Most other forms of  toxicology testing  are also bioassays. Animals or cell cultures may be put under a number of levels of a suspected toxin to ascertain whether the substance causes harmful changes and at what level it does so. The  LD 50  value, a common measure of acute toxicity, describes the dose at which a substance is lethal to 50% of tested animals. [ 14 ]


The potency of a drug may be measured using a bioassay. [ 15 ]


Environmental bioassays are generally a broad-range survey of  toxicity . [ 16 ]  A toxicity identification evaluation is conducted to determine what the relevant  toxicants  are. Although bioassays are beneficial in determining the biological activity within an organism, they can often be time-consuming and laborious. Organism-specific factors may result in data that are not applicable to others in that species. For these reasons, other biological techniques are often employed, including  radioimmunoassays .  See  bioindicator .


Water pollution  control requirements in the United States require some industrial dischargers and municipal  sewage treatment  plants to conduct bioassays. These procedures, called  whole effluent toxicity  tests, include acute toxicity tests as well as chronic test methods. [ 5 ]  The methods involve exposing living aquatic organisms to samples of wastewater for a specific length of time. [ 17 ] [ 18 ]  Another example is the bioassay ECOTOX, which uses the microalgae  Euglena gracilis  to test the toxicity of water samples. [ 19 ]  ( See   Bioindicator#Microalgae in water quality )


A  biological target  is anything within a living organism to which some other entity (like an endogenous  ligand  or a  drug ) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets are  proteins  and  nucleic acids . The definition is context-dependent, and can refer to the biological target of a   pharmacologically active   drug   compound , the receptor target of a  hormone  (like  insulin ), or some other target of an external stimulus.  Biological targets are most commonly proteins such as  enzymes ,  ion channels , and  receptors .


The external stimulus ( i.e. , the drug or ligand) physically binds to ("hits") the biological target. [ 1 ] [ 2 ]  The interaction between the substance and the target may be:


Depending on the nature of the stimulus, the following can occur: [ 3 ]


The term "biological target" is frequently used in  pharmaceutical  research to describe the native protein in the body whose activity is modified by a drug resulting in a specific effect, which may be a desirable  therapeutic effect  or an unwanted  adverse effect .  In this context, the biological target is often referred to as a  drug target . The most common drug targets of currently marketed drugs include: [ 4 ] [ 5 ] [ 6 ]


Identifying the biological origin of a disease, and the potential targets for intervention, is the first step in the discovery of a medicine using the  reverse pharmacology  approach. Potential drug targets are not necessarily disease causing but must by definition be disease modifying. [ 8 ]   An alternative means of identifying new drug targets is  forward pharmacology  based on phenotypic screening to identify "orphan" ligands [ 9 ]  whose targets are subsequently identified through target deconvolution. [ 10 ] [ 11 ] [ 12 ]


Databases containing biological targets information:


These biological targets are conserved across species, making pharmaceutical pollution of the environment a danger to species who possess the same targets. [ 13 ]  For example, the synthetic  estrogen  in human  contraceptives ,  17-R-ethinylestradiol , has been shown to increase the  feminization  of fish downstream from sewage treatment plants, thereby unbalancing reproduction and creating an additional  selective pressure  on fish survival. [ 14 ]  Pharmaceuticals are usually found at ng/L to low-μg/L concentrations in the aquatic environment. [ 15 ]  Adverse effects may occur in non-target species as a consequence of specific drug target interactions. [ 16 ]  Therefore,  evolutionarily well-conserved  drug targets are likely to be associated with an increased risk for non-targeted pharmacological effects. [ 13 ]


A  British Approved Name  ( BAN ) is the official, non-proprietary, or generic name given to a  pharmaceutical   substance , as defined in the  British Pharmacopoeia (BP) . [ 1 ]  The BAN is also the official name used in some countries around the world, because starting in 1953, proposed new names were evaluated by a panel of experts from  WHO  in conjunction with the BP commission  to ensure naming consistency worldwide [ 2 ]  (an effort leading to the  International Nonproprietary Name  system). There is also a  British Approved Name (Modified)  ( BANM ). [ 3 ]


BANs are unique in that names are assigned for combination preparations as well as single-drug preparations. For example, the BAN  co-amoxiclav  is assigned to preparations containing  amoxicillin  and  clavulanic acid . Most other pharmacopoeias simply refer to combination products by both ingredients in the preparation, in this example "amoxicillin with clavulanic acid".


The prefix of "co-" is used for many combination drugs, including opioid with paracetamol or aspirin  analgesics  (e.g.,  co-codamol ,  co-codaprin ,  co-dydramol ,  co-proxamol ); the  anti-diarrhoeal , non-analgesic mixture of  diphenoxylate  and  atropine ,  co-phenotrope  (trade name  Lomotil );  antibiotics  (e.g.,  co-fluampicil  and  co-trimoxazole );  antihypertensives  (e.g.,  co-tenidone );  diuretics  (e.g.,  co-amilofruse  and  co-amilozide );  gastrointestinal  drugs (e.g.,  co-danthrusate ); and anti- Parkinsonism  agents such as  co-careldopa ,  co-beneldopa , and  co-cyprindiol . [ citation needed ]


European Union  legislation from 2001 required harmonisation of the BP with the  European Pharmacopoeia (EP) , as well as the adoption of  International Nonproprietary Names  through directives (2001/82/EC [ 4 ]  and 2001/83/EC, [ 5 ]  as amended, and 2003/63/EC [ 6 ] ). Across the EU has meant that, with the notable exception of  adrenaline/epinephrine , [ 7 ]  BANs are now the same as the INNs. For example, the old BAN  methicillin  was replaced with the current BAN  meticillin , matching the INN.


This has resulted in an interesting situation in other countries that use BANs. While the British Pharmacopoeia and BANs are the official pharmacopoeia/names defined by legislation in many of these countries, the former BANs often continue to be used, purportedly because of the difficulty of changeover.  Despite the importance of the BP, there appears to be little or no movement in the direction of changing these names. In Australia, the  Australian Approved Names  are generally the same as BANs, but a few exceptions remain.


Cinacalcet , sold under the brand name  Sensipar  among others, is a medication used to treat  primary hyperparathyroidism ,  tertiary hyperparathyroidism  and  parathyroid carcinoma . [ 4 ] [ 6 ] [ 5 ]  Cinacalcet acts as a  calcimimetic  (i.e., it mimics the action of  calcium  on  tissues ) by  allosteric  activation of the  calcium-sensing receptor  that is expressed in various human organ tissues.


The most common side effects include  nausea  and  vomiting . [ 5 ]


Cinacalcet was approved in the United States in March 2004, [ 4 ] [ 7 ] [ 8 ]  and in the European Union in October 2004. [ 5 ] [ 3 ]  It was the first allosteric G protein-coupled receptor modulator to enter the pharmaceutical market. [ 9 ]  In 2013, cinacalcet was the 76th most prescribed medicine in the United States. [ 10 ] [ 11 ]


In the United States, cinacalcet is indicated for the treatment of  secondary hyperparathyroidism  in people with chronic kidney disease on dialysis and  hypercalcemia  in people with parathyroid carcinoma. [ 4 ] [ 12 ]  Cinacalcet can also be used to treat severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo  parathyroidectomy . [ 4 ] [ 13 ]


In the European Union cinacalcet is indicated for:


Cinacalcet has pregnancy category C in the US, meaning that adequate and well-controlled studies involving cinacalcet in pregnant women have not been done. [ 4 ] [ 1 ]


Studies have not been done in lactating women; therefore, it is not known whether cinacalcet is excreted into human milk. [ 4 ] [ 1 ]


Hypocalcemia  (decreased calcium levels) is a contraindication to the use of cinacalcet. Those who have serum calcium levels less than 7.5 mg/dL should not be started on cinacalcet. Hypocalcemia symptoms include  paresthesias ,  myalgias , muscle cramping,  tetany , and  convulsions . Cinacalcet should not be administered until serum calcium levels are above 8.0 mg/dL and/or hypocalcemia symptoms are resolved. [ 4 ]  Cinacalcet is not approved for pediatric use in the United States. [ 6 ] [ 4 ] [ 5 ]


Common side effects of cinacalcet include upset stomach, vomiting, diarrhea, dizziness, nausea, weakness, and chest pain. [ 13 ]


Clinical trials conducted in the United States by Amgen to determine whether the drug is safe in children were halted by the U.S.  Food and Drug Administration  (FDA) in February 2013, following the death of a 14-year-old participant. [ 6 ] [ 14 ]


Serious side effects, including overdose symptoms, of cinacalcet include: [ 13 ]


Cinacalcet is a strong inhibitor of the liver enzyme  CYP2D6  and is partially metabolized by  CYP3A4  and  CYP1A2 . Dose adjustments may be necessary if people are treated with CYP3A4 and CYP1A2 inhibitors and medications that are metabolized by CYP2D6. [ 4 ] [ 3 ]


Cinacalcet is a drug that acts as a  calcimimetic [ 4 ] [ 5 ]  (i.e. it mimics the action of calcium on tissues) by  allosteric activation  of the  calcium-sensing receptor  that is expressed in various human organ tissues. The calcium-sensing receptors on the surface of the chief cell of the  parathyroid gland  is the principal negative regulator of parathyroid hormone secretion. [ 15 ]  Cinacalcet increases the sensitivity of calcium receptors on parathyroid cells to reduce parathyroid hormone (PTH) levels and thus decrease serum calcium levels. [ 12 ]


In the field of  drug discovery ,  classical pharmacology , [ 1 ]  also known as  forward pharmacology , [ 2 ] [ 3 ] [ 4 ]  or  phenotypic drug discovery  (PDD), [ 5 ]  relies on  phenotypic screening  (screening in intact cells or whole organisms) of  chemical libraries  of synthetic  small molecules ,  natural products  or  extracts  to identify substances that have a desirable  therapeutic  effect. Using the techniques of  medicinal chemistry , the potency, selectivity, and other properties of these screening hits are optimized to produce candidate drugs.


Classical pharmacology traditionally has been the basis for the discovery of new drugs.  Compounds are screened in cellular or animal models of disease to identify compounds that cause a desirable change in phenotype.  Only after the compounds have been discovered, an effort is made to determine the  biological target  of the compounds through target validation experiments often involving  chemoproteomics . More recently it has become popular to develop a hypothesis that a certain biological target is disease modifying and  screen  for compounds that modulate the activity of this purified target.  Afterwards, these compounds are tested in animals to see if they have the desired effect.  This approach is known as " reverse pharmacology " [ 1 ]  or "target based drug discovery" (TDD). [ 5 ]  However, recent statistical analysis reveals that a disproportionate number of first-in-class drugs with novel mechanisms of action come from phenotypic screening, [ 6 ]  which has led to a resurgence of interest in this method. [ 7 ]


Pharmacognosy , the investigation of botanics used in indigenous medical traditions is essentially classical pharmacology. Pharmacognosy and classical pharmacology are both often contrasted with  reverse pharmacology , that is, working from the target backward to identify new drugs starting with screening libraries of compounds for affinity for particular target. In pharmacognosy,  folk medicines  are first tested in clinical trials for efficacy.  Only after efficacy has been established, is an effort made to determine the biologic target of the drug.


Clozapine  N -oxide  (CNO) is a synthetic  drug  used mainly in  biomedical research  as a  ligand  to activate  Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) , [ 1 ]  despite the initial belief that it was biologically inert. However, it has been shown to not enter the brain after administration [ 2 ]  and to reverse metabolize in peripheral tissues to form clozapine. Clozapine can bind to a number of different serotonergic, dopaminergic and adrenergic receptors within the brain. [ 3 ]  These off-target effects mean behavioral data using the CNO-DREADD system have to be interpreted with caution. [ 4 ]


Alternatives to CNO with more affinity, more inert character, and faster kinetics include Compound 21 (C21) [ 5 ]  and deschloroclozapine (DCZ). [ 6 ]


Coinduction  in  anesthesia  is a  pharmacological  tool whereby a combination of  sedative drugs  may be used to greater effect than a single agent, achieving a smoother onset of  general anesthesia . The use of coinduction allows lower doses of the same  anesthetic agents  to be used which provides enhanced safety, faster recovery, fewer side-effects, and more predictable  pharmacodynamics . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Coinduction is used in human medicine and  veterinary medicine [ 5 ]  as standard practice to provide optimum anesthetic induction. The onset or  induction  phase of anesthesia is a critical period involving the  loss of consciousness  and reactivity in the patient, and is arguably the most dangerous period of a general anesthetic. A great variety of coinduction combinations are in use and selection is dependent on the patient's age and health, the specific situation, and the indication for anesthesia. As with all forms of anesthesia the resources available in the environment are a key factor.


A standard coinduction regimen for an adult might consist of a  benzodiazepine  sedative  amnesic  such as  midazolam , followed by an  opioid   analgesic  with further sedating properties such as  fentanyl  which has a fast onset, then an  intravenous  induction agent:  propofol . A  muscle relaxant  such as  atracurium  would be administered after this, though this would not strictly be a part of coinduction. For a child on the other hand, a commonly used regimen would be  fentanyl ,  ketamin  and  rocuronium . In all cases the choice of agents would be tailored to the situation; for a  neonatal   intubation  the aforementioned regimes would be inappropriate as sedation and especially  amnesia  are less important.  Fentanyl  alone would be used, followed by the short-action muscle relaxant  suxamethonium : coinduction is typically not used in neonatal anesthesia. [ citation needed ]


Combination therapy  or  polytherapy  is  therapy  that uses more than one  medication  or modality. Typically, the term refers to using multiple therapies to treat a  single   disease , and often all the therapies are pharmaceutical (although it can also involve non-medical therapy, such as the combination of medications and  talk therapy  to treat depression). 'Pharmaceutical' combination therapy may be achieved by prescribing/administering separate drugs, or, where available,  dosage forms  that contain more than one  active ingredient  (such as fixed-dose combinations).


Polypharmacy  is a related term, referring to the use of multiple medications (without regard to whether they are for the same or separate conditions/diseases). Sometimes "polymedicine" is used to refer to pharmaceutical combination therapy. Most of these kinds of terms lack a universally consistent definition, so caution and clarification are often advisable.


Conditions treated with combination therapy include  tuberculosis ,  leprosy ,  cancer ,  malaria , and  HIV / AIDS . One major benefit of combination therapies is that they reduce development of  drug resistance  since a pathogen or tumor is less likely to have resistance to multiple drugs simultaneously.   Artemisinin -based monotherapies for malaria are explicitly discouraged to avoid the problem of developing resistance to the newer treatment.


Combination therapy may seem costlier than monotherapy in the short term, but when it is used appropriately, it causes significant savings: lower treatment failure rate, lower case-fatality ratios, fewer side-effects than monotherapy, slower development of resistance, and thus less money needed for the development of new drugs. [ 1 ]


Combination therapy has gained momentum in oncology in recent years, with various studies demonstrating higher response rates with combinations of drugs compared to monotherapies, [ 2 ] [ 3 ]  and the FDA recently approving therapeutic combination regimens that demonstrated superior safety and efficacy to monotherapies. [ 4 ]  In a recent study about solid cancers,  Martin Nowak ,  Bert Vogelstein , and colleagues showed that in most clinical cases, combination therapies are needed to avoid the evolution of resistance to targeted drugs. Furthermore, they find that the simultaneous administration of multiple targeted drugs minimizes the chance of relapse when no single mutation confers cross-resistance to both drugs. [ 1 ]


Various systems biology methods must be used to discover combination therapies to overcome drug resistance in select cancer types. [ 5 ] [ 6 ]  Recent  precision medicine  approaches have focused on targeting multiple biomarkers found in individual tumors by using combinations of drugs. [ 7 ] [ 8 ]  However, with 300 FDA-approved cancer drugs on the market, there almost 45,000 possible two-drug combinations and almost 4.5 million three-drug combinations for to choose from. [ 9 ]  That level of complexity is one of the primary impediments to the growth of combination therapy in oncology. [ 7 ]


The  National Cancer Institute  has recently highlighted combination therapy as a top research priority in oncology. [ 10 ]


Combination therapy with two or more antibiotics are often used in an effort to treat multi-drug resistant Gram-negative bacteria. [ 11 ]


Monotherapy, or the use of a single therapy, can be applied to any therapeutic approach, but it is most commonly used to describe the use of a single  medication .  Normally, monotherapy is selected because a single medication is adequate to treat the medical condition.  However, monotherapies may also be used because of  unwanted side effects  or dangerous  drug interactions . [ 12 ]


The  Department of Pharmacology at the University College London ,  the first of its kind in  England , was founded in 1905 and remained in existence until 2007.


University College London  (UCL) was founded in 1826. It was born in the ferment of radical London in the 1820s and 1830s and was heavily influenced by the Scottish and French  Enlightenments . UCL was part of the radical opposition to the hegemony of  Oxford  and  Cambridge . [ 1 ]  In medicine, UCL was a force in combatting the conservative and religious monopoly of the  Royal Colleges of Physicians  and  Surgeons [ 1 ]


Although Edinburgh University was well ahead at the time, [ 2 ]  UCL had a professor of Materia Medica and Pharmacy,  A.T.Thomson, from the start. Later this was renamed as the chair of Materia Medica and Therapeutics.  Its best known holder was  Sydney Ringer  (1878–87), who worked on the isolated beating heart and is renowned for his eponymous salt solution which he designed to maximise the  viability of isolated hearts. His textbook  ‘Handbook of Therapeutics’  ran for 13 editions between 1869 and 1897.


In 1905. Pharmacology was established as a distinct discipline within basic medical sciences at UCL. It was the first Department of Pharmacology in England. [ citation needed ]


Most of the people involved in the development of quantitative analysis of drug-receptor interactions worked at some time in UCL's Departments of Pharmacology, or of Physiology or of Biophysics. [ 3 ]


Arthur Cushny (1866–1926) was the first holder of the newly instituted Chair of Pharmacology, from 1905 until 1918.
After graduating in medicine from Aberdeen, Cushny had studied in Berne, Würzburg, and Strasbourg, where he became Assistant to the famed  Oswald Schmiedeberg . In 1893, at the age of 27, he was appointed Professor of Pharmacology at the  University of Michigan, Ann Arbor . Eight years later Cushny came to the chair at UCL where he soon expanded the department from the single room he had been given. He raised the funds for the building which the remnants of the department still occupies.


His main interests were in the heart and kidney. His work on the involvement of calcium in the action of digitalis was prescient.  He was interested in optical isomers. Data from an early clinical trial [ 4 ]  using hyoscine isomers was used by  William Sealy Gossett  who, under the pseudonym "Student" published in 1908 the first small-sample test of significance, Student's  t  test. [ 5 ]  His use of these data has given rise to much discussion. [ 6 ]  Later reanalysis of the same data by a randomisation tests [ 7 ] [ 8 ]  gave a similar result.


Cushny published a textbook  Textbook of Pharmacology and Therapeutics  (eighth edition 1924). He introduced the Cushny  myograph , an ingenious  arrangement of  counterbalanced levers that allowed the faithful recording of the rate and force of contraction of the rapidly beating animal heart. It was still in use in practical classes at UCL, and elsewhere, in the 1960s.


Cushny left UCL in 1918, to become Professor of Materia Medica and Pharmacology at Edinburgh. he was succeeded by A.J. Clark/


A.J. Clark , FRS (1885–1941) [ 9 ]  held the established Chair of Pharmacology from 1918 to 1926. After qualifying in medicine, and serving as a field medical officer throughout the First World War, Clark had been appointed Professor of Pharmacology at the  University of Cape Town  where he remained until accepting the Chair of Pharmacology at UCL in 1920. His influence on the subject was profound. The distinguished physiologist and Nobel laureate A.V. Hill ( Archibald Hill ) had begun the quantitative study of the action of agonists on an isolated tissue (frog skeletal muscle) some years earlier. Clark took this much further and extended it to examine the actions of antagonists. The data he gathered on the exact relationship between agonist concentration and response, and on how this changed in the presence of a competitive antagonist, were published in two classic papers in the  Journal of Physiology  in 1926,. [ 10 ] [ 11 ]   But he failed to work out a method for analysing properly the results of experiments with antagonists: that had to wait for his successor, Heinz Schild. [ 3 ]


Nevertheless, Clark was largely responsible for the transition of pharmacology from a descriptive subject to the quantitative science that it is today - this emphasis on quantitative approaches has remained strong throughout the subsequent history of the department. Clark's book  The Mode of Action of Drugs on Cells [ 12 ]  (Williams & Wilkins, 1933) is a classic and the following quotation from it set the tone for the department for many years.


While at UCL Clark wrote the first edition of his textbook  Applied Pharmacology [ 13 ]  in 1923, a book that was to be updated by two of his successors as Head of department, first by H.O. Schild and later by H.P. Rang, and is still extant in the form of the widely used textbook  Rang & Dale's Pharmacology . [ 14 ]


In 1926 Clark followed his predecessor in moving to the University of Edinburgh.


Ernest Basil Verney  (1894–1967) [ 15 ]  succeeded Clark. He held the Chair of Pharmacology from 1926 to 1934.
While at UCL Verney discovered the antidiuretic hormone and also the mechanism by which structures in the brain sense minute changes in blood osmotic pressure.  Both findings were of profound importance for the understanding of water and electrolyte balance. Verney was also instrumental in arranging for  Otto Krayer  to come to the department, albeit for only a short period, following Krayer's exclusion from all academic positions in German universities because of his objection to the expulsion of Jewish scientists from their posts. Krayer was later to head the Department of Pharmacology at Harvard with the greatest distinction.
In 1934 Verney moved to an academic post at the University of Cambridge where he later became the first Sheild Professor of Pharmacology


John Gaddum  (1900–1965) held the Chair of Pharmacology from 1935 to 1938.
Like A.J. Clark, he had a profound interest in quantitative methods.


He extended A.J. Clark's work on competitive antagonism, and applied the law of mass action to describe the relationship (the Gaddum equation) between receptor occupancy and the concentrations of an agonist and a competitive antagonist at equilibrium with the receptors in a tissue. The theory for two or more competing ligands had been known since Michaelis & Menten (1914), [ 3 ]  but Gaddum was the first to apply it in a pharmacological context). Like Clark before him, Gaddum failed to spot how to use the theory to estimate equilibrium constants. [ 3 ]


Gaddum was also a master of bioassay which was then the preferred, and usually the only, way to determine the concentrations of biologically active molecules such as labile neurotransmitters and the neuropeptides.


Frank Winton (1894–1985) [ 16 ]  held the Chair of Pharmacology from 1938 to 1961. His main scientific interest was in the control of blood flow to the kidney. Winton ran the department through the difficult war years when the Medical School was evacuated to  Leatherhead, Surrey .


He appointed the first two female academics in the department. Mary Lockett (1911–1982) [ 17 ]  was a lecturer in the department from 1945 - 1950.  Hannah Steinberg  arrived in the UK from Vienna on a  Kindertransport  train while still a schoolgirl, and she eventually became Professor of Psychopharmacology.


Winton also worked hard and successfully to ensure that pharmacology had an appropriate place in the preclinical curriculum. He oversaw the extension of the department, including the Pharmacology Lecture Theatre (now the Schild Theatre).


He was the author, with  Leonard Bayliss , of a widely used textbook  Human Physiology , first published in 1932. The 6th edition, 1968 was written by Olof J.C. Lippold and F.R Winton [ 18 ]


Heinz Otto Schild (1906–1984) [ 19 ]  held the Chair of Pharmacology from 1961 to 1973.


He was born in Fiume (now  Rijeka , Croatia), in 1908, when it was part of the  Austro-Hungarian empire . He qualified in medicine in Munich and then worked with Straub, the leading German pharmacologist of the time. By good fortune, Schild had been accepted as a visiting worker by  Sir Henry Dale  and was in England when the National Socialists came to power in Germany. He decided to stay in Britain and became an assistant in the Department of Pharmacology in Edinburgh, then headed by A.J. Clark. When J. H. Gaddum was appointed to the chair at UCL, he invited Schild to join him as a Demonstrator. So began his long association with UCL, interrupted only by his bizarre internment on the Isle of Man as an ‘enemy alien’ at the outbreak of the Second World War. Following his release (greatly aided by F.R Winton's and Sir  Henry Dale 's appeals to the Home Office) he returned to his work in the department, then based in Leatherhead, and in 1961 became Winton's successor as Head of Department and Professor of Pharmacology.


Schild made major contributions to receptor pharmacology, to the understanding of the mechanism of histamine release and to bioassay. Like Gaddum and Clark, he used quantitative approaches whenever possible. His name is immortalised by the Schild equation. [ 3 ]   He built on the work of Clark and Gaddum on competitive antagonism, by realising that the null method was key to extraction of physical equilibrium constants  from simple functional experiments. Rather than looking at the depression by antagonist of the response to a fixed agonist concentration, he measured the  dose-ratio , the factor by which the agonist concentration had to be increased in order to restore a given response in the presence of the antagonist. By measuring the dose-ratio as a function of antagonist, it was possible to estimate the dissociation equilibrium constant for the combination of the antagonist with its receptor. [ 3 ]  Crucially the estimate is not dependent on the nature of the agonist.  Although Schild's derivation used the simplest possible model, it was subsequently shown that his equation is valid under much more general conditions. [ 20 ]


A.J. Clark's textbook was continued by Schild as  Clark's Applied Pharmacology  by Wilson & Schild. [ 21 ]


Heinz Schild was a generous and kindly Head of department. He appointed the third female member of academic staff, Dr M. Maureen Dale, a co-author of Rang & Dales Pharmacology. [ 14 ]  He oversaw the planning and introduction of a three-year B.Sc. course in Pharmacology which began in 1967 and continues to this day. Medical students were able to enter its final year and Schild, who never lost sight of the roots of the subject in medicine, was delighted that many took this opportunity.


Sir James Whyte Black   OM   FRS   FRSE   FRCP  (1924–2010) held the Chair of Pharmacology from 1973 to 1978.


Jim Black and Heinz Schild knew each other well because Schild had acted as a consultant to the then Smith, Kline & French company during the time when Black was leading the team that developed the histamine receptor antagonists, [ 22 ]   H 2  antagonists , which reduce secretion of gastric acid and which, at the time, transformed the treatment of gastric ulcers. Schild's methods for quantitative methods for analysis of drug antagonists [ 3 ] [ 20 ]  were crucial for this work.


Black introduced many changes to teaching in the department. One of the most important was the introduction of a BSc course in Medicinal Chemistry. His long experience in the pharmaceutical industry had convinced him that organic and physical chemists working on drug development with pharmacologists and biochemists would benefit greatly from a substantial knowledge of biology, certainly enough to allow them to understand and assess the kinds of measurements that their biological colleagues undertook.  Though the students were based in the Department of Chemistry, they took also courses in physiology and pharmacology, particularly its molecular aspects. This BSc course, like that in Pharmacology, also flourished and continues today. Another important change was a sharp reduction in the number of experiments with animal tissues undertaken by medical students during their course in pharmacology. At the same time, the emphasis on the importance of observations on human subjects was increased.


Black's appointment coincided with the onset of the straitened circumstances that all UK universities were to experience and that have continued in one form or another ever since. The changes he made helped the department to adjust to these harder times. To the regret of his Departmental staff, Black found that only the pharmaceutical industry could provide the facilities needed for the work he wished to pursue, and in 1978 he left to join the Wellcome Foundation.


Black was knighted in 1981 and in 1988 he got the  Nobel Prize in Physiology or Medicine  along with  Gertrude B. Elion  and  George H. Hitchings  for their work on drug development.


Humphrey Rang (born 1936) held the Chair of Pharmacology from 1979 to 1983.


Rang qualified in medicine at UCL and had worked in H.O.Schild's laboratory while a medical student. He was the author of the first successful ligand-binding experiment of the modern era. [ 23 ]  This was based on his PhD work in Oxford, under  William D.M. Paton . Rang had previously been the Professor of Pharmacology at Southampton and at St. George's Hospital Medical School. He brought with him  David Colquhoun  who was also returning to the department, having been appointed in 1964 as an assistant lecturer by H.O. Schild. These appointments greatly strengthened the interests and achievements of the department in fundamental aspects of pharmacology, particularly the study of ion channels and receptors.


In collaboration with M. Maureen Dale (also appointed during Schild's Headship), Rang prepared the first edition of  Pharmacology , [ 14 ]  the successor to Wilson & Schild's   Applied Pharmacology .


In 1983 Rang was offered and accepted the Directorship of the Sandoz Institute of Medical Research, a division of   Sandoz , then an independent pharmaceutical company. The new Institute was located in UCL and developed a close relationship with the department, both in teaching, to which members of the Institute contributed, and in research.


After Rang's resignation, the Chair of Pharmacology became vacant.  The Head of department from 1983 to 1987 was  Donald.H Jenkinson   He had done his PhD under  Bernard Katz . in UCL's famous Department of Biophysics, and was yet  another member of staff who had been invited to join the Department by Heinz Schild.  During his tenure the Middlesex Hospital Medical School was merged with UCL's, including the two Departments of Pharmacology.


During the 1980s the traditional role of Heads of department was replaced by rotating headships that were no longer associated necessarily with an established chair.  Established chairs were,  de facto , abolished as part of the move to corporatise universities.


David Colquhoun  FRS  was appointed to the established chair in 1985. It was subsequently dubbed the A.J. Clark chair, in honour of Clark's role in the establishment of quantitative pharmacology.  His work, with statistician Alan Hawkes and  Bert Sakmann  (Nobel prize 1991) established the department as the world leader in the theory and experiment of single ion channels. After retiring from the A.J.Clark chair in 2004, he worked on the misinterpretation of  p  values and its contribution to the irreproducibility that has come to light in some areas of science. [ 24 ] [ 25 ] [ 26 ]


D. A. Brown FRS  (1936 - 2023) was appointed in 1987 as head of department (he had previously held the same position at the School of Pharmacy). In 1987, the merger with the  Middlesex Hospital  Medical School was completed  and David Brown inherited the  title Astor Chair of Pharmacology from Professor F Hobbiger who had held that title at the Middlesex.


Brown's appointment was intended initially to be the start of a 5-year rotating headship, but when Colquhoun's turn became due, he decided that the job of Head of department would not allow enough time to do the algebra and program development with which he was involved.  Donald Jenkinson likewise declined to take another turn. Luckily David Brown agreed to continue and he remained Head of department until 2002.  His tenure saw a second merger, this time with the Department of Pharmacology at the  Royal Free Medical School , headed by Professor  Annette Dolphin , FRS. David Brown is renowned for his discovery of the acetylcholine (muscarinic)-sensitive potassium channel (M channel).


The Wellcome Lab for Molecular Pharmacology
The growing importance of molecular biology led Brown & Colquhoun to apply to the  Wellcome Trust  in 1990. They funded the building of the Lab for Molecular Pharmacology  which Colquhoun directed until his retirement in 2004.


Trevor G. Smart [ 27 ]  became Head of department in 2002, with the title of Schild Chair of Pharmacology.  He also works in the ion channel field. After the demise of the department in 2007. Smart became head of the new Research Department of Neuroscience, Physiology and Pharmacology. [ 28 ]


Stephanie Schorge . [ 29 ]  In 2021, Professor Schorge succeeded Trevor Smart as head of the Research Department of Neuroscience, Physiology and Pharmacology. She is the first female head of pharmacology since 1905.


Stuart Cull-Candy  FRS . Stuart G. Cull-Candy works on glutamate-activated ion channels. He joined the Department from UCL's Department of Biophysics and holds the Gaddum Chair of Pharmacology.


Lucia Sivilotti  was appointed to the A.J. Clark chair in 2014.  She has run the UCL Single Ion Channel group after Colquhoun's retirement in 2004. She  continued and greatly extended the work in the field of single channel kinetics. She owns the web site OneMol  [1]  where the group's analysis programs and publications can be downloaded.  The association of the A.J. Clark chair with quantitative work on receptors has thus continued to the present day.


The first of the nationwide  Research Assessment Exercises  took place in 1986. The UCL Department headed the list. It continued to be rated as the top Department of Pharmacology in each of the four research assessments that followed in 1989, 1992, 1996 and 2002.   But this performance was not enough to save the department.


In 2004,  Malcolm Grant  became provost of UCL. He commissioned external reports on the reorganisation of the college. The distinguished vice-president of the University of Manchester,  Richard Alan North  FRS, was asked to assess several options for the reorganisation of the Faculty of Life Sciences. One was to create large Research Departments, including one of Neuroscience, Physiology and Pharmacology, from the existing academic Departments. Professor North's only comment on the options was that the proposed "research departments in Life Sciences were too big". Grant accepted the conclusions except for the part about the size of departments.


On 24 May 2007 Grant persuaded the Academic Board to authorise him to act on its behalf [ 30 ]   and on 13 June 2007 the Department of Pharmacology was disestablished, after a century of distinction and innovation.


The academic staff at the time had three main concerns about the proposals. (a) The separation of teaching from research is bad, especially for teaching: the fact that a degree is offered in, for example, Pharmacology without a Pharmacology department to support it, means that there is no guarantee that there will be staff qualified or fully motivated to teach it. Moreover, the collegiality that comes from designing and providing a first-rate degree course is lost. (b) The size of the merged department of Neurosciences, Physiology and Pharmacology means less interaction between staff, and less collegiate spirit. (c) The changes created two extra levels of administration, so that now five levels existed between academics and the provost.


Staff were told at the time that the new organisation would be rolled out to other Faculties across UCL, though this has not happened.    David Colquhoun  has kept a personal diary of the process on his blog:  In Memoriam Department of Pharmacology, UCL 1905 – 2007 . [ 31 ]   On the positive side, UCL's current provost,  Michael Arthur , has put much emphasis on the quality of teaching, and maintaining its connections with research.


As of 2019, UCL still offers pharmacology degrees, though within the now merged Neuroscience, Physiology and Pharmacology department.


A history of the combined department appears on UCL's web site. [ 32 ]


Excretion  is elimination of  metabolic waste , which is an essential process in all  organisms . In  vertebrates , this is primarily carried out by the  lungs ,  kidneys , and  skin . [ 1 ]  This is in contrast with  secretion , where the substance may have specific tasks after leaving the  cell . For example,  placental mammals  expel  urine  from the  bladder  through the  urethra , [ 2 ]  which is part of the  excretory system .  Unicellular organisms  discharge waste products directly through the surface of the cell.


During life activities such as  cellular respiration , several chemical reactions take place in the body. These are known as  metabolism . These chemical reactions produce waste products such as  carbon dioxide , water,  salts ,  urea  and  uric acid . Accumulation of these wastes beyond a level inside the body is harmful to the body. The excretory organs remove these wastes. This process of removal of metabolic waste from the body is known as excretion.


Green  plants  excrete carbon dioxide and water as respiratory products. In green plants, the  carbon dioxide  released during respiration gets used during photosynthesis.  Oxygen  is a byproduct generated during  photosynthesis , and exits through  stomata , root cell walls, and other routes. Plants can get rid of excess water by transpiration and  guttation . It has been shown that the leaf acts as an 'excretophore' and, in addition to being a primary organ of photosynthesis, is also used as a method of excreting toxic wastes via diffusion. Other waste materials that are exuded by some plants —  resin , saps,  latex , etc. are forced from the interior of the plant by hydrostatic pressures inside the plant and by absorptive forces of plant cells. These latter processes do not need added energy, they act passively. However, during the pre-abscission phase, the metabolic levels of a leaf are high. [ 3 ] [ 4 ]  Plants also excrete some waste substances into the soil around them. [ 5 ]


In animals, the main excretory products are  carbon dioxide ,  ammonia  (in  ammoniotelics ),  urea  (in  ureotelics ),  uric acid  (in  uricotelics ),  guanine  (in  Arachnida ), and  creatine . The liver and kidneys  clear  many substances from the  blood  (for example, in  renal excretion ), and the cleared substances are then excreted from the body in the  urine  and  feces . [ 6 ]


Aquatic animals  usually excrete  ammonia  directly into the external environment, as this compound has high  solubility  and there is ample water available for dilution. In  terrestrial animals , ammonia-like compounds are converted into other nitrogenous materials, i.e.  urea , that are less harmful as there is less water in the environment and ammonia itself is  toxic . This process is called detoxification. [ 7 ]


Birds  excrete their nitrogenous wastes as  uric acid  in the form of a paste. Although this process is metabolically more expensive, it allows more efficient  water  retention and it can be stored more easily in the  egg . Many avian species, especially  seabirds , can also excrete salt via specialized nasal salt glands, the saline solution leaving through nostrils in the  beak .


In  insects , a system involving  Malpighian tubules  is used to excrete  metabolic waste . Metabolic waste diffuses or is actively transported into the tubule, which transports the wastes to the intestines. The metabolic waste is then released from the body along with fecal matter.


The excreted material may be called  ejecta . [ 8 ]  In  pathology  the word ejecta is more commonly used. [ 9 ]


FK962  is a compound which acts as an enhancer of  somatostatin  release. It stimulates nerve growth and  neurite  elongation, and has been researched in animal models for potential applications in the treatment of conditions such as  Alzheimer's disease  and  retinal neuropathy . [ 1 ] [ 2 ] [ 3 ] [ 4 ]


This  hormonal preparation  article is a  stub . You can help Wikipedia by  expanding it .


The  IUPHAR/BPS Guide to PHARMACOLOGY  is an  open-access  website, acting as a portal to information on the biological targets of licensed drugs and other small molecules. The Guide to PHARMACOLOGY (with GtoPdb being the standard abbreviation) is developed as a joint venture between the  International Union of Basic and Clinical Pharmacology  (IUPHAR) and the  British Pharmacological Society  (BPS). This replaces and expands upon the original 2009 IUPHAR Database (standard abbreviation IUPHAR-DB). The Guide to PHARMACOLOGY aims to provide a concise overview of all pharmacological targets, accessible to all members of the scientific and clinical communities and the interested public, with links to details on a selected set of targets. The information featured includes pharmacological data, target, and gene nomenclature, as well as curated chemical information for ligands. Overviews and commentaries on each target family are included, with links to key references.


The  Guide to PHARMACOLOGY  was initially made available online in December 2011 with additional material released in July 2012. Maintained by a team of curators based at the University of Edinburgh, the Guide to PHARMACOLOGY is developed by an international network of contributors, including the editors of the  Concise Guide to PHARMACOLOGY . As with the original IUPHAR-DB, the International Union of Basic and Clinical Pharmacology (IUPHAR) Committee on Receptor Nomenclature and Drug Classification  (NC-IUPHAR), acts as the scientific advisory and editorial board for the database. Its network of over 500 specialist advisors (organized into ~90 subcommittees) contribute expertise and data. The current PI and Grant holder of the GtoPdb project is Prof.  Jamie A. Davies . The development and release of the first version of the GtoPdb in 2012 were described in an editorial published in the  British Journal of Pharmacology  entitled 'Guide to Pharmacology.org- an update'. [ 2 ]  The IUPHAR-DB is no longer being developed and all the information contained within this site is now available through the Guide to PHARMACOLOGY (IUPHAR-DB links should now re-direct).


The target groups currently included on the Guide to PHARMACOLOGY are:


Information for each target group is subdivided into families based on classification, with a separate data page for each family. Within each page, targets are arranged into lists of tables, with each table including the protein and gene nomenclature for the target with links to gene nomenclature databases, and listing selected ligands with activity at the target, including agonists, antagonists, inhibitors and radioligands. Pharmacological data and references are given and each ligand is hyperlinked to a ligand page displaying nomenclature and a chemical structure or peptide sequence, along with synonyms and relevant database links. The Guide to PHARMACOLOGY also includes a list of all ligand molecules included on the site, subdivided into categories including small organic molecules (including mammalian  metabolites ,  hormones  and  neurotransmitters ), synthetic organic molecules,  natural products ,  peptides , inorganic molecules and  antibodies . A complete list of all the approved drugs included on the website is also available via the ligand list. The Guide to PHARMACOLOGY is being expanded to include clinical information on targets and ligands, in addition to educational resources.
Search features on the website include quick and advanced search options, and receptor and ligand searches, including support for ligand structures using chemical structures. Other features include 'Hot topic' news items and a recent receptor-ligand pairing list.


Between November 2015 and October 2018, the  Wellcome Trust  supported a project to develop the IUPHAR Guide to IMMUNOPHARMACOLOGY [ 3 ]  (GtoImmuPdb), based on the GtoPdb schema. The GtoImmuPdb is an open-access resource that brings an immunological perspective to the high-quality, expert-curated pharmacological data found in the existing IUPHAR/BPS Guide to PHARMACOLOGY. Protein targets and ligands relevant to immunopharmacology have been tagged and curated into GtoImmuPdb. These have also been associated with new immunological data types such as immunological processes, cell types, and disease. GtoImmuPdb provides a knowledge base that connects immunology with pharmacology, bringing added value and supporting research and development of drugs targeted at modulating immune, inflammatory or infectious components of the disease. [ 4 ]


The Guide to PHARMACOLOGY includes an online, open-access database version of the  Concise Guide to PHARMACOLOGY , previously "The Guide to Receptors and Channels" [ 5 ]  available in HTML, PDF and printed formats. A hard copy summary of the online database is published as  The Concise Guide to Pharmacology 2017/2018 [ 6 ]  as a series of papers as a bi-annual supplement to the  British Journal of Pharmacology .


The Guide to PHARMACOLOGY includes links to other relevant resources via target and ligand pages on both the concise and detailed view pages. Many of these resources maintain reciprocal links with the relevant Guide to PHARMACOLOGY pages.


Following funding from the  Wellcome Trust , from 2012 to 2015 the Guide to PHARMACOLOGY was expanded to include the biological targets of all prescription drugs and other likely targets of future small molecule drugs. Overviews of the key features of a wide range of targets are provided on the summary view pages, with detailed view pages providing more in-depth information on the properties of a selected subset of targets. As of January 2018 the  Medicines for Malaria Venture  is supporting a new extension to develop the Guide to Malaria Pharmacology. [ 7 ]  The core GtoPdb continues to be supported by the  British Pharmacological Society .


For over two millennia, texts in  Chinese herbology  and  traditional Chinese medicine  have recorded medicinal plants that are also  hallucinogens  and  psychedelics . Some are familiar  psychoactive plants  in Western  herbal medicine  (e.g.,  Chinese :  莨菪 ;  pinyin :  làngdàng , i.e.  Hyoscyamus niger ), but several Chinese plants have not been noted as hallucinogens in modern works (e.g., Chinese :  雲實 ;  pinyin :  yúnshí ;  lit.  'cloud seed', i.e.  Caesalpinia decapetala ). Chinese  herbals  are an important resource for the  history of botany , for instance,  Zhang Hua 's c. 290  Bowuzhi  is the earliest record of the  psilocybin mushroom   xiàojùn   笑菌  (lit. "laughing mushroom", i.e.  Gymnopilus junonius ).


There is a  lexical gap  between Chinese names and descriptions of hallucinogenic plants and English pharmacological terminology for hallucinogens, which are commonly divided into psychedelics, dissociatives, and deliriants.


The  English lexicon  has a complex  semantic field  for  psychoactive drugs , and most terms are  neologisms . [ a ]


Hallucination  (from Latin  alucinor  "to wander in mind") is defined as: "The apparent, often strong subjective perception of an external object or event when no such stimulus or situation is present; may be visual, auditory, olfactory, gustatory, or tactile."  Hallucinogen  (coined in 1952 from Latin  alucinor  and  -gen  "producing"): "A mind-altering chemical, drug, or agent, specifically a chemical the most prominent pharmacologic action of which is on the central nervous system (mescaline); in normal people, it elicits optic or auditory hallucinations, depersonalization, perceptual disturbances, and disturbances of thought processes."


Pharmacology  divides hallucinogens into three classes.  Psychedelic  (first used in 1956 from Greek  psyche-  "mind; soul" and  delein  "to manifest"): "Pertaining to a rather imprecise category of drugs with mainly central nervous system action, and with effects said to be the expansion or heightening of consciousness, LSD, hashish, mescaline, psilocybin."  Dissociative  is a class of hallucinogen that produces feelings of  dissociation  (Latin  dissocioatus  "to disjoin, separate" from  socius  "partner, ally") meaning "(3) An unconscious separation of a group of mental processes from the rest, resulting in an independent functioning of these processes and a loss of the usual associations, a separation of affect from cognition."  Dissociative disorders  is defined as "a group of mental disorders characterized by disturbances in the functions of identity, memory, consciousness, or perception of the environment; this diagnostic group includes dissociative (older term, psychogenic) amnesia, dissociative fugue, dissociative identity (older term, multiple personality) disorder, and depersonalization disorder."  Deliriant  is a technical term introduced to distinguish hallucinogens that primarily cause  delirium  (1982, from Latin  deliro  "to be crazy" and  delira  "go out of the furrow"): "An altered state of consciousness, consisting of confusion, distractibility, disorientation, disordered thinking and memory, defective perception (illusions and hallucinations), prominent hyperactivity, agitation, and autonomic nervous system overactivity; caused by illness, medication, or toxic, structural, and metabolic disorders."


The equivalent semantic field in the  Chinese lexicon  comprises contemporary  loanwords . [ b ]   Huànjué  ( 幻覺  "hallucination; delusion; illusion")  compounds   huàn  ( 幻  "unreal; imaginary; illusory") and ( jué''   覺  "feeling; sensation; perception").  Zhìhuànjì  ( 致幻劑  "psychedelic; hallucinogen") compounds  zhì  ( 致  "incur; cause"),  huàn  "unreal; imaginary; illusory", and  jì  ( 劑  "medicinal preparation; dose").  Zhìhuànyào  ( 致幻藥  "hallucinogenic drug") with  yào  ( 藥  "medicine; drug") is a less common synonym.


Míhuànyàowù  ( 迷幻藥物  "psychedelic") combines  míhuàn  ( 迷幻  "phantasmagoric; surreal; mysterious; psychedelic") and  yàowù  ( 藥物  "medicine; pharmaceutical; medicament"). The Chinese technical names for the last two classes of hallucinogens are rare:  Yóulíyàopǐn  ( 游离藥品  "dissociative") compounds  yóulí  ( 游离  "dissociated; drifting") and  yàopǐn  ( 藥品  " medicine; chemical reagent; drug"); and  Zhìzhānwàngyào  ( 致谵妄藥  "deliriant") combines  zhì  "incur; cause",  zhānwàng  ( 譫妄  "(medical) delirium"), and  yào  "medicine; drug".


Chinese  pharmaceutical  literature mainly comprises texts called  bencao  ( Chinese :  本草 ;  pinyin :  běncǎo ;  Wade–Giles :  pen-ts'ao ), translatable as English  herbal ,  pharmacopoeia , or  materia medica . This word  compounds   ben  "(plant) root/stem; basis, origin; foundation; book" and  cao  "grass; herb; straw". Although  bencao  is sometimes misinterpreted as "roots and herbs", the approximate meaning is "[pharmaceutics whose] basis [ ben ] [is] herbs [ cao ]". [ 1 ] [ failed verification ]  These works deal with drugs of all origins, mainly vegetable but also mineral, animal, and even the  human body .


The Chinese  botanist , academic, and researcher  Hui-lin Li  (1911-2002) wrote seminal articles about the history and use of hallucinogenic plants in China. Li cites a story in  Li Shizhen 's 1596 magnum opus  Bencao gangmu  as the first discussion about the general use of psychoactive plants. In 1561, after horrific murders in  Changli , the  Ming dynasty   Jiajing Emperor  proclaimed a nationwide edict warning about the dangers of hallucinogens.


Lang-tang ( Hyoscyamus niger ), Yün-shih ( Caesalpinia Sepiaria ), Fang-k'uei ( Peucedanum japonica ) and Red Shanglu ( Phytolacca acinosa ) all can cause hallucination in peoples. In the past, this significance has not been fully divulged. Plants of this kind are all toxic, which can obscure the mind, alter one's consciousness, and confuse one's perception of sight and sound. In the T'ang times, An Lu-shan [a foreign warlord in the Chinese army service] once enticed the Kitan [tribesmen surrendered to his command] to drink Lang-tang wine and buried them alive while they were unconscious. Again in the second month of the 43rd year of the Chia-ch'in period (1561 A.D.), a wandering monk, Wu Ju-hsiang of Shensi province, who possessed wizardry, arrived at Ch'ang-li and stopped over at the house of a resident, Chang Shu. Upon finding the latter's wife being very beautiful, he asked that the entire family sit together at the table with him when he was being offered a meal. He put some reddish potion in the rice and after a while the whole family became unconscious and submitted to his assault. He then blew a magic spell into the ears of Chang Shu and the latter turned crazy and violent. Chang visualized his entire family as all devils and thereby killed them all, sixteen altogether, without any blood shed. The local authorities captured Chang Shu and kept him in prison. After ten days, he spat out nearly two spittoonsful of phlegm, became conscious, and found out himself that those he killed were his parents, brothers, sisters-in-law, his wife, sons, sisters, nephews. Both Chang and Wu were committed to the death sentence. The Emperor, Shih-tsung, proclaimed throughout the country about the case. The particular magic potion must be of the kind of Lang-tang or similar drugs. When the man was under the spell, he saw everyone else as a devil. It is thus very important to find out the remedy that counteracts such a thing. [ 2 ]


The following eight examples of confirmed and possible hallucinogens recorded in Chinese herbals are primarily based on the ten in Li Hui-Lin's 1977 article. [ 3 ]  Two edible plants, with only one Chinese source and no Western ones mentioning psychoactive properties, are omitted as unlikely:  fangfeng  ( 防风 ;  防風 ;  fángfēng ;  fang-feng  " Saposhnikovia divaricata ;  Chinese parsnip ") and  longli  ( 龙荔 ;  龍荔 ;  lónglì ;  lung-li  " Nephelium  topengii"; a type of  lychee "). [ 4 ]


The  làngdàng  ( 莨菪 ;  làngdàng ;  lang-tang  " Hyoscyamus niger ; black henbane") is one of the most famous hallucinogenic drugs in Chinese herbals. The seeds, which contain psychoactive  tropane alkaloids , are called  làngdàngzi  ( 莨菪子 , with  -zi  "child; seed") or  tiānxiānzi  ( 天仙子  "heavenly  transcendent  seeds").


For use in medicine, the seeds are supposedly treated by soaking in vinegar and milk to reduce their toxicity. The  Shennong Bencaojing  says, "[The seeds] when taken [when properly prepared] for a prolonged period enable one to walk for long distances, benefiting to the mind and adding to the strength ... and to communicate with spirits and seeing devils. When taken in excess, it causes one to stagger madly." [ 5 ]  Lei Xiao's 470  Leigong paozhilun  ( 雷公炮炙論  "Master Lei's Treatise on the Decoction and Preparation of Drugs") states that the seed "is extremely poisonous, and when accidentally taken, it causes delirium and seeing sparks and flashes", and Zhen Chuan's c. 620  Bencao yaoxing  ( 本草藥性  "Nature of Drugs in Materia Medica") says the seeds "should not be taken raw as it hurts people, causing them to see devils, acting madly like picking needles". [ 6 ]


The  yunshi  ( 云实 ;  雲實 ;  yúnshí ;  yun-shih  " Caesalpinia decapetala ; cat's claw") was a versatile drug plant in the Chinese pharmacopeia, and the root, flowers, and seeds were all used in medicine.


The  Shennong Bencao  says, "[The flowers] could enable one to see spirits, and when taken in excess, cause one to stagger madly. If taken over a prolonged period, they produce somatic levitation and effect communication with spirits."  Tao Hongjing , who edited the official  Shangqing Daoist  canon, also compiled the c. 510  Mingyi bielu  ( 名醫別錄  "Supplementary Records of Famous Physicians") that says "[The flowers] will drive away evil spirits. When put in water and burned, spirits can be summoned" and "The seeds are like  langdang  ( Hyoscyamus niger ), if burned, spirits can be summoned; but this [sorcery] method has not been observed." [ 7 ]


Li Hui-Lin notes this plant "has not been noted as a hallucinogenic plant in modern works. In fact, as far as I am aware, it has not been investigated medicinally or chemically". [ 8 ]


The  fangkui  ( 防葵 ;  fángkuí ;  fang-k'ui  " Peucedanum japonicum ") root is used in Chinese medicine, and like the previous cat's claw, has not been noted as a hallucinogenic in modern works. The c. 510  Tao Hongjing mingyi bielu  states, "Feverish people should not take it, because it causes one to be delirious and see spirits"; and Chen Yanzhi's ( 陳延之 ) c. 454-473  Xiaoping fang  ( 小品方  "Minor Prescriptions") says that  fangkui , "if taken in excess, makes one become delirious and act somewhat like mad". [ 9 ]


P. japonicum  is also used quite extensively in Korean cuisine - not only as a culinary herb, but also as a leaf vegetable, raising the question as to what constitutes consumption 'to excess'. It may be the case that the strain of plant grown in Korea is less toxic / medicinal than that found in China, or that very substantial quantities of the plant must be eaten before any psychoactive effects are manifested. Alternatively, the psychoactive components of the plant may be deactivated by the cooking processes employed in the preparation of the plant in Korea. [ 10 ] [ 11 ]


The  shanglu  ( 商陆 ;  商陸 ;  shānglù ;  shang-lu  " Phytolacca  acinosa ; India pokeweed") has edible leaves and poisonous roots. China's oldest extant dictionary, the c. 3rd-century BCE  Erya  (13: 110) gives two names for pokeweed:  chùtāng  ( 蓫薚 ) and  mǎwěi  ( 馬尾  "horsetail").


Chinese herbals distinguish two kinds of  shanglu , white with white flowers and white root, and red with red flowers and purple root. The white root is edible when cooked but the red root is extremely poisonous. The  Tao Hongjing mingyi bielu  records how Daoists used the red variety, "By boiling or brewing and then taken, it can be used for abdominal parasitic worms and for seeing spirits";  Su Song 's 1061  Bencao tujing  ( 本草圖經  "Illustrated Pharmacopeia") says, "It was much used by sorcerers in ancient times". [ 12 ]  Su Gong's 659  Tang bencao  (唐本草 " Tang dynasty  pharmacopeia") says "The red kind can be used to summon spirits; it is very poisonous. It can be only used as external application for inflammation. When ingested, it is extremely harmful, causing unceasing bloody stool. It may be fatal. It causes one to see spirits." [ 13 ]


The 1406  Jiuhuang Bencao  "Famine Relief Herbal" lists pokeweed as a  famine food . It gives instructions for removing the poisonous phytolaccatoxin from the white roots and mentions Daoist  xian  using the flowers: "Cut them up into slices, scald, then soak and wash repeatedly (throwing away the extract) until the material is clean; then just eat it with garlic. … Plants with white flowers can (it is said) confer longevity; the immortals collected them to make savouries to take with their wine." [ 14 ]


Dama  ( 大麻 ;  dàmá ;  ta-ma  " Cannabis sativa ; hemp; marijuana") has been grown in China since  Neolithic  times. At a very early period the Chinese recognized the Cannabis plant as  dioecious , the male plants produce better fibers and the female plants produce more  cannabinoids . In modern usage, the names are  xǐ  ( 枲  "male cannabis") and  jū  ( 苴  "female cannabis"). [ 15 ]


Reflecting the importance of cannabis in ancient China, the ca. 3rd century BCE  Erya  dictionary (13) has four definitions:  fén  ( 黂 ;  蕡 ) and  xǐshí  ( 枲實 ) mean "cannabis flower";  xǐ  ( 枲 ) and  má  ( 麻 ) mean "cannabis" generally and not "male cannabis";  fú  ( 莩 , lit. "reed membrane") and  mámǔ  ( 麻母 , "cannabis mother") mean "female cannabis"; and  bò  ( 薜 ) and  shānmá  ( 山麻  "mountain cannabis") mean "wild cannabis", possibly  C. ruderalis .


The  Shennong bencao  calls "cannabis flowers/buds"  mafen  ( 麻蕡 ) or  mabo  ( 麻勃 ) and says: "To take much makes people see demons and throw themselves about like maniacs [ 多食令人見鬼狂走 ]. But if one takes it over a long period of time one can communicate with the spirits, and one's body becomes light [ 久服通神明輕身 ]". [ 16 ]  The  Mingyi bielu  records that in the 6th century,  mabo  were, "very little used in medicine, but the magician-technicians [ shujia   術家 ] say that if one consumes them with ginseng it will give one preternatural knowledge of events in the future." [ 17 ]  Meng Shen's c. 670  Shiliao bencao  ( 食療本草  "Nutritional Therapy Pharmacopeia") says people will combine equal parts of raw cannabis flowers,  Japanese sweet flag , and  wild mandrake , "pound them into pills of the size of marbles and take one facing the sun every day. After one hundred days, one can see spirits." [ 18 ]  Tang Shengwei's 1108  Zhenglei bencao  ( 證類本草  "Reorganized Pharmacopeia") gives a more complete account on the pharmaceutical uses of cannabis: "Ma-fen has a spicy taste; it is toxic; it is used for waste diseases and injuries; it clears blood and cools temperature; it relieves fluxes; it undoes rheumatism; it discharges pus. If taken in excess, it produces hallucinations and a staggering gait. If taken over a long term, it causes one to communicate with spirits and lightens one's body." [ 19 ]


According to the sinologists and historians  Joseph Needham  and  Lu Gwei-djen , some early Daoists adapted censers for the  religious and spiritual use of cannabis . The c. 570 Daoist encyclopedia  Wushang Biyao  ( 無上秘要  "Supreme Secret Essentials") recorded adding cannabis into ritual censers, and they suggest  Yang Xi  (330-c. 386), who wrote the Shangqing scriptures during alleged visitations by Daoist  xian , was "aided almost certainly by cannabis". [ 20 ]


The  mantuoluo  ( 曼陀罗 ;  曼陀羅 ;  màntuóluó ;  man-t'o-lo  " Datura stramonium ; jimsonweed" or "(Buddhism)  mandala ") contains highly  toxic   Tropane alkaloids . Several Datura species were introduced into China from India, and Li Shizhen's 1596  Bencao gangmu  was the first herbal to record the medicinal use of flowers and seeds. The drug is used in combination with  Cannabis sativa  and taken with wine as an anesthetic for small operations and cauterizations. Li Shizhen personally experimented with jimsonweed and recorded his experience as follows: "According to traditions, it is alleged that when the flowers are picked for use with wine while one is laughing, the wine will cause one to produce laughing movements; and when the flowers are picked while one is dancing, the wine will cause one to produce dancing movements. [I have found out] that such movements will be produced when one becomes half-drunk with the wine and someone else laughs or dances to induce these actions." [ 21 ]


The  maogen  ( 毛茛 ;  máogèn ;  mao-ken  " Ranunculus  japonicus ; buttercup") is a poisonous plant with bright yellow flowers. The Daoist alchemist  Ge Hong 's c. 340  Zhouhou jiuzu fang  ( 肘後救卒方  "Remedies for Emergencies", [ 22 ]  says, "Among the herbs there is the Shui Lang (water Lang, a kind of Mao-ken) a plant with rounded leaves which grows along water courses and is eaten by crabs. It is poisonous to man and when eaten by mistake, it produces a maniacal delirium, appearing like a stroke and sometimes with blood-spitting. The remedy is to use licorice." Later herbals, which do not mention  maogen  as a deliriant, say the whole plant is considered poisonous and is should only be externally used as a medicine for irritation and inflammation.


The  xiaojun  ( 笑菌 ;  xiàojùn ;  hsiao-ch'un  "laughing mushroom") was known to Chinese herbalists for centuries before modern botanists identified it as a type of  psilocybin mushroom , most likely either  Gymnopilus junonius  or Laughing Gym or  Panaeolus papilionaceus  or Petticoat Mottlegill.


The earliest record of a mushroom that causes uncontrollable laughter appears in  Zhang Hua 's c. 290  Bowuzhi  compendium of natural wonders, in a context describing two unusual kinds of  jùn  ( 菌  "mushroom; fungus") that grow on tree bark.


In all the mountain commanderies to the South of the Yangzi, there is a fungus which grows [ 生菌 ] throughout the spring and summer on the large trees that have fallen down; it is known as the Zhen [ 椹  "chopping block (for execution)"]. If one eats it, it is tasty, but suddenly the poison takes effect and kills the eater. … If one eats Sweet gum tree growths [ 生者 ], they will induce uncontrollable laughter. If one drinks "earth sauce" [ tǔjiāng   土漿 ] one will recover. [ 23 ]


The  Bencao gangmu  records Tao Hongjing's recipe for preparing "earth sauce": "Dig out a pit three chi deep in a place where there is yellow earth. Take freshly-drawn water and pour it into the pit, stirring the water so as to make it turbid. After a short while, draw off the clear water and use this. It is called either 'soil sauce' or 'earth sauce'." [ 24 ]  Hui-lin Li quotes a Chinese-language study of "laughing mushrooms" that this "soil infusion" is the clear liquid after soil is mixed with water and allowed to settle, and an effective  antidote  for poisons. [ 25 ]


Subsequent Chinese authors give many similar records. Chen Renyu's ( 陳仁玉 ) I245  Jùnpǔ  ( 菌譜  "Mushroom Guidebook") says this fungus is named   tǔxùn  ( 土蕈  "earth mushroom") or  dùxùn  ( 杜蕈  "pear mushroom") and "grows in the ground. People believe it to be formed by the air from poisonous vermin, and kills people if taken.... Those poisoned by it will laugh. As an antidote, use strong tea, mixed with  alum  and fresh clear water. Upon swallowing this, it will cure immediately". [ 25 ]


The c. 304  Nanfang Caomu Zhuang  mentions sweetgum tree growths in a quite different context, the shamans in the southern state of  Yue  use a magical  fēngrén  ( 楓人  "sweetgum person") that is a kind of  liúyǐng  ( 瘤癭  " gall ") found growing on sweetgum trees. "When aged they develop tumors. Sometimes in a violent thunder storm, the tree tumors grow suddenly three to five feet in one night, and these are called Feng-jen. The witches of Yueh collect these for witchcraft, saying that they have proof of their supernatural quality." [ 26 ]  Later sources gave two explanations of the sweetgum tree growths, either as galls that resemble humans and have magical powers or as parasitic plants with rain-giving powers. [ 27 ]


In Japan, both medieval and modern sources record laughing mushrooms. An 11th-century story in the  Konjaku Monogatarishū  describes a group of Buddhist nuns who ate  maitake  ( 舞茸  "dancing mushrooms") and began to laugh and dance uncontrollably. It is also known as the  waraitake  ( 笑茸  "laughing mushroom"), which scholars have identified as the  Panaeolus papilionaceus  or Petticoat Mottlegill; the related  Panaeolus cinctulus  or Banded Mottlegill; and the psilocybin mushroom  Gymnopilus junonius  or Laughing Cap also called  ōwaraitake  ( 大笑茸  "Big Laughing Mushroom"). [ 28 ]


In a study on early Daoist practitioners searching for the  elixir of Immortality , Needham and Lu mention the possible use of hallucinogenic plants, such as  Amanita muscaria  "fly agaric" and  xiaojun  "laughing mushrooms". Based on  Tang dynasty  and  Song dynasty  references, they tentatively identify it as a  Panaeolus  or  Pholiota  and suggest that the properties of at least some psychoactive mushrooms were widely known. They predict the further exploration of hallucinogenic fungi and other plants in Daoism and in Chinese culture in general "will be an exciting task". [ 29 ]


Footnotes


In  biochemistry  and  pharmacology , the  Hill equation  refers to two closely related equations that reflect the binding of  ligands  to macromolecules, as a function of the ligand  concentration . A ligand is "a substance that forms a complex with a biomolecule to serve a biological purpose" ( ligand definition ), and a macromolecule is a very large molecule, such as a protein, with a complex structure of components ( macromolecule definition ).  Protein-ligand binding typically changes the structure of the target protein, thereby changing its function in a cell.


The distinction between the two Hill equations is whether they measure  occupancy  or  response . The  Hill equation  reflects the occupancy of macromolecules: the fraction that is saturated or bound by the  ligand . [ 1 ] [ 2 ] [ nb 1 ]  This equation is formally equivalent to the  Langmuir isotherm . [ 3 ]  Conversely, the  Hill equation  proper reflects the cellular or tissue response to the ligand: the physiological output of the system, such as muscle contraction.


The Hill equation was originally formulated by  Archibald Hill  in 1910 to describe the  sigmoidal  O 2  binding curve of  haemoglobin . [ 4 ]


The binding of a  ligand  to a  macromolecule  is often enhanced if there are already other ligands present on the same macromolecule (this is known as  cooperative binding ). The Hill equation is useful for determining the degree of  cooperativity  of the ligand(s) binding to the enzyme or receptor. The  Hill coefficient  provides a way to quantify the degree of interaction between ligand binding sites. [ 5 ]


The Hill equation (for response) is important in the construction of  dose-response curves .


The Hill equation is commonly expressed in the following ways. [ 2 ] [ 7 ] [ 8 ]


The special case where

 n
 =
 1

 {\displaystyle n=1}

  is a  Monod equation .


In pharmacology,

 θ

 {\displaystyle \theta }

  is often written as

 p

 AR

 {\displaystyle p_{{\ce {AR}}}}

 , where

 A

 {\displaystyle {\ce {A}}}

  is the ligand, equivalent to L, and

 R

 {\displaystyle {\ce {R}}}

  is the receptor.

 θ

 {\displaystyle \theta }

  can be expressed in terms of the total amount of receptor and ligand-bound receptor concentrations:

 θ
 =

 [
 LR
 ]

 [

 R

 total

 ]

 {\displaystyle \theta ={\frac {\ce {[LR]}}{\ce {[R_{\rm {total}}]}}}}

 .

 K

 d

 {\displaystyle K_{d}}

  is equal to the ratio of the dissociation rate of the ligand-receptor complex to its association rate (

 K

 d

 =

 k

 d

 k

 a

 {\textstyle K_{\rm {d}}={k_{\rm {d}} \over k_{\rm {a}}}}

 ). [ 8 ]  Kd is the equilibrium constant for dissociation.

 K

 A

 {\textstyle K_{A}}

  is defined so that

 (

 K

 A

 )

 n

 =

 K

 d

 =

 k

 d

 k

 a

 {\textstyle (K_{A})^{n}=K_{\rm {d}}={k_{\rm {d}} \over k_{\rm {a}}}}

 , this is also known as the microscopic  dissociation constant  and is the ligand concentration occupying half of the binding sites. In recent literature, this constant is sometimes referred to as

 K

 D

 {\textstyle K_{D}}

 . [ 8 ]


The  Gaddum  equation is a further generalisation of the Hill-equation, incorporating the presence of a reversible competitive antagonist. [ 1 ]  The Gaddum equation is derived similarly to the Hill-equation but with 2 equilibria: both the ligand with the receptor and the antagonist with the receptor. Hence, the Gaddum equation has 2 constants: the equilibrium constants of the ligand and that of the antagonist


The Hill plot is the rearrangement of the Hill equation into a straight line.


Taking the reciprocal of both sides of the Hill equation, rearranging, and inverting again yields:

 θ

 1
 −
 θ

 =

 [

 L

 ]

 n

 K

 d

 =

 [

 L

 ]

 n

 (

 K

 A

 )

 n

 {\displaystyle {\theta  \over 1-\theta }={[{\ce {L}}]^{n} \over K_{d}}={[{\ce {L}}]^{n} \over (K_{A})^{n}}}

 . Taking the logarithm of both sides of the equation leads to an alternative formulation of the Hill-Langmuir equation:


This last form of the Hill equation is advantageous because a plot of

 log

 (

 θ

 1
 −
 θ

 )

 {\textstyle \log \left({\theta  \over 1-\theta }\right)}

  versus

 log

 [

 L

 ]

 {\displaystyle \log {[{\ce {L}}]}}

  yields a  linear plot , which is called a  Hill plot. [ 7 ] [ 8 ]  Because the slope of a Hill plot is equal to the Hill coefficient for the biochemical interaction, the slope is denoted by

 n

 H

 {\displaystyle n_{H}}

 . A slope greater than one thus indicates positively cooperative binding between the receptor and the ligand, while a slope less than one indicates negatively cooperative binding.


Transformations of equations into linear forms such as this were very useful before the widespread use of computers, as they allowed researchers to determine parameters by fitting lines to data. However, these transformations affect error propagation, and this may result in undue weight to error in data points near 0 or 1. [ nb 2 ]  This impacts the parameters of linear regression lines fitted to the data. Furthermore, the use of computers enables more robust analysis involving  nonlinear regression .


A distinction should be made between quantification of drugs binding to receptors and drugs producing responses. There may not necessarily be a linear relationship between the two values. In contrast to this article's previous definition of the Hill equation, the  IUPHAR  defines the Hill equation in terms of the tissue response

 (
 E
 )

 {\displaystyle (E)}

 , as [ 1 ]

 E

 E

 m
 a
 x

 =

 [
 A

 ]

 n

 EC

 50

 n

 +
 [
 A

 ]

 n

 =

 1

 1
 +

 (

 EC

 50

 [
 A
 ]

 )

 n

 {\displaystyle {\begin{aligned}{\frac {E}{E_{\mathrm {max} }}}&={\frac {[A]^{n}}{{\text{EC}}_{50}^{n}+[A]^{n}}}\\&={\frac {1}{1+\left({\frac {{\text{EC}}_{50}}{[A]}}\right)^{n}}}\end{aligned}}}

where

 [
 A
 ]

 {\displaystyle {\ce {[A]}}}

  is the drug concentration,

 n

 {\displaystyle n}

  is the Hill coefficient, and

 EC

 50

 {\displaystyle {\text{EC}}_{50}}

  is the drug concentration that produces a 50% maximal response. Dissociation constants (in the previous section) relate to ligand binding, while

 EC

 50

 {\displaystyle {\text{EC}}_{50}}

  reflects tissue response.


This form of the equation can reflect tissue/cell/population responses to drugs and can be used to generate  dose response curves . The relationship between

 K

 d

 {\displaystyle K_{d}}

  and EC50 may be quite complex as a biological response will be the sum of myriad factors; a drug will have a different biological effect if more receptors are present, regardless of its affinity.


The Del-Castillo Katz model is used to relate the Hill equation to receptor activation by including a second equilibrium of the ligand-bound receptor to an  activated  form of the ligand-bound receptor.


Statistical analysis of response as a function of stimulus may be performed by regression methods such as the  probit model  or  logit model , or other methods such as the  Spearman–Kärber method . [ 9 ]  Empirical models based on nonlinear regression are usually preferred over the use of some transformation of the data that linearizes the dose-response relationship. [ 10 ]


The Hill coefficient is a measure of  ultrasensitivity  (i.e. how steep is the response curve).


The Hill coefficient,

 n

 {\displaystyle n}

  or

 n

 H

 {\displaystyle n_{H}}

 , may describe cooperativity (or possibly other biochemical properties, depending on the context in which the Hill equation is being used). When appropriate, [ clarification needed ]  the value of the Hill coefficient describes the cooperativity of ligand binding in the following way:


The Hill coefficient can be calculated approximately in terms of the  cooperativity index  of Taketa and Pogell [ 12 ]   as follows: [ 13 ]


where

 EC

 90

 {\displaystyle {\ce {EC90}}}

  and

 EC

 10

 {\displaystyle {\ce {EC10}}}

  are the input values needed to produce the 10% and 90% of the maximal response, respectively.


The most common form of the Hill equation is its irreversible form. However, when building computational models a reversible form is often required in order to model product inhibition.  For this reason, Hofmeyr and Cornish-Bowden devised the  reversible Hill equation . [ 14 ]


The Hill coefficient is also intimately connected to the  elasticity coefficient  where the Hill coefficient can be shown to equal:


n
 =

 ε

 s

 v

 1

 1
 −
 θ

 {\displaystyle n=\varepsilon _{s}^{v}{\frac {1}{1-\theta }}}


where

 θ

 {\displaystyle \theta }

  is the fractional saturation,

 E
 S

 /

 E

 t

 {\displaystyle ES/E_{t}}

 , and

 ε

 s

 v

 {\displaystyle \varepsilon _{s}^{v}}

  the elasticity coefficient.


This is derived by taking the slope of the Hill equation:


n
 =

 d
 log

 θ

 1
 −
 θ

 d
 log

 s

 {\displaystyle n={\frac {d\log {\frac {\theta }{1-\theta }}}{d\log s}}}


and expanding the slope using the quotient rule. The result shows that the elasticity can never exceed

 n

 {\displaystyle n}

  since the equation above can be rearranged to:


ε

 s

 v

 =
 n
 (
 1
 −
 θ
 )

 {\displaystyle \varepsilon _{s}^{v}=n(1-\theta )}


The Hill equation is used extensively in pharmacology to quantify the functional parameters of a drug [ citation needed ]  and are also used in other areas of biochemistry.


The Hill equation can be used to describe dose-response relationships, for example  ion channel  open-probability (P-open) vs. ligand concentration. [ 15 ]


The Hill equation can be applied in modelling the rate at which a gene product is produced when its parent gene is being regulated by  transcription factors  (e.g.,  activators  and/or  repressors ). [ 11 ]  Doing so is appropriate when a gene is regulated by multiple binding sites for transcription factors, in which case the transcription factors may bind the DNA in a cooperative fashion. [ 16 ]


If the production of protein from gene  X  is up-regulated ( activated ) by a transcription factor  Y , then the rate of production of protein  X  can be modeled as a differential equation in terms of the concentration of activated  Y  protein:


where  k  is the maximal transcription rate of gene  X .


Likewise, if the production of protein from gene  Y  is down-regulated ( repressed ) by a transcription factor  Z , then the rate of production of protein  Y  can be modeled as a differential equation in terms of the concentration of activated  Z  protein:


where  k  is the maximal transcription rate of gene  Y .


Because of its assumption that ligand molecules bind to a receptor simultaneously, the Hill equation has been criticized as a physically unrealistic model. [ 5 ]  Moreover, the Hill coefficient should not be considered a reliable approximation of the number of cooperative ligand binding sites on a receptor [ 5 ] [ 17 ]  except when the binding of the first and subsequent ligands results in extreme positive cooperativity. [ 5 ]


Unlike more complex models, the relatively simple Hill equation provides little insight into underlying physiological mechanisms of protein-ligand interactions. This simplicity, however, is what makes the Hill equation a useful empirical model, since its use requires little  a priori  knowledge about the properties of either the protein or ligand being studied. [ 2 ]  Nevertheless, other, more complex models of cooperative binding have been proposed. [ 7 ]  For more information and examples of such models, see  Cooperative binding .


Global sensitivity measure such as Hill coefficient do not characterise the local behaviours of the s-shaped curves. Instead, these features are well captured by the response coefficient measure. [ 18 ]


There is a link between Hill Coefficient and Response coefficient, as follows. Altszyler et al. (2017) have shown that these ultrasensitivity measures can be linked. [ 13 ]


An  International Nonproprietary Name  ( INN ) is an official  generic  and nonproprietary name given to a  pharmaceutical substance  or an  active ingredient , [ 1 ]  encompassing  compounds ,  peptides  and low-molecular-weight  proteins  (e.g.,  insulin ,  hormones ,  cytokines ), as well as complex biological products, such as those used for  gene therapy . [ 2 ]  INNs are intended to make communication more precise by providing a unique standard name for each active ingredient, to avoid  prescribing  errors. [ 3 ]  The INN system was initiated by the  World Health Organization  (WHO) in 1953. [ 4 ]


Having unambiguous standard names for each pharmaceutical substance ( standardization  of  drug nomenclature ) is important because a drug may be sold under many different brand names, or a branded medication may contain more than one drug. For example, the branded medications Celexa, Celapram and Citrol all contain the same active ingredient whose INN is  citalopram . The antibacterial medication known as  co-trimoxazole  as well as those under the brand names  Bactrim  and  Septran  all contain two active ingredients easily recognisable by their INN:  trimethoprim  and  sulfamethoxazole .


The WHO publishes INNs in English,  Latin , French, Russian, Spanish,  Arabic , and  Chinese , and a drug's INNs are often  cognate  across most or all of the languages, with minor spelling or pronunciation differences, for example:  paracetamol  ( en )  paracetamolum  ( la ),  paracétamol  ( fr ) and  парацетамол  ( ru ). An established INN is known as a  recommended  INN  ( rINN ), while a name that is still being considered is called a  proposed  INN  ( pINN ). [ 4 ]


National nonproprietary names such as British Approved Names (BAN), Dénominations Communes Françaises (DCF), Japanese Adopted Names (JAN) and United States Adopted Names (USAN) are nowadays, with rare exceptions, identical to the INN. [ 3 ]


Mandate
The  World Health Organization  has a constitutional mandate to  "develop, establish and promote international standards with respect to biological, pharmaceutical and similar products".
The World Health Organization collaborates closely with INN experts and national nomenclature committees to select a single name of worldwide acceptability for each active substance that is to be marketed as a pharmaceutical. To avoid confusion, which could jeopardize the safety of patients, trade-marks should neither be derived from INNs nor contain common stems used in INNs.


Each drug's INN is unique but may contain a  stem  that is shared with other drugs of the same  class.  In this context, a stem is a syllable (or syllables) created to evoke in the name the pharmacological mechanism of action or the chemical structure of the substance. Stems are mostly placed word-finally (suffixes), but in some cases word-initial stems (prefixes) are used. For example, the  beta blocker  drugs  propranolol  and  atenolol  share the  stem  -olol  (as a  suffix ), and the benzodiazepine drugs  lorazepam  and  diazepam  share the stem  -azepam  (also a suffix)  The list of stems in use are collected in a publication informally known as the  Stem Book . [ 5 ]


Some examples of stems are:


The  School of INN  is a WHO International Nonproprietary Name Programme initiative launched in 2019, [ 6 ]  which aims to provide information to pharmacy, medical and health students, as well as health professionals and other stakeholders on how an INN is designed and constructed. [ 7 ]


Users can take self-administered courses on several topics using this free and open source learning platform. For example, the course  An Introduction to Drug Nomenclature and INN  provides the user with a general overview of drug nomenclature and how INN are obtained and constructed. The course  Learning Clinical Pharmacology (ATC classification, INN system)  provides the student with the first steps to learn pharmacology using  INN stems .


Registered students can take other courses provided by the School of INN, such as the  Stem in a pill  course,  in which each topic or course contains information correlating INN and pharmacology for a given stem, including  indications ,  mechanism of action ,  pharmacokinetics ,  contraindications , and  drug interactions  for the drugs sharing the stem. [ citation needed ]


There is also a  "How to ..."  section about INN Programme services and  MedNet INN  which enables users to carry out searches in the INN database to retrieve information on INN, its chemical information and ATC codes amonsgt other things. [ citation needed ]


The School of INN has created pilot sites in collaboration with several Universities around the globe:  University of the Western Cape (South Africa),  University of Eastern Piedmont  (Italy),  Université Grenoble Alpes  (France) and  University Ramon Lull  and  University of Alcalá  in Spain. These pilot sites are involved in disseminating the use of INN, teaching based on INN and related research activities. [ 8 ]


The term  stem  is not used consistently in  linguistics . It has been defined as a form to which  affixes  (of any type) can be attached. [ 9 ]  Under a different and apparently more common view, this is the definition of a  root , [ 10 ]  while a stem consists of the root plus optional  derivational  affixes, meaning that it is the part of a word to which  inflectional  affixes are added. [ 11 ]  INN stems employ the first definition, while under the more common alternative they would be described as roots.


Pharmacology  and  pharmacotherapy  (like  health care  generally) are universally relevant around the world, making  translingual communication  about them an important goal. An  interlingual  perspective is thus useful in  drug nomenclature . The WHO issues INNs in English, Latin, French, Russian, Spanish, Arabic, and Chinese. A drug's INNs are often  cognates  across most or all of the languages, but they also allow small  inflectional ,  diacritic , and  transliterational  differences that are usually transparent and trivial for nonspeakers (as is true of most  international scientific vocabulary ). For example, although  ibuprofenum  ( la ) has an inflectional difference from  ibuprofen  ( en ), and although  ibuprofène  ( fr ) has a diacritic difference, the differences are trivial; users can easily recognize the "same word". Although  Ибупрофе́н   ( ru ) and  ibuprofen  ( en ) have a transliteration difference, they sound similar, and for Russian speakers who can recognize  Latin script  or English speakers who can recognize  Cyrillic script , they look similar; users can recognize the "same word". Thus, INNs make medicines bought anywhere in the world as easily identifiable as possible to people who do not speak that language. Notably, the "same word" principle allows health professionals and patients who do not speak the same language to communicate to some degree and to avoid potentially life-threatening confusions from drug interactions.


To facilitate the translation and pronunciation of INN, "f" should be used instead of "ph", "t" instead of "th", "e" instead of "ae" or "oe", and "i" instead of "y"; the use of the letters "h" and "k" should be avoided. [ 12 ]  Thus a predictable spelling system, approximating  phonemic orthography , is used, as follows:


Many drugs are supplied as  salts , with a cation and an anion. The way the INN system handles these is explained by the  WHO  at its "Guidance on INN" webpage. [ 1 ]  For example,  amfetamine  and  oxacillin  are INNs, whereas various salts of these compounds – e.g.,  amfetamine sulfate  and  oxacillin sodium  – are  modified INNs  ( INNM ). [ 1 ] [ 13 ]


Several countries had created their own nonproprietary naming system before the INN was created, and in many cases, the names created under the old systems continue to be used in those countries. As one example, in English the INN name for a common painkiller is  paracetamol ; the table below gives the alternative names for this in different systems:


Other naming systems not listed above include  France 's  Dénomination Commune Française  (DCF) and  Italy 's  Denominazione Comune Italiana  (DCIT). [ 16 ]


In the realms of  toxicology  and  pathology , the  Irwin screen  is utilised to determine whether the subject(s) show adverse effects from a course of  pharmaceutical  treatment or  environmental pollution . It is an  observational   methodology . [ 1 ]


Mice were first used systematically to determine a  drug 's  central nervous system   side effects  by  S. Irwin  in 1962 and then again in 1968. [ 1 ]   Its use in the  pharmaceutical industry  has become ingrained since then, as below.


The  National Academy of Sciences  issued in 1975 a position paper on the "Principles for Evaluating Chemicals in the Environment." This paper influenced government and academic circles, and was adopted by e.g.  Brimblecombe  for his study of  atmospheric   arsenic  levels. [ 2 ]  The critical review in 1982 by Mitchell and Tilson, [ 3 ]  caused the US  EPA  to develop guidelines for several behavioural tests including a test series based on the Irwin Screen, named the Functional Observational Battery (FOB) by Sette in 1989. [ 4 ]  In 1998, the FOB was published in the late 1990s as EPA Human Health 870 Series Test Guidelines, [ 1 ] [ 5 ] [ 6 ]  and in praxis the Irwin screen and the FOB "overlap and to some extent are interchangeable." [ 1 ]


The American batteries were harmonised with the  OECD 's from the same era. [ 7 ] [ 8 ] [ 9 ] [ 10 ]  Similar tests on food chemicals were recommended by the  FDA  in their  Red Book . [ 11 ]  Behavioural test batteries are now required for new drugs by the S7A group of the  International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use  (ICH). [ citation needed ]


The Irwin screen was as of 2010 in the pharmaceutical industry almost exclusively used with  lab mice , whereas the FOB, or some modification thereof, was used with  lab rats  and other nonrodent species, such as  rabbits ,  dogs ,  guinea pigs  and  nonhuman primates . [ 1 ]


A sample Irwin screen [ 12 ]  includes overt behavior observations and autonomic observations:


Overt Behavior


Autonomic Observations


The  John J. Abel Award  is an annual award presented by the  American Society for Pharmacology and Experimental Therapeutics  (ASPET). The award is given for outstanding research in the field of pharmacology and/or experimental therapeutics; which comes with a $5000 prize, An  engraved  plaque, and all travel expenses paid to attend the ASPET Annual Meeting at Experimental Biology. [ 1 ]  The Award is named after American  biochemist  and  pharmacologist ,  John Jacob Abel .


Metreleptin , sold under the brand name  Myalept  among others, is a synthetic  analog  of the hormone  leptin  used to treat various forms of  dyslipidemia .  It has been approved in Japan for metabolic disorders including  lipodystrophy  and in the United States as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. [ 9 ]


The most common side effects include  hypoglycaemia  (low blood glucose) and weight loss. [ 8 ]


It was approved for medical use in Canada in January 2024. [ 2 ]


In the European Union, metreleptin is  indicated  in addition to diet to treat lipodystrophy, where people have a loss of fatty tissue under the skin and a build-up of fat elsewhere in the body such as in the liver and muscles. It is used in adults and children above the age of two years with  generalised lipodystrophy  ( Berardinelli-Seip syndrome  and  Lawrence syndrome ); and in adults and children above the age of twelve years with  partial lipodystrophy  (including  Barraquer-Simons syndrome ), when standard treatments have failed. [ 8 ]


In the United States, it is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in people with congenital or acquired generalized lipodystrophy. [ 7 ]


Metreleptin is being investigated for the treatment of diabetes and/or  hypertriglyceridemia , in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities. [ 10 ]  The FDA approved Metreleptin injection for treating complications of leptin deficiency in February 2014. [ medical citation needed ]


In a three-year study of metreleptin in patients with lipodystrophy organized by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, metreleptin treatment was associated with a significant decrease in blood glucose (A1c decreased from 9.4% at baseline to 7.0% at study end) and triglyceride concentration (from 500 mg/dl at baseline to 200 mg/dl at study end). [ 11 ]  Metreleptin is effective in most patients with generalized lipodystrophy where circulating leptin levels are extremely low. Analogous to  insulin replacement  for patients with  type 1 Diabetes , metreleptin restores the function of a deficient hormone. However, in patients with partial lipodystrophy where there is only a relative leptin deficiency, the response to metreleptin is not universal. [ 12 ]  This may or may not be due to anti-leptin antibodies.


Metreleptin is undergoing research for its potential benefit in the treatment of anorexia nervosa. [ 13 ]  It is hypothesized that the gradual loss of body fat mass, and more specifically the ensuing low leptin levels, escalate the preexisting drive for thinness into an obsessive-compulsive-like and addictive-like state. It was shown that short-term metreleptin treatment of patients with anorexia nervosa had rapid on-set of beneficial cognitive, emotional, and behavioral effects. [ 14 ]   Among other things, depression, drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased rapidly. Whether metreleptin (or another leptin analogue) is a suitable treatment for anorexia nervosa remains to be seen. Potential side effects are weight loss and the development of anti-metreleptin antibodies.


In a clinical study, metreleptin treatment improved  non-alcoholic steatohepatitis  (fatty liver disease) both in patients with partial lipodystrophy and in those with relative leptin deficiency. Both  steatosis  and hepatic injury scores decreased. [ 15 ]  Metreleptin reduces body weight in overweight people with low leptin levels. [ 16 ]


Although it is not very effective as a weight loss drug, leptin levels are lowered in people who have lost weight and it is hypothesized that supplemental leptin could help them with  weight loss  maintenance. However, there is no regulatory pathway for drug approval for this indication. [ 17 ]


The  micro-atmosphere method  is an  antimicrobial sensitivity testing  method involving the use of potentially  bacteriostatic  or  fungicidal  compounds which are obtained from the volatile oils of plants, such as  citronella grass . This method involves the use of  essential oils , a  growth medium , a selection of bacterial or fungal cultures, and an  incubator .


In this microbiological procedure, theoretically, the antibacterial or anti-fungal activity of the  volatile oils  from a chosen plant may be tested against a selection of  gram-positive  and  gram-negative bacteria  or a species of  fungus . The growth of the bacteria or fungi are then monitored on a timely basis to measure the  bacteriostatic  or anti-fungal activity of the volatile oils. In some cases, a complete inhibition of growth for the bacteria tested can be observed. [ citation needed ]


Before it can be tested, the  essential oils  are first diluted to produce solutions of varying concentrations. In this way, the  minimum inhibitory concentration  can be calculated to obtain the most cost-effective antimicrobial agent. [ 1 ]


Until recently, the antibacterial activity of essential oils has been primarily evaluated through direct contact methods between the pathogen and the antimicrobial agent through diffusion and dilution methods, [ 1 ] [ 2 ]  however the role of essential oils in the vapour phase as antimicrobial agents is gaining increasing significance. [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ]