint inhibitors ====
Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies are the two types of checkpoint inhibitors currently available to patients. The approval of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) antibodies for human use has already resulted in significant improvements in disease outcomes for various cancers.
Although these molecules were originally discovered as molecules playing a role in T cell activation or apoptosis, subsequent preclinical research showed their important role in the maintenance of peripheral immune tolerance.
Immune checkpoint inhibitors are approved to treat some patients with a variety of cancer types, including melanoma, breast cancer, bladder cancer, cervical cancer, colon cancer, lung cancer head and neck cancer, or Hodgkin lymphoma.
These therapies have revolutionized cancer immunotherapy as they showed for the first time in many years of research in metastatic melanoma, which is considered one of the most immunogenic human cancers, an improvement in overall survival, with an increasing group of patients benefiting long-term from these treatments, although caution remains needed for specific subgroups.
The next generation of checkpoint inhibitors targets other receptors such as lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). Antibodies against these receptors have been evaluated in clinical studies, but have not yet been approved for widespread use.
== Immune enhancement therapy ==
Autologous immune enhancement therapy use a person's own peripheral blood-derived natural killer cells, cytotoxic T lymphocytes, epithelial cells and other relevant immune cells are expanded in vitro and then re-infused. The therapy has been tested against hepatitis C, chronic fatigue syndrome and HHV6 infection.
== Suppression immunotherapies ==
Immune suppression dampens an abnormal immune response in autoimmune diseases or reduces a normal immune response to prevent rejection of transplanted organs or cells.
=== Immunosuppressive drugs ===
Immunosuppressive drugs can be used to control the immune system with organ transplantation and with autoimmune disease. Immune responses depend on lymphocyte proliferation. Lymphocyte proliferation is the multiplication of lymphocyte cells used to fight and remember foreign invaders. Cytostatic drugs are a type of immunosuppressive drug that aids in slowing down the growth of rapidly dividing cells. Another example of an immunosuppressive drug is Glucocorticoids which are more specific inhibitors of lymphocyte activation. Glucocorticoids work by emulating actions of natural actions of the body's adrenal glands to help suppress the immune system, which is helpful with autoimmune diseases|, Alternatively, inhibitors of immunophilins more specifically target T lymphocyte activation, the process by which T-lymphocytes stimulate and begin to respond to a specific antigen, There is also Immunosuppressive antibodies which target steps in the immune response to prevent the body from attacking its tissues, which is a problem with autoimmune diseases, There are various other drugs that modulate immune responses and can be used to induce immune regulation. It was observed in a preclinical trial that regulation of the immune system by small immunosuppressive molecules such as vitamin D, dexamethasone, and curcumin could be helpful in preventing or treating chronic inflation. Given that the molecules are administered under a low-dose regimen and subcutaneously. A study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Valrubicin-loaded immunoliposomes (Val-ILs) as a novel nanoparticle technology to target immunosuppressive cells. Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death of immunosuppressive cells.
=== Immune tolerance ===
The body naturally does not launch an immune system attack on its own tissues. Models generally identify CD4+ T-cells at the centre of the autoimmune response. Loss of T-cell tolerance then unleashes B-cells and other immune effector cells on to the target tissue. The ideal tolerogenic therapy would target the specific T-cell clones co-ordinating the autoimmune attack.
Immune tolerance therapies seek to reset the immune system so that the body stops mistakenly attacking its own organs or cells in autoimmune disease or accepts foreign tissue in organ transplantation. A recent therapeutic approach is the infusion of regulatory immune cells into transplant recipients. The transfer of regulatory immune cells has the potential to inhibit the activity of effector.
Creating immune tolerance reduces or eliminates the need for lifelong immunosuppression and attendant side effects. It has been tested on transplantations, rheumatoid arthritis, type 1 diabetes and other autoimmune disorders.
=== Allergen immunotherapy ===
Immunotherapy can also be used to treat allergies. While allergy treatments (such as antihistamines or corticosteroids) treat allergic symptoms, immunotherapy can reduce sensitivity to allergens, lessening its severity. Allergen immunotherapy can also be referred to as allergen desensitization or hypo-sensitization. Immunotherapy may produce long-term benefits. Immunotherapy is partly effective in some people and ineffective in others, but it offers people with allergies a chance to reduce or stop their symptoms.
Subcutaneous allergen immunotherapy was first introduced in 1911 through the hypothesis that people with hay fever were sensitive to pollen from grass. A process was developed to create an extract by drawing out timothy pollen in distilled water and then boiling it. This was injected into patients in increasing doses to help alleviate symptoms.
Allergen Immunotherapy is indicated for people who are extremely allergic or who cannot avoid specific allergens and when there is evidence of an IgE-mediated reaction that correlates with allergen symptoms. These IgE-mediated reactions can be identified via a blood IgE test or skin testing. If a specific IgE antibody is negative, there is no evidence that allergen immunotherapy will be effective for that patient.
However, there are risks associated with allergen immunotherapy as it is the administration of an agent the patient is known to be highly allergic to. Patients are at increased risk of fatal anaphylaxis, local reaction at the site of injection, or life-threatening systemic allergic reactions.
A promising approach to treat food allergies is the use of oral immunotherapy (OIT). OIT consists in a gradual exposure to increasing amounts of allergen can lead to the majority of subjects tolerating doses of food sufficient to prevent reaction on accidental exposure. Dosages increase over time, as the person becomes desensitized. This technique has been tested on infants to prevent peanut allergies.
== Helminthic therapies ==
Whipworm ova (Trichuris suis) and hookworm (Necator americanus) have been tested for immunological diseases and allergies, and have proved beneficial on multiple fronts, yet it is not entirely understood. Scientists have found that the immune response triggered by the burrowing of hookworm larvae to pass through the lungs and blood so the production of mast cells and specific antibodies are now present. They also reduce inflammation or responses ties to autoimmune diseases, but despite this, the hookworm's effects are considered to be negative typically. Helminthic therapy has been investigated as a treatment for relapsing remitting multiple sclerosis, Crohn's, allergies and asthma. While there is much to be learned about this, many researchers think that the change in the immune response is thanks to the parasites shifting to a more anti-inflammatory or regulatory system, which would in turn decrease inflammation and self inflicted immune damage as seen in Crohn's and multiple sclerosis. Specifically, MS patients saw lower relapse rates and calmer symptoms in some cases when experimenting with helminthic therapy. Hypothesized mechanisms include re-polarisation of the Th1 / Th2 response and modulation of dendritic cell function. The helminths downregulate the pro-inflammatory Th1 cytokines, interleukin-12 (IL-12), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), while promoting the production of regulatory Th2 cytokines such as IL-10, IL-4, IL-5 and IL-13.
Co-evolution with helminths has shaped some of the genes associated with interleukin expression and immunological disorders, such Crohn's, ulcerative colitis and celiac disease. Helminths' relationship to humans as hosts should be classified as mutualistic or symbiotic. In some ways, the relationship is symbiotic because the worms themselves need the host (humans) for survival, because this body supplies them with nutrients and a home. From another perspective, it could be reasoned that it is mutualistic, being that the above information about benefits in autoimmune disorders continues to remain true and supported. Also, some say that the worms can regulate gut bacteria. Another possibility is one of this being a parasitic relationship, arguing that the possible risks of anemia and other disorders outweighs the benefits, yet this is significantly less supported, with the research alluding to the mutualistic and symbiotic approach being much more likely.
== See also ==
Biological response modifier
Sepsivac
Checkpoint inhibitor
Interleukin-2 immunotherapy
Immunostimulant
Microtransplantation
Photoimmunotherapy in vitro or in vivo
== References ==
== External links == | Wikipedia/Immunotherapy |
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.
The term non-steroidal, common from around 1960, distinguishes these drugs from corticosteroids, another class of anti-inflammatory drugs, which during the 1950s had acquired a bad reputation due to overuse and side-effect problems after their introduction in 1948.
NSAIDs work by inhibiting the activity of cyclooxygenase enzymes (the COX-1 and COX-2 isoenzymes). In cells, these enzymes are involved in the synthesis of key biological mediators, namely prostaglandins, which are involved in inflammation, and thromboxanes, which are involved in blood clotting.
There are two general types of NSAIDs available: non-selective and COX-2 selective. Most NSAIDs are non-selective, and inhibit the activity of both COX-1 and COX-2. These NSAIDs, while reducing inflammation, also inhibit platelet aggregation and increase the risk of gastrointestinal ulcers and bleeds. COX-2 selective inhibitors have fewer gastrointestinal side effects, but promote thrombosis, and some of these agents substantially increase the risk of heart attack. As a result, certain COX-2 selective inhibitors—such as rofecoxib—are no longer used due to the high risk of undiagnosed vascular disease. These differential effects are due to the different roles and tissue localisations of each COX isoenzyme. By inhibiting physiological COX activity, NSAIDs may cause deleterious effects on kidney function, and, perhaps as a result of water and sodium retention and decreases in renal blood flow, may lead to heart problems. In addition, NSAIDs can blunt the production of erythropoietin, resulting in anaemia, since haemoglobin needs this hormone to be produced.
The most prominent NSAIDs are aspirin, ibuprofen, diclofenac and naproxen; all available over the counter (OTC) in most countries. Paracetamol (acetaminophen) is generally not considered an NSAID because it has only minor anti-inflammatory activity. Paracetamol treats pain mainly by blocking COX-2 and inhibiting endocannabinoid reuptake almost exclusively within the brain, and only minimally in the rest of the body.
== Medical uses ==
NSAIDs are often suggested for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are generally used for the symptomatic relief of the following conditions:
=== Chronic pain and cancer-related pain ===
The effectiveness of NSAIDs for treating non-cancer chronic pain and cancer-related pain in children and adolescents is not clear. There have not been sufficient numbers of high-quality randomised controlled trials conducted.
=== Inflammation ===
Differences in anti-inflammatory activity between the various individual NSAIDs are small, but there is considerable variation among individual patients in therapeutic response and tolerance to these drugs. About 60% of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose, and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to three weeks. If appropriate responses are not obtained within these times, another NSAID should be tried.
=== Surgical pain ===
Pain following surgery can be significant, and many people require strong pain medications such as opioids. There is some low-certainty evidence that starting NSAID painkiller medications in adults early, before surgery, may help reduce post-operative pain, and also reduce the dose or quantity of opioid medications required after surgery. Any increase risk of surgical bleeding, bleeding in the gastrointestinal system, myocardial infarctions, or injury to the kidneys has not been well studied. When used in combination with paracetamol, the analgesic effect on post-operative pain may be improved.
=== Aspirin ===
Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for antithrombosis through inhibition of platelet aggregation. This is useful for the management of arterial thrombosis, and prevention of adverse cardiovascular events like heart attacks. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane A2.
=== Dentistry ===
NSAIDs are useful in the management of post-operative dental pain following invasive dental procedures such as dental extraction. When not contra-indicated, they are favoured over the use of paracetamol alone due to the anti-inflammatory effect they provide. There is weak evidence suggesting that taking pre-operative analgesia can reduce the length of post operative pain associated with placing orthodontic spacers under local anaesthetic.
=== Alzheimer's disease ===
Based on observational studies and randomized controlled trials, NSAID use is not effective for the treatment or prevention of Alzheimer's disease.
== Contraindications ==
NSAIDs may be used with caution by people with the following conditions:
Persons who are over age 50, and who have a family history of gastrointestinal (GI) problems
Persons who have had previous gastrointestinal problems from NSAID use
NSAIDs should usually be avoided by people with the following conditions:
== Adverse effects ==
The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases risk of a range of gastrointestinal (GI) problems, kidney disease and adverse cardiovascular events. As commonly used for post-operative pain, there is evidence of increased risk of kidney complications. Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowel anastomosis created.
An estimated 10–20% of people taking NSAIDs experience indigestion. In the 1990s, high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding.
NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs and quinolone antibiotics may increase the risk of quinolones' adverse central nervous system effects, including seizure.
There is an argument over the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a benefit-risk profile and balancing the risk of no treatment with the competing potential risks of various therapies should be considered. For people over the age of 65 years old, the balance between the benefits of pain-relief medications such as NSAIDS and the potential for adverse effects has not been well determined.
There is some evidence suggesting that, for some people, use of NSAIDs (or other anti-inflammatories) may contribute to the initiation of chronic pain.
Side effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10–20% of NSAID patients experience dyspepsia, and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits.
Aspirin should not be taken by people who have salicylate intolerance or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm. Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers, mild diabetes, or gastritis seek medical advice before using aspirin. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. People with kidney disease, hyperuricemia, or gout should not take aspirin because it inhibits the kidneys' ability to excrete uric acid, and thus may exacerbate these conditions.
=== Combinational risk ===
If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time.
Rofecoxib (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions (ADRs) compared with naproxen. The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs (COX-2 inhibitors). A statistically significant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo—which caused a worldwide withdrawal of rofecoxib in October 2004.
Use of methotrexate together with NSAIDs in rheumatoid arthritis is safe, if adequate monitoring is done.
=== Cardiovascular ===
NSAIDs, aside from aspirin, increase the risk of myocardial infarction and stroke. This occurs at least within a week of use. They are not recommended in those who have had a previous heart attack as they increase the risk of death or recurrent MI. Evidence indicates that naproxen may be the least harmful out of these.
NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of heart failure in people without a history of cardiac disease. In people with such a history, use of NSAIDs (aside from low-dose aspirin) was associated with a more than 10-fold increase in heart failure. If this link is proven causal, researchers estimate that NSAIDs would be responsible for up to 20 percent of hospital admissions for congestive heart failure. In people with heart failure, NSAIDs increase mortality risk (hazard ratio) by approximately 1.2–1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac.
On 9 July 2015, the Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin.
=== Possible erectile dysfunction risk ===
A 2005 Finnish survey study found an association between long term (over three months) use of NSAIDs and erectile dysfunction.
A 2011 publication in The Journal of Urology received widespread publicity. According to the study, men who used NSAIDs regularly were at significantly increased risk of erectile dysfunction. A link between NSAID use and erectile dysfunction still existed after controlling for several conditions. However, the study was observational and not controlled, with low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusion regarding cause.
=== Gastrointestinal ===
The main adverse drug reactions (ADRs) associated with NSAID use relate to direct and indirect irritation of the gastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic effects on the epithelial mucosa.
Common gastrointestinal side effects include:
Nausea or vomiting
Indigestion
Gastric ulceration or bleeding
Diarrhea
Clinical NSAID ulcers are related to the systemic effects of NSAID administration. Such damage occurs irrespective of the route of administration of the NSAID (e.g., oral, rectal, or parenteral) and can occur even in people who have achlorhydria.
Ulceration risk increases with therapy duration, and with higher doses. To minimize GI side effects, it is prudent to use the lowest effective dose for the shortest period of time—a practice that studies show is often not followed. Over 50% of patients who take NSAIDs have sustained some mucosal damage to their small intestine.
The risk and rate of gastric adverse effects is different depending on the type of NSAID medication a person is taking. Indomethacin, ketoprofen, and piroxicam use appear to lead to the highest rate of gastric adverse effects, while ibuprofen (lower doses) and diclofenac appear to have lower rates.
Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations that manufacturers claim reduce the incidence of gastrointestinal ADRs. Similarly, some believe that rectal formulations may reduce gastrointestinal ADRs. However, consistent with the systemic mechanism of such ADRs, and in clinical practice, these formulations have not demonstrated a reduced risk of GI ulceration.
Numerous "gastro-protective" drugs have been developed with the goal of preventing gastrointestinal toxicity in people who need to take NSAIDs on a regular basis. Gastric adverse effects may be reduced by taking medications that suppress acid production such as proton pump inhibitors (e.g.: omeprazole and esomeprazole), or by treatment with a drug that mimics prostaglandin in order to restore the lining of the GI tract (e.g.: a prostaglandin analog misoprostol). Diarrhea is a common side effect of misoprostol; however, higher doses of misoprostol have been shown to reduce the risk of a person having a complication related to a gastric ulcer while taking NSAIDs. While these techniques may be effective, they are expensive for maintenance therapy.
Hydrogen sulfide NSAID hybrids prevent the gastric ulceration/bleeding associated with taking the NSAIDs alone. Hydrogen sulfide is known to have a protective effect on the cardiovascular and gastrointestinal system.
=== Inflammatory bowel disease ===
NSAIDs should be used with caution in individuals with inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) due to their tendency to cause gastric bleeding and form ulceration in the gastric lining.
=== Renal ===
NSAIDs are also associated with a fairly high incidence of adverse drug reactions (ADRs) on the kidney and over time can lead to chronic kidney disease. The mechanism of these kidney ADRs is due to changes in kidney blood flow. Prostaglandins normally dilate the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of kidney function. This is particularly important in kidney failure where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent arteriole into the glomerulus in addition to the efferent arteriole it normally constricts. Since NSAIDs block this prostaglandin-mediated effect of afferent arteriole dilation, particularly in kidney failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased RPF (renal perfusion flow) and GFR.
Common ADRs associated with altered kidney function include:
Sodium and fluid retention
Hypertension (high blood pressure)
These agents may also cause kidney impairment, especially in combination with other nephrotoxic agents. Kidney failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor (which removes angiotensin II's vasoconstriction of the efferent arteriole) and a diuretic (which drops plasma volume, and thereby RPF)—the so-called "triple whammy" effect.
In rarer instances NSAIDs may also cause more severe kidney conditions:
Interstitial nephritis
Nephrotic syndrome
Acute kidney injury
Acute tubular necrosis
Renal papillary necrosis
NSAIDs in combination with excessive use of phenacetin or paracetamol (acetaminophen) may lead to analgesic nephropathy.
=== Photosensitivity ===
Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. The 2-arylpropionic acids are the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac, and benzydamine.
Benoxaprofen, since withdrawn due to its liver toxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism.
=== During pregnancy ===
While NSAIDs as a class are not direct teratogens, use of NSAIDs in late pregnancy can cause premature closure of the fetal ductus arteriosus and kidney ADRs in the fetus. Thus, NSAIDs are not recommended during the third trimester of pregnancy because of the increased risk of premature constriction of the ductus arteriosus. Additionally, they are linked with premature birth and miscarriage. Aspirin, however, is used together with heparin in pregnant women with antiphospholipid syndrome. Additionally, indomethacin can be used in pregnancy to treat polyhydramnios by reducing fetal urine production via inhibiting fetal renal blood flow.
In contrast, paracetamol (acetaminophen) is regarded as being safe and well tolerated during pregnancy, but Leffers et al. released a study in 2010, indicating that there may be associated male infertility in the unborn. Doses should be taken as prescribed, due to risk of liver toxicity with overdoses.
In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.
In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications, to describe the risk of kidney problems in unborn babies which can then lead to low amniotic fluid levels, as a result of the use of NSAIDs. They are recommending avoiding the use of NSAIDs by pregnant women at 20 weeks or later in pregnancy.
=== Allergy and allergy-like hypersensitivity reactions ===
A variety of allergic or allergic-like NSAID hypersensitivity reactions follow the ingestion of NSAIDs. These hypersensitivity reactions differ from the other adverse reactions listed here which are toxicity reactions, i.e. unwanted reactions that result from the pharmacological action of a drug, are dose-related, and can occur in any treated individual; hypersensitivity reactions are idiosyncratic reactions to a drug. Some NSAID hypersensitivity reactions are truly allergic in origin: 1) repetitive IgE-mediated urticarial skin eruptions, angioedema, and anaphylaxis following immediately to hours after ingesting one structural type of NSAID but not after ingesting structurally unrelated NSAIDs; and 2) Comparatively mild to moderately severe T cell-mediated delayed onset (usually more than 24 hour), skin reactions such as maculopapular rash, fixed drug eruptions, photosensitivity reactions, delayed urticaria, and contact dermatitis; or 3) far more severe and potentially life-threatening t-cell-mediated delayed systemic reactions such as the DRESS syndrome, acute generalized exanthematous pustulosis, the Stevens–Johnson syndrome, and toxic epidermal necrolysis. Other NSAID hypersensitivity reactions are allergy-like symptoms but do not involve true allergic mechanisms; rather, they appear due to the ability of NSAIDs to alter the metabolism of arachidonic acid in favor of forming metabolites that promote allergic symptoms. Affected individuals may be abnormally sensitive to these provocative metabolites or overproduce them and typically are susceptible to a wide range of structurally dissimilar NSAIDs, particularly those that inhibit COX1. Symptoms, which develop immediately to hours after ingesting any of various NSAIDs that inhibit COX-1, are: 1) exacerbations of asthmatic and rhinitis (see aspirin-exacerbated respiratory disease) symptoms in individuals with a history of asthma or rhinitis and 2) exacerbation or first-time development of wheals or angioedema in individuals with or without a history of chronic urticarial lesions or angioedema.
=== Possible effects on bone and soft tissue healing ===
It has been hypothesized that NSAIDs may delay healing from bone and soft-tissue injuries by inhibiting inflammation. On the other hand, it has also been hypothesized that NSAIDs might speed recovery from soft tissue injuries by preventing inflammatory processes from damaging adjacent, non-injured muscles.
There is moderate evidence that they delay bone healing. Their overall effect on soft-tissue healing is unclear.
=== Ototoxicity ===
Long-term use of NSAID analgesics and paracetamol is associated with an increased risk of hearing loss.
=== Other ===
The use of NSAIDs for analgesia following gastrointestinal surgery remains controversial, given mixed evidence of an increased risk of leakage from any bowel anastomosis created. This risk may vary according to the class of NSAID prescribed.
Common adverse drug reactions (ADR), other than listed above, include: raised liver enzymes, headache, dizziness. Uncommon ADRs include an abnormally high level of potassium in the blood, confusion, spasm of the airways, and rash. Ibuprofen may also rarely cause irritable bowel syndrome symptoms. NSAIDs are also implicated in some cases of Stevens–Johnson syndrome.
Most NSAIDs penetrate poorly into the central nervous system (CNS). However, the COX enzymes are expressed constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as somnolence and dizziness.
NSAIDs may increase the risk of bleeding in patients with Dengue fever For this reason, NSAIDs are only available with a prescription in India.
In very rare cases, ibuprofen can cause aseptic meningitis.
As with other drugs, allergies to NSAIDs might exist. While many allergies are specific to one NSAID, up to 1 in 5 people may have unpredictable cross-reactive allergic responses to other NSAIDs as well.
=== Immune response ===
Although small doses generally have little to no effect on the immune system, large doses of NSAIDs significantly suppress the production of immune cells. As NSAIDs affect prostaglandins, they affect the production of most fast growing cells. This includes immune cells. Unlike corticosteroids, they do not directly suppress the immune system and so their effect on the immune system is not immediately obvious. They suppress the production of new immune cells, but leave existing immune cells functional. Large doses slowly reduce the immune response as the immune cells are renewed at a much lower rate. Causing a gradual reduction of the immune system, much slower and less noticeable than the immediate effect of Corticosteroids. The effect significantly increases with dosage, in a nearly exponential rate. Doubling of dose reduced cells by nearly four times. Increasing dose by five times reduced cell counts to only a few percent of normal levels. This is likely why the effect was not immediately obvious in low dose trials, as the effect is not apparent until much higher dosages are tested.
== Interactions ==
NSAIDs reduce kidney blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate.
NSAIDs cause decreased ability to form blood clots, which can increase the risk of bleeding when combined with other drugs that also decrease blood clotting, such as warfarin.
NSAIDs may aggravate hypertension (high blood pressure) and thereby antagonize the effect of antihypertensives, such as ACE inhibitors.
NSAIDs may interfere and reduce effectiveness of SSRI antidepressants through inhibiting TNFα and IFNγ, both of which are cytokine derivatives. NSAIDs, when used in combination with SSRIs, increase the risk of adverse gastrointestinal effects. NSAIDs, when used in combination with SSRIs, increase the risk of internal bleeding and brain hemorrhages.
Various widely used NSAIDs enhance endocannabinoid signaling by blocking the anandamide-degrading membrane enzyme fatty acid amide hydrolase (FAAH).
NSAIDs may reduce the effectiveness of antibiotics. An in-vitro study on cultured bacteria found that adding NSAIDs to antibiotics reduced their effectiveness by around 20%.
The concomitant use of NSAIDs with alcohol and/or tobacco products significantly increases the already elevated risk of peptic ulcers during NSAID therapy.
== Mechanism of action ==
Most NSAIDs act as nonselective inhibitors of the cyclooxygenase (COX) enzymes, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is competitively reversible (albeit at varying degrees of reversibility), as opposed to the mechanism of aspirin, which is irreversible inhibition. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated in 1970 by John Vane (1927–2004), who received a Nobel Prize for his work (see Mechanism of action of aspirin).
COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.
When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum and internal bleeding can result. The discovery of COX-2 led to research to the development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs.
NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately, different assays provide differing ratios.
Paracetamol (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body.
However, many aspects of the mechanism of action of NSAIDs remain unexplained, and for this reason, further COX pathways are hypothesized. The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed.
NSAIDs interact with the endocannabinoid system and its endocannabinoids, as COX2 have been shown to utilize endocannabinoids as substrates, and may have a key role in both the therapeutic effects and adverse effects of NSAIDs, as well as in NSAID-induced placebo responses.
NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase.
=== Antipyretic activity ===
NSAIDs have antipyretic activity and can be used to treat fever. Fever is caused by elevated levels of prostaglandin E2 (PGE2), which alters the firing rate of neurons within the hypothalamus that control thermoregulation. Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus. PGE2 signals to the hypothalamus to increase the body's thermal setpoint. Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen).
Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D, and E.
== Classification ==
NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action.
=== Salicylates ===
=== Propionic acid derivatives ===
=== Acetic acid derivatives ===
=== Enolic acid (oxicam) derivatives ===
=== Anthranilic acid derivatives (Fenamates) ===
The following NSAIDs are derived from fenamic acid, which is a derivative of anthranilic acid,: 235 which in turn is a nitrogen isostere of salicylic acid, which is the active metabolite of aspirin.: 235 : 17
=== Selective COX-2 inhibitors (Coxibs) ===
=== Sulfonanilides ===
Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity)
=== Others ===
Benzydamine (commonly branded as Tantum Verde or Difflam) is an indazole derivative with local anaesthetic and analgesic properties
Clonixin
Licofelone acts by inhibiting LOX (lipooxygenase) and COX and hence known as 5-LOX/COX inhibitor
H-harpagide in figwort or devil's claw
Some NSAIDs are also given intravenously, such as Ketorolac and Diclofenac sodium.
=== Chirality ===
Most NSAIDs are chiral molecules; diclofenac and the oxicams are exceptions. However, the majority are prepared as racemic mixtures. Typically, only a single enantiomer is pharmacologically active. For some drugs (typically profens), an isomerase enzyme in vivo converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely responsible for the poor correlation between NSAID efficacy and plasma concentration observed in older studies when specific analysis of the active enantiomer was not performed.
Ibuprofen and ketoprofen are now available in single-enantiomer preparations (dexibuprofen and dexketoprofen), which purport to offer quicker onset and an improved side-effect profile. Naproxen has always been marketed as the single active enantiomer.
=== Main practical differences ===
NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather, differences among compounds usually relate to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile.
Regarding adverse effects, selective COX-2 inhibitors have lower risk of gastrointestinal bleeding. With the exception of naproxen, nonselective NSAIDs increase the risk of having a heart attack. Some data also supports that the partially selective nabumetone is less likely to cause gastrointestinal events.
A consumer report noted that ibuprofen, naproxen, and salsalate are less expensive than other NSAIDs, and essentially as effective and safe when used appropriately to treat osteoarthritis and pain.
== Pharmacokinetics ==
Most nonsteroidal anti-inflammatory drugs are weak acids, with a pKa of 3–5. They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to albumin, so that their volume of distribution typically approximates to plasma volume. Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites that typically are excreted in the urine, though some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.
NSAIDs can also be divided into short-acting (plasma half-life less than 6 h) such as aspirin, diclofenac and ibuprofen and long-acting (half-life approximately greater than 10 h) such as naproxen, celecoxib.
== History ==
It is widely believed that naturally occurring salicin in willow trees and other plants was used by the ancients as a form of analgesic or anti-inflammatory drug, but this story, although compelling, is not entirely true. Hippocrates does not mention willow at all. Dioscorides's De materia medica was arguably the most influential herbal from Roman to Medieval times but, if he mentions willow at all (there is doubt about the identity of 'Itea'), then he used the ashes, steeped in vinegar, as a treatment for corns, which corresponds well with modern uses of salicylic acid.
Willow bark (from trees of the Salix genus) was widely known to be used as a medicine by multiple First Nations communities. The bark would be chewed or steeped in water for its pain relieving and antipyretic effects. The effects are a result of the bark's salicin content. Meadowsweet, another plant to contain salicin, has strong roots in British folk medicine for the same maladies. Willow bark was first reported in Western science by Edward Stone in 1763 as a treatment for ague (fever) according to the pseudoscientific doctrine of signatures.
In the body, salicin is turned into salicylic acid, which produces the antipyretic and analgesic effects that the plants are known for.
Salicin was first isolated by Johann Andreas Buchner in 1827. By 1829, French chemist Henri Leroux had improved the extraction process to obtain about 30g of purified salicin from 1.5 kg of willow bark. By hydrolysis, salicin releases glucose and salicyl alcohol which can be converted into salicylic acid, both in vivo and through chemical methods. In 1869, Hermann Kolbe synthesised salicylic acid, although it was too acidic for the gastric mucosa. The reaction used to synthesise aromatic acid from a phenol in the presence of CO2 is known as the Kolbe-Schmitt reaction.
By 1897, the German chemist Felix Hoffmann and the Bayer company prompted a new age of pharmacology by converting salicylic acid into acetylsalicylic acid—named aspirin by Heinrich Dreser. Other NSAIDs like ibuprofen were developed from the 1950s forward.
In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States.
== Veterinary use ==
Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves. The best effect is obtained by combining a short-term local anesthetic such as lidocaine with an NSAID acting as a longer term analgesic. However, as different species have varying reactions to different medications in the NSAID family, little of the existing research data can be extrapolated to animal species other than those specifically studied, and the relevant government agency in one area sometimes prohibits uses approved in other jurisdictions.
In the United States, meloxicam is approved for use only in canines, whereas (due to concerns about liver damage) it carries warnings against its use in cats except for one-time use during surgery. In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species. In other countries, for example The European Union (EU), there is a label claim for use in cats.
== See also ==
Discovery and development of cyclooxygenase 2 inhibitors
== References ==
== External links ==
"Nonsteroidal Anti-inflammatory Drugs (NSAIDs)". U.S. Food and Drug Administration (FDA). 30 December 2020. Archived from the original on 12 June 2019. | Wikipedia/Non-steroidal_anti-inflammatory_drug |
A motivation-enhancing drug, also known as a pro-motivational drug, is a drug which increases motivation. Drugs enhancing motivation can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). They can also be used in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, disorders that can be caused by conditions like stroke, traumatic brain injury (TBI), and neurodegenerative diseases. Motivation-enhancing drugs are used non-medically by healthy people to increase motivation and productivity as well, for instance in educational contexts.
There are limited clinical data on medications in treating motivational deficits and disorders. In any case, drugs used for pro-motivational purposes are generally dopaminergic agents, for instance dopamine reuptake inhibitors (DRIs) like methylphenidate and modafinil, dopamine releasing agents (DRAs) like amphetamine, and other dopaminergic medications. Adenosine receptor antagonists, like caffeine and istradefylline, can also produce pro-motivational effects. Acetylcholinesterase inhibitors, like donepezil, have been used as well.
Some drugs do not appear to increase motivation and can actually have anti-motivational effects. Examples of these drugs include selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (NRIs), and antipsychotics (which are dopamine receptor antagonists or partial agonists). Cannabinoids, for instance those found in cannabis, have also been associated with motivational deficits.
== Types of motivation-enhancing drugs ==
=== Dopaminergic agents ===
Dopaminergic agents that have been found to produce pro-motivational effects in animals and/or humans include the following:
Dopamine reuptake inhibitors (DRIs) like bupropion, CE-123, CE-158, CT-005404, JJC8-088, JJC8-089, methylphenidate, (S)-MK-26, modafinil, MRZ-9547 ((R)-phenylpiracetam), nomifensine, PRX-14040, pyrovalerone, RDS03-94, and vanoxerine (GBR-12909)
Dopamine releasing agents (DRAs) like amphetamine and lisdexamfetamine
Dopamine D1 receptor agonists like razpipadon
Dopamine precursors like levodopa (L-DOPA)
Catecholaminergic activity enhancers (CAEs) like selegiline, PPAP, and BPAP
==== Other dopaminergic agents ====
Dopamine D2-like receptor agonists, including pramipexole, ropinirole, rotigotine, piribedil, bromocriptine, cabergoline, pergolide, and lisuride, have also been used to treat disorders of diminished motivation in humans. The clinical data on these agents for this use is very limited, but therapeutic successes have been reported. D2-like receptor agonists are known to have sedative-like and non-rewarding effects in humans. In any case, dopamine D2-like receptor antagonists, like haloperidol and other antipsychotics, are known to produce anti-motivational effects in animals and humans. Bromocriptine has been reported to improve anergia and motivation in humans in very limited clinical reports. On the other hand, pergolide failed to show pro-motivational effects in animals.
Other dopaminergic drugs that have been used or suggested in the treatment of disorders of diminished motivation include rasagiline (a selective monoamine oxidase B (MAO-B) inhibitor; but see more below), tolcapone (a centrally-acting catechol-O-methyltransferase (COMT) inhibitor), and amantadine (an indirectly acting dopaminergic agent that acts via unknown mechanisms). Tolcapone, the only marketed COMT inhibitor that is centrally acting (as opposed to peripherally selective), shows antidepressant- and anti-anhedonia-like effects, stimulates exploratory behavior, and enhances the locomotor hyperactivity induced by psychostimulants like amphetamine and nomifensine in animals. Amantadine is widely used to treat multiple sclerosis-related fatigue, among other fatigue- and motivation-related disorders, and is recommended by the United Kingdom National Institute for Health and Care Excellence (NICE) guidelines for this use, although clinical data are limited.
==== Mechanistic aspects of specific dopaminergic agents ====
Dopamine levels and signaling in the nucleus accumbens, part of the ventral striatum and the mesolimbic reward pathway, are thought to play a key role in mediating behavioral activation and motivation. Dopamine releasing agents like dextroamphetamine are able to rapidly increase striatal dopamine levels by 700 to 1,500% of baseline in rodents. These drugs show greater magnitudes of impact on dopamine levels than do dopamine reuptake inhibitors like methylphenidate. In addition, whereas dopamine reuptake inhibitors show a clear dose–effect ceiling in their effects on dopamine levels, dopamine releasing agents do not and have been found to maximally increase dopamine levels by more than 5,000%. Atypical dopamine reuptake inhibitors like modafinil can also increase dopamine levels in the striatum and nucleus accumbens in animals, but have further reduced impacts on dopamine levels compared to psychostimulants like amphetamine and methylphenidate.
==== Limitations of specific dopaminergic agents ====
A limitation of certain dopaminergic medications used to improve motivation, like psychostimulants, is development of tolerance to their effects. Rapid acute tolerance to amphetamines is believed to be responsible for the dissociation between their relatively short durations of action (~4 hours for main desired effects) and their much longer elimination half-lives (~10 hours) and durations in the body (~2 days). It appears that continually increasing or ascending concentration–time curves are beneficial for prolonging effects, which has resulted in administration multiple times per day and development of delayed- and extended-release formulations. Drug holidays and breaks can be helpful in resetting tolerance.
Another possible limitation of amphetamine specifically is dopaminergic neurotoxicity, which might occur even at therapeutic doses.
A limitation of bupropion as a dopaminergic agent is that it achieves very limited clinical occupancy of the dopamine transporter (DAT).
=== Adenosinergic agents ===
Adenosine receptor antagonists, including caffeine, istradefylline (KW-6002), Lu AA47070, MSX-3, MSX-4, preladenant (SCH-420814), and theophylline, have shown pro-motivational effects in animals and humans. Caffeine and theophylline act as non-selective antagonists of the adenosine receptors (including A1, A2A, A2B, and A3). Conversely, agents like istradefylline and preladenant are selective adenosine A2A receptor antagonists. Adenosine A2A receptor antagonists, including the non-selective antagonists like caffeine, show pro-motivational effects in animals, whereas selective adenosine A1 receptor antagonists, like DPCPX and CPX, do not. Adenosine A2A receptor antagonists appear to exert their pro-motivational effects in the nucleus accumbens core and can reverse the anti-motivational effects of dopamine D2 receptor antagonists like haloperidol in animals. Istradefylline is approved in the treatment of Parkinson's disease and has been found to improve symptoms of apathy, anhedonia, and depression in people with the condition.
=== Cholinergic agents ===
Acetylcholinesterase inhibitors, like donepezil, rivastigmine, and galantamine, have been used in the treatment of disorders of diminished motivation. These drugs inhibit acetylcholinesterase, which metabolizes the neurotransmitter acetylcholine, thereby increasing acetylcholine levels in the brain and augmenting activation of the muscarinic acetylcholine and nicotinic acetylcholine receptors. They are approved and used in the treatment of Alzheimer's disease and provide modest cognitive improvements in people with the disease. Although acetylcholinesterase inhibitors have been used to treat disorders of diminished motivation, the muscarinic acetylcholine receptor agonist pilocarpine has actually shown anti-motivational effects in animals that can be reversed by the muscarinic acetylcholine receptor antagonist scopolamine. In addition, xanomeline, a muscarinic acetylcholine M1 and M4 receptor agonist, shows indirect antidopaminergic effects in the mesolimbic pathway in animals and, in combination with trospium, is approved as an antipsychotic in the treatment of schizophrenia. Furthermore, scopolamine has been found to reverse the anti-motivational effects of the dopamine D2 receptor antagonist haloperidol in animals. In any case, in spite of the preceding findings, acetylcholinesterase inhibitors have been found to be clinically effective, albeit modestly, for apathy in dementia and Parkinson's disease.
=== Other agents ===
Serotonin 5-HT2C receptor antagonists, such as SB-242084, show pro-motivational effects in animals. In addition, SB-242084 has shown modest stimulant-like and reinforcing effects in monkeys. In accordance with the preceding, serotonin 5-HT2C receptor antagonists like SB-242084 and SB-206553 have been found to increase dopamine levels in the nucleus accumbens.
Agomelatine is a potent melatonin MT1 and MT2 receptor agonist and weak serotonin 5-HT2B and 5-HT2C receptor antagonist that is marketed as an antidepressant. It has been found to increase norepinephrine and dopamine levels in the frontal cortex in rodents, though notably not in the striatum or nucleus accumbens (in contrast to other serotonin 5-HT2C receptor antagonists), and for this reason has sometimes been described as a "norepinephrine–dopamine disinhibitor" ("NDDI"). Due to its indirect dopaminergic effects, the drug has been suggested as a possible treatment for disorders of diminished motivation like anhedonia and abulia. It has been found to be effective in the treatment of apathy in people with dementia and was reported to reverse escitalopram-associated apathy in a case report.
The GPR139 agonist zelatriazin (TAK-041; NBI-1065846) has shown pro-motivational effects in animals. On the basis of these findings, it has been speculated that the drug might be useful in the treatment of apathy in humans. Zelatriazin was under development for the treatment of anhedonia in major depressive disorder and the negative symptoms of schizophrenia and reached phase 3 clinical trials. However, its development was discontinued due to lack of clinical effectiveness.
The tumor necrosis factor α (TNF-α) monoclonal antibody infliximab has been found to increase motivation in people with depression with high inflammation (as measured by high C-reactive protein levels). It has also been found to reduce symptoms of depression and anhedonia, for instance in people with high inflammation.
The DOx serotonergic psychedelic 2,5-dimethoxy-4-propylamphetamine (DOPR), which acts as an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors, has shown pro-motivational effects in rodents at sub-hallucinogenic doses or so-called "microdoses". DOPR's close analogue 2,5-dimethoxy-4-ethylamphetamine (DOET) has also been clinically studied at sub-hallucinogenic doses as a "psychic energizer". The non-hallucinogenic 4C analogue Ariadne (4C-DOM) has indirect dopaminergic effects in rodents and pro-motivational effects in monkeys as well. ASR-2001 (2CB-5PrO), a non-hallucinogenic TWEETIO analogue of the related 2C serotonergic psychedelic 2C-B, is under development for use as a stimulant-like medication for the treatment of psychiatric disorders.
=== Ineffective agents ===
==== Serotonergic and noradrenergic agents ====
Selective serotonin reuptake inhibitors (SSRIs) like escitalopram and norepinephrine reuptake inhibitors (NRIs) like atomoxetine have been used and recommended in the treatment of disorders of diminished motivation. However, SSRIs like fluoxetine and citalopram, NRIs like desipramine and atomoxetine, and MAO-A-inhibiting monoamine oxidase inhibitors (MAOIs) like moclobemide and pargyline, have all not shown pro-motivational effects in animals. In fact, these drugs can produce further motivational deficits in animals. Serotonergic antidepressants like SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs) have also been implicated in inducing apathy and emotional blunting in humans. Activation of the serotonin 5-HT2C receptor by serotonergic agents like SSRIs may contribute to or mediate their anti-motivational effects, whereas co-administration of serotonin 5-HT2C receptor antagonists may reverse the effects.
==== Selective MAO-B inhibitors ====
In contrast to selegiline, selective MAO-B inhibitors without concomitant catecholaminergic activity enhancer (CAE) actions, like rasagiline, SU-11739, and lazabemide, are poorly effective in reversing behavioral deficits induced by the dopamine depleting agent tetrabenazine in animals.
==== Dopamine receptor antagonists and partial agonists ====
Antipsychotics, which classically act as dopamine receptor antagonists (mostly of the D2-like receptors), are well-known as having robust and dose-dependent anti-motivational effects. In fact, these effects may play a key role in their effectiveness against the positive and psychotic symptoms of schizophrenia by blunting the emotions underlying delusions.
A novel class of antipsychotics, sometimes referred to as third-generation antipsychotics, act as dopamine D2-like receptor partial agonists instead of as pure antagonists, and hence have mixed agonistic and antagonistic effects. These drugs include aripiprazole, brexpiprazole, and cariprazine. Aripiprazole has been suggested, at low doses, as a possible treatment for disorders of diminished motivation. However, aripiprazole and cariprazine showed anti-motivational effects in animals and failed to reverse the motivational deficits induced by the dopamine depleting agent tetrabenazine. Accordingly, aripiprazole reduced activation of the mesolimbic motivational pathway in humans similarly to but less robustly than haloperidol. On the other hand, another study found that aripiprazole reversed stress-induced motivational anhedonia in animals, an antidepressant-like effect. Different dopamine receptor partial agonists that are used in the treatment of schizophrenia are known to vary in their intrinsic activities at the dopamine receptors, so each drug may be expected to have a different profile of effects.
==== Certain atypical dopamine reuptake inhibitors ====
Some atypical DRIs, like JJC8-091, in contrast to other DRIs, are not effective in producing pro-motivational effects in animals. This has been attributed to binding to an occluded conformation of the dopamine transporter (DAT) that results in a diminished increase in dopamine levels.
== See also ==
Tetrabenazine § Animal model of motivational dysfunction
Conditioned avoidance response test § Test of other drug effects
== References == | Wikipedia/Motivation-enhancing_drug |
Pharmacotherapy, also known as pharmacological therapy or drug therapy, is defined as medical treatment that utilizes one or more pharmaceutical drugs to improve ongoing symptoms (symptomatic relief), treat the underlying condition, or act as a prevention for other diseases (prophylaxis).
It can be distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement (physical therapy), or other modes. Among physicians, sometimes the term medical therapy refers specifically to pharmacotherapy as opposed to surgical or other therapy; for example, in oncology, medical oncology is thus distinguished from surgical oncology.
Today's pharmacological therapy has evolved from a long history of medication use, and it has changed most rapidly in the last century due to advancements in drug discovery. The therapy is administered and adjusted by healthcare professionals according to the evidence-based guidelines and the patient's health condition. Personalized medicine also plays a crucial role in pharmacological therapy. Personalized medicine, or precision medicine, takes account of the patient's genetic variation, liver function, kidney function, etc, to provide a tailor-made treatment for a patient. In pharmacological therapy, pharmacists will also consider medication compliance. Medication compliance, or medication adherence, is defined as the degree to which the patient follows the therapy that is recommended by the healthcare professionals.
== History ==
=== From natural compounds to pharmaceutical drugs ===
The use of medicinal substances can be traced back to 4000 BC in the Sumer civilization. Healers at the time (called apothecaries), for example, understood the application of opium for pain relief. The history of natural remedies can also be found in other cultures, including traditional Chinese medicine in China and Ayurvedic medicine in India, which are still in use nowadays. Dioscorides, a 1st -century Greek surgeon, described more than six hundred animals, plants, and their derivatives in his medical botany, which remained the most influential pharmacopeia for fourteen hundred years. Besides substances derived from living organisms, metals, including copper, mercury, and antimony, were also used as medical therapies. They were said to cure various diseases during the late Renaissance. In 1657, tartar emetic, which is an antimony compound, was credited with curing Louis XIV of typhoid fever. The drug was also administered intravenously for the treatment of schistosomiasis in the 20th century. However, due to the concern over acute and chronic antimony poisoning, the role of tartar emetic as an antischistosomal agent was gradually replaced after the advent of praziquantel.
Other than using natural products, humans also learned to compound medicine by themselves. The first pharmaceutical text was found on clay tablets from the Mesopotamians, who lived around 2100 BC. Later in the 2nd century AD, compounding was formally introduced by Galen as “a process of mixing two or more medicines to meet the individual needs of a patient”. Initially, compounding was only done by individual pharmacists, but in the post-World War II period, pharmaceutical manufacturers surged in number and took over the role of making medicine. Meanwhile, there was a marked increase in pharmaceutical research, which led to a growing number of new drugs. Most drug discovery milestones were made in the last hundred years, from antibiotics to biologics, contributing to the foundation of current pharmacological therapy.
=== Drug discovery ===
Most drugs were discovered by empirical means, including observation, accident, and trial and error. One famous example is the discovery of penicillin, the first antibiotic in the world. The substance was discovered by Alexander Fleming in 1928 after a combination of unanticipated events occurred in his laboratory during his summer vacation. The Penicillium mold on the petri dish was believed to secrete a substance (later named "penicillin") that inhibited bacterial growth. Large pharmaceutical companies then started to establish their microbiological departments and search for new antibiotics. The screening program for antimicrobial compounds also led to the discovery of drugs with other pharmacological properties, such as immunosuppressants like Cyclosporin A.The discovery of penicillin was a serendipitous (i.e. chance) discovery. Another, more advanced approach to drug discovery is rational drug design. The method is underpinned by an understanding of the biological targets of the drugs, including enzymes, receptors, and other proteins. In the late 19th century, Paul Ehrlich observed the selective affinity of dyes for different tissues and proposed the existence of chemoreceptors in our bodies. Receptors were believed to be the specific binding sites for drugs. The drug-receptor recognition was described as a key-and-lock interplay by Emil Fischer in the early 1890s. It was later found that the receptors can either be stimulated or inhibited by chemotherapeutic agents to attain the desired physiological response. Once the ligand interacting with the target macromolecule is identified, drug candidates can be designed and optimized based on the structure-activity relationship. Nowadays, artificial intelligence is employed in drug design to predict drug-protein interactions, drug activity, the 3D configuration of proteins, etc.
== Evidence-based medicine ==
Evidence-based medicine is defined as deploying the best current scientific evidence that is available to give the best treatment and make the best decision effectively and efficiently. Clinical guidelines are developed based on scientific evidence; for example, the ACC/AHA guidelines (for cardiovascular diseases), the GOLD guidelines (for chronic obstructive pulmonary disease), the GINA guidelines (for asthma), etc. They convert and classify the evidence using a systematic method, aiming to provide care with quality. The guidelines cannot substitute clinical judgment, as they cannot meet all the circumstances. Healthcare professionals can use the clinical guidelines as references or evidence to support their clinical judgement when prescribing therapy to patients.
Example: Clinical Guideline for controlling blood pressure (hypertension)
If there is an Asian male patient who is 40 years old and has recently been diagnosed with high blood pressure (with a blood pressure of 140/90) and without any other chronic diseases (comorbidities), such as type-2 diabetes, gout, benign prostatic hyperplasia, etc. His estimated 10-year risk of cardiovascular disease is 15%.
According to the NICE 2019 Hypertension guideline, the healthcare professional can consider starting anti-hypertensive therapy after a discussion with the patient. The first-line therapy will be either an Angiotensin Converting Enzyme Inhibitor (ACEi) or an Angiotensin receptor blocker (ARB) (if the patient cannot tolerate ACEi). If the blood pressure of the patient is not well controlled, the healthcare professionals can consider adding a calcium channel blocker (CCB) or a Thiazide-like diuretic to the previous therapy, i,e, ACEi or ARBs with a CCB or a thiazide-like diuretic.
== Personalized medicine ==
Every patient has their own body condition, for example, kidney function, liver function, genetic variations, medical history, etc. These are all the factors that should be considered by healthcare professionals before giving any pharmacological therapy. Most importantly, the advancing technology in genetics guides us to have more insight into the linkage between health and genes. In pharmacological therapy, two areas of study are evolving: pharmacogenetics and pharmacogenomics. Age will affect the pharmacokinetics and pharmacodynamics of drugs, and hence the efficacy of the therapy. The effect of age causes deterioration of organ function, like liver function and kidney function. Pharmacokinetics is the study of drugs' effects on absorption, distribution, metabolism, and elimination. Pharmacodynamics is the study of drugs' effects on our body and their mechanisms.
=== Pharmacogenetics and pharmacogenomics ===
Pharmacogenetics is defined as the study of inherited genes causing different drug metabolisms that vary from each other, such as the rate of metabolism and metabolites. Pharmacogenomics is defined as the study of associating the drug response with one's gene. Both terms are similar in nature, so they are used interchangeably.
Multiple alleles can contribute together to a change in response to a drug by expressing a different form of an enzyme that responds differently than the normal ones. The different forms of enzymes (phenotypes) include ultra-rapid metabolizers, moderate metabolizers, no-enzyme activity, etc. The genetic variations can also be used to match the particular adverse drug reaction in order to prevent the patient from suffering the unfavorable outcomes. The genetic make-up can affect the pharmacokinetics.
=== Example: Azathioprine Therapy ===
Azathioprine is an immunomodulator for inflammatory bowel disease, for instance. Its metabolite relies on two different enzymes (TPMT and NUDT15) to eliminate its effect on our body during its metabolism. If the patient has the phenotype of the enzymes that metabolize it poorly, i.e., the poor metabolizer, more toxic metabolites are accumulated in the body. Thus, the patient has a greater risk of the related side-effect. The side effect causes the adjustment of dosage or switching to another drug.
=== Example: Omalizumab Therapy ===
Omalizumab is a humanized monoclonal antibody for the treatment of various allergic diseases, including asthma, urticaria, and allergic rhinitis. It targets the immunoglobulin E (IgE) in human body, which plays an important role in allergic reactions. The efficacy of omalizumab may vary among patients. To identify responders to omalizumab, the level of several biomarkers can be measured, including serum eosinophils, fractional exhaled nitric oxide, and serum IgE. For instance, patients with higher baseline eosinophil counts are likely to respond better to omalizumab therapy.
== Medication compliance ==
Medication compliance is defined as the degree to which the patient follows the therapy that is recommended by healthcare professionals. There are direct and indirect methods to evaluate compliance. Direct method refers to the measurement that the healthcare professionals observed or measure the patient's drug-taking behavior. Indirect method refers to the healthcare professionals do not observe or measure the drug-taking behavior of the patient but use the other source of information to evaluate the compliance.
The direct method includes measurement of drug (or the corresponding metabolite) concentration, while the indirect method includes pill counting and the self-report from the patient. The direct method is more time-consuming, more expensive, more invasive, but it is more accurate. The indirect method has a lower accuracy but is easier to administer to the patient. If the patient fails to comply with treatment, for example, by not taking the medication according to the instructions, it leads to risk and a poor treatment outcome.
=== Example: Tuberculosis treatment ===
For tuberculosis patients, directly observed therapy is still part of the treatment. This is to increase medication compliance. This is to prevent treatment failure, relapse, and transmission in the community. Apart from the traditional direct observed therapy (DOT), there is another method proposed to try increasing medication compliance. Video-observed therapy (VOT) is one of the methods. It has some advantages and disadvantages. It reduces the cost of healthcare and the travel costs for the patient. The downside of the intervention is the need for quality control training as it would be hard to confirm the patient's adherence.
== Role of Pharmacists ==
Pharmacists are experts in pharmacotherapy and are responsible for ensuring the safe, appropriate, and economical use of pharmaceutical drugs. The skills required to function as a pharmacist require knowledge, training and experience in biomedical, pharmaceutical and clinical sciences. Pharmacology is the science that aims to continually improve pharmacotherapy. The pharmaceutical industry and academia use basic science, applied science, and translational science to create new pharmaceutical drugs.
As pharmacotherapy specialists and pharmacists have responsibility for direct patient care, often functioning as a member of a multidisciplinary team, and acting as the primary source of drug-related information for other healthcare professionals. A pharmacotherapy specialist is an individual who is specialized in administering and prescribing medication, and requires extensive academic knowledge in pharmacotherapy.
In the US, a pharmacist can gain Board Certification in the area of pharmacotherapy upon fulfilling eligibility requirements and passing a certification examination. While pharmacists provide valuable information about medications for patients and healthcare professionals, they are not typically considered covered pharmacotherapy providers by insurance companies.
== See also ==
== References == | Wikipedia/Pharmacotherapy |
Cancer treatments are a wide range of treatments available for the many different types of cancer, with each cancer type needing its own specific treatment. Treatments can include surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy including small-molecule drugs or monoclonal antibodies, and PARP inhibitors such as olaparib. Other therapies include hyperthermia, immunotherapy, photodynamic therapy, and stem-cell therapy. Most commonly cancer treatment involves a series of separate therapies such as chemotherapy before surgery. Angiogenesis inhibitors are sometimes used to enhance the effects of immunotherapies.
The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient. Biomarker testing can help to determine the type of cancer, and indicate the best therapy. A number of experimental cancer treatments are continuously under development. In 2023 it was estimated that one in five people will be diagnosed with cancer at some point in their lifetime.
The primary goal of cancer treatment is to either cure the cancer by its complete removal, or to considerably prolong the life of the individual. Palliative care is involved when the prognosis is poor and the cancer termed as terminal. There are many types of cancer, and many of these can be successfully treated if detected early enough.
== Types of treatments ==
The treatment of cancer has undergone evolutionary changes as understanding of the underlying biological processes has increased. Tumor removal surgeries have been documented in ancient Egypt, hormone therapy and radiation therapy were developed in the late 19th century. Chemotherapy, immunotherapy and newer targeted therapies are products of the 20th century. As new information about the biology of good cancer emerges, treatments will be developed and modified to increase effectiveness, precision, survivability, and quality of life.
=== Surgery ===
Malignant tumours can be cured if entirely removed by surgery. But if the cancer has already spread (metastasized) to other sites, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential.
Examples of surgical procedures for cancer include mastectomy, and lumpectomy for breast cancer, prostatectomy for prostate cancer, and lung cancer surgery for non-small cell lung cancer. The goal of the surgery can be either the removal of only the tumor, the entire organ, or part of the organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.
In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy. Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.
Surgery may be performed before or after other forms of treatment. Treatment before surgery is often described as neoadjuvant. In breast cancer, the survival rate of patients who receive neoadjuvant chemotherapy are no different from those who are treated following surgery. Giving chemotherapy earlier allows oncologists to evaluate the effectiveness of the therapy, and may make removal of the tumor easier. However, the survival advantages of neoadjuvant treatment in lung cancer are less clear.
=== Radiation therapy ===
Radiation therapy (radiotherapy) is the use of ionizing radiation to kill cancer cells and shrink tumors by damaging their DNA causing cellular death. Radiation therapy can either damage DNA directly or create charged particles (free radicals) within the cells that can in turn damage the DNA. Radiation therapy can be administered externally via external beam radiotherapy or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.
Radiation therapy may be used to treat almost every type of solid tumor, and may also be used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radio sensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.
Radiation therapy can lead to dry mouth from exposure of salivary glands to radiation, resulting in decreased saliva secretion. Post therapy, the salivary glands will resume functioning but rarely in the same fashion. Dry mouth caused by radiation can be a permanent problem.
=== Chemotherapy ===
Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. Chemotherapy can be given in a variety of ways such as injections into the muscles, skin, artery, or vein, or it could even be taken by mouth in the form of a pill. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.
Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.
Since chemotherapy affects the whole body, it can have a wide range of side effects. Patients often find that they start losing their hair since the drugs that are combatting the cancer cells also attack the cells in the hair roots. This powerful treatment can also lead to fatigue, loss of appetite, and vomiting depending on the person.
The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation.
=== Targeted therapies ===
Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule drugs are targeted therapy drugs that are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib (Gleevec/Glivec) and gefitinib (Iressa).
Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.
Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.
Photodynamic therapy (PDT) is a ternary treatment for cancer involving a photosensitizer, tissue oxygen, and light (often using lasers). PDT can be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT can also be useful in removing traces of malignant tissue after surgical removal of large tumors. In February 2019, medical scientists announced that iridium attached to albumin, creating a photosensitized molecule, can penetrate cancer cells and, after being irradiated with light, destroy the cancer cells.
High-energy therapeutic ultrasound could increase higher-density anti-cancer drug load and nanomedicines to target tumor sites by 20x fold higher than traditional target cancer therapy.
Targeted therapies under pre-clinical development as potential cancer treatments include morpholino splice switching oligonucleotides, which induce ERG exon skipping in prostate cancer models, multitargeted kinase inhibitors that inhibit the PI3K with other pathways including MEK and PIM, and inhibitors of NF-κB in models of chemotherapy resistance.
A systematic review published in Cochrane database found that targeted therapies significantly improve progression-free survival by 35 to 40% in metastatic or relapsed cancer. While the research points to promising clinical outcomes, there is still limited evidence on the long-term effects of targeted therapies in terms of overall survival, quality of life, and severe adverse events.
=== Immunotherapy ===
Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Cancer vaccines to generate specific immune responses are the subject of intensive research for a number of tumors, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells. It gained FDA approval in 2010.
Allogeneic hematopoietic stem cell transplantation (usually from the bone marrow) from a genetically non-identical donor can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.
The cell based immunotherapy in which the patients own natural killer cells (NKs) and cytotoxic T cells are used has been in practice in Japan since 1990. NK cells and TCs primarily kill the cancer cells when they are developed. This treatment is given together with the other modes of treatment such as surgery, radiotherapy or chemotherapy and termed autologous immune enhancement therapy (AIET).
Immune checkpoint therapy focuses on two immune checkpoint proteins, cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Under normal conditions, the immune system utilizes checkpoint proteins as negative feedback mechanisms to return to homeostasis once pathogens have been cleared from the body. In a tumor microenvironment, cancer cells can commandeer this physiological regulatory system to "put a brake" on the anti-cancer immune response and evade immune surveillance. 2018 Nobel Prize in medicine is awarded to Dr. James Allison of University of Texas MD Anderson Cancer Center in U.S. and Dr. Tasuku Honjo Kyoto University in Japan for their contributions in advance of PD-1 and CTLA-4 immune checkpoint therapy.
=== Hormonal therapy ===
The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. Although the side effects from hormone therapy vary depending on the type, patients can experience symptoms such as hot flashes, nausea, and fatigue.
=== Angiogenesis inhibitors ===
Angiogenesis inhibitors prevent the extensive growth of blood vessels (angiogenesis) that tumors need to survive and grow. Continued growth allows the invasion of cells into neighbouring tissues, and metastasis into distal tissues. There are many approved angiogenesis inhibitors including bevacizumab, axitinib, and cabozantinib.
Flavonoids have been shown to downregulate the angiogenic stimulation of VEGF and Hypoxia-inducible factor (HIF) but none have reached clinical trials.
=== Exercise prescription ===
Exercise prescription is becoming a mainstream adjunct treatment for cancer, based on studies which show that exercise (compared to no exercise) is associated with reduced recurrence rates, improved mortality outcomes, reduction of side effects from traditional cancer treatments. Although it is uncertain whether improved outcomes with exercise are correlated or causative, the benefit-risk ratio of including exercise as part of cancer treatment is large, as exercise has further benefits (e.g. cardiovascular, mental health) without major risks, although there is a small risk of overuse injury if added too aggressively. Exercise physiologists and exercise medicine specialists can assist oncologists and primary care practitioners with exercise prescription in cancer patients.
=== Synthetic lethality ===
Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutations, epigenetic alterations or inhibitors of one or both of the genes.
Cancer cells are frequently deficient in a DNA repair gene. (Also see DNA repair deficiency in cancer.) This DNA repair defect either may be due to mutation or, often, epigenetic silencing (see epigenetic silencing of DNA repair). If this DNA repair defect is in one of seven DNA repair pathways (see DNA repair pathways), and a compensating DNA repair pathway is inhibited, then the tumor cells may be killed by synthetic lethality. Non-tumorous cells, with the initial pathway intact, can survive.
==== Ovarian cancer ====
Mutations in DNA repair genes BRCA1 or BRCA2 (active in homologous recombinational repair) are synthetically lethal with inhibition of DNA repair gene PARP1 (active in the base excision repair and in the microhomology-mediated end joining pathways of DNA repair).
Ovarian cancers have a mutational defect in BRCA1 in about 18% of patients (13% germline mutations and 5% somatic mutations) (see BRCA1). Olaparib, a PARP inhibitor, was approved in 2014 by the US FDA for use in BRCA-associated ovarian cancer that had previously been treated with chemotherapy. The FDA, in 2016, also approved the PARP inhibitor rucaparib to treat women with advanced ovarian cancer who have already been treated with at least two chemotherapies and have a BRCA1 or BRCA2 gene mutation.
==== Colon cancer ====
In colon cancer, epigenetic defects in the WRN gene appear to be synthetically lethal with inactivation of TOP1. In particular, irinotecan inactivation of TOP1 was synthetically lethal with deficient expression of the DNA repair WRN gene in patients with colon cancer. In a 2006 study, 45 patients had colonic tumors with hypermethylated WRN gene promoters (silenced WRN expression), and 43 patients had tumors with unmethylated WRN gene promoters, so that WRN protein expression was high. Irinotecan was more strongly beneficial for patients with hypermethylated WRN promoters (39.4 months survival) than for those with unmethylated WRN promoters (20.7 months survival). The WRN gene promoter is hypermethylated in about 38% of colorectal cancers.
There are five different stages of colon cancer, and these five stages all have treatment:
Stage 0, is where the patient is required to undergo surgery to remove the polyp (American Cancer Society).
Stage 1, depending on the location of the cancer in the colon and lymph nodes, the patient undergoes surgery just like Stage 0.
Stage 2 patients undergoes removing nearby lymph nodes, but depending on what the doctor says, the patent might have to undergo chemotherapy after surgery (if the cancer is at higher risk of coming back).
Stage 3, is where the cancer has spread all throughout the lymph nodes but not yet to other organs or body parts. When getting to this stage, Surgery is conducted on the colon and lymph nodes, then the doctor orders Chemotherapy (FOLFOX or CapeOx) to treat the colon cancer in the location needed (American Cancer Society). The last a patient can get is Stage 4.
Stage 4 patients only undergo surgery if it is for the prevention of the cancer, along with pain relief. If the pain continues with these two options, the doctor might recommended radiation therapy. The main treatment strategy is chemotherapy due to how aggressive the cancer becomes in this stage, not only to the colon but to the lymph nodes.
== Symptom control and palliative care ==
Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. In general, doctors have the therapeutic skills to reduce pain including, chemotherapy-induced nausea and vomiting, diarrhea, hemorrhage and other common problems in cancer patients. The multidisciplinary specialty of palliative care has increased specifically in response to the symptom control needs for these groups of patients.
Pain medication, such as morphine, oxycodone, and antiemetics are drugs to suppress nausea and vomiting. These are very commonly used in patients with cancer-related symptoms. Improved antiemetics such as ondansetron and analogues, as well as aprepitant have made aggressive treatments much more feasible in cancer patients.
Cancer pain can be associated with continuing tissue damage due to the disease process, or the treatment (i.e. surgery, radiation, chemotherapy). There is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, However these are not usually the predominant etiologic factors in patients with cancer pain. Some patients with severe pain associated with cancer are nearing the end of their lives, but in all cases, palliative therapies should be used to control the pain. Issues such as the social stigma of using opioids and health care consumption can be concerns and may need to be addressed for the person to feel comfortable taking the medications required to control his or her symptoms. The typical strategy for cancer pain management is to get the patient as comfortable as possible using the least amount of medications possible, even if that means using opioids, surgery, and physical measures.
Historically, doctors were reluctant to prescribe narcotics to terminal cancer patients due to addiction and respiratory function suppression. The palliative care movement, a more recent offshoot of the hospice movement, has engendered more widespread support for preemptive pain treatment for cancer patients. The World Health Organization also noted uncontrolled cancer pain as a worldwide problem and established a "ladder" as a guideline for how practitioners should treat pain in patients who have cancer
Cancer-related fatigue is a very common symptom of cancer, and there are a number of approaches put forward for helping with this.
=== Mental struggles/pain ===
Cancer patients undergo many obstacles and one of these includes mental strain. It is very common for cancer patients to become stressed, overwhelmed, uncertain, and even depressed. The use of chemo is a very harsh treatment causing the cells of the body to die. Physical effects like this do not only inflict pain but also cause patients to become mentally exhausted and want to give up. For a lot of reasons including these, hospitals offer many types of therapy and mental healing. Some of these include yoga, meditation, communication therapy, and spiritual ideas. All of these are meant to calm and relax the mind, or to give hope for the patients that may feel drained.
=== Insomnia ===
A common disorder experienced by people that have survived cancer treatments is insomnia. Almost 60% of cancer survivors experience insomnia, and if it is not treated properly it can have long term effects on physiological and physical health. Insomnia is defined as dissatisfaction with sleep duration or quality and difficulties initiating or maintaining sleep. Insomnia can heavily reduce one's quality of life. Cognitive behavioral therapy has been seen to reduce insomnia and depression for cancer survivors.
=== Muscle strength ===
Decreased muscle strength is a common side effect to many different cancer treatments. Because of this, exercise is very important especially in the first year after treatment. It has been shown that yoga, water exercise, and pilates can improve the emotional well-being and quality of life of breast cancer survivors.
=== Fatigue ===
Fatigue is an unrelenting feeling of physical and mental tiredness that cannot be traced back to activity levels. It is a very common experience in cancer survivors, with most patients reporting some level of fatigue before, during, and after treatment. The cause of the fatigue can be due to the cancer itself, but frequently it is medical interventions to treat the cancer – like chemotherapy, radiation, surgery, and hormone therapy – that cause the feelings of extreme tiredness. The exact processes behind cancer-related fatigue are unknown. However, evidence suggests that biological processes like inflammation and stress hormone disruption may play a role. In addition, pre-existing risk factors like a genetic predisposition, sleeping troubles, a pre-existing mood disorder, adverse childhood experiences, and low levels of physical activity are associated with increased levels of cancer-related fatigue.
Treatment options for cancer-related fatigue can be pharmacological or non-pharmacological. Medications like erythropoietin, stimulants, and antidepressants can be prescribed, but their efficacy is modest. Thus, non-pharmacological interventions are the preferred treatment for cancer-related fatigue. Aerobic exercise and psychosocial interventions like cognitive behavioral therapy and mindfulness show promise in reducing feelings of fatigue in cancer patients.
=== Hospice care ===
Hospice care provides palliative care at home, or in a dedicated hospice institution, for a person with an advanced illness termed as terminal. Untreated cancer will prove terminal, and sometimes a choice is made to forgo treatment and its unpleasant side effects, and opt instead for hospice care. Hospice care aims to provide support for the person's medical, emotional, social, practical, psychological, and spiritual needs.
Advance care planning (ACP) can help a person to decide for themself their future care wishes as they approach end of life. ACP helps adults at any stage of health to decide, and record in writing, their wishes for medical treatment preferences, and future wants, preferably as previously discussed with relatives or carers.
== Research ==
Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.
A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.
Patients who take part may be helped personally by the treatment they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. At the same time, new treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit. There is no guarantee that a new treatment being tested or a standard treatment will produce good results. In children with cancer, a survey of trials found that those enrolled in trials were on average not more likely to do better or worse than those on standard treatment; this confirms that success or failure of an experimental treatment cannot be predicted.
=== Exosome research ===
Exosomes are lipid-covered microvesicles shed by solid tumors into bodily fluids, such as blood and urine. Current research is being done attempting to use exosomes as a detection and monitoring method for a variety of cancers. The hope is to be able to detect cancer with a high sensitivity and specificity via detection of specific exosomes in the blood or urine. The same process can also be used to more accurately monitor a patient's treatment progress. Enzyme linked lectin specific assay or ELLSA Archived 13 July 2011 at the Wayback Machine has been proven to directly detect melanoma derived exosomes from fluid samples. Previously, exosomes had been measured by total protein content in purified samples and by indirect immunomodulatory effects. ELLSA directly measures exosome particles in complex solutions, and has already been found capable of detecting exosomes from other sources, including ovarian cancer and tuberculosis-infected macrophages.
Exosomes, secreted by tumors, are also believed to be responsible for triggering programmed cell death (apoptosis) of immune cells; interrupting T-cell signaling required to mount an immune response; inhibiting the production of anti-cancer cytokines, and has implications in the spread of metastasis and allowing for angiogenesis. Studies are currently being done with "Lectin affinity plasmapheresis" (LAP), LAP is a blood filtration method which selectively targets the tumor based exosomes and removes them from the bloodstream. It is believed that decreasing the tumor-secreted exosomes in a patient's bloodstream will slow down progression of the cancer while at the same time increasing the patients own immune response.
== Complementary and alternative ==
Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not part of conventional medicine and have not been shown to be effective. "Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine. CAM use is common among people with cancer; a 2000 study found that 69% of cancer patients had used at least one CAM therapy as part of their cancer treatment. Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments which have been investigated and shown to be ineffective continue to be marketed and promoted.
== Special circumstances ==
=== In pregnancy ===
The incidence of pregnancy-associated cancer has risen due to the increasing age of pregnant mothers. Cancers may also be detected incidentally during maternal screening.
Cancer treatment needs to be selected to do least harm to both the woman and her embryo/fetus. In some cases a therapeutic abortion may be recommended.
Radiation therapy is out of the question, and chemotherapy always poses the risk of miscarriage and congenital malformations. Little is known about the effects of medications on the child.
Even if a drug has been tested as not crossing the placenta to reach the child, some cancer forms can harm the placenta and make the drug pass over it anyway. Some forms of skin cancer may even metastasize to the child's body.
Diagnosis is also made more difficult, since computed tomography is infeasible because of its high radiation dose. Still, magnetic resonance imaging works normally. However, contrast media cannot be used, since they cross the placenta.
As a consequence of the difficulties to properly diagnose and treat cancer during pregnancy, the alternative methods are either to perform a Cesarean section when the child is viable in order to begin a more aggressive cancer treatment, or, if the cancer is malignant enough that the mother is unlikely to be able to wait that long, to perform an abortion in order to treat the cancer.
=== In utero ===
Fetal tumors are sometimes diagnosed while still in utero. Teratoma is the most common type of fetal tumor, and usually is benign. In some cases these are surgically treated while the fetus is still in the uterus.
== Society and culture ==
=== Racial and social disparities ===
Cancer is a significant issue that is affecting the world. Specifically in the U.S., 1,735,350 new cases of cancer, and 609,640 deaths were expected by the end of 2018. Adequate treatment can prevent many cancer deaths but there are racial and social disparities in treatments which has a significant factor in high death rates. Minorities are more likely to receive inadequate treatment while white patients are more likely to receive efficient treatments in a timely manner. Having satisfactory treatment in a timely manner can increase the patient's likelihood of survival. It has been shown that chances of survival are significantly greater for white patients than for African American patients.
The annual average mortality of patients with colorectal cancer between 1992 and 2000 was 27 and 18.5 per 100,000 white patients and 35.4 and 25.3 per 100,000 black patients. In a journal that analyzed multiple studies testing racial disparities when treating colorectal cancer found contradicting findings. The US Veterans Administration and an adjuvant trial found that there was no evidence to support racial differences in treating colorectal cancer. However, two studies suggested that African American patients received less satisfactory and poorer quality treatment compared to white patients. One of these studies specifically was provided by the Center for Intramural Research. They found that black patients were 41% less likely to receive colorectal treatment and were more likely to be hospitalized in a teaching hospital with less certified physicians compared to white patients. Furthermore, black patients were more likely to be diagnosed with oncologic sequelae, which is a severity of the illness in result of poorly treated cancer. Lastly, for every 1,000 patients in the hospital, there were 137.4 black patient deaths and 95.6 white patient deaths.
An article in a breast cancer journal analyzed the disparities of breast cancer treatments in the Appalachian Mountains. African American women were found to be three times more likely to die compared to Asians and two times more likely to die compared to white women. According to the study, African American women are at a survival disadvantage compared to other races. Black women are also more likely to receive less successful treatment than white women by not receiving surgery or therapy. Furthermore, the US National Cancer Institute panel identified breast cancer treatments, given to black women, as inappropriate and not adequate compared to the treatment given to white women.
From these studies, researchers have noted that there are definite disparities in the treatment of cancer, specifically who has access to the best treatment and can receive it in a timely manner. This eventually leads to disparities between who dies from cancer and who is more likely to survive.
The cause of these disparities is generally that African Americans have less medical care coverage, insurance and access cancer centers than other races. For an example, black patients with breast cancer and colorectal cancer were shown to be more likely to have Medicaid or no insurance compared to other races. The location of the health care facility also plays a role in why African Americans receive less treatment in comparison to other races. However, some studies say that African Americans do not trust doctors and do not always seek the help they need and that this explains why fewer African Americans receive treatment. Others suggest that African Americans seek more treatment than whites and that it is simply a lack of the resources available to them. In this case, analyzing these studies will identify the treatment disparities and look to prevent them by discovering potential causes of these disparities.
=== Public perception ===
Despite recognition of improvements in outcomes, visceral fear of the disease is ubiquitous, and people may have to struggle to control it.
Among lung cancer patients, stigma, shame, social isolation, and discrimination are common. Such patients are sometimes told that they deserve cancer because of their smoking. Those patients also may have feelings of guilt for having cancer. Stigma in cervical cancer was predominantly driven by fear of social judgment and rejection, self-blame, and shame, with notable negative influences from gender and social norms, as both human papillomavirus infection and cervical cancer were stigmatized due to the perception that they arise from reckless behavior such as having multiple sexual partners or neglecting screening. Resilience may be a potent protective mechanism against stigmatization. Resilience in context of cancer treatment is patient's physiological and psychological capacity to effectively adapt, recover, and maintain optimal functioning in the face of the medical challenges. It encompasses the ability to cope with and overcome adversity, maintain emotional well-being, and promote overall health and healing.
== See also ==
== References ==
== Bibliography ==
"Understanding What Cancer Is: Ancient Times to Present". www.cancer.org.
Chahine S, Urquhart R (October 2019). "A cross-sectional population-based survey looking at the impact of cancer survivorship care plans on meeting the needs of cancer survivors in the posttreatment stage". Supportive Care in Cancer. 27 (10): 3785–3792. doi:10.1007/s00520-019-04685-5. PMID 30721368. S2CID 59604164.
Colby DA, Shifren K (1 January 2013). "Optimism, mental health, and quality of life: A study among breast cancer patients". Psychology, Health & Medicine. 18 (1): 10–20. doi:10.1080/13548506.2012.686619. PMID 22690751. S2CID 205772143.
"How Does Radiation Therapy Work?" American Cancer Society. N.p., n.d. Web. 21 March 2017.
Piazza MF, Galletta M, Portoghese I, Pilia I, Ionta MT, Contu P, Mereu A, Campagna M (August 2017). "Meeting psychosocial and health information needs to ensure quality of cancer care in outpatients". European Journal of Oncology Nursing. 29: 98–105. doi:10.1016/j.ejon.2017.06.001. PMID 28720273.
Northouse LL (1 September 2012). "Helping Patients and Their Family Caregivers Cope With Cancer". Oncology Nursing Forum. 39 (5): 500–506. doi:10.1188/12.ONF.500-506. PMID 22940514. S2CID 21512508.
"Radiation Therapy for Brain Cancer | CTCA." CancerCenter.com. N.p., 1 January 0001. Web. 21 March 2017.
"Radiation Therapy for Cancer." National Cancer Institute. N.p., n.d. Web. 21 March 2017. | Wikipedia/Cancer_treatment |
In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; the terms are equivalent in the literature. Larger structures such as nucleic acids and proteins, and many polysaccharides are not small molecules, although their constituent monomers (ribo- or deoxyribonucleotides, amino acids, and monosaccharides, respectively) are often considered small molecules. Small molecules may be used as research tools to probe biological function as well as leads in the development of new therapeutic agents. Some can inhibit a specific function of a protein or disrupt protein–protein interactions.
Pharmacology usually restricts the term "small molecule" to molecules that bind specific biological macromolecules and act as an effector, altering the activity or function of the target. Small molecules can have a variety of biological functions or applications, serving as cell signaling molecules, drugs in medicine, pesticides in farming, and in many other roles. These compounds can be natural (such as secondary metabolites) or artificial (such as antiviral drugs); they may have a beneficial effect against a disease (such as drugs) or may be detrimental (such as teratogens and carcinogens).
== Molecular weight cutoff ==
The upper molecular-weight limit for a small molecule is approximately 900 daltons, which allows for the possibility to rapidly diffuse across cell membranes so that it can reach intracellular sites of action. This molecular weight cutoff is also a necessary but insufficient condition for oral bioavailability as it allows for transcellular transport through intestinal epithelial cells. In addition to intestinal permeability, the molecule must also possess a reasonably rapid rate of dissolution into water and adequate water solubility and moderate to low first pass metabolism. A somewhat lower molecular weight cutoff of 500 daltons (as part of the "rule of five") has been recommended for oral small molecule drug candidates based on the observation that clinical attrition rates are significantly reduced if the molecular weight is kept below this limit.
== Drugs ==
Most pharmaceuticals are small molecules, although some drugs can be proteins (e.g., insulin and other biologic medical products). With the exception of therapeutic antibodies, many proteins are degraded if administered orally and most often cannot cross cell membranes. Small molecules are more likely to be absorbed, although some of them are only absorbed after oral administration if given as prodrugs. One advantage that small molecule drugs (SMDs) have over "large molecule" biologics is that many small molecules can be taken orally whereas biologics generally require injection or another parenteral administration. Small molecule drugs are also typically simpler to manufacture and cheaper for the purchaser. A downside is that not all targets are amenable to modification with small-molecule drugs; bacteria and cancers are often resistant to their effects.
== Secondary metabolites ==
A variety of organisms including bacteria, fungi, and plants, produce small molecule secondary metabolites also known as natural products, which play a role in cell signaling, pigmentation and in defense against predation. Secondary metabolites are a rich source of biologically active compounds and hence are often used as research tools and leads for drug discovery. Examples of secondary metabolites include:
== Research tools ==
Enzymes and receptors are often activated or inhibited by endogenous protein, but can be also inhibited by endogenous or exogenous small molecule inhibitors or activators, which can bind to the active site or on the allosteric site.
An example is the teratogen and carcinogen phorbol 12-myristate 13-acetate, which is a plant terpene that activates protein kinase C, which promotes cancer, making it a useful investigative tool. There is also interest in creating small molecule artificial transcription factors to regulate gene expression, examples include wrenchnolol (a wrench shaped molecule).
Binding of ligand can be characterised using a variety of analytical techniques such as surface plasmon resonance, microscale thermophoresis or dual polarisation interferometry to quantify the reaction affinities and kinetic properties and also any induced conformational changes.
== Anti-genomic therapeutics ==
Small-molecule anti-genomic therapeutics, or SMAT, refers to a biodefense technology that targets DNA signatures found in many biological warfare agents. SMATs are new, broad-spectrum drugs that unify antibacterial, antiviral and anti-malarial activities into a single therapeutic that offers substantial cost benefits and logistic advantages for physicians and the military.
== See also ==
Pharmacology
Druglikeness
Lipinski's rule of five
Metabolite
Chemogenomics
Neurotransmitter
Peptidomimetic
Macromolecule
== References ==
== External links ==
Small+Molecule+Libraries at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Small-molecule_drug |
Hormonal therapy in oncology is hormone therapy for cancer and is one of the major modalities of medical oncology (pharmacotherapy for cancer), others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous or external administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones (hormone antagonists). Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.
Hormonal therapy is used for several types of cancers derived from hormonally responsive tissues, including the breast, prostate, endometrium, and adrenal cortex. Hormonal therapy may also be used in the treatment of paraneoplastic syndromes or to ameliorate certain cancer- and chemotherapy-associated symptoms, such as anorexia. Perhaps the most familiar example of hormonal therapy in oncology is the use of the selective estrogen-response modulator tamoxifen for the treatment of breast cancer, although another class of hormonal agents, aromatase inhibitors, now have an expanding role in that disease.
== Inhibitors of hormone synthesis ==
One effective strategy for starving tumor cells of growth- and survival-promoting hormones is to use drugs which inhibit the production of those hormones in their organ of origin.
=== Aromatase inhibitors ===
Aromatase inhibitors are an important class of drugs used for the treatment of breast cancer in postmenopausal women. At menopause, estrogen production in the ovaries ceases, but other tissues continue to produce estrogen through the action of the enzyme aromatase on androgens produced by the adrenal glands. When the action of aromatase is blocked, estrogen levels in post-menopausal women can drop to extremely low levels, causing growth arrest and/or apoptosis of hormone-responsive cancer cells.
Letrozole and anastrozole are aromatase inhibitors which have been shown to be superior to tamoxifen for the first-line treatment of breast cancer in postmenopausal women. Exemestane is an irreversible "aromatase inactivator" which is superior to megestrol acetate for treatment of tamoxifen-refractory metastatic breast cancer, and does not appear to have the osteoporosis-promoting side effects of other drugs in this class.
Aminoglutethimide inhibits both aromatase and other enzymes critical for steroid hormone synthesis in the adrenal glands. It was formerly used for breast cancer treatment, but has since been replaced by more selective aromatase inhibitors. It can also be used for the treatment of hyperadrenocortical syndromes, such as Cushing's syndrome and hyperaldosteronism in adrenocortical carcinoma.
=== GnRH analogues ===
Analogs of gonadotropin-releasing hormone (GnRH) can be used to induce a chemical castration, that is, complete suppression of the production of estrogen and progesterone from the female ovaries, or complete suppression of testosterone production from the male testes. This is due to a negative feedback effect of continuous stimulation of the pituitary gland by these hormones. Leuprorelin and goserelin are GnRH analogs which are used primarily for the treatment of hormone-responsive prostate cancer. Because the initial endocrine response to GnRH analogs is actually hypersecretion of gonadal steroids, hormone receptor antagonists such as flutamide are typically used to prevent a transient boost in tumor growth.
== Hormone receptor antagonists ==
Hormone receptor antagonists bind to the normal receptor for a given hormone and prevent its activation. The target receptor may be on the cell surface, as in the case of peptide and glycoprotein hormones, or it may be intracellular, as in the case of steroid hormone receptors.
=== Selective estrogen receptor modulators ===
Selective estrogen receptor modulators (SERMs) are an important class of hormonal therapy agents which act as antagonists of the estrogen receptor and are used primarily for the treatment and chemoprevention of breast cancer. Some members of this family, such as tamoxifen, are actually partial agonists, which can actually increase estrogen receptor signalling in some tissues, such as the endometrium. Tamoxifen is currently first-line treatment for nearly all pre-menopausal women with hormone receptor-positive breast cancer. Raloxifene is another partial agonist SERM which does not seem to promote endometrial cancer, and is used primarily for chemoprevention of breast cancer in high-risk individuals, as well as to prevent osteoporosis. Toremifene and fulvestrant are SERMs with little or no agonist activity, and are used for treatment of metastatic breast cancer.
=== Antiandrogens ===
Antiandrogens are a class of drug which bind and inhibit the androgen receptor, blocking the growth- and survival-promoting effects of testosterone on certain prostate cancers. Flutamide and bicalutamide are antiandrogens which are frequently used in the treatment of prostate cancer, either as long-term monotherapy, or in the initial few weeks of GnRH analog therapy. (See also Androgen deprivation therapy)
== Hormone supplementation ==
While most hormonal therapy strategies seek to block hormone signalling to cancer cells, there are some instances in which supplementation with specific hormone agonists may have a growth-inhibiting, or even cytotoxic effect on tumor cells. Because many hormones can produce antagonism and feedback inhibition of the synthesis of other hormones, there is significant overlap between this concept and those discussed above.
=== Progestogens ===
Progestins (progesterone-like drugs) such as megestrol acetate and medroxyprogesterone acetate have been used for the treatment of hormone-responsive, advanced breast cancer, endometrial cancer, and prostate cancer. Progestins are also used in the treatment of endometrial hyperplasia, a precursor to endometrial adenocarcinoma. The exact mechanism of action of these hormones is unclear, and may involve both direct effect on the tumor cells (suppression of estrogen receptor levels, alteration of hormone metabolism, direct cytotoxicity) and indirect endocrine effects (suppression of adrenal androgen production and plasma estrone sulfate formation).
=== Androgens ===
Fluoxymesterone, an anabolic steroid (testosterone-like) medication, is occasionally used for the treatment of advanced breast cancer. The mechanism of the anticancer effects of this androgen in breast cancer are unclear, but may be analogous to those of progestins.
=== Estrogens ===
The estrogen diethylstilbestrol (DES) is occasionally used to treat prostate cancer through suppression of testosterone production. It was previously used in the treatment of breast cancer, but has been replaced by more effective and less toxic agents. Estrace is an estrogen which was also formerly used for antiandrogen therapy of prostate cancer. Polyestradiol phosphate is a long-acting derivative of estradiol that is applied as an intramuscular injection.
=== Somatostatin analogs ===
Octreotide is an analog of the peptide hormone somatostatin, which inhibits the production of the growth hormone as well as numerous peptide hormones of the gastrointestinal system, including insulin, glucagon, pancreatic polypeptide, gastric inhibitory polypeptide, and gastrin. Octreotide is used for suppression of the hormonal syndromes which accompany several pancreatic islet cell tumors, including the Zollinger-Ellison syndrome of gastrinoma and the chronic hypoglycemia of insulinoma. It is also effective in suppression of the carcinoid syndrome, caused by advanced or extra-gastrointestinal carcinoid tumors. Octreotide may also be used for treatment of severe diarrhea caused by 5-fluorouracil chemotherapy or radiation therapy.
== Non-medical hormonal interventions ==
In addition to the use of medication to produce tumor-suppressing endocrine alterations, destruction of endocrine organs through surgery or radiation therapy are also possible. Surgical castration, or removal of the testes in males and ovaries in females, have been widely used in the past to treat hormone-responsive prostate cancer and breast cancer respectively. However, these invasive methods have been widely supplanted by the use of GnRH agonists, and other forms of pharmacologic castration.
There are still situations in which surgical castration may be beneficial such as in special cases for women with high risk BRCA mutations.
== Hormonal immunotherapy ==
For more information on this topic, see Immunotherapy
Hormonal stimulation of the immune system with interferons and cytokines has been used to treat specific cancers, including renal cell carcinoma and melanoma.
== See also ==
List of hormonal cytostatic antineoplastic agents
Antiestrogen withdrawal response
Endocrine therapy resistance in breast cancer
== References == | Wikipedia/Hormonal_therapy_(oncology) |
Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches use three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout uses RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths. In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.
== History ==
Chester M. Southam, a researcher at Memorial Sloan Kettering Cancer Center, pioneered the study of viruses as potential agents to treat cancer.
== Oncolytic virotherapy ==
Oncolytic virotherapy is not a new idea – as early as the mid 1950s doctors were noticing that cancer patients who suffered a non-related viral infection, or who had been vaccinated recently, showed signs of improvement; this has been largely attributed to the production of interferon and tumour necrosis factors in response to viral infection, but oncolytic viruses are being designed that selectively target and lyse only cancerous cells.
In the 1940s and 1950s, studies were conducted in animal models to evaluate the use of viruses in the treatment of tumours. In the 1940s–1950s some of the earliest human clinical trials with oncolytic viruses were started.
=== Mechanism ===
It is believed that oncolytic virus achieve their goals by two mechanisms: selective killing of tumor cells as well as recruitment of host immune system. One of the major challenges in cancer treatment is finding treatments that target tumor cells while ignoring non-cancerous host cells. Viruses are chosen because they can target specific receptors expressed by cancer cells that allow for virus entry. One example of this is the targeting of CD46 on multiple myeloma cells by measles virus. The expression of these receptors are often increased in tumor cells. Viruses can also be engineered to target specific receptors on tumor cells as well. Once viruses have entered the tumor cell, the rapid growth and division of tumor cells as well as decreased ability of tumor cells to fight off viruses make them advantageous for viral replication compared to non-tumorous cells. The replication of viruses in tumor cells causes tumor cells to lyse killing them and also release signal to activate the host's own immune system, overcoming immunosuppression. This is done through the disruption of the microenvironment of the tumor cells that prevents recognition by host immune cells. Tumor antigens and danger-associated molecular patterns are also released during the lysis process which helps recruit host immune cells. Currently, there are many viruses being used and tested, all differing in their ability to lyse cells, activate the immune system, and transfer genes.
=== Clinical development ===
As of 2019, there are over 100 clinical trials looking at different viruses, cancers, doses, routes and administrations. Most of the work has been done on herpesvirus, adenovirus, and vaccinia virus, but other viruses include measles virus, coxsackievirus, polio virus, newcastle disease virus, and more. Methods of delivery tested include intratumoral, intravenous, intraperitoneal, and more. Types of tumor that are currently being study with oncolytic viruses include CNS tumors, renal cancer, head and neck cancer, ovarian cancer, and more. Oncolytic virotherapy as a monotherapy has also been tested in combination with other therapies including chemotherapy, radiotherapy, surgery, and immunotherapy.
==== Approved for clinical use ====
In 2015 the FDA approved the marketing of talimogene laherparepvec, a genetically engineered herpes virus, to treat melanoma lesions that cannot be operated on; as of 2019, it is the only oncolytic virus approved for clinical use. It is injected directly into the lesion. As of 2016 there was no evidence that it extends the life of people with melanoma, or that it prevents metastasis. Two genes were removed from the virus – one that shuts down an individual cell's defenses, and another that helps the virus evade the immune system – and a gene for human GM-CSF was added. The drug works by replicating in cancer cells, causing them to burst; it was also designed to stimulate an immune response but as of 2016, there was no evidence of this. The drug was created and initially developed by BioVex, Inc. and was continued by Amgen, which acquired BioVex in 2011. It was the first oncolytic virus approved in the West.
==== Others ====
RIGVIR is a virotherapy drug that was approved by the State Agency of Medicines of the Republic of Latvia in 2004. It is wild type ECHO-7, a member of echovirus family. The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s. The data used to register the drug in Latvia is not sufficient to obtain approval to use it in the US, Europe, or Japan. As of 2017 there was no good evidence that RIGVIR is an effective cancer treatment. On March 19, 2019, the manufacturer of ECHO-7, SIA LATIMA, announced the drug's removal from sale in Latvia, quoting financial and strategic reasons and insufficient profitability. However, several days later an investigative TV show revealed that State Agency of Medicines had run laboratory tests on the vials, and found that the amount of ECHO-7 virus is of a much smaller amount than claimed by the manufacturer. In March 2019, the distribution of ECHO-7 in Latvia has been stopped.
=== Challenges and future prospective ===
Although oncolytic viruses are engineered to specifically target tumor cells, there is always the potential for off-target effects leading to symptoms that are usually associated with that virus. The most common symptom that has been reported has been flu-like symptoms. The HSV virus used as an oncolytic virus has retained their native thymidine kinase gene which allows it to be targeted with antiviral therapy in the event of unwarranted side effects.
Other challenges include developing an optimal method of delivery either directly to the tumor site or intravenously and allowing for target of multiple sites. Clinical trials include the tracking of viral replication and spread using various laboratory techniques in order to find the optimal treatment.
Another major challenge with using oncolytic viruses as therapy is avoiding the host's natural immune system which will prevent the virus from infecting the tumor cells. Once the oncolytic virus is introduced to the host system, a healthy host's immune system will naturally try to fight off the virus. Because of this, if less virus is able to reach the target site, it can reduce the efficacy of the oncolytic virus. This leads to the idea that inhibiting the host's immune response may be necessary early in the treatment, but this is brought with safety concerns. Due to these safety concerns of immunosuppression, clinical trials have excluded patients who are immunocompromised and have active viral infections.
== Viral gene therapy ==
Viral gene therapy uses genetically engineered viral vectors to deliver therapeutic genes to cells with genetic malfunctions.
=== Mechanism ===
The use of viral material to deliver a gene starts with the engineering of the viral vector. Though the molecular mechanism of the viral vector differ from vector to vector, there are some general principles that are considered.
In diseases that are secondary to a genetic mutation that causes the lack of a gene, the gene is added back in. In diseases that are due to the overexpression of a gene, viral genetic engineering may be introduced to turn off the gene.
Viral gene therapy may be done in vivo or ex vivo. In the former, the viral vector is delivered directly to the organ or the tissue of the patient. In the later, the desired tissue is first retrieved, genetically modified, and then transferred back to the patient. The molecular mechanisms of gene delivery and/or integration into cells vary based on the viral vector that is used.
Rather than delivery of drugs that require multiple and continuous treatments. Delivery of a gene has the potential to create a long lasting cell that can continuously produce gene product.
=== Clinical development ===
There has been a few successful clinical use of viral gene therapy since the 2000s, specifically with adeno-associated virus vectors and chimeric antigen receptor T-cell therapy.
==== Approved for clinical use ====
===== Adeno-associated virus =====
Vectors made from Adeno-associated virus are one of the most established products used in clinical trials today. It was initially attractive for the use of gene therapy due to it not being known to cause any disease along with several other features. It has also been engineered so that it does not replicate after the delivery of the gene.
In 2017, the FDA approved Spark Therapeutics' Luxturna, an AAV vector-based gene therapy product for the treatment of RPE65 mutation-associated retinal dystrophy in adults. Luxturna is the first gene therapy approved in the US for the treatment of a monogenetic disorder. It has been authorized for use in the EU since 2018.
In 2019, the FDA approved Zolgensma, an AAV vector-based gene therapy product for the treatment of spinal muscular atrophy in children under the age of two. As of August 2019, it is the world's most expensive treatment, at a cost of over two million USD. Novartis is still seeking marketing approval for the drug in the EU as of 2019.
In additional, other clinical trials involving AAV-gene therapy looks to treat diseases such as Haemophilia along with various neurological, cardiovascular, and muscular diseases.
===== Chimeric antigen receptor T cells =====
Chimeric antigen receptor T cell (CAR T cell) are a type of immunotherapy that makes use of viral gene editing. CAR T cell use an ex vivo method in which T lymphocytes are extracted and engineered with a virus typically gammaretrovirus or lentivirus to recognize specific proteins on cell surfaces. This causes the T-lymphocytes to attack the cells that express the undesired protein. Currently two therapies, Tisagenlecleucel and Axicabtagene ciloleucel are FDA-approved to treat acute lymphoblastic leukemia and diffuse large B-cell lymphoma respectively. Clinical trials are underway to explore its potential benefits in solid malignancies.
==== Others ====
In 2012 the European Commission approved Glybera, an AAV vector-based gene therapy product for the treatment of lipoprotein lipase deficiency in adults. It was the first gene therapy approved in the EU. The drug never received FDA approval in the US, and was discontinued by its manufacturer uniQure in 2017 due to profitability concerns. As of 2019 it is no longer authorized for use in the EU.
=== Challenges and future prospective ===
Currently, there are still many challenges of viral gene therapy. Immune responses to viral gene therapies pose a challenge to successful treatment. However, responses to viral vectors at immune privileged sites such as the eye may be reduced compared to other sites of the body. As with other forms of virotherapy, prevention of off-target genome editing is a concern. In addition to viral gene editing, other genome editing technologies such as CRISPR gene editing have been shown to be more precise with more control over the delivery of genes. As genome editing become a reality, it is also necessary to consider the ethical implications of the technology.
== Viral immunotherapy ==
Viral immunotherapy is the use of virus to stimulate the body's immune system. Unlike traditional vaccines, in which attenuated or killed virus/bacteria is used to generate an immune response, viral immunotherapy uses genetically engineered viruses to present a specific antigen to the immune system. That antigen could be from any species of virus/bacteria or even human disease antigens, for example cancer antigens.
Vaccines are another method of virotherapy that use attenuated or inactivated viruses to develop immunity to disease. An attenuated virus is a weakened virus that incites a natural immune response in the host that is often undetectable. The host also develops potentially life-long immunity due to the attenuated virus's similarity to the actual virus. Inactivated viruses are killed viruses that present a form of the antigen to the host. However, long-term immune response is limited.
=== Cancer treatment ===
Viral immunotherapy in the context of cancer stimulates the body's immune system to better fight against cancer cells. Rather than preventing causes of cancer, as one would traditionally think in the context of vaccines, vaccines against cancer are used to treat cancer. The mechanism is dependent upon the virus and treatment. Oncolytic viruses, as discussed in previous section, is stimulate host immune system through the release of tumor-associated antigens upon lysis as well as through the disruption of the cancer's microenvironment which helps them avoid the host immune system. CAR T Cells, also mentioned in previous section, is another form of viral immunotherapy that uses viruses to genetically engineer immune cells to kill cancer cells.
== Other projects and products ==
=== Protozoal virotherapy ===
Viruses have been explored as a means to treat infections caused by protozoa. One such protozoa that potential virotherapy treatments have explored is Naegleria fowleri, which causes primary amebic meningoencephalitis (PAM). With a mortality rate of 95%, this disease-causing eukaryote has one of the highest pathogenic fatality rates known. Chemotherapeutic agents that target this amoeba for treating PAM have difficulty crossing blood-brain barriers. However, virulent viruses of protozoal pathogens (VVPPs) can be used as viral therapies that can more easily access this eukaryotic disease organism by crossing the blood-brain barrier in a process analogous to bacteriophages. These VVPPs would also be self-replicating and therefore require infrequent administration, with lower doses, thus potentially reducing toxicity. While these treatment methods for protozoal disease may show great promise in a manner similar to bacteriophage viral therapy, a notable hazard is the evolutionary consequence of using viruses capable of eukaryotic pathogenicity. VVPPs will have evolved mechanisms of DNA insertion and replication that manipulate eukaryotic surface proteins and DNA editing proteins. VVPP engineering must therefore control for viruses that may be able to mutate and thereby bind to surface proteins and manipulate the DNA of the infected host.
== See also ==
Cancer
Gene therapy
Oncolytic virus
Vector
Virosome, using modified viruses for drug delivery
Dog parasite press article
== References ==
== Further reading ==
Ring, Christopher J. A.; Blair, Edward D. (2000). Genetically engineered viruses: development and applications. Oxford: Bios. ISBN 978-1859961032. OCLC 45828140. | Wikipedia/Virotherapy |
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.
The underlying mechanisms vary depending on the disease. It is estimated that dietary risk factors are associated with 53% of CVD deaths. Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This may be caused by high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, excessive alcohol consumption, and poor sleep, among other things. High blood pressure is estimated to account for approximately 13% of CVD deaths, while tobacco accounts for 9%, diabetes 6%, lack of exercise 6%, and obesity 5%. Rheumatic heart disease may follow untreated strep throat.
It is estimated that up to 90% of CVD may be preventable. Prevention of CVD involves improving risk factors through: healthy eating, exercise, avoidance of tobacco smoke and limiting alcohol intake. Treating risk factors, such as high blood pressure, blood lipids and diabetes is also beneficial. Treating people who have strep throat with antibiotics can decrease the risk of rheumatic heart disease. The use of aspirin in people who are otherwise healthy is of unclear benefit.
Cardiovascular diseases are the leading cause of death worldwide except Africa. Together CVD resulted in 17.9 million deaths (32.1%) in 2015, up from 12.3 million (25.8%) in 1990. Deaths, at a given age, from CVD are more common and have been increasing in much of the developing world, while rates have declined in most of the developed world since the 1970s. Coronary artery disease and stroke account for 80% of CVD deaths in males and 75% of CVD deaths in females. Most cardiovascular disease affects older adults. In the United States 11% of people between 20 and 40 have CVD, while 37% between 40 and 60, 71% of people between 60 and 80, and 85% of people over 80 have CVD. The average age of death from coronary artery disease in the developed world is around 80, while it is around 68 in the developing world. CVD is typically diagnosed seven to ten years earlier in men than in women.: 48
== Types ==
There are many cardiovascular diseases involving the blood vessels. They are known as vascular diseases.
Coronary artery disease (coronary heart disease or ischemic heart disease)
Peripheral arterial disease – a disease of blood vessels that supply blood to the arms and legs
Cerebrovascular disease – a disease of blood vessels that supply blood to the brain (includes stroke)
Renal artery stenosis
Aortic aneurysm
There are also many cardiovascular diseases that involve the heart.
Cardiomyopathy – diseases of cardiac muscle
Hypertensive heart disease – diseases of the heart secondary to high blood pressure or hypertension
Heart failure – a clinical syndrome caused by the inability of the heart to supply sufficient blood to the tissues to meet their metabolic requirements
Pulmonary heart disease – a failure at the right side of the heart with respiratory system involvement
Cardiac dysrhythmias – abnormalities of heart rhythm
Inflammatory heart diseases
Endocarditis – inflammation of the inner layer of the heart, the endocardium. The structures most commonly involved are the heart valves.
Inflammatory cardiomegaly
Myocarditis – inflammation of the myocardium, the muscular part of the heart, caused most often by viral infection and less often by bacterial infections, certain medications, toxins, and autoimmune disorders. It is characterized in part by infiltration of the heart by lymphocyte and monocyte types of white blood cells.
Eosinophilic myocarditis – inflammation of the myocardium caused by pathologically activated eosinophilic white blood cells. This disorder differs from myocarditis in its causes and treatments.
Valvular heart disease
Congenital heart disease – heart structure malformations existing at birth
Rheumatic heart disease – heart muscles and valves damage due to rheumatic fever caused by Streptococcus pyogenes a group A streptococcal infection.
== Risk factors ==
There are many risk factors for heart diseases: age, sex, tobacco use, physical inactivity, non-alcoholic fatty liver disease, excessive alcohol consumption, unhealthy diet, obesity, genetic predisposition and family history of cardiovascular disease, raised blood pressure (hypertension), raised blood sugar (diabetes mellitus), raised blood cholesterol (hyperlipidemia), undiagnosed celiac disease, psychosocial factors, poverty and low educational status, air pollution, and poor sleep. While the individual contribution of each risk factor varies between different communities or ethnic groups the overall contribution of these risk factors is very consistent. Some of these risk factors, such as age, sex or family history/genetic predisposition, are immutable; however, many important cardiovascular risk factors are modifiable by lifestyle change, social change, drug treatment (for example prevention of hypertension, hyperlipidemia, and diabetes). People with obesity are at increased risk of atherosclerosis of the coronary arteries.
=== Genetics ===
Cardiovascular disease in a person's parents increases their risk by ~3 fold, and genetics is an important risk factor for cardiovascular diseases. Genetic cardiovascular disease can occur either as
a consequence of single variant (Mendelian) or polygenic influences. There are more than 40 inherited cardiovascular disease that can be traced to a single disease-causing DNA variant, although these conditions are rare. Most common cardiovascular diseases are non-Mendelian and are thought to be due to hundreds or thousands of genetic variants (known as single nucleotide polymorphisms), each associated with a small effect.
=== Age ===
Age is the most important risk factor in developing cardiovascular or heart diseases, with approximately a tripling of risk with each decade of life. Coronary fatty streaks can begin to form in adolescence. It is estimated that 82 percent of people who die of coronary heart disease are 65 and older. Simultaneously, the risk of stroke doubles every decade after age 55.
Multiple explanations are proposed to explain why age increases the risk of cardiovascular/heart diseases. One of them relates to serum cholesterol level. In most populations, the serum total cholesterol level increases as age increases. In men, this increase levels off around age 45 to 50 years. In women, the increase continues sharply until age 60 to 65 years.
Aging is also associated with changes in the mechanical and structural properties of the vascular wall, which leads to the loss of arterial elasticity and reduced arterial compliance and may subsequently lead to coronary artery disease.
=== Sex ===
Men are at greater risk of heart disease than pre-menopausal women. Once past menopause, it has been argued that a woman's risk is similar to a man's although more recent data from the WHO and UN disputes this. If a female has diabetes, she is more likely to develop heart disease than a male with diabetes. Women who have high blood pressure and had complications in their pregnancy have three times the risk of developing cardiovascular disease compared to women with normal blood pressure who had no complications in pregnancy.
Coronary heart diseases are 2 to 5 times more common among middle-aged men than women. In a study done by the World Health Organization, sex contributes to approximately 40% of the variation in sex ratios of coronary heart disease mortality. Another study reports similar results finding that sex differences explains nearly half the risk associated with cardiovascular diseases One of the proposed explanations for sex differences in cardiovascular diseases is hormonal difference. Among women, estrogen is the predominant sex hormone. Estrogen may have protective effects on glucose metabolism and hemostatic system, and may have direct effect in improving endothelial cell function. The production of estrogen decreases after menopause, and this may change the female lipid metabolism toward a more atherogenic form by decreasing the HDL cholesterol level while increasing LDL and total cholesterol levels.
Among men and women, there are differences in body weight, height, body fat distribution, heart rate, stroke volume, and arterial compliance. In the very elderly, age-related large artery pulsatility and stiffness are more pronounced among women than men. This may be caused by the women's smaller body size and arterial dimensions which are independent of menopause.
=== Tobacco ===
Cigarettes are the major form of smoked tobacco. Risks to health from tobacco use result not only from direct consumption of tobacco, but also from exposure to second-hand smoke. Approximately 10% of cardiovascular disease is attributed to smoking; however, people who quit smoking by age 30 have almost as low a risk of death as never smokers.
=== Physical inactivity ===
Insufficient physical activity (defined as less than 5 x 30 minutes of moderate activity per week, or less than 3 x 20 minutes of vigorous activity per week) is currently the fourth leading risk factor for mortality worldwide. In 2008, 31.3% of adults aged 15 or older (28.2% men and 34.4% women) were insufficiently physically active.
The risk of ischemic heart disease and diabetes mellitus is reduced by almost a third in adults who participate in 150 minutes of moderate physical activity each week (or equivalent). In addition, physical activity assists weight loss and improves blood glucose control, blood pressure, lipid profile and insulin sensitivity. These effects may, at least in part, explain its cardiovascular benefits.
=== Diet ===
High dietary intakes of saturated fat, trans-fats and salt, and low intake of fruits, vegetables and fish are linked to cardiovascular risk, although whether all these associations indicate causes is disputed. The World Health Organization attributes approximately 1.7 million deaths worldwide to low fruit and vegetable consumption. Frequent consumption of high-energy foods, such as processed foods that are high in fats and sugars, promotes obesity and may increase cardiovascular risk. The amount of dietary salt consumed may also be an important determinant of blood pressure levels and overall cardiovascular risk. There is moderate quality evidence that reducing saturated fat intake for at least two years reduces the risk of cardiovascular disease. High trans-fat intake has adverse effects on blood lipids and circulating inflammatory markers, and elimination of trans-fat from diets has been widely advocated. In 2018 the World Health Organization estimated that trans fats were the cause of more than half a million deaths per year. There is evidence that higher consumption of sugar is associated with higher blood pressure and unfavorable blood lipids, and sugar intake also increases the risk of diabetes mellitus. High consumption of processed meats is associated with an increased risk of cardiovascular disease, possibly in part due to increased dietary salt intake.
=== Alcohol ===
The relationship between alcohol consumption and cardiovascular disease is complex, and may depend on the amount of alcohol consumed. There is a direct relationship between high levels of drinking alcohol and cardiovascular disease. Drinking at low levels without episodes of heavy drinking may be associated with a reduced risk of cardiovascular disease, but there is evidence that associations between moderate alcohol consumption and protection from stroke are non-causal. Moderate drinking is defined as one drink per day for women or two drinks a day for men. At the population level, the health risks of drinking alcohol exceed any potential benefits. Exercising regularly can provide the same benefits as potentially consuming small amounts of alcohol and is a much safer alternative. Consuming too much alcohol can cause a high blood pressure, heart failure, and cardiomyopathy. Drinking alcohol can also cause obesity, which can contribute to cardiovascular issues as well.
=== Celiac disease ===
Untreated celiac disease can cause the development of many types of cardiovascular diseases, most of which improve or resolve with a gluten-free diet and intestinal healing. However, delays in recognition and diagnosis of celiac disease can cause irreversible heart damage.
=== Sleep ===
A lack of good sleep, in amount or quality, is documented as increasing cardiovascular risk in both adults and teens. Recommendations suggest that infants typically need 12 or more hours of sleep per day, adolescents at least eight or nine hours, and adults seven or eight. About one-third of adult Americans get less than the recommended seven hours of sleep per night, and in a study of teenagers, just 2.2 percent of those studied got enough sleep, many of whom did not get good quality sleep. Studies have shown that short sleepers getting less than seven hours sleep per night have a 10 percent to 30 percent higher risk of cardiovascular disease.
Sleep disorders such as sleep-disordered breathing and insomnia, are also associated with a higher cardiometabolic risk.
An estimated 50 to 70 million Americans have insomnia, sleep apnea or other chronic sleep disorders.
In addition, sleep research displays differences in race and class. Short sleep and poor sleep tend to be more frequently reported in ethnic minorities than in whites. African-Americans report experiencing short durations of sleep five times more often than whites, possibly as a result of social and environmental factors. Black children and children living in disadvantaged neighborhoods have much higher rates of sleep apnea.
One study found that of adults who are 45 and older, subjects that fell asleep at different times each night and slept inconsistent numbers of hours each night were more likely to develop atherosclerosis. Poor sleep habits, such as too little sleep, too much sleep, or fragmented sleep, were associated with cardiovascular disease, obesity, and high blood pressure. Another study noted that participants whose sleep duration varied by more than two hours within the course of a week were 1.4 times more likely to have elevated levels of coronary artery calcium, a predictor of cardiovascular events.
=== Socioeconomic disadvantage ===
Cardiovascular disease has a greater impact on low- and middle-income countries compared to those with higher income. Although data on the social patterns of cardiovascular disease in low- and middle-income countries is limited, reports from high-income countries consistently demonstrate that low educational status or income are associated with a greater risk of cardiovascular disease. Policies that have resulted in increased socio-economic inequalities have been associated with greater subsequent socio-economic differences in cardiovascular disease implying a cause and effect relationship. Psychosocial factors, environmental exposures, health behaviours, and health-care access and quality contribute to socio-economic differentials in cardiovascular disease. The Commission on Social Determinants of Health recommended that more equal distributions of power, wealth, education, housing, environmental factors, nutrition, and health care were needed to address inequalities in cardiovascular disease and non-communicable diseases.
=== Air pollution ===
Particulate matter has been studied for its short- and long-term exposure effects on cardiovascular disease. Currently, airborne particles under 2.5 micrometers in diameter (PM2.5) are the major focus, in which gradients are used to determine CVD risk. Overall, long-term PM exposure increased rate of atherosclerosis and inflammation. In regards to short-term exposure (2 hours), every 25 μg/m3 of PM2.5 resulted in a 48% increase of CVD mortality risk. In addition, after only 5 days of exposure, a rise in systolic (2.8 mmHg) and diastolic (2.7 mmHg) blood pressure occurred for every 10.5 μg/m3 of PM2.5. Other research has implicated PM2.5 in irregular heart rhythm, reduced heart rate variability (decreased vagal tone), and most notably heart failure. PM2.5 is also linked to carotid artery thickening and increased risk of acute myocardial infarction.
=== Cardiovascular risk assessment ===
Existing cardiovascular disease or a previous cardiovascular event, such as a heart attack or stroke, is the strongest predictor of a future cardiovascular event. Age, sex, smoking, blood pressure, blood lipids and diabetes are important predictors of future cardiovascular disease in people who are not known to have cardiovascular disease. These measures, and sometimes others, may be combined into composite risk scores to estimate an individual's future risk of cardiovascular disease. Numerous risk scores exist although their respective merits are debated. Other diagnostic tests and biomarkers remain under evaluation but currently these lack clear-cut evidence to support their routine use. They include family history, coronary artery calcification score, high sensitivity C-reactive protein (hs-CRP), ankle–brachial pressure index, lipoprotein subclasses and particle concentration, lipoprotein(a), apolipoproteins A-I and B, fibrinogen, white blood cell count, homocysteine, N-terminal pro B-type natriuretic peptide (NT-proBNP), and markers of kidney function. High blood phosphorus is also linked to an increased risk.
=== Psychological stress ===
There is evidence that mental health problems, in particular depression and traumatic stress, is linked to cardiovascular diseases. Whereas mental health problems are known to be associated with risk factors for cardiovascular diseases such as smoking, poor diet, and a sedentary lifestyle, these factors alone do not explain the increased risk of cardiovascular diseases seen in depression, stress, and anxiety. Moreover, posttraumatic stress disorder is independently associated with increased risk for incident coronary heart disease, even after adjusting for depression and other covariates.
Many studies recognize depression and anxiety as two important disorders that can cause an increase in the risk of developing cardiovascular disease. Only half of the instances of cardiovascular disease are explained by factors such as age and gender that cannot be changed. The other half of instances are due to other sources, including psychological stress. Studies have shown that the prevalence of depression in patients with heart failure is higher than 20%.
Another study assessed the link between men and women who had been divorced and instance of cardiovascular disease. The study found that women who had gone through at least two divorces were just as likely to experience cardiovascular disease as a smoker or diabetic. Men, on the other hand, also had a higher risk of cardiovascular disease, however, their health improved upon remarriage while women did not.
This study also found that during a World Cup soccer event in Germany, heart attacks more than doubled during the days when the nation's team was playing. Researchers assume this link is due to the fact that stress can increase inflammation in the body, which can cause high blood pressure and low HDL cholesterol. Chronic stress can also affect sleep, exercise, and food choices.
=== Anxiety ===
Patients who suffer from generalized anxiety disorder are more likely to develop some form of cardiovascular disease. It is hypothesized that anxiety makes one more likely to develop cardiovascular disease due to the fact that it can change the body's stress response through hormonal and physiological reactions. People with anxiety often experience high blood pressure, arrhythmias, and heart attacks. The stress response caused by anxiety can increase inflammation in the body. It was also discovered that patients with anxiety had lower levels of omega-3-fatty acids which is linked to an increased risk of developing cardiovascular disease.
=== Occupational exposure ===
Little is known about the relationship between work and cardiovascular disease, but links have been established between certain toxins, extreme heat and cold, exposure to tobacco smoke, and mental health concerns such as stress and depression.
==== Non-chemical risk factors ====
A 2015 SBU-report looking at non-chemical factors found an association for those:
with mentally stressful work with a lack of control over their working situation — with an effort-reward imbalance
who experience low social support at work; who experience injustice or experience insufficient opportunities for personal development; or those who experience job insecurity
those who work night schedules; or have long working weeks
those who are exposed to noise
Specifically the risk of stroke was also increased by exposure to ionizing radiation. Hypertension develops more often in those who experience job strain and who have shift-work. Differences between women and men in risk are small, however men risk having and dying of heart attacks or stroke twice as often as women during working life.
==== Chemical risk factors ====
A 2017 SBU report found evidence that workplace exposure to silica dust, engine exhaust or welding fumes is associated with heart disease. Associations also exist for exposure to arsenic, benzopyrenes, lead, dynamite, carbon disulphide, carbon monoxide, metalworking fluids and occupational exposure to tobacco smoke. Working with the electrolytic production of aluminium or the production of paper when the sulphate pulping process is used is associated with heart disease. An association was also found between heart disease and exposure to compounds which are no longer permitted in certain work environments, such as phenoxy acids containing TCDD(dioxin) or asbestos.
Workplace exposure to silica dust or asbestos is also associated with pulmonary heart disease. There is evidence that workplace exposure to lead, carbon disulphide, phenoxyacids containing TCDD, as well as working in an environment where aluminum is being electrolytically produced, is associated with stroke.
=== Somatic mutations ===
As of 2017, evidence suggests that certain leukemia-associated mutations in blood cells may also lead to increased risk of cardiovascular disease. Several large-scale research projects looking at human genetic data have found a robust link between the presence of these mutations, a condition known as clonal hematopoiesis, and cardiovascular disease-related incidents and mortality.
=== Radiation therapy ===
Radiation treatments (RT) for cancer can increase the risk of heart disease and death, as observed in breast cancer therapy. Therapeutic radiation increases the risk of a subsequent heart attack or stroke by 1.5 to 4 times; the increase depends on the dose strength, volume, and location. Use of concomitant chemotherapy, e.g. anthracyclines, is an aggravating risk factor. The occurrence rate of RT induced cardiovascular disease is estimated between 10% and 30%.
Side-effects from radiation therapy for cardiovascular diseases have been termed radiation-induced heart disease or radiation-induced cardiovascular disease. Symptoms are dose-dependent and include cardiomyopathy, myocardial fibrosis, valvular heart disease, coronary artery disease, heart arrhythmia and peripheral artery disease. Radiation-induced fibrosis, vascular cell damage and oxidative stress can lead to these and other late side-effect symptoms.
== Pathophysiology ==
Population-based studies show that atherosclerosis, the major precursor of cardiovascular disease, begins in childhood. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study demonstrated that intimal lesions appear in all the aortas and more than half of the right coronary arteries of youths aged 7–9 years.
Obesity and diabetes mellitus are linked to cardiovascular disease, as are a history of chronic kidney disease and hypercholesterolaemia. In fact, cardiovascular disease is the most life-threatening of the diabetic complications and diabetics are two- to four-fold more likely to die of cardiovascular-related causes than nondiabetics.
== Screening ==
Screening ECGs (either at rest or with exercise) are not recommended in those without symptoms who are at low risk. This includes those who are young without risk factors. In those at higher risk the evidence for screening with ECGs is inconclusive. Additionally echocardiography, myocardial perfusion imaging, and cardiac stress testing is not recommended in those at low risk who do not have symptoms. Some biomarkers may add to conventional cardiovascular risk factors in predicting the risk of future cardiovascular disease; however, the value of some biomarkers is questionable. Ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP), and coronary artery calcium, are also of unclear benefit in those without symptoms as of 2018.
The NIH recommends lipid testing in children beginning at the age of 2 if there is a family history of heart disease or lipid problems. It is hoped that early testing will improve lifestyle factors in those at risk such as diet and exercise.
Screening and selection for primary prevention interventions has traditionally been done through absolute risk using a variety of scores (ex. Framingham or Reynolds risk scores). This stratification has separated people who receive the lifestyle interventions (generally lower and intermediate risk) from the medication (higher risk). The number and variety of risk scores available for use has multiplied, but their efficacy according to a 2016 review was unclear due to lack of external validation or impact analysis. Risk stratification models often lack sensitivity for population groups and do not account for the large number of negative events among the intermediate and low risk groups. As a result, future preventative screening appears to shift toward applying prevention according to randomized trial results of each intervention rather than large-scale risk assessment.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Currently practised measures to prevent cardiovascular disease include:
Maintaining a healthy diet, such as the Mediterranean diet, a vegetarian, vegan or another plant-based diet.
Replacing saturated fat with healthier choices: Clinical trials show that replacing saturated fat with polyunsaturated vegetable oil reduced CVD by 30%. Prospective observational studies show that in many populations lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD.
Decrease body fat if overweight or obese. The effect of weight loss is often difficult to distinguish from dietary change, and evidence on weight reducing diets is limited. In observational studies of people with severe obesity, weight loss following bariatric surgery is associated with a 46% reduction in cardiovascular risk.
Limit alcohol consumption to the recommended daily limits. People who moderately consume alcoholic drinks have a 25–30% lower risk of cardiovascular disease. However, people who are genetically predisposed to consume less alcohol have lower rates of cardiovascular disease suggesting that alcohol itself may not be protective. Excessive alcohol intake increases the risk of cardiovascular disease and consumption of alcohol is associated with increased risk of a cardiovascular event in the day following consumption.
Decrease non-HDL cholesterol. Statin treatment reduces cardiovascular mortality by about 31%.
Stopping smoking and avoidance of second-hand smoke. Stopping smoking reduces risk by about 35%.
At least 150 minutes (2 hours and 30 minutes) of moderate exercise per week.
Lower blood pressure, if elevated. A 10 mmHg reduction in blood pressure reduces risk by about 20%. Lowering blood pressure appears to be effective even at normal blood pressure ranges.
Not enough sleep also raises the risk of high blood pressure. Adults need about 7–9 hours of sleep. Sleep apnea is also a major risk as it causes breathing to stop briefly, which can put stress on the body which can raise the risk of heart disease.
Most guidelines recommend combining preventive strategies. There is some evidence that interventions aiming to reduce more than one cardiovascular risk factor may have beneficial effects on blood pressure, body mass index and waist circumference; however, evidence was limited and the authors were unable to draw firm conclusions on the effects on cardiovascular events and mortality.
There is additional evidence to suggest that providing people with a cardiovascular disease risk score may reduce risk factors by a small amount compared to usual care. However, there was some uncertainty as to whether providing these scores had any effect on cardiovascular disease events. It is unclear whether or not dental care in those with periodontitis affects their risk of cardiovascular disease. According to a 2021 WHO study, working 55+ hours a week raises the risk of stroke by 35% and the risk of dying from heart conditions by 17%, when compared to a 35-40 hours week.
=== Psychological prevention ===
Decrease psychosocial stress. This measure may be complicated by imprecise definitions of what constitute psychosocial interventions. Mental stress–induced myocardial ischemia is associated with an increased risk of heart problems in those with previous heart disease. Severe emotional and physical stress leads to a form of heart dysfunction known as Takotsubo syndrome in some people. Specific relaxation therapies are of unclear benefit. Decreasing psychological stress can be accomplished by receiving access to services and support, recognizing signs and symptoms of mental health disorders, awareness of family history, and understanding which mental health disorders increase the risk of cardiovascular disease. Psychosocial intervention programs have been shown to improve risk of developing cardiovascular disease in the high-risk population.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death.
A 2021 review found that plant-based diets can provide a risk reduction for CVD if a healthy plant-based diet is consumed. Unhealthy plant-based diets do not provide benefits over diets including meat. A similar meta-analysis and systematic review also looked into dietary patterns and found "that diets lower in animal foods and unhealthy plant foods, and higher in healthy plant foods are beneficial for CVD prevention". A 2018 meta-analysis of observational studies concluded that "In most countries, a vegan diet is associated with a more favourable cardio-metabolic profile compared to an omnivorous diet."
Evidence suggests that the Mediterranean diet may improve cardiovascular outcomes. There is also evidence that a Mediterranean diet may be more effective than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure).
The DASH diet (high in nuts, fish, fruits and vegetables, and low in sweets, red meat and fat) has been shown to reduce blood pressure, lower total and low density lipoprotein cholesterol and improve metabolic syndrome; but the long-term benefits have been questioned. A high-fiber diet is associated with lower risks of cardiovascular disease.
Worldwide, dietary guidelines recommend a reduction in saturated fat, and although the role of dietary fat in cardiovascular disease is complex and controversial there is a long-standing consensus that replacing saturated fat with unsaturated fat in the diet is sound medical advice. Total fat intake has not been found to be associated with cardiovascular risk. A 2020 systematic review found moderate quality evidence that reducing saturated fat intake for at least 2 years caused a reduction in cardiovascular events. A 2015 meta-analysis of observational studies however did not find a convincing association between saturated fat intake and cardiovascular disease. Variation in what is used as a substitute for saturated fat may explain some differences in findings. The benefit from replacement with polyunsaturated fats appears greatest, while replacement of saturated fats with carbohydrates does not appear to have a beneficial effect. A diet high in trans fatty acids is associated with higher rates of cardiovascular disease, and in 2015 the Food and Drug Administration (FDA) determined that there was 'no longer a consensus among qualified experts that partially hydrogenated oils (PHOs), which are the primary dietary source of industrially produced trans fatty acids (IP-TFA), are generally recognized as safe (GRAS) for any use in human food'. There is conflicting evidence concerning whether dietary supplements of omega-3 fatty acids (a type of polyunsaturated essential fatty acid) added to diet improve cardiovascular risk.
The benefits of recommending a low-salt diet in people with high or normal blood pressure are not clear. In those with heart failure, after one study was left out, the rest of the trials show a trend to benefit. Another review of dietary salt concluded that there is strong evidence that high dietary salt intake increases blood pressure and worsens hypertension, and that it increases the number of cardiovascular disease events; both as a result of the increased blood pressure and probably through other mechanisms. Moderate evidence was found that high salt intake increases cardiovascular mortality; and some evidence was found for an increase in overall mortality, strokes, and left ventricular hypertrophy.
==== Intermittent fasting ====
Overall, the current body of scientific evidence is uncertain on whether intermittent fasting could prevent cardiovascular disease. Intermittent fasting may help people lose more weight than regular eating patterns, but was not different from energy restriction diets.
=== Medication ===
Blood pressure medication reduces cardiovascular disease in people at risk, irrespective of age, the baseline level of cardiovascular risk, or baseline blood pressure. The commonly-used drug regimens have similar efficacy in reducing the risk of all major cardiovascular events, although there may be differences between drugs in their ability to prevent specific outcomes. Larger reductions in blood pressure produce larger reductions in risk, and most people with high blood pressure require more than one drug to achieve adequate reduction in blood pressure. Adherence to medications is often poor, and while mobile phone text messaging has been tried to improve adherence, there is insufficient evidence that it alters secondary prevention of cardiovascular disease.
Statins are effective in preventing further cardiovascular disease in people with a history of cardiovascular disease. As the event rate is higher in men than in women, the decrease in events is more easily seen in men than women. In those at risk, but without a history of cardiovascular disease (primary prevention), statins decrease the risk of death and combined fatal and non-fatal cardiovascular disease. The benefit, however, is small. A United States guideline recommends statins in those who have a 12% or greater risk of cardiovascular disease over the next ten years. Niacin, fibrates and CETP Inhibitors, while they may increase HDL cholesterol do not affect the risk of cardiovascular disease in those who are already on statins. Fibrates lower the risk of cardiovascular and coronary events, but there is no evidence to suggest that they reduce all-cause mortality.
Anti-diabetic medication may reduce cardiovascular risk in people with Type 2 diabetes, although evidence is not conclusive. A meta-analysis in 2009 including 27,049 participants and 2,370 major vascular events showed a 15% relative risk reduction in cardiovascular disease with more-intensive glucose lowering over an average follow-up period of 4.4 years, but an increased risk of major hypoglycemia.
Aspirin has been found to be of only modest benefit in those at low risk of heart disease, as the risk of serious bleeding is almost equal to the protection against cardiovascular problems. In those at very low risk, including those over the age of 70, it is not recommended. The United States Preventive Services Task Force recommends against use of aspirin for prevention in women less than 55 and men less than 45 years old; however, it is recommended for some older people.
The use of vasoactive agents for people with pulmonary hypertension with left heart disease or hypoxemic lung diseases may cause harm and unnecessary expense.
Antibiotics for secondary prevention of coronary heart disease
Antibiotics may help patients with coronary disease to reduce the risk of heart attacks and strokes. However, evidence in 2021 suggests that antibiotics for secondary prevention of coronary heart disease are harmful, with increased mortality and occurrence of stroke; the use of antibiotics is not supported for preventing secondary coronary heart disease.
=== Physical activity ===
Exercise-based cardiac rehabilitation following a heart attack reduces the risk of death from cardiovascular disease and leads to less hospitalizations. There have been few high-quality studies of the benefits of exercise training in people with increased cardiovascular risk but no history of cardiovascular disease.
A systematic review estimated that inactivity is responsible for 6% of the burden of disease from coronary heart disease worldwide. The authors estimated that 121,000 deaths from coronary heart disease could have been averted in Europe in 2008 if people had not been physically inactive. Low-quality evidence from a limited number of studies suggest that yoga has beneficial effects on blood pressure and cholesterol. Tentative evidence suggests that home-based exercise programs may be more efficient at improving exercise adherence.
=== Dietary supplements ===
While a healthy diet is beneficial, the effect of antioxidant supplementation (vitamin E, vitamin C, etc.) or vitamins has not been shown to protect against cardiovascular disease and in some cases may possibly result in harm. Mineral supplements have also not been found to be useful. Niacin, a type of vitamin B3, may be an exception with a modest decrease in the risk of cardiovascular events in those at high risk. Magnesium supplementation lowers high blood pressure in a dose-dependent manner. Magnesium therapy is recommended for people with ventricular arrhythmia associated with torsades de pointes who present with long QT syndrome, and for the treatment of people with digoxin intoxication-induced arrhythmias. There is no evidence that omega-3 fatty acid supplementation is beneficial. A 2022 review found that some dietary supplements, including micronutrients, may reduce risk factors for cardiovascular disease.
== Management ==
Cardiovascular disease is treatable with initial treatment primarily focused on diet and lifestyle interventions. Influenza may make heart attacks and strokes more likely and therefore influenza vaccination may decrease the chance of cardiovascular events and death in people with heart disease.
Proper CVD management necessitates a focus on MI and stroke cases due to their combined high mortality rate, keeping in mind the cost-effectiveness of any intervention, especially in developing countries with low or middle-income levels. Regarding MI, strategies using aspirin, atenolol, streptokinase or tissue plasminogen activator have been compared for quality-adjusted life-year (QALY) in regions of low and middle income. The costs for a single QALY for aspirin and atenolol were less than US$25, streptokinase was about $680, and t-PA was $16,000. Aspirin, ACE inhibitors, beta-blockers, and statins used together for secondary CVD prevention in the same regions showed single QALY costs of $350.
There are also surgical or procedural interventions that can save someone's life or prolong it. For heart valve problems, a person could have surgery to replace the valve. For arrhythmias, a pacemaker can be put in place to help reduce abnormal heart rhythms and for a heart attack, there are multiple options two of these are a coronary angioplasty and a coronary artery bypass surgery.
There is probably no additional benefit in terms of mortality and serious adverse events when blood pressure targets were lowered to ≤ 135/85 mmHg from ≤ 140 to 160/90 to 100 mmHg.
== Epidemiology ==
Cardiovascular diseases are the leading cause of death worldwide and in all regions except Africa. In 2008, 30% of all global death was attributed to cardiovascular diseases. Death caused by cardiovascular diseases are also higher in low- and middle-income countries as over 80% of all global deaths caused by cardiovascular diseases occurred in those countries. It is also estimated that by 2030, over 23 million people will die from cardiovascular diseases each year.
It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue.
== Research ==
There is evidence that cardiovascular disease existed in pre-history, and research into cardiovascular disease dates from at least the 18th century. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis.
Recent areas of research include the link between inflammation and atherosclerosis the potential for novel therapeutic interventions, and the genetics of coronary heart disease.
== References ==
== External links ==
WHO fact sheet on cardiovascular diseases
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
Heart Disease MedicineNet Slides, photos, descriptions
Risk calculator
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Chemotherapy-induced acral erythema, also known as palmar-plantar erythrodysesthesia or hand-foot syndrome is reddening, swelling, numbness and desquamation (skin sloughing or peeling) on palms of the hands and soles of the feet (and, occasionally, on the knees, elbows, and elsewhere) that can occur after chemotherapy in patients with cancer. Hand-foot syndrome is also rarely seen in sickle-cell disease. These skin changes usually are well demarcated. Acral erythema typically disappears within a few weeks after discontinuation of the offending drug.
== Signs and symptoms ==
The symptoms can occur anywhere between days to months after administration of the offending medication, depending on the dose and speed of administration. The patient first experiences tingling and/or numbness of the palms and soles. This is followed 2–4 days later by bright redness, which is symmetrical and sharply defined.
In severe cases this may be followed by burning pain and swelling, blistering and ulceration, peeling of the skin. Healing occurs without scarring unless there has been skin ulceration or necrosis (skin loss/death). With each subsequent cycle of chemotherapy, the reaction will appear more quickly, be more severe and will take longer to heal.
== Causes ==
Acral erythema is a common adverse reaction to cytotoxic chemotherapy drugs, particularly cabozantinib, cytarabine, doxorubicin (including pegylated liposomal doxorubicin, PLD), and fluorouracil and its prodrug capecitabine.
Targeted cancer therapies, especially the tyrosine kinase inhibitors sorafenib and sunitinib, have also been associated with a high incidence of acral erythema. However, acral erythema due to tyrosine kinase inhibitors seems to differ somewhat from acral erythema due to classic chemotherapy drugs.
== Pathogenesis ==
The cause of palmar-plantar erythrodysesthesia (PPE) is unknown. Existing hypotheses are based on the fact that only the hands and feet are involved and posit the role of temperature differences, vascular anatomy, differences in the types of cells (rapidly dividing epidermal cells and eccrine glands).
In the case of PPE caused by pegylated liposomal doxorubicin (PLD), the following mechanism has been demonstrated: sweat deposits and spreads the drug on the skin surface; then the drug penetrates into the stratum corneum like an external agent; palms and soles have high density of sweat glands, and their stratum corneum is approximately 10 times thicker than the rest of the body, and becomes an efficient long-term reservoir for the penetrating PLD, which was deposited on the skin before.
== Diagnosis ==
Painful red swelling of the hands and feet in a patient receiving chemotherapy is usually enough to make the diagnosis. The problem can also arise in patients after bone marrow transplants, as the clinical and histologic features of PPE can be similar to cutaneous manifestations of acute (first three weeks) graft-versus-host disease. It is important to differentiate PPE, which is benign, from the more dangerous graft-versus-host disease. As time progresses, patients with graft-versus-host disease progress to have other body parts affected, while PPE is limited to hands and feet. Serial biopsies every 3 to 5 days can also be helpful in differentiating the two disorders.
== Prevention ==
The cooling of hands and feet during chemotherapy may help prevent PPE. Support for this and a variety of other approaches to treat or prevent acral erythema comes from small clinical studies, although none has been proven in a randomised controlled clinical trial of sufficient size.
Modifying some daily activities to reduce friction and heat exposure to your hands and feet for a period of time following treatment (approximately one week after IV medication, much as possible during the time you are taking oral medication such as capecitabine).
== Treatment ==
The main treatment for acral erythema is discontinuation of the offending drug, and symptomatic treatment to provide analgesia, lessen edema, and prevent superinfection. However, the treatment for the underlying cancer of the patient must not be neglected. Often, the discontinued drug can be substituted with another cancer drug or cancer treatment.
Symptomatic treatment can include wound care, elevation, and pain medication. Various emollients (creams) are recommended to keep skin moist. Corticosteroids and pyridoxine have also been used to relieve symptoms. Other studies do not support the conclusion. A number of additional remedies are listed in recent medical literature. Among them henna and 10% uridine ointment which went through clinical trial.
== Prognosis ==
Hand-foot invariably recurs with the resumption of chemotherapy. Long-term chemotherapy may also result in reversible palmoplantar keratoderma. Symptoms resolve 1–2 weeks after cessation of chemotherapy. The range is 1–5 weeks, so it has recovered by the time the next cycle is due. Healing occurs without scarring unless there has been skin ulceration or necrosis. With each subsequent cycle of chemotherapy, the reaction will appear more quickly, be more severe and will take longer to heal.
== History ==
Hand-foot syndrome was first reported in association with chemotherapy by Zuehlke in 1974.
Synonyms for acral erythema (AE) include: hand-foot syndrome, palmar-plantar erythrodysesthesia, peculiar AE, chemotherapy-induced AE, toxic erythema of the palms and soles, palmar-plantar erythema, and Burgdorf's reaction. Common abbreviations are HFS and PPE.
== References ==
== Further reading ==
Farr, Katherina Podlekareva; Safwat, Akmal (2011). "Palmar-Plantar Erythrodysesthesia Associated with Chemotherapy and Its Treatment". Case Reports in Oncology. 4 (1): 229–235. doi:10.1159/000327767. PMC 3085037. PMID 21537373.
Hand-Foot Syndrome or Palmar-Plantar Erythrodysesthesia (1 & 2) | Wikipedia/Chemotherapy-induced_acral_erythema |
Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective (e.g. by preventing receptor binding), to induce a specific cell signal (by activating receptors), to cause the immune system to attack specific cells, or to bring a drug to a specific cell type (such as with radioimmunotherapy which delivers cytotoxic radiation).
Major applications include cancer, autoimmune diseases, asthma, organ transplants, blood clot prevention, and certain infections.
== Antibody structure and function ==
Immunoglobulin G (IgG) antibodies are large heterodimeric molecules, approximately 150 kDa and are composed of two kinds of polypeptide chain, called the heavy (~50kDa) and the light chain (~25kDa). The two types of light chains are kappa (κ) and lambda (λ). By cleavage with enzyme papain, the Fab (fragment-antigen binding) part can be separated from the Fc (fragment crystallizable region) part of the molecule. The Fab fragments contain the variable domains, which consist of three antibody hypervariable amino acid domains responsible for the antibody specificity embedded into constant regions. The four known IgG subclasses are involved in antibody-dependent cellular cytotoxicity.
Antibodies are a key component of the adaptive immune response, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens presented on the surfaces of tumors. Monoclonal antibodies can be acquired in the immune system via passive immunity or active immunity. The advantage of active monoclonal antibody therapy is the fact that the immune system will produce antibodies long-term, with only a short-term drug administration to induce this response. However, the immune response to certain antigens may be inadequate, especially in the elderly. Additionally, adverse reactions from these antibodies may occur because of long-lasting response to antigens. Passive monoclonal antibody therapy can ensure consistent antibody concentration, and can control for adverse reactions by stopping administration. However, the repeated administration and consequent higher cost for this therapy are major disadvantages.
Monoclonal antibody therapy may prove to be beneficial for cancer, autoimmune diseases, and neurological disorders that result in the degeneration of body cells, such as Alzheimer's disease. Monoclonal antibody therapy can aid the immune system because the innate immune system responds to the environmental factors it encounters by discriminating against foreign cells from cells of the body. Therefore, tumor cells that are proliferating at high rates, or body cells that are dying which subsequently cause physiological problems are generally not specifically targeted by the immune system, since tumor cells are the patient's own cells. Tumor cells, however are highly abnormal, and many display unusual antigens. Some such tumor antigens are inappropriate for the cell type or its environment. Monoclonal antibodies can target tumor cells or abnormal cells in the body that are recognized as body cells, but are debilitating to one's health.
== History ==
Immunotherapy developed in the 1970s following the discovery of the structure of antibodies and the development of hybridoma technology, which provided the first reliable source of monoclonal antibodies. These advances allowed for the specific targeting of tumors both in vitro and in vivo. Initial research on malignant neoplasms found mAb therapy of limited and generally short-lived success with blood malignancies. Treatment also had to be tailored to each individual patient, which was impracticable in routine clinical settings.
Four major antibody types that have been developed are murine, chimeric, humanised and human. Antibodies of each type are distinguished by suffixes on their name.
=== Murine ===
Initial therapeutic antibodies were murine analogues (suffix -omab). These antibodies have: a short half-life in vivo (due to immune complex formation), limited penetration into tumour sites and inadequately recruit host effector functions. Chimeric and humanized antibodies have generally replaced them in therapeutic antibody applications. Understanding of proteomics has proven essential in identifying novel tumour targets.
Initially, murine antibodies were obtained by hybridoma technology, for which Jerne, Köhler and Milstein received a Nobel prize. However the dissimilarity between murine and human immune systems led to the clinical failure of these antibodies, except in some specific circumstances. Major problems associated with murine antibodies included reduced stimulation of cytotoxicity and the formation of complexes after repeated administration, which resulted in mild allergic reactions and sometimes anaphylactic shock. Hybridoma technology has been replaced by recombinant DNA technology, transgenic mice and phage display.
=== Chimeric and humanized ===
To reduce murine antibody immunogenicity (attacks by the immune system against the antibody), murine molecules were engineered to remove immunogenic content and to increase immunologic efficiency. This was initially achieved by the production of chimeric (suffix -ximab) and humanized antibodies (suffix -zumab). Chimeric antibodies are composed of murine variable regions fused onto human constant regions. Taking human gene sequences from the kappa light chain and the IgG1 heavy chain results in antibodies that are approximately 65% human. This reduces immunogenicity, and thus increases serum half-life.
Humanised antibodies are produced by grafting murine hypervariable regions on amino acid domains into human antibodies. This results in a molecule of approximately 95% human origin. Humanised antibodies bind antigen much more weakly than the parent murine monoclonal antibody, with reported decreases in affinity of up to several hundredfold. Increases in antibody-antigen binding strength have been achieved by introducing mutations into the complementarity determining regions (CDR), using techniques such as chain-shuffling, randomization of complementarity-determining regions and antibodies with mutations within the variable regions induced by error-prone PCR, E. coli mutator strains and site-specific mutagenesis.
=== Human monoclonal antibodies ===
Human monoclonal antibodies (suffix -umab) are produced using transgenic mice or phage display libraries by transferring human immunoglobulin genes into the murine genome and vaccinating the transgenic mouse against the desired antigen, leading to the production of appropriate monoclonal antibodies. Murine antibodies in vitro are thereby transformed into fully human antibodies.
The heavy and light chains of human IgG proteins are expressed in structural polymorphic (allotypic) forms. Human IgG allotype is one of the many factors that can contribute to immunogenicity.
== Targeted conditions ==
=== Cancer ===
Anti-cancer monoclonal antibodies can be targeted against malignant cells by several mechanisms. Ramucirumab is a recombinant human monoclonal antibody and is used in the treatment of advanced malignancies. In childhood lymphoma, phase I and II studies have found a positive effect of using antibody therapy.
Monoclonal antibodies used to boost an anticancer immune response is another strategy to fight cancer where cancer cells are not targeted directly. Strategies include antibodies engineered to block mechanisms which downregulate anticancer immune responses, checkpoints such as PD-1 and CTLA-4 (checkpoint therapy), and antibodies modified to stimulate activation of immune cells.
=== Autoimmune diseases ===
Monoclonal antibodies used for autoimmune diseases include infliximab and adalimumab, which are effective in rheumatoid arthritis, Crohn's disease and ulcerative colitis by their ability to bind to and inhibit TNF-α. Basiliximab and daclizumab inhibit IL-2 on activated T cells and thereby help preventing acute rejection of kidney transplants. Omalizumab inhibits human immunoglobulin E (IgE) and is useful in moderate-to-severe allergic asthma.
=== Alzheimer's disease ===
Alzheimer's disease (AD) is a multi-faceted, age-dependent, progressive neurodegenerative disorder, and is a major cause of dementia. According to the Amyloid hypothesis, the accumulation of extracellular amyloid beta peptides (Aβ) into plaques via oligomerization leads to hallmark symptomatic conditions of AD through synaptic dysfunction and neurodegeneration. Immunotherapy via exogenous monoclonal antibody (mAb) administration has been known to treat various central nervous disorders. In the case of AD, immunotherapy is believed to inhibit Aβ-oligomerization or clearing of Aβ from the brain and thereby prevent neurotoxicity.
However, mAbs are large molecules and due to the blood–brain barrier, uptake of mAb into the brain is extremely limited, only approximately 1 of 1000 mAb molecules is estimated to pass. However, the Peripheral Sink hypothesis proposes a mechanism where mAbs may not need to cross the blood–brain barrier. Therefore, many research studies are being conducted from failed attempts to treat AD in the past.
However, anti-Aβ vaccines can promote antibody-mediated clearance of Aβ plaques in transgenic mice models with amyloid precursor proteins (APP), and can reduce cognitive impairments. Vaccines can stimulate the immune system to produce its own antibodies, in the case of Alzheimer's disease by administration of the antigen Aβ. This is also known as active immunotherapy. Another strategy is so called passive immunotherapy. In this case the antibodies is produced externally in cultured cells and are delivered to the patient in the form of a drug. In mice expressing APP, both active and passive immunization of anti-Aβ antibodies has been shown to be effective in clearing plaques, and can improve cognitive function.
Currently, there are two FDA approved antibody therapies for Alzheimer's disease, Aducanemab and Lecanemab. Aducanemab has received accelerated approval while Lecanemab has received full approval. Several clinical trials using passive and active immunization have been performed and some are on the way with expected results in a couple of years. The implementation of these drugs is often during the early onset of AD. One trial testing Foralumab seeks to determine if there is benefit in later stages of AD by reduction of brain inflammation. Other research and drug development for early intervention and AD prevention is ongoing. Examples of important mAb drugs that have been or are under evaluation for treatment of AD include Bapineuzumab, Solanezumab, Gautenerumab, Crenezumab, Aducanemab, Lecanemab and Donanemab.
==== Bapineuzumab ====
Bapineuzumab, a humanized anti-Aβ mAb, is directed against the N-terminus of Aβ. Phase II clinical trials of Bapineuzumab in mild to moderate AD patients resulted in reduced Aβ concentration in the brain. However, in patients with increased apolipoprotein (APOE) e4 carriers, Bapineuzumab treatment is also accompanied by vasogenic edema, a cytotoxic condition where the blood brain barrier has been disrupted thereby affecting white matter from excess accumulation of fluid from capillaries in intracellular and extracellular spaces of the brain.
In Phase III clinical trials, Bapineuzumab showed promising positive effect on biomarkers of AD but failed to show effect on cognitive decline. Therefore, Bapineuzumab was discontinued after failing in the Phase III clinical trial.
==== Solanezumab ====
Solanezumab, an anti-Aβ mAb, targets the N-terminus of Aβ. In Phase I and Phase II of clinical trials, Solanezumab treatment resulted in cerebrospinal fluid elevation of Aβ, thereby showing a reduced concentration of Aβ plaques. Additionally, there are no associated adverse side effects. Phase III clinical trials of Solanezumab brought about significant reduction in cognitive impairment in patients with mild AD, but not in patients with severe AD. However, Aβ concentration did not significantly change, along with other AD biomarkers, including phospho-tau expression, and hippocampal volume. Phase III clinical trials of Solanezumab failed as it did not show effect on cognitive decline in comparison to placebo.
==== Lecanemab ====
Lecanemab (BAN2401), is a humanized mAb that selectively targets toxic soluble Aβ protofibrils, In phase 3 clinical trials, Lecanemab showed a 27% slower cognitive decline after 18 months of treatment in comparison to placebo. The phase 3 clinical trials also reported infusion related reactions, amyloid-related imaging abnormalities and headaches as the most common side effects of Lecanemab. In July 2023 the FDA gave Lecanemab full approval for the treatment of Alzheimer's Disease and it was given the commercial name Leqembi.
==== Preventive trials ====
Failure of several drugs in Phase III clinical trials has led to AD prevention and early intervention for onset AD treatment endeavours. Passive anti-Aβ mAb treatment can be used for preventive attempts to modify AD progression before it causes extensive brain damage and symptoms. Trials using mAb treatment for patients positive for genetic risk factors, and elderly patients positive for indicators of AD are underway. This includes anti-AB treatment in Asymptomatic Alzheimer's Disease (A4), the Alzheimer's Prevention Initiative (API), and DIAN-TU.
The A4 study on older individuals who are positive for indicators of AD but are negative for genetic risk factors will test Solanezumab in Phase III Clinical Trials, as a follow-up of previous Solanezumab studies.
DIAN-TU, launched in December 2012, focuses on young patients positive for genetic mutations that are risks for AD. This study uses Solanezumab and Gautenerumab. Gautenerumab, the first fully human MAB that preferentially interacts with oligomerized Aβ plaques in the brain, caused significant reduction in Aβ concentration in Phase I clinical trials, preventing plaque formation and concentration without altering plasma concentration of the brain. Phase II and III clinical trials are currently being conducted.
== Therapy types ==
=== Radioimmunotherapy ===
Radioimmunotherapy (RIT) involves the use of radioactively-conjugated murine antibodies against cellular antigens. Most research involves their application to lymphomas, as these are highly radio-sensitive malignancies. To limit radiation exposure, murine antibodies were chosen, as their high immunogenicity promotes rapid tumor clearance. Tositumomab is an example used for non-Hodgkin's lymphoma.
=== Antibody-directed enzyme prodrug therapy ===
Antibody-directed enzyme prodrug therapy (ADEPT) involves the application of cancer-associated monoclonal antibodies that are linked to a drug-activating enzyme. Systemic administration of a non-toxic agent results in the antibody's conversion to a toxic drug, resulting in a cytotoxic effect that can be targeted at malignant cells. The clinical success of ADEPT treatments is limited.
=== Antibody-drug conjugates ===
Antibody-drug conjugates (ADCs) are antibodies linked to one or more drug molecules. Typically when the ADC meets the target cell (e.g. a cancerous cell) the drug is released to kill it. Many ADCs are in clinical development. As of 2016 a few have been approved.
=== Immunoliposome therapy ===
Immunoliposomes are antibody-conjugated liposomes. Liposomes can carry drugs or therapeutic nucleotides and when conjugated with monoclonal antibodies, may be directed against malignant cells. Immunoliposomes have been successfully used in vivo to convey tumour-suppressing genes into tumours, using an antibody fragment against the human transferrin receptor. Tissue-specific gene delivery using immunoliposomes has been achieved in brain and breast cancer tissue.
=== Checkpoint therapy ===
Checkpoint therapy uses antibodies and other techniques to circumvent the defenses that tumors use to suppress the immune system. Each defense is known as a checkpoint. Compound therapies combine antibodies to suppress multiple defensive layers. Known checkpoints include CTLA-4 targeted by ipilimumab, PD-1 targeted by nivolumab and pembrolizumab and the tumor microenvironment.
The tumor microenvironment (TME) features prevents the recruitment of T cells to the tumor. Ways include chemokine CCL2 nitration, which traps T cells in the stroma. Tumor vasculature helps tumors preferentially recruit other immune cells over T cells, in part through endothelial cell (EC)–specific expression of FasL, ETBR, and B7H3. Myelomonocytic and tumor cells can up-regulate expression of PD-L1, partly driven by hypoxic conditions and cytokine production, such as IFNβ. Aberrant metabolite production in the TME, such as the pathway regulation by IDO, can affect T cell functions directly and indirectly via cells such as Treg cells. CD8 cells can be suppressed by B cells regulation of TAM phenotypes. Cancer-associated fibroblasts (CAFs) have multiple TME functions, in part through extracellular matrix (ECM)–mediated T cell trapping and CXCL12-regulated T cell exclusion.
== FDA-approved therapeutic antibodies ==
The first FDA-approved therapeutic monoclonal antibody was a murine IgG2a CD3 specific transplant rejection drug, OKT3 (also called muromonab), in 1986. This drug found use in solid organ transplant recipients who became steroid resistant. Hundreds of therapies are undergoing clinical trials. Most are concerned with immunological and oncological targets.
Tositumomab – Bexxar – 2003 – CD20
Mogamulizumab – Poteligeo – August 2018 – CCR4
Moxetumomab pasudotox – Lumoxiti – September 2018 – CD22
Cemiplimab – Libtayo – September 2018 – PD-1
Polatuzumab vedotin – Polivy – June 2019 – CD79B
The bispecific antibodies have arrived in the clinic. In 2009, the bispecific antibody catumaxomab was approved in the European Union and was later withdrawn for commercial reasons. Others include amivantamab, blinatumomab, teclistamab, and emicizumab.
== Economics ==
Since 2000, the therapeutic market for monoclonal antibodies has grown exponentially. In 2006, the "big 5" therapeutic antibodies on the market were bevacizumab, trastuzumab (both oncology), adalimumab, infliximab (both autoimmune and inflammatory disorders, 'AIID') and rituximab (oncology and AIID) accounted for 80% of revenues in 2006. In 2007, eight of the 20 best-selling biotechnology drugs in the U.S. are therapeutic monoclonal antibodies. This rapid growth in demand for monoclonal antibody production has been well accommodated by the industrialization of mAb manufacturing.
== References ==
== External links ==
Cancer Management Handbook: Principles of Oncologic Pharmacotherapy(registration required) Archived 2009-05-15 at the Wayback Machine | Wikipedia/Monoclonal_antibody_therapy |
P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substrate specificity. It exists in animals, fungi, and bacteria, and it likely evolved as a defense mechanism against harmful substances.
P-gp is extensively distributed and expressed in the intestinal epithelium where it pumps xenobiotics (such as toxins or drugs) back into the intestinal lumen, in liver cells where it pumps them into bile ducts, in the cells of the proximal tubule of the kidney where it pumps them into urinary filtrate (in the proximal tubule), and in the capillary endothelial cells composing the blood–brain barrier and blood–testis barrier, where it pumps them back into the capillaries.
P-gp is a glycoprotein that in humans is encoded by the ABCB1 gene. P-gp is a well-characterized ABC-transporter (which transports a wide variety of substrates across extra- and intracellular membranes) of the MDR/TAP subfamily. The normal excretion of xenobiotics back into the gut lumen by P-gp pharmacokinetically reduces the efficacy of some pharmaceutical drugs (which are said to be P-gp substrates). In addition, some cancer cells also express large amounts of P-gp, further amplifying that effect and rendering these cancers multidrug resistant. Many drugs inhibit P-gp, typically incidentally rather than as their main mechanism of action; some foods do as well. Any such substance can sometimes be called a P-gp inhibitor.
P-gp was discovered in 1971 by Victor Ling.
== Gene ==
A 2015 review of polymorphisms in ABCB1 found that "the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance."
== Protein ==
P-gp is a 170 kDa transmembrane glycoprotein, which includes 10–15 kDa of N-terminal glycosylation. The N-terminal half of the protein contains six transmembrane helixes, followed by a large cytoplasmic domain with an ATP-binding site, and then a second section with six transmembrane helixes and an ATP-binding domain that shows over 65% of amino acid similarity with the first half of the polypeptide. In 2009, the first structure of a mammalian P-glycoprotein was solved (3G5U). The structure was derived from the mouse MDR3 gene product heterologously expressed in Pichia pastoris yeast. The structure of mouse P-gp is similar to structures of the bacterial ABC transporter MsbA (3B5W and 3B5X) that adopt an inward facing conformation that is believed to be important for binding substrate along the inner leaflet of the membrane. Additional structures (3G60 and 3G61) of P-gp were also solved revealing the binding site(s) of two different cyclic peptide substrate/inhibitors. The promiscuous binding pocket of P-gp is lined with aromatic amino acid side chains.
Through Molecular Dynamic (MD) simulations, this sequence was proved to have a direct impact in the transporter's structural stability (in the nucleotide-binding domains) and defining a lower boundary for the internal drug-binding pocket.
== Species, tissue, and subcellular distribution ==
P-gp is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum. P-gp is also found in brain capillary endothelial cells.
== Function ==
Substrate enters P-gp either from an opening within the inner leaflet of the membrane or from an opening at the cytoplasmic side of the protein. ATP binds at the cytoplasmic side of the protein. Following binding of each, ATP hydrolysis shifts the substrate into a position to be excreted from the cell. Release of the phosphate (from the original ATP molecule) occurs concurrently with substrate excretion. ADP is released, and a new molecule of ATP binds to the secondary ATP-binding site. Hydrolysis and release of ADP and a phosphate molecule resets the protein, so that the process can start again.
The protein belongs to the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. P-gp is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood–brain barrier. Mutations in this gene are associated with colchicine resistance and Inflammatory bowel disease 13. Alternative splicing and the use of alternative promoters results in multiple transcript variants.
P-gp transports various substrates across the cell membrane including:
Drugs such as colchicine, desloratadine, tacrolimus and quinidine.
Chemotherapeutic agents such as topoisomerase inhibitors (i.e. etoposide, doxorubicin), microtubule-targeted drugs (i.e. vinblastine), and tyrosine kinase inhibitors (i.e. gefitinib, sunitinib).
Lipids
Steroids
Xenobiotics
Peptides
Bilirubin
Cardiac glycosides like digoxin
Immunosuppressive agents
Glucocorticoids like dexamethasone
HIV-type 1 antiretroviral therapy agents like protease inhibitors and nonnucleoside reverse transcriptase inhibitors
Its ability to transport the above substrates accounts for the many roles of P-gp including:
Regulating the distribution and bioavailability of drugs
Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Thus, there is a reduced bioavailability, and therapeutic plasma concentrations are not attained. On the other hand, supratherapeutic plasma concentrations and drug toxicity may result because of decreased P-glycoprotein expression
Active cellular transport of antineoplastics resulting in multidrug resistance to these drugs
The removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestinal lumen
The transport of compounds out of the brain across the blood–brain barrier
Digoxin uptake
Prevention of ivermectin and loperamide entry into the central nervous system
The migration of dendritic cells
Protection of hematopoietic stem cells from toxins.
It is inhibited by many drugs, such as amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, and verapamil.
== Regulation of expression and function of P-gp in cancer cells ==
At the transcriptional level, the expression of P-gp has been intensively studied, and numerous transcription factors and pathways are known to play roles. A variety of transcription factors, such as p53, YB-1, and NF-κB are involved in the direct regulation of P-gp by binding to the promoter regions of the P-gp gene. Many cell signaling pathways are also involved in transcriptional regulation of P-gp. For example, the PI3K/Akt pathway and the Wnt/β-catenin pathway were reported to positively regulate the expression of P-gp. Mitogen-activated protein kinase (MAPK) signaling includes three pathways: the classical MAPK/ERK pathway, the p38 MAPK pathway, and the c-Jun N-terminal kinase (JNK) pathway, all of which were reported to have implications in the regulation of the expression of P-gp. Studies suggested that the MAPK/ERK pathway is involved in the positive regulation of P-gp; the p38 MAPK pathway negatively regulates the expression of the P-gp gene; and the JNK pathway was reported to be involved in both positive regulation and negative regulation of P-gp.
After 2008, microRNAs (miRNAs) were identified as new players in regulating the expression of P-gp in both transcriptional and post-transcriptional levels. Some miRNAs decrease the expression of P-gp. For example, miR-200c down-regulates the expression of P-gp through the JNK signaling pathway or ZEB1 and ZEB2; miR-145 down-regulates the mRNA of P-gp by directly binding to the 3'-UTR of the gene of P-gp and thus suppresses the translation of P-gp. Some other miRNAs increase the expression of P-gp. For example, miR-27a up-regulates P-gp expression by suppressing the Raf kinase inhibitor protein (RKIP); alternatively, miR-27a can also directly bind to the promoter of the P-gp gene, which works in a similar way with the mechanism of action of transcriptional factors.
The expression of P-gp is also regulated by post-translational events, such as post-transcriptional modification, degradation, and intracellular trafficking of P-gp. Pim-1 protects P-gp from ubiquitination and the following degradation in the proteasome. Small GTPases Rab5 down-regulates the endocytotic trafficking of P-gp and thus increases the functional P-gp level on the cell membrane; while Small GTPases Rab4 work in an opposite way: Rab4 down-regulates the exocytotic trafficking of P-gp from intracellular compartments to the cell membrane, and therefore decreases the functional P-gp level on the cell membrane.
== Clinical significance ==
=== Drug interactions ===
Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil, and duloxetine. Elacridar and CP 100356 are other common P-gp inhibitors. Zosuquidar and tariquidar were also developed with this in mind. Lastly, valspodar and reversan are other examples of such agents. ABCB1 is linked to the daily dose of warfarin required to maintain the INR to a target of 2.5. Patients with the GT or TT genotypes of the 2677G>T SNP require around 20% more warfarin daily.
Common pharmacological inducers of P-glycoprotein include carbamazepine, dexamethasone, doxorubicin, nefazodone, phenobarbital, phenytoin, prazosin, rifampicin, St. John's wort, tenofovir, tipranavir, trazodone, and vinblastine.
Substrates of P-glycoprotein are susceptible to changes in pharmacokinetics due to drug interactions with P-gp inhibitors or inducers. Some of these substrates include colchicine, ciclosporin, dabigatran, digoxin, diltiazem, fexofenadine, indinavir, morphine, and sirolimus.
=== Diseases (non-cancer) ===
Decreased P-gp expression has been found in Alzheimer's disease brains.
Altered P-gp function has also been linked to inflammatory bowel diseases (IBD); however, due to its ambivalent effects in intestinal inflammation many questions remain so far unanswered. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD. Mice deficient in MDR1A develop chronic intestinal inflammation spontaneously, which appears to resemble human ulcerative colitis.
=== Cancer ===
P-gp efflux activity is capable of lowering intracellular concentrations of otherwise beneficial compounds, such as chemotherapeutics and other medications, to sub-therapeutic levels. Consequently, P-gp overexpression is one of the main mechanisms behind decreased intracellular drug accumulation and development of multidrug resistance in human multidrug-resistant (MDR) cancers.
== History ==
P-gp was first characterized in 1976. P-gp was shown to be responsible for conferring multidrug resistance upon mutant cultured cancer cells that had developed resistance to cytotoxic drugs.
The structure of mouse P-gp, which has 87% sequence identity to human P-gp, was resolved by x-ray crystallography in 2009. The first structure of human P-gp was solved in 2018, with the protein in its ATP-bound, outward-facing conformation.
== Research ==
Radioactive verapamil can be used for measuring P-gp function with positron emission tomography.
P-gp is also used to differentiate transitional B cells from naive B cells. Dyes such as rhodamine 123 and MitoTracker dyes from Invitrogen can be used to make this differentiation.
=== MDR1 as a drug target ===
It has been suggested that MDR1 inhibitors might treat various diseases, especially cancers, but none have done well in clinical trials.
== Single nucleotide polymorphism rs1045642 ==
Single Nucleotide Polymorphism rs1045642 (3435T>C or 3435C>T) is important for the differential activity of the P-gp pump.
Homozygous subjects, identified with the TT genotype, are usually more able to extrude xenobiotics from the cell. A Homozygous genotype for the allele ABCB1/MDR1 is capable of a higher absorption from the blood vessels and a lower extrusion into the lumen.
Xenobiotics are extruded at a lower rate with heterozygous (CT) alleles compared to homozygous ones.
== References ==
== Further reading ==
== External links ==
P-Glycoprotein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
ABCB1 human gene location in the UCSC Genome Browser.
ABCB1 human gene details in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain. | Wikipedia/P-glycoprotein |
Hepatic veno-occlusive disease (VOD) or veno-occlusive disease with immunodeficiency is a potentially life-threatening condition in which some of the small veins in the liver are obstructed. It is a complication of high-dose chemotherapy given before a bone marrow transplant or excessive exposure to hepatotoxic pyrrolizidine alkaloids. It is classically marked by weight gain due to fluid retention, increased liver size, and raised levels of bilirubin in the blood. The name sinusoidal obstruction syndrome (SOS) is preferred if hepatic veno-occlusive disease happens as a result of chemotherapy or bone marrow transplantation.
Apart from chemotherapy, hepatic veno-occlusive disease may also occur after ingestion of certain plant alkaloids such as pyrrolizidine alkaloids (in some herbal teas), and has been described as part of a rare hereditary disease called hepatic venoocclusive disease with immunodeficiency (which results from mutations in the gene coding for a protein called SP110).
== Signs and symptoms ==
Features of hepatic veno-occlusive disease include weight gain, tender enlargement of the liver, ascites, and yellow discoloration of the skin; it often is associated with acute kidney failure.
== Pathophysiology ==
In the bone marrow transplant setting, hepatic veno-occlusive disease is felt to be due to injury to the hepatic venous endothelium from the conditioning regimen. Toxic agents causing veno-occlusive disease include plants as well as the medication cyclophosphamide.
== Diagnosis ==
Doppler ultrasound of the liver is typically utilized to confirm or suggest the diagnosis. Common findings on liver doppler ultrasound include increased phasicity of portal veins with eventual development of portal flow reversal. The liver is usually enlarged but maintained normal echogenicity. A liver biopsy is required for a definitive diagnosis.
== Treatment ==
Treatment generally includes supportive care including pain management and possibly diuretics. In those with severe disease due to a bone marrow transplant, defibrotide is a proposed treatment. It has been approved for use in severe cases in Europe and the United States. A placebo controlled trial, however, has not been done as of 2016.
== Prognosis ==
Mild disease has a risk of death of about 10% while moderate disease has a risk of death of 20%. When it occurs as a result of bone marrow transplant and multiorgan failure is present, the risk of death is greater than 80%.
== History ==
The first report on veno-occlusive disease, in 1920, was as a result of senecio poisoning in South Africa. Subsequent reports were mostly in Jamaicans who had consumed herbal teas. With the advent of bone marrow transplantation, most cases since its introduction have been in those undergoing treatment for leukemia.
== See also ==
Budd-Chiari syndrome (large liver vein obstruction due to hepatic vein thrombosis)
== References ==
== Further reading ==
Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. ISBN 978-0-7216-0187-8.
Wingard JR, Nichols WG, McDonald GB (2004). "Supportive care". Hematology Am Soc Hematol Educ Program. 1: 372–89. doi:10.1182/asheducation-2004.1.372. PMID 15561693.
Dignan, Fiona L.; Wynn, Robert F.; Hadzic, Nedim; Karani, John; Quaglia, Alberto; Pagliuca, Antonio; Veys, Paul; Potter, Michael N. (1 November 2013). "BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation". British Journal of Haematology. 163 (4): 444–457. doi:10.1111/bjh.12558. ISSN 1365-2141. PMID 24102514.
== External links == | Wikipedia/Hepatic_veno-occlusive_disease |
Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs), or it may aim only to prolong life or to reduce symptoms (palliative chemotherapy). Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.
The term chemotherapy now means the non-specific use of intracellular poisons to inhibit mitosis (cell division) or to induce DNA damage (so that DNA repair can augment chemotherapy). This meaning excludes the more-selective agents that block extracellular signals (signal transduction). Therapies with specific molecular or genetic targets, which inhibit growth-promoting signals from classic endocrine hormones (primarily estrogens for breast cancer and androgens for prostate cancer), are now called hormonal therapies. Other inhibitions of growth-signals, such as those associated with receptor tyrosine kinases, are targeted therapy.
The use of drugs (whether chemotherapy, hormonal therapy, or targeted therapy) is systemic therapy for cancer: they are introduced into the blood stream (the system) and therefore can treat cancer anywhere in the body. Systemic therapy is often used with other, local therapy (treatments that work only where they are applied), such as radiation, surgery, and hyperthermia.
Traditional chemotherapeutic agents are cytotoxic by means of interfering with cell division (mitosis) but cancer cells vary widely in their susceptibility to these agents. To a large extent, chemotherapy can be thought of as a way to damage or stress cells, which may then lead to cell death if apoptosis is initiated. Many of the side effects of chemotherapy can be traced to damage to normal cells that divide rapidly and are thus sensitive to anti-mitotic drugs: cells in the bone marrow, digestive tract and hair follicles. This results in the most common side-effects of chemotherapy: myelosuppression (decreased production of blood cells, hence that also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss). Because of the effect on immune cells (especially lymphocytes), chemotherapy drugs often find use in a host of diseases that result from harmful overactivity of the immune system against self (so-called autoimmunity). These include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, vasculitis and many others.
== Treatment strategies ==
There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.
Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.: 55–59
Combined modality chemotherapy is the use of drugs with other cancer treatments, such as surgery, radiation therapy, or hyperthermia therapy.
Consolidation chemotherapy is given after remission in order to prolong the overall disease-free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission.: 55–59
Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.: 55–59
Combination chemotherapy involves treating a person with a number of different drugs simultaneously. The drugs differ in their mechanism and side-effects. The biggest advantage is minimising the chances of resistance developing to any one agent. Also, the drugs can often be used at lower doses, reducing toxicity.: 55–59 : 17–18
Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor.: 55–59 It is also given for cancers with a high risk of micrometastatic disease.: 42
Adjuvant chemotherapy is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence.: 55–59 It is also useful in killing any cancerous cells that have spread to other parts of the body. These micrometastases can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells.
Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.: 55–59
Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, in general, a better toxicity profile is expected.: 55–59
All chemotherapy regimens require that the recipient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a person can receive chemotherapy, or whether dose reduction is required. Because only a fraction of the cells in a tumor die with each treatment (fractional kill), repeated doses must be administered to continue to reduce the size of the tumor. Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity.
=== Effectiveness ===
The effectiveness of chemotherapy depends on the type of cancer and the stage. The overall effectiveness ranges from being curative for some cancers, such as some leukemias, to being ineffective, such as in some brain tumors, to being needless in others, like most non-melanoma skin cancers.
=== Dosage ===
Dosage of chemotherapy can be difficult: If the dose is too low, it will be ineffective against the tumor, whereas, at excessive doses, the toxicity (side-effects) will be intolerable to the person receiving it. The standard method of determining chemotherapy dosage is based on calculated body surface area (BSA). The BSA is usually calculated with a mathematical formula or a nomogram, using the recipient's weight and height, rather than by direct measurement of body area. This formula was originally derived in a 1916 study and attempted to translate medicinal doses established with laboratory animals to equivalent doses for humans. The study only included nine human subjects. When chemotherapy was introduced in the 1950s, the BSA formula was adopted as the official standard for chemotherapy dosing for lack of a better option.
The validity of this method in calculating uniform doses has been questioned because the formula only takes into account the individual's weight and height. Drug absorption and clearance are influenced by multiple factors, including age, sex, metabolism, disease state, organ function, drug-to-drug interactions, genetics, and obesity, which have major impacts on the actual concentration of the drug in the person's bloodstream. As a result, there is high variability in the systemic chemotherapy drug concentration in people dosed by BSA, and this variability has been demonstrated to be more than ten-fold for many drugs. In other words, if two people receive the same dose of a given drug based on BSA, the concentration of that drug in the bloodstream of one person may be 10 times higher or lower compared to that of the other person. This variability is typical with many chemotherapy drugs dosed by BSA, and, as shown below, was demonstrated in a study of 14 common chemotherapy drugs.
The result of this pharmacokinetic variability among people is that many people do not receive the right dose to achieve optimal treatment effectiveness with minimized toxic side effects. Some people are overdosed while others are underdosed. For example, in a randomized clinical trial, investigators found 85% of metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) did not receive the optimal therapeutic dose when dosed by the BSA standard—68% were underdosed and 17% were overdosed.
There has been controversy over the use of BSA to calculate chemotherapy doses for people who are obese. Because of their higher BSA, clinicians often arbitrarily reduce the dose prescribed by the BSA formula for fear of overdosing. In many cases, this can result in sub-optimal treatment.
Several clinical studies have demonstrated that when chemotherapy dosing is individualized to achieve optimal systemic drug exposure, treatment outcomes are improved and toxic side effects are reduced. In the 5-FU clinical study cited above, people whose dose was adjusted to achieve a pre-determined target exposure realized an 84% improvement in treatment response rate and a six-month improvement in overall survival (OS) compared with those dosed by BSA.
In the same study, investigators compared the incidence of common 5-FU-associated grade 3/4 toxicities between the dose-adjusted people and people dosed per BSA. The incidence of debilitating grades of diarrhea was reduced from 18% in the BSA-dosed group to 4% in the dose-adjusted group and serious hematologic side effects were eliminated. Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time. BSA-dosed people were treated for a total of 680 months while people in the dose-adjusted group were treated for a total of 791 months. Completing the course of treatment is an important factor in achieving better treatment outcomes.
Similar results were found in a study involving people with colorectal cancer who have been treated with the popular FOLFOX regimen. The incidence of serious diarrhea was reduced from 12% in the BSA-dosed group of patients to 1.7% in the dose-adjusted group, and the incidence of severe mucositis was reduced from 15% to 0.8%.
The FOLFOX study also demonstrated an improvement in treatment outcomes. Positive response increased from 46% in the BSA-dosed group to 70% in the dose-adjusted group. Median progression free survival (PFS) and overall survival (OS) both improved by six months in the dose adjusted group.
One approach that can help clinicians individualize chemotherapy dosing is to measure the drug levels in blood plasma over time and adjust dose according to a formula or algorithm to achieve optimal exposure. With an established target exposure for optimized treatment effectiveness with minimized toxicities, dosing can be personalized to achieve target exposure and optimal results for each person. Such an algorithm was used in the clinical trials cited above and resulted in significantly improved treatment outcomes.
Oncologists are already individualizing dosing of some cancer drugs based on exposure. Carboplatin: 4 and busulfan dosing rely upon results from blood tests to calculate the optimal dose for each person. Simple blood tests are also available for dose optimization of methotrexate, 5-FU, paclitaxel, and docetaxel.
The serum albumin level immediately prior to chemotherapy administration is an independent prognostic predictor of survival in various cancer types.
=== Types ===
==== Alkylating agents ====
Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from mustard gas used in World War I, there are now many types of alkylating agents in use. They are so named because of their ability to alkylate many molecules, including proteins, RNA and DNA. This ability to bind covalently to DNA via their alkyl group is the primary cause for their anti-cancer effects. DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during cell division, or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called apoptosis. Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason, the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug.
The subtypes of alkylating agents are the nitrogen mustards, nitrosoureas, tetrazines, aziridines, cisplatins and derivatives, and non-classical alkylating agents. Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan. Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin. Tetrazines include dacarbazine, mitozolomide and temozolomide. Aziridines include thiotepa, mytomycin and diaziquone (AZQ). Cisplatin and derivatives include cisplatin, carboplatin and oxaliplatin. They impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules. Non-classical alkylating agents include procarbazine and hexamethylmelamine.
==== Antimetabolites ====
Anti-metabolites are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are nucleotides; a molecule comprising a nucleobase, a sugar and a phosphate group. The nucleobases are divided into purines (guanine and adenine) and pyrimidines (cytosine, thymine and uracil). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered chemical groups. These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting the enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, DNA damage can occur and programmed cell death (apoptosis) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case S-phase (the DNA synthesis phase). For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the anti-folates, fluoropyrimidines, deoxynucleoside analogues and thiopurines.
The anti-folates include methotrexate and pemetrexed. Methotrexate inhibits dihydrofolate reductase (DHFR), an enzyme that regenerates tetrahydrofolate from dihydrofolate. When the enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for thymidylate and purine production, which are both essential for DNA synthesis and cell division.: 55–59 : 11 Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme thymidylate synthase, but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase. The fluoropyrimidines include fluorouracil and capecitabine. Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death.: 11 Capecitabine is a prodrug of 5-fluorouracil that is broken down in cells to produce the active drug. The deoxynucleoside analogues include cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, and pentostatin. The thiopurines include thioguanine and mercaptopurine.
==== Anti-microtubule agents ====
Anti-microtubule agents are plant-derived chemicals that block cell division by preventing microtubule function. Microtubules are an important cellular structure composed of two proteins, α-tubulin and β-tubulin. They are hollow, rod-shaped structures that are required for cell division, among other cellular functions. Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite: Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. By doing so, they can induce mitotic catastrophe in the cancer cells. Following this, cell cycle arrest occurs, which induces programmed cell death (apoptosis). These drugs can also affect blood vessel growth, an essential process that tumours utilise in order to grow and metastasise.
Vinca alkaloids are derived from the Madagascar periwinkle, Catharanthus roseus, formerly known as Vinca rosea. They bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules. The original vinca alkaloids are natural products that include vincristine and vinblastine. Following the success of these drugs, semi-synthetic vinca alkaloids were produced: vinorelbine (used in the treatment of non-small-cell lung cancer), vindesine, and vinflunine. These drugs are cell cycle-specific. They bind to the tubulin molecules in S-phase and prevent proper microtubule formation required for M-phase.
Taxanes are natural and semi-synthetic drugs. The first drug of their class, paclitaxel, was originally extracted from Taxus brevifolia, the Pacific yew. Now this drug and another in this class, docetaxel, are produced semi-synthetically from a chemical found in the bark of another yew tree, Taxus baccata.
Podophyllotoxin is an antineoplastic lignan obtained primarily from the American mayapple (Podophyllum peltatum) and Himalayan mayapple (Sinopodophyllum hexandrum). It has anti-microtubule activity, and its mechanism is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation. Podophyllotoxin is used to produce two other drugs with different mechanisms of action: etoposide and teniposide.
==== Topoisomerase inhibitors ====
Topoisomerase inhibitors are drugs that affect the activity of two enzymes: topoisomerase I and topoisomerase II. When the DNA double-strand helix is unwound, during DNA replication or transcription, for example, the adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single- or double-strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes.
Two topoisomerase I inhibitors, irinotecan and topotecan, are semi-synthetically derived from camptothecin, which is obtained from the Chinese ornamental tree Camptotheca acuminata. Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and transcription, causes DNA strand breaks, and leads to programmed cell death (apoptosis). These agents include etoposide, doxorubicin, mitoxantrone and teniposide. The second group, catalytic inhibitors, are drugs that block the activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes novobiocin, merbarone, and aclarubicin, which also have other significant mechanisms of action.
==== Cytotoxic antibiotics ====
The cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action. The common theme that they share in their chemotherapy indication is that they interrupt cell division. The most important subgroup is the anthracyclines and the bleomycins; other prominent examples include mitomycin C and actinomycin.
Among the anthracyclines, doxorubicin and daunorubicin were the first, and were obtained from the bacterium Streptomyces peucetius. Derivatives of these compounds include epirubicin and idarubicin. Other clinically used drugs in the anthracycline group are pirarubicin, aclarubicin, and mitoxantrone. The mechanisms of anthracyclines include DNA intercalation (molecules insert between the two strands of DNA), generation of highly reactive free radicals that damage intercellular molecules and topoisomerase inhibition.
Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis.
Bleomycin, a glycopeptide isolated from Streptomyces verticillus, also intercalates DNA, but produces free radicals that damage DNA. This occurs when bleomycin binds to a metal ion, becomes chemically reduced and reacts with oxygen.: 87
Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.
=== Delivery ===
Most chemotherapy is delivered intravenously, although a number of agents can be administered orally (e.g., melphalan, busulfan, capecitabine). According to a recent (2016) systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans.
There are many intravenous methods of drug delivery, known as vascular access devices. These include the winged infusion device, peripheral venous catheter, midline catheter, peripherally inserted central catheter (PICC), central venous catheter and implantable port. The devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent.: 94–95
Depending on the person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or an outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access.: 113–118 Commonly used systems are the Hickman line, the Port-a-Cath, and the PICC line. These have a lower infection risk, are much less prone to phlebitis or extravasation, and eliminate the need for repeated insertion of peripheral cannulae.
Isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumors. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases.
Topical chemotherapies, such as 5-fluorouracil, are used to treat some cases of non-melanoma skin cancer.
If the cancer has central nervous system involvement, or with meningeal disease, intrathecal chemotherapy may be administered.
== Adverse effects ==
Chemotherapeutic techniques have a range of side effects that depend on the type of medications used. The most common medications affect mainly the fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. Chemotherapy-related iatrogenic toxicities can occur acutely after administration, within hours or days, or chronically, from weeks to years.: 265
=== Immunosuppression and myelosuppression ===
Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells, and platelets.
Anemia and thrombocytopenia may require blood transfusion. Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can be improved with synthetic G-CSF (granulocyte-colony-stimulating factor, e.g., filgrastim, lenograstim, efbemalenograstim alfa).
In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells that produce white and red blood cells) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the person before the treatment, multiplied and then re-injected afterward; in allogenic BMTs, the source is a donor.) However, some people still develop diseases because of this interference with bone marrow.
Although people receiving chemotherapy are encouraged to wash their hands, avoid sick people, and take other infection-reducing steps, about 85% of infections are due to naturally occurring microorganisms in the person's own gastrointestinal tract (including oral cavity) and skin.: 130 This may manifest as systemic infections, such as sepsis, or as localized outbreaks, such as Herpes simplex, shingles, or other members of the Herpesviridea. The risk of illness and death can be reduced by taking common antibiotics such as quinolones or trimethoprim/sulfamethoxazole before any fever or sign of infection appears. Quinolones show effective prophylaxis mainly with hematological cancer. However, in general, for every five people who are immunosuppressed following chemotherapy who take an antibiotic, one fever can be prevented; for every 34 who take an antibiotic, one death can be prevented. Sometimes, chemotherapy treatments are postponed because the immune system is suppressed to a critically low level.
In Japan, the government has approved the use of some medicinal mushrooms like Trametes versicolor, to counteract depression of the immune system in people undergoing chemotherapy.
Trilaciclib is an inhibitor of cyclin-dependent kinase 4/6 approved for the prevention of myelosuppression caused by chemotherapy. The drug is given before chemotherapy to protect bone marrow function.
=== Neutropenic enterocolitis ===
Due to immune system suppression, neutropenic enterocolitis (typhlitis) is a "life-threatening gastrointestinal complication of chemotherapy." Typhlitis is an intestinal infection which may manifest itself through symptoms including nausea, vomiting, diarrhea, a distended abdomen, fever, chills, or abdominal pain and tenderness.
Typhlitis is a medical emergency. It has a very poor prognosis and is often fatal unless promptly recognized and aggressively treated. Successful treatment hinges on early diagnosis provided by a high index of suspicion and the use of CT scanning, nonoperative treatment for uncomplicated cases, and sometimes elective right hemicolectomy to prevent recurrence.
=== Gastrointestinal distress ===
Nausea, vomiting, anorexia, diarrhea, abdominal cramps, and constipation are common side-effects of chemotherapeutic medications that kill fast-dividing cells. Malnutrition and dehydration can result when the recipient does not eat or drink enough, or when the person vomits frequently, because of gastrointestinal damage. This can result in rapid weight loss, or occasionally in weight gain, if the person eats too much in an effort to allay nausea or heartburn. Weight gain can also be caused by some steroid medications. These side-effects can frequently be reduced or eliminated with antiemetic drugs. Low-certainty evidence also suggests that probiotics may have a preventative and treatment effect of diarrhoea related to chemotherapy alone and with radiotherapy. However, a high index of suspicion is appropriate, since diarrhoea and bloating are also symptoms of typhlitis, a very serious and potentially life-threatening medical emergency that requires immediate treatment.
=== Anemia ===
Anemia can be a combined outcome caused by myelosuppressive chemotherapy, and possible cancer-related causes such as bleeding, blood cell destruction (hemolysis), hereditary disease, kidney dysfunction, nutritional deficiencies or anemia of chronic disease. Treatments to mitigate anemia include hormones to boost blood production (erythropoietin), iron supplements, and blood transfusions. Myelosuppressive therapy can cause a tendency to bleed easily, leading to anemia. Medications that kill rapidly dividing cells or blood cells can reduce the number of platelets in the blood, which can result in bruises and bleeding. Extremely low platelet counts may be temporarily boosted through platelet transfusions and new drugs to increase platelet counts during chemotherapy are being developed. Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover.
Fatigue may be a consequence of the cancer or its treatment, and can last for months to years after treatment. One physiological cause of fatigue is anemia, which can be caused by chemotherapy, surgery, radiotherapy, primary and metastatic disease or nutritional depletion. Aerobic exercise has been found to be beneficial in reducing fatigue in people with solid tumours.
=== Nausea and vomiting ===
Nausea and vomiting are two of the most feared cancer treatment-related side-effects for people with cancer and their families. In 1983, Coates et al. found that people receiving chemotherapy ranked nausea and vomiting as the first and second most severe side-effects, respectively. Up to 20% of people receiving highly emetogenic agents in this era postponed, or even refused potentially curative treatments. Chemotherapy-induced nausea and vomiting (CINV) are common with many treatments and some forms of cancer. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to successfully manage these symptoms in many people. Effective mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the recipient and more efficient treatment cycles, as patients are less likely to avoid or refuse treatment.
=== Hair loss ===
Hair loss (alopecia) can be caused by chemotherapy that kills rapidly dividing cells; other medications may cause hair to thin. These are most often temporary effects: hair usually starts to regrow a few weeks after the last treatment, but sometimes with a change in color, texture, thickness or style. Sometimes hair has a tendency to curl after regrowth, resulting in "chemo curls." Severe hair loss occurs most often with drugs such as doxorubicin, daunorubicin, paclitaxel, docetaxel, cyclophosphamide, ifosfamide and etoposide. Permanent thinning or hair loss can result from some standard chemotherapy regimens.
Chemotherapy induced hair loss occurs by a non-androgenic mechanism, and can manifest as alopecia totalis, telogen effluvium, or less often alopecia areata. It is usually associated with systemic treatment due to the high mitotic rate of hair follicles, and more reversible than androgenic hair loss, although permanent cases can occur. Chemotherapy induces hair loss in women more often than men.
Scalp cooling offers a means of preventing both permanent and temporary hair loss; however, concerns about this method have been raised.
=== Secondary neoplasm ===
Development of secondary neoplasia after successful chemotherapy or radiotherapy treatment can occur. The most common secondary neoplasm is secondary acute myeloid leukemia, which develops primarily after treatment with alkylating agents or topoisomerase inhibitors. Survivors of childhood cancer are more than 13 times as likely to get a secondary neoplasm during the 30 years after treatment than the general population. Not all of this increase can be attributed to chemotherapy.
=== Infertility ===
Some types of chemotherapy are gonadotoxic and may cause infertility. Chemotherapies with high risk include procarbazine and other alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil, and chlormethine. Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin. On the other hand, therapies with low risk of gonadotoxicity include plant derivatives such as vincristine and vinblastine, antibiotics such as bleomycin and dactinomycin, and antimetabolites such as methotrexate, mercaptopurine, and 5-fluorouracil.
Female infertility by chemotherapy appears to be secondary to premature ovarian failure by loss of primordial follicles. This loss is not necessarily a direct effect of the chemotherapeutic agents, but could be due to an increased rate of growth initiation to replace damaged developing follicles.
People may choose between several methods of fertility preservation prior to chemotherapy, including cryopreservation of semen, ovarian tissue, oocytes, or embryos. As more than half of cancer patients are elderly, this adverse effect is only relevant for a minority of patients. A study in France between 1999 and 2011 came to the result that embryo freezing before administration of gonadotoxic agents to females caused a delay of treatment in 34% of cases, and a live birth in 27% of surviving cases who wanted to become pregnant, with the follow-up time varying between 1 and 13 years.
Potential protective or attenuating agents include GnRH analogs, where several studies have shown a protective effect in vivo in humans, but some studies show no such effect. Sphingosine-1-phosphate (S1P) has shown similar effect, but its mechanism of inhibiting the sphingomyelin apoptotic pathway may also interfere with the apoptosis action of chemotherapy drugs.
In chemotherapy as a conditioning regimen in hematopoietic stem cell transplantation, a study of people conditioned with cyclophosphamide alone for severe aplastic anemia came to the result that ovarian recovery occurred in all women younger than 26 years at time of transplantation, but only in five of 16 women older than 26 years.
=== Teratogenicity ===
Chemotherapy is teratogenic during pregnancy, especially during the first trimester, to the extent that abortion usually is recommended if pregnancy in this period is found during chemotherapy. Second- and third-trimester exposure does not usually increase the teratogenic risk and adverse effects on cognitive development, but it may increase the risk of various complications of pregnancy and fetal myelosuppression.
Female patients of reproductive potential should use effective contraception during chemotherapy and for a few months after the last dose (e.g. 6 month for doxorubicin).
In males previously having undergone chemotherapy or radiotherapy, there appears to be no increase in genetic defects or congenital malformations in their children conceived after therapy. The use of assisted reproductive technologies and micromanipulation techniques might increase this risk. In females previously having undergone chemotherapy, miscarriage and congenital malformations are not increased in subsequent conceptions. However, when in vitro fertilization and embryo cryopreservation is practised between or shortly after treatment, possible genetic risks to the growing oocytes exist, and hence it has been recommended that the babies be screened.
=== Peripheral neuropathy ===
Between 30 and 40 percent of people undergoing chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), a progressive, enduring, and often irreversible condition, causing pain, tingling, numbness and sensitivity to cold, beginning in the hands and feet and sometimes progressing to the arms and legs. Chemotherapy drugs associated with CIPN include thalidomide, epothilones, vinca alkaloids, taxanes, proteasome inhibitors, and the platinum-based drugs. Whether CIPN arises, and to what degree, is determined by the choice of drug, duration of use, the total amount consumed and whether the person already has peripheral neuropathy. Though the symptoms are mainly sensory, in some cases motor nerves and the autonomic nervous system are affected. CIPN often follows the first chemotherapy dose and increases in severity as treatment continues, but this progression usually levels off at completion of treatment. The platinum-based drugs are the exception; with these drugs, sensation may continue to deteriorate for several months after the end of treatment. Some CIPN appears to be irreversible. Pain can often be managed with drug or other treatment but the numbness is usually resistant to treatment.
=== Cognitive impairment ===
Some people receiving chemotherapy report fatigue or non-specific neurocognitive problems, such as an inability to concentrate; this is sometimes called post-chemotherapy cognitive impairment, referred to as "chemo brain" in popular and social media.
=== Tumor lysis syndrome ===
In particularly large tumors and cancers with high white cell counts, such as lymphomas, teratomas, and some leukemias, some people develop tumor lysis syndrome. The rapid breakdown of cancer cells causes the release of chemicals from the inside of the cells. Following this, high levels of uric acid, potassium and phosphate are found in the blood. High levels of phosphate induce secondary hypoparathyroidism, resulting in low levels of calcium in the blood. This causes kidney damage and the high levels of potassium can cause cardiac arrhythmia. Although prophylaxis is available and is often initiated in people with large tumors, this is a dangerous side-effect that can lead to death if left untreated.: 202
=== Organ damage ===
Cardiotoxicity (heart damage) is especially prominent with the use of anthracycline drugs (doxorubicin, epirubicin, idarubicin, and liposomal doxorubicin). The cause of this is most likely due to the production of free radicals in the cell and subsequent DNA damage. Other chemotherapeutic agents that cause cardiotoxicity, but at a lower incidence, are cyclophosphamide, docetaxel and clofarabine.
Hepatotoxicity (liver damage) can be caused by many cytotoxic drugs. The susceptibility of an individual to liver damage can be altered by other factors such as the cancer itself, viral hepatitis, immunosuppression and nutritional deficiency. The liver damage can consist of damage to liver cells, hepatic sinusoidal syndrome (obstruction of the veins in the liver), cholestasis (where bile does not flow from the liver to the intestine) and liver fibrosis.
Nephrotoxicity (kidney damage) can be caused by tumor lysis syndrome and also due direct effects of drug clearance by the kidneys. Different drugs will affect different parts of the kidney and the toxicity may be asymptomatic (only seen on blood or urine tests) or may cause acute kidney injury.
Ototoxicity (damage to the inner ear) is a common side effect of platinum based drugs that can produce symptoms such as dizziness and vertigo. Children treated with platinum analogues have been found to be at risk for developing hearing loss.
=== Other side-effects ===
Less common side-effects include red skin (erythema), dry skin, damaged fingernails, a dry mouth (xerostomia), water retention, and sexual impotence. Some medications can trigger allergic or pseudoallergic reactions.
Specific chemotherapeutic agents are associated with organ-specific toxicities, including cardiovascular disease (e.g., doxorubicin), interstitial lung disease (e.g., bleomycin) and occasionally secondary neoplasm (e.g., MOPP therapy for Hodgkin's disease).
Hand-foot syndrome is another side effect to cytotoxic chemotherapy.
Nutritional problems are also frequently seen in cancer patients at diagnosis and through chemotherapy treatment. Research suggests that in children and young people undergoing cancer treatment, parenteral nutrition may help with this leading to weight gain and increased calorie and protein intake, when compared to enteral nutrition.
== Limitations ==
Chemotherapy does not always work, and even when it is useful, it may not completely destroy the cancer. People frequently fail to understand its limitations. In one study of people who had been newly diagnosed with incurable, stage 4 cancer, more than two-thirds of people with lung cancer and more than four-fifths of people with colorectal cancer still believed that chemotherapy was likely to cure their cancer.
The blood–brain barrier poses an obstacle to delivery of chemotherapy to the brain. This is because the brain has an extensive system in place to protect it from harmful chemicals. Drug transporters can pump out drugs from the brain and brain's blood vessel cells into the cerebrospinal fluid and blood circulation. These transporters pump out most chemotherapy drugs, which reduces their efficacy for treatment of brain tumors. Only small lipophilic alkylating agents such as lomustine or temozolomide are able to cross this blood–brain barrier.
Blood vessels in tumors are very different from those seen in normal tissues. As a tumor grows, tumor cells furthest away from the blood vessels become low in oxygen (hypoxic). To counteract this they then signal for new blood vessels to grow. The newly formed tumor vasculature is poorly formed and does not deliver an adequate blood supply to all areas of the tumor. This leads to issues with drug delivery because many drugs will be delivered to the tumor by the circulatory system.
== Resistance ==
Resistance is a major cause of treatment failure in chemotherapeutic drugs. There are a few possible causes of resistance in cancer, one of which is the presence of small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. Cancer cells produce high amounts of these pumps, known as p-glycoprotein, in order to protect themselves from chemotherapeutics. Research on p-glycoprotein and other such chemotherapy efflux pumps is currently ongoing. Medications to inhibit the function of p-glycoprotein are undergoing investigation, but due to toxicities and interactions with anti-cancer drugs their development has been difficult. Another mechanism of resistance is gene amplification, a process in which multiple copies of a gene are produced by cancer cells. This overcomes the effect of drugs that reduce the expression of genes involved in replication. With more copies of the gene, the drug can not prevent all expression of the gene and therefore the cell can restore its proliferative ability. Cancer cells can also cause defects in the cellular pathways of apoptosis (programmed cell death). As most chemotherapy drugs kill cancer cells in this manner, defective apoptosis allows survival of these cells, making them resistant. Many chemotherapy drugs also cause DNA damage, which can be repaired by enzymes in the cell that carry out DNA repair. Upregulation of these genes can overcome the DNA damage and prevent the induction of apoptosis. Mutations in genes that produce drug target proteins, such as tubulin, can occur which prevent the drugs from binding to the protein, leading to resistance to these types of drugs. Drugs used in chemotherapy can induce cell stress, which can kill a cancer cell; however, under certain conditions, cells stress can induce changes in gene expression that enables resistance to several types of drugs. In lung cancer, the transcription factor NFκB is thought to play a role in resistance to chemotherapy, via inflammatory pathways.
== Cytotoxics and targeted therapies ==
Targeted therapies are a relatively new class of cancer drugs that can overcome many of the issues seen with the use of cytotoxics. They are divided into two groups: small molecule and antibodies. The massive toxicity seen with the use of cytotoxics is due to the lack of cell specificity of the drugs. They will kill any rapidly dividing cell, tumor or normal. Targeted therapies are designed to affect cellular proteins or processes that are utilised by the cancer cells. This allows a high dose to cancer tissues with a relatively low dose to other tissues. Although the side effects are often less severe than that seen of cytotoxic chemotherapeutics, life-threatening effects can occur. Initially, the targeted therapeutics were supposed to be solely selective for one protein. Now it is clear that there is often a range of protein targets that the drug can bind. An example target for targeted therapy is the BCR-ABL1 protein produced from the Philadelphia chromosome, a genetic lesion found commonly in chronic myelogenous leukemia and in some patients with acute lymphoblastic leukemia. This fusion protein has enzyme activity that can be inhibited by imatinib, a small molecule drug.
== Mechanism of action ==
Cancer is the uncontrolled growth of cells coupled with malignant behaviour: invasion and metastasis (among other features). It is caused by the interaction between genetic susceptibility and environmental factors. These factors lead to accumulations of genetic mutations in oncogenes (genes that control the growth rate of cells) and tumor suppressor genes (genes that help to prevent cancer), which gives cancer cells their malignant characteristics, such as uncontrolled growth.: 93–94
In the broad sense, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells, they are termed cytotoxic. They prevent mitosis by various mechanisms including damaging DNA and inhibition of the cellular machinery involved in cell division. One theory as to why these drugs kill cancer cells is that they induce a programmed form of cell death known as apoptosis.
As chemotherapy affects cell division, tumors with high growth rates (such as acute myelogenous leukemia and the aggressive lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time. Malignancies with slower growth rates, such as indolent lymphomas, tend to respond to chemotherapy much more modestly. Heterogeneic tumours may also display varying sensitivities to chemotherapy agents, depending on the subclonal populations within the tumor.
Cells from the immune system also make crucial contributions to the antitumor effects of chemotherapy. For example, the chemotherapeutic drugs oxaliplatin and cyclophosphamide can cause tumor cells to die in a way that is detectable by the immune system (called immunogenic cell death), which mobilizes immune cells with antitumor functions. Chemotherapeutic drugs that cause cancer immunogenic tumor cell death can make unresponsive tumors sensitive to immune checkpoint therapy.
== Other uses ==
Some chemotherapy drugs are used in diseases other than cancer, such as in autoimmune disorders, and noncancerous plasma cell dyscrasia. In some cases they are often used at lower doses, which means that the side effects are minimized, while in other cases doses similar to ones used to treat cancer are used. Methotrexate is used in the treatment of rheumatoid arthritis (RA), psoriasis, ankylosing spondylitis and multiple sclerosis. The anti-inflammatory response seen in RA is thought to be due to increases in adenosine, which causes immunosuppression; effects on immuno-regulatory cyclooxygenase-2 enzyme pathways; reduction in pro-inflammatory cytokines; and anti-proliferative properties. Although methotrexate is used to treat both multiple sclerosis and ankylosing spondylitis, its efficacy in these diseases is still uncertain. Cyclophosphamide is sometimes used to treat lupus nephritis, a common symptom of systemic lupus erythematosus. Dexamethasone along with either bortezomib or melphalan is commonly used as a treatment for AL amyloidosis. Recently, bortezomid in combination with cyclophosphamide and dexamethasone has also shown promise as a treatment for AL amyloidosis. Other drugs used to treat myeloma such as lenalidomide have shown promise in treating AL amyloidosis.
Chemotherapy drugs are also used in conditioning regimens prior to bone marrow transplant (hematopoietic stem cell transplant). Conditioning regimens are used to suppress the recipient's immune system in order to allow a transplant to engraft. Cyclophosphamide is a common cytotoxic drug used in this manner and is often used in conjunction with total body irradiation. Chemotherapeutic drugs may be used at high doses to permanently remove the recipient's bone marrow cells (myeloablative conditioning) or at lower doses that will prevent permanent bone marrow loss (non-myeloablative and reduced intensity conditioning). When used in non-cancer setting, the treatment is still called "chemotherapy", and is often done in the same treatment centers used for people with cancer.
== Occupational exposure and safe handling ==
In the 1970s, antineoplastic (chemotherapy) drugs were identified as hazardous, and the American Society of Health-System Pharmacists (ASHP) has since then introduced the concept of hazardous drugs after publishing a recommendation in 1983 regarding handling hazardous drugs. The adaptation of federal regulations came when the U.S. Occupational Safety and Health Administration (OSHA) first released its guidelines in 1986 and then updated them in 1996, 1999, and, most recently, 2006.
The National Institute for Occupational Safety and Health (NIOSH) has been conducting an assessment in the workplace since then regarding these drugs. Occupational exposure to antineoplastic drugs has been linked to multiple health effects, including infertility and possible carcinogenic effects. A few cases have been reported by the NIOSH alert report, such as one in which a female pharmacist was diagnosed with papillary transitional cell carcinoma. Twelve years before the pharmacist was diagnosed with the condition, she had worked for 20 months in a hospital where she was responsible for preparing multiple antineoplastic drugs. The pharmacist did not have any other risk factor for cancer, and therefore, her cancer was attributed to the exposure to the antineoplastic drugs, although a cause-and-effect relationship has not been established in the literature. Another case happened when a malfunction in biosafety cabinetry is believed to have exposed nursing personnel to antineoplastic drugs. Investigations revealed evidence of genotoxic biomarkers two and nine months after that exposure.
=== Routes of exposure ===
Antineoplastic drugs are usually given through intravenous, intramuscular, intrathecal, or subcutaneous administration. In most cases, before the medication is administered to the patient, it needs to be prepared and handled by several workers. Any worker who is involved in handling, preparing, or administering the drugs, or with cleaning objects that have come into contact with antineoplastic drugs, is potentially exposed to hazardous drugs. Health care workers are exposed to drugs in different circumstances, such as when pharmacists and pharmacy technicians prepare and handle antineoplastic drugs and when nurses and physicians administer the drugs to patients. Additionally, those who are responsible for disposing antineoplastic drugs in health care facilities are also at risk of exposure.
Dermal exposure is thought to be the main route of exposure due to the fact that significant amounts of the antineoplastic agents have been found in the gloves worn by healthcare workers who prepare, handle, and administer the agents. Another noteworthy route of exposure is inhalation of the drugs' vapors. Multiple studies have investigated inhalation as a route of exposure, and although air sampling has not shown any dangerous levels, it is still a potential route of exposure. Ingestion by hand to mouth is a route of exposure that is less likely compared to others because of the enforced hygienic standard in the health institutions. However, it is still a potential route, especially in the workplace, outside of a health institute. One can also be exposed to these hazardous drugs through injection by needle sticks. Research conducted in this area has established that occupational exposure occurs by examining evidence in multiple urine samples from health care workers.
=== Hazards ===
Hazardous drugs expose health care workers to serious health risks. Many studies show that antineoplastic drugs could have many side effects on the reproductive system, such as fetal loss, congenital malformation, and infertility. Health care workers who are exposed to antineoplastic drugs on many occasions have adverse reproductive outcomes such as spontaneous abortions, stillbirths, and congenital malformations. Moreover, studies have shown that exposure to these drugs leads to menstrual cycle irregularities. Antineoplastic drugs may also increase the risk of learning disabilities among children of health care workers who are exposed to these hazardous substances.
Moreover, these drugs have carcinogenic effects. In the past five decades, multiple studies have shown the carcinogenic effects of exposure to antineoplastic drugs. Similarly, there have been research studies that linked alkylating agents with humans developing leukemias. Studies have reported elevated risk of breast cancer, nonmelanoma skin cancer, and cancer of the rectum among nurses who are exposed to these drugs. Other investigations revealed that there is a potential genotoxic effect from anti-neoplastic drugs to workers in health care settings.
=== Safe handling in health care settings ===
As of 2018, there were no occupational exposure limits set for antineoplastic drugs, i.e., OSHA or the American Conference of Governmental Industrial Hygienists (ACGIH) have not set workplace safety guidelines.
==== Preparation ====
NIOSH recommends using a ventilated cabinet that is designed to decrease worker exposure. Additionally, it recommends training of all staff, the use of cabinets, implementing an initial evaluation of the technique of the safety program, and wearing protective gloves and gowns when opening drug packaging, handling vials, or labeling. When wearing personal protective equipment, one should inspect gloves for physical defects before use and always wear double gloves and protective gowns. Health care workers are also required to wash their hands with water and soap before and after working with antineoplastic drugs, change gloves every 30 minutes or whenever punctured, and discard them immediately in a chemotherapy waste container.
The gowns used should be disposable gowns made of polyethylene-coated polypropylene. When wearing gowns, individuals should make sure that the gowns are closed and have long sleeves. When preparation is done, the final product should be completely sealed in a plastic bag.
The health care worker should also wipe all waste containers inside the ventilated cabinet before removing them from the cabinet. Finally, workers should remove all protective wear and put them in a bag for their disposal inside the ventilated cabinet.
==== Administration ====
Drugs should only be administered using protective medical devices such as needle lists and closed systems and techniques such as priming of IV tubing by pharmacy personnel inside a ventilated cabinet. Workers should always wear personal protective equipment such as double gloves, goggles, and protective gowns when opening the outer bag and assembling the delivery system to deliver the drug to the patient, and when disposing of all material used in the administration of the drugs.
Hospital workers should never remove tubing from an IV bag that contains an antineoplastic drug, and when disconnecting the tubing in the system, they should make sure the tubing has been thoroughly flushed. After removing the IV bag, the workers should place it together with other disposable items directly in the yellow chemotherapy waste container with the lid closed. Protective equipment should be removed and put into a disposable chemotherapy waste container. After this has been done, one should double bag the chemotherapy waste before or after removing one's inner gloves. Moreover, one must always wash one's hands with soap and water before leaving the drug administration site.
==== Employee training ====
All employees whose jobs in health care facilities expose them to hazardous drugs must receive training. Training should include shipping and receiving personnel, housekeepers, pharmacists, assistants, and all individuals involved in the transportation and storage of antineoplastic drugs. These individuals should receive information and training to inform them of the hazards of the drugs present in their areas of work. They should be informed and trained on operations and procedures in their work areas where they can encounter hazards, different methods used to detect the presence of hazardous drugs and how the hazards are released, and the physical and health hazards of the drugs, including their reproductive and carcinogenic hazard potential. Additionally, they should be informed and trained on the measures they should take to avoid and protect themselves from these hazards. This information ought to be provided when health care workers come into contact with the drugs, that is, perform the initial assignment in a work area with hazardous drugs. Moreover, training should also be provided when new hazards emerge as well as when new drugs, procedures, or equipment are introduced.
==== Housekeeping and waste disposal ====
When performing cleaning and decontaminating the work area where antineoplastic drugs are used, one should make sure that there is sufficient ventilation to prevent the buildup of airborne drug concentrations. When cleaning the work surface, hospital workers should use deactivation and cleaning agents before and after each activity as well as at the end of their shifts. Cleaning should always be done using double protective gloves and disposable gowns. After employees finish up cleaning, they should dispose of the items used in the activity in a yellow chemotherapy waste container while still wearing protective gloves. After removing the gloves, they should thoroughly wash their hands with soap and water. Anything that comes into contact or has a trace of the antineoplastic drugs, such as needles, empty vials, syringes, gowns, and gloves, should be put in the chemotherapy waste container.
==== Spill control ====
A written policy needs to be in place in case of a spill of antineoplastic products. The policy should address the possibility of various sizes of spills as well as the procedure and personal protective equipment required for each size. A trained worker should handle a large spill and always dispose of all cleanup materials in the chemical waste container according to EPA regulations, not in a yellow chemotherapy waste container.
=== Occupational monitoring ===
A medical surveillance program must be established. In case of exposure, occupational health professionals need to ask for a detailed history and do a thorough physical exam. They should test the urine of the potentially exposed worker by doing a urine dipstick or microscopic examination, mainly looking for blood, as several antineoplastic drugs are known to cause bladder damage.
Urinary mutagenicity is a marker of exposure to antineoplastic drugs that was first used by Falck and colleagues in 1979 and uses bacterial mutagenicity assays. Apart from being nonspecific, the test can be influenced by extraneous factors such as dietary intake and smoking and is, therefore, used sparingly. However, the test played a significant role in changing the use of horizontal flow cabinets to vertical flow biological safety cabinets during the preparation of antineoplastic drugs because the former exposed health care workers to high levels of drugs. This changed the handling of drugs and effectively reduced workers' exposure to antineoplastic drugs.
Biomarkers of exposure to antineoplastic drugs commonly include urinary platinum, methotrexate, urinary cyclophosphamide and ifosfamide, and urinary metabolite of 5-fluorouracil. In addition to this, there are other drugs used to measure the drugs directly in the urine, although they are rarely used. A measurement of these drugs directly in one's urine is a sign of high exposure levels and that an uptake of the drugs is happening either through inhalation or dermally.
== Available agents ==
There is an extensive list of antineoplastic agents. Several classification schemes have been used to subdivide the medicines used for cancer into several different types.
== History ==
The first use of small-molecule drugs to treat cancer was in the early 20th century, although the specific chemicals first used were not originally intended for that purpose. Mustard gas was used as a chemical warfare agent during World War I and was discovered to be a potent suppressor of hematopoiesis (blood production). A similar family of compounds known as nitrogen mustards were studied further during World War II at the Yale School of Medicine. It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in December 1942, several people with advanced lymphomas (cancers of the lymphatic system and lymph nodes) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. Concurrently, during a military operation in World War II, following a German air raid on the Italian harbour of Bari, several hundred people were accidentally exposed to mustard gas, which had been transported there by the Allied forces to prepare for possible retaliation in the event of German use of chemical warfare. The survivors were later found to have very low white blood cell counts. After WWII was over and the reports declassified, the experiences converged and led researchers to look for other substances that might have similar effects against cancer. The first chemotherapy drug to be developed from this line of research was mustine. Since then, many other drugs have been developed to treat cancer, and drug development has exploded into a multibillion-dollar industry, although the principles and limitations of chemotherapy discovered by the early researchers still apply.
=== The term chemotherapy ===
The word chemotherapy without a modifier usually refers to cancer treatment, but its historical meaning was broader. The term was coined in the early 1900s by Paul Ehrlich as meaning any use of chemicals to treat any disease (chemo- + -therapy), such as the use of antibiotics (antibacterial chemotherapy). Ehrlich was not optimistic that effective chemotherapy drugs would be found for the treatment of cancer. The first modern chemotherapeutic agent was arsphenamine, an arsenic compound discovered in 1907 and used to treat syphilis. This was later followed by sulfonamides (sulfa drugs) and penicillin. In today's usage, the sense "any treatment of disease with drugs" is often expressed with the word pharmacotherapy.
== Research ==
=== Targeted delivery vehicles ===
Specially targeted delivery vehicles aim to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This should result in an increased tumor kill or reduced toxicity or both.
==== Antibody-drug conjugates ====
Antibody-drug conjugates (ADCs) comprise an antibody, drug and a linker between them. The antibody will be targeted at a preferentially expressed protein in the tumour cells (known as a tumor antigen) or on cells that the tumor can utilise, such as blood vessel endothelial cells. They bind to the tumor antigen and are internalised, where the linker releases the drug into the cell. These specially targeted delivery vehicles vary in their stability, selectivity, and choice of target, but, in essence, they all aim to increase the maximum effective dose that can be delivered to the tumor cells. Reduced systemic toxicity means that they can also be used in people who are sicker and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches.
The first approved drug of this type was gemtuzumab ozogamicin (Mylotarg), released by Wyeth (now Pfizer). The drug was approved to treat acute myeloid leukemia. Two other drugs, trastuzumab emtansine and brentuximab vedotin, are both in late clinical trials, and the latter has been granted accelerated approval for the treatment of refractory Hodgkin's lymphoma and systemic anaplastic large cell lymphoma.
==== Nanoparticles ====
Nanoparticles are 1–1000 nanometer (nm) sized particles that can promote tumor selectivity and aid in delivering low-solubility drugs. Nanoparticles can be targeted passively or actively. Passive targeting exploits the difference between tumor blood vessels and normal blood vessels. Blood vessels in tumors are "leaky" because they have gaps from 200 to 2000 nm, which allow nanoparticles to escape into the tumor. Active targeting uses biological molecules (antibodies, proteins, DNA and receptor ligands) to preferentially target the nanoparticles to the tumor cells. There are many types of nanoparticle delivery systems, such as silica, polymers, liposomes and magnetic particles. Nanoparticles made of magnetic material can also be used to concentrate agents at tumor sites using an externally applied magnetic field. They have emerged as a useful vehicle in magnetic drug delivery for poorly soluble agents such as paclitaxel.
=== Electrochemotherapy ===
Electrochemotherapy is the combined treatment in which injection of a chemotherapeutic drug is followed by application of high-voltage electric pulses locally to the tumor. The treatment enables the chemotherapeutic drugs, which otherwise cannot or hardly go through the membrane of cells (such as bleomycin and cisplatin), to enter the cancer cells. Hence, greater effectiveness of antitumor treatment is achieved.
Clinical electrochemotherapy has been successfully used for treatment of cutaneous and subcutaneous tumors irrespective of their histological origin. The method has been reported as safe, simple and highly effective in all reports on clinical use of electrochemotherapy. According to the ESOPE project (European Standard Operating Procedures of Electrochemotherapy), the Standard Operating Procedures (SOP) for electrochemotherapy were prepared, based on the experience of the leading European cancer centres on electrochemotherapy. Recently, new electrochemotherapy modalities have been developed for treatment of internal tumors using surgical procedures, endoscopic routes or percutaneous approaches to gain access to the treatment area.
=== Hyperthermia therapy ===
Hyperthermia therapy is heat treatment for cancer that can be a powerful tool when used in combination with chemotherapy (thermochemotherapy) or radiation for the control of a variety of cancers. The heat can be applied locally to the tumor site, which will dilate blood vessels to the tumor, allowing more chemotherapeutic medication to enter the tumor. Additionally, the tumor cell membrane will become more porous, further allowing more of the chemotherapeutic medicine to enter the tumor cell.
Hyperthermia has also been shown to help prevent or reverse "chemo-resistance." Chemotherapy resistance sometimes develops over time as the tumors adapt and can overcome the toxicity of the chemo medication. "Overcoming chemoresistance has been extensively studied within the past, especially using CDDP-resistant cells. In regard to the potential benefit that drug-resistant cells can be recruited for effective therapy by combining chemotherapy with hyperthermia, it was important to show that chemoresistance against several anticancer drugs (e.g. mitomycin C, anthracyclines, BCNU, melphalan) including CDDP could be reversed at least partially by the addition of heat.
== Other animals ==
Chemotherapy is used in veterinary medicine similar to how it is used in human medicine.
== See also ==
== References ==
== External links ==
Chemotherapy, American Cancer Society
Hazardous Drug Exposures in Health Care, National Institute for Occupational Safety and Health
NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016, National Institute for Occupational Safety and Health
Wikiversity page for the International Ototoxicity Management Group: https://en.wikiversity.org/wiki/International_Ototoxicity_Management_Group_(IOMG) | Wikipedia/Anticancer_drugs |
In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.
While many medications treat Parkinson's, none actually reverses the effects of the disease. Furthermore, the gold-standard treatment varies with the disease state. People with Parkinson's, therefore, often must take a variety of medications to manage the disease's symptoms. Several medications currently in development seek to better address motor fluctuations and nonmotor symptoms of PD. However, none is yet on the market with specific approval to treat Parkinson's.
== Medication ==
The main families of drugs useful for treating motor symptoms are levodopa, dopamine agonists, and MAO-B inhibitors. The most commonly used treatment approach varies depending on the disease stage. Two phases are usually distinguished: an initial phase in which the individual with PD has already developed some disability which requires pharmacological treatment, and a second stage in which the patient develops motor complications related to levodopa usage. Treatment in the initial state aims to attain an optimal tradeoff between good management of symptoms and side effects resulting from enhancement of dopaminergic function. The start of L-DOPA treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias. In the second stage, the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication, and overuse by some patients, also must be controlled. When medications are not enough to control symptoms, surgical techniques such as deep brain stimulation can relieve the associated movement disorders.
=== Levodopa ===
Levodopa (or L-DOPA) has been the most widely used treatment for over 30 years. L-DOPA is transformed into dopamine in the dopaminergic neurons by dopa-decarboxylase. Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.
Only 5–10% of L-DOPA crosses the blood–brain barrier. The remainder is often metabolised to dopamine elsewhere, causing a wide variety of side effects including nausea, dyskinesias, and stiffness. Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors. They inhibit the metabolism of L-DOPA in the periphery, thereby increasing levodopa delivery to the central nervous system. They are generally given as combination preparations with levodopa. Existing preparations are carbidopa/levodopa (co-careldopa, trade names Sinemet, Pharmacopa, Atamet) and benserazide/levodopa (co-beneldopa, trade name Madopar). Levodopa has also been related to a dopamine dysregulation syndrome, which is a compulsive overuse of the medication, and punding.
Controlled, slow-release versions of Sinemet and Madopar spread out the effect of the levodopa. Duodopa is a combination of levodopa and carbidopa. Slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate-release preparations.
Tolcapone inhibits the catechol-O-methyltransferase (COMT) enzyme, which degrades dopamine and levadopa, thereby prolonging the therapeutic effects of levodopa. It, alongside inhibitors of peripheral dopa decarboxylase, have been used to complement levodopa. However, due to its possible side effects such as liver failure, it is limited in its availability. A similar drug, entacapone, has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time. Entacapone is available for treatment alone (COMTan) or combined with carbidopa and levodopa (Stalevo).
Levodopa results in a reduction in the endogenous formation of L-DOPA, and eventually becomes counterproductive. Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication. When this occurs, PD patients change rapidly from stages with good response to medication and few symptoms ("on" state) to phases with no response to medication and important motor symptoms ("off" state). For this reason, levodopa doses are kept as low as possible while maintaining functionality. Delaying the initiation of dopatherapy, using instead alternatives for some time, is also common practice. A former strategy to reduce motor complications was to withdraw patients from L-DOPA for some time. It is discouraged now since it can bring dangerous side effects such as neuroleptic malignant syndrome. Most people eventually need levodopa and later develop motor complications.
The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate the importance of levodopa handling has been underestimated and progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Redistribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction and the use of selegiline and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intraduodenal administration of levodopa.
In animal models it was shown that the intake of adenosine receptor antagonists together with levodopa can amplify its therapeutic effects.
=== Dopamine agonists ===
Dopamine agonists in the brain have a similar effect to levodopa since they bind to dopaminergic postsynaptic receptors. Dopamine agonists were initially used for patients experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa, but they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications. When used in late PD, they are useful at reducing the off periods. Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride.
Agonists produce significant, although mild, side effects including somnolence, hallucinations, insomnia, nausea, and constipation. Sometimes, side effects appear even at the minimal clinically efficacious dose, leading the physician to search for a different agonist or kind of drug. When compared with levodopa, while they delay motor complications, they control worse symptoms. Nevertheless, they are usually effective enough to manage symptoms in the initial years. They are also more expensive. Dyskinesias with dopamine agonists are rare in younger patients, but along other side effects, more common in older patients. All this has led to agonists being the preferential initial treatment for the former as opposed to levodopa in the latter. Agonists at higher doses have also been related to a wide variety of impulse-control disorders.
Apomorphine, which is a dopamine agonist not orally administered, may be used to reduce off periods and dyskinesia in late PD. Since secondary effects such as confusion and hallucinations are not rare, patients under apomorphine treatment should be closely monitored. Apomorphine can be administered by subcutaneous injection using a small pump which is carried by the patient. A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. After an initial "apomorphine challenge" in hospital to test its effectiveness and brief patient and primary caregiver (often a spouse or partner), the latter of whom takes over maintenance of the pump. The injection site must be changed daily and rotated around the body to avoid the formation of nodules. Apomorphine is also available in a more acute dose as an autoinjector pen for emergency doses such as after a fall or first thing in the morning. Nausea and vomiting are common, and may require domperidone (an antiemetic).
In a study evaluating the efficacy of dopamine agonists compared to levodopa, the results showed patients who took dopamine agonists were less likely to develop dyskinesia, dystonia, and motor fluctuations, although were more likely to discontinue therapy due to negative side effects such as nausea, edema, constipation, etc.
=== MAO-B inhibitors ===
Monoamine oxidase inhibitors (selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolization. They inhibit monoamine oxidase-B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. Therefore, reducing MAO-B results in higher quantities of L-DOPA in the striatum. Similarly to dopamine agonists, MAO-B inhibitors improve motor symptoms and delay the need of taking levodopa when used as monotherapy in the first stages of the disease, but produce more adverse effects and are less effective than levodopa. Evidence on their efficacy in the advanced stage is reduced, although it points towards them being useful to reduce fluctuations between on and off periods. Although an initial study indicated selegiline in combination with levodopa increased the risk of death, this has been later disproven.
Metabolites of selegiline include L-amphetamine and L-methamphetamine (not to be confused with the more potent dextrorotary isomers). This might result in side effects such as insomnia. Another side effect of the combination can be stomatitis. Unlike other nonselective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.
=== Other drugs ===
Some evidence indicates other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms in early and late PD, but since the quality of evidence on efficacy is reduced, they are not first-choice treatments. In addition to motor symptoms, PD is accompanied by a range of different symptoms. Different compounds are used to improve some of these problems. Examples are the use of clozapine for psychosis, cholinesterase inhibitors for dementia, modafinil for day somnolence, and atomoxetine for executive dysfunction.
One study suggests Botulinum neurotoxin(BoNT) is useful in treating several motor and non-motor symptoms of Parkinson’s. However, this form of treatment is also not considered a first-choice treatment but is usually used to treat a specific symptom of PD or when typical treatment for PD is insufficient. These specific symptoms include Gastrointestinal Dysfunction, eye twitching, and Sialorrhea also known as excessive salivating or drooling. There have been several studies that have established efficacy of BoNT, particularly for Sialorrhea and Gastrointestinal Dysfunction.
A preliminary study indicates taking donepezil (Aricept) may help prevent falls in people with Parkinson's. Donepezil boosts the levels of the neurotransmitter acetylcholine, and is currently an approved therapy for the cognitive symptoms of Alzheimer's disease. In the study, participants taking donepezil experienced falls half as often as those taking a placebo, and those who previously fell the most showed the most improvement.
The introduction of clozapine (Clozaril) represents a breakthrough in the treatment of psychotic symptoms of PD. Prior to its introduction, treatment of psychotic symptoms relied on reduction of dopamine therapy or treatment with first generation antipsychotics, all of which worsened motor function. Other atypical antipsychotics useful in treatment include quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), and paliperidone (Invega). Clozapine is believed to have the highest efficacy and lowest risk of extrapyramidal side effect.
=== Getting medication on time ===
Parkinson's patients who do not get the correct medicine at the right time when they are in hospital, (frequently they are in hospital due to unrelated illnesses) sometimes cannot talk or walk. The health of a majority deteriorated due to unsatisfactory medication management when they are in hospital. Parkinson's UK believes the NHS could save up to £10m a year and improve the care of Parkinson's patients if mandatory training is introduced for all hospital staff.
Parkinson UK found:
"Nearly two thirds of people who have Parkinson's don't always get their medication on time in hospital."
"More than three quarters of people with Parkinson's that we asked reported that their health deteriorated as a result of poor medication management in hospital."
"Only 21% of respondents told us they got their medication on time without having to remind hospital staff."
== Diet ==
Muscles and nerves that control the digestive process may be affected by PD, so it is common to experience constipation and gastroparesis (food remaining in the stomach for a longer period of time than normal). A balanced diet is recommended to help improve digestion. Diet should include high-fiber foods and plenty of water. Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, competing between them for access. When taken together, the consequences of such competition is a reduced effectiveness of the drug. Therefore, when levodopa is introduced, excessive proteins are discouraged, while in advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons. To minimize interaction with proteins, levodopa is recommended to be taken 30 minutes before meals. At the same time, regimens for PD restrict proteins during breakfast and lunch and are usually taken at dinner. As the disease advances, dysphagia may appear. In such cases, specific measures include the use of thickening agents for liquid intake, special postures when eating, and gastrostomy in the worst cases.
== Surgery ==
Treating PD with surgery was once a common practice, but after the discovery of levodopa, surgery was restricted to only a few cases. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.
Less than 10% of those with PD qualify as suitable candidates for a surgical response. The three different mechanisms of surgical response for PD are: ablative surgery, (the irreversible burning or freezing of brain tissue), stimulation surgery or deep brain stimulation (DBS), and transplantation or restorative surgery.
Target areas for DBS or lesions include the thalamus, the globus pallidus (the lesion technique being called pallidotomy), or the subthalamic nucleus.
=== Neuroablative lesion surgery ===
Neuroablative lesion surgery locates and destroys, by heat, the parts of the brain associated with producing Parkinsonian neurological symptoms. The procedures generally involve a thalamotomy and/or pallidotomy. A thalamotomy is the destruction of a part of the thalamus, in particular the ventralis intermedius, to suppress tremor in 80-90% of patients. If rigidity and akinesia are apparent, the subthalamis nucleus is then the site of ablation.
A pallidotomy involves the destruction of the globus pallidus, in particular the globus pallidus interna, in patients with Parkinson's who have rigidity and akinesia.
Because it is difficult to accurately measure the amount of tissue to be destroyed, tremors not uncommonly persist through multiple courses of surgery, since tissue is irreversibly damaged and removed and testing smaller areas of tissue is safer to prevent serious complications, such as a stroke or paralysis.. This method has been generally replaced by deep brain surgery.
=== Deep brain stimulation ===
Deep brain stimulation (DBS) is presently the most used method of surgical treatment because it does not destroy brain tissue, it is reversible, and it can be tailored to individuals at their particular stage of disease. DBS employs three hardware components: a neurostimulator, also called an implanted pulse generator (IPG), which generates electrical impulses used to modulate neural activity, a lead wire which directs the impulses to a number of metallic electrodes towards the tip of the lead near the stimulation target, and an extension wire that connects the lead to the IPG. The IPG, which is battery-powered and encased in titanium, is traditionally implanted under the collarbone, and is connected by the subcutaneous extension to the lead, which extends from outside the skull under the scalp down into the brain to the target of stimulation. The IPG, or the entire three-component system, are sometimes referred to as a brain pacemaker, due to the precedence and renown of cardiac pacemakers and similarities in the components of both types of systems.
The preoperative targeting of proper implantation sites can be accomplished by the indirect and direct methods. The indirect method uses computer tomography, magnetic resonance imaging, or ventriculography to locate the anterior and posterior commissures and then employs predetermined coordinates and distances from the intercommissural line to define the target area. Subsequent histologically defined atlas maps can also be used to verify the target area. The direct method provides visualization and targeting of deep nuclei by applying stereotactic preoperative MRI, which unlike the indirect method, takes into account the anatomic variation of the nuclei's size, position, and functional segregation amongst individuals.
Electrophysial functional mapping, a tool used in both methods to verify the target nuclei, has come under scrutiny due to its associated risks of hemorrhages, dysarthria or tetanic contractions. Recently, susceptibility-weighted imaging, a type of MRI, has shown incredible power in its ability to distinguish these deep brain nuclei and is being used in DBS to reduce the overuse of EFM.
DBS is recommended to PD patients without important neuropsychiatric contraindications who have motor fluctuations and tremor badly controlled by medication, or to those who are intolerant to medication.
DBS is effective in suppressing symptoms of PD, especially tremor. A recent clinical study led to recommendations on identifying which Parkinson's patients are most likely to benefit from DBS.
== Rehabilitation ==
Studies of rehabilitation in Parkinson's disease are scarce and are of low quality. Partial evidence indicates speech or mobility problems can improve with rehabilitation. Regular physical exercise and/or therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. Exercise may also improve constipation. Exercise interventions have been shown to benefit patients with Parkinson's disease in regards to physical functioning, health-related quality of life, and balance and fall risk. In a review of 14 studies examining the effects of exercise on persons with Parkinson's disease, no adverse events or side effects occurred following any of the exercise interventions, a more recent, larger review in 2023 similar results were found. Five proposed mechanisms by which exercise enhances neuroplasticity are known. Intensive activity maximizes synaptic plasticity; complex activities promote greater structural adaptation; activities that are rewarding increase dopamine levels and therefore promote learning/relearning; dopaminergic neurones are highly responsive to exercise and inactivity ("use it or lose it"); and where exercise is introduced at an early stage of the disease, progression can be slowed. One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the Lee Silverman voice treatment (LSVT), which focuses on increasing vocal loudness and has an intensive approach of one month. Speech therapy and specifically LSVT may improve voice and speech function. Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many activities of their daily living as possible. Few studies have been conducted on the effectiveness of OT and their quality is poor, although some indication shows it may improve motor skills and quality of life for the duration of the therapy.
For monitoring patients with Parkinson's disease, research teams are examining whether virtual house calls can replace visits to clinical facilities. In a trial of such video visits, patients preferred the remote specialist after 1 year. The home care was considered convenient but requires access to and familiarity with Internet-enabled technologies.
=== Exercise ===
Regular physical exercise with or without physiotherapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. Parkinson's Disease often causes sedentary behaviours resulting in lower quality of life in the long term. In terms of improving flexibility and range of motion for patients experiencing rigidity, generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques. Common changes in gait associated with the disease such as hypokinesia (slowness of movement), shuffling and decreased arm swing are addressed by a variety of strategies to improve functional mobility and safety. Goals with respect to gait during rehabilitation programs include improving gait speed, base of support, stride length, trunk and arm swing movement. Strategies include utilizing assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and varying environments (surfaces, inputs, open vs. closed).
Strengthening exercises have led to improvements in strength and motor functions in patients with primary muscular weakness and weakness related to inactivity in cases of mild to moderate Parkinson's disease. Patients perform exercises when at their best, 45 minutes to one hour after medication. An 8-week resistance training study geared towards the lower legs found that patients with Parkinson's Disease gained abdominal strength, and improved in their stride length, walking velocity and postural angles. Also, due to the forward flexed posture and respiratory dysfunctions in advanced Parkinson's disease, deep diaphragmatic breathing exercises are beneficial for improving chest wall mobility and vital capacity. Exercise may correct constipation.
Exercise training on a vibratory platform, also called whole body vibration (WBV) training, has been recently introduced as a training tool complementing standard physical rehabilitation programs for people with Parkinson's disease. Compared to no intervention, single sessions of WBV have resulted in improved motor ability, as reflected by Unified Parkinson's Disease Rating Scale (UPDRS) tremor and rigidity scores. However, longer-term (3–5 weeks) WBV programs have not led to improved UPDRS motor scores compared to conventional exercises. Furthermore, multiple sessions of WBV have failed to enhance mobility measures (i.e., the Timed Up and Go Test and 10-Meter Walking Test) in people with Parkinson's disease. A recent review deemed that the evidence of the effects of WBV training on sensorimotor and functional performance remains inconclusive.
Newer data has provided another benefit of exercise for patients with Parkinson's disease. The external and internal stressors provided by engaging in exercise induce production of brain neurotrophic factors. This finding is significant because it provides evidence that exercise contributes to neuroplasticity which is especially beneficial in a neurodegenerative disease such as Parkinson's disease. Another study reported that regular aerobic exercise increases brain derived neurotrophic factor in patients with either Parkinson's, multiple sclerosis, or people who have had a stroke. Exercise has additional benefits to the central and peripheral nervous system in Parkinson's disease, including pain management. Pain is a common, but underdiscussed symptom. Central neuropathic pain is characterized by tingling or burning of a nerve and is not due to the musculoskeletal decline that occurs in Parkinson's disease, rather, it is caused by the disease process within the brain.
=== Psychological treatments ===
Psychological treatment is based on cognitive-behavioral interventions. Cognitive behavioral therapy is confirmed as efficient for treatment of parkinsonian pain, insomnia, anxiety, depression, and impulse control disorders. Treating Parkinson's disease engages a multidisciplinary approach, and includes a psychologist, because motor symptoms can be worsened by psychosocial factors like anxiety, phobia, and panic attacks. Psychological treatment is tailored to each individual, based on clinical recommendations, especially if they have severe motor disability or cognitive problems.
=== Gait training ===
Patients with Parkinson's disease have an altered gait. There is a reduced gait speed and step length, increased axial rigidity, and impaired rhythmicity. These gait problems worsen as the disease continues. This is a major disease burden that markedly affects independence and quality of life. Since it is proven that tremor-dominant and akinetic rigid types of Parkinson's disease have various different visuomotor deficiencies, like problems in visual perception and motor coordination, that can influence their gait training, it is recommended for them to receive neuropsychological assessment before physical therapy.
Task-specific gait training may also lead to long-term gait improvement for patients with Parkinson's disease. Previous research studies have utilized body weight support systems during gait training, where individuals are suspended from an overhead harness with straps around the pelvic girdle as they walk on a treadmill. This form of gait training has been shown to improve long-term walking speed and a shuffling gait following a one-month intervention period.
Studies are also looking at the effect of tai chi on gait performance, and balance in people with Parkinson's Disease. The first study concluded that tai chi was ineffective since there was no improvement on gait performance and no improvement on the Part III score of the Unified Parkinson's Disease Rating Scale (UPDRS). The second study found that patients taking tai chi improved on their UPDRS score, Timed Up and Go test, six-minute walk and backwards walking. It did not however, show any improvements on their forward walking or their one leg stance test.
=== Speech and occupational therapy ===
One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the Lee Silverman voice treatment (LSVT). Speech therapy and specifically LSVT may improve speech.
People with Parkinson's disease can develop dysarthria which is characterized by reduced speech intelligibility. Prosodically based treatments may help.
Occupational therapy aims to promote health and quality of life by helping people with the disease to participate in as much of their daily routine as possible. There is indication that occupational therapy may improve motor skills and quality of life for the duration of the therapy.
=== Rhythmic auditory stimulation ===
Rhythmic auditory stimulation (RAS) is a neurological rehabilitation technique consisting in compensating the loss of motor regulation through an external sensory stimulation, mediated by the sound. This technique relies on the strong interaction between auditory and motor neural system. By synchronizing his footsteps on the emitted sound (that can be "metronome-like" cues or complex music) the patient can improves his gait speed and his stride length.
=== Telemedicine ===
A 2017 one-year randomized controlled trial found that providing remote neurologic care to individuals with Parkinson's Disease in their own homes was feasible and as effective as in-person care. While it can be more difficult for remote caregivers to establish trust while providing remote care, that assessment of video visits in a patient's home found that, after four virtual visits over one year, individuals with Parkinson's Disease preferred their connection with the remote specialist to their local clinician.
Benefits of telemedicine include convenience and cost-effectiveness, as the virtual in-home visits have been found to reduce travel costs and time for patients relative to in-office visits. Some studies have found that the technology supports personalized connections similar to the house calls of the past. Five randomized controlled trials indicated that quality of life was similar or improved for those receiving telemedicine care.
Challenges related to telemedicine in treatment of individuals with Parkinson's Disease are related to the technological requirements, as patients and their friends or families must have access to and familiarity with Internet-based technologies. In part because of these technological requirements, studies in the United States have tended to include few participants from ethnic minorities and disproportionately include more highly educated populations. One solution proposed to reduce social and economic barriers to access to remote care is to establish satellite teleneurology clinics in underserved regions. Physicians cite barriers with inability to perform a full neurologic exam in addition to technology and reimbursement issues.
New telemedicine technologies being used or evaluated in the context of telemedicine include proprietary wearables, self-sensing and adjusting closed loop systems, robotic technologies, smart devices to detect movements, programs to improve medication adherence, smart home integration, and artificial intelligence or machine learning-based systems.
== Palliative care ==
Palliative care is often required in the final stages of the disease, often when dopaminergic treatments have become ineffective. The aim of palliative care is to achieve the maximum quality of life for the person with the disease and those surrounding him or her. Some central issues of palliative are caring for patients at home while adequate care can be given there, reducing or withdrawing dopaminergic drug intake to reduce drug side effects and complications, preventing pressure ulcers by management of pressure areas of inactive patients, and facilitating the patient's end-of-life decisions for the patient, as well as involved friends and relatives.
== Other treatments ==
Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias. Its full usefulness in PD is an open research field. Different nutrients have been proposed as possible treatments; however, no evidence shows vitamins or food additives improve symptoms. Not enough evidence exists to suggest that acupuncture, and practice of qigong or tai chi have any effect on symptoms. Fava and velvet beans are natural sources of L-DOPA and are taken by many people with PD. While they have shown some effectiveness, their intake is not free of risks. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome. Faecal transplants may have a beneficial impact on symptoms.
== History ==
The positive albeit modest effects of anticholinergic alkaloids obtained from the plant of the belladonna were described during the 19th century by Charcot, Erb, and others. Modern surgery for tremor, consisting of the lesioning of some of the basal ganglia structures was first tried in 1939, and was improved over the following 20 years. Before this date, surgery consisted in lesioning the corticospinal pathway with paralysis instead of tremor as result. Anticholinergics and surgery were the only treatments until the arrival of levodopa, which reduced their use dramatically.
Levodopa was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid-20th century. It entered clinical practice in 1967, and the first large study reporting improvements in people with Parkinson's disease resulting from treatment with levodopa was published in 1968. Levodopa brought about a revolution in the management of PD. By the late 1980s deep brain stimulation emerged as a possible treatment, and it was approved for clinical use by the FDA in 1997.
== Research directions ==
No new PD treatments are expected in the short term, but several lines of research are active for new treatments. Such research directions include the search of new animal models of the disease, and the potential usefulness of gene therapy, stem cells transplants, and neuroprotective agents.
=== Animal models ===
The tragedy of a group of drug addicts in California in the early 1980s who consumed a contaminated and illicitly produced batch of the synthetic opiate MPPP brought to light MPTP as a cause of parkinsonian symptoms. Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat, and the fungicide maneb. Models based on toxins are most commonly used in primates. Transgenic rodent models also exist.
=== Gene therapy ===
Present treatments of Parkinson's disease provide satisfactory disease control for most early-stage patients. However, present gold-standard treatment of PD using levodopa is associated with motor complications, and does not prevent disease progression. More effective and long-term treatment of PD are urgently needed to control its progression. In vivo gene therapy is a new approach for treatment of PD. The use of somatic-cell gene transfer to alter gene expression in brain neurochemical systems is a novel alternative conventional treatment.
Gene therapy is currently under investigation. It involves the use of a noninfectious virus to shuttle a gene into a part of the brain. The gene used leads to the production of an enzyme which helps to manage PD symptoms or protects the brain from further damage.
One of the gene therapy based approach involves gene delivery of neurturin and glial cell line-derived neurotrophic factor (GDNF) to the putamen in patients with advanced Parkinson's disease. GDNF protects dopamine neurons in vitro and animal models of parkinsonism; neurturin is a structural and functional analogue of GDNF that protected dopamine neuron in animal model of the disease. Despite open-label trials showing benefits of continuous infusion of GDNF, the results were not confirmed in double-blind studies. This may be due to the distribution factor; the trophic factor was not distributed sufficiently throughout the target place.
Another gene therapy of PD involved insertion of the glutamic acid decarboxylase (GAD) into the subthalamic nucleus. GAD enzyme controls GABA productions. In Parkinson's disease, the activity of both GABA efferents to the subthalamic nucleus and its target within the basal ganglia circuitry are affected. This strategy used adeno-associated viral vector (AAV2) to deliver GAD to the subthalamic nucleus. The trial was done to compare the effect of bilateral delivery of AAV2-GAD into the subthalamic nucleus with bilateral sham surgery in patients with advanced Parkinson's disease. The study showed the first success of randomised, double-blind gene therapy trial for a neurodegenerative disease and justified the continued development of AAV2-GAD for treatment of PD.
=== Neuroprotective treatments ===
Investigations on neuroprotection are at the forefront of PD research. Currently, no proven neuroprotective agents or treatments are available for PD. While still theoretical, neuroprotective therapy is based on the idea that certain neurons that produce dopamine and are susceptible to premature degeneration and cell death can be protected by the introduction of neuroprotective pharmaceuticals. This protection can occur before any symptoms manifest based on genetic risk, and also during early- or late-stage PD when other treatments have ceased their impact due to the progression of the disease. Accordingly, neuroprotective therapy seeks to delay the introduction of levodopa.
Several molecules have been proposed as potential treatments. However, none of them has been conclusively demonstrated to reduce degeneration. Agents currently under investigation include antiapoptotics (omigapil, CEP-1347), antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF). Preclinical research also targets alpha-synuclein.
==== Selegiline ====
Selegiline is in a group of medications called monoamine oxidase type B (MAO-B) inhibitors.
Selegiline is used to help control the symptoms of Parkinson's disease in people who are taking levodopa and carbidopa combination (Sinemet). Selegiline may help people with PD by stopping the effects of levodopa/carbidopa from wearing off, and increasing the length of time levodopa/carbidopa continues to control symptoms.
==== Rasagiline ====
In response to potentially toxic amphetamine metabolites caused by selegiline, another promising treatment is in MAO B propargyl amine inhibitor rasagiline (N-propargyl-1-R-aminoindan, Azilect((R))). The oral bioavailability of rasagiline is 35%, it reaches T(max) after 0.5–1.0 hours and its half-life is 1.5–3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2). Rasagiline is initiated at 1-mg once-daily dose as monotherapy in early PD patients and at 0.5–1.0 mg once-daily as adjunctive to levodopa in advanced PD patients.
=== Neural transplantation ===
Since early in the 1980s fetal, porcine, carotid or retinal tissues have been used in cell transplants for PD patients.
Although there was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, the best constructed studies up to date indicate that cell transplants have no effect. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias. Stem cell transplants are a main research recent target: they are easy to manipulate and when transplanted into the brains of rodents and monkeys, cells survive and improve behavioral abnormalities of the animals. Nevertheless, use of fetal stem cells is controversial. Some have proposed that such controversy may be overcome with the use of induced pluripotent stem cells from adults.
== References ==
== External links ==
Parkinson's Medication Chart at the Parkinson's Disease Foundation
PDtrials
Find What Treatments Are Possible | Wikipedia/Management_of_Parkinson's_disease |
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal anti-inflammatory drugs (which refers to agents that treat the inflammation, but not the underlying cause) and steroids (which blunt the immune response but are insufficient to slow down the progression of the disease).
The term "antirheumatic" can be used in similar contexts, but without making a claim about an effect on the disease course. Other terms that have historically been used to refer to the same group of drugs are "remission-inducing drugs" (RIDs) and "slow-acting antirheumatic drugs" (SAARDs).
== Terminology ==
Although the use of the term DMARDs was first propagated in rheumatoid arthritis (hence their name), the term has come to pertain to many other diseases, such as Crohn's disease, lupus erythematosus, Sjögren syndrome, immune thrombocytopenic purpura, myasthenia gravis, sarcoidosis, and various others.
The term was originally introduced to indicate a drug that reduces evidence of processes thought to underlie the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level, and more recently, a raised C-reactive protein level. More recently, the term has been used to indicate a drug that reduces the rate of damage to bone and cartilage. DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer "biological" agents produced through genetic engineering.
Some DMARDs (e.g. the purine synthesis inhibitors) are mild chemotherapeutics, but use a side effect of chemotherapy—immunosuppression—as their main therapeutical benefit.
== Subdivision ==
DMARDs have been classified as:
synthetic (sDMARD)
conventional synthetic and targeted synthetic DMARDs (csDMARDs and tsDMARDs, respectively)
csDMARDs are the traditional drugs (such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, gold salts)
tsDMARDs are drugs that were developed to target a particular molecular structure
biological (bDMARD) can be further separated into original and biosimilar DMARDs (boDMARDs and bsDMARDs)
bsDMARDs are those that have the same primary, secondary, and tertiary structure as an original (boDMARD) and possess similar efficacy and safety as the original protein
== Members ==
Although these agents operate by different mechanisms, many of them can have similar impacts upon the course of a condition. Some of the drugs can be used in combination. A common triple therapy for rheumatoid arthritis is methotrexate, sulfasalazine, and hydroxychloroquine.
== Alternatives ==
When treatment with DMARDs fails, cyclophosphamide or steroid pulse therapy is often used to stabilise uncontrolled autoimmune disease. Some severe autoimmune diseases are being treated with bone marrow transplants in clinical trials, usually after cyclophosphamide therapy has failed. Furthermore, should DMARDs fail, tocilizumab can be used for tumor necrosis factor (TNF) inhibitor treatments in NICE guidance.
Combinations of DMARDs are often used, because each drug in the combination can be used in a smaller dose than if it were given alone, thus reducing the risk of side effects.
Many patients receive an NSAID and at least one DMARD, sometimes with low-dose oral glucocorticoids. If disease remission is observed, regular NSAIDs or glucocorticoid treatment may no longer be needed. DMARDs help control arthritis, but do not cure the disease. For that reason, if remission or optimal control is achieved with a DMARD, it is often continued as a maintenance dosage. Discontinuing a DMARD may reactivate disease or cause a "rebound flare", with no assurance that disease control will be re-established upon resumption of the medication.
== References == | Wikipedia/Disease-modifying_antirheumatic_drug |
Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue) and space around the alveoli (air sacs) of the lungs. It concerns alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and perilymphatic tissues. It may occur when an injury to the lungs triggers an abnormal healing response. Ordinarily, the body generates just the right amount of tissue to repair damage, but in interstitial lung disease, the repair process is disrupted, and the tissue around the air sacs (alveoli) becomes scarred and thickened. This makes it more difficult for oxygen to pass into the bloodstream. The disease presents itself with the following symptoms: shortness of breath, nonproductive coughing, fatigue, and weight loss, which tend to develop slowly, over several months. The average rate of survival for someone with this disease is between three and five years. The term ILD is used to distinguish these diseases from obstructive airways diseases.
There are specific types in children, known as children's interstitial lung diseases. The acronym ChILD is sometimes used for this group of diseases. In children, the pathophysiology involves a genetic component, exposure-related injury, autoimmune dysregulation, or all of the components.
Thirty to 40% of those with interstitial lung disease eventually develop pulmonary fibrosis which has a median survival of 2.5-3.5 years. Idiopathic pulmonary fibrosis is interstitial lung disease for which no obvious cause can be identified (idiopathic) and is associated with typical findings both radiographic (basal and pleural-based fibrosis with honeycombing) and pathologic (temporally and spatially heterogeneous fibrosis, histopathologic honeycombing, and fibroblastic foci).
In 2015, interstitial lung disease, together with pulmonary sarcoidosis, affected 1.9 million people. They resulted in 122,000 deaths.
== Causes ==
ILD may be classified as to whether its cause is not known (idiopathic) or known (secondary).
=== Idiopathic ===
Idiopathic interstitial pneumonia is the term given to ILDs with an unknown cause. They represent the majority of cases of interstitial lung diseases (up to two-thirds of cases). They were subclassified by the American Thoracic Society in 2002 into 7 subgroups:
Idiopathic pulmonary fibrosis (IPF): the most common subgroup, representing more than 30% of ILD
Desquamative interstitial pneumonia (DIP)
Acute interstitial pneumonia (AIP): also known as Hamman-Rich syndrome
Nonspecific interstitial pneumonia (NSIP)
Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)
Cryptogenic organizing pneumonia (COP): also known by the older name bronchiolitis obliterans organizing pneumonia (BOOP)
Lymphoid interstitial pneumonia (LIP)
=== Secondary ===
Secondary ILDs are those diseases with a known etiology, including:
==== Connective tissue and autoimmune diseases ====
Connective tissue related disease represents approximately 25% of all cases of ILD.
Sarcoidosis
Rheumatoid arthritis
Systemic lupus erythematosus
Systemic sclerosis
Polymyositis
Dermatomyositis
Antisynthetase syndrome
==== Inhaled substances (pneumoconiosis) ====
Inorganic
Silicosis
Asbestosis
Berylliosis
Industrial printing chemicals (e.g. carbon black, ink mist)
Organic
Hypersensitivity pneumonitis (extrinsic allergic alveolitis), representing approximately 15% of cases of ILD.
==== Drug-induced ====
Antibiotics (e.g., nitrofurantoin and sulfa drugs)
Chemotherapeutic drugs
Antiarrhythmic agents
Cigarette smoking
Smoking-related interstitial fibrosis (SRIF) is an example of a type of interstitial lung disease known to be caused by smoking.
==== Infection ====
Coronavirus disease 2019 (COVID-19)
Atypical pneumonia
Pneumocystis pneumonia (PCP)
Tuberculosis
Chlamydia trachomatis
Respiratory syncytial virus
==== Malignancy ====
Lymphangitic carcinomatosis
==== Childhood interstitial lung disease and ILD predominately in children ====
Diffuse developmental disorders
Growth abnormalities and deficient alveolarisation
Infant conditions of undefined cause
ILD related to alveolar surfactant region
== Diagnosis ==
Diagnosis of ILD involves assessing the signs and symptoms as well as a detailed history investigating occupational exposures. ILD usually presents with dyspnea, worsening exercise intolerance and 30-50% of those with ILD have a chronic cough. On examination, velcro crackles, in which the crackles compare to the sound of velcro being unfastened, are common in ILD. Pulmonary function tests usually show a restrictive defect with decreased diffusion capacity of carbon monoxide (DLCO) indicating reduced alveolar to blood capillary transport. Pulmonary function testing is indicated for all people with ILD and the FVC loss and DLCO is prognostic, with an FVC loss of greater than 5% per year associated with a poor prognosis in fibrosis subtypes of ILD.
A chest x-ray is 63% sensitive and 93% specific for ILD. With advances in computed tomography, CT scans of the chest have supplanted lung biopsy as the preferred diagnostic test for ILD. A thoracic CT scan is 91% sensitive and 71% specific for ILD. In higher income countries, less than 10% of people with ILD undergo a lung biopsy as part of the diagnostic evaluation.
A lung biopsy may be required if the clinical history and imaging are not clearly suggestive of a specific diagnosis or malignancy cannot otherwise be ruled out. Surgical lung biopsy or via a video-assisted thoracoscopic surgery (VATS) biopsy is associated with a mortality rate up to 1-2%. A bronchoscopic transbronchial cryobiopsy, in which a camera is introduced into the airways followed by rapid freezing of an area of lung tissue prior to biopsy is associated a lower complication rate and a much lower mortality rate compared to VATS or surgical biopsy with near comparable diagnostic accuracy. There are four types of histopathologic patterns seen in ILD: usual interstitial pneumonia, non-specific interstitial pneumonia, organizing pneumonia, and diffuse alveolar damage. There is significant overlap of the histopathological and radiologic features of each ILD type making diagnosis challenging; even with lung biopsy, 15% of cases of ILD cannot be classified.
=== Pulmonary function testing ===
Most patients with suspected ILD are likely to undergo complete pulmonary function testing. These tests are useful in diagnosis and determining severity of the disease.
Although there is large diversity in interstitial lung disease, most follow a restrictive pattern. Restrictive defects are defined by decreased TLC (total lung capacity), RV (residual volume), FVC (forced vital capacity) and FEV1 (forced expiratory volume in one second). As both FVC and FEV1 are reduced, the FVC to FEV1 ratio remains normal or is increased.
As disease progression increases and the lungs become stiffer lung volumes will continue to decrease; lower TLC, RV, FVC and FEV1 scores are associated with a more severe disease progression and poorer prognosis.
=== X-ray and CT (computed tomography) ===
Chest radiography is usually the first test to detect interstitial lung diseases, but the chest radiograph can be normal in up to 10% of patients, especially early in the disease process.
High-resolution CT of the chest is the preferred modality and differs from routine CT of the chest. Conventional (regular) CT chest examines 7–10 mm slices obtained
at 10 mm intervals; high resolution CT examines 1–1.5 mm slices at 10 mm intervals using a high-spatial-frequency reconstruction algorithm. The HRCT therefore provides approximately 10 times more resolution than the conventional CT chest, allowing the HRCT to elicit details that cannot otherwise be visualized.
Radiologic appearance alone, however, is not adequate and should be interpreted in the clinical context, keeping in mind the temporal profile of the disease process.
Interstitial lung diseases can be classified according to radiologic patterns.
==== Pattern of opacities ====
Consolidation
Acute:
Alveolar hemorrhage syndromes
Acute eosinophilic pneumonia
Acute interstitial pneumonia
Cryptogenic organizing pneumonia
Chronic:
Chronic eosinophilic pneumonia
Cryptogenic organizing pneumonia
Lymphoproliferative disorders
Pulmonary alveolar proteinosis
Sarcoidosis
Linear or reticular opacities
Acute:
Pulmonary edema
Chronic:
Idiopathic pulmonary fibrosis
Connective tissue-associated interstitial lung diseases
Asbestosis
Sarcoidosis
Hypersensitivity pneumonitis
Drug-induced lung disease
Small nodules
Acute:
Hypersensitivity pneumonitis
Chronic:
Hypersensitivity pneumonitis
Sarcoidosis
Silicosis
Coal workers pneumoconiosis
Respiratory bronchiolitis
Alveolar microlithiasis
Cystic airspaces
Chronic:
Pulmonary Langerhans cell histiocytosis
Pulmonary lymphangioleiomyomatosis
Honeycomb lung caused by idiopathic pulmonary fibrosis (IPF) or other diseases
Ground glass opacities
Acute:
Alveolar hemorrhage syndromes
Pulmonary edema
Hypersensitivity pneumonitis
Acute inhalational exposures
Drug-induced lung diseases
Acute interstitial pneumonia
Chronic:
Nonspecific interstitial pneumonia
Respiratory bronchiolitis-associated interstitial lung disease
Desquamative interstitial pneumonia
Drug-induced lung diseases
Pulmonary alveolar proteinosis
Thickened alveolar septa
Acute:
Pulmonary edema
Chronic:
Lymphangitic carcinomatosis
Pulmonary alveolar proteinosis
Sarcoidosis
Pulmonary veno-occlusive disease
==== Distribution ====
Upper lung predominance
Pulmonary Langerhans cell histiocytosis
Silicosis
Coal workers pneumoconiosis
Carmustine-related pulmonary fibrosis
Respiratory broncholitis associated with interstitial lung disease
Lower lung predominance
Idiopathic pulmonary fibrosis
Pulmonary fibrosis associated with connective tissue diseases (ILD-CTD)
Asbestosis
Chronic aspiration
Central predominance (perihilar)
Sarcoidosis
Berylliosis
Peripheral predominance
Idiopathic pulmonary fibrosis
Chronic eosinophilic pneumonia
Cryptogenic organizing pneumonia
==== Associated findings ====
Pleural effusion or thickening
Pulmonary edema
Connective tissue diseases
Asbestosis
Lymphangitic carcinomatosis
Lymphoma
Lymphangioleiomyomatosis
Drug-induced lung diseases
Lymphadenopathy
Sarcoidosis
Silicosis
Berylliosis
Lymphangitic carcinomatosis
Lymphoma
Lymphocytic interstitial pneumonia
=== Genetic testing ===
For some types of paediatric ILDs and few forms adult ILDs, genetic causes have been identified. These may be identified by blood tests. For a limited number of cases, this is a definite advantage, as a precise molecular diagnosis can be done; frequently then there is no need for a lung biopsy. Testing is available for
==== ILDs related to alveolar surfactant region ====
Surfactant protein B deficiency (mutations in SFTPB)
Surfactant protein C deficiency (mutations in SFTPC)
ABCA3 deficiency (mutations in ABCA3)
Brain–lung–thyroid syndrome (Mutations in TTF1)
Congenital pulmonary alveolar proteinosis (mutations in CSFR2A and/or CSFR2B)
==== Diffuse developmental disorder ====
Alveolar capillary dysplasia (mutations in FoxF1)
==== Idiopathic pulmonary fibrosis ====
Mutations in telomerase reverse transcriptase (TERT)
Mutations in telomerase RNA component (TERC)
Mutations in the regulator of telomere elongation helicase 1 (RTEL1)
Mutations in poly(A)-specific ribonuclease (PARN)
== Treatment ==
ILD is not a single disease but encompasses many different pathological processes, hence treatment is different for each disease. If a specific occupational exposure cause is found, the person should avoid that environment. If a drug cause is suspected, that drug should be discontinued.
=== Oxygen therapy ===
Oxygen therapy at home is recommended in those with significantly low oxygen levels. Oxygen therapy in ILD is associated with improvements in quality of life but reductions in mortality are uncertain. Long-term oxygen therapy can be beneficial to people with ILD and hypoxemia to enhance gas exchange, lessen dyspnea, and increase physical activity.
=== Pulmonary rehabilitation ===
Pulmonary rehabilitation appears to be useful with the benefits being sustainable longer term with improvements in exercise capacity (as measured by a six minute walking test), dyspnea, and quality of life.
=== Lung transplantation ===
Lung transplantation is an option if the ILD progresses despite therapy in appropriately selected patients with no other contraindications. Life expectancy after lung transplant is 5.2 years in those with idiopathic interstitial pneumonias (including idiopathic pulmonary fibrosis) and 6.7 years in those with other types of ILD.
=== Medications ===
The antifibrotics pirfenidone and nintedanib have been shown to slow the decline in lung function (as measured by forced vital capacity [FVC]) in those with ILD compared to placebo. Pirfenidone was associated with a 45% less decline in FVC at 52 weeks compared to placebo in a trial involving people with idiopathic pulmonary fibrosis, and was associated with a slower FVC decline in those with progressive pulmonary fibrosis. Nintedanib was also associated with a slower FVC decline and increased mean survival in people with ILD.
The immunomodulator tocilizumab has a benefit in scleroderma associated ILD by helping to preserve lung function (as measured by FVC) at 48 weeks. The immunomodulators cyclophosphamide, mycophenolate mofetil and rituximab all showed improved lung function (as measured by % predicted FVC) compared to placebo in systemic sclerosis or scleroderma associated ILD.
The inhaled vasodilator treprostinil (a synthetic prostacyclin which acts as a prostaglandin I2 analogue) is indicated in the treatment of pulmonary hypertension secondary to interstitial lung disease and is associated with improved exercise capacity as measured by a 6-minute walk test.
=== Supportive care ===
Those with ILD should stop smoking cigarettes if they smoke. Vaccinations against pneumococcus, Covid-19, RSV and influenza are indicated in all those with ILD. Short acting opiates are known to improve breathlessness symptoms in those with end stage lung disease. The opiate agonist-antagonist nalbuphine and morphine are also known to improve coughing in those with ILD and other end stage lung diseases.
== Prognosis ==
The median survival in idiopathic pulmonary fibrosis is 3-3.5 years. In those who receive a lung transplant, the medial survival in idiopathic pulmonary fibrosis is 5.2 years, as compared to 6.7 years in those with other types of ILD. ILD is associated with a 3-fold increased risk of lung cancer.
== References ==
== External links ==
00736 at CHORUS | Wikipedia/Interstitial_lung_disease |
Magnetic nanoparticle-based drug delivery is a means in which magnetic particles such as iron oxide nanoparticles are a component of a delivery vehicle for magnetic drug delivery, due to the simplicity with which the particles can be drawn to (external) magnetopuissant targets. Magnetic nanoparticles can impart imaging and controlled release capabilities to drug delivery materials such as micelles, liposomes, and polymers.
== Synopsis ==
Molecular magnets (single-molecule magnets) are a platform that incorporates insoluble (toxic) drugs into biocompatible carrier materials, without adding magnetic iron oxide nanoparticles which might adversely affect patients susceptible to iron overdose. The drawbacks in conventional magnetic drug delivery methods can be overcome by switching from typical iron oxide nanoparticles to ones based on molecular magnets, such as Fe(salen)-based "anticancer nanomagnet" with proven cancer-fighting ability. However, insoluble drugs including Fe(salen) also have some inherent drawbacks, such as poor water solubility, loss of magnetic activity in solvents, and potential cytotoxicity when accumulated in tissues and organs.
As an alternative synthetic method of magnetic drug delivery, a "non-iron oxide"-based smart delivery platform has been very recently developed by self-assembly of the Fe(salen) drugs into nano-cargoes encapsulated by a smart polymer, exhibiting bio-safe multifunctional magnetic capabilities, including MRI, magnetic field- and pH-responsive heat-releasing hyperthermia effects, and controlled release.
== References == | Wikipedia/Magnetic_drug_delivery |
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells (e.g. with traditional chemotherapy). Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy (and thus distinguished from chemotherapy, that is, cytotoxic therapy). However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
Another form of targeted therapy involves the use of nanoengineered enzymes to bind to a tumor cell such that the body's natural cell degradation process can digest the cell, effectively eliminating it from the body.
Targeted cancer therapies are expected to be more effective than older forms of treatments and less harmful to normal cells. Many targeted therapies are examples of immunotherapy (using immune mechanisms for therapeutic goals) developed by the field of cancer immunology. Thus, as immunomodulators, they are one type of biological response modifiers.
The most successful targeted therapies are chemical entities that target or preferentially target a protein or enzyme that carries a mutation or other genetic alteration that is specific to cancer cells and not found in normal host tissue. One of the most successful molecular targeted therapeutics is imatinib, marketed as Gleevec, which is a kinase inhibitor with exceptional affinity for the oncofusion protein BCR-Abl which is a strong driver of tumorigenesis in chronic myelogenous leukemia. Although employed in other indications, imatinib is most effective targeting BCR-Abl. Other examples of molecular targeted therapeutics targeting mutated oncogenes, include PLX27892 which targets mutant B-raf in melanoma.
There are targeted therapies for lung cancer, colorectal cancer, head and neck cancer, breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers.
Biomarkers are usually required to aid the selection of patients who will likely respond to a given targeted therapy.
Co-targeted therapy involves the use of one or more therapeutics aimed at multiple targets, for example PI3K and MEK, in an attempt to generate a synergistic response and prevent the development of drug resistance.
The definitive experiments that showed that targeted therapy would reverse the malignant phenotype of tumor cells involved treating Her2/neu transformed cells with monoclonal antibodies in vitro and in vivo by Mark Greene's laboratory and reported from 1985.
Some have challenged the use of the term, stating that drugs usually associated with the term are insufficiently selective. The phrase occasionally appears in scare quotes: "targeted therapy". Targeted therapies may also be described as "chemotherapy" or "non-cytotoxic chemotherapy", as "chemotherapy" strictly means only "treatment by chemicals". But in typical medical and general usage "chemotherapy" is now mostly used specifically for "traditional" cytotoxic chemotherapy.
== Types ==
The main categories of targeted therapy are currently small molecules and monoclonal antibodies.
=== Small molecules ===
Many are tyrosine-kinase inhibitors.
Imatinib (Gleevec, also known as STI–571) is approved for chronic myelogenous leukemia, gastrointestinal stromal tumor and some other types of cancer. Early clinical trials indicate that imatinib may be effective in treatment of dermatofibrosarcoma protuberans.
Gefitinib (Iressa, also known as ZD1839), targets the epidermal growth factor receptor (EGFR) tyrosine kinase and is approved in the U.S. for non small cell lung cancer.
Erlotinib (marketed as Tarceva). Erlotinib inhibits epidermal growth factor receptor, and works through a similar mechanism as gefitinib. Erlotinib has been shown to increase survival in metastatic non small cell lung cancer when used as second line therapy. Because of this finding, erlotinib has replaced gefitinib in this setting.
Sorafenib (Nexavar)
Sunitinib (Sutent)
Dasatinib (Sprycel)
Lapatinib (Tykerb)
Nilotinib (Tasigna)
Bosutinib (Bosulif)
Ponatinib (Iclusig)
Asciminib (Scemblix)
Bortezomib (Velcade) is an apoptosis-inducing proteasome inhibitor drug that causes cancer cells to undergo cell death by interfering with proteins. It is approved in the U.S. to treat multiple myeloma that has not responded to other treatments.
The selective estrogen receptor modulator tamoxifen has been described as the foundation of targeted therapy.
Janus kinase inhibitors, e.g. FDA approved tofacitinib
ALK inhibitors, e.g. crizotinib
Bcl-2 inhibitors (e.g. FDA approved venetoclax, obatoclax in clinical trials, navitoclax, and gossypol.
PARP inhibitors (e.g. FDA approved olaparib, rucaparib, niraparib and talazoparib)
PI3K inhibitors (e.g. perifosine in a phase III trial)
Apatinib is a selective VEGF Receptor 2 inhibitor which has shown encouraging anti-tumor activity in a broad range of malignancies in clinical trials. Apatinib is currently in clinical development for metastatic gastric carcinoma, metastatic breast cancer and advanced hepatocellular carcinoma.
Zoptarelin doxorubicin (AN-152), doxorubicin linked to [D-Lys(6)]- LHRH, Phase II results for ovarian cancer.
Braf inhibitors (vemurafenib, dabrafenib, LGX818) used to treat metastatic melanoma that harbors BRAF V600E mutation
MEK inhibitors (trametinib, MEK162) are used in experiments, often in combination with BRAF inhibitors to treat melanoma
CDK inhibitors, e.g. PD-0332991, LEE011 in clinical trials
Hsp90 inhibitors, some in clinical trials
Hedgehog pathway inhibitors (e.g. FDA approved vismodegib and sonidegib).
Salinomycin has demonstrated potency in killing cancer stem cells in both laboratory-created and naturally occurring breast tumors in mice.
VAL-083 (dianhydrogalactitol), a “first-in-class” DNA-targeting agent with a unique bi-functional DNA cross-linking mechanism. NCI-sponsored clinical trials have demonstrated clinical activity against a number of different cancers including glioblastoma, ovarian cancer, and lung cancer. VAL-083 is currently undergoing Phase 2 and Phase 3 clinical trials as a potential treatment for glioblastoma (GBM) and ovarian cancer. As of July 2017, four different trials of VAL-083 are registered.
Ibrutinib blocks Bruton's tyrosine kinase (BTK) and is used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia.
=== Small molecule drug conjugates ===
Vintafolide is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor. It is currently in clinical trials for platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study (TARGET trial) in non-small-cell lung carcinoma (NSCLC).
=== Serine/threonine kinase inhibitors (small molecules) ===
Temsirolimus (Torisel)
Everolimus (Afinitor)
Vemurafenib (Zelboraf)
Trametinib (Mekinist)
Dabrafenib (Tafinlar)
=== Monoclonal antibodies ===
Several are in development and a few have been licensed by the FDA and the European Commission. Examples of licensed monoclonal antibodies include:
Pembrolizumab (Keytruda) binds to PD-1 proteins found on T cells. Pembrolizumab blocks PD-1 and help the immune system kill cancer cells. It is used to treat melanoma, Hodgkin's lymphoma, non-small cell lung carcinoma and several other types of cancer.
Rituximab targets CD20 found on B cells. It is used in non Hodgkin lymphoma
Trastuzumab targets the Her2/neu (also known as ErbB2) receptor expressed in some types of breast cancer
Alemtuzumab
Cetuximab target the epidermal growth factor receptor (EGFR). It is approved for use in the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck.
Panitumumab also targets the EGFR. It is approved for the use in the treatment of metastatic colorectal cancer.
Bevacizumab targets circulating VEGF ligand. It is approved for use in the treatment of colon cancer, breast cancer, non-small cell lung cancer, and is investigational in the treatment of sarcoma. Its use for the treatment of brain tumors has been recommended.
Ipilimumab (Yervoy)
Brentuximab targets CD30 and is useful in some types of lymphoma.
Many antibody-drug conjugates (ADCs) are being developed. See also antibody-directed enzyme prodrug therapy (ADEPT).
== Progress and future ==
In the U.S., the National Cancer Institute's Molecular Targets Development Program (MTDP) aims to identify and evaluate molecular targets that may be candidates for drug development. A systematic review published in Cochrane database found that targeted therapies significantly improve progression-free survival by 35 to 40% in metastatic or relapsed cancer. While the research points to promising clinical outcomes, there is still limited evidence on the long-term effects of targeted therapies in terms of overall survival, quality of life, and severe adverse events.
== See also ==
== References ==
== External links ==
Targeted Therapy Database (TTD) [1] from the Melanoma Molecular Map Project [2]
Targeted therapy Fact sheet from the U.S. National Cancer Institute
Molecular Oncology: Receptor-Based Therapy Special issue of Journal of Clinical Oncology (April 10, 2005) dedicated to targeted therapies in cancer treatment
Targeting Targeted Therapy New England Journal of Medicine (2004)
Targeting tumors with medicinal cannabis oil – publication list from Spain | Wikipedia/Targeted_therapy |
Anti-Cancer Drugs is an international medical journal, which aims to promote and encourage research on anti-cancer agents. It was first published in 1990 and it includes reports on clinical and experimental research results, from conventional cytotoxic chemotherapy to hormonal or biological response modalities. The journal has 10 issues per year and the current editor in chief is Mels Sluyser. According to the 2014 Journal Citation Reports, the journal has an impact factor of 1.784, ranking it 164th out of 211 in the category Oncology and 162nd out of 254 in the category Pharmacology & Pharmacy.
== References ==
== External links ==
Official website | Wikipedia/Anti-Cancer_Drugs_(journal) |
Adjuvant therapy, also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used in cancer therapy have led the term to be used mainly to describe adjuvant cancer treatments. An example of such adjuvant therapy is the additional treatment usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to the presence of undetected disease. If known disease is left behind following surgery, then further treatment is not technically adjuvant.
An adjuvant used on its own specifically refers to an agent that improves the effect of a vaccine. Medications used to help primary medications are known as add-ons.
== History ==
The term "adjuvant therapy," derived from the Latin term adjuvāre, meaning "to help," was first coined by Paul Carbone and his team at the National Cancer Institute in 1963. In 1968, the National Surgical Adjuvant Breast and Bowel Project (NSABP) published its B-01 trial results for the first randomized trial that evaluated the effect of an adjuvant alkylating agent in breast cancer. The results indicated that the adjuvant therapy given after the initial radical mastectomy "significantly decreased recurrence rate in pre-menopausal women with four or more positive axillary lymph nodes."
The budding theory of using additional therapies to supplement primary surgery was put into practice by Gianni Bonadonna and his colleagues from the Instituto Tumori in Italy in 1973, where they conducted a randomized trial that demonstrated more favorable survival outcomes that accompanied use of Cyclophosphamide Methotrexate Fluorouracil (CMF) after the initial mastectomy.
In 1976, shortly after Bonadonna's landmark trial, Bernard Fisher at the University of Pittsburgh initiated a similar randomized trial that compared the survival of breast cancer patients treated with radiation after the initial mastectomy to those who only received the surgery. His results, published in 1985, indicated increased disease-free survival for the former group.
Despite the initial pushback from the breast cancer surgeons who believed that their radical mastectomies were sufficient in removing all traces of cancer, the success of Bonadonna's and Fisher's trials brought adjuvant therapy to the mainstream in oncology. Since then, the field of adjuvant therapy has expanded to include a range of adjuvant therapies to include chemotherapy, immunotherapy, hormone therapy, and radiation.
== Neoadjuvant therapy ==
Neoadjuvant therapy, in contrast to adjuvant therapy, is given before the main treatment. For example, systemic therapy for breast cancer that is given before removal of a breast is considered neoadjuvant chemotherapy. The most common reason for neoadjuvant therapy for cancer is to reduce the size of the tumor so as to facilitate more effective surgery.
In the context of breast cancer, neoadjuvant chemotherapy administered before surgery can improve survival in patients. If no active cancer cells are present in a tissue extracted from the tumor site after neoadjuvant therapy, physicians classify a case as "pathologic complete response" or "pCR." While response to therapy has been demonstrated to be a strong predictor of outcome, the medical community has still not reached a consensus in regard to the definition of pCR across various breast cancer subtypes. It remains unclear whether pCR can be used as a surrogate end point in breast cancer cases.
== Adjuvant cancer therapy ==
For example, radiotherapy or systemic therapy is commonly given as adjuvant treatment after surgery for breast cancer. Systemic therapy consists of chemotherapy, immunotherapy or biological response modifiers or hormone therapy. Oncologists use statistical evidence to assess the risk of disease relapse before deciding on the specific adjuvant therapy. The aim of adjuvant treatment is to improve disease-specific symptoms and overall survival. Because the treatment is essentially for a risk, rather than for provable disease, it is accepted that a proportion of patients who receive adjuvant therapy will already have been cured by their primary surgery.
Adjuvant systemic therapy and radiotherapy are often given following surgery for multiple types of cancer, including colon cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and some gynaecological cancers. Some forms of cancer fail to benefit from adjuvant therapy, however. Such cancers include renal cell carcinoma, and certain forms of brain cancer.
Hyperthermia therapy or heat therapy is also a kind of adjuvant therapy that is sometimes given in combination with radiotherapy or chemotherapy to boost the effects of these conventional treatments in treating advanced cancers. Heating the tumour area sensitises it making it more responsive to the other therapies used. It is cost-effective and safe, and is seen to have a promising role in cancer treatment.
=== Controversy ===
A motif found throughout the history of cancer therapy is the tendency for overtreatment. From the time of its inception, the use of adjuvant therapy has received scrutiny for its adverse effects on the quality of life of cancer patients. For example, because side effects of adjuvant chemotherapy can range from nausea to loss of fertility, physicians regularly practice caution when prescribing chemotherapy.
In the context of melanoma, certain treatments, such as Ipilimumab, result in high grade adverse events, or immune-related adverse events, in 10-15% of patients that parallel the effects of metastatic melanoma itself. Similarly, several common adjuvant therapies are noted for having the potential of causing cardiovascular disease. In such cases, physicians must weigh the cost of recurrence against more immediate consequences and consider factors, like age and relative cardiovascular health of a patient, before prescribing certain types of adjuvant therapy.
One of the most notable side effects of adjuvant therapy is the loss of fertility. For pre-pubescent males, testicular tissue cryopreservation is an option for preserving future fertility. For post-pubescent males, this side effect can be assuaged through semen cryopreservation. For pre-menopausal females, options to preserve fertility are oftentimes much more complex. For example, breast cancer patients of fertile age oftentimes have to weigh the risks and benefits associated with starting an adjuvant therapy regimen after primary treatment. In the some low-risk, low-benefit situations, forgoing adjuvant treatment altogether can be a reasonable decision, but in cases where the risk of metastasis is high, patients may be forced to make a difficult decision. Though options for fertility preservation exist (e.g., embryo preservation, oocyte cryopreservation, ovarian suppression, etc.), they are more often than not time-consuming and costly.
As a result of complications that can stem from liberal use of adjuvant therapy, the philosophy surrounding the use of adjuvant therapy in the clinical setting has shifted towards the goal of doing as little harm as possible to patients. The standards for dose intensity of adjuvant treatments and treatment duration are regularly updated to optimize regimen efficiency while minimizing toxic side effects that patients must shoulder.
=== Concomitant or concurrent systemic cancer therapy ===
Concomitant or concurrent systemic cancer therapy refers to administering medical treatments at the same time as other therapies, such as radiation. Adjuvant hormonal therapy is given after prostate removal in prostate cancer, but there are concerns that the side effects, in particular the cardiovascular ones, may outweigh the risk of recurrence. In breast cancer, adjuvant therapy may consist of chemotherapy (doxorubicin, trastuzumab, paclitaxel, docetaxel, cyclophosphamide, fluorouracil, and methotrexate) and radiotherapy, especially after lumpectomy, and hormonal therapy (tamoxifen, letrozole). Adjuvant therapy in breast cancer is used in stage one and two breast cancer following lumpectomy, and in stage three breast cancer due to lymph node involvement.
In glioblastoma multiforme, adjuvant chemoradiotherapy is critical in the case of a completely removed tumor, as with no other therapy, recurrence occurs in 1–3 months.
In early stage one small cell lung carcinoma, adjuvant chemotherapy with gemcitabine, cisplatin, paclitaxel, docetaxel, and other chemotherapeutic agents, and adjuvant radiotherapy is administered to either the lung, to prevent a local recurrence, or the brain to prevent metastases.
In testicular cancer, adjuvant either radiotherapy or chemotherapy may be used following orchidectomy. Previously, mainly radiotherapy was used, as a full course of cytotoxic chemotherapy produced far more side effects then a course of external beam radiotherapy (EBRT). However, it has been found a single dose of carboplatin is as effective as EBRT in stage II testicular cancer, with only mild side effects (transient myelosuppressive action vs severe and prolonged myelosuppressive neutropenic illness in normal chemotherapy, and much less vomiting, diarrhea, mucositis, and no alopecia in 90% of cases.
Adjuvant therapy is particularly effective in certain types of cancer, including colorectal carcinoma, lung cancer, and medulloblastoma. In completely resected medulloblastoma, 5-year survival rate is 85% if adjuvant chemotherapy and/or craniospinal irradiation is performed, and just 10% if no adjuvant chemotherapy or craniospinal irradiation is used. Prophylactic cranial irradiation for acute lymphoblastic leukemia (ALL) is technically adjuvant, and most experts agree that cranial irradiation decreases risk of central nervous system (CNS) relapse in ALL and possibly acute myeloid leukemia (AML), but it can cause severe side effects, and adjuvant intrathecal methotrexate and hydrocortisone may be just as effective as cranial irradiation, without severe late effects, such as developmental disability, dementia, and increased risk for second malignancy.
=== Dose-dense chemotherapy ===
Dose-dense chemotherapy (DDC) has recently emerged as an effective method of adjuvant chemotherapy administration. DDC uses the Gompertz curve to explain tumor cell growth after initial surgery removes most of the tumor mass. Cancer cells that are left over after a surgery are typically rapidly dividing cells, leaving them the most vulnerable to chemotherapy. Standard chemotherapy regimens are usually administered every 3 weeks to allow normal cells time to recover. This practice has led scientists to the hypothesis that the recurrence of cancer after surgery and chemo may be due to the rapidly diving cells outpacing the rate of chemotherapy administration. DDC tries to circumvent this issue by giving chemotherapy every 2 weeks. To lessen the side effects of chemotherapy that can be exacerbated with more closely administered chemotherapy treatments, growth factors are typically given in conjunction with DDC to restore white blood cell counts. A recent 2018 meta-analysis of DDC clinical trials in early stage breast cancer patients indicated promising results in premenopausal women, but DDC has yet to become the standard of treatment in clinics.
=== Specific cancers ===
==== Malignant melanoma ====
The role of adjuvant therapy in malignant melanoma is and has been hotly debated by oncologists. In 1995 a multicenter study reported improved long-term and disease-free survival in melanoma patients using interferon alpha 2b as an adjuvant therapy. Thus, later that year the U.S. Food and Drug Administration (FDA) approved interferon alpha 2b for melanoma patients who are currently free of disease, to reduce the risk of recurrence. Since then, however, some doctors have argued that interferon treatment does not prolong survival or decrease the rate of relapse, but only causes harmful side effects. Those claims have not been validated by scientific research.
Adjuvant chemotherapy has been used in malignant melanoma, but there is little hard evidence to use chemotherapy in the adjuvant setting. However, melanoma is not a chemotherapy-resistant malignancy. Dacarbazine, temozolomide, and cisplatin all have a reproducible 10–20% response rate in metastatic melanoma.; however, these responses are often short-lived and almost never complete. Multiple studies have shown that adjuvant radiotherapy improves local recurrence rates in high-risk melanoma patients. The studies include at least two M.D. Anderson cancer center studies. However, none of the studies showed that adjuvant radiotherapy had a statistically significant survival benefit.
A number of studies are currently underway to determine whether immunomodulatory agents which have proven effective in the metastatic setting are of benefit as adjuvant therapy for patients with resected stage 3 or 4 disease.
==== Colorectal cancer ====
Adjuvant chemotherapy is effective in preventing the outgrowth of micrometastatic disease from colorectal cancer that has been removed surgically. Studies have shown that fluorouracil is an effective adjuvant chemotherapy among patients with microsatellite stability or low-frequency microsatellite instability, but not in patients with high-frequency microsatellite instability.
==== Pancreatic cancer ====
===== Exocrine =====
Exocrine pancreatic cancer has one of the lowest 5-year survival rates out of all cancers. Because of the poor outcomes associated with surgery alone, the role of adjuvant therapy has been extensively evaluated. A series of studies has established that 6 months of chemotherapy with either gemcitabine or fluorouracil, as compared with observation, improves overall survival. Newer trials incorporating immune checkpoint inhibitors such as the inhibitors to programmed death 1 (PD-1) and the PD-1 ligand PD-L1 are under way.
==== Lung Cancer ====
===== Non-small cell lung cancer (NSCLC) =====
In 2015, a comprehensive meta-analysis of 47 trials and 11,107 patients revealed that NSCLC patients benefit from adjuvant therapy in the form of chemotherapy and/or radiotherapy. The results found that patients given chemotherapy after the initial surgery lived 4% longer than those who did not receive chemotherapy. The toxicity resulting from adjuvant chemotherapy was believed to be manageable.
==== Bladder cancer ====
Neoadjuvant chemotherapy (NAC) followed by a radical cystectomy (RC) and pelvic lymph node dissection is current standard of care to treat muscle-invasive bladder cancer (MIBC). NAC was justified for use in MIBC due to a randomized control trial which showed an improved median overall survival (OS; 77 months vs. 46 months, p = 0.06) and downstaging of pathology (pT0 in 38% vs. 15%) in those who received cisplatin-based NAC followed by surgery vs. surgery alone. These findings were later substantiated by a meta-analysis of 11 clinical trials that showed a 5% and 9% absolute improvement in 5-year overall survival and disease free survival, respectively. Neoadjuvant platinum-based chemotherapy has been demonstrated to improve OS in advanced bladder cancer, but there exists some controversy in the administration. Unpredictable patient response remains the drawback of NAC therapy. While it may shrink tumors in some patients, others may not respond to the treatment at all. It has been demonstrated that a delay in surgery of greater than 12 weeks from the time of diagnosis can decrease OS. Thus, the timing for NAC becomes critical, as a course of NAC therapy could delay a RC and allow the tumor to grow and further metastasize.
Micometastases cannot be ruled out in locally advanced disease, and surgery alone is not always sufficient for complete cancer control. In certain situations, acquiring precise pathologic staging can make adjuvant chemotherapy (AC) an appealing option. Stage specific pathologic treatment and reduced time to surgery can predict prognosis and the absolute OS benefits in patients with at least cT3 disease A systematic review that studied 7,056 patients showed there was a known 9-11% absolute survival benefit at five years attributable to earlier administration of AC; there was a survival benefit seen with earlier administration, as well as a benefit that persisted when compared to controls who received no AC. One limitation of AC is that poor postoperative healing or complications can limit early administration, leading to a potential propagation of potential micrometastases, early recurrence, or reduction in cancer-specific survival. Enhanced recovery after surgery protocols have recently improved perioperative care and may make earlier time to AC administration less challenging. The recent approval of adjuvant immunotherapy for patients with adverse pathology may make earlier adjuvant administration more tolerable, and be provided to patients who received NAC prior to their RC.
==== Breast cancer ====
It has been known for at least 30 years that adjuvant chemotherapy increases the relapse-free survival rate for patients with breast cancer In 2001 after a national consensus conference, a US National Institute of Health panel concluded: "Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status."
Agents used include:
However, ethical concerns have been raised about the magnitude of benefit of this therapy since it involves further treatment of patients without knowing the possibility of relapse. Dr. Bernard Fisher, among the first to conduct a clinical trial evaluating the efficacy of adjuvant therapy on patients with breast cancer, described it as a "value judgement" in which the potential benefits must be evaluated against the toxicity and cost of treatment and other potential side effects.
Often related to fear of side effects, more recent work has indicated that women do not take adjuvant therapy as prescribed or may stop before they should. A study in 2023 exploring the extent to which an information leaflet could help women to understand the benefits and to reduce their concerns and found that quotes from other women with breast cancer contributes to more positive beliefs.
==== Combination adjuvant chemotherapy for breast cancer ====
Giving two or more chemotherapeutic agents at once may decrease the chances of recurrence of the cancer, and increase overall survival in patients with breast cancer. Commonly used combination chemotherapy regimens used include:
Doxorubicin and cyclophosphamide
Doxorubicin and cyclophosphamide followed by docetaxel
Doxorubicin and cyclophosphamide followed by cyclophosphamide, methotrexate, and fluorouracil
Cyclophosphamide, methotrexate, and fluorouracil.
Docetaxel and cyclophosphamide.
Docetaxel, doxorubicin, and cyclophosphamide
Cyclophosphamide, epirubicin, and fluorouracil.
==== Ovarian Cancer ====
Roughly 15% of ovarian cancers are detected at the early stage, at which the 5-year survival rate is 92%. A Norwegian meta-analysis of 22 randomized studies involving early-stage ovarian cancer revealed the likelihood that 8 out of 10 women treated with cisplatin after the initial surgery were overtreated. Patients diagnosed at an early stage who were treated with cisplatin immediately after surgery fared worse than patients who were left untreated. An additional surgical focus for young women with early-stage cancers is on the conservation of the contralateral ovary for the preservation of fertility.
Most cases of ovarian cancers are detected at the advanced stages, when the survival is greatly reduced.
==== Cervical cancer ====
In early stage cervical cancers, research suggests that adjuvant platinum-based chemotherapy after chemo-radiation may improve survival. For advanced cervical cancers, further research is needed to determine the efficacy, toxicity and effect on the quality of life of adjuvant chemotherapy.
==== Endometrial cancer ====
Since most early-stage endometrial cancer cases are diagnosed early and are typically curable with surgery, adjuvant therapy is only given after surveillance and histological factors determine that a patient is at high risk for recurrence. Adjuvant pelvic radiation therapy has received scrutiny for its use in women under 60, as studies have indicated decreased survival and increased risk of second malignancies following treatment.
In advanced-stage endometrial cancer, adjuvant therapy is typically radiation, chemotherapy, or a combination of the two. While advanced-stage cancer makes up only about 15% of diagnoses, it accounts for 50% of deaths from endometrial cancer. Patients who undergo radiation and/or chemotherapy treatment will sometimes experience modest benefits before relapse.
==== Testicular cancer ====
===== Stage I =====
For seminoma, the three standard options are: active surveillance, adjuvant radiotherapy, or adjuvant chemotherapy.
For non-seminoma, the options include: active surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection.
As is the case for all reproductive cancers, a degree of caution is taken when deciding to use adjuvant therapy to treat early stage testicular cancer. Though the 5-year survival rates for stage I testicular cancers is approximately 99%, there still exists controversy over whether to overtreat stage I patients to prevent relapse or to wait until patients experience relapse. Patients treated with standard chemotherapy regimens can experience "second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems." As such to minimize overtreatment and avoid potential long-term toxicity caused by adjuvant therapy, most patients today are treated with active surveillance.
=== Side effects of adjuvant cancer therapy ===
Depending on what form of treatment is used, adjuvant therapy can have side effects, like all therapy for neoplasms. Chemotherapy frequently causes vomiting, nausea, alopecia, mucositis, myelosuppression particularly neutropenia, sometimes resulting in septicaemia. Some chemotherapeutic agents can cause acute myeloid leukaemia, in particular the alkylating agents. Rarely, this risk may outweigh the risk of recurrence of the primary tumor. Depending on the agents used, side effects such as chemotherapy-induced peripheral neuropathy, leukoencephalopathy, bladder damage, constipation or diarrhea, hemorrhage, or post-chemotherapy cognitive impairment. Radiotherapy causes radiation dermatitis and fatigue, and, depending on the area being irradiated, may have other side effects. For instance, radiotherapy to the brain can cause memory loss, headache, alopecia, and radiation necrosis of the brain. If the abdomen or spine is irradiated, nausea, vomiting, diarrhea, and dysphagia can occur. If the pelvis is irradiated, prostatitis, proctitis, dysuria, metritis, diarrhea, and abdominal pain can occur. Adjuvant hormonal therapy for prostate cancer may cause cardiovascular disease, and other, possibly severe, side effects.
== See also ==
Analgesic adjuvant
== References == | Wikipedia/Adjuvant_chemotherapy |
Antibody–drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs.
ADCs are complex molecules composed of an antibody linked to a biologically active cytotoxic (anticancer) payload or drug. Antibody–drug conjugates are an example of bioconjugates and immunoconjugates.
ADCs combine the targeting properties of monoclonal antibodies with the cancer-killing capabilities of cytotoxic drugs, designed to discriminate between healthy and diseased tissue.
== Mechanism of action ==
An anticancer drug is coupled to an antibody that targets a specific tumor antigen (or protein) that, ideally, is only found in or on tumor cells. Antibodies attach themselves to the antigens on the surface of cancerous cells. The biochemical reaction that occurs upon attaching triggers a signal in the tumor cell, which then absorbs, or internalizes, the antibody together with the linked cytotoxin. After the ADC is internalized, the cytotoxin kills the cancer. Their targeting ability was believed to limit side effects for cancer patients and to give a wider therapeutic window than other chemotherapeutic agents, although this promise hasn't yet been realized in the clinic.
ADC technologies have been featured in many publications, including scientific journals.
== History ==
The idea of drugs that would target tumor cells and ignore others was conceived in 1900 by German Nobel laureate Paul Ehrlich; he described the drugs as a "magic bullet" due to their targeting properties.
In 2001 Pfizer/Wyeth's drug Gemtuzumab ozogamicin (brand name: Mylotarg) was approved based on a study with a surrogate endpoint, through the accelerated approval process. In June 2010, after evidence accumulated showing no evidence of benefit and significant toxicity, the U.S. Food and Drug Administration (FDA) forced the company to withdraw it. It was reintroduced into the US market in 2017.
Brentuximab vedotin (brand name: Adcetris, marketed by Seattle Genetics and Millennium/Takeda) was approved for relapsed HL and relapsed systemic anaplastic large-cell lymphoma (sALCL)) by the FDA on August 19, 2011, and received conditional marketing authorization from the European Medicines Agency in October 2012.
Trastuzumab emtansine (ado-trastuzumab emtansine or T-DM1, brand name: Kadcyla, marketed by Genentech and Roche) was approved in February 2013 for the treatment of people with HER2-positive metastatic breast cancer (mBC) who had received prior treatment with trastuzumab and a taxane chemotherapy.
The European Commission approved Inotuzumab ozogamicin as a monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) on June 30, 2017, under the brand name Besponsa (Pfizer/Wyeth), followed on August 17, 2017, by the FDA.
The first immunology antibody–drug conjugate (iADC), ABBV-3373, showed an improvement in disease activity in a Phase 2a study of patients with rheumatoid arthritis and a study with the second iADC, ABBV-154 to evaluate adverse events and change in disease activity in participants treated with subcutaneous injection of ABBV-154 is ongoing.
In July 2018, Daiichi Sankyo Company, Limited and Glycotope GmbH have inked a pact regarding the combination of Glycotope's investigational tumor-associated TA-MUC1 antibody gatipotuzumab and Daiichi Sankyo's proprietary ADC technology for developing gatipotuzumab antibody drug conjugate.
In 2019 AstraZeneca agreed to pay up to US$6.9 billion to jointly develop DS-8201 with Japan's Daiichi Sankyo. It is intended to replace Herceptin for treating breast cancer. DS8201 carries eight payloads, compared to the usual four.
== Commercial products ==
== Components of an ADC ==
An antibody–drug conjugate consists of three components:
Antibody - targets the cancer cell surface and may also elicit a therapeutic response.
Payload - elicits the desired therapeutic response.
Linker - attaches the payload to the antibody and should be stable in circulation only releasing the payload at the desired target. Multiple approaches to conjugation have been developed for attachment to the antibody and reviewed. DAR is the drug to antibody ratio and indicates the level of loading of the payload on the ADC.
== Payloads ==
Many of the payloads for oncology ADCs (oADC) are natural product based with some making covalent interactions with their target. Payloads include the microtubulin inhibitors monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF) and mertansine, DNA binder calicheamicin and topoisomerase 1 inhibitors SN-38 and exatecan resulting in a renaissance for natural product total synthesis. Glucocorticoid receptor modulators (GRMs) represent to most active payload class for iADCs. Approaches releasing marketed GRM molecules such as dexamethasone and budesonide have been developed. Modified GRM molecules have also been developed that enable the attachment of the linker with the term ADCidified describing the medicinal chemistry process of payload optimization to facilitate linker attachment. Alternatives to small molecule payloads have also been investigated, for example, siRNA.
== Linkers ==
A stable link between the antibody and cytotoxic (anti-cancer) agent is a crucial aspect of an ADC. A stable ADC linker ensures that less of the cytotoxic payload falls off before reaching a tumor cell, improving safety, and limiting dosages.
Linkers are based on chemical motifs including disulfides, hydrazones or peptides (cleavable), or thioethers (noncleavable). Cleavable and noncleavable linkers were proved to be safe in preclinical and clinical trials. Brentuximab vedotin includes an enzyme-sensitive cleavable linker that delivers the antimicrotubule agent monomethyl auristatin E or MMAE, a synthetic antineoplastic agent, to human-specific CD30-positive malignant cells. MMAE inhibits cell division by blocking the polymerization of tubulin. Because of its high toxicity MMAE cannot be used as a single-agent chemotherapeutic drug. However, MMAE linked to an anti-CD30 monoclonal antibody (cAC10, a cell membrane protein of the tumor necrosis factor or TNF receptor) was stable in extracellular fluid. It is cleavable by cathepsin and safe for therapy. Trastuzumab emtansine is a combination of the microtubule-formation inhibitor mertansine (DM-1) and antibody trastuzumab that employs a stable, non-cleavable linker.
The availability of better and more stable linkers has changed the function of the chemical bond. The type of linker, cleavable or noncleavable, lends specific properties to the cytotoxic drug. For example, a non-cleavable linker keeps the drug within the cell. As a result, the entire antibody, linker and cytotoxic (anti-cancer) agent enter the targeted cancer cell where the antibody is degraded into an amino acid. The resulting complex – amino acid, linker and cytotoxic agent – is considered to be the active drug. In contrast, cleavable linkers are detached by enzymes in the cancer cell. The cytotoxic payload can then escape from the targeted cell and, in a process called "bystander killing", attack neighboring cells.
Another type of cleavable linker, currently in development, adds an extra molecule between the cytotoxin and the cleavage site. This allows researchers to create ADCs with more flexibility without changing cleavage kinetics. Researchers are developing a new method of peptide cleavage based on Edman degradation, a method of sequencing amino acids in a peptide. Also under development are site-specific conjugation (TDCs) and novel conjugation techniques to further improve stability and therapeutic index, α emitting immunoconjugates, antibody-conjugated nanoparticles and antibody-oligonucleotide conjugates.
== Anything Drug Conjugates ==
As the antibody–drug conjugate field has matured, a more accurate definition of ADC is now Anything-Drug Conjugate. Alternatives for the antibody targeting component now include multiple smaller antibody fragments like diabodies, Fab, scFv, and bicyclic peptides.
== Research ==
=== Non-natural amino acids ===
The first generation uses linking technologies that conjugate drugs non-selectively to cysteine or lysine residues in the antibody, resulting in a heterogeneous mixture. This approach leads to suboptimal safety and efficacy and complicates optimization of the biological, physical and pharmacological properties. Site-specific incorporation of unnatural amino acids generates a site for controlled and stable attachment. This enables the production of homogeneous ADCs with the antibody precisely linked to the drug and controlled ratios of antibody to drug, allowing the selection of a best-in-class ADC. An Escherichia coli-based open cell-free synthesis (OCFS) allows the synthesis of proteins containing site-specifically incorporated non-natural amino acids and has been optimized for predictable high-yield protein synthesis and folding. The absence of a cell wall allows the addition of non-natural factors to the system to manipulate transcription, translation and folding to provide precise protein expression modulation.
=== Other disease areas ===
The majority of ADCs under development or in clinical trials are for oncological and hematological indications. This is primarily driven by the inventory of monoclonal antibodies, which target various types of cancer. However, some developers are looking to expand the application to other important disease areas.
== References == | Wikipedia/Antibody-drug_conjugate |
Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform everyday activities. This typically involves problems with memory, thinking, behavior, and motor control. Aside from memory impairment and a disruption in thought patterns, the most common symptoms of dementia include emotional problems, difficulties with language, and decreased motivation. The symptoms may be described as occurring in a continuum over several stages. Dementia is a life-limiting condition, having a significant effect on the individual, their caregivers, and their social relationships in general. A diagnosis of dementia requires the observation of a change from a person's usual mental functioning and a greater cognitive decline than might be caused by the normal aging process.
Several diseases and injuries to the brain, such as a stroke, can give rise to dementia. However, the most common cause is Alzheimer's disease, a neurodegenerative disorder. Dementia is a neurocognitive disorder with varying degrees of severity (mild to major) and many forms or subtypes. Dementia is an acquired brain syndrome, marked by a decline in cognitive function, and is contrasted with neurodevelopmental disorders. It has also been described as a spectrum of disorders with subtypes of dementia based which known disorder caused its development, such as Parkinson's disease for Parkinson's disease dementia, Huntington's disease for Huntington's disease dementia, vascular disease for vascular dementia, HIV infection causing HIV dementia, frontotemporal lobar degeneration for frontotemporal dementia, Lewy body disease for dementia with Lewy bodies, and prion diseases. Subtypes of neurodegenerative dementias may also be based on the underlying pathology of misfolded proteins, such as synucleinopathies and tauopathies. The coexistence of more than one type of dementia is known as mixed dementia.
Many neurocognitive disorders may be caused by another medical condition or disorder, including brain tumours and subdural hematoma, endocrine disorders such as hypothyroidism and hypoglycemia, nutritional deficiencies including thiamine and niacin, infections, immune disorders, liver or kidney failure, metabolic disorders such as Kufs disease, some leukodystrophies, and neurological disorders such as epilepsy and multiple sclerosis. Some of the neurocognitive deficits may sometimes show improvement with treatment of the causative medical condition.
Diagnosis of dementia is usually based on history of the illness and cognitive testing with imaging. Blood tests may be taken to rule out other possible causes that may be reversible, such as hypothyroidism (an underactive thyroid), and imaging can be used to help determine the dementia subtype and exclude other causes. One of the cognitive tests used is the mini–mental state examination.
Although the greatest risk factor for developing dementia is aging, dementia is not a normal part of the aging process; many people aged 90 and above show no signs of dementia. Several risk factors for dementia, such as smoking and obesity, are preventable by lifestyle changes. Screening the general older population for the disorder is not seen to affect the outcome.
Dementia is currently the seventh leading cause of death worldwide and has 10 million new cases reported every year (approximately one every three seconds). There is no known cure for dementia. Acetylcholinesterase inhibitors such as donepezil are often used in some dementia subtypes and may be beneficial in mild to moderate stages, but the overall benefit may be minor. There are many measures that can improve the quality of life of a person with dementia and their caregivers. Cognitive and behavioral interventions may be appropriate for treating the associated symptoms of depression.
== Signs and symptoms ==
The signs and symptoms of dementia may vary depending on the underlying subtype. However, there are some common features that may be grouped into three areas: cognitive, neuropsychiatric (also known as behavioural and psychological), and physical.
The cognitive symptoms of dementia relate to the area of the brain affected. Typically this includes memory plus one other cognitive region. The most commonly affected areas of brain function include memory, language, attention, problem solving, and visuospatial function affecting perception and orientation. Signs of dementia include getting lost in a familiar neighborhood, using unusual words to refer to familiar objects, forgetting the name of a close family member or friend, forgetting old memories, and being unable to complete tasks independently. People with developing dementia can often fall behind on bill payments; specifically mortgage and credit cards, and a crashing credit score can be an early indicator of the disease. The symptoms progress at a continuous rate over several stages, and they vary across the dementia subtypes. Most types of dementia are slowly progressive with some deterioration of the brain well established before signs of the disorder become apparent.
The behavioral symptoms can include agitation, restlessness, inappropriate behavior, sexual disinhibition, and verbal or physical aggression. Psychological symptoms can include depression, hallucinations (most often visual), delusions, apathy, and anxiety. Behavioural symptoms in dementia are thought to be often due to unmet needs or untreated physical symptoms. Many of these symptoms may be improved by non-pharmacological measures such as appropriate exercise and empowering carers. Underlying physical causes of distress may also need to be targeted.
Dementias may also produce a number of physical manifestations. These may include changes in gait, falls, repetitive movements, parkinsonism, or seizures. People with dementia are more likely to have problems with incontinence than those of a comparable age without dementia; they are three times more likely to have urinary incontinence and four times more likely to have fecal incontinence. Dementia can also affect the person’s eating and drinking, often causing swallowing issues and weight loss that worsen as the illness progresses to later stages. Pain can also affect people with dementia, potentially as many as 79.6% of people with dementia in nursing homes may experience pain. However pain can be difficult to assess as people with dementia may be unable to communicate this verbally and instead it may manifest as behavioural symptoms.
People with dementia may often have other health conditions present, such as high blood pressure or diabetes, and there can sometimes be as many as four of these comorbidities. There is also increased prevalence of sarcopenia (muscle loss) and frailty among people with dementia.
== Stages ==
The course of dementia is often described in four stages (pre-dementia, early, middle, and late) that show a pattern of progressive cognitive and functional impairment.
More detailed descriptions can be arrived at by the use of numeric scales. These scales include:
The GDS/FAST Staging System
Global Deterioration Scale (GDS or Reisberg Scale)
Functional Assessment Staging Tool (FAST)
Brief Cognitive Rating Scale (BCRS)
Clinical Dementia Rating (CDR)
Using the GDS, which more accurately identifies each stage of the disease progression, a more detailed course is described in seven stages – two of which are broken down further into five and six degrees. Stage 7(f) is the final stage.
=== Pre-dementia ===
Pre-dementia includes pre-clinical and prodromal stages. The latter stage includes mild cognitive impairment (MCI), delirium-onset, and psychiatric-onset presentations.
==== Pre-clinical ====
Sensory dysfunction is claimed for the pre-clinical stage, which may precede the first clinical signs of dementia by up to ten years. Most notably the sense of smell is lost, associated with depression and a loss of appetite leading to poor nutrition. It is suggested that this dysfunction may come about because the olfactory epithelium is exposed to the environment, and the lack of blood–brain barrier protection allows toxic elements to enter and cause damage to the chemosensory networks.
==== Prodromal ====
Pre-dementia states considered as prodromal are mild cognitive impairment (MCI) and mild behavioral impairment (MBI). Signs and symptoms at the prodromal stage may be subtle, and the early signs often become apparent only in hindsight. Of those diagnosed with MCI, 70% later progress to dementia. In mild cognitive impairment, changes in the person's brain have been happening for a long time, but the symptoms are just beginning to appear. These problems, however, are not severe enough to affect daily function. If and when they do, the diagnosis becomes dementia. The person may have some memory problems and trouble finding words, but they can solve everyday problems and competently handle their life affairs. During this stage, it is ideal to ensure that advance care planning has occurred to protect the person's wishes. Advance directives exist that are specific to people living with dementia. These can be particularly helpful in addressing the decisions related to feeding which come with the progression of the illness. Mild cognitive impairment has been relisted in both DSM-5 and ICD-11 as "mild neurocognitive disorders", i.e. milder forms of the major neurocognitive disorder (dementia) subtypes.
Kynurenine is a metabolite of tryptophan that regulates microbiome signaling, immune cell response, and neuronal excitation. A disruption in the kynurenine pathway may be associated with the neuropsychiatric symptoms and cognitive prognosis in mild dementia.
=== Early ===
In the early stage of dementia, symptoms become noticeable to other people. In addition, the symptoms begin to interfere with daily activities, and will register a score on a mini–mental state examination (MMSE). MMSE scores are set at 24 to 30 for a normal cognitive rating and lower scores reflect severity of symptoms. The symptoms are dependent on the type of dementia. More complicated chores and tasks around the house or at work become more difficult. The person can usually still take care of themselves but may forget things like taking pills or doing laundry and may need prompting or reminders.
The symptoms of early dementia usually include memory difficulty, but can also include some word-finding problems, and problems with executive functions of planning and organization. Managing finances may prove difficult. Other signs might be getting lost in new places, repeating things, and personality changes.
In some types of dementia, such as dementia with Lewy bodies and frontotemporal dementia, personality changes and difficulty with organization and planning may be the first signs.
=== Middle ===
As dementia progresses, initial symptoms generally worsen. The rate of decline is different for each person. MMSE scores between 6 and 17 signal moderate dementia. For example, people with moderate Alzheimer's dementia lose almost all new information. People with dementia may be severely impaired in solving problems, and their social judgment is often impaired. They cannot usually function outside their own home, and generally should not be left alone. They may be able to do simple chores around the house but not much else, and begin to require assistance for personal care and hygiene beyond simple reminders. A lack of insight into having the condition will become evident.
=== Late ===
People with late-stage dementia typically turn increasingly inward and need assistance with most or all of their personal care. People with dementia in the late stages usually need 24-hour supervision to ensure their personal safety, and meeting of basic needs. If left unsupervised, they may wander or fall; may not recognize common dangers such as a hot stove; or may not realize that they need to use the bathroom and become incontinent. They may not want to get out of bed, or may need assistance doing so. Commonly, the person no longer recognizes familiar faces. They may have significant changes in sleeping habits or have trouble sleeping at all.
Changes in eating frequently occur. Cognitive awareness is needed for eating and swallowing and progressive cognitive decline results in eating and swallowing difficulties. This can cause food to be refused, or choked on, and help with feeding will often be required. For ease of feeding, food may be liquidized into a thick purée. They may also struggle to walk, particularly among those with Alzheimer's disease. In some cases, terminal lucidity, a form of paradoxical lucidity, occurs immediately before death; in this phenomenon, there is an unexpected recovery of mental clarity.
== Causes ==
Many causes of dementia are neurodegenerative, and protein misfolding is a cardinal feature of these. Other common causes include vascular dementia, dementia with Lewy bodies, frontotemporal dementia, and mixed dementia (commonly Alzheimer's disease and vascular dementia). Less common causes include normal pressure hydrocephalus, Parkinson's disease dementia, syphilis, HIV, and Creutzfeldt–Jakob disease.
=== Alzheimer's disease ===
Alzheimer's disease accounts for 60–70% of cases of dementia worldwide. The most common symptoms of Alzheimer's disease are short-term memory loss and word-finding difficulties. Trouble with visuospatial functioning (getting lost often), reasoning, judgment and insight fail. Insight refers to whether or not the person realizes they have memory problems.
The part of the brain most affected by Alzheimer's is the hippocampus. Other parts that show atrophy (shrinking) include the temporal and parietal lobes. Although this pattern of brain shrinkage suggests Alzheimer's, it is variable and a brain scan is insufficient for a diagnosis.
Little is known about the events that occur during and that actually cause Alzheimer's disease. This is due to the fact that, historically, brain tissue from people with the disease could only be studied after the person's death. Brain scans can now help diagnose and distinguish between different kinds of dementia and show severity. These include magnetic resonance imaging (MRI), computerized tomography (CT), and positron emission tomography (PET). However, it is known that one of the first aspects of Alzheimer's disease is overproduction of amyloid. Extracellular senile plaques (SPs), consisting of beta-amyloid (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs) that are formed by hyperphosphorylated tau proteins, are two well-established pathological hallmarks of AD. Amyloid causes inflammation around the senile plaques of the brain, and too much buildup of this inflammation leads to changes in the brain that cannot be controlled, leading to the symptoms of Alzheimer's.
Several articles have been published on a possible relationship (as an either primary cause or exacerbation of Alzheimer's disease) between general anesthesia and Alzheimer's in specifically the elderly.
=== Vascular ===
Vascular dementia accounts for at least 20% of dementia cases, making it the second most common type. It is caused by disease or injury affecting the blood supply to the brain, typically involving a series of mini-strokes. The symptoms of this dementia depend on where in the brain the strokes occurred and whether the blood vessels affected were large or small. Repeated injury can cause progressive dementia over time, while a single injury located in an area critical for cognition such as the hippocampus, or thalamus, can lead to sudden cognitive decline. Elements of vascular dementia may be present in all other forms of dementia.
Brain scans may show evidence of multiple strokes of different sizes in various locations. People with vascular dementia tend to have risk factors for disease of the blood vessels, such as tobacco use, high blood pressure, atrial fibrillation, high cholesterol, diabetes, or other signs of vascular disease such as a previous heart attack or angina.
=== Lewy bodies ===
The prodromal symptoms of dementia with Lewy bodies (DLB) include mild cognitive impairment, and delirium onset.
The symptoms of DLB are more frequent, more severe, and earlier presenting than in the other dementia subtypes.
Dementia with Lewy bodies has the primary symptoms of fluctuating cognition, alertness or attention; REM sleep behavior disorder (RBD); one or more of the main features of parkinsonism, not due to medication or stroke; and repeated visual hallucinations. The visual hallucinations in DLB are generally vivid hallucinations of people or animals and they often occur when someone is about to fall asleep or wake up. Other prominent symptoms include problems with planning (executive function) and difficulty with visual-spatial function, and disruption in autonomic bodily functions. Abnormal sleep behaviors may begin before cognitive decline is observed and are a core feature of DLB. RBD is diagnosed either by sleep study recording or, when sleep studies cannot be performed, by medical history and validated questionnaires.
=== Parkinson's disease ===
Parkinson's disease is associated with Lewy body dementia that often progresses to Parkinson's disease dementia following a period of dementia-free Parkinson's disease.
=== Frontotemporal ===
Frontotemporal dementias (FTDs) are characterized by drastic personality changes and language difficulties. In all FTDs, the person has a relatively early social withdrawal and early lack of insight. Memory problems are not a main feature. There are six main types of FTD. The first has major symptoms in personality and behavior. This is called behavioral variant FTD (bv-FTD) and is the most common. The hallmark feature of bv-FTD is impulsive behavior, and this can be detected in pre-dementia states. In bv-FTD, the person shows a change in personal hygiene, becomes rigid in their thinking, and rarely acknowledges problems; they are socially withdrawn, and often have a drastic increase in appetite. They may become socially inappropriate. For example, they may make inappropriate sexual comments, or may begin using pornography openly. One of the most common signs is apathy, or not caring about anything. Apathy, however, is a common symptom in many dementias.
Two types of FTD feature aphasia (language problems) as the main symptom. One type is called semantic variant primary progressive aphasia (SV-PPA). The main feature of this is the loss of the meaning of words. It may begin with difficulty naming things. The person eventually may lose the meaning of objects as well. For example, a drawing of a bird, dog, and an airplane in someone with FTD may all appear almost the same. In a classic test for this, a person is shown a picture of a pyramid and below it a picture of both a palm tree and a pine tree. The person is asked to say which one goes best with the pyramid. In SV-PPA the person cannot answer that question. The other type is called non-fluent agrammatic variant primary progressive aphasia (NFA-PPA). This is mainly a problem with producing speech. They have trouble finding the right words, but mostly they have a difficulty coordinating the muscles they need to speak. Eventually, someone with NFA-PPA only uses one-syllable words or may become totally mute.
A frontotemporal dementia associated with amyotrophic lateral sclerosis (ALS) known as (FTD-ALS) includes the symptoms of FTD (behavior, language and movement problems) co-occurring with amyotrophic lateral sclerosis (loss of motor neurons). Two FTD-related disorders are progressive supranuclear palsy (also classed as a Parkinson-plus syndrome), and corticobasal degeneration. These disorders are tau-associated.
=== Huntington's disease ===
Huntington's disease is a neurodegenerative disease caused by mutations in a single gene HTT, that encodes for huntingtin protein. Symptoms include cognitive impairment and this usually declines further into dementia.
The first main symptoms of Huntington's disease often include:
difficulty concentrating
memory lapses
depression - this can include low mood, lack of interest in things, or just abnormal feelings of hopelessness
stumbling and clumsiness that is out of the ordinary
mood swings, such as irritability or aggressive behavior to insignificant things
=== HIV ===
HIV-associated dementia results as a late stage from HIV infection, and mostly affects younger people. The essential features of HIV-associated dementia are disabling cognitive impairment accompanied by motor dysfunction, speech problems and behavioral change. Cognitive impairment is characterised by mental slowness, trouble with memory and poor concentration. Motor symptoms include a loss of fine motor control leading to clumsiness, poor balance and tremors. Behavioral changes may include apathy, lethargy and diminished emotional responses and spontaneity. Histopathologically, it is identified by the infiltration of monocytes and macrophages into the central nervous system (CNS), gliosis, pallor of myelin sheaths, abnormalities of dendritic processes and neuronal loss.
=== Creutzfeldt–Jakob disease ===
Creutzfeldt–Jakob disease is a rapidly progressive prion disease that typically causes dementia that worsens over weeks to months. Prions are disease-causing pathogens created from abnormal proteins.
=== Alcoholism ===
Alcohol-related dementia, also called alcohol-related brain damage, occurs as a result of excessive use of alcohol particularly as a substance abuse disorder. Different factors can be involved in this development including thiamine deficiency and age vulnerability. A degree of brain damage is seen in more than 70% of those with alcohol use disorder. Brain regions affected are similar to those that are affected by aging, and also by Alzheimer's disease. Regions showing loss of volume include the frontal, temporal, and parietal lobes, as well as the cerebellum, thalamus, and hippocampus. This loss can be more notable, with greater cognitive impairments seen in those aged 65 years and older.
=== Mixed dementia ===
More than one type of dementia, known as mixed dementia, may exist together in about 10% of dementia cases. The most common type of mixed dementia is Alzheimer's disease and vascular dementia. This particular type of mixed dementia's main onsets are a mixture of old age, high blood pressure, and damage to blood vessels in the brain.
Diagnosis of mixed dementia can be difficult, as often only one type will predominate. This makes the treatment of people with mixed dementia uncommon, with many people missing out on potentially helpful treatments. Mixed dementia can mean that symptoms onset earlier, and worsen more quickly since more parts of the brain will be affected.
=== Other ===
Chronic inflammatory conditions that may affect the brain and cognition include Behçet's disease, multiple sclerosis, sarcoidosis, Sjögren's syndrome, lupus, celiac disease, and non-celiac gluten sensitivity. These types of dementias can rapidly progress, but usually have a good response to early treatment. This consists of immunomodulators or steroid administration, or in certain cases, the elimination of the causative agent.
Celiac disease does not seem to raise the risk of dementia in general but it may increase the risk of vascular dementia. Both celiac disease or non-celiac gluten sensitivity might raise the risk of cognitive impairment which can be one of the early signs of subsequent dementia. A strict gluten-free diet started early may protect against dementia associated with gluten-related disorders.
Cases of easily reversible dementia include hypothyroidism, vitamin B12 deficiency, Lyme disease, and neurosyphilis. For Lyme disease and neurosyphilis, testing should be done if risk factors are present. Because risk factors are often difficult to determine, testing for neurosyphilis and Lyme disease, as well as other mentioned factors, may be undertaken as a matter of course where dementia is suspected.: 31–32
Many other medical and neurological conditions include dementia only late in the illness. For example, a proportion of people with Parkinson's disease develop dementia, though widely varying figures are quoted for this proportion. When dementia occurs in Parkinson's disease, the underlying cause may be dementia with Lewy bodies or Alzheimer's disease, or both. Cognitive impairment also occurs in the Parkinson-plus syndromes of progressive supranuclear palsy and corticobasal degeneration (and the same underlying pathology may cause the clinical syndromes of frontotemporal lobar degeneration). Although the acute porphyrias may cause episodes of confusion and psychiatric disturbance, dementia is a rare feature of these rare diseases. Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a type of dementia that primarily affects people in their 80s or 90s and in which TDP-43 protein deposits in the limbic portion of the brain.
Hereditary disorders that can also cause dementia include: some metabolic disorders such as lysosomal storage disorders, leukodystrophies, and spinocerebellar ataxias.
Persistent loneliness may significantly increase the risk of dementia. Loneliness is associated with a 31% higher likelihood of developing any form of dementia, and can also raise the risk of cognitive impairment by 15%.
== Diagnosis ==
Symptoms are similar across dementia types and it is difficult to diagnose by symptoms alone. Diagnosis may be aided by brain scanning techniques. In many cases, the diagnosis requires a brain biopsy to become final, but this is rarely recommended (though it can be performed at autopsy). In those who are getting older, general screening for cognitive impairment using cognitive testing or early diagnosis of dementia has not been shown to improve outcomes. However, screening exams are useful in 65+ persons with memory complaints.
Normally, symptoms must be present for at least six months to support a diagnosis. Cognitive dysfunction of shorter duration is called delirium. Delirium can be easily confused with dementia due to similar symptoms. Delirium is characterized by a sudden onset, fluctuating course, a short duration (often lasting from hours to weeks), and is primarily related to a somatic (or medical) disturbance. In comparison, dementia has typically a long, slow onset (except in the cases of a stroke or trauma), slow decline of mental functioning, as well as a longer trajectory (from months to years).
Some mental illnesses, including depression and psychosis, may produce symptoms that must be differentiated from both delirium and dementia. These are differently diagnosed as pseudodementias, and any dementia evaluation needs to include a depression screening such as the Neuropsychiatric Inventory or the Geriatric Depression Scale. Physicians used to think that people with memory complaints had depression and not dementia (because they thought that those with dementia are generally unaware of their memory problems). However, researchers have realized that many older people with memory complaints in fact have mild cognitive impairment the earliest stage of dementia. Depression should always remain high on the list of possibilities, however, for an elderly person with memory trouble. Changes in thinking, hearing and vision are associated with normal ageing and can cause problems when diagnosing dementia due to the similarities. Given the challenging nature of predicting the onset of dementia and making a dementia diagnosis clinical decision making aids underpinned by machine learning and artificial intelligence have the potential to enhance clinical practice.
=== Cognitive testing ===
Various brief cognitive tests (5–15 minutes) have reasonable reliability to screen for dementia, but may be affected by factors such as age, education and ethnicity. Age and education have a significant influence on the diagnosis of dementia. For example, Individuals with lower education are more likely to be diagnosed with dementia than their educated counterparts. While many tests have been studied, presently the mini mental state examination (MMSE) is the best studied and most commonly used. The MMSE is a useful tool for helping to diagnose dementia if the results are interpreted along with an assessment of a person's personality, their ability to perform activities of daily living, and their behaviour. Other cognitive tests include the abbreviated mental test score (AMTS), the, "modified mini–mental state examination" (3MS), the Cognitive Abilities Screening Instrument (CASI), the Trail-making test, and the clock drawing test. The MoCA (Montreal Cognitive Assessment) is a reliable screening test and is available online for free in 35 different languages. The MoCA has also been shown somewhat better at detecting mild cognitive impairment than the MMSE. People with hearing loss, which commonly occurs alongside dementia, score worse in the MoCA test, which could lead to a false diagnosis of dementia. Researchers have developed an adapted version of the MoCA test, which is accurate and reliable and avoids the need for people to listen and respond to questions. The AD-8 – a screening questionnaire used to assess changes in function related to cognitive decline – is potentially useful, but is not diagnostic, is variable, and has risk of bias. An integrated cognitive assessment (CognICA) is a five-minute test that is highly sensitive to the early stages of dementia, and uses an application deliverable to an iPad. Previously in use in the UK, in 2021 CognICA was given FDA approval for its commercial use as a medical device.
Another approach to screening for dementia is to ask an informant (relative or other supporter) to fill out a questionnaire about the person's everyday cognitive functioning. Informant questionnaires provide complementary information to brief cognitive tests. Probably the best known questionnaire of this sort is the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Evidence is insufficient to determine how accurate the IQCODE is for diagnosing or predicting dementia. The Alzheimer's Disease Caregiver Questionnaire is another tool. It is about 90% accurate for Alzheimer's when by a caregiver. The General Practitioner Assessment Of Cognition combines both a patient assessment and an informant interview. It was specifically designed for use in the primary care setting.
Clinical neuropsychologists provide diagnostic consultation following administration of a full battery of cognitive testing, often lasting several hours, to determine functional patterns of decline associated with varying types of dementia. Tests of memory, executive function, processing speed, attention and language skills are relevant, as well as tests of emotional and psychological adjustment. These tests assist with ruling out other etiologies and determining relative cognitive decline over time or from estimates of prior cognitive abilities.
=== Laboratory tests ===
Routine blood tests are usually performed to rule out treatable causes. These include tests for vitamin B12, folic acid, thyroid-stimulating hormone (TSH), C-reactive protein, full blood count, electrolytes, calcium, renal function, and liver enzymes. Abnormalities may suggest vitamin deficiency, infection, or other problems that commonly cause confusion or disorientation in the elderly.
=== Imaging ===
A CT scan or MRI scan is commonly performed to possibly find either normal pressure hydrocephalus, a potentially reversible cause of dementia, or connected tumor. The scans can also yield information relevant to other types of dementia, such as infarction (stroke) that would point at a vascular type of dementia. These tests do not pick up diffuse metabolic changes associated with dementia in a person who shows no gross neurological problems (such as paralysis or weakness) on a neurological exam.
The functional neuroimaging modalities of SPECT and PET are more useful in assessing long-standing cognitive dysfunction, since they have shown similar ability to diagnose dementia as a clinical exam and cognitive testing. The ability of SPECT to differentiate vascular dementia from Alzheimer's disease, appears superior to differentiation by clinical exam.
The value of PiB-PET imaging using Pittsburgh compound B (PiB) as a radiotracer has been established in predictive diagnosis, particularly Alzheimer's disease.
== Prevention ==
=== Risk factors ===
Risk factors for dementia include high blood pressure, high levels of LDL cholesterol, vision loss, hearing loss, smoking, obesity, depression, inactivity, diabetes, lower levels of education and low social contact. Over-indulgence in alcohol, lack of sleep, anemia, traumatic brain injury, and air pollution can also increase the chance of developing dementia. Many of these risk factors, including the lower level of education, smoking, physical inactivity and diabetes, are modifiable. Several of the group are known as vascular risk factors that may be possible to be reduced or eliminated. Managing these risk factors can reduce the risk of dementia in individuals in their late midlife or older age. A reduction in a number of these risk factors can give a positive outcome. The decreased risk achieved by adopting a healthy lifestyle is seen even in those with a high genetic risk.
In addition to the above risk factors, other psychological features, including certain personality traits (high neuroticism, and low conscientiousness), low purpose in life, and high loneliness, are risk factors for Alzheimer's disease and related dementias. For example, based on the English Longitudinal Study of Ageing (ELSA), research found that loneliness in older people can increase the risk of dementia by one-third. Not having a partner (being single, divorced, or widowed) can double the risk of dementia. However, having two or three closer relationships might reduce the risk by three-fifths.
The two most modifiable risk factors for dementia are physical inactivity and lack of cognitive stimulation. Physical activity, in particular aerobic exercise, is associated with a reduction in age-related brain tissue loss, and neurotoxic factors thereby preserving brain volume and neuronal integrity. Cognitive activity strengthens neural plasticity and together they help to support cognitive reserve. The neglect of these risk factors diminishes this reserve.
Sensory impairments of vision and hearing are modifiable risk factors for dementia. These impairments may precede the cognitive symptoms of Alzheimer's disease for example, by many years. Hearing loss may lead to social isolation which negatively affects cognition. Social isolation is also identified as a modifiable risk factor. Age-related hearing loss in midlife is linked to cognitive impairment in late life, and is seen as a risk factor for the development of Alzheimer's disease and dementia. Such hearing loss may be caused by a central auditory processing disorder that makes the understanding of speech against background noise difficult. Age-related hearing loss is characterised by slowed central processing of auditory information. Worldwide, mid-life hearing loss may account for around 9% of dementia cases.
Frailty may increase the risk of cognitive decline, and dementia, and the inverse also holds of cognitive impairment increasing the risk of frailty. Prevention of frailty may help to prevent cognitive decline.
There are no medications that can prevent cognitive decline and dementia. However blood pressure lowering medications might decrease the risk of dementia or cognitive problems by around 0.5%.
Economic disadvantage has been shown to have a strong link to higher dementia prevalence, which cannot yet be fully explained by other risk factors.
A modelling study suggested that population-level interventions that target risk factors for dementia (such as high blood pressure, smoking and obesity) in England could save money and give people extra years in good health. For example, reduced salt in food could give 39,433 quality-adjusted life-years and save £2.4 billion.
A recent 2025 study reported highlights that over 37% of dementia cases in the United States are associated with cardiometabolic conditions, though the risk varies across regions. The research identified eight key contributors: diabetes, heart failure, atrial fibrillation, coronary artery disease, heart attacks, strokes, hypertension and high cholesterol. Among these, stroke emerged as the most significant factor, doubling the risk of developing dementia (2.2 times higher), followed closely by heart failure (2.1 times) and hypertension (78% increased risk). In contrast, high cholesterol showed the weakest correlation, associated with a 27% increased risk. The study also emphasized geographic disparities, noting that individuals living in the U.S. South face a higher likelihood of dementia related to cardiovascular conditions and diabetes.
=== Dental health ===
Limited evidence links poor oral health to cognitive decline. However, failure to perform tooth brushing and gingival inflammation can be used as dementia risk predictors.
==== Oral bacteria ====
There is some evidence that oral bacteria in people with gum disease may be a link to declines in cognitive health. The proposed mechanism is still being studied, but research has linked specific types of bacteria in the mouth to those found in some people's brain who have Alzheimer's disease. There is also some evidence that people with a high level of tooth plaque are also at a greater risk of cognitive decline. Poor oral hygiene can have an adverse effect on speech and nutrition, causing general and cognitive health decline.
==== Oral viruses ====
Herpes simplex virus (HSV) has been found in more than 70% of those aged over 50. HSV persists in the peripheral nervous system and can be triggered by stress, illness or fatigue. High proportions of viral-associated proteins in amyloid plaques or neurofibrillary tangles (NFTs) confirm the involvement of HSV-1 in Alzheimer's disease pathology. NFTs are known as the primary marker of Alzheimer's disease. HSV-1 produces the main components of NFTs. A Swedish cohort study from 2024 suggests that persons infected with HSV have twice the risk of developing dementia compared to non-infected participants.
=== Diet ===
Diet is seen to be a modifiable risk factor for the development of dementia. Thiamine deficiency is identified to increase the risk of Alzheimer's disease in adults. The role of thiamine in brain physiology is unique and essential for the normal cognitive function of older people. Many dietary choices of the elderly population, including the higher intake of gluten-free products, compromise the intake of thiamine as these products are not fortified with thiamine.
The Mediterranean and DASH diets are both associated with less cognitive decline. A different approach has been to incorporate elements of both of these diets into one known as the MIND diet. These diets are generally low in saturated fats while providing a good source of carbohydrates, mainly those that help stabilize blood sugar and insulin levels. Raised blood sugar levels over a long time, can damage nerves and cause memory problems if they are not managed. Nutritional factors associated with the proposed diets for reducing dementia risk include unsaturated fatty acids, vitamin E, vitamin C, flavonoids, vitamin B, and vitamin D. A study conducted at the University of Exeter in the United Kingdom seems to have confirmed these findings with fruits, vegetables, whole grains, and healthy fats creating an optimum diet that can help reduce the risk of dementia by roughly 25%.
The MIND diet may be more protective but further studies are needed. The Mediterranean diet seems to be more protective against Alzheimer's than DASH but there are no consistent findings against dementia in general. The role of olive oil needs further study as it may be one of the most important components in reducing the risk of cognitive decline and dementia.
In those with celiac disease or non-celiac gluten sensitivity, a strict gluten-free diet may relieve the symptoms given a mild cognitive impairment. Once dementia is advanced no evidence suggests that a gluten-free diet is useful.
Omega-3 fatty acid supplements do not appear to benefit or harm people with mild to moderate symptoms. However, there is good evidence that omega-3 incorporation into the diet is of benefit in treating depression, a common symptom, and potentially modifiable risk factor for dementia.
== Management ==
There are limited options for treating dementia, with most approaches focused on managing or reducing individual symptoms. There are no treatment options available to delay the onset of dementia.
Acetylcholinesterase inhibitors are often used early in the disorder course; however, benefit is generally small.
More than half of people with dementia may experience psychological or behavioral symptoms including agitation, sleep problems, aggression, and/or psychosis. Treatment for these symptoms is aimed at reducing the person's distress and keeping the person safe. Treatments other than medication appear to be better for agitation and aggression. Cognitive and behavioral interventions may be appropriate. Some evidence suggests that education and support for the person with dementia, as well as caregivers and family members, improves outcomes. Exercise programs are beneficial with respect to activities of daily living. As with all brain disorders, some people with dementia could potentially be a danger to themselves or others. Such behavioral symptoms might result in the person being involuntarily admitted to a mental health ward for assessment, care and treatment. However, this is a last resort, and potential alternatives could be considered by family or friends of people with dementia.
Palliative care interventions may lead to improvements in comfort in dying, but it is not yet clear from the evidence how it can be best used to support people dying with advanced dementia and their families.
The effect of therapies can be evaluated for example by assessing agitation using the Cohen-Mansfield Agitation Inventory (CMAI); by assessing mood and engagement with the Menorah Park Engagement Scale (MPES); and the Observed Emotion Rating Scale (OERS) or by assessing indicators for depression using the Cornell Scale for Depression in Dementia (CSDD) or a simplified version thereof.
Often overlooked in treating and managing dementia is the role of the caregiver and what is known about how they can support multiple interventions. Caregivers of people with dementia in nursing homes do not have sufficient tools or clinical guidance for behavioral and psychological symptoms of dementia (BPSD) along with medication use. Simple measures like talking to people about their interests can improve the quality of life for care home residents living with dementia. A programme showed that such simple measures reduced residents' agitation and depression. They also needed fewer GP visits and hospital admissions, which also meant that the programme was cost-saving.
=== Psychological and psychosocial therapies ===
Psychological therapies for dementia include some limited evidence for reminiscence therapy (namely, some positive effects in the areas of quality of life, cognition, communication and mood – the first three particularly in care home settings), some benefit for cognitive reframing for caretakers, unclear evidence for validation therapy and tentative evidence for mental exercises, such as cognitive stimulation programs for people with mild to moderate dementia. Offering personally tailored activities may help reduce challenging behavior and may improve quality of life. It is not clear if personally tailored activities have an impact on affect or improve for the quality of life for the caregiver.
Adult daycare centers as well as special care units in nursing homes often provide specialized care for dementia patients. Daycare centers offer supervision, recreation, meals, and limited health care to participants, as well as providing respite for caregivers. In addition, home care can provide one-to-one support and care in the home allowing for more individualized attention that is needed as the disorder progresses. Psychiatric nurses can make a distinctive contribution to people's mental health.
Since dementia impairs normal communication due to changes in receptive and expressive language, as well as the ability to plan and problem solve, agitated behavior is often a form of communication for the person with dementia. Actively searching for a potential cause, such as pain, physical illness, or overstimulation can be helpful in reducing agitation. Additionally, using an "ABC analysis of behavior" can be a useful tool for understanding behavior in people with dementia. It involves looking at the antecedents (A), behavior (B), and consequences (C) associated with an event to help define the problem and prevent further incidents that may arise if the person's needs are misunderstood. The strongest evidence for non-pharmacological therapies for the management of changed behaviors in dementia is for using such approaches. Low quality evidence suggests that regular (at least five sessions of) music therapy may help institutionalized residents. It may reduce depressive symptoms and improve overall behaviors. It may also supply a beneficial effect on emotional well-being and quality of life, as well as reduce anxiety. In 2003, The Alzheimer's Society established 'Singing for the Brain' (SftB) a project based on pilot studies which suggested that the activity encouraged participation and facilitated the learning of new songs. The sessions combine aspects of reminiscence therapy and music. Musical and interpersonal connectedness can underscore the value of the person and improve quality of life.
Some London hospitals found that using color, designs, pictures and lights helped people with dementia adjust to being at the hospital. These adjustments to the layout of the dementia wings at these hospitals helped patients by preventing confusion.
Life story work as part of reminiscence therapy, and video biographies have been found to address the needs of clients and their caregivers in various ways, offering the client the opportunity to leave a legacy and enhance their personhood and also benefitting youth who participate in such work. Such interventions can be more beneficial when undertaken at a relatively early stage of dementia. They may also be problematic in those who have difficulties in processing past experiences
Animal-assisted therapy has been found to be helpful. Drawbacks may be that pets are not always welcomed in a communal space in the care setting. An animal may pose a risk to residents, or may be perceived to be dangerous. Certain animals may also be regarded as "unclean" or "dangerous" by some cultural groups.
Occupational therapy also addresses psychological and psychosocial needs of patients with dementia through improving daily occupational performance and caregivers' competence. When compensatory intervention strategies are added to their daily routine, the level of performance is enhanced and reduces the burden commonly placed on their caregivers. Occupational therapists can also work with other disciplines to create a client centered intervention. To manage cognitive disability, and coping with behavioral and psychological symptoms of dementia, combined occupational and behavioral therapies can support patients with dementia even further.
==== Cognitive training and rehabilitation ====
There is no strong evidence to suggest that cognitive training is beneficial for people with Parkinson's disease, dementia, or mild cognitive impairment. However, a 2023 review found that cognitive rehabilitation may be effective in helping individuals with mild to moderate dementia to manage their daily activities.
==== Personally tailored activities ====
Offering personally tailored activity sessions to people with dementia in long-term care homes may slightly reduce challenging behavior.
=== Medications ===
No medications have been shown to prevent or cure dementia. Medications may be used to treat the behavioral and cognitive symptoms, but have no effect on the underlying disease process.
Acetylcholinesterase inhibitors, such as donepezil, may be useful for Alzheimer's disease, Parkinson's disease dementia, DLB, or vascular dementia. The quality of the evidence is poor and the benefit is small. No difference has been shown between the agents in this family. In a minority of people side effects include a slow heart rate and fainting. Rivastigmine is recommended for treating symptoms in Parkinson's disease dementia.
Medications that have anticholinergic effects increase all-cause mortality in people with dementia, although the effect of these medications on cognitive function remains uncertain, according to a systematic review published in 2021.
Before prescribing antipsychotic medication in the elderly, an assessment for an underlying cause of the behavior is needed. Severe and life-threatening reactions occur in almost half of people with DLB, and can be fatal after a single dose. People with Lewy body dementias who take neuroleptics are at risk for neuroleptic malignant syndrome, a life-threatening illness. Extreme caution is required in the use of antipsychotic medication in people with DLB because of their sensitivity to these agents. Antipsychotic drugs are used to treat dementia only if non-drug therapies have not worked, and the person's actions threaten themselves or others. Aggressive behavior changes are sometimes the result of other solvable problems, that could make treatment with antipsychotics unnecessary. Because people with dementia can be aggressive, resistant to their treatment, and otherwise disruptive, sometimes antipsychotic drugs are considered as a therapy in response. These drugs have risky adverse effects, including increasing the person's chance of stroke and death. Given these adverse events and small benefit antipsychotics are avoided whenever possible. Generally, stopping antipsychotics for people with dementia does not cause problems, even in those who have been on them a long time.
N-methyl-D-aspartate (NMDA) receptor blockers such as memantine may be of benefit but the evidence is less conclusive than for AChEIs. Due to their differing mechanisms of action memantine and acetylcholinesterase inhibitors can be used in combination however the benefit is slight.
An extract of Ginkgo biloba known as EGb 761 has been widely used for treating mild to moderate dementia and other neuropsychiatric disorders. Its use is approved throughout Europe. The World Federation of Biological Psychiatry guidelines lists EGb 761 with the same weight of evidence (level B) given to acetylcholinesterase inhibitors, and memantine. EGb 761 is the only one that showed improvement of symptoms in both AD and vascular dementia. EGb 761 is seen as being able to play an important role either on its own or as an add-on particularly when other therapies prove ineffective. EGb 761 is seen to be neuroprotective; it is a free radical scavenger, improves mitochondrial function, and modulates serotonin and dopamine levels. Many studies of its use in mild to moderate dementia have shown it to significantly improve cognitive function, activities of daily living, neuropsychiatric symptoms, and quality of life. However, its use has not been shown to prevent the progression of dementia.
While depression is frequently associated with dementia, the use of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) do not appear to affect outcomes. However, the SSRIs sertraline and citalopram have been demonstrated to reduce symptoms of agitation, compared to placebo.
No solid evidence indicates that folate or vitamin B12 improves outcomes in those with cognitive problems. Statins have no benefit in dementia. Medications for other health conditions may need to be managed differently for a person who has a dementia diagnosis. It is unclear whether blood pressure medication and dementia are linked. People may experience an increase in cardiovascular-related events if these medications are withdrawn.
The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) criteria can help identify ways that a diagnosis of dementia changes medication management for other health conditions. These criteria were developed because people with dementia live with an average of five other chronic diseases, which are often managed with medications. The systematic review that informed the criteria were published subsequently in 2018 and updated in 2022.
=== Palliative care ===
Given the progressive and terminal nature of dementia, palliative care can be helpful to people with dementia and caregivers. Palliative care is the active total care of people with an incurable condition like dementia and their families by a multi-professional team. It aims to improve quality of life and is provided through person-centered and integrated care. A palliative care approach can support people affected by dementia at any stage of the condition. It can help people with dementia and their caregivers to understand what to expect, deal with loss of physical and mental abilities, support the person's wishes and goals including surrogate decision making, and discuss wishes for or against CPR and life support.
Because there is uncertainty around how and when people with dementia decline, and because most people prefer to allow the person with dementia to make their own decisions, palliative care involvement before the late stages of dementia is recommended. For example, in England, it is estimated that 40% of people at any stage of dementia would benefit from palliative care. This proportion of people is expected to increase dramatically by 2040.
In the early stages of dementia, palliative care can involve advocacy around establishing goals of care in the future, reassurance of continued support, planning for future scenarios of care and establishing long-term relationships with care providers. In later stages, a palliative approach to dementia care may have specific benefit to goals of care and end-of-life conversations, symptom management, prescribing practices and emergency department visits. However, more research is needed to know how palliative care can be best used to support people dying with advanced dementia and their families.
Towards the end of life, people with dementia frequently present to the emergency department with unmet palliative care needs. Community palliative care is associated with the reduced likelihood of attending the emergency department among people with dementia nearing the end of life. Palliative care for people with dementia living at home may help improve end-of-life care outcomes such as neuropsychiatric symptoms.
People with advanced dementia may not readily receive specialist palliative care input. Reasons for this are varied but may include lack of agreement of when to refer people with dementia, and a lack of coordination across care settings, communication challenges, limited training opportunities for healthcare staff and because dementia is not considered to be a life-limiting condition. In fact, 58% of surveyed public in England did not know that dementia is a terminal condition.
Further research is needed to determine the appropriate palliative care interventions and how they can be implemented to help people with dementia.
==== Person-centered care ====
Person-centered care is an approach that places the individual at the heart of care, taking into account their unique needs, preferences, experiences, and values. It is built on getting to know the person with the condition through a personal relationship. This is especially important for people living with dementia, as the approach aims to maintain the dignity of people with dementia and sense of identity throughout the course of their illness.
Person-centered care interventions could not only reduce agitation, neuropsychiatric symptoms, and depression but also help improve the quality of life for people with dementia. Moreover, the potential benefits of a person-centered care approach for dementia care workers have been reported, indicating its effectiveness in reducing stress, burnout, and job dissatisfaction.
==== Person centered assessment ====
Person-centered outcome measures (PCOMs) are standardized, validated questionnaires that measure people’s opinions of their own health and well-being. They emphasize person-centered care by focusing on the symptoms and concerns that are most important to people and their families. PCOMs comprise patient-reported outcome measures (PROMs) and proxy-reported outcome measures for those unable to self-report. Used in routine care PCOMs support systematic assessment and monitoring of an individual’s health and wellbeing, enable shared decision-making, enable changes in care provision (such as improved communication or referral to other services), improve outcomes (such as improved symptom management) and enable evaluation of care provision. The use of PCOMs have the potential to serve as a scalable and sustainable way to support integrated palliative care for older people including those living with dementia.
PCOMs can be single-domain or multi-domain tools, focussing on individual symptoms or multiple symptoms, depending on the scope of assessment. Single-domain PCOMs focus on one specific area of care. For example, the Pain Assessment in Advanced Dementia (PAINAD) scale is used to assess pain in individuals living with advanced dementia. Multi-domain PCOMs could assess multiple domains, including the symptom burden, function, psychological or spiritual problems, treatment satisfaction, health-related quality of life. The Integrated Palliative Care Outcome Scale for Dementia (IPOS-Dem) is an example of a comprehensive palliative dementia PCOM, used to measure symptoms and concerns for people with dementia.
=== Sleep disturbances ===
Over 40% of people with dementia report sleep problems. Approaches to treating these sleep problems include medications and non-pharmacological approaches. The use of medications to alleviate sleep disturbances that people with dementia often experience has not been well researched, even for medications that are commonly prescribed. In 2012 the American Geriatrics Society recommended that benzodiazepines such as diazepam, and non-benzodiazepine hypnotics, be avoided for people with dementia due to the risks of increased cognitive impairment and falls. Benzodiazepines are also known to promote delirium. Additionally, little evidence supports the effectiveness of benzodiazepines in this population. No clear evidence shows that melatonin or ramelteon improves sleep for people with dementia due to Alzheimer's, but it is used to treat REM sleep behavior disorder in dementia with Lewy bodies. Limited evidence suggests that a low dose of trazodone may improve sleep, however more research is needed.
Non-pharmacological approaches have been suggested for treating sleep problems for those with dementia, however, there is no strong evidence or firm conclusions on the effectiveness of different types of interventions, especially for those who are living in an institutionalized setting such as a nursing home or long-term care home.
=== Pain ===
As people age, they experience more health problems, and most health problems associated with aging carry a substantial burden of pain; therefore, between 25% and 50% of older adults experience persistent pain. Seniors with dementia experience the same prevalence of conditions likely to cause pain as seniors without dementia. Pain is often overlooked in older adults and, when screened for, is often poorly assessed, especially among those with dementia, since they become incapable of informing others of their pain. Beyond the issue of humane care, unrelieved pain has functional implications. Persistent pain can lead to decreased ambulation, depressed mood, sleep disturbances, impaired appetite, and exacerbation of cognitive impairment and pain-related interference with activity is a factor contributing to falls in the elderly.
Although persistent pain in people with dementia is difficult to communicate, diagnose, and treat, failure to address persistent pain has profound functional, psychosocial and quality of life implications for this vulnerable population. Health professionals often lack the skills and usually lack the time needed to recognize, accurately assess and adequately monitor pain in people with dementia. Family members and friends can make a valuable contribution to the care of a person with dementia by learning to recognize and assess their pain. Educational resources and observational assessment tools are available.
=== Eating difficulties ===
Persons with dementia may have difficulty eating. Whenever it is available as an option, the recommended response to eating problems is having a caretaker assist them. For people who do not have dementia, a secondary option when they cannot swallow effectively would be to consider gastrostomy feeding tube placement as a way to give nutrition. However, for people with dementia, assistance with oral feeding is at least as good as tube feeding in bringing comfort and maintaining functional status while lowering risk of aspiration pneumonia and death It can be tried if the reasons for the person’s problems with eating, drinking or swallowing are treatable and it’s expected that they will be able to start eating and drinking normally afterwards. Tube-feeding is associated with agitation, increased use of physical and chemical restraints and worsening pressure ulcers. Tube feedings may cause fluid overload, diarrhea, abdominal pain, local complications, less human interaction and may increase the risk of aspiration.
Benefits in those with advanced dementia has not been shown. The risks of using tube feeding include agitation, rejection by the person (pulling out the tube, or otherwise physical or chemical immobilization to prevent them from doing this), or developing pressure ulcers. The procedure is directly related to a 1% fatality rate with a 3% major complication rate. The percentage of people at end of life with dementia using feeding tubes in the US has dropped from 12% in 2000 to 6% as of 2014.
The immediate and long-term effects of modifying the thickness of fluids for swallowing difficulties in people with dementia are not well known. While thickening fluids may have an immediate positive effect on swallowing and improving oral intake, the long-term impact on the health of the person with dementia should also be considered.
=== Exercise ===
Exercise programs may improve the ability of people with dementia to perform daily activities, but the best type of exercise is still unclear. Getting more exercise can slow the development of cognitive problems such as dementia, proving to reduce the risk of Alzheimer's disease by about 50%. A balance of strength exercise, to help muscles pump blood to the brain, and balance exercises are recommended for aging people. A suggested amount of about 2+1⁄2 hours per week can reduce risks of cognitive decay as well as other health risks like falling.
=== Assistive technology and digital health ===
There is a lack of high-quality scientific evidence to determine whether assistive technology effectively supports people with dementia to manage memory issues. Some of the specific things that are used today that helps with dementia today are: clocks, communication aids, electrical appliances the use monitoring, GPS location/ tracking devices, home care robots, in-home cameras, and medication management are just to name a few. As the technology advances, virtual reality is also being explored as a powerful technology to elicit memories and to improve wellbeing.
Technology has the potential to be a valuable intervention for alleviating loneliness and promoting social connections. It could facilitate activities of daily living, and provide ways to connect people that are geographically distant.
Other types of developed technologies to aid services include telehealth or telemedicine services, utilising digital communication for delivery of health-related services and information through phone calls, mobile apps, and video conferencing.
Telemedicine has given results for cognitive assessment and diagnosis that are similar to in-person visits, and it has also helped improve outcomes after rehabilitation. Telemedicine is often well received by people affected by dementia who can rely on the support of staff and family to navigate the technology. While it has potential to widen access to services, those with sensory impairment may be excluded.
Digital health interventions can play a role in supporting family caregivers of people with dementia, by offering a source of support from connective platforms, with 24/7 accessibility, as well as opportunity for remote monitoring. However, challenges such as the digital divide, privacy concerns and the need for greater personalisation for individual users are recognised issues.
==== Remotely delivered information for caregivers ====
Remotely delivered interventions including support, training and information may reduce the burden for the informal caregiver and improve their depressive symptoms. There is no certain evidence that they improve health-related quality of life.
In several localities in Japan, digital surveillance may be made available to family members, if a person with dementia is prone to wandering and going missing.
=== Alternative medicine ===
Scientific evidence of the therapeutic values of aromatherapy and massage is unclear and limited. There is no convincing evidence about their effectiveness but no general conclusions can be drawn about the benefits or harms of these alternative treatments. It is not clear if cannabinoids have any harmful or beneficial effects on dementia.
== Epidemiology ==
The number of cases of dementia worldwide in 2021 was estimated at 55 million, with close to 10 million new cases each year. According to a report by the World Health Organization, "In 2021, Alzheimer’s disease and other forms of dementia ranked as the seventh leading cause of death, killing 1.8 million lives." By 2050, the number of people living with dementia is estimated to be over 150 million globally.
Around 7% of people over the age of 65 have dementia, with slightly higher rates (up to 10% of those over 65) in places with relatively high life expectancy. An estimated 58% of people with dementia are living in low and middle income countries.
The prevalence of dementia differs in different world regions, ranging from 4.7% in Central Europe to 8.7% in North Africa/Middle East; the prevalence in other regions is estimated to be between 5.6 and 7.6%. The number of people living with dementia is estimated to double every 20 years. In 2016 dementia resulted in about 2.4 million deaths, up from 0.8 million in 1990.
Estimates show that in 2024 there were 982,000 people living with dementia in the UK and this is expected to rise to 1.4 million people by 2040.
The annual incidence of dementia diagnosis is nearly 10 million worldwide. Almost half of new dementia cases occur in Asia, followed by Europe (25%), the Americas (18%) and Africa (8%). The incidence of dementia increases exponentially with age, doubling with every 6.3-year increase in age. Dementia affects 5% of the population older than 65 and 20–40% of those older than 85. Rates are slightly higher in women than men at ages 65 and greater. The disease trajectory is varied and the median time from diagnosis to death depends strongly on age at diagnosis, from 6.7 years for people diagnosed aged 60–69 to 1.9 years for people diagnosed at 90 or older.
In 2019, there were 1.62 million dementia-related deaths worldwide. This is expected to increase to 4.91 million by 2050.
In 2022 and 2023, dementia was the leading cause of death in England and Wales.
Deaths from dementia in the U.S. have tripled in the past 21 years, rising from around 150,000 in 1999 to over 450,000 in 2020, and the likelihood of dying from dementia increased across all demographic groups.
The genetic and environmental risk factors for dementia disorders vary by ethnicity. For instance, Alzheimer's disease among Hispanic/Latino and African American subjects exhibit lower risks associated with gene changes in the apolipoprotein E gene than do non-Hispanic white subjects.
=== Affected ages ===
About 3% of people between the ages of 65–74 have dementia, 19% between 75 and 84, and nearly half of those over 85 years of age. As more people are living longer, dementia is becoming more common. For people of a specific age, however, it may be becoming less frequent in the developed world, due to a decrease in modifiable risk factors made possible by greater financial and educational resources. It is one of the most common causes of disability among the elderly but can develop before the age of 65 when it is known as early-onset dementia or presenile dementia.
Less than 1% of those with Alzheimer's have gene mutations that cause a much earlier development of the disease, around the age of 45, known as early-onset Alzheimer's disease. More than 95% of people with Alzheimer's disease have the sporadic form (late onset, 80–90 years of age).
People with dementia are often physically or chemically restrained to a greater degree than necessary, raising issues of human rights. Social stigma is commonly perceived by those with the condition, and also by their caregivers.
=== Inequities and inequalities ===
A growing body of scientific evidence suggests that inequalities and inequities in dementia exist. Inequalities and inequities are observed in the risk of developing dementia, ability to take part in prevention efforts, access to high-quality dementia care from diagnosis until the end of life, including bereavement support.
People affected by dementia report experiencing an absence of clinical oversight and specialist support after diagnosis. Unlike other conditions, dementia was described as not sitting neatly in the health and social care system. A lack of parity between dementia and other life-limiting conditions is noted. Furthermore, substantially less dementia research funding and financial support for the care of people with dementia compared to other life-limiting conditions also exists.
Differences in access to high-quality care among dementia subtypes are also noted. People with rare types of dementia compared to those with Alzheimer’s Disease, and those with other physical conditions are less likely to experience high-quality care.
==== Socioeconomic status and deprivation ====
While aging is the largest risk factor for developing dementia, other factors at early (e.g., receiving less education), middle (e.g., physical inactivity) and later stages (e.g., air pollution) are often linked to increased risk.
There are significant advantages associated with having a timely dementia diagnosis (i.e., receiving the diagnosis at the milder stages of the condition). However, access to dementia diagnosis can be inequitable. Compared to individuals with high socioeconomic status, those with low socioeconomic status can have more than three-times higher risk of early-onset dementia. Additionally, individuals of low socioeconomic status with unhealthy lifestyles, can have 440% greater risk of developing early-onset dementia compared with individuals of high socioeconomic status with healthy lifestyles. Measures to improve social determinants of health are warranted, as healthy lifestyle promotion alone might not substantially reduce the socioeconomic inequity in early-onset dementia and late-onset dementia risk.
People with dementia residing in rural areas often experience challenges in receiving a timely diagnosis and accessing health and social care compared to people living in urban areas.
Among older people diagnosed with dementia, those from most deprived areas can be more likely to experience hospitalisations, emergency department visits, potentially inappropriate medication prescriptions, and higher 1-year mortality. People living in the most deprived areas are more likely to experience multiple hospitalisations in the last three months of life and emergency department visits in the last year of life. In high-income countries, low socioeconomic position is a risk factor for dying in hospital as well as other indicators of potentially poor-quality end-of-life care.
==== Race and ethnicity ====
Significant differences in dementia incidence and risk exist based on race and ethnicity. The mechanisms responsible for these differences are not yet understood. People who are Black in the US are at risk of receiving more futile and invasive treatment towards the end of life. Emerging evidence from other countries also suggest that minority groups from different cultures, ethnicities may experience sub-optimal care from diagnosis to the end-of-life.
==== Gender ====
Globally, women are bearing a disproportionate weight of the dementia impact. Two in three people with dementia are women. Yet, medical data from women are lacking compared to men. Women are more likely to care for another person with dementia (in the workforce and informally). The proportion of women caregivers in low and middle income countries is higher. Gender disparities exist towards the end-of-life in palliative caregiving and end-of-life care experiences.
== History ==
Until the end of the 19th century, dementia was a much broader clinical concept. It included mental illness and any type of psychosocial incapacity, including reversible conditions. Dementia at this time simply referred to anyone who had lost the ability to reason, and was applied equally to psychosis, "organic" diseases like syphilis that destroy the brain, and to the dementia associated with old age, which was attributed to "hardening of the arteries".
Dementia has been referred to in medical texts since antiquity. One of the earliest known allusions to dementia is attributed to the 7th-century BC Greek philosopher Pythagoras, who divided the human lifespan into six distinct phases: 0–6 (infancy), 7–21 (adolescence), 22–49 (young adulthood), 50–62 (middle age), 63–79 (old age), and 80–death (advanced age). The last two he described as the "senium", a period of mental and physical decay, and that the final phase was when "the scene of mortal existence closes after a great length of time that very fortunately, few of the human species arrive at, where the mind is reduced to the imbecility of the first epoch of infancy". In 550 BC, the Athenian statesman and poet Solon argued that the terms of a man's will might be invalidated if he exhibited loss of judgement due to advanced age. Chinese medical texts made allusions to the condition as well, and the characters for "dementia" translate literally to "foolish old person".
Athenian philosophers Aristotle and Plato discussed the mental decline that can come with old age and predicted that this affects everyone who becomes old and nothing can be done to stop this decline from taking place. Plato specifically talked about how the elderly should not be in positions that require responsibility because, "There is not much acumen of the mind that once carried them in their youth, those characteristics one would call judgement, imagination, power of reasoning, and memory. They see them gradually blunted by deterioration and can hardly fulfill their function."
For comparison, the Roman statesman Cicero held a view much more in line with modern-day medical wisdom that loss of mental function was not inevitable in the elderly and "affected only those old men who were weak-willed". He spoke of how those who remained mentally active and eager to learn new things could stave off dementia. However, Cicero's views on aging, although progressive, were largely ignored in a world that would be dominated for centuries by Aristotle's medical writings. Physicians during the Roman Empire, such as Galen and Celsus, simply repeated the beliefs of Aristotle while adding few new contributions to medical knowledge.
Byzantine physicians sometimes wrote of dementia. It is recorded that at least seven emperors whose lifespans exceeded 70 years displayed signs of cognitive decline. In Constantinople, special hospitals housed those diagnosed with dementia or insanity, but these did not apply to the emperors, who were above the law and whose health conditions could not be publicly acknowledged.
Otherwise, little is recorded about dementia in Western medical texts for nearly 1700 years. One of the few references was the 13th-century friar Roger Bacon, who viewed old age as divine punishment for original sin. Although he repeated existing Aristotelian beliefs that dementia was inevitable, he did make the progressive assertion that the brain was the center of memory and thought rather than the heart.
Poets, playwrights, and other writers made frequent allusions to the loss of mental function in old age. William Shakespeare notably mentions it in plays such as Hamlet and King Lear.
During the 19th century, doctors generally came to believe that elderly dementia was the result of cerebral atherosclerosis, although opinions fluctuated between the idea that it was due to blockage of the major arteries supplying the brain or small strokes within the vessels of the cerebral cortex.
In 1907, Bavarian psychiatrist Alois Alzheimer was the first to identify and describe the characteristics of progressive dementia in the brain of 51-year-old Auguste Deter. Deter had begun to behave uncharacteristically, including accusing her husband of adultery, neglecting household chores, exhibiting difficulties writing and engaging in conversations, heightened insomnia, and loss of directional sense. At one point, Deter was reported to have "dragged a bed sheet outside, wandered around wildly, and cried for hours at midnight." Alzheimer began treating Deter when she entered a Frankfurt mental hospital on November 25, 1901. During her ongoing treatment, Deter and her husband struggled to afford the cost of the medical care, and Alzheimer agreed to continue her treatment in exchange for Deter's medical records and donation of her brain upon death. Deter died on April 8, 1906, after succumbing to sepsis and pneumonia. Alzheimer conducted the brain biopsy using the Bielschowsky stain method, which was a new development at the time, and he observed senile plaques, neurofibrillary tangles, and atherosclerotic alteration. At the time, the consensus among medical doctors had been that senile plaques were generally found in older patients, and the occurrence of neurofibrillary tangles was an entirely new observation at the time. Alzheimer presented his findings at the 37th psychiatry conference of southwestern Germany in Tübingen on April 11, 1906; however, the information was poorly received by his peers. By 1910, Alois Alzheimer's teacher, Emil Kraepelin, published a book in which he coined the term "Alzheimer's disease" in an attempt to acknowledge the importance of Alzheimer's discovery.
By the 1960s, the link between neurodegenerative diseases and age-related cognitive decline had become more established. By the 1970s, the medical community maintained that vascular dementia was rarer than previously thought and Alzheimer's disease caused the vast majority of old age mental impairments. More recently however, it is believed that dementia is often a mixture of conditions.
In 1976, neurologist Robert Katzmann suggested a link between senile dementia and Alzheimer's disease. Katzmann suggested that much of the senile dementia occurring (by definition) after the age of 65, was pathologically identical with Alzheimer's disease occurring in people under age 65 and therefore should not be treated differently. Katzmann thus suggested that Alzheimer's disease, if taken to occur over age 65, is actually common, not rare, and was the fourth- or 5th-leading cause of death, even though rarely reported on death certificates in 1976.
A helpful finding was that although the incidence of Alzheimer's disease increased with age (from 5–10% of 75-year-olds to as many as 40–50% of 90-year-olds), no threshold was found by which age all persons developed it. This is shown by documented supercentenarians (people living to 110 or more) who experienced no substantial cognitive impairment. Some evidence suggests that dementia is most likely to develop between ages 80 and 84 and individuals who pass that point without being affected have a lower chance of developing it. Women account for a larger percentage of dementia cases than men. This can be attributed in part to their longer overall lifespan and greater odds of attaining an age where the condition is likely to occur.
Much like other diseases associated with aging, dementia was comparatively rare before the 20th century, because few people lived past 80. Conversely, syphilitic dementia was widespread in the developed world until it was largely eradicated by the use of penicillin after World War II. With significant increases in life expectancy thereafter, the number of people over 65 started rapidly climbing. While elderly persons constituted an average of 3–5% of the population prior to 1945, by 2010 many countries reached 10–14% and in Germany and Japan, this figure exceeded 20%. Public awareness of Alzheimer's Disease greatly increased in 1994 when former US president Ronald Reagan announced that he had been diagnosed with the condition.
In the 21st century, other types of dementia were differentiated from Alzheimer's disease and vascular dementias (the most common types). This differentiation is on the basis of pathological examination of brain tissues, by symptomatology, and by different patterns of brain metabolic activity in nuclear medical imaging tests such as SPECT and PET scans of the brain. The various forms have differing prognoses and differing epidemiologic risk factors. The main cause for many diseases, including Alzheimer's disease, remains unclear.
=== Terminology ===
Dementia in the elderly was once called senile dementia or senility, and viewed as a normal and somewhat inevitable aspect of aging.
By 1913–20 the term dementia praecox was introduced to suggest the development of senile-type dementia at a younger age. Eventually the two terms fused, so that until 1952 physicians used the terms dementia praecox (precocious dementia) and schizophrenia interchangeably. Since then, science has determined that dementia and schizophrenia are two different disorders, though they share some similarities. The term precocious dementia for a mental illness suggested that a type of mental illness like schizophrenia (including paranoia and decreased cognitive capacity) could be expected to arrive normally in all persons with greater age (see paraphrenia). After about 1920, the beginning use of dementia for what is now understood as schizophrenia and senile dementia helped limit the word's meaning to "permanent, irreversible mental deterioration". This began the change to the later use of the term. In recent studies, researchers have seen a connection between those diagnosed with schizophrenia and patients who are diagnosed with dementia, finding a positive correlation between the two diseases.
The view that dementia must always be the result of a particular disease process led for a time to the proposed diagnosis of "senile dementia of the Alzheimer's type" (SDAT) in persons over the age of 65, with "Alzheimer's disease" diagnosed in persons younger than 65 who had the same pathology. Eventually, however, it was agreed that the age limit was artificial, and that Alzheimer's disease was the appropriate term for persons with that particular brain pathology, regardless of age.
After 1952, mental illnesses including schizophrenia were removed from the category of organic brain syndromes, and thus (by definition) removed from possible causes of "dementing illnesses" (dementias). At the same, however, the traditional cause of senile dementia – "hardening of the arteries" – now returned as a set of dementias of vascular cause (small strokes). These were now termed multi-infarct dementias or vascular dementias.
== Society and culture ==
Dementia impacts not only individuals with dementia, but also their carers and the wider society. Among people aged 60 years and over, dementia is ranked the 9th most burdensome condition according to the 2010 Global Burden of Disease (GBD) estimates.
The societal cost of dementia is high, especially for caregivers. According to research conducted in the UK, almost two out of three carers of people with dementia feel lonely. Most of the carers in the study were family members or friends. Family carers of people with dementia are at higher risk of developing psychological and physical conditions.
=== Impact on society ===
Globally, the fastest increase in serious health-related suffering by 2060 is expected to occur among people with dementia. Many countries consider the care of people living with dementia a national priority and invest in resources and education to better inform health and social service workers, unpaid caregivers, relatives and members of the wider community. Several countries have authored national plans or strategies. These plans recognize that people can live reasonably with dementia for years, as long as the right support and timely access to a diagnosis are available.
Former British Prime Minister David Cameron described dementia as a "national crisis", affecting then 800,000 people in the United Kingdom.
=== Financial costs ===
The financial costs of care in people with dementia are high and tend to increase toward death. Long-term care facility and informal care costs are among the highest cost components, while non-White ethnicity, female sex, married status, higher education level, more severe dementia, and higher number of chronic conditions are associated with higher costs.
The global costs of dementia was around US$818 billion in 2015, a 35.4% increase from US$604 billion in 2010. By 2050 the estimated global cost will be $9.12 trillion.
In 2015, the annual cost per person with Alzheimer's in the United States was around $19,144.36. The total costs for the country was estimated to be about $167.74 billion. By 2030, it is predicted the annual socioeconomic cost will total to about $507 billion, and by 2050 that number is expected to reach $1.89 trillion.
The total cost of dementia care in the UK is projected to increase by 172%, from £34.7 billion in 2019 to £94.1 billion in 2040.
The estimated costs of dementia in low- and middle-income countries (LMICs) are lower compared to high-income countries, with indirect costs making up the largest proportion in LMICs. However, these estimates are likely an underrepresentation, as there have been limited research studies on dementia costs in LMICs, particularly low-income countries.
=== Awareness ===
Despite ongoing efforts, there still remains relatively little public understanding of dementia. For example only 42% of surveyed public in England knew that dementia is a terminal condition. There is also persistent stigma, which can be a barrier for people seeking help for dementia and accessing care. 88% of people living with dementia report experiencing discrimination. Stigma is worse among those who have limited knowledge of the condition or contact with people affected by dementia, and is likely to shape the stigma held by people affected by dementia. Over 64% of the general public believe people with dementia are impulsive and unpredictable.
According to Alzheimer’s Disease International’s 2024 survey consisting of more than 40,000 responses from people living with dementia, carers, health and care practitioners, and the general public from over 166 countries and territories, 80% of general public and 65% of health and care professionals incorrectly believe dementia is a normal part of ageing.
Celebrities have used their platforms to raise awareness for the different forms of dementia and the need for further support, including former First Lady of California Maria Shriver, actor Samuel L. Jackson, editor-in-chief of ELLE Magazine Nina Garcia, professional skateboarder Tony Hawk, and others.
Additional Alzheimer's awareness has been raised through the diagnoses of high-profile persons themselves, including actors Bruce Willis and Robin Williams, actress and pin-up model Rita Hayworth, activist Rosa Parks, former US President Ronald Reagan, TV host Wendy Williams, musicians Tony Bennett and Maureen McGovern.
=== Philanthropy ===
In 2015, Atlantic Philanthropies announced a $177 million gift aimed at understanding and reducing dementia. The recipient was Global Brain Health Institute, a program co-led by the University of California, San Francisco and Trinity College Dublin. This donation is the largest non-capital grant Atlantic has ever made, and the biggest philanthropic donation in Irish history.
In October 2020, the Caretaker's last music release, Everywhere at the End of Time, was popularized by TikTok users for its depiction of the stages of dementia. Caregivers were in favor of this phenomenon; Leyland Kirby, the creator of the record, echoed this sentiment, explaining it could cause empathy among a younger public.
On November 2, 2020, Scottish billionaire Sir Tom Hunter donated £1 million to dementia charities, after watching a former music teacher with dementia, Paul Harvey, playing one of his own compositions on the piano in a viral video. The donation was announced to be split between the Alzheimer's Society and Music for Dementia.
=== Other ===
Driving with dementia can lead to injury or death. Doctors should advise appropriate testing on when to quit driving. The United Kingdom DVLA (Driver & Vehicle Licensing Agency) states that people with dementia who specifically have poor short-term memory, disorientation, or lack of insight or judgment are not allowed to drive, and in these instances the DVLA must be informed so that the driving license can be revoked. They acknowledge that in low-severity cases and those with an early diagnosis, drivers may be permitted to continue driving.
== Research directions ==
=== Diagnosis ===
Artificial intelligence (AI) and machine learning (ML) algorithms have the potential to improve early diagnosis and treatment planning for dementia.
=== Oral bacteria ===
Research is being conducted linking oral bacterial to dementia. In the oral cavity, bacterial species include P. gingivalis, F. nucleatum, P. intermedia, and T. forsythia. Six oral treponema spirochetes have been examined in the brains of people with Alzheimer's disease. Spirochetes are neurotropic in nature, meaning they act to destroy nerve tissue and create inflammation. Inflammatory pathogens are an indicator of Alzheimer's disease and bacteria related to gum disease have been found in the brains of people with dementia. The proposed mechanism is that bacteria invade nerve tissue in the brain, increasing the permeability of the blood–brain barrier and promoting the onset of Alzheimer's.
== Notes ==
== References ==
== External links ==
Alzheimer's Association
National Institute on Aging – Alzheimer's disease | Wikipedia/Antidementia_drug |
In pharmacology, hazardous drugs are drugs that are known to cause harm, which may or may not include genotoxicity (the ability to cause a change or mutation in genetic material). Genotoxicity might involve carcinogenicity, the ability to cause cancer in animal models, humans or both; teratogenicity, which is the ability to cause defects on fetal development or fetal malformation; and lastly hazardous drugs are known to have the potential to cause fertility impairment, which is a major concern for most clinicians. These drugs can be classified as antineoplastics, cytotoxic agents, biologic agents, antiviral agents and immunosuppressive agents. This is why safe handling of hazardous drugs is crucial.
== Safe handling ==
Safe handling refers to the process in which health care workers adhere to practices set forth by national health and safety organizations, that have been designed to eliminate or significantly reduce occupational exposure. Some of these practices include but are not limited to, donning of personal protective equipment such as a disposable gown, gloves, masks and the utilization of a closed-system drug transfer device. The key safe handling is to protect the health care worker throughout the three phases of contact with the hazardous drugs. These phases are drug preparation, administration and disposal. Some studies have shown that while compounding hazardous drugs in a Class II BSC in conjunction with a closed-system drug transfer device, a significant decrease in drug contaminants inside a Class II BSC has resulted. This led the Oncology Nursing Society (ONS) to make the statement in 2003 that a closed-system drug transfer device is viewed as one of safest measures to prevent hazardous drug exposure in a clinician’s working environment. However, a Cochrane review published in 2018 that synthesized all available controlled studies found no evidence of a closed-system drug transfer device offering an additional decrease in contamination or exposure to safe handling practices alone.
It has been determined that current personal protective equipment (PPE) does not provide adequate protection against workers handling hazardous drugs - NIOSH states that “... measurable concentrations of some hazardous drugs have been documented in the urine of health care workers who prepared or administered them − even after safety precautions had been employed.” Further, NIOSH recommends that institutions should "consider using devices such as closed-system transfer devices. Closed systems limit the potential for generating aerosols and exposing workers". Other guidelines outline that "As other products become available, they should meet the definition of a closed system drug transfer device established by NIOSH and should be required to demonstrate their effectiveness in independent studies".
== See also ==
USP 800
== References ==
== External links ==
American Society of Health-System Pharmacists (ASHP)
National Institute for Occupational Safety and Health (NIOSH)
Oncology Nursing Society (ONS)
The International Agency for Research on Cancer (IARC) Archived 2011-06-11 at the Wayback Machine Classification of Hazardous Drugs
International Society of Oncology Pharmacy Practitioners (ISOPP) | Wikipedia/Hazardous_drugs |
Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the patient, and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles.
== Types ==
There are several subtypes of CINV. The classifications of nausea and vomiting are:
Acute: occurring within 24 hours of chemotherapy
Delayed: occurring between 24 hours and 5 days after treatment
Breakthrough: occurring despite prophylactic treatment
Anticipatory: triggered by taste, odor, memories, visions, or anxiety related to chemotherapy
Refractory: occurring during subsequent cycles when antiemetics have failed in earlier cycles
== Cause ==
Vomiting is a defense mechanism controlled by the area postrema of the medulla oblongata. There are various sources of input to the vomiting center. Receptors on the floor of the fourth ventricle of the brain represent the chemoreceptor trigger zone. The chemoreceptor trigger zone contains dopamine D2 receptors, serotonin 5-HT3 receptors, opioid receptors, acetylcholine receptors, and receptors for substance P. Stimulation of different receptors are involved in different pathways leading to emesis. In the final common pathway, substance P, which activates the neurokinin-1 receptor, appears to be involved. Additionally, the vagal and enteric nervous system inputs transmit information regarding the state of the gastrointestinal system.
Chemotherapy interferes with cell division, which particularly affects rapidly dividing cells like those of the gastrointestinal mucosa and immune cells. Irritation of the GI mucosa by chemotherapy, radiation, distention, or acute infectious gastroenteritis activates the 5-HT3 receptors of these inputs. It is now widely known that cytotoxic chemotherapeutic agents cause enterochromaffin cells to produce more serotonin in response to free radical damage, leading to a detectable increase in blood levels of serotonin (5-HT) and its major metabolite, 5-Hydroxyindoleacetic acid (5-HIAA). The presence of these chemicals in the blood activate 5-HT3 receptors in the chemoreceptor trigger zone, in turn releasing substance P, which activates NK1 receptors to cause an emetic response (vomiting).
== Risk factors ==
The risk of chemotherapy-induced nausea and vomiting varies based on the type of treatment received as well as several outside factors. Some types of chemotherapy are more prone to causing nausea and vomiting than others. Some chemotherapeutic agents may not cause nausea and vomiting on their own, but may when used in combination with other agents. Regimens that are linked to a high incidence (90% or higher) of nausea and vomiting are referred to as "highly emetogenic chemotherapy", and those causing a moderate incidence (30–90%) of nausea and vomiting are referred to as "moderately emetogenic chemotherapy".
Some highly emetogenic agents and chemotherapy regimens include:
ABVD
AC
BEP
Cisplatin
Carmustine (>250 mg/m2)
CBV
Cyclophosphamide (>1500 mg/m2)
Dacarbazine
Mechlorethamine
MOPP/COPP/BEACOPP
Streptozocin
VIP
Some moderately emetogenic agents and regimens include:
Carboplatin
CHOP/CHOP-R
Cyclophosphamide (≤1500 mg/m2)
Docetaxel
Doxorubicin/Adriamycin
Etoposide
Ifosfamide
Methotrexate
Paclitaxel
Besides the type of treatment, personal factors may put a patient at greater risk for CINV. Other risk factors include:
Anticipation of CINV
Anxiety or depression
Female sex
History of light alcohol use
History of motion sickness
History of nausea and vomiting during pregnancy
History of previous CINV
Patient age (under 55 years old)
== Treatments ==
Several treatment methods are available to help prevent CINV. Pharmaceutical treatment is generally separated into two types: prophylactic (preventative) treatment, given before the dose of chemotherapy agents, and rescue treatment, given to treat breakthrough nausea and vomiting.
=== 5-HT3 inhibitors ===
5-HT3 receptor antagonists are very effective antiemetics and constitute a great advance in the management of CINV. These drugs block one or more of the nerve signals that cause nausea and vomiting. During the first 24 hours after chemotherapy, the most effective approach appears to be blocking the 5-HT3 nerve signal. Approved 5-HT3 inhibitors include dolasetron (Anzemet), granisetron (Kytril, Sancuso), and ondansetron (Zofran). Their antiemetic effect due to blockade of 5HT3 receptor on vagal afferent in the gut. in addition they also block 5-HT3 receptors in CTZ and STN. The newest 5-HT3 inhibitor, palonosetron (Aloxi), also prevents delayed nausea and vomiting, which can occur during the 2–5 days after treatment. Since some patients have trouble swallowing pills, these drugs are often available by injection, as orally disintegrating tablets, or as transdermal patches.
=== NK1 inhibitors ===
A newer class of drugs known as the NK1 antagonists are a recently developed class of very efficacious drugs for controlling CINV. These drugs are often used alongside 5HT3 inhibitors and corticosteroids to form a very potent cocktail of antiemetics that verge on achieving a nearly complete patient response (that is, completely stopping CINV). The substance P inhibitor aprepitant (Emend), which became available in 2005, is highly effective in controlling nausea and vomiting associated with cancer chemotherapy. Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brains neurons. Indeed, positron emission tomography (PET) studies have shown that aprepitant can penetrate the brain and NK1 receptors in the brain. Aprepitant has also been shown to increase the activity of the 5-HT3 receptor antagonists ondansetron and the corticosteroid dexamethasone, which are also used to prevent nausea and vomiting caused by chemotherapy. Netupitant has recently been approved by USFDA. It has also been marketed in combination with palonosetron. Rolapitant is the newest addition in the approved NK1 antagonist list. It has advantage of a very long half life, duration of action is around 150 hours. Rolapitant got its approval by USFDA in 2015.
=== Other drugs ===
Olanzapine, as well as several other neuroleptic drugs, have also has been investigated for the control of CINV. A 2007 study demonstrated Olanzapine's successful potential for this use, achieving a complete response in the acute prevention of nausea and vomiting in 100% of patients treated with moderately and highly emetogenic chemotherapy, when used in combination with palonosetron and dexamethasone. Neuroleptic agents are now indicated for rescue treatment and the control of breakthrough nausea and vomiting.
Some studies and patient groups say that the use of cannabinoids derived from cannabis during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Synthesized tetrahydrocannabinol (also one of the main active substances in marijuana) is marketed as Marinol and may be practical for this application. Natural medical cannabis is also used and recommended by some oncologists, though its use is regulated and it is not legal in all jurisdictions. However, Marinol was less effective than megestrol acetate in helping cancer patients regain lost appetites. A phase III study found no difference in effects of an oral cannabis extract or THC on appetite and quality of life (QOL) in patients with cancer-related anorexia-cachexia syndrome (CACS) to placebo.
Dexamethasone, a corticosteroid, is often used alongside other antiemetic drugs, as it has synergistic action with many of them, although its specific antiemetic mechanism of action is not fully understood. Metoclopramide, a dopamine D2 receptor antagonist with possible other mechanisms, is an older drug that is sometimes used, either on its own or in combination with others. Histamine blockers such as diphenhydramine or meclozine may be used in rescue treatment. Lorazepam and diazepam may sometimes be used to relieve anxiety associated with CINV before administration of chemotherapy, and are also often used in the case of rescue treatment.
=== Alternative treatments ===
==== Ginger (Zingiber officinale) ====
There are several compounds that have been identified within ginger that have been shown to possess properties that are likely to be beneficial in the treatment of CINV. This includes 5-HT3 and substance P antagonism, modulation of gastrointestinal motility, and antioxidant properties. There have been multiple clinical trials that have investigated the use of ginger supplementation as a treatment for CINV. However, due to conflicting results and methodological issues, a 2013 systematic review of seven clinical trials summarized the current evidence as stating that "Despite the widespread use of ginger in the treatment of nausea in other contexts such as gestational nausea, the current literature provides mixed support for the use of ginger as a standard part of anti-CINV control for patients undergoing chemotherapy."
==== Other ====
Non-pharmacological approaches to remedy CINV typically involve small lifestyle alterations, such as using unscented deodorants and soaps, avoiding strong scents altogether, and dietary modifications such as eating several small meals throughout the day, eating high-protein, high-calorie food, drinking many clear liquids, and removing spicy, fatty, fried, or acidic foods from the diet. Patients may also participate in alternative practices such as self-hypnosis, relaxation and imagery therapy, distraction, music therapy, biofeedback, desensitization, or acupressure.
== See also ==
Cancer and nausea
== References == | Wikipedia/Chemotherapy-induced_nausea_and_vomiting |
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified in cells, by internal metabolic by-products, and by external ionizing radiation, ultraviolet light, and medicines, resulting in spontaneous DNA damage involving tens of thousands of individual molecular lesions per cell per day. DNA modifications can also be programmed.
Molecular lesions can cause structural damage to the DNA molecule, and can alter or eliminate the cell's ability for transcription and gene expression. Other lesions may induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells following mitosis. Consequently, DNA repair as part of the DNA damage response (DDR) is constantly active. When normal repair processes fail, including apoptosis, irreparable DNA damage may occur, that may be a risk factor for cancer.
The degree of DNA repair change made within a cell depends on various factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage or can no longer effectively repair its DNA may enter one of three possible states:
an irreversible state of dormancy, known as senescence
apoptosis a form of programmed cell death
unregulated division, which can lead to the formation of a tumor that is cancerous
The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection.
The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their work on the molecular mechanisms of DNA repair processes.
== DNA damage ==
DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day. While this constitutes at most only 0.03% of the human genome's approximately 3.2 billion bases, unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation and contribute to tumor heterogeneity.
The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around "packaging" proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.
=== Sources ===
DNA damage can be subdivided into two main types:
endogenous damage such as attack by reactive oxygen species produced from normal metabolic byproducts (spontaneous mutation), especially the process of oxidative deamination
also includes replication errors
exogenous damage caused by external agents such as
ultraviolet (UV) radiation (200–400 nm) from the sun or other artificial light sources
other radiation frequencies, including x-rays and gamma rays, and particles like electrons, neutrons, or alpha particles.
hydrolysis or thermal disruption
certain plant toxins
human-made mutagenic chemicals, especially aromatic compounds that act as DNA intercalating agents
viruses
The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a back mutation, for example, through gene conversion).
=== Types ===
There are several types of damage to DNA due to endogenous cellular processes:
oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species,
alkylation of bases (usually methylation), such as formation of 7-methylguanosine, 1-methyladenine, 6-O-Methylguanine
hydrolysis of bases, such as deamination, depurination, and depyrimidination.
"bulky adduct formation" (e.g., benzo[a]pyrene diol epoxide-dG adduct, aristolactam I-dA adduct)
mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.
Monoadduct damage cause by change in single nitrogenous base of DNA
Di adduct damage
Damage caused by exogenous agents comes in many forms. Some examples are:
Absorption of UV light directly by DNA induces photochemical reactions, leading to the formation of pyrimidine dimers, and photoionization, provoking oxidative damage.
UV-A light creates mostly free radicals. The damage caused by free radicals is called indirect DNA damage.
Ionizing radiation such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands. Intermediate-level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.
Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA backbone) and single-strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria, which grow in hot springs at 40–80 °C. The rate of depurination (300 purine residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an adaptive response cannot be ruled out.
Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic aromatic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethanoates, oxidized bases, alkylated phosphodiesters and crosslinking of DNA, just to name a few.
UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift. Constitutive (spontaneous) DNA damage caused by endogenous oxidants can be detected as a low level of histone H2AX phosphorylation in untreated cells.
=== Nuclear versus mitochondrial ===
In eukaryotic cells, DNA is found in two cellular locations – inside the nucleus and inside the mitochondria. Nuclear DNA (nDNA) exists as chromatin during non-replicative stages of the cell cycle and is condensed into aggregate structures known as chromosomes during cell division. In either state the DNA is highly compacted and wound up around bead-like proteins called histones. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unraveled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation, create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is superoxide dismutase, which is present in both the mitochondria and cytoplasm of eukaryotic cells.
=== Senescence and apoptosis ===
Senescence, an irreversible process in which the cell no longer divides, is a protective response to the shortening of the chromosome ends, called telomeres. The telomeres are long regions of repetitive noncoding DNA that cap chromosomes and undergo partial degradation each time a cell undergoes division (see Hayflick limit). In contrast, quiescence is a reversible state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism, which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of a tumor (see cancer), which is potentially lethal to an organism. Therefore, the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.
=== Mutation ===
It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damage and mutation are fundamentally different. Damage results in physical abnormalities in the DNA, such as single- and double-strand breaks, 8-hydroxydeoxyguanosine residues, and polycyclic aromatic hydrocarbon adducts. DNA damage can be recognized by enzymes, and thus can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented, and thus translation into a protein will also be blocked. Replication may also be blocked or the cell may die.
In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce.
Although distinctly different from each other, DNA damage and mutation are related because DNA damage often causes errors of DNA synthesis during replication or repair; these errors are a major source of mutation.
Given these properties of DNA damage and mutation, it can be seen that DNA damage is a special problem in non-dividing or slowly-dividing cells, where unrepaired damage will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damage that does not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell's survival. Thus, in a population of cells composing a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism because such mutant cells can give rise to cancer. Thus, DNA damage in frequently dividing cells, because it gives rise to mutations, is a prominent cause of cancer. In contrast, DNA damage in infrequently-dividing cells is likely a prominent cause of aging.
== Mechanisms ==
Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when non-essential genes are missing or damaged). Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.
Damage to DNA alters the spatial configuration of the helix, and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place.
=== Direct reversal ===
Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can occur in only one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone.
The formation of pyrimidine dimers upon irradiation with UV light results in an abnormal covalent bond between adjacent pyrimidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from blue/UV light (300–500 nm wavelength) to promote catalysis. Photolyase, an old enzyme present in bacteria, fungi, and most animals no longer functions in humans, who instead use nucleotide excision repair to repair damage from UV irradiation.
Another type of damage, methylation of guanine bases, is directly reversed by the enzyme methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called ogt. This is an expensive process because each MGMT molecule can be used only once; that is, the reaction is stoichiometric rather than catalytic. A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes.
The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.
=== Single-strand damage ===
When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.
Base excision repair (BER): damaged single bases or nucleotides are most commonly repaired by removing the base or the nucleotide involved and then inserting the correct base or nucleotide. In base excision repair, a glycosylase enzyme removes the damaged base from the DNA by cleaving the bond between the base and the deoxyribose. These enzymes remove a single base to create an apurinic or apyrimidinic site (AP site). Enzymes called AP endonucleases nick the damaged DNA backbone at the AP site. DNA polymerase then removes the damaged region using its 5' to 3' exonuclease activity and correctly synthesizes the new strand using the complementary strand as a template. The gap is then sealed by enzyme DNA ligase.
Nucleotide excision repair (NER): bulky, helix-distorting damage, such as pyrimidine dimerization caused by UV light is usually repaired by a three-step process. First the damage is recognized, then 12-24 nucleotide-long strands of DNA are removed both upstream and downstream of the damage site by endonucleases, and the removed DNA region is then resynthesized. NER is a highly evolutionarily conserved repair mechanism and is used in nearly all eukaryotic and prokaryotic cells. In prokaryotes, NER is mediated by Uvr proteins. In eukaryotes, many more proteins are involved, although the general strategy is the same.
Mismatch repair systems are present in essentially all cells to correct errors that are not corrected by proofreading. These systems consist of at least two proteins. One detects the mismatch, and the other recruits an endonuclease that cleaves the newly synthesized DNA strand close to the region of damage. In E. coli , the proteins involved are the Mut class proteins: MutS, MutL, and MutH. In most Eukaryotes, the analog for MutS is MSH and the analog for MutL is MLH. MutH is only present in bacteria. This is followed by removal of damaged region by an exonuclease, resynthesis by DNA polymerase, and nick sealing by DNA ligase.
=== Double-strand breaks ===
Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. In fact, when a double-strand break is accompanied by a cross-linkage joining the two strands at the same point, neither strand can be used as a template for the repair mechanisms, so that the cell will not be able to complete mitosis when it next divides, and will either die or, in rare cases, undergo a mutation. Three mechanisms exist to repair double-strand breaks (DSBs): non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination (HR):
In NHEJ, DNA Ligase IV, a specialized DNA ligase that forms a complex with the cofactor XRCC4, directly joins the two ends. To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate. NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms insertions or translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are "backup" NHEJ pathways in higher eukaryotes. Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.
MMEJ starts with short-range end resection by MRE11 nuclease on either side of a double-strand break to reveal microhomology regions. In further steps, Poly (ADP-ribose) polymerase 1 (PARP1) is required and may be an early step in MMEJ. There is pairing of microhomology regions followed by recruitment of flap structure-specific endonuclease 1 (FEN1) to remove overhanging flaps. This is followed by recruitment of XRCC1–LIG3 to the site for ligating the DNA ends, leading to an intact DNA. MMEJ is always accompanied by a deletion, so that MMEJ is a mutagenic pathway for DNA repair.
HR requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.
In an in vitro system, MMEJ occurred in mammalian cells at the levels of 10–20% of HR when both HR and NHEJ mechanisms were also available.
The extremophile Deinococcus radiodurans has a remarkable ability to survive DNA damage from ionizing radiation and other sources. At least two copies of the genome, with random DNA breaks, can form DNA fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions through a moving D-loop that can continue extension until complementary partner strands are found. In the final step, there is crossover by means of RecA-dependent homologous recombination.
Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNA's state of supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.
Another type of DNA double-strand breaks originates from the DNA heat-sensitive or heat-labile sites. These DNA sites are not initial DSBs. However, they convert to DSB after treating with elevated temperature. Ionizing irradiation can induces a highly complex form of DNA damage as clustered damage. It consists of different types of DNA lesions in various locations of the DNA helix. Some of these closely located lesions can probably convert to DSB by exposure to high temperatures. But the exact nature of these lesions and their interactions is not yet known
=== Translesion synthesis ===
Translesion synthesis (TLS) is a DNA damage tolerance process that allows the DNA replication machinery to replicate past DNA lesions such as thymine dimers or AP sites. It involves switching out regular DNA polymerases for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication processivity factor PCNA. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, Pol η mediates error-free bypass of lesions induced by UV irradiation, whereas Pol ι introduces mutations at these sites. Pol η is known to add the first adenine across the T^T photodimer using Watson-Crick base pairing and the second adenine will be added in its syn conformation using Hoogsteen base pairing. From a cellular perspective, risking the introduction of point mutations during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death. In short, the process involves specialized polymerases either bypassing or repairing lesions at locations of stalled DNA replication. For example, Human DNA polymerase eta can bypass complex DNA lesions like guanine-thymine intra-strand crosslink, G[8,5-Me]T, although it can cause targeted and semi-targeted mutations. Paromita Raychaudhury and Ashis Basu studied the toxicity and mutagenesis of the same lesion in Escherichia coli by replicating a G[8,5-Me]T-modified plasmid in E. coli with specific DNA polymerase knockouts. Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these specialized DNA polymerases.
A bypass platform is provided to these polymerases by Proliferating cell nuclear antigen (PCNA). Under normal circumstances, PCNA bound to polymerases replicates the DNA. At a site of lesion, PCNA is ubiquitinated, or modified, by the RAD6/RAD18 proteins to provide a platform for the specialized polymerases to bypass the lesion and resume DNA replication. After translesion synthesis, extension is required. This extension can be carried out by a replicative polymerase if the TLS is error-free, as in the case of Pol η, yet if TLS results in a mismatch, a specialized polymerase is needed to extend it; Pol ζ. Pol ζ is unique in that it can extend terminal mismatches, whereas more processive polymerases cannot. So when a lesion is encountered, the replication fork will stall, PCNA will switch from a processive polymerase to a TLS polymerase such as Pol ι to fix the lesion, then PCNA may switch to Pol ζ to extend the mismatch, and last PCNA will switch to the processive polymerase to continue replication.
== Global response to DNA damage ==
Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double-strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids, and RNA. The accumulation of damage, to be specific, double-strand breaks or adducts stalling the replication forks, are among known stimulation signals for a global response to DNA damage. The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance, or apoptosis. The common features of global response are induction of multiple genes, cell cycle arrest, and inhibition of cell division.
=== Initial steps ===
The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow DNA repair, the chromatin must be remodeled. In eukaryotes, ATP dependent chromatin remodeling complexes and histone-modifying enzymes are two predominant factors employed to accomplish this remodeling process.
Chromatin relaxation occurs rapidly at the site of a DNA damage. In one of the earliest steps, the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to double-strand breaks or other DNA damage. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites, and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. PARP1 protein starts to appear at DNA damage sites in less than a second, with half maximum accumulation within 1.6 seconds after the damage occurs. PARP1 synthesizes polymeric adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chains on itself. Next the chromatin remodeler ALC1 quickly attaches to the product of PARP1 action, a poly-ADP ribose chain, and ALC1 completes arrival at the DNA damage within 10 seconds of the occurrence of the damage. About half of the maximum chromatin relaxation, presumably due to action of ALC1, occurs by 10 seconds. This then allows recruitment of the DNA repair enzyme MRE11, to initiate DNA repair, within 13 seconds.
γH2AX, the phosphorylated form of H2AX is also involved in the early steps leading to chromatin decondensation after DNA double-strand breaks. The histone variant H2AX constitutes about 10% of the H2A histones in human chromatin. γH2AX (H2AX phosphorylated on serine 139) can be detected as soon as 20 seconds after irradiation of cells (with DNA double-strand break formation), and half maximum accumulation of γH2AX occurs in one minute. The extent of chromatin with phosphorylated γH2AX is about two million base pairs at the site of a DNA double-strand break. γH2AX does not, itself, cause chromatin decondensation, but within 30 seconds of irradiation, RNF8 protein can be detected in association with γH2AX. RNF8 mediates extensive chromatin decondensation, through its subsequent interaction with CHD4, a component of the nucleosome remodeling and deacetylase complex NuRD.
DDB2 occurs in a heterodimeric complex with DDB1. This complex further complexes with the ubiquitin ligase protein CUL4A and with PARP1. This larger complex rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds. The PARP1 protein, attached to both DDB1 and DDB2, then PARylates (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein ALC1. Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the nucleotide excision repair pathway to enter the chromatin and repair UV-induced cyclobutane pyrimidine dimer damages.
After rapid chromatin remodeling, cell cycle checkpoints are activated to allow DNA repair to occur before the cell cycle progresses. First, two kinases, ATM and ATR are activated within 5 or 6 minutes after DNA is damaged. This is followed by phosphorylation of the cell cycle checkpoint protein Chk1, initiating its function, about 10 minutes after DNA is damaged.
=== DNA damage response ===
In the DNA damage response (DDR), cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure, whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified. These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.
DNA damage checkpoint is a signal transduction pathway that blocks cell cycle progression in G1, G2 and metaphase and slows down the rate of S phase progression when DNA is damaged. It leads to a pause in cell cycle allowing the cell time to repair the damage before continuing to divide.
Checkpoint Proteins can be separated into four groups: phosphatidylinositol 3-kinase (PI3K)-like protein kinase, proliferating cell nuclear antigen (PCNA)-like group, two serine/threonine(S/T) kinases and their adaptors. Central to all DNA damage induced checkpoints responses is a pair of large protein kinases belonging to the first group of PI3K-like protein kinases-the ATM (Ataxia telangiectasia mutated) and ATR (Ataxia- and Rad-related) kinases, whose sequence and functions have been well conserved in evolution. All DNA damage response requires either ATM or ATR because they have the ability to bind to the chromosomes at the site of DNA damage, together with accessory proteins that are platforms on which DNA damage response components and DNA repair complexes can be assembled.
An important downstream target of ATM and ATR is p53, as it is required for inducing apoptosis following DNA damage. The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and p53-independent mechanisms and can arrest the cell cycle at the G1/S and G2/M checkpoints by deactivating cyclin/cyclin-dependent kinase complexes.
=== The prokaryotic SOS response ===
The SOS response is the changes in gene expression in Escherichia coli and other bacteria in response to extensive DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA. The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS boxes. In Escherichia coli it is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes. The SOS response is known to be widespread in the Bacteria domain, but it is mostly absent in some bacterial phyla, like the Spirochetes.
The most common cellular signals activating the SOS response are regions of single-stranded DNA (ssDNA), arising from stalled replication forks or double-strand breaks, which are processed by DNA helicase to separate the two DNA strands. In the initiation step, RecA protein binds to ssDNA in an ATP hydrolysis driven reaction creating RecA–ssDNA filaments. RecA–ssDNA filaments activate LexA autoprotease activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation. The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.
In Escherichia coli, SOS boxes are 20-nucleotide long sequences near promoters with palindromic structure and a high degree of sequence conservation. In other classes and phyla, the sequence of SOS boxes varies considerably, with different length and composition, but it is always highly conserved and one of the strongest short signals in the genome. The high information content of SOS boxes permits differential binding of LexA to different promoters and allows for timing of the SOS response. The lesion repair genes are induced at the beginning of SOS response. The error-prone translesion polymerases, for example, UmuCD'2 (also called DNA polymerase V), are induced later on as a last resort. Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer, which then binds to the SOS boxes near promoters and restores normal gene expression.
=== Eukaryotic transcriptional responses to DNA damage ===
Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed among different organs that have evolved different sensitivities to DNA damage.
In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay, and many others. A large amount of damage to a cell leaves it with an important decision: undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival that will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase η are members of Y family translesion DNA polymerases present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.
== Aging ==
=== Pathological effects of poor DNA repair ===
Experimental animals with genetic deficiencies in DNA repair often show decreased life span and increased cancer incidence. For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get lymphoma and infections more often, and, as a consequence, have shorter lifespans than wild-type mice. In similar manner, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan. However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened life span without correspondingly higher rates of mutation.
The maximum life spans of mice, naked mole-rats and humans are respectively ~3, ~30 and ~129 years. Of these, the shortest lived species, mouse, expresses DNA repair genes, including core genes in several DNA repair pathways, at a lower level than do humans and naked mole rats. Furthermore several DNA repair pathways in humans and naked mole-rats are up-regulated compared to mouse. These observations suggest that elevated DNA repair facilitates greater longevity.
If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis, or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging, increased sensitivity to carcinogens and correspondingly increased cancer risk (see below). On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus radiodurans, the most radiation-resistant known organism, exhibit remarkable resistance to the double-strand break-inducing effects of radioactivity, likely due to enhanced efficiency of DNA repair and especially NHEJ.
=== Longevity and caloric restriction ===
A number of individual genes have been identified as influencing variations in life span within a population of organisms. The effects of these genes is strongly dependent on the environment, in particular, on the organism's diet. Caloric restriction reproducibly results in extended lifespan in a variety of organisms, likely via nutrient sensing pathways and decreased metabolic rate. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction. Several agents reported to have anti-aging properties have been shown to attenuate constitutive level of mTOR signaling, an evidence of reduction of metabolic activity, and concurrently to reduce constitutive level of DNA damage induced by endogenously generated reactive oxygen species.
For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan. The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction. Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents, although similar effects have not been observed in mitochondrial DNA.
The C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended life span under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction. This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.
== Medicine and DNA repair modulation ==
=== Hereditary DNA repair disorders ===
Defects in the NER mechanism are responsible for several genetic disorders, including:
Xeroderma pigmentosum: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and premature aging
Cockayne syndrome: hypersensitivity to UV and chemical agents
Trichothiodystrophy: sensitive skin, brittle hair and nails
Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.
Other DNA repair disorders include:
Werner's syndrome: premature aging and retarded growth
Bloom's syndrome: sunlight hypersensitivity, high incidence of malignancies (especially leukemias).
Ataxia telangiectasia: sensitivity to ionizing radiation and some chemical agents
All of the above diseases are often called "segmental progerias" ("accelerated aging diseases") because those affected appear elderly and experience aging-related diseases at an abnormally young age, while not manifesting all the symptoms of old age.
Other diseases associated with reduced DNA repair function include Fanconi anemia, hereditary breast cancer and hereditary colon cancer.
== Cancer ==
Because of inherent limitations in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. There are at least 34 Inherited human DNA repair gene mutations that increase cancer risk. Many of these mutations cause DNA repair to be less effective than normal. In particular, Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA1 and BRCA2, two important genes whose mutations confer a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.
Cancer therapy procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing – most typically cancer cells – are preferentially affected. The side-effect is that other non-cancerous but rapidly dividing cells such as progenitor cells in the gut, skin, and hematopoietic system are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body). In the context of therapies targeting DNA damage response genes, the latter approach has been termed 'synthetic lethality'.
Perhaps the most well-known of these 'synthetic lethality' drugs is the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor olaparib, which was approved by the Food and Drug Administration in 2015 for the treatment in women of BRCA-defective ovarian cancer. Tumor cells with partial loss of DNA damage response (specifically, homologous recombination repair) are dependent on another mechanism – single-strand break repair – which is a mechanism consisting, in part, of the PARP1 gene product. Olaparib is combined with chemotherapeutics to inhibit single-strand break repair induced by DNA damage caused by the co-administered chemotherapy. Tumor cells relying on this residual DNA repair mechanism are unable to repair the damage and hence are not able to survive and proliferate, whereas normal cells can repair the damage with the functioning homologous recombination mechanism.
Many other drugs for use against other residual DNA repair mechanisms commonly found in cancer are currently under investigation. However, synthetic lethality therapeutic approaches have been questioned due to emerging evidence of acquired resistance, achieved through rewiring of DNA damage response pathways and reversion of previously inhibited defects.
=== DNA repair defects in cancer ===
Studies have shown that the DNA damage response acts as a barrier to the malignant transformation of preneoplastic cells. Early studies have shown an elevated DNA damage response in cell-culture models with oncogene activation, and preneoplastic colon adenomas. DNA damage response mechanisms trigger cell-cycle arrest, and attempt to repair DNA lesions or promote cell death/senescence if repair is not possible. Replication stress is observed in preneoplastic cells due to increased proliferation signals from oncogenic mutations. Replication stress is characterized by: increased replication initiation/origin firing; increased transcription and collisions of transcription-replication complexes; nucleotide deficiency; increase in reactive oxygen species (ROS).
Replication stress, along with the selection for inactivating mutations in DNA damage response genes in the evolution of the tumor, leads to downregulation and/or loss of some DNA damage response mechanisms, and hence loss of DNA repair and/or senescence/programmed cell death. In experimental mouse models, loss of DNA damage response-mediated cell senescence was observed after using a short hairpin RNA (shRNA) to inhibit the double-strand break response kinase ataxia telangiectasia (ATM), leading to increased tumor size and invasiveness. Humans born with inherited defects in DNA repair mechanisms (for example, Li-Fraumeni syndrome) have a higher cancer risk.
The prevalence of DNA damage response mutations differs across cancer types; for example, 30% of breast invasive carcinomas have mutations in genes involved in homologous recombination. In cancer, downregulation is observed across all DNA damage response mechanisms (base excision repair (BER), nucleotide excision repair (NER), DNA mismatch repair (MMR), homologous recombination repair (HR), non-homologous end joining (NHEJ) and translesion DNA synthesis (TLS). As well as mutations to DNA damage repair genes, mutations also arise in the genes responsible for arresting the cell cycle to allow sufficient time for DNA repair to occur, and some genes are involved in both DNA damage repair and cell cycle checkpoint control, for example ATM and checkpoint kinase 2 (CHEK2) – a tumor suppressor that is often absent or downregulated in non-small cell lung cancer.
=== Epigenetic DNA repair defects in cancer ===
Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal aberrations. However, it has become apparent that cancer is also driven by epigenetic alterations.
Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification, changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1) and changes caused by microRNAs. Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes usually remain through cell divisions, last for multiple cell generations, and can be considered to be epimutations (equivalent to mutations).
While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, appear to be particularly important. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.
Reduced expression of DNA repair genes causes deficient DNA repair. When DNA repair is deficient DNA damages remain in cells at a higher than usual level and these excess damages cause increased frequencies of mutation or epimutation. Mutation rates increase substantially in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.
Higher levels of DNA damage not only cause increased mutation, but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.
Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations). However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.
=== Frequencies of epimutations in DNA repair genes ===
Deficiencies in DNA repair enzymes are occasionally caused by a newly arising somatic mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. For example, when 113 colorectal cancers were examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.
Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.
In a further example, epigenetic defects were found in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in the expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of 49 colon cancers evaluated by Facista et al.
The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.
Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Review articles, and broad experimental survey articles also document most of these epigenetic DNA repair deficiencies in cancers.
Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see translesion synthesis) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to carcinogenesis.
The two gray-highlighted genes RAD51 and BRCA2, are required for homologous recombinational repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. As indicated in the Wikipedia articles on RAD51 and BRCA2, such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of RAD51 and BRCA2 seen in these cancers may reflect selective pressures for compensatory RAD51 or BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where RAD51 or BRCA2 are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis) could cause increased mutations and cancer, so that under-expression of RAD51 or BRCA2 would be carcinogenic in itself.
Cyan-highlighted genes are in the microhomology-mediated end joining (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone inaccurate repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5–25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway. FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung. PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer and BRCA-mutated serous ovarian cancer. Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are also shown in cyan.
=== Genome-wide distribution of DNA repair in human somatic cells ===
Differential activity of DNA repair pathways across various regions of the human genome causes mutations to be very unevenly distributed within tumor genomes. In particular, the gene-rich, early-replicating regions of the human genome exhibit lower mutation frequencies than the gene-poor, late-replicating heterochromatin. One mechanism underlying this involves the histone modification H3K36me3, which can recruit mismatch repair proteins, thereby lowering mutation rates in H3K36me3-marked regions. Another important mechanism concerns nucleotide excision repair, which can be recruited by the transcription machinery, lowering somatic mutation rates in active genes and other open chromatin regions.
== Epigenetic alterations due to DNA repair ==
Damage to DNA is very common and is constantly being repaired. Epigenetic alterations can accompany DNA repair of oxidative damage or double-strand breaks. In human cells, oxidative DNA damage occurs about 10,000 times a day and DNA double-strand breaks occur about 10 to 50 times a cell cycle in somatic replicating cells (see DNA damage (naturally occurring)). The selective advantage of DNA repair is to allow the cell to survive in the face of DNA damage. The selective advantage of epigenetic alterations that occur with DNA repair is not clear.
=== Repair of oxidative DNA damage can alter epigenetic markers ===
In the steady state (with endogenous damages occurring and being repaired), there are about 2,400 oxidatively damaged guanines that form 8-oxo-2'-deoxyguanosine (8-OHdG) in the average mammalian cell DNA. 8-OHdG constitutes about 5% of the oxidative damages commonly present in DNA. The oxidized guanines do not occur randomly among all guanines in DNA. There is a sequence preference for the guanine at a methylated CpG site (a cytosine followed by guanine along its 5' → 3' direction and where the cytosine is methylated (5-mCpG)). A 5-mCpG site has the lowest ionization potential for guanine oxidation.
Oxidized guanine has mispairing potential and is mutagenic. Oxoguanine glycosylase (OGG1) is the primary enzyme responsible for the excision of the oxidized guanine during DNA repair. OGG1 finds and binds to an 8-OHdG within a few seconds. However, OGG1 does not immediately excise 8-OHdG. In HeLa cells half maximum removal of 8-OHdG occurs in 30 minutes, and in irradiated mice, the 8-OHdGs induced in the mouse liver are removed with a half-life of 11 minutes.
When OGG1 is present at an oxidized guanine within a methylated CpG site it recruits TET1 to the 8-OHdG lesion (see Figure). This allows TET1 to demethylate an adjacent methylated cytosine. Demethylation of cytosine is an epigenetic alteration.
As an example, when human mammary epithelial cells were treated with H2O2 for six hours, 8-OHdG increased about 3.5-fold in DNA and this caused about 80% demethylation of the 5-methylcytosines in the genome. Demethylation of CpGs in a gene promoter by TET enzyme activity increases transcription of the gene into messenger RNA. In cells treated with H2O2, one particular gene was examined, BACE1. The methylation level of the BACE1 CpG island was reduced (an epigenetic alteration) and this allowed about 6.5 fold increase of expression of BACE1 messenger RNA.
While six-hour incubation with H2O2 causes considerable demethylation of 5-mCpG sites, shorter times of H2O2 incubation appear to promote other epigenetic alterations. Treatment of cells with H2O2 for 30 minutes causes the mismatch repair protein heterodimer MSH2-MSH6 to recruit DNA methyltransferase 1 (DNMT1) to sites of some kinds of oxidative DNA damage. This could cause increased methylation of cytosines (epigenetic alterations) at these locations.
Jiang et al. treated HEK 293 cells with agents causing oxidative DNA damage, (potassium bromate (KBrO3) or potassium chromate (K2CrO4)). Base excision repair (BER) of oxidative damage occurred with the DNA repair enzyme polymerase beta localizing to oxidized guanines. Polymerase beta is the main human polymerase in short-patch BER of oxidative DNA damage. Jiang et al. also found that polymerase beta recruited the DNA methyltransferase protein DNMT3b to BER repair sites. They then evaluated the methylation pattern at the single nucleotide level in a small region of DNA including the promoter region and the early transcription region of the BRCA1 gene. Oxidative DNA damage from bromate modulated the DNA methylation pattern (caused epigenetic alterations) at CpG sites within the region of DNA studied. In untreated cells, CpGs located at −189, −134, −29, −19, +16, and +19 of the BRCA1 gene had methylated cytosines (where numbering is from the messenger RNA transcription start site, and negative numbers indicate nucleotides in the upstream promoter region). Bromate treatment-induced oxidation resulted in the loss of cytosine methylation at −189, −134, +16 and +19 while also leading to the formation of new methylation at the CpGs located at −80, −55, −21 and +8 after DNA repair was allowed.
=== Homologous recombinational repair alters epigenetic markers ===
At least four articles report the recruitment of DNA methyltransferase 1 (DNMT1) to sites of DNA double-strand breaks. During homologous recombinational repair (HR) of the double-strand break, the involvement of DNMT1 causes the two repaired strands of DNA to have different levels of methylated cytosines. One strand becomes frequently methylated at about 21 CpG sites downstream of the repaired double-strand break. The other DNA strand loses methylation at about six CpG sites that were previously methylated downstream of the double-strand break, as well as losing methylation at about five CpG sites that were previously methylated upstream of the double-strand break. When the chromosome is replicated, this gives rise to one daughter chromosome that is heavily methylated downstream of the previous break site and one that is unmethylated in the region both upstream and downstream of the previous break site. With respect to the gene that was broken by the double-strand break, half of the progeny cells express that gene at a high level and in the other half of the progeny cells expression of that gene is repressed. When clones of these cells were maintained for three years, the new methylation patterns were maintained over that time period.
In mice with a CRISPR-mediated homology-directed recombination insertion in their genome there were a large number of increased methylations of CpG sites within the double-strand break-associated insertion.
=== Non-homologous end joining can cause some epigenetic marker alterations ===
Non-homologous end joining (NHEJ) repair of a double-strand break can cause a small number of demethylations of pre-existing cytosine DNA methylations downstream of the repaired double-strand break. Further work by Allen et al. showed that NHEJ of a DNA double-strand break in a cell could give rise to some progeny cells having repressed expression of the gene harboring the initial double-strand break and some progeny having high expression of that gene due to epigenetic alterations associated with NHEJ repair. The frequency of epigenetic alterations causing repression of a gene after an NHEJ repair of a DNA double-strand break in that gene may be about 0.9%.
== Evolution ==
The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophages (viruses which infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms. The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.
The fossil record indicates that single-cell life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear. Nucleic acids became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich atmosphere (known as the "oxygen catastrophe") due to photosynthetic organisms, as well as the presence of potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by oxidative stress. The mechanism by which this came about, however, is unclear.
=== Rate of evolutionary change ===
On some occasions, DNA damage is not repaired or is repaired by an error-prone mechanism that results in a change from the original sequence. When this occurs, mutations may propagate into the genomes of the cell's progeny. Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential to be passed on to the organism's offspring. The rate of evolution in a particular species (or, in a particular gene) is a function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change. DNA damage protection and repair does not influence the rate of adaptation by gene regulation and by recombination and selection of alleles. On the other hand, DNA damage repair and protection does influence the rate of accumulation of irreparable, advantageous, code expanding, inheritable mutations, and slows down the evolutionary mechanism for expansion of the genome of organisms with new functionalities. The tension between evolvability and mutation repair and protection needs further investigation.
== Technology ==
A technology named clustered regularly interspaced short palindromic repeat (shortened to CRISPR-Cas9) was discovered in 2012. The new technology allows anyone with molecular biology training to alter the genes of any species with precision, by inducing DNA damage at a specific point and then altering DNA repair mechanisms to insert new genes. It is cheaper, more efficient, and more precise than other technologies. With the help of CRISPR–Cas9, parts of a genome can be edited by scientists by removing, adding, or altering parts in a DNA sequence.
== See also ==
== References ==
== External links ==
Media related to DNA repair at Wikimedia Commons
Roswell Park Cancer Institute DNA Repair Lectures
A comprehensive list of Human DNA Repair Genes
3D structures of some DNA repair enzymes
Machado CR, Menck CF (December 1997). "Human DNA repair diseases: From genome instability to cancer". Braz. J. Genet. 20 (4): 755–762. doi:10.1590/S0100-84551997000400032.
DNA repair special interest group
DNA Repair Archived 12 February 2018 at the Wayback Machine
DNA Damage and DNA Repair
Segmental Progeria
Hakem R (February 2008). "DNA-damage repair; the good, the bad, and the ugly". EMBO J. 27 (4): 589–605. doi:10.1038/emboj.2008.15. PMC 2262034. PMID 18285820.
Morales ME, Derbes RS, Ade CM, Ortego JC, Stark J, Deininger PL, et al. (2016). "Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes". PLOS ONE. 11 (3): e0151367. Bibcode:2016PLoSO..1151367M. doi:10.1371/journal.pone.0151367. PMC 4788447. PMID 26966913. | Wikipedia/DNA_damage |
Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.
== Treatment of acute symptoms ==
Examples of specific antimigraine drug classes include triptans (first line option), ergot alkaloids, ditans and gepants. Migraines can also be treated with unspecific analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen. Opioids are not recommended for treatment of migraines.
=== Triptans ===
The triptan drug class includes 1st generation sumatriptan (which has poor bioavailability), and second generation zolmitriptan. Due to their safety, efficacy and selectivity, triptans are considered first line agents for abortion of migraines. These medications are selective 5-HT1B/1D receptor agonists with some activity at 5-HT1F. They produce an antimigraine effect by vasoconstriction of the vessels in the brain, as well as inhibiting trigeminal CGRP release and pain transmission. They are normally well tolerated but the vasoconstrictor effects can lead to problematic side effects such as nausea, dizziness and chest discomfort, and therefore require caution in patients with cardiovascular disease. There is also an increased risk of gastrointestinal adverse events. Triptans use is limited to less than ten times per month in order to reduce Medication Overuse Headache (MOH).
=== Ergots alkaloids ===
Ergot alkaloids include ergotamine and dihydroergotamine. This medication class targets the CGRP receptor pathway due to their likeness to serotonin, dopamine and noradrenaline. They show activity at serotonin 5-HT1-2, dopamine D2-like and alpha1/alpha2-adrenoreceptors. Their lack of selectivity leads to more adverse effects, making them second line compared to triptans. However, they have been shown to prevent recurrence better than triptans. Adverse effects include nausea, vomiting, paresthesia, and ergotism. Their use is limited to less than ten times per month in order to reduce medication overuse headaches (MOH's). The oral dosage administrative form is considered less effective than nasal or parenteral forms and has been discontinued in Canada. Ergotamine is contraindicated during pregnancy.
=== Ditans ===
Ditans (eg. lasmiditan) are a new group of anti migraine drugs which were developed due some of the concerns with the 1st line triptans (eg. adverse effects, concern with use in cardiovascular disease, use of less than 10x per month to reduce MOH). Ditans are 5-HT1F receptors agonists. Lasmiditan has been suggested to have less pain relief when compared to the triptans at the 2 hour mark post taking the medication. Lasmiditan was shown to have higher adverse events (dizziness, fatigue and nausea) than the triptans or another novel medication class, CGRP antagonists. However, they could be an option for patients with cardiovascular risks due to their lack of vasoconstriction . Due to risk of dizziness, those who take lasmiditan should avoid driving 8 hours after taking.
=== Gepants ===
Gepants (eg. rimegepant, ubrogepant, and atogepant) are also a new group of anti migraine drugs, along with ditans. They are calcitonin gene-related peptide (CGRP) receptor antagonists. Gepants have been suggested to have less pain relief at 2 hours compared to triptans. Similar to ditans, they offer another therapy option that does not include vasoconstriction, thus may be suitable for those with cardiovascular risk factors. They are well tolerated with fewer adverse effects compared to triptans .
=== NSAIDS ===
NSAIDS are a nonspecific medication used for abortion of migraines due to their analgesic properties. They can be used for mild to moderate migraines, but are less effective against severe migraines. Similar to the triptans and ergots alkaloids, their use should be limited to less than 10x per month to reduce MOH. Acetaminophen is an analgesic that can also be used, but NSAIDS should be tried first due to their anti-inflammatory properties. However, acetaminophen would be considered first line in pregnant patients. Combination therapy of an NSAID with a triptan can be used when either medication is insufficient alone for migraine relief or recurrence . Long term NSAID use has risks including nephrotoxicity and cardiotoxicity, and long term acetaminophen use is associated with hepatoxicity. If warranted, an antiemetic can be used in combination with an NSAID.
=== Opioids ===
Opioids are not recommended for treatment of acute migraines due to their significant side effect profile, including twice the risk of medication overuse headache when compared to NSAIDS, acetaminophen or triptans. In addition, their strength of efficacy has shown to be low or insufficient for pain relief of migraines. Importantly, there is also risk of addiction and opioid use disorder.
== Prevention ==
For patients who require preventive therapy with symptoms such as more than 4 migraines per month or migraines lasting longer than 12 hours, first-line drugs for the prevention of migraine attacks include beta blockers, antidepressants, and anti convulsants.
=== Serotonin antagonists ===
Non-selective serotonin receptor antagonists like methysergide, pizotifen, and cyproheptadine are used to prevent migraines. Their antimigraine effects may be due specifically to serotonin 5-HT2B receptor blockade.
=== Beta Blockers ===
Beta blockers have been deemed effective options for the prevention of migraines. In particular, metoprolol, timolol and propranolol have the most strength of efficacy. The timeframe to effectiveness in generally within 3 months. Patients with cardiovascular risk factors should avoid the use of beta blockers for migraine prevention.
=== Antidepressants ===
Antidepressants are suggested to be both efficacious and tolerable in the treatment of migraine prevention for both migraine frequency and migraine index. The exact mechanism of action is unknown but seems to be related to serotonin's impact on migraine. In particular, amitryptyline (a tricyclic antidepressant) has the most evidence to suggest its efficacy. Selective serotonin reuptake inhibitors (SSRIs) as well Serotonin–norepinephrine reuptake inhibitors (SNRIs) are likely effective as well, but more studies are required in order to provide more evidence. Adverse events of antidepressants can include fatigue, nausea, drowsiness, dizziness, dry mouth, GI upset and weakness. Sedation is also common.
=== Anticonvulsants ===
Both sodium valproate and divalproex sodium have been established as efficacious for migraine prophylaxis. They are well tolerated short term, but should be monitored during long term therapy because of risks of pancreatitis, liver failure and teratogenicity. Valproate should not be used in females of childbearing age because studies suggest that children exposed to valproate in the prenatal period are associated with having lower IQ scores. Topiramate is another anticonvulsant with therapeutic efficacy in migraine prophylaxis. It is a safe medication but should be used in caution in females of childbearing ages because it is suggested to cause birth defects.
=== Calcitonin gene receptor peptide (CGRP) antagonists ===
CGRP antagonists can be used for both acute migraine treatment as well as prophylactically. CGRP is a neuropeptide which is thought to induce migraines via vasodilation of cranial arteries. CGRP can also release inflammatory agents and cause nervous system sensitization. It is theorized that by antagonizing the CGRP receptor of the trigeminal ganglia, lowered CGRP is released and less migraine occurs. Erenumab is a highly selective human monoclonal antibody which is a promising new development in migraine treatment. It has low risk of hepatoxicity like gepants can have, due to being mostly eliminated via proteolysis.
=== Melatonin ===
There have been some studies suggesting the benefit of using melatonin for prophylaxis of migraine, however, there is a lack of strength of evidence due to a low number of studies as well as conflicting results. Melatonin has a good safety profile but there have been rare instances of serious side effects. More studies are needed in order to suggest the therapeutic use of melatonin for prophylaxis of migraine.
== Prophylaxis in pediatric patients ==
There is not a strong degree of evidence for the use of anti migraine drugs prophylactically in children and adolescence. It is highly important to consider risk vs benefit when considering their use in the paediatric population.
== References == | Wikipedia/Antimigraine_drug |
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