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Rapid problem resolution diagnosis (or RPR diagnosis) is a method of problem diagnosis designed to determine the root cause of IT problems.
== History ==
The method was originally developed by Advance7 in 1990 as Advanced Network Troubleshooting, with the first fully documented version produced in 1995. Early versions included problem management guidance but this was removed over time as the method became more closely aligned to ITIL, and the method name was changed to Rapid Problem Resolution (RPR). RPR is now focused on Problem Diagnosis based on Root Cause Identification. Due to the highly practical nature of the Supporting Techniques and the ever changing IT landscape, Advance7 continues to develop RPR to keep it relevant to current IT environments.
Until November 2007 Advance7 made the RPR material available to its employees only, although a limited number of other IT professionals had been trained in the use of the method. In late 2007 the company announced its intention to make RPR training and material more widely available.
In March 2009 the TSO added a significant amount of RPR information to the ITIL Best Practice Live website within the areas dealing with Problem Management.
In September 2011, Advance7 published RPR: A Problem Diagnosis Method for IT Professionals which fully describes version 2.03 of the method.
== Overview ==
RPR deals with failures, incorrect output and performance issues, and its particular strengths are in the diagnosis of ongoing & recurring grey problems. The method comprises:
Core process
Supporting techniques
The core process defines a step-by-step approach to problem diagnosis and has three phases:
Discover
Gather and review existing information
Reach an agreed understanding
Investigate
Create and execute a diagnostic data capture plan
Analyse the results and iterate if necessary
Identify root cause
Fix
Translate diagnostic data
Determine and implement fix
Confirm root cause addressed
The supporting techniques detail how the objectives of the core-process steps are achieved, and cite examples using tools and techniques that are available in every business.
== Standards alignment ==
RPR has been fully aligned with ITIL v3 since RPR 2.01 was released in April 2008. RPR fits directly into the ITIL v3 problem management process as a sub-process. Some organisations handle ongoing recurring problems within incident management, and RPR also fits into the ITIL v3 incident management process as a sub-process.
COBIT also defines a problem management process (DS10) with key activity of Perform root cause analysis. RPR is a superset of this step in that it defines a process that covers all of the activities needed to perform Problem investigation & diagnosis, including Root Cause identification.
== Limitations and considerations ==
RPR has some limitations and considerations, including:
RPR deals with a single symptom at a time
RPR identifies the technical root cause of a problem, it can't be used to identify the non-technical root cause with people, process, etc.
RPR is not a forensic technique and so historical data alone is rarely sufficient
The Investigate phase requires the user to experience the problem one more time
== See also ==
ITIL v3 problem management
ITIL v3 incident management
COBIT
Grey problem
== Further reading ==
Offord, Paul (2011). RPR: A Problem Diagnosis Method for IT Professionals. Advance Seven Limited. ISBN 978-1-4478-4443-3.
RPR presentation to the British Computer Society | Wikipedia/RPR_problem_diagnosis |
As a subfield in artificial intelligence, diagnosis is concerned with the development of algorithms and techniques that are able to determine whether the behaviour of a system is correct. If the system is not functioning correctly, the algorithm should be able to determine, as accurately as possible, which part of the system is failing, and which kind of fault it is facing. The computation is based on observations, which provide information on the current behaviour.
The expression diagnosis also refers to the answer of the question of whether the system is malfunctioning or not, and to the process of computing the answer. This word comes from the medical context where a diagnosis is the process of identifying a disease by its symptoms.
== Example ==
An example of diagnosis is the process of a garage mechanic with an automobile. The mechanic will first try to detect any abnormal behavior based on the observations on the car and his knowledge of this type of vehicle. If he finds out that the behavior is abnormal, the mechanic will try to refine his diagnosis by using new observations and possibly testing the system, until he discovers the faulty component; the mechanic plays an important role in the vehicle diagnosis.
== Expert diagnosis ==
The expert diagnosis (or diagnosis by expert system) is based on experience with the system. Using this experience, a mapping is built that efficiently associates the observations to the corresponding diagnoses.
The experience can be provided:
By a human operator. In this case, the human knowledge must be translated into a computer language.
By examples of the system behaviour. In this case, the examples must be classified as correct or faulty (and, in the latter case, by the type of fault). Machine learning methods are then used to generalize from the examples.
The main drawbacks of these methods are:
The difficulty acquiring the expertise. The expertise is typically only available after a long period of use of the system (or similar systems). Thus, these methods are unsuitable for safety- or mission-critical systems (such as a nuclear power plant, or a robot operating in space). Moreover, the acquired expert knowledge can never be guaranteed to be complete. In case a previously unseen behaviour occurs, leading to an unexpected observation, it is impossible to give a diagnosis.
The complexity of the learning. The off-line process of building an expert system can require a large amount of time and computer memory.
The size of the final expert system. As the expert system aims to map any observation to a diagnosis, it will in some cases require a huge amount of storage space.
The lack of robustness. If even a small modification is made on the system, the process of constructing the expert system must be repeated.
A slightly different approach is to build an expert system from a model of the system rather than directly from an expertise. An example is the computation of a diagnoser for the diagnosis of discrete event systems. This approach can be seen as model-based, but it benefits from some advantages and suffers some drawbacks of the expert system approach.
== Model-based diagnosis ==
Model-based diagnosis is an example of abductive reasoning using a model of the system. In general, it works as follows:
We have a model that describes the behaviour of the system (or artefact). The model is an abstraction of the behaviour of the system and can be incomplete. In particular, the faulty behaviour is generally little-known, and the faulty model may thus not be represented. Given observations of the system, the diagnosis system simulates the system using the model, and compares the observations actually made to the observations predicted by the simulation.
The modelling can be simplified by the following rules (where
A
b
{\displaystyle Ab\,}
is the Abnormal predicate):
¬
A
b
(
S
)
⇒
I
n
t
1
∧
O
b
s
1
{\displaystyle \neg Ab(S)\Rightarrow Int1\wedge Obs1}
A
b
(
S
)
⇒
I
n
t
2
∧
O
b
s
2
{\displaystyle Ab(S)\Rightarrow Int2\wedge Obs2}
(fault model)
The semantics of these formulae is the following: if the behaviour of the system is not abnormal (i.e. if it is normal), then the internal (unobservable) behaviour will be
I
n
t
1
{\displaystyle Int1\,}
and the observable behaviour
O
b
s
1
{\displaystyle Obs1\,}
. Otherwise, the internal behaviour will be
I
n
t
2
{\displaystyle Int2\,}
and the observable behaviour
O
b
s
2
{\displaystyle Obs2\,}
. Given the observations
O
b
s
{\displaystyle Obs\,}
, the problem is to determine whether the system behaviour is normal or not (
¬
A
b
(
S
)
{\displaystyle \neg Ab(S)\,}
or
A
b
(
S
)
{\displaystyle Ab(S)\,}
). This is an example of abductive reasoning.
== Diagnosability ==
A system is said to be diagnosable if whatever the behavior of the system, we will be able to determine without ambiguity a unique diagnosis.
The problem of diagnosability is very important when designing a system because on one hand one may want to reduce the number of sensors to reduce the cost, and on the other hand one may want to increase the number of sensors to increase the probability of detecting a faulty behavior.
Several algorithms for dealing with these problems exist. One class of algorithms answers the question whether a system is diagnosable; another class looks for sets of sensors that make the system diagnosable, and optionally comply to criteria such as cost optimization.
The diagnosability of a system is generally computed from the model of the system. In applications using model-based diagnosis, such a model is already present and doesn't need to be built from scratch.
== Bibliography ==
Hamscher, W.; L. Console; J. de Kleer (1992). Readings in model-based diagnosis. San Francisco, CA, USA: Morgan Kaufmann Publishers Inc. ISBN 1-55860-249-6.
== See also ==
Artificial intelligence in healthcare
AI effect
Applications of artificial intelligence
Epistemology
List of emerging technologies
Outline of artificial intelligence
== External links ==
=== DX workshops ===
DX is the annual International Workshop on Principles of Diagnosis that started in 1989.
DX 2016
DX 2015
DX 2014
DX 2013
DX 2012 Archived 2015-05-24 at the Wayback Machine
DX 2011
DX 2010
DX 2009 Archived 2008-10-22 at the Wayback Machine
DX 2008 Archived 2008-09-08 at the Wayback Machine
DX 2007
DX 2006
DX 2005
DX 2004
DX 2003
DX 2002
DX 2001
DX 2000 Archived 2006-09-13 at the Wayback Machine
DX 1999
DX 1998
DX 1997 | Wikipedia/Diagnosis_(artificial_intelligence) |
Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.
The field encompasses drug composition and properties, functions, sources, synthesis and drug design, molecular and cellular mechanisms, organ/systems mechanisms, signal transduction/cellular communication, molecular diagnostics, interactions, chemical biology, therapy, and medical applications and antipathogenic capabilities. The two main areas of pharmacology are pharmacodynamics and pharmacokinetics. Pharmacodynamics studies the effects of a drug on biological systems, and pharmacokinetics studies the effects of biological systems on a drug. In broad terms, pharmacodynamics discusses the chemicals with biological receptors, and pharmacokinetics discusses the absorption, distribution, metabolism, and excretion (ADME) of chemicals from the biological systems.
Pharmacology is not synonymous with pharmacy and the two terms are frequently confused. Pharmacology, a biomedical science, deals with the research, discovery, and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals. In contrast, pharmacy, a health services profession, is concerned with the application of the principles learned from pharmacology in its clinical settings; whether it be in a dispensing or clinical care role. In either field, the primary contrast between the two is their distinctions between direct-patient care, pharmacy practice, and the science-oriented research field, driven by pharmacology.
== Etymology ==
The word pharmacology is derived from Greek word φάρμακον, pharmakon, meaning "drug" or "poison", together with another Greek word -λογία, logia with the meaning of "study of" or "knowledge of" (cf. the etymology of pharmacy). Pharmakon is related to pharmakos, the ritualistic sacrifice or exile of a human scapegoat or victim in Ancient Greek religion.
The modern term pharmacon is used more broadly than the term drug because it includes endogenous substances, and biologically active substances which are not used as drugs. Typically it includes pharmacological agonists and antagonists, but also enzyme inhibitors (such as monoamine oxidase inhibitors).
== History ==
The origins of clinical pharmacology date back to the Middle Ages, with pharmacognosy and Avicenna's The Canon of Medicine, Peter of Spain's Commentary on Isaac, and John of St Amand's Commentary on the Antedotary of Nicholas. Early pharmacology focused on herbalism and natural substances, mainly plant extracts. Medicines were compiled in books called pharmacopoeias. Crude drugs have been used since prehistory as a preparation of substances from natural sources. However, the active ingredient of crude drugs are not purified and the substance is adulterated with other substances.
Traditional medicine varies between cultures and may be specific to a particular culture, such as in traditional Chinese, Mongolian, Tibetan and Korean medicine. However much of this has since been regarded as pseudoscience. Pharmacological substances known as entheogens may have spiritual and religious use and historical context.
In the 17th century, the English physician Nicholas Culpeper translated and used pharmacological texts. Culpeper detailed plants and the conditions they could treat. In the 18th century, much of clinical pharmacology was established by the work of William Withering. Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period. Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such as morphine, quinine and digitalis were explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues. The first pharmacology department was set up by Rudolf Buchheim in 1847, at University of Tartu, in recognition of the need to understand how therapeutic drugs and poisons produced their effects. Subsequently, the first pharmacology department in England was set up in 1905 at University College London.
Pharmacology developed in the 19th century as a biomedical science that applied the principles of scientific experimentation to therapeutic contexts. The advancement of research techniques propelled pharmacological research and understanding. The development of the organ bath preparation, where tissue samples are connected to recording devices, such as a myograph, and physiological responses are recorded after drug application, allowed analysis of drugs' effects on tissues. The development of the ligand binding assay in 1945 allowed quantification of the binding affinity of drugs at chemical targets. Modern pharmacologists use techniques from genetics, molecular biology, biochemistry, and other advanced tools to transform information about molecular mechanisms and targets into therapies directed against disease, defects or pathogens, and create methods for preventive care, diagnostics, and ultimately personalized medicine.
== Divisions ==
The discipline of pharmacology can be divided into many sub disciplines each with a specific focus.
=== Systems of the body ===
Pharmacology can also focus on specific systems comprising the body. Divisions related to bodily systems study the effects of drugs in different systems of the body. These include neuropharmacology, in the central and peripheral nervous systems; immunopharmacology in the immune system. Other divisions include cardiovascular, renal and endocrine pharmacology. Psychopharmacology is the study of the use of drugs that affect the psyche, mind and behavior (e.g. antidepressants) in treating mental disorders (e.g. depression). It incorporates approaches and techniques from neuropharmacology, animal behavior and behavioral neuroscience, and is interested in the behavioral and neurobiological mechanisms of action of psychoactive drugs. The related field of neuropsychopharmacology focuses on the effects of drugs at the overlap between the nervous system and the psyche.
Pharmacometabolomics, also known as pharmacometabonomics, is a field which stems from metabolomics, the quantification and analysis of metabolites produced by the body. It refers to the direct measurement of metabolites in an individual's bodily fluids, in order to predict or evaluate the metabolism of pharmaceutical compounds, and to better understand the pharmacokinetic profile of a drug. Pharmacometabolomics can be applied to measure metabolite levels following the administration of a drug, in order to monitor the effects of the drug on metabolic pathways. Pharmacomicrobiomics studies the effect of microbiome variations on drug disposition, action, and toxicity. Pharmacomicrobiomics is concerned with the interaction between drugs and the gut microbiome. Pharmacogenomics is the application of genomic technologies to drug discovery and further characterization of drugs related to an organism's entire genome. For pharmacology regarding individual genes, pharmacogenetics studies how genetic variation gives rise to differing responses to drugs. Pharmacoepigenetics studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.
=== Clinical practice and drug discovery ===
Pharmacology can be applied within clinical sciences. Clinical pharmacology is the application of pharmacological methods and principles in the study of drugs in humans. An example of this is posology, which is the study of dosage of medicines.
Pharmacology is closely related to toxicology. Both pharmacology and toxicology are scientific disciplines that focus on understanding the properties and actions of chemicals. However, pharmacology emphasizes the therapeutic effects of chemicals, usually drugs or compounds that could become drugs, whereas toxicology is the study of chemical's adverse effects and risk assessment.
Pharmacological knowledge is used to advise pharmacotherapy in medicine and pharmacy.
==== Drug discovery ====
Drug discovery is the field of study concerned with creating new drugs. It encompasses the subfields of drug design and development. Drug discovery starts with drug design, which is the inventive process of finding new drugs. In the most basic sense, this involves the design of molecules that are complementary in shape and charge to a given biomolecular target. After a lead compound has been identified through drug discovery, drug development involves bringing the drug to the market. Drug discovery is related to pharmacoeconomics, which is the sub-discipline of health economics that considers the value of drugs. Pharmacoeconomics evaluates the cost and benefits of drugs in order to guide optimal healthcare resource allocation. The techniques used for the discovery, formulation, manufacturing and quality control of drugs discovery is studied by pharmaceutical engineering, a branch of engineering. Safety pharmacology specialises in detecting and investigating potential undesirable effects of drugs.
Development of medication is a vital concern to medicine, but also has strong economical and political implications. To protect the consumer and prevent abuse, many governments regulate the manufacture, sale, and administration of medication. In the United States, the main body that regulates pharmaceuticals is the Food and Drug Administration; they enforce standards set by the United States Pharmacopoeia. In the European Union, the main body that regulates pharmaceuticals is the European Medicines Agency (EMA), and they enforce standards set by the European Pharmacopoeia.
The metabolic stability and the reactivity of a library of candidate drug compounds have to be assessed for drug metabolism and toxicological studies. Many methods have been proposed for quantitative predictions in drug metabolism; one example of a recent computational method is SPORCalc. A slight alteration to the chemical structure of a medicinal compound could alter its medicinal properties, depending on how the alteration relates to the structure of the substrate or receptor site on which it acts: this is called the structural activity relationship (SAR). When a useful activity has been identified, chemists will make many similar compounds called analogues, to try to maximize the desired medicinal effect(s). This can take anywhere from a few years to a decade or more, and is very expensive. One must also determine how safe the medicine is to consume, its stability in the human body and the best form for delivery to the desired organ system, such as tablet or aerosol. After extensive testing, which can take up to six years, the new medicine is ready for marketing and selling.
Because of these long timescales, and because out of every 5000 potential new medicines typically only one will ever reach the open market, this is an expensive way of doing things, often costing over 1 billion dollars. To recoup this outlay pharmaceutical companies may do a number of things:
Carefully research the demand for their potential new product before spending an outlay of company funds.
Obtain a patent on the new medicine preventing other companies from producing that medicine for a certain allocation of time.
The inverse benefit law describes the relationship between a drugs therapeutic benefits and its marketing.
When designing drugs, the placebo effect must be considered to assess the drug's true therapeutic value.
Drug development uses techniques from medicinal chemistry to chemically design drugs. This overlaps with the biological approach of finding targets and physiological effects.
=== Wider contexts ===
Pharmacology can be studied in relation to wider contexts than the physiology of individuals. For example, pharmacoepidemiology concerns the variations of the effects of drugs in or between populations, it is the bridge between clinical pharmacology and epidemiology. Pharmacoenvironmentology or environmental pharmacology is the study of the effects of used pharmaceuticals and personal care products (PPCPs) on the environment after their elimination from the body. Human health and ecology are intimately related so environmental pharmacology studies the environmental effect of drugs and pharmaceuticals and personal care products in the environment.
Drugs may also have ethnocultural importance, so ethnopharmacology studies the ethnic and cultural aspects of pharmacology.
=== Emerging fields ===
Photopharmacology is an emerging approach in medicine in which drugs are activated and deactivated with light. The energy of light is used to change for shape and chemical properties of the drug, resulting in different biological activity. This is done to ultimately achieve control when and where drugs are active in a reversible manner, to prevent side effects and pollution of drugs into the environment.
Epigenetic therapy may offer an alternative 'master switch' to gene therapy to introduce persistent changes to the phenotype. Aging is well-known to be measurable through epigenetic clock.
Drugs mays induce persistent changes. When they cause drugs to lose efficacy, it is called drug tolerance. On the other hand, they may introduce benign changes to the body. Psychoplastogen produce profound effects by regulating neuroplasticity. Psychostimulants prevent grey matter loss in ADHD patients, at therapeutic doses.
== Theory of pharmacology ==
Pharmacology is the scientific study of drugs and their interactions with living systems. it is broadly divided into two main branches: Pharmacokinetics and Pharmacodynamics.
=== Pharmacokinetics(pk) ===
Pharmacokinetics refers to the movement of drugs within the body and describes what the body does to a drug. It includes four main processes:
Absorption- How the drug enters the bloodstream.
Distribution- How the drug spreads throughout the body's tissue and fluids.
Metabolism- How the drug is chemically altered, primarily in the liver.
Excretion- How the drug and its metabolites are eliminated, mainly through the kidneys.
Key parameters in pharmacokinetics include:
Half-life (t1/2): The time required for the drug's plasma concentration to reduce by half.
Volume of distribution (Vd): A theoretical volume that related the amount of drug in the body to the concentration in the blood.
Clearance (Cl): The rate at which a drug is removed from the body.
=== Pharmacodynamics (PD): ===
Pharmacodynamics refers to the biochemical and physiological effects of drugs on the body and the mechanism of the action. it answers the question, "What does the drug do to the body?"
This include :
Receptor binding- Most drugs exert their effects by binding to specific cell receptors (proteins on cell surfaces or inside cells)
Dose-response relationship: Illustrated using drug- response curves, these relationships show the effect of different drug doses on the magnitude of a response.
Therapeutic window- The range of doses between the minimum effective concentration and the minimum toxic concentration.
=== Systems, receptors and ligands ===
Pharmacology is typically studied with respect to particular systems, for example endogenous neurotransmitter systems. The major systems studied in pharmacology can be categorised by their ligands and include acetylcholine, adrenaline, glutamate, GABA, dopamine, histamine, serotonin, cannabinoid and opioid.
Molecular targets in pharmacology include receptors, enzymes and membrane transport proteins. Enzymes can be targeted with enzyme inhibitors. Receptors are typically categorised based on structure and function. Major receptor types studied in pharmacology include G protein coupled receptors, ligand gated ion channels and receptor tyrosine kinases.
Network pharmacology is a subfield of pharmacology that combines principles from pharmacology, systems biology, and network analysis to study the complex interactions between drugs and targets (e.g., receptors or enzymes etc.) in biological systems. The topology of a biochemical reaction network determines the shape of drug dose-response curve as well as the type of drug-drug interactions, thus can help designing efficient and safe therapeutic strategies. The topology Network pharmacology utilizes computational tools and network analysis algorithms to identify drug targets, predict drug-drug interactions, elucidate signaling pathways, and explore the polypharmacology of drugs.
=== Pharmacodynamics ===
Pharmacodynamics is defined as how the body reacts to the drugs. Pharmacodynamics theory often investigates the binding affinity of ligands to their receptors. Ligands can be agonists, partial agonists or antagonists at specific receptors in the body. Agonists bind to receptors and produce a biological response, a partial agonist produces a biological response lower than that of a full agonist, antagonists have affinity for a receptor but do not produce a biological response.
The ability of a ligand to produce a biological response is termed efficacy, in a dose-response profile it is indicated as percentage on the y-axis, where 100% is the maximal efficacy (all receptors are occupied).
Binding affinity is the ability of a ligand to form a ligand-receptor complex either through weak attractive forces (reversible) or covalent bond (irreversible), therefore efficacy is dependent on binding affinity.
Potency of drug is the measure of its effectiveness, EC50 is the drug concentration of a drug that produces an efficacy of 50% and the lower the concentration the higher the potency of the drug therefore EC50 can be used to compare potencies of drugs.
Medication is said to have a narrow or wide therapeutic index, certain safety factor or therapeutic window. This describes the ratio of desired effect to toxic effect. A compound with a narrow therapeutic index (close to one) exerts its desired effect at a dose close to its toxic dose. A compound with a wide therapeutic index (greater than five) exerts its desired effect at a dose substantially below its toxic dose. Those with a narrow margin are more difficult to dose and administer, and may require therapeutic drug monitoring (examples are warfarin, some antiepileptics, aminoglycoside antibiotics). Most anti-cancer drugs have a narrow therapeutic margin: toxic side-effects are almost always encountered at doses used to kill tumors.
The effect of drugs can be described with Loewe additivity which is one of several common reference models.
Other models include the Hill equation, Cheng-Prusoff equation and Schild regression.
=== Pharmacokinetics ===
Pharmacokinetics is the study of the bodily absorption, distribution, metabolism, and excretion of drugs.
When describing the pharmacokinetic properties of the chemical that is the active ingredient or active pharmaceutical ingredient (API), pharmacologists are often interested in L-ADME:
Liberation – How is the API disintegrated (for solid oral forms (breaking down into smaller particles), dispersed, or dissolved from the medication?
Absorption – How is the API absorbed (through the skin, the intestine, the oral mucosa)?
Distribution – How does the API spread through the organism?
Metabolism – Is the API converted chemically inside the body, and into which substances. Are these active (as well)? Could they be toxic?
Excretion – How is the API excreted (through the bile, urine, breath, skin)?
Drug metabolism is assessed in pharmacokinetics and is important in drug research and prescribing.
Pharmacokinetics is the movement of the drug in the body, it is usually described as 'what the body does to the drug' the physico-chemical properties of a drug will affect the rate and extent of absorption, extent of distribution, metabolism and elimination. The drug needs to have the appropriate molecular weight, polarity etc. in order to be absorbed, the fraction of a drug that reaches the systemic circulation is termed bioavailability, this is simply a ratio of the peak plasma drug levels after oral administration and the drug concentration after an IV administration (first pass effect is avoided and therefore no amount drug is lost). A drug must be lipophilic (lipid soluble) in order to pass through biological membranes because biological membranes are made up of a lipid bilayer (phospholipids etc.). Once the drug reaches the blood circulation it is then distributed throughout the body and being more concentrated in highly perfused organs.
=== Gene expression modulation and epigenetics ===
Apart from classical pharmacological targets, drugs may exert effects through direct or indirect gene expression modulation, or even introduce persistent state changes through epigenetic reprogramming.
Therefore, drugs should be screened for off-target activity by gene expression profiling, in addition to conventional ligand binding, enzyme assays, etc.
== Administration, drug policy and safety ==
=== Drug policy ===
In the United States, the Food and Drug Administration (FDA) is responsible for creating guidelines for the approval and use of drugs. The FDA requires that all approved drugs fulfill two requirements:
The drug must be found to be effective against the disease for which it is seeking approval (where 'effective' means only that the drug performed better than placebo or competitors in at least two trials).
The drug must meet safety criteria by being subject to animal and controlled human testing.
Gaining FDA approval usually takes several years. Testing done on animals must be extensive and must include several species to help in the evaluation of both the effectiveness and toxicity of the drug. The dosage of any drug approved for use is intended to fall within a range in which the drug produces a therapeutic effect or desired outcome.
The safety and effectiveness of prescription drugs in the U.S. are regulated by the federal Prescription Drug Marketing Act of 1987.
The Medicines and Healthcare products Regulatory Agency (MHRA) has a similar role in the UK.
Medicare Part D is a prescription drug plan in the U.S.
The Prescription Drug Marketing Act (PDMA) is an act related to drug policy.
Prescription drugs are drugs regulated by legislation.
== Societies and education ==
=== Societies and administration ===
The International Union of Basic and Clinical Pharmacology, Federation of European Pharmacological Societies and European Association for Clinical Pharmacology and Therapeutics are organisations representing standardisation and regulation of clinical and scientific pharmacology.
Systems for medical classification of drugs with pharmaceutical codes have been developed. These include the National Drug Code (NDC), administered by Food and Drug Administration; Drug Identification Number (DIN), administered by Health Canada under the Food and Drugs Act; Hong Kong Drug Registration, administered by the Pharmaceutical Service of the Department of Health (Hong Kong) and National Pharmaceutical Product Index in South Africa. Hierarchical systems have also been developed, including the Anatomical Therapeutic Chemical Classification System (AT, or ATC/DDD), administered by World Health Organization; Generic Product Identifier (GPI), a hierarchical classification number published by MediSpan and SNOMED, C axis. Ingredients of drugs have been categorised by Unique Ingredient Identifiers.
=== Education ===
The study of pharmacology overlaps with biomedical sciences and is the study of the effects of drugs on living organisms. Pharmacological research can lead to new drug discoveries, and promote a better understanding of human physiology. Students of pharmacology must have a detailed working knowledge of aspects in physiology, pathology, and chemistry. They may also require knowledge of plants as sources of pharmacologically active compounds. Modern pharmacology is interdisciplinary and involves biophysical and computational sciences, and analytical chemistry. A pharmacist needs to be well-equipped with knowledge on pharmacology for application in pharmaceutical research or pharmacy practice in hospitals or commercial organisations selling to customers. Pharmacologists, however, usually work in a laboratory undertaking research or development of new products. Pharmacological research is important in academic research (medical and non-medical), private industrial positions, science writing, scientific patents and law, consultation, biotech and pharmaceutical employment, the alcohol industry, food industry, forensics/law enforcement, public health, and environmental/ecological sciences. Pharmacology is often taught to pharmacy and medicine students as part of a Medical School curriculum.
== See also ==
== References ==
== External links ==
American Society for Pharmacology and Experimental Therapeutics
British Pharmacological Society
International Conference on Harmonisation
US Pharmacopeia
International Union of Basic and Clinical Pharmacology
IUPHAR Committee on Receptor Nomenclature and Drug Classification
IUPHAR/BPS Guide to Pharmacology
== Further reading ==
Foreman, John C.; Johansen, Torben; Gibb, Alasdair J., eds. (2010). Textbook of Receptor Pharmacology. doi:10.1201/9781420052558. ISBN 978-0-429-14730-2.
Brunton L (2011). Brunton LL, Chabner B, Knollmann BC (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12 ed.). New York: McGraw-Hill. ISBN 978-0-07-162442-8.
Whalen K (2014). Lippincott Illustrated Reviews: Pharmacology. | Wikipedia/pharmacology |
In pharmacology, pleiotropy includes all of a drug's actions other than those for which the agent was specifically developed. It may include adverse effects which are detrimental ones, but is often used to denote additional beneficial effects.
For example, statins are HMG-CoA reductase inhibitors that primarily act by decreasing cholesterol synthesis, but which are believed to have other beneficial effects, including acting as antioxidants and stabilizing atherosclerotic plaques. Steroid drugs, such as prednisone and prednisolone, have pleiotropic effects, including systemic ones, for the same reason that endogenous steroid hormones do: cells throughout the body have receptors that can respond to them, because the endogenous ones are endocrine messengers.
Another example is melatonin, which has a wide range of effects on biological systems on multiple scales, from modulating the circadian rhythm and inducing sleep via the activation of melatoninergic receptors, to recepto-independent antioxydative and anti-inflammatory effects over all organs down to cells.
== See also ==
Adverse effect
Pleiotropy in genetics
== References == | Wikipedia/Pleiotropy_(drugs) |
Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compounds undergo more extensive optimization in a subsequent step of drug discovery called lead optimization (LO). The drug discovery process generally follows the following path that includes a hit to lead stage:
Target validation (TV) → Assay development → High-throughput screening (HTS) → Hit to lead (H2L) → Lead optimization (LO) → Preclinical development → Clinical development
The hit to lead stage starts with confirmation and evaluation of the initial screening hits and is followed by synthesis of analogs (hit expansion). Typically the initial screening hits display binding affinities for their biological target in the micromolar (10−6 molar concentration) range. Through limited H2L optimization, the affinities of the hits are often improved by several orders of magnitude to the nanomolar (10−9 M) range. The hits also undergo limited optimization to improve metabolic half life so that the compounds can be tested in animal models of disease and also to improve selectivity against other biological targets binding that may result in undesirable side effects.
On average, only one in every 5,000 compounds that enters drug discovery to the stage of preclinical development becomes an approved drug.
== Hit confirmation ==
After hits are identified from a high throughput screen, the hits are confirmed and evaluated using the following methods:
Confirmatory testing: compounds that were found active against the selected target are re-tested using the same assay conditions used during the HTS to make sure that the activity is reproducible.
Dose response curve: the compound is tested over a range of concentrations to determine the concentration that results in half maximal binding or activity (IC50 or EC50 value respectively).
Orthogonal testing: confirmed hits are assayed using a different assay which is usually closer to the target physiological condition or using a different technology.
Secondary screening: confirmed hits are tested in a functional cellular assay to determine efficacy.
Synthetic tractability: medicinal chemists evaluate compounds according to their synthesis feasibility and other parameters such as up-scaling or cost of goods.
Biophysical testing: nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), dynamic light scattering (DLS), surface plasmon resonance (SPR), dual polarisation interferometry (DPI), microscale thermophoresis (MST) are commonly used to assess whether the compound binds effectively to the target, the kinetics, thermodynamics, and stoichiometry of binding, any associated conformational change and to rule out promiscuous binding.
Hit ranking and clustering: Confirmed hit compounds are then ranked according to the various hit confirmation experiments.
Freedom to operate evaluation: hit structures are checked in specialized databases to determine if they are patentable.
== Hit expansion ==
Following hit confirmation, several compound clusters will be chosen according to their characteristics in the previously defined tests. An Ideal compound cluster will contain members that possess:
high affinity towards the target (less than 1 μM)
selectivity versus other targets
significant efficacy in a cellular assay
druglikeness (moderate molecular weight and lipophilicity usually estimated as ClogP). Affinity, molecular weight and lipophilicity can be linked in single parameter such as ligand efficiency and lipophilic efficiency.
low to moderate binding to human serum albumin
low interference with P450 enzymes and P-glycoproteins
low cytotoxicity
metabolic stability
high cell membrane permeability
sufficient water solubility (above 10 μM)
chemical stability
synthetic tractability
patentability
The project team will usually select between three and six compound series to be further explored. The next step will allow the testing of analogous compounds to determine a quantitative structure-activity relationship (QSAR). Analogs can be quickly selected from an internal library or purchased from commercially available sources ("SAR by catalog" or "SAR by purchase"). Medicinal chemists will also start synthesizing related compounds using different methods such as combinatorial chemistry, high-throughput chemistry, or more classical organic chemistry synthesis.
== Lead optimization phase ==
The objective of this drug discovery phase is to synthesize lead compounds, new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics. This optimization is accomplished through chemical modification of the hit structure, with modifications chosen by employing knowledge of the structure–activity relationship (SAR) as well as structure-based design if structural information about the target is available.
Lead optimization is concerned with experimental testing and confirmation of the compound based on animal efficacy models and ADMET (in vitro and in situ) tools that may be followed by target identification and target validation.
== Best Practices for Hit Finding ==
For educational purposes the European Federation for Medicinal Chemistry and Chemical Biology (EFMC) shared a series of webinars including 'Best Practices for Hit Finding' as well as 'Hit Generation Case Studies'.
== See also ==
== References == | Wikipedia/Drug_Discovery_Hit_to_Lead |
Antimicrobial pharmacodynamics is the relationship between the concentration of an antibiotic and its ability to inhibit vital processes of endo- or ectoparasites and microbial organisms. This branch of pharmacodynamics relates the concentration of an anti-infective agent to its effect, specifically to its antimicrobial effect.
== Concentration-dependent effects ==
The minimum inhibitory concentration (MIC) and minimum bactericidal concentration are used to measure in vitro activity of antimicrobial agents. They are good indicators of antimicrobial potency, but don't give any information relating to time-dependent antimicrobial killing (the so-called post antibiotic effect).
== Post-antibiotic effect ==
The post-antibiotic effect (PAE) is defined as persistent suppression of bacterial growth after a brief exposure (1 or 2 hours) of bacteria to an antibiotic even in the absence of host defense mechanisms. Factors that affect the duration of the post-antibiotic effect include duration of antibiotic exposure, bacterial species, culture medium and class of antibiotic. It has been suggested that an alteration of DNA function is possibly responsible for the post-antibiotic effect following the observation that most inhibitors of protein and nucleic acid synthesis (aminoglycosides, fluoroquinolones, tetracyclines, clindamycin, certain newer macrolides/ketolides, and rifampicin and rifabutin) induce long-term PAE against susceptible bacteria. Theoretically, the ability of an antibiotic to induce a PAE is an attractive property since antibiotic concentrations could fall below the MIC for the bacterium yet retain their effectiveness in their ability to suppress the growth. Therefore, an antibiotic with PAE would require less frequent administration and it could improve patient adherence with regard to pharmacotherapy. Proposed mechanisms include (1) slow recovery after reversible nonlethal damage to cell structures; (2) persistence of the drug at a binding site or within the periplasmic space; and (3) the need to synthesize new enzymes before growth can resume. Most antimicrobials possess significant in vitro PAEs (≥ 1.5 hours) against susceptible gram-positive cocci. Antimicrobials with significant PAEs against susceptible gram-negative bacilli are limited to carbapenems and agents that inhibit protein or DNA synthesis.
== References == | Wikipedia/Antimicrobial_pharmacodynamics |
Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse through cell membranes. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, and α, β‚ and γ globulins.
== Binding (drug distribution) ==
A drug in blood exists in two forms: bound and unbound. Depending on a specific drug's affinity for plasma proteins, a proportion of the drug may become bound to the proteins, with the remainder being unbound. If the protein binding is reversible, then a chemical equilibrium will exist between the bound and unbound states, such that:
Protein + drug ⇌ Protein-drug complex
Notably, it is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be metabolized and/or excreted. For example, the "fraction bound" of the anticoagulant warfarin is 97%. This means that out of the amount of warfarin in the blood, 97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction that is actually active and may be excreted.
Protein binding can influence the drug's biological half-life. The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. Since the unbound form is being metabolized and/or excreted from the body, the bound fraction will be released in order to maintain equilibrium.
Since albumin is alkalotic, acidic and neutral drugs will primarily bind to albumin. If albumin becomes saturated, then these drugs will bind to lipoprotein. Basic drugs will bind to the acidic alpha-1 acid glycoprotein. This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins.
== Impact of the altered protein binding ==
Only the unbound fraction of the drug undergoes metabolism in the liver and other tissues. As the drug dissociates from the protein, more and more drug undergoes metabolism. Changes in the levels of free drug change the volume of distribution because free drug may distribute into the tissues leading to a decrease in plasma concentration profile. For the drugs which rapidly undergo metabolism, clearance is dependent on the hepatic blood flow. For drugs which slowly undergo metabolism, changes in the unbound fraction of the drug directly change the clearance of the drug.
The most commonly used methods for measuring drug concentration levels in the plasma measure bound as well as unbound fractions of the drug.
The fraction unbound can be altered by a number of variables, such as the concentration of drug in the body, the amount and quality of plasma protein, and other drugs that bind to plasma proteins. Higher drug concentrations would lead to a higher fraction unbound, because the plasma protein would be saturated with drug and any excess drug would be unbound. If the amount of plasma protein is decreased (such as in catabolism, malnutrition, liver disease, renal disease), there would also be a higher fraction unbound. Additionally, the quality of the plasma protein may affect how many drug-binding sites there are on the protein.
=== Drug interactions ===
Using 2 drugs at the same time can sometimes affect each other's fraction unbound. For example, assume that Drug A and Drug B are both protein-bound drugs. If Drug A is given, it will bind to the plasma proteins in the blood. If Drug B is also given, it can displace Drug A from the protein, thereby increasing Drug A's fraction unbound. This may increase the effects of Drug A, since only the unbound fraction may exhibit activity.
Note that for Drug A, the % increase in unbound fraction is 100% – hence, Drug A's pharmacological effect can potentially double (depending on whether the free molecules get to their target before they are eliminated by metabolism or excretion). This change in pharmacologic effect could have adverse consequences.
However, this effect is really only noticeable in closed systems where the pool of available proteins could potentially be exceeded by the number of drug molecules. Biological systems, such as humans and animals, are open systems where molecules can be gained, lost or redistributed and where the protein pool capacity is almost never exceeded by the number of drug molecules. A drug that is 99% bound means that 99% of the drug molecules are bound to blood proteins not that 99% of the blood proteins are bound with drug. When two, highly protein-bound drugs (A and B) are added into the same biological system it will lead to an initial small increase in the concentration of free drug A (as drug B ejects some of the drug A from its proteins). However, this free drug A is now more available for redistribution into the body tissues and/or for excretion. This means the total amount of drug in the system will decrease quite rapidly, keeping the free drug fraction (the concentration of free drug divided by the total drug concentration) constant and yielding almost no change in clinical effect.
The effects of drugs displacing each other and changing the clinical effect (though important in some examples) is vastly overestimated usually and a common example incorrectly used to display the importance of this effect is the anticoagulant warfarin. Warfarin is highly protein-bound (>95%) and has a low therapeutic index. Since a low therapeutic index indicates that there is a high risk of toxicity when using the drug, any potential increases in warfarin concentration could be very dangerous and lead to hemorrhage. In horses, it is very true that if warfarin and phenylbutazone are administered concurrently, the horse can develop bleeding issues which can be fatal. This is often explained as being due to the effect of phenylbutazone ejecting warfarin from its plasma protein, thus increasing the concentration of free warfarin and increasing its anticoagulant effect. However, the real problem is that phenylbutazone interferes with the liver's ability to metabolize warfarin so free warfarin cannot be metabolized properly or excreted. This leads to an increase in free warfarin and the resulting bleeding problems.
== See also ==
Blood proteins
Pharmacokinetics
== References ==
== Further reading ==
Shargel, Leon (2005). Applied Biopharmaceutics & Pharmacokinetics. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-137550-3. | Wikipedia/Plasma_protein_binding |
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops (three extracellular loops interacting with ligand molecules, three intracellular loops interacting with G proteins, an N-terminal extracellular region and a C-terminal intracellular region) of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (rhodopsin-like family). They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.
G protein-coupled receptors are found only in eukaryotes, including yeast, and choanoflagellates. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters. They vary in size from small molecules to peptides, to large proteins. G protein-coupled receptors are involved in many diseases.
There are two principal signal transduction pathways involving the G protein-coupled receptors:
the cAMP signal pathway and
the phosphatidylinositol signal pathway.
When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).: 1160
GPCRs are an important drug target, and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018. It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of the pharmaceutical research.
== History and significance ==
With the determination of the first structure of the complex between a G-protein coupled receptor (GPCR) and a G-protein trimer (Gαβγ) in 2011 a new chapter of GPCR research was opened for structural investigations of global switches with more than one protein being investigated. The previous breakthroughs involved determination of the crystal structure of the first GPCR, rhodopsin, in 2000 and the crystal structure of the first GPCR with a diffusible ligand (β2AR) in 2007. The way in which the seven transmembrane helices of a GPCR are arranged into a bundle was suspected based on the low-resolution model of frog rhodopsin from cryogenic electron microscopy studies of the two-dimensional crystals. The crystal structure of rhodopsin, that came up three years later, was not a surprise apart from the presence of an additional cytoplasmic helix H8 and a precise location of a loop covering retinal binding site. However, it provided a scaffold which was hoped to be a universal template for homology modeling and drug design for other GPCRs – a notion that proved to be too optimistic.
Results 7 years later were surprising because the crystallization of β2-adrenergic receptor (β2AR) with a diffusible ligand revealed quite a different shape of the receptor extracellular side than that of rhodopsin. This area is important because it is responsible for the ligand binding and is targeted by many drugs. Moreover, the ligand binding site was much more spacious than in the rhodopsin structure and was open to the exterior. In the other receptors crystallized shortly afterwards the binding side was even more easily accessible to the ligand. New structures complemented with biochemical investigations uncovered mechanisms of action of molecular switches which modulate the structure of the receptor leading to activation states for agonists or to complete or partial inactivation states for inverse agonists.
The 2012 Nobel Prize in Chemistry was awarded to Brian Kobilka and Robert Lefkowitz for their work that was "crucial for understanding how G protein-coupled receptors function". There have been at least seven other Nobel Prizes awarded for some aspect of G protein–mediated signaling. As of 2012, two of the top ten global best-selling drugs (Advair Diskus and Abilify) act by targeting G protein-coupled receptors.
== Classification ==
The exact size of the GPCR superfamily is unknown, but at least 831 different human genes (or about 4% of the entire protein-coding genome) have been predicted to code for them from genome sequence analysis. Although numerous classification schemes have been proposed, the superfamily was classically divided into three main classes (A, B, and C) with no detectable shared sequence homology between classes.
The largest class by far is class A, which accounts for nearly 85% of the GPCR genes. Of class A GPCRs, over half of these are predicted to encode olfactory receptors, while the remaining receptors are liganded by known endogenous compounds or are classified as orphan receptors. Despite the lack of sequence homology between classes, all GPCRs have a common structure and mechanism of signal transduction. The very large rhodopsin A group has been further subdivided into 19 subgroups (A1-A19).
According to the classical A-F system, GPCRs can be grouped into six classes based on sequence homology and functional similarity:
Class A (or 1) (Rhodopsin-like)
Class B (or 2) (Secretin receptor family)
Class C (or 3) (Metabotropic glutamate/pheromone)
Class D (or 4) (Fungal mating pheromone receptors)
Class E (or 5) (Cyclic AMP receptors)
Class F (or 6) (Frizzled/Smoothened)
More recently, an alternative classification system called GRAFS (Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin) has been proposed for vertebrate GPCRs. They correspond to classical classes C, A, B2, F, and B.
An early study based on available DNA sequence suggested that the human genome encodes roughly 750 G protein-coupled receptors, about 350 of which detect hormones, growth factors, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.
Some web-servers and bioinformatics prediction methods have been used for predicting the classification of GPCRs according to their amino acid sequence alone, by means of the pseudo amino acid composition approach.
== Physiological roles ==
GPCRs are involved in a wide variety of physiological processes. Some examples of their physiological roles include:
The visual sense: The opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose.
The gustatory sense (taste): GPCRs in taste cells mediate release of gustducin in response to bitter-, umami- and sweet-tasting substances.
The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
Behavioral and mood regulation: Receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, histamine, GABA, and glutamate
Regulation of immune system activity and inflammation: chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response. GPCRs are also involved in immune-modulation, e. g. regulating interleukin induction or suppressing TLR-induced immune responses from T cells.
Autonomic nervous system transmission: Both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
Cell density sensing: A novel GPCR role in regulating cell density sensing.
Homeostasis modulation (e.g., water balance).
Involved in growth and metastasis of some types of tumors.
Used in the endocrine system for peptide and amino-acid derivative hormones that bind to GCPRs on the cell membrane of a target cell. This activates cAMP, which in turn activates several kinases, allowing for a cellular response, such as transcription.
== Receptor structure ==
GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. Some seven-transmembrane helix proteins (channelrhodopsin) that resemble GPCRs may contain ion channels, within their protein.
In 2000, the first crystal structure of a mammalian GPCR, that of bovine rhodopsin (1F88), was solved. In 2007, the first structure of a human GPCR was solved This human β2-adrenergic receptor GPCR structure proved highly similar to the bovine rhodopsin. The structures of activated or agonist-bound GPCRs have also been determined. These structures indicate how ligand binding at the extracellular side of a receptor leads to conformational changes in the cytoplasmic side of the receptor. The biggest change is an outward movement of the cytoplasmic part of the 5th and 6th transmembrane helix (TM5 and TM6). The structure of activated beta-2 adrenergic receptor in complex with Gs confirmed that the Gα binds to a cavity created by this movement.
GPCRs exhibit a similar structure to some other proteins with seven transmembrane domains, such as microbial rhodopsins and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2). However, these 7TMH (7-transmembrane helices) receptors and channels do not associate with G proteins. In addition, ADIPOR1 and ADIPOR2 are oriented oppositely to GPCRs in the membrane (i.e. GPCRs usually have an extracellular N-terminus, cytoplasmic C-terminus, whereas ADIPORs are inverted).
== Structure–function relationships ==
In terms of structure, GPCRs are characterized by an extracellular N-terminus, followed by seven transmembrane (7-TM) α-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. The GPCR arranges itself into a tertiary structure resembling a barrel, with the seven transmembrane helices forming a cavity within the plasma membrane that serves a ligand-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is the case for bulkier ligands (e.g., proteins or large peptides), which instead interact with the extracellular loops, or, as illustrated by the class C metabotropic glutamate receptors (mGluRs), the N-terminal tail. The class C GPCRs are distinguished by their large N-terminal tail, which also contains a ligand-binding domain. Upon glutamate-binding to an mGluR, the N-terminal tail undergoes a conformational change that leads to its interaction with the residues of the extracellular loops and TM domains. The eventual effect of all three types of agonist-induced activation is a change in the relative orientations of the TM helices (likened to a twisting motion) leading to a wider intracellular surface and "revelation" of residues of the intracellular helices and TM domains crucial to signal transduction function (i.e., G-protein coupling). Inverse agonists and antagonists may also bind to a number of different sites, but the eventual effect must be prevention of this TM helix reorientation.
The structure of the N- and C-terminal tails of GPCRs may also serve important functions beyond ligand-binding. For example, The C-terminus of M3 muscarinic receptors is sufficient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary for its preassembly with Gq proteins. In particular, the C-terminus often contains serine (Ser) or threonine (Thr) residues that, when phosphorylated, increase the affinity of the intracellular surface for the binding of scaffolding proteins called β-arrestins (β-arr). Once bound, β-arrestins both sterically prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellular-signal regulated kinase (ERK) pathway activation or receptor endocytosis (internalization). As the phosphorylation of these Ser and Thr residues often occurs as a result of GPCR activation, the β-arr-mediated G-protein-decoupling and internalization of GPCRs are important mechanisms of desensitization. In addition, internalized "mega-complexes" consisting of a single GPCR, β-arr(in the tail conformation), and heterotrimeric G protein exist and may account for protein signaling from endosomes.
A final common structural theme among GPCRs is palmitoylation of one or more sites of the C-terminal tail or the intracellular loops. Palmitoylation is the covalent modification of cysteine (Cys) residues via addition of hydrophobic acyl groups, and has the effect of targeting the receptor to cholesterol- and sphingolipid-rich microdomains of the plasma membrane called lipid rafts. As many of the downstream transducer and effector molecules of GPCRs (including those involved in negative feedback pathways) are also targeted to lipid rafts, this has the effect of facilitating rapid receptor signaling.
GPCRs respond to extracellular signals mediated by a huge diversity of agonists, ranging from proteins to biogenic amines to protons, but all transduce this signal via a mechanism of G-protein coupling. This is made possible by a guanine-nucleotide exchange factor (GEF) domain primarily formed by a combination of IL-2 and IL-3 along with adjacent residues of the associated TM helices.
== Mechanism ==
The G protein-coupled receptor is activated by an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a G protein. Further effect depends on the type of G protein. G proteins are subsequently inactivated by GTPase activating proteins, known as RGS proteins.
=== Ligand binding ===
GPCRs include one or more receptors for the following ligands:
sensory signal mediators (e.g., light and olfactory stimulatory molecules);
adenosine, bombesin, bradykinin, endothelin, γ-aminobutyric acid (GABA), hepatocyte growth factor (HGF), melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, GH, tachykinins, members of the vasoactive intestinal peptide family, and vasopressin;
biogenic amines (e.g., dopamine, epinephrine, norepinephrine, histamine, serotonin, and melatonin);
glutamate (metabotropic effect);
glucagon;
acetylcholine (muscarinic effect);
chemokines;
lipid mediators of inflammation (e.g., prostaglandins, prostanoids, platelet-activating factor, and leukotrienes);
peptide hormones (e.g., calcitonin, C5a anaphylatoxin, follicle-stimulating hormone [FSH], gonadotropin-releasing hormone [GnRH], neurokinin, thyrotropin-releasing hormone [TRH], and oxytocin);
and endocannabinoids.
GPCRs that act as receptors for stimuli that have not yet been identified are known as orphan receptors.
However, in contrast to other types of receptors that have been studied, wherein ligands bind externally to the membrane, the ligands of GPCRs typically bind within the transmembrane domain. However, protease-activated receptors are activated by cleavage of part of their extracellular domain.
=== Conformational change ===
The transduction of the signal through the membrane by the receptor is not completely understood. It is known that in the inactive state, the GPCR is bound to a heterotrimeric G protein complex. Binding of an agonist to the GPCR results in a conformational change in the receptor that is transmitted to the bound Gα subunit of the heterotrimeric G protein via protein domain dynamics. The activated Gα subunit exchanges GTP in place of GDP which in turn triggers the dissociation of Gα subunit from the Gβγ dimer and from the receptor. The dissociated Gα and Gβγ subunits interact with other intracellular proteins to continue the signal transduction cascade while the freed GPCR is able to rebind to another heterotrimeric G protein to form a new complex that is ready to initiate another round of signal transduction.
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive biophysical states. The binding of ligands to the receptor may shift the equilibrium toward the active receptor states. Three types of ligands exist: Agonists are ligands that shift the equilibrium in favour of active states; inverse agonists are ligands that shift the equilibrium in favour of inactive states; and neutral antagonists are ligands that do not affect the equilibrium. It is not yet known how exactly the active and inactive states differ from each other.
=== G-protein activation/deactivation cycle ===
When the receptor is inactive, the GEF domain may be bound to an also inactive α-subunit of a heterotrimeric G-protein. These "G-proteins" are a trimer of α, β, and γ subunits (known as Gα, Gβ, and Gγ, respectively) that is rendered inactive when reversibly bound to Guanosine diphosphate (GDP) (or, alternatively, no guanine nucleotide) but active when bound to guanosine triphosphate (GTP). Upon receptor activation, the GEF domain, in turn, allosterically activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit. The cell maintains a 10:1 ratio of cytosolic GTP:GDP so exchange for GTP is ensured. At this point, the subunits of the G-protein dissociate from the receptor, as well as each other, to yield a Gα-GTP monomer and a tightly interacting Gβγ dimer, which are now free to modulate the activity of other intracellular proteins. The extent to which they may diffuse, however, is limited due to the palmitoylation of Gα and the presence of an isoprenoid moiety that has been covalently added to the C-termini of Gγ.
Because Gα also has slow GTP→GDP hydrolysis capability, the inactive form of the α-subunit (Gα-GDP) is eventually regenerated, thus allowing reassociation with a Gβγ dimer to form the "resting" G-protein, which can again bind to a GPCR and await activation. The rate of GTP hydrolysis is often accelerated due to the actions of another family of allosteric modulating proteins called regulators of G-protein signaling, or RGS proteins, which are a type of GTPase-activating protein, or GAP. In fact, many of the primary effector proteins (e.g., adenylate cyclases) that become activated/inactivated upon interaction with Gα-GTP also have GAP activity. Thus, even at this early stage in the process, GPCR-initiated signaling has the capacity for self-termination.
=== Crosstalk ===
GPCRs downstream signals have been shown to possibly interact with integrin signals, such as FAK. Integrin signaling will phosphorylate FAK, which can then decrease GPCR Gαs activity.
== Signaling ==
If a receptor in an active state encounters a G protein, it may activate it. Some evidence suggests that receptors and G proteins are actually pre-coupled. For example, binding of G proteins to receptors affects the receptor's affinity for ligands. Activated G proteins are bound to GTP.
Further signal transduction depends on the type of G protein. The enzyme adenylate cyclase is an example of a cellular protein that can be regulated by a G protein, in this case the G protein Gs. Adenylate cyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylate cyclase ends when the G protein returns to the GDP-bound state.
Adenylate cyclases (of which 9 membrane-bound and one cytosolic forms are known in humans) may also be activated or inhibited in other ways (e.g., Ca2+/calmodulin binding), which can modify the activity of these enzymes in an additive or synergistic fashion along with the G proteins.
The signaling pathways activated through a GPCR are limited by the primary sequence and tertiary structure of the GPCR itself but ultimately determined by the particular conformation stabilized by a particular ligand, as well as the availability of transducer molecules. Currently, GPCRs are considered to utilize two primary types of transducers: G-proteins and β-arrestins. Because β-arr's have high affinity only to the phosphorylated form of most GPCRs (see above or below), the majority of signaling is ultimately dependent upon G-protein activation. However, the possibility for interaction does allow for G-protein-independent signaling to occur.
=== G-protein-dependent signaling ===
There are three main G-protein-mediated signaling pathways, mediated by four sub-classes of G-proteins distinguished from each other by sequence homology (Gαs, Gαi/o, Gαq/11, and Gα12/13). Each sub-class of G-protein consists of multiple proteins, each the product of multiple genes or splice variations that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible βγ combinations do not appear to radically differ from one another, these classes are defined according to the isoform of their α-subunit.: 1163
While most GPCRs are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called functional selectivity (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular agonist may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR's GEF domain, even over the course of a single interaction. In addition, a conformation that preferably activates one isoform of Gα may activate another if the preferred is less available. Furthermore, feedback pathways may result in receptor modifications (e.g., phosphorylation) that alter the G-protein preference. Regardless of these various nuances, the GPCR's preferred coupling partner is usually defined according to the G-protein most obviously activated by the endogenous ligand under most physiological or experimental conditions.
==== Gα signaling ====
The effector of both the Gαs and Gαi/o pathways is the cyclic-adenosine monophosphate (cAMP)-generating enzyme adenylate cyclase, or AC. While there are ten different AC gene products in mammals, each with subtle differences in tissue distribution or function, all catalyze the conversion of cytosolic adenosine triphosphate (ATP) to cAMP, and all are directly stimulated by G-proteins of the Gαs class. In contrast, however, interaction with Gα subunits of the Gαi/o type inhibits AC from generating cAMP. Thus, a GPCR coupled to Gαs counteracts the actions of a GPCR coupled to Gαi/o, and vice versa. The level of cytosolic cAMP may then determine the activity of various ion channels as well as members of the ser/thr-specific protein kinase A (PKA) family. Thus cAMP is considered a second messenger and PKA a secondary effector.
The effector of the Gαq/11 pathway is phospholipase C-β (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) to elicit Ca2+ release from the ER, while DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called protein kinase C (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca2+, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca2+ also binds and allosterically activates proteins called calmodulins, which in turn tosolic small GTPase, Rho. Once bound to GTP, Rho can then go on to activate various proteins responsible for cytoskeleton regulation such as Rho-kinase (ROCK). Most GPCRs that couple to Gα12/13 also couple to other sub-classes, often Gαq/11.
==== Gβγ signaling ====
The above descriptions ignore the effects of Gβγ–signalling, which can also be important, in particular in the case of activated Gαi/o-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as G-protein-regulated inwardly rectifying K+ channels (GIRKs), P/Q- and N-type voltage-gated Ca2+ channels, as well as some isoforms of AC and PLC, along with some phosphoinositide-3-kinase (PI3K) isoforms.
=== G-protein-independent signaling ===
Although they are classically thought of working only together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteins may play functional roles independent of GPCRs. GPCRs may signal independently through many proteins already mentioned for their roles in G-protein-dependent signaling such as β-arrs, GRKs, and Srcs. Such signaling has been shown to be physiologically relevant, for example, β-arrestin signaling mediated by the chemokine receptor CXCR3 was necessary for full efficacy chemotaxis of activated T cells. In addition, further scaffolding proteins involved in subcellular localization of GPCRs (e.g., PDZ-domain-containing proteins) may also act as signal transducers. Most often the effector is a member of the MAPK family.
==== Examples ====
In the late 1990s, evidence began accumulating to suggest that some GPCRs are able to signal without G proteins. The ERK2 mitogen-activated protein kinase, a key signal transduction mediator downstream of receptor activation in many pathways, has been shown to be activated in response to cAMP-mediated receptor activation in the slime mold D. discoideum despite the absence of the associated G protein α- and β-subunits.
In mammalian cells, the much-studied β2-adrenoceptor has been demonstrated to activate the ERK2 pathway after arrestin-mediated uncoupling of G-protein-mediated signaling. Therefore, it seems likely that some mechanisms previously believed related purely to receptor desensitisation are actually examples of receptors switching their signaling pathway, rather than simply being switched off.
In kidney cells, the bradykinin receptor B2 has been shown to interact directly with a protein tyrosine phosphatase. The presence of a tyrosine-phosphorylated ITIM (immunoreceptor tyrosine-based inhibitory motif) sequence in the B2 receptor is necessary to mediate this interaction and subsequently the antiproliferative effect of bradykinin.
==== GPCR-independent signaling by heterotrimeric G-proteins ====
Although it is a relatively immature area of research, it appears that heterotrimeric G-proteins may also take part in non-GPCR signaling. There is evidence for roles as signal transducers in nearly all other types of receptor-mediated signaling, including integrins, receptor tyrosine kinases (RTKs), cytokine receptors (JAK/STATs), as well as modulation of various other "accessory" proteins such as GEFs, guanine-nucleotide dissociation inhibitors (GDIs) and protein phosphatases. There may even be specific proteins of these classes whose primary function is as part of GPCR-independent pathways, termed activators of G-protein signalling (AGS). Both the ubiquity of these interactions and the importance of Gα vs. Gβγ subunits to these processes are still unclear.
== Details of cAMP and PIP2 pathways ==
There are two principal signal transduction pathways involving the G protein-linked receptors: the cAMP signal pathway and the phosphatidylinositol signal pathway.
=== cAMP signal pathway ===
The cAMP signal transduction contains five main characters: stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri); stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi); adenylyl cyclase; protein kinase A (PKA); and cAMP phosphodiesterase.
Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules, while inhibitory hormone receptor (Ri) is a receptor that can bind with inhibitory signal molecules.
Stimulative regulative G-protein is a G-protein linked to stimulative hormone receptor (Rs), and its α subunit upon activation could stimulate the activity of an enzyme or other intracellular metabolism. On the contrary, inhibitory regulative G-protein is linked to an inhibitory hormone receptor, and its α subunit upon activation could inhibit the activity of an enzyme or other intracellular metabolism.
Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes the conversion of ATP to cAMP with the help of cofactor Mg2+ or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator of protein kinase A.
Protein kinase A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylating specific committed enzymes in the metabolic pathway. It can also regulate specific gene expression, cellular secretion, and membrane permeability. The protein enzyme contains two catalytic subunits and two regulatory subunits. When there is no cAMP, the complex is inactive. When cAMP binds to the regulatory subunits, their conformation is altered, causing the dissociation of the regulatory subunits, which activates protein kinase A and allows further biological effects.
These signals then can be terminated by cAMP phosphodiesterase, which is an enzyme that degrades cAMP to 5'-AMP and inactivates protein kinase A.
=== Phosphatidylinositol signal pathway ===
In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G-protein receptor (Gq) on the cell surface and activates phospholipase C, which is located on the plasma membrane. The lipase hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds with the IP3 receptor in the membrane of the smooth endoplasmic reticulum and mitochondria to open Ca2+ channels. DAG helps activate protein kinase C (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses.
The effects of Ca2+ are also remarkable: it cooperates with DAG in activating PKC and can activate the CaM kinase pathway, in which calcium-modulated protein calmodulin (CaM) binds Ca2+, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca2+-CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway.
== Receptor regulation ==
GPCRs become desensitized when exposed to their ligand for a long period of time. There are two recognized forms of desensitization: 1) homologous desensitization, in which the activated GPCR is downregulated; and 2) heterologous desensitization, wherein the activated GPCR causes downregulation of a different GPCR. The key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases.
=== Phosphorylation by cAMP-dependent protein kinases ===
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the receptor) via adenylate cyclase and cyclic AMP (cAMP). In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active the more kinases are activated and the more receptors are phosphorylated. In β2-adrenoceptors, this phosphorylation results in the switching of the coupling from the Gs class of G-protein to the Gi class. cAMP-dependent PKA mediated phosphorylation can cause heterologous desensitisation in receptors other than those activated.
=== Phosphorylation by GRKs ===
The G protein-coupled receptor kinases (GRKs) are protein kinases that phosphorylate only active GPCRs. G-protein-coupled receptor kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR) signaling. They constitute a family of seven mammalian serine-threonine protein kinases that phosphorylate agonist-bound receptor. GRKs-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization. Activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins.
Phosphorylation of the receptor can have two consequences:
Translocation: The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysozomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depending on the internalised vesicle's subcellular localisation.
Arrestin linking: The phosphorylated receptor can be linked to arrestin molecules that prevent it from binding (and activating) G proteins, in effect switching it off for a short period of time. This mechanism is used, for example, with rhodopsin in retina cells to compensate for exposure to bright light. In many cases, arrestin's binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β2-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus, the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β2-adrenoreceptors.
=== Mechanisms of GPCR signal termination ===
As mentioned above, G-proteins may terminate their own activation due to their intrinsic GTP→GDP hydrolysis capability. However, this reaction proceeds at a slow rate (≈0.02 times/sec) and, thus, it would take around 50 seconds for any single G-protein to deactivate if other factors did not come into play. Indeed, there are around 30 isoforms of RGS proteins that, when bound to Gα through their GAP domain, accelerate the hydrolysis rate to ≈30 times/sec. This 1500-fold increase in rate allows for the cell to respond to external signals with high speed, as well as spatial resolution due to limited amount of second messenger that can be generated and limited distance a G-protein can diffuse in 0.03 seconds. For the most part, the RGS proteins are promiscuous in their ability to deactivate G-proteins, while which RGS is involved in a given signaling pathway seems more determined by the tissue and GPCR involved than anything else. In addition, RGS proteins have the additional function of increasing the rate of GTP-GDP exchange at GPCRs, (i.e., as a sort of co-GEF) further contributing to the time resolution of GPCR signaling.
In addition, the GPCR may be desensitized itself. This can occur as:
a direct result of ligand occupation, wherein the change in conformation allows recruitment of GPCR-Regulating Kinases (GRKs), which go on to phosphorylate various serine/threonine residues of IL-3 and the C-terminal tail. Upon GRK phosphorylation, the GPCR's affinity for β-arrestin (β-arrestin-1/2 in most tissues) is increased, at which point β-arrestin may bind and act to both sterically hinder G-protein coupling as well as initiate the process of receptor internalization through clathrin-mediated endocytosis. Because only the liganded receptor is desensitized by this mechanism, it is called homologous desensitization
the affinity for β-arrestin may be increased in a ligand occupation and GRK-independent manner through phosphorylation of different ser/thr sites (but also of IL-3 and the C-terminal tail) by PKC and PKA. These phosphorylations are often sufficient to impair G-protein coupling on their own as well.
PKC/PKA may, instead, phosphorylate GRKs, which can also lead to GPCR phosphorylation and β-arrestin binding in an occupation-independent manner. These latter two mechanisms allow for desensitization of one GPCR due to the activities of others, or heterologous desensitization. GRKs may also have GAP domains and so may contribute to inactivation through non-kinase mechanisms as well. A combination of these mechanisms may also occur.
Once β-arrestin is bound to a GPCR, it undergoes a conformational change allowing it to serve as a scaffolding protein for an adaptor complex termed AP-2, which in turn recruits another protein called clathrin. If enough receptors in the local area recruit clathrin in this manner, they aggregate and the membrane buds inwardly as a result of interactions between the molecules of clathrin, in a process called opsonization. Once the pit has been pinched off the plasma membrane due to the actions of two other proteins called amphiphysin and dynamin, it is now an endocytic vesicle. At this point, the adapter molecules and clathrin have dissociated, and the receptor is either trafficked back to the plasma membrane or targeted to lysosomes for degradation.
At any point in this process, the β-arrestins may also recruit other proteins—such as the non-receptor tyrosine kinase (nRTK), c-SRC—which may activate ERK1/2, or other mitogen-activated protein kinase (MAPK) signaling through, for example, phosphorylation of the small GTPase, Ras, or recruit the proteins of the ERK cascade directly (i.e., Raf-1, MEK, ERK-1/2) at which point signaling is initiated due to their close proximity to one another. Another target of c-SRC are the dynamin molecules involved in endocytosis. Dynamins polymerize around the neck of an incoming vesicle, and their phosphorylation by c-SRC provides the energy necessary for the conformational change allowing the final "pinching off" from the membrane.
=== GPCR cellular regulation ===
Receptor desensitization is mediated through a combination phosphorylation, β-arr binding, and endocytosis as described above. Downregulation occurs when endocytosed receptor is embedded in an endosome that is trafficked to merge with an organelle called a lysosome. Because lysosomal membranes are rich in proton pumps, their interiors have low pH (≈4.8 vs. the pH≈7.2 cytosol), which acts to denature the GPCRs. In addition, lysosomes contain many degradative enzymes, including proteases, which can function only at such low pH, and so the peptide bonds joining the residues of the GPCR together may be cleaved. Whether or not a given receptor is trafficked to a lysosome, detained in endosomes, or trafficked back to the plasma membrane depends on a variety of factors, including receptor type and magnitude of the signal.
GPCR regulation is additionally mediated by gene transcription factors. These factors can increase or decrease gene transcription and thus increase or decrease the generation of new receptors (up- or down-regulation) that travel to the cell membrane.
== Receptor oligomerization ==
G-protein-coupled receptor oligomerisation is a widespread phenomenon. One of the best-studied examples is the metabotropic GABAB receptor. This so-called constitutive receptor is formed by heterodimerization of GABABR1 and GABABR2 subunits. Expression of the GABABR1 without the GABABR2 in heterologous systems leads to retention of the subunit in the endoplasmic reticulum. Expression of the GABABR2 subunit alone, meanwhile, leads to surface expression of the subunit, although with no functional activity (i.e., the receptor does not bind agonist and cannot initiate a response following exposure to agonist). Expression of the two subunits together leads to plasma membrane expression of functional receptor. It has been shown that GABABR2 binding to GABABR1 causes masking of a retention signal of functional receptors.
== Origin and diversification of the superfamily ==
Signal transduction mediated by the superfamily of GPCRs dates back to the origin of multicellularity. Mammalian-like GPCRs are found in fungi, and have been classified according to the GRAFS classification system based on GPCR fingerprints. Identification of the superfamily members across the eukaryotic domain, and comparison of the family-specific motifs, have shown that the superfamily of GPCRs have a common origin. Characteristic motifs indicate that three of the five GRAFS families, Rhodopsin, Adhesion, and Frizzled, evolved from the Dictyostelium discoideum cAMP receptors before the split of opisthokonts. Later, the Secretin family evolved from the Adhesion GPCR receptor family before the split of nematodes. Insect GPCRs appear to be in their own group and Taste2 is identified as descending from Rhodopsin. Note that the Secretin/Adhesion split is based on presumed function rather than signature, as the classical Class B (7tm_2, Pfam PF00002) is used to identify both in the studies.
== See also ==
G protein-coupled receptors database
List of MeSH codes (D12.776)
Metabotropic receptor
Orphan receptor
Pepducins, a class of drug candidates targeted at GPCRs
Receptor activated solely by a synthetic ligand, a technique for control of cell signaling through synthetic GPCRs
TOG superfamily
== References ==
== Further reading ==
Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, et al. (April 2003). "The G protein-coupled receptor repertoires of human and mouse". Proceedings of the National Academy of Sciences of the United States of America. 100 (8): 4903–8. Bibcode:2003PNAS..100.4903V. doi:10.1073/pnas.0230374100. PMC 153653. PMID 12679517.
"GPCR Reference Library". Retrieved 11 August 2008. Reference for molecular and mathematical models for the initial receptor response
"The Nobel Prize in Chemistry 2012" (PDF). Archived (PDF) from the original on 18 October 2012. Retrieved 10 October 2012.
== External links ==
G-protein-coupled+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GPCR Cell Line Archived 3 April 2015 at the Wayback Machine
"IUPHAR/BPS Guide to PHARMACOLOGY Database (GPCRs)". IUPHAR Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology. Retrieved 6 February 2019.
"GPCRdb". Data, diagrams and web tools for G protein-coupled receptors (GPCRs).; Munk C, Isberg V, Mordalski S, Harpsøe K, Rataj K, Hauser AS, et al. (July 2016). "GPCRdb: the G protein-coupled receptor database - an introduction". British Journal of Pharmacology. 173 (14): 2195–207. doi:10.1111/bph.13509. PMC 4919580. PMID 27155948.
"G Protein-Coupled Receptors on the NET". Archived from the original on 23 July 2011. Retrieved 10 November 2010. a classification of GPCRs
"PSI GPCR Network Center". Archived from the original on 25 July 2013. Retrieved 11 July 2013. a Protein Structure Initiative:Biology Network Center aimed at determining the 3D structures of representative GPCR family proteins
GPCR-HGmod Archived 1 February 2016 at the Wayback Machine, a database of 3D structural models of all human G-protein coupled receptors, built by the GPCR-I-TASSER pipeline Zhang J, Yang J, Jang R, Zhang Y (August 2015). "GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human Genome". Structure. 23 (8): 1538–1549. doi:10.1016/j.str.2015.06.007. PMC 4526412. PMID 26190572. | Wikipedia/G_protein_coupled_receptors |
Half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a particular inhibitory substance (e.g. drug) is needed to inhibit, in vitro, a given biological process or biological component by 50%. The biological component could be an enzyme, cell, cell receptor or microbe. IC50 values are typically expressed as molar concentration.
IC50 is commonly used as a measure of antagonist drug potency in pharmacological research. IC50 is comparable to other measures of potency, such as EC50 for excitatory drugs. EC50 represents the dose or plasma concentration required for obtaining 50% of a maximum effect in vivo.
IC50 can be determined with functional assays or with competition binding assays.
Sometimes, IC50 values are converted to the pIC50 scale.
pIC
50
=
−
log
10
(
IC
50
)
{\displaystyle {\ce {pIC_{50}}}=-\log _{10}{\ce {(IC_{50})}}}
Due to the minus sign, higher values of pIC50 indicate exponentially more potent inhibitors. pIC50 is usually given in terms of molar concentration (mol/L, or M), thus requiring IC50 in units of M.
The IC50 terminology is also used for some behavioral measures in vivo, such as the two bottle fluid consumption test. When animals decrease consumption from the drug-laced water bottle, the concentration of the drug that results in a 50% decrease in consumption is considered the IC50 for fluid consumption of that drug.
== Functional antagonist assay ==
The IC50 of a drug can be determined by constructing a dose-response curve and examining the effect of different concentrations of antagonist on reversing agonist activity. IC50 values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist. IC50 values can be used to compare the potency of two antagonists.
IC50 values are very dependent on conditions under which they are measured. In general, a higher concentration of inhibitor leads to lowered agonist activity. IC50 value increases as agonist concentration increases. Furthermore, depending on the type of inhibition, other factors may influence IC50 value; for ATP dependent enzymes, IC50 value has an interdependency with concentration of ATP, especially if inhibition is competitive.
== IC50 and affinity ==
=== Competition binding assays ===
In this type of assay, a single concentration of radioligand (usually an agonist) is used in every assay tube. The ligand is used at a low concentration, usually at or below its Kd value. The level of specific binding of the radioligand is then determined in the presence of a range of concentrations of other competing non-radioactive compounds (usually antagonists), in order to measure the potency with which they compete for the binding of the radioligand. Competition curves may also be computer-fitted to a logistic function as described under direct fit.
In this situation the IC50 is the concentration of competing ligand which displaces 50% of the specific binding of the radioligand. The IC50 value is converted to an absolute inhibition constant Ki using the Cheng-Prusoff equation formulated by Yung-Chi Cheng and William Prusoff (see Ki).
=== Cheng Prusoff equation ===
IC50 is not a direct indicator of affinity, although the two can be related at least for competitive agonists and antagonists by the Cheng-Prusoff equation. For enzymatic reactions, this equation is:
K
i
=
IC
50
1
+
[
S
]
K
m
{\displaystyle K_{i}={\frac {{\ce {IC50}}}{1+{\frac {[S]}{K_{m}}}}}}
where Ki is the binding affinity of the inhibitor, IC50 is the functional strength of the inhibitor, [S] is fixed substrate concentration and Km is the Michaelis constant i.e. concentration of substrate at which enzyme activity is at half maximal (but is frequently confused with substrate affinity for the enzyme, which it is not).
Alternatively, for inhibition constants at cellular receptors:
K
i
=
IC
50
[
A
]
EC
50
+
1
{\displaystyle K_{i}={\frac {{\ce {IC50}}}{{\frac {[A]}{{\ce {EC50}}}}+1}}}
where [A] is the fixed concentration of agonist and EC50 is the concentration of agonist that results in half maximal activation of the receptor. Whereas the IC50 value for a compound may vary between experiments depending on experimental conditions, (e.g. substrate and enzyme concentrations) the Ki is an absolute value. Ki is the inhibition constant for a drug; the concentration of competing ligand in a competition assay which would occupy 50% of the receptors if no ligand were present.
The Cheng-Prusoff equation produces good estimates at high agonist concentrations, but over- or under-estimates Ki at low agonist concentrations. In these conditions, other analyses have been recommended.
== See also ==
Certain safety factor
EC50 (half maximal effective concentration)
LD50 (median lethal dose)
Ki (equilibrium constant)
== References ==
== External links ==
AAT Bioquest Online IC50 Calculator
Online IC50 calculator (www.ic50.org.uk) based on the C programming language and gnuplot
Alternative online IC50 calculator (www.ic50.org) based on Python, NumPy, SciPy and Matplotlib
ELISA IC50/EC50 Online Tool (link seems broken)
IC50 to pIC50 calculator
Online tool for analysis of in vitro resistance to antimalarial drugs
IC50-to-Ki converter of an inhibitor and enzyme that obey classic Michaelis-Menten kinetics. | Wikipedia/Cheng-Prussoff_Equation |
Crude drugs are drugs of plant, animal and microbial origin that contain natural substances that have undergone only the processes of collection and drying. The term natural substances refers to those substances found in nature that have not had man-made changes made in their molecular structure. They are used as medicine for humans and animals, internally and externally for curing diseases, e.g., Senna and Cinchona.
A crude drug is any naturally occurring, unrefined substance derived from organic or inorganic sources such as plant, animal, bacteria, organs or whole organisms intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals.
== Overview ==
Crude drugs are unrefined natural medications in their raw forms. Prior to the 1950s, every pharmacy student learned about crude drugs in pharmacognosy class. Pharmacognosy is the study of the proper horticulture, harvesting and uses of the raw medications found in nature.
Raising, harvesting and selling crude drugs was how many large pharmaceutical companies started out. Companies such as Eli Lilly and Company sold crude drugs to pharmacists to save them time and money, but the early pharmacy graduate would know how to raise their own crude drugs if need be.
== Morphology and organoleptic characters of crude drugs ==
Identification of the crude drug by organoleptic characters is one of the important aspects of pharmacognostical study. Morphological study follows a special terminology which must be known to a pharmacognostist. The morphological terminology is derived from botany and zoology, depending upon the source of the crude drug. In general, color, odor, taste, size, shape, and special features, like touch, texture, fracture, presence of trichomes, and presence of ridges of crude drugs are studied under morphology. Aromatic odor of umbelliferous fruits and sweet taste of liquorice are the example of this type of evaluation. The study of form of a crude drug is morphology, while description of the form is morphography.
However, shape and size of crude drugs as described in official books should only be considered as guidelines and may vary depending upon several factors. For example, color of the crude drug may fade if it gets exposed to sunlight for very long duration or if, the drug is not stored properly. Depending upon the condition under which the drug is growing or cultivated, i.e., availability of proper irrigation, fertilizers or even high temperature, may influence the size may be available and the crude drugs if grown in adverse conditions may be of small size.
Color of the flowers as in case Catharanthus roseus and Catharanthus alba, presence of thorns in case of Asparagus recemosus and absence in Asparagus officinalis, arrangement of flowers in case of Withania semnifera or Witharia coagulens can help in differentiating the varieties of the same plant.
Arrangement of cracks and wrinkles in case of stem bark of varieties of Cinchona bark, or the color of aloe can separate in varieties.
The adulteration of seed of Strychnos nux-vomica with the seed of Strrychnos nux-blanda or Strychnos potatorum, caraway with Indian dill, Alexandrian senna with dog senna or palthe senna are identified by morphological means.
In case of cellular products (unorganized drugs), form of the drug depends totally on the method of preparation of the drug. Thus, gum acacia is found in the form of ovoid tears, while tragacanth is marketed as vermiform ribbon with longitudinal striations.
== Evaluation ==
To evaluate means to identify it and to determine its quality and purity, the identity of a drug can be established by actual collection of the drug from a plant or animal that has been positively identified. The evaluation of drug involves a number of methods that may be classified as follows:
Organoleptic and morphological evaluation: Evaluation by means of organs of senses; knowing the color, odor, taste, size, shape and special features like texture.
Microscopic: For identification of the pure powdered drug. This method allows more detailed examination of a drug and their identification by their known histological characters. Microscope by the virtue of its property to magnify, permits minute sections under study to enlarge so that leaf constants, stomatal index, palisade ratio can be determined.
Biologic: Pharmacological activities of drugs are evaluated by bioassays. When the estimation of potency of crude drug or its preparations are done by means of measuring its effect on living organisms like bacteria, fungal growth, or animal tissue, it is known as biological effect of the drug, compared to the standard drug. By these methods, a crude drug can be assessed and further clinical trial can be recommended.
Chemical: Chemical assays are best to determine potency and active constituents. It comprises different test and assays. The isolation, purification and identification of active constituents are the methods of evaluation. Quantitative chemical test such as acid value, saponification value etc. are also covered under these techniques.
Physical: Physical constants are applied to active principles. These are helpful in evaluation with reference to moisture content, specific gravity, density, optic rotation etc.
== History ==
The usage of crude drugs dates to prehistoric times. Traditional medicine often incorporates the gathering and preparation of material from natural sources, particularly herbs. In such practice, the active ingredients and method of action are largely unknown to the practitioner.
In recent history, the development of modern chemistry and application of the scientific method shaped the use of crude drugs. Eventually, the use of crude drugs reach a zenith in the early 1900s and eventually gave way to the use of purified active ingredients from the natural source. Currently the use and exploration of crude drugs has again gained prominence in the medical community. The realization that many completely unknown substances are yet to be discovered from crude drugs has created a new interest in pharmacognosy and has led to many medical breakthroughs.
In 1907, the Pure Food and Drug Act was implemented and standardization of crude drugs took place. Often the USP would specify what percentage of active ingredient was needed to claim a crude drug met USP standards.
An example of standardization would be as follows (from the United States Pharmacopeia):
Opium is the air-dried milky exudate obtained by incising the unripe capsules of Papaver somniferum Linne or its variety album De Candolle (Fam. Papaveraceae). Opium in its normal air-dried condition yields not less than 9.5 percent of anhydrous morphine.
== Use in Chinese medicine ==
Crude medicine (simplified Chinese: 药材; traditional Chinese: 藥材; pinyin: yàocái), (also known as crude drug in the Chinese materia medica) are bulk drugs from the Chinese materia medica basic processing and treatment.
== References ==
== See also ==
Traditional Chinese medicine
Chinese herbology
Chinese patent medicine | Wikipedia/Crude_drug |
Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction. The process of tolerance development is reversible (e.g., through a drug holiday) and can involve both physiological factors and psychological factors.
One may also develop drug tolerance to side effects, in which case tolerance is a desirable characteristic. A medical intervention that has an objective to increase tolerance (e.g., allergen immunotherapy, in which one is exposed to larger and larger amounts of allergen to decrease one's allergic reactions) is called drug desensitization.
The opposite concept to drug tolerance is reverse tolerance, in which case the subject's reaction or effect will increase following its repeated use. The two notions are not incompatible and tolerance may sometimes lead to reverse tolerance. For example, heavy drinkers initially develop tolerance to alcohol (requiring them to drink larger amounts to achieve a similar effect) but excessive drinking can cause liver damage, which then puts them at risk of intoxication when drinking even very small amounts of alcohol.
Drug tolerance should not be confused with drug tolerability, which refers to the degree to which overt adverse effects of a drug can be tolerated by a patient.
== Tachyphylaxis ==
Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.
== Pharmacodynamic tolerance ==
Pharmacodynamic tolerance begins when the cellular response to a substance is reduced with repeated use. A common cause of pharmacodynamic tolerance is high concentrations of a substance constantly binding with the receptor, desensitizing it through constant interaction. Other possibilities include a reduction in receptor density (usually associated with receptor agonists), other mechanisms leading to changes in action potential firing rate, or alterations in protein transcription among others adaptations. Pharmacodynamic tolerance to a receptor antagonist involves the reverse, i.e., increased receptor firing rate, an increase in receptor density, or other mechanisms.
While most occurrences of pharmacodynamic tolerance occur after sustained exposure to a drug, instances of acute or instant tolerance (tachyphylaxis) can occur.
== Pharmacokinetic (metabolic) tolerance ==
Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs (ADME). All psychoactive drugs are first absorbed into the bloodstream, carried in the blood to various parts of the body including the site of action (distribution), broken down in some fashion (metabolism), and ultimately removed from the body (excretion). All of these factors are very important determinants of crucial pharmacological properties of a drug, including its potency, side effects, and duration of action.
Pharmacokinetic tolerance (dispositional tolerance) occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as ethanol.
This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass first-pass metabolism. Enzyme induction is partly responsible for the phenomenon of tolerance, in which repeated use of a drug leads to a reduction of the drug's effect. However, it is only one of several mechanisms leading to tolerance.
== Behavioral tolerance ==
Behavioral tolerance occurs with the use of certain psychoactive drugs, where tolerance to a behavioral effect of a drug, such as increased motor activity by methamphetamine, occurs with repeated use. It may occur through drug-independent learning or as a form of pharmacodynamic tolerance in the brain; the former mechanism of behavioral tolerance occurs when one learns how to actively overcome drug-induced impairment through practice. Behavioral tolerance is often context-dependent, meaning tolerance depends on the environment in which the drug is administered, and not on the drug itself. Behavioral sensitization describes the opposite phenomenon.
== See also ==
== References == | Wikipedia/Drug_tolerance |
Any product defined as a drug under the Canadian Food and Drugs Act must have an associated drug identification number (or DIN). A DIN also pertains to veterinary drugs permitted for sale in Canada.
The drug identification number (DIN) is the 8 digit number located on the label of prescription and over-the-counter drug products that have been evaluated by the Therapeutic Products Directorate (TPD) and approved for sale in Canada.
Once a drug has been approved, the Therapeutic Products Directorate issues a DIN, which permits the manufacturer to market the drug in Canada. For drugs, where there is minimal market history in Canada, there is a more stringent review and the drug is required to have a Notice of Compliance and a DIN in order to be marketed in Canada.
A DIN lets the user know that the product has undergone and passed a review of its formulation, labeling, and instructions for use. A drug product sold in Canada without a DIN is not in compliance with Canadian law, with limited exceptions, such as foreign drug products imported under emergency authorization.
The DIN is also a tool to help in the follow-up of products on the market, recall of products, inspections, and quality monitoring.
A drug product can be looked up via its DIN with the Health Canada's Drug Product Database (DPD) to find specific information of drugs approved by the Ministry.
== See also ==
National Drug Code United States
Pharmaceutical code
== References ==
== External links ==
Health Canada DIN fact sheet
Drug Product Database (DPD) | Wikipedia/Drug_Identification_Number |
The Prescription Drug Marketing Act (PDMA) of 1987 (P.L. 100-293, 102 Stat. 95) is a law of the United States federal government. It establishes legal safeguards for prescription drug distribution to ensure safe and effective pharmaceuticals and is designed to discourage the sale of counterfeit, adulterated, misbranded, sub potent, and expired prescription drugs. It was passed in response to the development of a wholesale sub-market (known as the "diversion market") for prescription drugs.
The PDMA was modified by the Prescription Drug Amendments of 1992 (P.L. 102-353, 106 Stat. 941) on August 26, 1992.
The U.S. Food and Drug Administration (FDA) issued regulations implementing the PDMA in 1990 (21 C.F.R. Part 205) and 1999 (21 C.F.R. Part 203).
== See also ==
Food and Drug Administration (FDA, USA)
Drug distribution
Inverse benefit law
Regulation of therapeutic goods
== External links ==
PDMA article | Wikipedia/Prescription_Drug_Marketing_Act_(PDMA) |
Clinical pharmacology is "that discipline that teaches, does research, frames policy, gives information and advice about the actions and proper uses of medicines in humans and implements that knowledge in clinical practice". Clinical pharmacology is inherently a translational discipline underpinned by the basic science of pharmacology, engaged in the experimental and observational study of the disposition and effects of drugs in humans, and committed to the translation of science into evidence-based therapeutics. It has a broad scope, from the discovery of new target molecules to the effects of drug usage in whole populations. The main aim of clinical pharmacology is to generate data for optimum use of drugs and the practice of 'evidence-based medicine'.
Clinical pharmacologists have medical and scientific training that enables them to evaluate evidence and produce new data through well-designed studies. Clinical pharmacologists must have access to enough patients for clinical care, teaching and education, and research. Their responsibilities to patients include, but are not limited to, detecting and analysing adverse drug effects and reactions, therapeutics, and toxicology including reproductive toxicology, perioperative drug management, and psychopharmacology.
Modern clinical pharmacologists are also trained in data analysis skills. Their approaches to analyse data can include modelling and simulation techniques (e.g. population analysis, non-linear mixed-effects modelling).
== Branches ==
Clinical pharmacology consists of multiple branches listed below:
Pharmacodynamics – what drugs do to the body and how. This includes not just the cellular and molecular aspects, but also more relevant clinical measurements. For example, not just the pharmacological actions of salbutamol, a beta2-adrenergic receptor agonist, but the respiratory peak flow rate of both healthy volunteers and patients.
Pharmacokinetics – what happens to the drug while in the body. This involves the body systems for handling the drug, usually divided into the following classification:
Absorption – the processes by which the drug move into the bloodstream from the site of administration (e.g. the gut)
Distribution – the extent to which the drug enters and leaves different tissues of the body
Metabolism – the processes by which the drug is metabolized in the liver, i.e. transformed into molecules that are usually less pharmacologically active
Excretion – the processes by which the drug is eliminated from the body, which mostly happens in the liver and kidneys.
Rational Prescribing – using the right medication, in the right dose, using the right route and frequency of administration, and for the right duration of time.
Adverse drug effects – unwanted effects of a medicine that are typically not noticed by the individual (e.g. a reduction in the white cell count or a change in the serum uric acid concentration)
Adverse drug reactions – unwanted effects of the drug that the individual experiences (e.g. a sore throat because of a reduced white cell count or an attack of gout because of an increased serum uric acid concentration)
Toxicology – the discipline that deals with the adverse effects of chemicals
Drug interactions – the study of how drugs interact with each other. A drug may negatively or positively affect the effects of another drug; drugs can also interact with other agents, such as foods, alcohol, and devices.
Drug development – the processes of bringing a new medicine from its discovery to clinical use, usually culminating in some form of clinical trials and marketing authorization applications to country-specific drug regulators, such as the US FDA and the UK's MHRA.
Molecular pharmacology – the discipline of studying drug actions at the molecular level; it is a branch of pharmacology in general.
Pharmacogenomics – the study of the human genome in order to understand the ways in which genetic factors determine the actions of medicines.
== History ==
Medicinal uses of plant and animal resources have been common since prehistoric times. Many countries, such as China, Egypt, and India, have written documentation of many traditional remedies. A few of these remedies are still regarded as helpful today, but most have them have been discarded, because they were ineffective and potentially harmful.
For many years, therapeutic practices were based on Hippocratic humoral theory, popularized by the Greek physician Galen (129 – c. AD 216) and not on experimentation.
In around the 17th century physicians started to apply use methods to study traditional remedies, although they still lacked methods to test the hypotheses they had about how drugs worked.
By the late 18th century and early 19th century, methods of experimental physiology and pharmacology began to be developed by scientists such as François Magendie and his student Claude Bernard.
From the late 18th century to the early 20th century, advances were made in chemistry and physiology that laid the foundations needed to understand how drugs act at the tissue and organ levels. The advances that were made at this time gave manufacturers the ability to make and sell medicines that they claimed to be effective, but were in many cases worthless. There were no methods for evaluating such claims until rational therapeutic concepts were established in medicine, starting at about the end of the 19th century.
The development of receptor theory at the start of the 20th century and later developments led to better understanding of how medicines act and the development of many new medicines that are both safe and effective. Expansion of the scientific principles of pharmacology and clinical pharmacology continues today.
== See also ==
Dormant therapy
== References ==
== External links ==
International Union of Basic and Clinical Pharmacology (IUPHAR)
European Association for Clinical Pharmacology and Therapeutics (EACPT)
Dutch Society on Clinical Pharmacology and Biopharmaceutics (NVKF&B)
American Society for Clinical Pharmacology and Therapeutics (ASCPT)
American College of Clinical Pharmacology (ACCP)
British Pharmacological Society (BPS)
Korean Society for Clinical Pharmacology and Therapeutics (KSCPT)
Japanese Society for Clinical Pharmacology and Therapeutics (JSCPT) | Wikipedia/Clinical_pharmacology |
Half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a particular inhibitory substance (e.g. drug) is needed to inhibit, in vitro, a given biological process or biological component by 50%. The biological component could be an enzyme, cell, cell receptor or microbe. IC50 values are typically expressed as molar concentration.
IC50 is commonly used as a measure of antagonist drug potency in pharmacological research. IC50 is comparable to other measures of potency, such as EC50 for excitatory drugs. EC50 represents the dose or plasma concentration required for obtaining 50% of a maximum effect in vivo.
IC50 can be determined with functional assays or with competition binding assays.
Sometimes, IC50 values are converted to the pIC50 scale.
pIC
50
=
−
log
10
(
IC
50
)
{\displaystyle {\ce {pIC_{50}}}=-\log _{10}{\ce {(IC_{50})}}}
Due to the minus sign, higher values of pIC50 indicate exponentially more potent inhibitors. pIC50 is usually given in terms of molar concentration (mol/L, or M), thus requiring IC50 in units of M.
The IC50 terminology is also used for some behavioral measures in vivo, such as the two bottle fluid consumption test. When animals decrease consumption from the drug-laced water bottle, the concentration of the drug that results in a 50% decrease in consumption is considered the IC50 for fluid consumption of that drug.
== Functional antagonist assay ==
The IC50 of a drug can be determined by constructing a dose-response curve and examining the effect of different concentrations of antagonist on reversing agonist activity. IC50 values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist. IC50 values can be used to compare the potency of two antagonists.
IC50 values are very dependent on conditions under which they are measured. In general, a higher concentration of inhibitor leads to lowered agonist activity. IC50 value increases as agonist concentration increases. Furthermore, depending on the type of inhibition, other factors may influence IC50 value; for ATP dependent enzymes, IC50 value has an interdependency with concentration of ATP, especially if inhibition is competitive.
== IC50 and affinity ==
=== Competition binding assays ===
In this type of assay, a single concentration of radioligand (usually an agonist) is used in every assay tube. The ligand is used at a low concentration, usually at or below its Kd value. The level of specific binding of the radioligand is then determined in the presence of a range of concentrations of other competing non-radioactive compounds (usually antagonists), in order to measure the potency with which they compete for the binding of the radioligand. Competition curves may also be computer-fitted to a logistic function as described under direct fit.
In this situation the IC50 is the concentration of competing ligand which displaces 50% of the specific binding of the radioligand. The IC50 value is converted to an absolute inhibition constant Ki using the Cheng-Prusoff equation formulated by Yung-Chi Cheng and William Prusoff (see Ki).
=== Cheng Prusoff equation ===
IC50 is not a direct indicator of affinity, although the two can be related at least for competitive agonists and antagonists by the Cheng-Prusoff equation. For enzymatic reactions, this equation is:
K
i
=
IC
50
1
+
[
S
]
K
m
{\displaystyle K_{i}={\frac {{\ce {IC50}}}{1+{\frac {[S]}{K_{m}}}}}}
where Ki is the binding affinity of the inhibitor, IC50 is the functional strength of the inhibitor, [S] is fixed substrate concentration and Km is the Michaelis constant i.e. concentration of substrate at which enzyme activity is at half maximal (but is frequently confused with substrate affinity for the enzyme, which it is not).
Alternatively, for inhibition constants at cellular receptors:
K
i
=
IC
50
[
A
]
EC
50
+
1
{\displaystyle K_{i}={\frac {{\ce {IC50}}}{{\frac {[A]}{{\ce {EC50}}}}+1}}}
where [A] is the fixed concentration of agonist and EC50 is the concentration of agonist that results in half maximal activation of the receptor. Whereas the IC50 value for a compound may vary between experiments depending on experimental conditions, (e.g. substrate and enzyme concentrations) the Ki is an absolute value. Ki is the inhibition constant for a drug; the concentration of competing ligand in a competition assay which would occupy 50% of the receptors if no ligand were present.
The Cheng-Prusoff equation produces good estimates at high agonist concentrations, but over- or under-estimates Ki at low agonist concentrations. In these conditions, other analyses have been recommended.
== See also ==
Certain safety factor
EC50 (half maximal effective concentration)
LD50 (median lethal dose)
Ki (equilibrium constant)
== References ==
== External links ==
AAT Bioquest Online IC50 Calculator
Online IC50 calculator (www.ic50.org.uk) based on the C programming language and gnuplot
Alternative online IC50 calculator (www.ic50.org) based on Python, NumPy, SciPy and Matplotlib
ELISA IC50/EC50 Online Tool (link seems broken)
IC50 to pIC50 calculator
Online tool for analysis of in vitro resistance to antimalarial drugs
IC50-to-Ki converter of an inhibitor and enzyme that obey classic Michaelis-Menten kinetics. | Wikipedia/Cheng-Prusoff_equation |
Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms. The MDR types most threatening to public health are MDR bacteria that resist multiple antibiotics; other types include MDR viruses, parasites (resistant to multiple antifungal, antiviral, and antiparasitic drugs of a wide chemical variety).
Recognizing different degrees of MDR in bacteria, the terms extensively drug-resistant (XDR) and pandrug-resistant (PDR) have been introduced. Extensively drug-resistant (XDR) is the non-susceptibility of one bacteria species to all antimicrobial agents except in two or less antimicrobial categories. Within XDR, pandrug-resistant (PDR) is the non-susceptibility of bacteria to all antimicrobial agents in all antimicrobial categories. The definitions were published in 2011 in the journal Clinical Microbiology and Infection and are openly accessible.
== Common multidrug-resistant organisms (MDROs) ==
Common multidrug-resistant organisms, typically bacteria, include:
Vancomycin-Resistant Enterococci (VRE)
Methicillin-resistant Staphylococcus aureus (MRSA)
Extended-spectrum β-lactamase (ESBLs) producing Gram-negative bacteria
Klebsiella pneumoniae carbapenemase (KPC) producing Gram-negatives
Multidrug-resistant Gram negative rods (MDR GNR) MDRGN bacteria such as Enterobacter species, E.coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa
Multi-drug-resistant tuberculosis
Overlapping with MDRGN, a group of Gram-positive and Gram-negative bacteria of particular recent importance have been dubbed as the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species).
== Bacterial resistance to antibiotics ==
Various microorganisms have survived for thousands of years by their ability to adapt to antimicrobial agents. They do so via spontaneous mutation or by DNA transfer. This process enables some bacteria to oppose the action of certain antibiotics, rendering the antibiotics ineffective. These microorganisms employ several mechanisms in attaining multi-drug resistance:
No longer relying on a glycoprotein cell wall
Enzymatic deactivation of antibiotics
Decreased cell wall permeability to antibiotics
Altered target sites of antibiotic
Efflux mechanisms to remove antibiotics
Increased mutation rate as a stress response
Many different bacteria now exhibit multi-drug resistance, including staphylococci, enterococci, gonococci, streptococci, salmonella, as well as numerous other Gram-negative bacteria and Mycobacterium tuberculosis. Antibiotic resistant bacteria are able to transfer copies of DNA that code for a mechanism of resistance to other bacteria even distantly related to them, which then are also able to pass on the resistance genes, resulting in generations of antibiotics resistant bacteria. This initial transfer of DNA is called horizontal gene transfer.
== Bacterial resistance to bacteriophages ==
Phage-resistant bacteria variants have been observed in human studies. As for antibiotics, horizontal transfer of phage resistance can be acquired by plasmid acquisition.
== Antifungal resistance ==
Yeasts such as Candida species can become resistant under long-term treatment with azole preparations, requiring treatment with a different drug class.
Lomentospora prolificans infections are often fatal because of their resistance to multiple antifungal agents.
== Antiviral resistance ==
HIV is the prime example of MDR against antivirals, as it mutates rapidly under monotherapy.
Influenza virus has become increasingly MDR; first to amantadines, then to neuraminidase inhibitors such as oseltamivir, (2008-2009: 98.5% of Influenza A tested resistant), also more commonly in people with weak immune systems. Cytomegalovirus can become resistant to ganciclovir and foscarnet under treatment, especially in immunosuppressed patients. Herpes simplex virus rarely becomes resistant to acyclovir preparations, mostly in the form of cross-resistance to famciclovir and valacyclovir, usually in immunosuppressed patients.
== Antiparasitic resistance ==
The prime example for MDR against antiparasitic drugs is malaria. Plasmodium vivax has become chloroquine and sulfadoxine-pyrimethamine resistant a few decades ago, and as of 2012 artemisinin-resistant Plasmodium falciparum has emerged in western Cambodia and western Thailand.
Toxoplasma gondii can also become resistant to artemisinin, as well as atovaquone and sulfadiazine, but is not usually MDR
Antihelminthic resistance is mainly reported in the veterinary literature, for example in connection with the practice of livestock drenching and has been recent focus of FDA regulation.
== Preventing the emergence of antimicrobial resistance ==
To limit the development of antimicrobial resistance, it has been suggested to:
Use the appropriate antimicrobial for an infection; e.g. no antibiotics for viral infections
Identify the causative organism whenever possible
Select an antimicrobial which targets the specific organism, rather than relying on a broad-spectrum antimicrobial
Complete an appropriate duration of antimicrobial treatment (not too short and not too long)
Use the correct dose for eradication; subtherapeutic dosing is associated with resistance, as demonstrated in food animals.
More thorough education of and by prescribers on their actions' implications globally.
Vaccination to prevent drug resistance for instance pneumococcus vaccine or flu vaccine
The medical community relies on education of its prescribers, and self-regulation in the form of appeals to voluntary antimicrobial stewardship, which at hospitals may take the form of an antimicrobial stewardship program. It has been argued that depending on the cultural context government can aid in educating the public on the importance of restrictive use of antibiotics for human clinical use, but unlike narcotics, there is no regulation of its use anywhere in the world at this time. Antibiotic use has been restricted or regulated for treating animals raised for human consumption with success, in Denmark for example.
Infection prevention is the most efficient strategy of prevention of an infection with a MDR organism within a hospital, because there are few alternatives to antibiotics in the case of an extensively resistant or panresistant infection; if an infection is localized, removal or excision can be attempted (with MDR-TB the lung for example), but in the case of a systemic infection only generic measures like boosting the immune system with immunoglobulins may be possible. The use of bacteriophages (viruses which kill bacteria) is a developing area of possible therapeutic treatments.
It is necessary to develop new antibiotics over time since the selection of resistant bacteria cannot be prevented completely. This means with every application of a specific antibiotic, the survival of a few bacteria which already have a resistance gene against the substance is promoted, and the concerning bacterial population amplifies. Therefore, the resistance gene is farther distributed in the organism and the environment, and a higher percentage of bacteria means they no longer respond to a therapy with this specific antibiotic. In addition to developing new antibiotics, new strategies entirely must be implemented in order to keep the public safe from the event of total resistance. New strategies are being tested such as UV light treatments and bacteriophage utilization, however more resources must be dedicated to this cause.
== See also ==
Drug resistance
MDRGN bacteria
Xenobiotic metabolism
NDM1 enzymatic resistance
Herbicide resistance
P-glycoprotein
== References ==
== Further reading ==
== External links ==
BURDEN of Resistance and Disease in European Nations - An EU project to estimate the financial burden of antibiotic resistance in European Hospitals
European Centre of Disease Prevention and Control and (ECDC): Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance Disease Programmes Unit
State of Connecticut Department of Public Health MDRO information MultidrugResistant Organisms MDROs What Are They | Wikipedia/Multiple_drug_resistance |
The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to start human clinical trials and to ship an experimental drug across state lines (usually to clinical investigators) before a marketing application for the drug has been approved. Regulations are primarily at 21 CFR 312. Similar procedures are followed in the European Union, Japan, and Canada due to regulatory harmonization efforts by the International Council for Harmonisation.
== Types ==
Research or investigator INDs are non-commercial INDs filed by researchers to study an unapproved drug or to study an approved drug for a new indication or in a new patient population.
Emergency Use INDs, also called compassionate use or single-patient INDs, are filed for emergency use of an unapproved drug when the clinical situation does not allow sufficient time to submit an IND in accordance with 21 CFR §§ 312.23, 312.24. These are most commonly used for life-threatening conditions for which there is no standard treatment.
Treatment INDs are filed to make a drug available for the treatment of serious or immediately life-threatening conditions prior to FDA approval. Serious diseases or conditions are stroke, schizophrenia, rheumatoid arthritis, osteoarthritis, chronic depression, seizures, Alzheimer's dementia, amyotrophic lateral sclerosis (ALS), and narcolepsy.
Screening INDs are filed for multiple, closely related compounds in order to screen for the preferred compounds or formulations. The preferred compound can then be developed under a separate IND. Used for screening different salts, esters and other drug derivatives that are chemically different, but pharmacodynamically similar.
== Application ==
The IND application may be divided into the following categories:
Preclinical testing consists of animal pharmacology and toxicology studies to assess whether the drug is safe for testing in humans. Also included are any previous experience with the drug in humans (often foreign use).
Manufacturing Information includes composition, manufacturer, and stability of, and the controls used for, manufacturing the drug. Used to ensure that the company can adequately produce and supply consistent batches of the drug.
Investigator information on the qualifications of clinical investigators, that is, the professionals (generally physicians) who oversee the administration of the experimental drug to the study subjects. Used to assess whether the investigators are qualified to fulfill their clinical trial duties.
Clinical trial protocols are the centerpiece of the IND. Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose the subjects to unnecessary risks.
Other commitments are commitments to obtain informed consent from the research subjects, to obtain a review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.
An IND application must also include an Investigator's Brochure intended to educate the trial investigators of the significant facts about the trial drug they need to know to conduct their clinical trial with the least hazard to the subjects or patients.
Once an IND application is submitted, the FDA has 30 days to object to the IND or it automatically becomes effective and clinical trials may begin. If the FDA detects a problem, it may place a clinical hold on the IND, prohibiting the start of the clinical studies until the problem is resolved, as outlined in 21 CFR 312.42.
An IND must be labeled "Caution: New Drug – Limited by Federal (or United States) law to investigational use," per 21 CFR 312.6
== Prevalence ==
Approximately two-thirds of both INDs and new drug applications (NDAs) are small-molecule drugs. The rest is biopharmaceuticals. About half of the INDs fail in preclinical and clinical phases of drug development.
== Examples ==
The FDA runs a medical marijuana IND program (the Compassionate Investigational New Drug program). It stopped accepting new patients in 1992 after public health authorities concluded there was no scientific value to it, and due to President George H. W. Bush administration's desire to "get tough on crime and drugs." As of 2011, four patients continue to receive cannabis from the government under the program.
Sanctioned by Executive Order 13139, the US Department of Defense employed an anthrax vaccine classified as an investigational new drug (IND) in its Anthrax Vaccine Immunization Program (AVIP).
== See also ==
Abigail Alliance for Better Access to Developmental Drugs
Animal drug
Biologics license application
Drug discovery
FDA Fast Track Development Program
Good Manufacturing Practice
Inverse benefit law
Orphan drug
TOL101
== References ==
== External links ==
Investigational New Drug (IND) Application Process Center for Drug Evaluation and Research, Food and Drug Administration.
ICH Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance. BROKEN LINK
Troetel, W.M.: Achieving a Successful US IND Filing (1) The Regulatory Affairs Journal. 6: 22–28, January 1995.
Troetel, W.M.: Achieving a Successful US IND Filing (2) The Regulatory Affairs Journal. 6: 104–108, February 1995.
Henninger, Daniel (2002). "Drug Lag". In David R. Henderson (ed.). Concise Encyclopedia of Economics (1st ed.). Library of Economics and Liberty. OCLC 317650570, 50016270, 163149563
IND Forms and Instructions from the US Food and Drug Administration | Wikipedia/Investigational_New_Drug |
The Food and Drugs Act (French: Loi sur les aliments et drogues) is an act of the Parliament of Canada regarding the production, import, export, transport across provinces and sale of food, drugs, contraceptive devices and cosmetics (including personal cleaning products such as soap and toothpaste). It was first passed in 1920 and most recently revised in 1985. It attempts to ensure that these products are safe, that their ingredients are disclosed and that drugs are effective and are not sold as food or cosmetics. It also states that cures for disease listed in Schedule A (including cancer, obesity, anxiety, asthma, depression, appendicitis, and sexually transmitted diseases), cannot be advertised to the general public.
== Background ==
After the launch of the Federal Department of Health in 1919, the Food and Drugs Act was presented in late 1920. Rules and regulations developed under the Act established the requirements for licensing and creating drugs in Canada. The law granted the Minister of Health the right to cancel or suspend licenses of companies failing to comply with the requirements.
The Food and Drugs Act was not significantly modified until 1947 when the foundations were laid for the current market today. In 1951, drug manufacturers were required to submit a file for each new drug prior to marketing their product. However, during the early 1960s, the drug thalidomide, which had been approved to enter the market, resulted in the deaths of thousands of infants and severe birth defects in others when the drug was taken by women in early stages of pregnancy.
As a result of the problems caused by the drug thalidomide, the Act was revisited and strengthened by Health Canada. The revised version placed new requirements on manufacturers to provide evidence for efficacy in seeking a Notice of Compliance, which must be obtained before any drug could be sold. The manufacturer must meet all the requirements before making any drug available to the public, but once the drug passes with no adverse reactions and without any changes needed to the drug's formula, it may never be subjected to review by Health Canada again. Some health advocates want post-approval surveillance to watch for unexpected problems.
== Part I ==
Part I provides general interpretations of the terms, and provides details of each of the topics discussed on what the Act entails:
Food
Drugs
Cosmetics
Devices
== Part II ==
Part II of the Act focuses the administration and the Enforcement that allows the government to intervene with the manufacturer.
It entails:
Inspection, Seizure and forfeiture
Analysis
Power of the Minister
Incorporation by Reference
Regulations
Interim Orders
Marketing Authorization
Offense and Punishment
Exports
== Parts III and IV ==
Parts III (enacted in 1961) and IV (enacted in 1969) provided for implementation of controls required by the Convention on Psychotropic Substances. Part III dealt with "controlled" drugs such as amphetamine, methaqualone, and phenmetrazine, which have legitimate medical uses. Part IV focused on Schedule H "restricted drugs", those whose only legitimate use is for scientific research, such as the hallucinogens LSD, DMT, and MDMA. These parts established eight classes of regulated substances, ranging from Schedules A to H.
The 1996 Controlled Drugs and Substances Act repealed Parts III and IV.
== 2008 proposed amendment ==
In April 2008, an amendment to the Food and Drugs Act, Canadian Bill C-51 was tabled in the House of Commons. The purpose of this bill was to modernize the regulatory system for foods and therapeutic products, to strengthen the oversight of the benefits and risks of therapeutic products throughout their life cycle, to support effective compliance and enforcement actions and to enable a greater transparency and openness of the regulatory system. Some of the proposed amendments are as follows:
Illegalize the sale and importation of products that have knowingly been adulterated.
Illegalize the sale of counterfeit therapeutic products.
Clarify in the Food and Drugs Act the requirement of therapeutic products to have market authorization, which has been required by Health Canada for many years.
The bill has been subject to criticism due to a perception that the bill would illegalize all food and Natural Health Products by categorizing them as drug products. Natural health products in Canada have been regulated as a subset of drugs since the Natural Health Products Regulations were put into place on January 1, 2004. Health Canada has stated "The Natural Health Product Regulations, introduced in 2004, will continue to operate the same way under Bill C-51. Canadians will continue to have access to natural health products that are safe, effective and of high quality.
In spite of this claim, The Natural Health Industry remained skeptical. A watchdog group was employed to investigate the concerns and a number of hidden camera videos surfaced that further aggravated the NHP industry concerns.
== Regulations Amending the Food and Drug Regulations (Nutrition Symbols, Other Labelling Provisions, Vitamin D and Hydrogenated Fats or Oils) ==
=== Overview ===
Frequent consumption of foods rich in sodium, sugars, or saturated fats is associated with elevated health risks, including but not limited to:
Stroke
Obesity
Heart disease
Type 2 diabetes
High blood pressure
Certain types of cancers
To address this concern, a front-of-package nutrition symbol has been introduced. This symbol serves the dual purpose of aiding consumers in making informed choices while grocery shopping and assisting health professionals in educating the public about the nutritional content of foods high in sodium, sugars, and saturated fat.
=== Front-of-Package Nutrition Labelling ===
The front-of-package nutrition symbol is mandatory for prepackaged foods that meet or exceed specified levels for sodium, sugars, or saturated fat. However, certain foods are exempt from displaying this symbol, including:
Packaged individual portions intended for restaurant or commercial consumption
Milk and cream sold in refillable glass containers -
Foods in very small packages
Raw, single-ingredient whole cuts of meat, poultry, and fish without a nutrition facts table
Additionally, certain foods with health-promoting properties, such as fruits, vegetables without added sodium, sugars, or saturated fats, plain dairy products, and specific dairy items contributing to bone health, are exempt from the requirement.
Certain products, such as butter, sugar, salt, honey, celery salt, maple syrup, vegetable oils, and seasoning salt, used for the same purpose, are also exempt from displaying the front-of-package nutrition symbol.
=== Appearance of the Front-of-Package Nutrition Symbol ===
The front-of-package nutrition symbol is depicted in black and white and features a magnifying glass, emphasizing whether the food product is high in sodium, sugars, saturated fat, or a combination of these components.
=== Symbol Selection Process ===
The selection of the front-of-package nutrition symbol was informed by feedback from Canadian residents and consumer research, ensuring its relevance and comprehensibility.
=== Placement Requirements ===
For uniformity and ease of identification, the nutrition symbol must adhere to specific requirements concerning size, location, and language:
Size: The size of the symbol is determined by the package size to ensure visibility on packages of varying dimensions.
Location: Generally, the symbol appears in the upper half of the label for most package shapes. However, on wider-than-tall labels, it is situated on the right half.
Language: The front-of-package nutrition symbol is presented in both English and French. It may manifest as two separate symbols, each in one language, or as a combined symbol featuring both languages.
== See also ==
Therapeutic Products Directorate
Food safety
Medical device
Food Bill 160-2 of New Zealand
Food Safety Modernization Act
Pledge to Africa Act
== References ==
== External links ==
Food and Drugs Act Justice Canada
Canada's Previous Drug Laws (before the Controlled Drugs and Substances Act came into force in May 1997), Canadian Foundation for Drug Policy.
Cannabis Canada Issue 7.
Co-operation between Canada and other countries and territories to promote countermeasures against illicit drug trafficking, 1987.
Debates of the House of Commons of Canada, Oct. 30, 1995.
Official Government of Canada webpage for information on Bill C-51
Complete transcript of C51
Bill C-51 and the Regulation of Natural Health Products – Fast Facts
Brief History of Drug Regulation in Canada | Wikipedia/Food_and_Drugs_Act |
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", and a macromolecule is a very large molecule, such as a protein, with a complex structure of components. 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. This equation is formally equivalent to the Langmuir isotherm. 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 O2 binding curve of hemoglobin.
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.
The Hill equation (for response) is important in the construction of dose-response curves.
== Proportion of ligand-bound receptors ==
The Hill equation is commonly expressed in the following ways:
θ
=
[
L
]
n
K
d
+
[
L
]
n
=
[
L
]
n
(
K
A
)
n
+
[
L
]
n
=
1
1
+
(
K
A
[
L
]
)
n
{\displaystyle {\begin{aligned}\theta &={[{\ce {L}}]^{n} \over K_{d}+[{\ce {L}}]^{n}}\\&={[{\ce {L}}]^{n} \over (K_{A})^{n}+[{\ce {L}}]^{n}}\\&={1 \over 1+\left({K_{A} \over [{\ce {L}}]}\right)^{n}}\end{aligned}}}
,
where
θ
{\displaystyle \theta }
is the fraction of the receptor protein concentration that is bound by the ligand,
[
L
]
{\displaystyle {\ce {[L]}}}
is the total ligand concentration,
K
d
{\displaystyle K_{d}}
is the apparent dissociation constant derived from the law of mass action,
K
A
{\displaystyle K_{A}}
is the ligand concentration producing half occupation,
n
{\displaystyle n}
is the Hill coefficient.
The special case where
n
=
1
{\displaystyle n=1}
is a Monod equation.
=== Constants ===
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}}}}
). 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}}
.
=== Gaddum equation ===
The Gaddum equation is a further generalisation of the Hill-equation, incorporating the presence of a reversible competitive antagonist. 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
=== Hill plot ===
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:
log
(
θ
1
−
θ
)
=
n
log
[
L
]
−
log
K
d
=
n
log
[
L
]
−
n
log
K
A
{\displaystyle {\begin{aligned}\log \left({\theta \over 1-\theta }\right)&=n\log {[{\ce {L}}]}-\log {K_{d}}\\&=n\log {[{\ce {L}}]}-n\log {K_{A}}\end{aligned}}}
.
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. 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. This impacts the parameters of linear regression lines fitted to the data. Furthermore, the use of computers enables more robust analysis involving nonlinear regression.
== Tissue response ==
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
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. Empirical models based on nonlinear regression are usually preferred over the use of some transformation of the data that linearizes the dose-response relationship.
== Hill coefficient ==
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, the value of the Hill coefficient describes the cooperativity of ligand binding in the following way:
n
>
1
{\displaystyle n>1}
. Positively cooperative binding: Once one ligand molecule is bound to the enzyme, its affinity for other ligand molecules increases. For example, the Hill coefficient of oxygen binding to haemoglobin (an example of positive cooperativity) falls within the range of 1.7–3.2.
n
<
1
{\displaystyle n<1}
. Negatively cooperative binding: Once one ligand molecule is bound to the enzyme, its affinity for other ligand molecules decreases.
n
=
1
{\displaystyle n=1}
. Noncooperative (completely independent) binding: The affinity of the enzyme for a ligand molecule is not dependent on whether or not other ligand molecules are already bound. When n=1, we obtain a model that can be modeled by Michaelis–Menten kinetics, in which
K
D
=
K
A
=
K
M
{\textstyle K_{D}=K_{A}=K_{M}}
, the Michaelis–Menten constant.
The Hill coefficient can be calculated approximately in terms of the cooperativity index of Taketa and Pogell as follows:
n
=
log
10
(
81
)
log
10
(
EC
90
/
EC
10
)
{\displaystyle n={\frac {\log _{10}(81)}{\log _{10}({\ce {EC90}}/{\ce {EC10}})}}}
.
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.
== Reversible form ==
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.
== Relationship to the elasticity coefficients ==
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 )}
== Applications ==
The Hill equation is used extensively in pharmacology to quantify the functional parameters of a drug 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.
=== Regulation of gene transcription ===
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). 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.
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:
d
d
t
[
X
p
r
o
d
u
c
e
d
]
=
k
⋅
[
Y
a
c
t
i
v
e
]
n
(
K
A
)
n
+
[
Y
a
c
t
i
v
e
]
n
{\displaystyle {\mathrm {d} \over \mathrm {d} t}[{\rm {X_{produced}}}]=k\ \cdot {{[{\rm {Y_{active}}}]^{\mathit {n}}} \over {(K_{A})^{n}\ +\ {[{\rm {Y_{active}}}]^{\mathit {n}}}}}}
,
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:
d
d
t
[
Y
p
r
o
d
u
c
e
d
]
=
k
⋅
(
K
A
)
n
(
K
A
)
n
+
[
Z
a
c
t
i
v
e
]
n
{\displaystyle {\mathrm {d} \over \mathrm {d} t}[{\rm {Y_{produced}}}]=k\ \cdot {{(K_{A})^{\mathit {n}}} \over {(K_{A})^{n}\ +\ {[{\rm {Z_{active}}}]^{\mathit {n}}}}}}
,
where k is the maximal transcription rate of gene Y.
== Limitations ==
Because of its assumption that ligand molecules bind to a receptor simultaneously, the Hill equation has been criticized as a physically unrealistic model. Moreover, the Hill coefficient should not be considered a reliable approximation of the number of cooperative ligand binding sites on a receptor except when the binding of the first and subsequent ligands results in extreme positive cooperativity.
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. Nevertheless, other, more complex models of cooperative binding have been proposed. 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.
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.
== See also ==
Binding coefficient
Bjerrum plot
Cooperative binding
Gompertz curve
Langmuir adsorption model
Logistic function
Michaelis–Menten kinetics
Monod equation
== Notes ==
== References ==
== Further reading ==
Dorland's Illustrated Medical Dictionary
Coval, ML (December 1970). "Analysis of Hill interaction coefficients and the invalidity of the Kwon and Brown equation". J. Biol. Chem. 245 (23): 6335–6. doi:10.1016/S0021-9258(18)62614-6. PMID 5484812.
d'A Heck, Henry (1971). "Statistical theory of cooperative binding to proteins. Hill equation and the binding potential". J. Am. Chem. Soc. 93 (1): 23–29. Bibcode:1971JAChS..93...23H. doi:10.1021/ja00730a004. PMID 5538860.
Atkins, Gordon L. (1973). "A simple digital-computer program for estimating the parameter of the Hill Equation". Eur. J. Biochem. 33 (1): 175–180. doi:10.1111/j.1432-1033.1973.tb02667.x. PMID 4691349.
Endrenyi, Laszlo; Kwong, F. H. F.; Fajszi, Csaba (1975). "Evaluation of Hill slopes and Hill coefficients when the saturation binding or velocity is not known". Eur. J. Biochem. 51 (2): 317–328. doi:10.1111/j.1432-1033.1975.tb03931.x. PMID 1149734.
Voet, Donald; Voet, Judith G. (2004). Biochemistry.
Weiss, J. N. (1997). "The Hill equation revisited: uses and misuses". FASEB Journal. 11 (11): 835–841. doi:10.1096/fasebj.11.11.9285481. PMID 9285481. S2CID 827335.
Kurganov, B. I.; Lobanov, A. V. (2001). "Criterion for Hill equation validity for description of biosensor calibration curves". Anal. Chim. Acta. 427 (1): 11–19. Bibcode:2001AcAC..427...11K. doi:10.1016/S0003-2670(00)01167-3.
Goutelle, Sylvain; Maurin, Michel; Rougier, Florent; Barbaut, Xavier; Bourguignon, Laurent; Ducher, Michel; Maire, Pascal (2008). "The Hill equation: a review of its capabilities in pharmacological modelling". Fundamental & Clinical Pharmacology. 22 (6): 633–648. doi:10.1111/j.1472-8206.2008.00633.x. PMID 19049668. S2CID 4979109.
Gesztelyi R; Zsuga J; Kemeny-Beke A; Varga B; Juhasz B; Tosaki A (2012). "The Hill equation and the origin of quantitative pharmacology". Archive for History of Exact Sciences. 66 (4): 427–38. doi:10.1007/s00407-012-0098-5. S2CID 122929930.
Colquhoun D (2006). "The quantitative analysis of drug-receptor interactions: a short history". Trends Pharmacol Sci. 27 (3): 149–57. doi:10.1016/j.tips.2006.01.008. PMID 16483674.
Rang HP (2006). "The receptor concept: pharmacology's big idea". Br J Pharmacol. 147 (Suppl 1): S9–16. doi:10.1038/sj.bjp.0706457. PMC 1760743. PMID 16402126.
== External links ==
Hill equation calculator | Wikipedia/Del_Castillo_Katz_model |
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is the object of pharmacokinetics. Metabolism is one of the stages (see ADME) of the drug's transit through the body that involves the breakdown of the drug so that it can be excreted by the body.
The metabolism of pharmaceutical drugs is an important aspect of pharmacology and medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer, and the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down during bioremediation, or persist in the environment. The enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides.
Drug metabolism is divided into three phases. In phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters and pumped out of cells. Drug metabolism often converts lipophilic compounds into hydrophilic products that are more readily excreted.
== Permeability barriers and detoxification ==
The exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time; these are major characteristics of xenobiotic toxic stress. The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normal metabolism. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity enzymatic systems.
All organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membranes, and the uptake of useful molecules is mediated through transport proteins that specifically select substrates from the extracellular mixture. This selective uptake means that most hydrophilic molecules cannot enter cells, since they are not recognised by any specific transporters. In contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-soluble xenobiotics using membrane barriers.
However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.
The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the glyoxalase system, which removes the reactive aldehyde methylglyoxal, and the various antioxidant systems that eliminate reactive oxygen species.
== Phases of detoxification ==
The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells.
=== Phase I – modification ===
In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system. These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates. The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactive oxyferryl species, according to the following scheme:
O2 + NADPH + H+ + RH → NADP+ + H2O + ROH
Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, decyclization, and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines, paracetamol, and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate.
A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one (toxification). Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions. For example, phase I metabolism converts acetonitrile to HOCH2CN, which rapidly dissociates into formaldehyde and hydrogen cyanide.
Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts. This example of a biomimetic reaction tends to give products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceutical trimebutine, desmethyltrimebutine (nor-trimebutine), can be efficiently produced by in vitro oxidation of the commercially available drug. Hydroxylation of an N-methyl group leads to expulsion of a molecule of formaldehyde, while oxidation of the O-methyl groups takes place to a lesser extent.
==== Oxidation ====
Cytochrome P450 monooxygenase system
Flavin-containing monooxygenase system
Alcohol dehydrogenase and aldehyde dehydrogenase
Monoamine oxidase
Co-oxidation by peroxidases
==== Reduction ====
NADPH-cytochrome P450 reductase
Cytochrome P450 reductase, also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR, is a membrane-bound enzyme required for electron transfer to cytochrome P450 in the microsome of the eukaryotic cell from a FAD- and FMN-containing enzyme NADPH:cytochrome P450 reductase
The general scheme of electron flow in the POR/P450 system is:
NADPH
→
FAD
→
FMN
→
P450
→
O2
Reduced (ferrous) cytochrome P450
During reduction reactions, a chemical can enter futile cycling, in which it gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion).
==== Hydrolysis ====
Esterases and amidase
Epoxide hydrolase
=== Phase II – conjugation ===
In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid. Sites on drugs where conjugation reactions occur include carboxy (-COOH), hydroxy (-OH), amino (NH2), and thiol (-SH) groups. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce active metabolites. The addition of large anionic groups (such as GSH) detoxifies reactive electrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.
These reactions are catalysed by a large group of broad-specificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups. One of the most important classes of this group is that of the glutathione S-transferases (GSTs).
=== Phase III – further modification and excretion ===
After phase II reactions, the xenobiotic conjugates may be further metabolized. A common example is the processing of glutathione conjugates to acetylcysteine (mercapturic acid) conjugates. Here, the γ-glutamate and glycine residues in the glutathione molecule are removed by gamma-glutamyl transpeptidase and dipeptidases. In the final step, the cysteine residue in the conjugate is acetylated.
Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the multidrug resistance protein (MRP) family. These proteins are members of the family of ATP-binding cassette transporters and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions, and thus act to remove phase II products to the extracellular medium, where they may be further metabolized or excreted.
== Endogenous toxins ==
The detoxification of endogenous reactive metabolites such as peroxides and reactive aldehydes often cannot be achieved by the system described above. This is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the glyoxalase system, which acts to dispose of the reactive aldehyde methylglyoxal, and the various antioxidant systems that remove reactive oxygen species.
== Sites ==
Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug metabolism, although every biological tissue has some ability to metabolize drugs.
Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the gut, and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs.
If a drug is taken into the GI tract, where it enters hepatic circulation through the portal vein, it becomes well-metabolized and is said to show the first pass effect.
Other sites of drug metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin.
These sites are usually responsible for localized toxicity reactions.
== Factors affecting drug metabolism ==
The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase system is a crucial pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true, as in enzyme inhibition. However, in cases where an enzyme is responsible for metabolizing a pro-drug into a drug, enzyme induction can accelerate this conversion and increase drug levels, potentially causing toxicity.
Various physiological and pathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition, sex differences or gut microbiota. This last factor has significance because gut microorganisms are able to chemically modify the structure of drugs through degradation and biotransformation processes, thus altering the activity and toxicity of drugs. These processes can decrease the efficacy of drugs, as is the case of digoxin in the presence of Eggerthella lenta in the microbiota. Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs.
In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults. Inherited genetic variations in drug metabolising enzymes result in their different catalytic activity levels. For example, N-acetyltransferases (involved in Phase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly (rapid acetylators), split roughly 50:50 in the population of Canada. However, variability in NAT2 alleles distribution across different populations is high and some ethnicities have higher proportion of slow acetylators. This variation in metabolising capacity may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity. NAT2 enzyme is a primary metaboliser of antituberculosis (isoniazid), some antihypertensive (hydralazine), anti-arrythmic drugs (procainamide), antidepressants (phenelzine) and many more and increased toxicity as well as drug adverse reactions in slow acetylators have been widely reported. Similar phenomenons of altered metabolism due to inherited variations have been described for other drug-metabolising enzymes, like CYP2D6, CYP3A4, DPYD, UGT1A1. DPYD and UGT1A1 genotyping is now required before administration of the corresponding substrate compounds (5-FU and capecitabine for DPYD and irinotecan for UGT1A1) to determine the activity of DPYD and UGT1A1 enzyme and reduce the dose of the drug in order to avoid severe adverse reactions.
Dose, frequency, route of administration, tissue distribution and protein binding of the drug affect its metabolism. Pathological factors can also influence drug metabolism, including liver, kidney, or heart diseases.
In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects. This can be used to identify individuals most at risk from adverse reaction.
== History ==
Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as benzaldehyde could be oxidized and conjugated to amino acids in the human body. During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as methylation, acetylation, and sulfonation.
In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by Richard Williams of the book Detoxication mechanisms in 1947. This modern biochemical research resulted in the identification of glutathione S-transferases in 1961, followed by the discovery of cytochrome P450s in 1962, and the realization of their central role in xenobiotic metabolism in 1963.
== See also ==
Biodegradation
Microbial biodegradation
== References ==
== Further reading ==
== External links ==
Databases
Drug metabolism database
Directory of P450-containing Systems
University of Minnesota Biocatalysis/Biodegradation Database
SPORCalc
Drug metabolism
Small Molecule Drug Metabolism
Drug metabolism portal
Microbial biodegradation
Microbial Biodegradation, Bioremediation and Biotransformation
History
History of Xenobiotic Metabolism at the Wayback Machine (archived July 13, 2007) | Wikipedia/Drug_metabolism |
In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect of grapefruit on the metabolism of drugs.
Interactions may occur by simultaneous targeting of receptors, directly or indirectly. For example, both Zolpidem and alcohol affect GABAA receptors, and their simultaneous consumption results in the overstimulation of the receptor, which can lead to loss of consciousness. When two drugs affect each other, it is a drug–drug interaction (DDI). The risk of a DDI increases with the number of drugs used.
A large share of elderly people regularly use five or more medications or supplements, with a significant risk of side-effects from drug–drug interactions.
Drug interactions can be of three kinds:
additive (the result is what you expect when you add together the effect of each drug taken independently),
synergistic (combining the drugs leads to a larger effect than expected), or
antagonistic (combining the drugs leads to a smaller effect than expected).
It may be difficult to distinguish between synergistic or additive interactions, as individual effects of drugs may vary.
Direct interactions between drugs are also possible and may occur when two drugs are mixed before intravenous injection. For example, mixing thiopentone and suxamethonium can lead to the precipitation of thiopentone.
== Interactions based on pharmacodynamics ==
Pharmacodynamic interactions are the drug–drug interactions that occur at a biochemical level and depend mainly on the biological processes of organisms. These interactions occur due to action on the same targets; for example, the same receptor or signaling pathway.
Pharmacodynamic interactions can occur on protein receptors. Two drugs can be considered to be homodynamic, if they act on the same receptor. Homodynamic effects include drugs that act as (1) pure agonists, if they bind to the main locus of the receptor, causing a similar effect to that of the main drug, (2) partial agonists if, on binding to a secondary site, they have the same effect as the main drug, but with a lower intensity and (3) antagonists, if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. These may be competitive antagonists, if they compete with the main drug to bind with the receptor. or uncompetitive antagonists, when the antagonist binds to the receptor irreversibly. The drugs can be considered heterodynamic competitors, if they act on distinct receptor with similar downstream pathways.
The interaction my also occur via signal transduction mechanisms. For example, low blood glucose leads to a release of catecholamines, triggering symptoms that hint the organism to take action, like consuming sugary foods. If a patient is on insulin, which reduces blood sugar, and also beta-blockers, the body is less able to cope with an insulin overdose.
== Interactions based on pharmacokinetics ==
Pharmacokinetics is the field of research studying the chemical and biochemical factors that directly affect dosage and the half-life of drugs in an organism, including absorption, transport, distribution, metabolism and excretion. Compounds may affect any of those process, ultimately interfering with the flux of drugs in the human body, increasing or reducing drug availability.
=== Based on absorption ===
Drugs that change intestinal motility may impact the level of other drugs taken. For example, prokinetic agents increase the intestinal motility, which may cause drugs to go through the digestive system too fast, reducing absorption.
The pharmacological modification of pH can affect other compounds. Drugs can be present in ionized or non-ionized forms depending on pKa, and neutral compounds are usually better absorbed by membranes. Medication like antacids can increase pH and inhibit the absorption of other drugs such as zalcitabine, tipranavir and amprenavir. The opposite is more common, with, for example, the antacid cimetidine stimulating the absorption of didanosine. Some resources describe that a gap of two to four hours between taking the two drugs is needed to avoid the interaction.
Factors such as food with high-fat content may also alter the solubility of drugs and impact its absorption. This is the case for oral anticoagulants and avocado. The formation of non-absorbable complexes may occur also via chelation, when cations can make certain drugs harder to absorb, for example between tetracycline or the fluoroquinolones and dairy products, due to the presence of calcium ions. . Other drugs bind to proteins. Some drugs such as sucralfate bind to proteins, especially if they have a high bioavailability. For this reason its administration is contraindicated in enteral feeding.
Some drugs also alter absorption by acting on the P-glycoprotein of the enterocytes. This appears to be one of the mechanisms by which grapefruit juice increases the bioavailability of various drugs beyond its inhibitory activity on first pass metabolism.
=== Based on transport and distribution ===
Drugs also may affect each other by competing for transport proteins in plasma, such as albumin. In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, modifying its expected concentration. The organism has mechanisms to counteract these situations (by, for example, increasing plasma clearance), and thus they are not usually clinically relevant. They may become relevant if other problems are present, such as issues with drug excretion.
=== Based on metabolism ===
Many drug interactions are due to alterations in drug metabolism. Further, human drug-metabolizing enzymes are typically activated through the engagement of nuclear receptors. One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases.
==== CYP450 ====
Cytochrome P450 is a very large family of haemoproteins (hemoproteins) that are characterized by their enzymatic activity and their role in the metabolism of a large number of drugs. Of the various families that are present in humans, the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.
The majority of the enzymes are also involved in the metabolism of endogenous substances, such as steroids or sex hormones, which is also important should there be interference with these substances. The function of the enzymes can either be stimulated (enzyme induction) or inhibited (enzyme inhibition).
==== Through enzymatic inhibition and induction ====
If a drug is metabolized by a CYP450 enzyme and drug B blocks the activity of these enzymes, it can lead to pharmacokinetic alterations. A. This alteration results in drug A remaining in the bloodstream for an extended duration, and eventually increase in concentration.
In some instances, the inhibition may reduce the therapeutic effect, if instead the metabolites of the drug is responsible for the effect.
Compounds that increase the efficiency of the enzymes, on the other hand, may have the opposite effect and increase the rate of metabolism.
==== Examples of metabolism-based interactions ====
An example of this is shown in the following table for the CYP1A2 enzyme, showing the substrates (drugs metabolized by this enzyme) and some inductors and inhibitors of its activity:
Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:
=== Based on excretion ===
==== Renal and biliary excretion ====
Drugs tightly bound to proteins (i.e. not in the free fraction) are not available for renal excretion.
Filtration depends on a number of factors including the pH of the urine. Drug interactions may affect those points.
== With herbal medicines ==
Herb-drug interactions are drug interactions that occur between herbal medicines and conventional drugs. These types of interactions may be more common than drug-drug interactions because herbal medicines often contain multiple pharmacologically active ingredients, while conventional drugs typically contain only one. Some such interactions are clinically significant, although most herbal remedies are not associated with drug interactions causing serious consequences. Most catalogued herb-drug interactions are moderate in severity. The most commonly implicated conventional drugs in herb-drug interactions are warfarin, insulin, aspirin, digoxin, and ticlopidine, due to their narrow therapeutic indices. The most commonly implicated herbs involved in such interactions are those containing St. John’s Wort, magnesium, calcium, iron, or ginkgo.
=== Examples ===
Examples of herb-drug interactions include, but are not limited to:
St. John's wort affects the clearance of numerous drugs, including cyclosporin, SSRI antidepressants, digoxin, indinavir, and phenprocoumon. It may also interact with the anti-cancer drugs irinotecan and imatinib.
Salvia miltiorrhiza may enhance anticoagulation and bleeding among people taking warfarin.
Allium sativum has been found to decrease the plasma concentration of saquinavir, and may cause hypoglycemia when taken with chlorpropamide.
Ginkgo biloba can cause bleeding when combined with warfarin or aspirin.
Concomitant Ephedra and caffeine use has been reported to, in rare cases, cause fatalities.
=== Mechanisms ===
The mechanisms underlying most herb-drug interactions are not fully understood. Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize cytochrome P450. For example, St. John's Wort has been shown to induce CYP3A4 and P-glycoprotein in vitro and in vivo.
== Underlying factors ==
The factors or conditions that predispose the appearance of interactions include factors such as old age. This is where human physiology changing with age may affect the interaction of drugs. For example, liver metabolism, kidney function, nerve transmission, or the functioning of bone marrow all decrease with age. In addition, in old age, there is a sensory decrease that increases the chances of errors being made in the administration of drugs. The elderly are also more vulnerable to polypharmacy, and the more drugs a patient takes, the higher is the chance of an interaction.
Genetic factors may also affect the enzymes and receptors, thus altering the possibilities of interactions.
Patients with hepatic or renal diseases already may have difficulties metabolizing and excreting drugs, which may exacerbate the effect of interactions.
Some drugs present an intrinsic increased risk for a harmful interaction, including drugs with a narrow therapeutic index, where the difference between the effective dose and the toxic dose is small. The drug digoxin is an example of this type of drug.
Risks are also increased when the drug presents a steep dose-response curve, and small changes in the dosage produce large changes in the drug's concentration in the blood plasma.
== Epidemiology ==
As of 2008, among adults in the United States of America older than 56, 4% were taking medication and/ or supplements that put them at risk of a major drug interaction. Potential drug-drug interactions have increased over time and are more common in the less-educated elderly even after controlling for age, sex, place of residence, and comorbidity.
== See also ==
Deprescribing
Cytochrome P450
Classification of Pharmaco-Therapeutic Referrals
== Notes ==
== References ==
== Bibliography ==
MA Cos. Interacciones de fármacos y sus implicancias clínicas. In: Farmacología Humana. Chap. 10, pp. 165–176. (J. Flórez y col. Eds). Masson SA, Barcelona. 1997.
== External links ==
Drug Interactions: What You Should Know. U.S. Food and Drug Administration, Center for Drug Evaluation and Research, September 2013
COVID 19 Drug interaction check tool University of Liverpool | Wikipedia/Drug_interaction |
Clinical pharmacy is the branch of pharmacy in which clinical pharmacists provide direct patient care that optimizes the use of medication and promotes health, wellness, and disease prevention. Clinical pharmacists care for patients in all health care settings but the clinical pharmacy movement initially began inside hospitals and clinics. Clinical pharmacists often work in collaboration with physicians, physician assistants, nurse practitioners, and other healthcare professionals. Clinical pharmacists can enter into a formal collaborative practice agreement with another healthcare provider, generally one or more physicians, that allows pharmacists to prescribe medications and order laboratory tests.
== Education and credentialing ==
Clinical pharmacists have extensive education in the biomedical, pharmaceutical, socio-behavioural and clinical sciences. Most clinical pharmacists have a Doctor of Pharmacy (Pharm.D.) degree and many have completed one or more years of post-graduate training (for example, a general and/or specialty pharmacy residency). In the United States, clinical pharmacists can choose to become Board-certified through the Board of Pharmacy Specialties (BPS), which was organized in 1976 as an independent certification agency of the American Pharmacists Association. The BPS certifies pharmacists in the following specialties:
Ambulatory care pharmacy (BCACP)
Critical care pharmacy (BCCCP)
Nuclear pharmacy (BCNP)
Nutrition support pharmacy (BCNSP)
Oncology pharmacy (BCOP)
Pediatric pharmacy (BCPPS)
Geriatric pharmacy (BCGP)
Pharmacotherapy (BCPS)
Infectious disease pharmacy (BCIDP)
Compounded sterile preparations pharmacy (BCSCP)
Cardiology pharmacy (BCCP)
Emergency medicine pharmacy (BCEMP)
Transplant Pharmacist (BCTXP)
Psychiatric pharmacy (BCPP)
There are several types of clinical pharmacists in the United States. In California they are called advanced practice pharmacists (APh). In New Mexico, they are known as Pharmacist Clinicians (PhC) and lastly in Montana and North Carolina they are known as Clinical Pharmacist Practitioners (CPP). Clinical pharmacists in the Veteran Administration are known as Clinical Pharmacy Specialists (CPS).
Role in the health care system
Within the system of health care, clinical pharmacists are experts in the therapeutic use of medications. They routinely provide medication therapy evaluations and recommendations to patients and other health care professionals. Clinical pharmacists are a primary source of scientifically valid information and advice regarding the safe, appropriate, and cost-effective use of medications. Clinical pharmacists are also making themselves more readily available to the public. In the past, access to a clinical pharmacist was limited to hospitals, clinics, or educational institutions. However, clinical pharmacists are making themselves available through a medication information hotline, and reviewing medication lists, all in an effort to prevent medication errors in the foreseeable future. In the United Kingdom, clinical pharmacists are routinely involved in the direct care of patients within hospitals, and increasingly, in doctors surgeries. They also develop post registration professional education, professional curricula for workforce development, provide expertise on the use of medicines to national organizations such as NICE, the Department of Health, and the MHRA, and develop medicines guidelines for use in therapeutic areas.
Clinical pharmacists interact directly with patients in several different ways. They use their knowledge of medication (including dosage, drug interactions, side effects, expense, effectiveness, etc.) to determine if a medication plan is appropriate for their patient. If it is not, the pharmacist will consult the primary physician to ensure that the patient is on the proper medication plan. The pharmacist also works to educate their patients on the importance of taking and finishing their medications. Studies conducted into Pharmacist-led Chronic Disease Management show that it was associated with effects similar to usual care and might improve physiological goal attainment.
In some states in the USA, clinical pharmacists are given prescriptive authority under protocol with a medical provider, and their scope of practice is constantly evolving. In the United Kingdom clinical pharmacists are given independent prescriptive authority.
Basic components of clinical pharmacy practice include prescribing drugs, administering drugs, monitoring prescriptions, managing drug use, and counselling patients.
== See also ==
History of pharmacy
Hospital pharmacy
== References ==
=== Citations ===
=== Sources ===
== External links ==
Academy of Managed Care Pharmacy
American College of Clinical Pharmacy
Board of Pharmacy Specialties
Journal of Clinical Pharmacy and Therapeutics
The British Journal of Clinical Pharmacy
United Kingdom Clinical Pharmacy Association
Clinical Pharmacy Education, Practice and Research | Wikipedia/Clinical_pharmacy |
A myograph is any device used to measure the force produced by a muscle when under contraction. Such a device is commonly used in myography, the study of the velocity and intensity of muscular contraction.
A myograph can take several forms: for tubular structures such as blood vessels these include the pressure myograph (where a segment of a blood vessel is cannulated at either or both ends) and the wire myograph (where the blood vessel segment is threaded onto a pair of pins or wires); for skeletal muscle other devices such as the acceleromyograph can be used.
In pharmacology, myography is used to record muscle contraction in organ bath preparations. The related technique of electromyography (EMG) is used to measure the electrical activity of the muscle instead of force. In addition, there is an optomyography (OMG) technique that uses active near-infra-red optical sensors.
== Wire Myograph ==
A wire myograph is a type of laboratory apparatus that can measure the contractility of luminal tissue segments smaller than 2 mm in diameter. It is used by pharmacologists to measure the effect of test articles on blood pressure or on airway contractility.
=== History of the wire myograph ===
Diagrams of the first ever wire myograph were revealed by Mulvany and Halpern in their 1976 paper "Contractile properties of small arterial resistance vessels in [...] rats". The group based the design of this apparatus on a technique developed by Bevan and Osher to measure arterial contractility ex vivo. Development of the wire myograph was significant because it allowed researchers to estimate the effect of novel drugs on blood pressure for the first time.
=== Structure of the wire myograph ===
The structure of the wire myograph has not changed much since its invention in 1977. Tissues are mounted in the myograph bath via two wires threaded through their lumen. These wires are attached to two opposing stainless steel jaws which secure tissue in place throughout the culture period. Multi-myograph units can contain up to four separate tissue baths, allowing four different tissue segments to be cultured simultaneously.
== References ==
== External links ==
Information on microvessel studies (wire myograph)
Various types of blood vessel myographs
Blood vessel myographs | Wikipedia/Myograph |
Non-specific effects of vaccines (also called "heterologous effects" or "off-target effects") are effects which go beyond the specific protective effects against the targeted diseases. Non-specific effects from live vaccines can be strongly beneficial by increasing protection against non-targeted infections. This has been shown with two live attenuated vaccines, BCG vaccine and measles vaccine, through multiple randomized controlled trials. Non-specific effects of non-live vaccination may be detrimental, increasing overall mortality at least 30% by some estimates, despite providing protection against the target disease. Observational studies suggest that diphtheria-tetanus-pertussis vaccine (DTP) may be highly detrimental, and although a WHO report described such studies as at high risk of bias, the direction of such bias was not predicted; although the conclusions have failed to replicate in some similar studies conducted by independent groups, randomized controlled trials (RCTs) provide additional evidence that vaccines have potent nonspecific effects.
Ongoing research suggests that non-specific effects of vaccines may depend on the vaccine, the vaccination sequence, and the sex of the infant. For example, one hypothesis suggests that all live attenuated vaccines reduce mortality more than explained by prevention of target infections, while all inactivated vaccines may increase overall mortality despite providing protection against the target disease. These effects may be long-lasting, at least up to the time point where a new type of vaccine is given. The non-specific effects can be very pronounced, with significant effects on overall mortality and morbidity. In a situation with herd immunity to the target disease, the non-specific effects can be more important for overall health than the specific vaccine effects.
The non-specific effects should not be confused with the side effects of vaccines (such as local reactions at the site of vaccination or general reactions such as fever, head ache or rash, which usually resolve within days to weeks – or in rare cases anaphylaxis). Rather, non-specific effects represent a form of general immunomodulation, with important consequences for the immune system's ability to handle subsequent challenges.
It is estimated that millions of child deaths in low income countries could be prevented every year if the non-specific effects of vaccines were taken into consideration in immunization programs.
== History ==
The hypothesis that vaccines have non-specific effects was formulated in the early 1990s by Peter Aaby at the Bandim Health Project in West Africa.
The first indication of the importance of the non-specific effects of vaccines came in a series of randomized controlled trials (RCTs) in the late 1980s. It was tested whether a high-titer (high concentration) measles vaccine (HTMV) given at 4–6 months of age was as effective against measles infection as the standard measles vaccine (MV) given at 9 months of age. Early administration of the HTMV prevented measles infection just as effectively as did the standard MV given at 9 months of age.
However, early administration of the HTMV was associated with twofold higher overall mortality among females (there was no difference in mortality for males). In other words, the girls given HTMV died more often despite having the same protection against measles as the infants given standard MV. The discovery forced WHO to withdraw the HTMV in 1992. It was later discovered that it was not the HTMV, but rather a subsequent inactivated vaccine (DTP or IPV for different children), that caused the increase in female mortality. Although the mechanism was different than initially thought, this finding represents unexpected effects of a change in the vaccine program not attributable to the disease-specific protection provided by the vaccines.
This first observation that vaccines could protect against the target disease but at the same time affect mortality after infection with other pathogens, in a sex-differential manner, led to several further studies showing that other vaccines might also have such nonspecific effects.
== Live attenuated versus inactivated vaccines ==
Numerous observational studies and randomised trials (RCTs) have found that the impact on mortality of live and inactivated vaccines differ markedly. All live vaccines studied so far (BCG, measles vaccine, oral polio vaccine (OPV) and smallpox vaccine) have been shown to reduce mortality more than can be explained by prevention of the targeted infection(s). In contrast, inactivated vaccines (diphtheria-tetanus-pertussis (DTP), hepatitis B, inactivated polio vaccine) may have deleterious effects in spite of providing target disease protection.
=== BCG vaccine ===
The live attenuated BCG vaccine developed against tuberculosis has been shown to have strong beneficial effects on the ability to combat non-tuberculosis infections.
Several studies have suggested that BCG vaccination may reduce atopy, particularly when given early in life. Furthermore, in multiple observational studies BCG vaccination has been shown to provide beneficial effects on overall mortality. These observations encouraged randomised controlled trials to examine BCG vaccination's beneficial non-specific effects on overall health. Since BCG vaccination is recommended to be given at birth in countries that have a high incidence of tuberculosis it would have been unethical to randomize children into "BCG" vs. "no BCG" groups. However, many low-income countries delay BCG vaccination for low-birth-weight (LBW) infants; this offered the opportunity to directly test the effect of BCG on overall mortality.
In the first two randomised controlled trials receipt of BCG+OPV at birth vs. OPV only ('delayed BCG') was associated with strong reductions in neonatal mortality; these effects were seen as early as 3 days after vaccination. BCG protected against sepsis as well as respiratory infections.
Among BCG vaccinated children, those who develop a BCG scar or a positive skin test (TST) are less likely to develop sepsis and exhibit an overall reduction in child mortality of around 50%.
In a recent WHO-commissioned review based on five clinical trials and nine observational studies, it was concluded that "the results indicated a beneficial effect of BCG on overall mortality in the first 6–12 months of life. Relevant follow-up in some of the trials was short, and all of the observational studies were regarded as being at risk of bias, so the confidence in the findings was rated as very low according to the GRADE criteria and "There was a suggestion that BCG vaccination may be more beneficial the earlier it is given". Furthermore, "estimated effects are in the region of a halving of mortality risk" and "any effect of BCG vaccine on all-cause mortality is not likely to be attributable to any great extent to fewer deaths from tuberculosis (i.e. to a specific effect of BCG vaccine against tuberculosis)". Based on the evidence, the WHO's Strategic Group of Experts on Immunization (SAGE) concluded that "the non-specific effects on all-cause mortality warrant further research".
=== Oral Poliovirus Vaccine ===
Oral Poliovirus Vaccine (OPV) was developed in the 1950s by Dr. Albert Sabin and is made from live attenuated polioviruses of three serotypes. The first evidence of non-specific effects of OPV was protection by vaccination with OPV of serotype 2 against disease caused by serotype 1 poliovirus without any evidence of cross-neutralization. Vaccination with trivalent OPV helped to stop outbreak of paralytic disease caused by Enterovirus 71 in Bulgaria. In large prospective clinical trials OPV was shown to protect against seasonal influenza and other acute respiratory diseases. Immunization with OPV was also shown to lead to a faster healing of genital herpes lesions. Immunization with OPV was found to reduce all-cause childhood mortality even in the absence of wild poliovirus circulation, hospital admission rate, incidence of bacterial diarrhea, and otitis media. Vaccination with OPV results in Interferon induction that is believed to be the main mediator of the non-specific protective effects of OPV.
=== Measles vaccine ===
Standard titer measles vaccine is recommended at 9 months of age in low-income countries where measles infection is endemic and often fatal. Many observational studies have shown that measles-vaccinated children have substantially lower mortality than can be explained by the prevention of measles-related deaths. Many of these observational studies were natural experiments, such as studies comparing the mortality before and after the introduction of measles vaccine and other studies where logistical factors rather than maternal choice determined whether a child was vaccinated or not.
These findings were later supported in randomized trials from 2003 to 2009 in Guinea-Bissau. An intervention group of children given standard titer measles vaccine at 4.5 and 9 month of age had a 30% reduction in all-cause mortality compared to the children in the control group, which were only vaccinated against measles at 9 month of age.
In a recent WHO-commissioned review based on four randomized trials and 18 observational studies, it was concluded that "There was consistent evidence of a beneficial effect of measles vaccine, although all observational studies were assessed as being at risk of bias and the GRADE rating was of low confidence. There was an apparent difference between the effect in girls and boys, with girls benefitting more from measles vaccination", and furthermore "estimated effects are in the region of a halving of mortality risk" and "if these effects are real then they are not fully explained by deaths that were established as due to measles". Based on the evidence, the Strategic Group of Experts on Immunization concluded that "the non-specific effects on all-cause mortality warrant further research".
=== Diphtheria-tetanus-pertussis vaccine ===
DTP vaccine against diphtheria, tetanus and pertussis does not seem to have the same beneficial effects as BCG, measles vaccine, OPV and smallpox vaccine, and in fact opposite effects are observed. The negative effects are seen as long as DTP vaccine is the most recent vaccine. BCG or measles vaccine given after DTP reverses the negative effects of DTP. The negative effects are seen mostly in females.
The negative effects are found in several observational studies. However, six WHO-commissioned studies concluded that there were strong beneficial effects of DTP on overall mortality. However, controversy ensued as these studies had important methodological shortcomings. For example, the WHO-commissioned studies had counted "no information about vaccination" as "unvaccinated", and they had retrospectively updated vaccine information from surviving children, while no similar update could be made for dead children, creating a so-called "survival bias" which will always produce highly beneficial effect estimates for the most recent vaccine.
In a recent WHO-commissioned review of DTP based on ten observational studies, it was concluded that, "the findings were inconsistent, with a majority of the studies indicating a detrimental effect of DTP, and two studies indicating a beneficial effect. All of the studies were regarded as being at risk of bias, so the confidence in the findings was rated as very low according to the GRADE criteria."
Furthermore, "three observational studies provided a suggestion that simultaneous administration of BCG and DTP may be preferable to the recommended schedule of BCG before DTP; and there was suggestion that mortality risk may be higher when DTP is given with, or after, measles vaccine compared with when it is given before measles vaccine (from five, and three, observational studies, respectively). These results are consistent with hypotheses that DTP vaccine may have detrimental effects on mortality, although a majority of the evidence was generated by a group centred in Guinea-Bissau who have often written in defence of such a hypothesis."
A large cohort study of over one million Danish children came even to the conclusion that the group of children with fewer DTP vaccinations (without MMR) experienced increased mortality.
=== Smallpox vaccine ===
When smallpox vaccine was introduced in the early 19th century, there were anecdotal descriptions of non-specific beneficial effects. In the second half of the 20th century the potential for beneficial non-specific effects of smallpox vaccine was reviewed, and new evidence on "para-immune effects" was added. More recent studies have focused on the phasing out of smallpox vaccine in the 1970s and compared vaccinated and unvaccinated cohorts.
Smallpox vaccine leaves a very characteristic scar. In low-income countries, having a smallpox vaccine scar has been associated with reductions of more than 40% in overall mortality among adults; in high-income countries smallpox vaccination has been associated with a tendency for reduced risk of asthma, and significantly reduced risk of malignant melanoma and infectious disease hospitalizations. There are no studies that contradict these observations. However no randomized trials testing the effect of smallpox vaccine on overall mortality and morbidity have been conducted.
== Sex differences ==
Non-specific effects are frequently different in males and females. There are accumulating data illustrating that males and females may respond differently to vaccination, both in terms of the quality and quantity of the immune response.
== Interactions between health interventions ==
The non-specific effects of vaccines can be boosted or diminished when other immunomodulating health interventions such as other vaccines, or vitamins, are provided.
== Influence of pre-existing specific immunity ==
The beneficial non-specific effects of live vaccines are stronger with earlier vaccination, possibly due to maternal antibodies. Boosting with live vaccines also seems to enhance the beneficial effects.
== High-income countries ==
The non-specific effects were primarily observed in low-income countries with high infectious disease burdens, but they may not be limited to these areas. Recent Danish register-based studies have shown that the live attenuated measles-mumps-rubella vaccine (MMR) protects against hospital admissions with infectious diseases and specifically getting ill by respiratory syncytial virus.
== Immunological mechanisms ==
The findings from the epidemiological studies on the non-specific effects of vaccines pose a challenge to the current understanding of vaccines, and how they affect the immune system, and also question whether boys and girls have identical immune systems and should receive the same treatment.
The mechanisms for these effects are unclear. It is not known how vaccination induces rapid beneficial or harmful changes in the general susceptibility to infectious diseases, but the following mechanisms are likely to be involved.
=== Heterologous T-cell immunity ===
It is well known from animal studies that infections, apart from inducing pathogen-specific T-cells, also induce cross-reactive T-cells through epitope sharing, so-called heterologous immunity. Heterologous T-cell immunity can lead to improved clearance of a subsequent cross-reactive challenge, but it may also lead to increased morbidity. This mechanism may explain why DTP could have negative effects.
It would, however, not explain effects occurring shortly after vaccination, as for instance the rapidly occurring beneficial effects of BCG vaccine, as the heterologous effect would only be expected to be present after some weeks, as the adaptive immune response need time to develop. Also, it is difficult to explain why the effect would vanish once a child receives a new vaccine.
=== Trained innate immunity ===
The concept that not only plants and insects, but also humans have innate immune memory may provide new clues to why vaccines have non-specific effects. Studies into BCG have recently revealed that BCG induces epigenetic changes in the monocytes in adults, leading to increased pro-inflammatory cytokine production upon challenges with unrelated mitogens and pathogens (trained innate immunity).
In SCID mice that have no adaptive immune system, BCG reduced mortality from an otherwise lethal candida infection. The effects of BCG presented when tested after 2 weeks, but would be expected to occur rapidly after vaccination, and hence might be able to explain the very rapid protection against neonatal septicaemia seen after BCG vaccine.
Trained innate immunity may also explain the generally increased resistance against broad disease categories, such as fevers and lower respiratory tract infections; such effects would be difficult to explain merely by shared epitopes, unless such epitopes were almost universally common on pathogens.
Lastly, it is plausible that the effects are reversible by a different vaccine. Hence, trained innate immunity may provide a biological mechanism for the observed non-specific effects of vaccines.
== Controversy ==
In 2000 Aaby and colleagues presented data from Guinea-Bissau which suggested that DTP vaccination could, under some circumstances (e.g. absence of pertussis) be associated with increases in overall mortality, at least until children received measles vaccine. In response, WHO sponsored the analysis of a variety of data sets in other populations to test the hypothesis. None of these studies replicated the observation of increased mortality associated with DTP vaccination. WHO subsequently concluded, that the evidence was sufficient to reject the hypothesis for an increased nonspecific mortality following DTP vaccination.
However, Aaby and colleagues subsequently pointed out that the studies which failed to show any mortality increase associated with DTP vaccination used methods of analysis that can introduce a bias against finding such an effect.
In these studies, data on childhood vaccinations were typically collected in periodic surveys, and the information on vaccinations, which occurred between successive home visits, was updated at the time of the second visit. The person-time at risk in unvaccinated and vaccinated states was then divided up according to the date of vaccination during the time interval between visits. This method opens up a potential bias, insofar as the updating of person time at risk from unvaccinated to vaccinated is only possible for children who survive to the second follow-up. Those who die between visits typically do not have vaccinations between the first visit and death recorded, and thus they will tend to be allocated as deaths in unvaccinated children – thus incorrectly inflating the mortality rate among unvaccinated children.
This bias has been described before, but in different contexts, as the distinction between "landmark" and "retrospective updating" analysis of cohort data. The retrospective updating method can lead to a considerable bias in vaccine studies, biasing observed mortality rate ratios towards zero (a large effect), whereas the landmark method leads to a non-specific misclassification and biases the mortality rate ratio towards unity(no effect).
An additional problem with the literature on the nonspecific effects of vaccines has been the variety and unexpected nature of the hypotheses which have appeared (in particular relating to sex-specific effects), which has meant that it has not always been clear whether some apparent "effects" were the result of post hoc analyses or whether they were reflections of a priori hypotheses.
This was discussed at length at a review of the work of Aaby and his colleagues in Copenhagen in 2005. The review was convened by the Danish National Research Foundation and the Novo Nordisk Foundation who have sponsored much of the work of Aaby and his colleagues. An outcome of the review was the explicit formulation of a series of testable hypotheses, agreed by the Aaby group. It was hoped that independent investigators would design and conduct studies powered to confirm or refute these hypotheses.
Also, the two foundations sponsored a workshop on the analysis of vaccine effects, which was held in London in 2008. The workshop resulted in three papers. The proceedings were forwarded to WHO which subsequently concluded that "conclusive evidence for or against non-specific effects of vaccines on mortality, including a potential deleterious effect of DTP vaccination on children's survival as has been reported in some studies, was unlikely to be obtained from observational studies. The GACVS will keep a watch on the evidence of nonspecific effects of vaccination.".
In 2013, WHO established a working group tasked with reviewing the evidence for the non-specific effects of BCG, measles and DTP vaccines. Two independent reviews were conducted, an immunological review and an epidemiological review. The results were presented at the April 2014 meeting of WHO's Strategic Group of Experts on Immunization (SAGE). WHO/SAGE "concluded that the findings from the immunological systematic review neither exclude nor confirm the possibility of beneficial or deleterious non-specific immunological effects of the vaccines under study on all-cause mortality. The published literature does not provide confidence in the quality, quantity, or kinetics of impact of any non-specific immunological effects in young children after vaccination. [...] SAGE considered that the non-specific effects on all-cause mortality warrant further research. [...] SAGE considered that additional observational studies with substantial risk of bias would be unlikely to contribute to policy decision making and therefore should not be encouraged."
== The Arc of the Swallow ==
In 2008, Danish crime novel author Sissel-Jo Gazan (author of the Danish crime novel Dinosaur Feather) became interested in the work of the Bandim Health Project and based her science crime novel The Arc of the Swallow (Svalens Graf) on the research into non-specific effects of vaccines.
The novel was published in Danish in 2013; it was on the best-seller list for months and won the Readers' Prize 2014 in Denmark. It was published in English in the UK on November 6, 2014, and in the US on April 7, 2015.
== References ==
== External links ==
Bandim Health Project on non-specific effects Archived 2015-04-15 at the Wayback Machine | Wikipedia/Non-specific_effect_of_vaccines |
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", and a macromolecule is a very large molecule, such as a protein, with a complex structure of components. 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. This equation is formally equivalent to the Langmuir isotherm. 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 O2 binding curve of hemoglobin.
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.
The Hill equation (for response) is important in the construction of dose-response curves.
== Proportion of ligand-bound receptors ==
The Hill equation is commonly expressed in the following ways:
θ
=
[
L
]
n
K
d
+
[
L
]
n
=
[
L
]
n
(
K
A
)
n
+
[
L
]
n
=
1
1
+
(
K
A
[
L
]
)
n
{\displaystyle {\begin{aligned}\theta &={[{\ce {L}}]^{n} \over K_{d}+[{\ce {L}}]^{n}}\\&={[{\ce {L}}]^{n} \over (K_{A})^{n}+[{\ce {L}}]^{n}}\\&={1 \over 1+\left({K_{A} \over [{\ce {L}}]}\right)^{n}}\end{aligned}}}
,
where
θ
{\displaystyle \theta }
is the fraction of the receptor protein concentration that is bound by the ligand,
[
L
]
{\displaystyle {\ce {[L]}}}
is the total ligand concentration,
K
d
{\displaystyle K_{d}}
is the apparent dissociation constant derived from the law of mass action,
K
A
{\displaystyle K_{A}}
is the ligand concentration producing half occupation,
n
{\displaystyle n}
is the Hill coefficient.
The special case where
n
=
1
{\displaystyle n=1}
is a Monod equation.
=== Constants ===
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}}}}
). 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}}
.
=== Gaddum equation ===
The Gaddum equation is a further generalisation of the Hill-equation, incorporating the presence of a reversible competitive antagonist. 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
=== Hill plot ===
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:
log
(
θ
1
−
θ
)
=
n
log
[
L
]
−
log
K
d
=
n
log
[
L
]
−
n
log
K
A
{\displaystyle {\begin{aligned}\log \left({\theta \over 1-\theta }\right)&=n\log {[{\ce {L}}]}-\log {K_{d}}\\&=n\log {[{\ce {L}}]}-n\log {K_{A}}\end{aligned}}}
.
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. 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. This impacts the parameters of linear regression lines fitted to the data. Furthermore, the use of computers enables more robust analysis involving nonlinear regression.
== Tissue response ==
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
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. Empirical models based on nonlinear regression are usually preferred over the use of some transformation of the data that linearizes the dose-response relationship.
== Hill coefficient ==
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, the value of the Hill coefficient describes the cooperativity of ligand binding in the following way:
n
>
1
{\displaystyle n>1}
. Positively cooperative binding: Once one ligand molecule is bound to the enzyme, its affinity for other ligand molecules increases. For example, the Hill coefficient of oxygen binding to haemoglobin (an example of positive cooperativity) falls within the range of 1.7–3.2.
n
<
1
{\displaystyle n<1}
. Negatively cooperative binding: Once one ligand molecule is bound to the enzyme, its affinity for other ligand molecules decreases.
n
=
1
{\displaystyle n=1}
. Noncooperative (completely independent) binding: The affinity of the enzyme for a ligand molecule is not dependent on whether or not other ligand molecules are already bound. When n=1, we obtain a model that can be modeled by Michaelis–Menten kinetics, in which
K
D
=
K
A
=
K
M
{\textstyle K_{D}=K_{A}=K_{M}}
, the Michaelis–Menten constant.
The Hill coefficient can be calculated approximately in terms of the cooperativity index of Taketa and Pogell as follows:
n
=
log
10
(
81
)
log
10
(
EC
90
/
EC
10
)
{\displaystyle n={\frac {\log _{10}(81)}{\log _{10}({\ce {EC90}}/{\ce {EC10}})}}}
.
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.
== Reversible form ==
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.
== Relationship to the elasticity coefficients ==
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 )}
== Applications ==
The Hill equation is used extensively in pharmacology to quantify the functional parameters of a drug 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.
=== Regulation of gene transcription ===
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). 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.
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:
d
d
t
[
X
p
r
o
d
u
c
e
d
]
=
k
⋅
[
Y
a
c
t
i
v
e
]
n
(
K
A
)
n
+
[
Y
a
c
t
i
v
e
]
n
{\displaystyle {\mathrm {d} \over \mathrm {d} t}[{\rm {X_{produced}}}]=k\ \cdot {{[{\rm {Y_{active}}}]^{\mathit {n}}} \over {(K_{A})^{n}\ +\ {[{\rm {Y_{active}}}]^{\mathit {n}}}}}}
,
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:
d
d
t
[
Y
p
r
o
d
u
c
e
d
]
=
k
⋅
(
K
A
)
n
(
K
A
)
n
+
[
Z
a
c
t
i
v
e
]
n
{\displaystyle {\mathrm {d} \over \mathrm {d} t}[{\rm {Y_{produced}}}]=k\ \cdot {{(K_{A})^{\mathit {n}}} \over {(K_{A})^{n}\ +\ {[{\rm {Z_{active}}}]^{\mathit {n}}}}}}
,
where k is the maximal transcription rate of gene Y.
== Limitations ==
Because of its assumption that ligand molecules bind to a receptor simultaneously, the Hill equation has been criticized as a physically unrealistic model. Moreover, the Hill coefficient should not be considered a reliable approximation of the number of cooperative ligand binding sites on a receptor except when the binding of the first and subsequent ligands results in extreme positive cooperativity.
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. Nevertheless, other, more complex models of cooperative binding have been proposed. 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.
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.
== See also ==
Binding coefficient
Bjerrum plot
Cooperative binding
Gompertz curve
Langmuir adsorption model
Logistic function
Michaelis–Menten kinetics
Monod equation
== Notes ==
== References ==
== Further reading ==
Dorland's Illustrated Medical Dictionary
Coval, ML (December 1970). "Analysis of Hill interaction coefficients and the invalidity of the Kwon and Brown equation". J. Biol. Chem. 245 (23): 6335–6. doi:10.1016/S0021-9258(18)62614-6. PMID 5484812.
d'A Heck, Henry (1971). "Statistical theory of cooperative binding to proteins. Hill equation and the binding potential". J. Am. Chem. Soc. 93 (1): 23–29. Bibcode:1971JAChS..93...23H. doi:10.1021/ja00730a004. PMID 5538860.
Atkins, Gordon L. (1973). "A simple digital-computer program for estimating the parameter of the Hill Equation". Eur. J. Biochem. 33 (1): 175–180. doi:10.1111/j.1432-1033.1973.tb02667.x. PMID 4691349.
Endrenyi, Laszlo; Kwong, F. H. F.; Fajszi, Csaba (1975). "Evaluation of Hill slopes and Hill coefficients when the saturation binding or velocity is not known". Eur. J. Biochem. 51 (2): 317–328. doi:10.1111/j.1432-1033.1975.tb03931.x. PMID 1149734.
Voet, Donald; Voet, Judith G. (2004). Biochemistry.
Weiss, J. N. (1997). "The Hill equation revisited: uses and misuses". FASEB Journal. 11 (11): 835–841. doi:10.1096/fasebj.11.11.9285481. PMID 9285481. S2CID 827335.
Kurganov, B. I.; Lobanov, A. V. (2001). "Criterion for Hill equation validity for description of biosensor calibration curves". Anal. Chim. Acta. 427 (1): 11–19. Bibcode:2001AcAC..427...11K. doi:10.1016/S0003-2670(00)01167-3.
Goutelle, Sylvain; Maurin, Michel; Rougier, Florent; Barbaut, Xavier; Bourguignon, Laurent; Ducher, Michel; Maire, Pascal (2008). "The Hill equation: a review of its capabilities in pharmacological modelling". Fundamental & Clinical Pharmacology. 22 (6): 633–648. doi:10.1111/j.1472-8206.2008.00633.x. PMID 19049668. S2CID 4979109.
Gesztelyi R; Zsuga J; Kemeny-Beke A; Varga B; Juhasz B; Tosaki A (2012). "The Hill equation and the origin of quantitative pharmacology". Archive for History of Exact Sciences. 66 (4): 427–38. doi:10.1007/s00407-012-0098-5. S2CID 122929930.
Colquhoun D (2006). "The quantitative analysis of drug-receptor interactions: a short history". Trends Pharmacol Sci. 27 (3): 149–57. doi:10.1016/j.tips.2006.01.008. PMID 16483674.
Rang HP (2006). "The receptor concept: pharmacology's big idea". Br J Pharmacol. 147 (Suppl 1): S9–16. doi:10.1038/sj.bjp.0706457. PMC 1760743. PMID 16402126.
== External links ==
Hill equation calculator | Wikipedia/Hill_equation_(biochemistry) |
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
Neurotransmitters are released from synaptic vesicles into the synaptic cleft where they are able to interact with neurotransmitter receptors on the target cell. Some neurotransmitters are also stored in large dense core vesicles. The neurotransmitter's effect on the target cell is determined by the receptor it binds to. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available and often require a small number of biosynthetic steps for conversion.
Neurotransmitters are essential to the function of complex neural systems. The exact number of unique neurotransmitters in humans is unknown, but more than 100 have been identified. Common neurotransmitters include glutamate, GABA, acetylcholine, glycine, dopamine and norepinephrine.
== Mechanism and cycle ==
=== Synthesis ===
Neurotransmitters are generally synthesized in neurons and are made up of, or derived from, precursor molecules that are found abundantly in the cell. Classes of neurotransmitters include amino acids, monoamines, and peptides. Monoamines are synthesized by altering a single amino acid. For example, the precursor of serotonin is the amino acid tryptophan. Peptide neurotransmitters, or neuropeptides, are protein transmitters which are larger than the classical small-molecule neurotransmitters and are often released together to elicit a modulatory effect. Purine neurotransmitters, like ATP, are derived from nucleic acids. Metabolic products such as nitric oxide and carbon monoxide have also been reported to act like neurotransmitters.
=== Storage ===
Neurotransmitters are generally stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. However, some neurotransmitters, like the metabolic gases carbon monoxide and nitric oxide, are synthesized and released immediately following an action potential without ever being stored in vesicles.
=== Release ===
Generally, a neurotransmitter is released via exocytosis at the presynaptic terminal in response to an electrical signal called an action potential in the presynaptic neuron. However, low-level "baseline" release also occurs without electrical stimulation. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron.
=== Receptor interaction ===
After being released into the synaptic cleft, neurotransmitters diffuse across the synapse where they are able to interact with receptors on the target cell. The effect of the neurotransmitter is dependent on the identity of the target cell's receptors present at the synapse. Depending on the receptor, binding of neurotransmitters may cause excitation, inhibition, or modulation of the postsynaptic neuron.
=== Elimination ===
In order to avoid continuous activation of receptors on the post-synaptic or target cell, neurotransmitters must be removed from the synaptic cleft. Neurotransmitters are removed through one of three mechanisms:
Diffusion – neurotransmitters drift out of the synaptic cleft, where they are absorbed by glial cells. These glial cells, usually astrocytes, absorb the excess neurotransmitters.
Astrocytes, a type of glial cell in the brain, actively contribute to synaptic communication through astrocytic diffusion or gliotransmission. Neuronal activity triggers an increase in astrocytic calcium levels, prompting the release of gliotransmitters, such as glutamate, ATP, and D-serine. These gliotransmitters diffuse into the extracellular space, interacting with nearby neurons and influencing synaptic transmission. By regulating extracellular neurotransmitter levels, astrocytes help maintain proper synaptic function. This bidirectional communication between astrocytes and neurons add complexity to brain signaling, with implications for brain function and neurological disorders.
Enzyme degradation – proteins called enzymes break the neurotransmitters down.
Reuptake – neurotransmitters are reabsorbed into the pre-synaptic neuron. Transporters, or membrane transport proteins, pump neurotransmitters from the synaptic cleft back into axon terminals (the presynaptic neuron) where they are stored for reuse.
For example, acetylcholine is eliminated by having its acetyl group cleaved by the enzyme acetylcholinesterase; the remaining choline is then taken in and recycled by the pre-synaptic neuron to synthesize more acetylcholine. Other neurotransmitters are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be targeted by the body's regulatory system or medication. Cocaine blocks a dopamine transporter responsible for the reuptake of dopamine. Without the transporter, dopamine diffuses much more slowly from the synaptic cleft and continues to activate the dopamine receptors on the target cell.
== Discovery ==
Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through histological examinations by Ramón y Cajal, a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine (ACh) – the first known neurotransmitter.
== Identification ==
To identify neurotransmitters, the following criteria are typically considered:
Synthesis: The chemical must be produced within the neuron or be present in it as a precursor molecule.
Release and response: When the neuron is activated, the chemical must be released and elicit a response in target cells or neurons.
Experimental response: Application of the chemical directly to the target cells should produce the same response observed when the chemical is naturally released from neurons.
Removal mechanism: There must be a mechanism in place to remove the neurotransmitter from its site of action once its signaling role is complete.
However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term "neurotransmitter" can be applied to chemicals that:
Carry messages between neurons via influence on the postsynaptic membrane.
Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse.
Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters.
The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localized, that is, a neuron may release more than one transmitter from its synaptic terminal. Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.
== Actions ==
Neurons communicate with each other through synapses, specialized contact points where neurotransmitters transmit signals. When an action potential reaches the presynaptic terminal, the action potential can trigger the release of neurotransmitters into the synaptic cleft. These neurotransmitters then bind to receptors on the postsynaptic membrane, influencing the receiving neuron in either an inhibitory or excitatory manner. If the overall excitatory influences outweigh the inhibitory influences, the receiving neuron may generate its own action potential, continuing the transmission of information to the next neuron in the network. This process allows for the flow of information and the formation of complex neural networks.
=== Modulation ===
A neurotransmitter may have an excitatory, inhibitory or modulatory effect on the target cell. The effect is determined by the receptors the neurotransmitter interacts with at the post-synaptic membrane. Neurotransmitter influences trans-membrane ion flow either to increase (excitatory) or to decrease (inhibitory) the probability that the cell with which it comes in contact will produce an action potential. Synapses containing receptors with excitatory effects are called Type I synapses, while Type II synapses contain receptors with inhibitory effects. Thus, despite the wide variety of synapses, they all convey messages of only these two types. The two types are different appearance and are primarily located on different parts of the neurons under its influence. Receptors with modulatory effects are spread throughout all synaptic membranes and binding of neurotransmitters sets in motion signaling cascades that help the cell regulate its function. Binding of neurotransmitters to receptors with modulatory effects can have many results. For example, it may result in an increase or decrease in sensitivity to future stimulus by recruiting more or less receptors to the synaptic membrane.
Type I (excitatory) synapses are typically located on the shafts or the spines of dendrites, whereas type II (inhibitory) synapses are typically located on a cell body. In addition, Type I synapses have round synaptic vesicles, whereas the vesicles of type II synapses are flattened. The material on the presynaptic and post-synaptic membranes is denser in a Type I synapse than it is in a Type II, and the Type I synaptic cleft is wider. Finally, the active zone on a Type I synapse is larger than that on a Type II synapse.
The different locations of Type I and Type II synapses divide a neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. From an inhibitory perspective, excitation comes in over the dendrites and spreads to the axon hillock to trigger an action potential. If the message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the axon hillock where the action potential originates. Another way to conceptualize excitatory–inhibitory interaction is to picture excitation overcoming inhibition. If the cell body is normally in an inhibited state, the only way to generate an action potential at the axon hillock is to reduce the cell body's inhibition. In this "open the gates" strategy, the excitatory message is like a racehorse ready to run down the track, but first, the inhibitory starting gate must be removed.
=== Neurotransmitter actions ===
As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors.
Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain. Excessive glutamate release can overstimulate the brain and lead to excitotoxicity causing cell death resulting in seizures or strokes. Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington disease, and Parkinson's disease.
GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA.
Glycine is the primary inhibitory neurotransmitter in the spinal cord.
Acetylcholine was the first neurotransmitter discovered in the peripheral and central nervous systems. It activates skeletal muscles in the somatic nervous system and may either excite or inhibit internal organs in the autonomic system. It is main neurotransmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain as a neuromodulatory, but using different types of receptors, including nicotinic and muscarinic receptors.
Dopamine has a number of important functions in the brain. This includes critical role in the reward system, motivation and emotional arousal. It also plays an important role in fine motor control and Parkinson's disease has been linked to low levels of dopamine due to the loss of dopaminergic neurons in substantia nigra pars compacta. Schizophrenia, a highly heterogeneous and complicated disorder has been linked to high levels of dopamine.
Serotonin is a monoamine neurotransmitter. Most of it is produced by the intestine (approximately 90%), and the remainder by central nervous system neurons at the raphe nuclei. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and the functions of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients have been reported to exhibit lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.
Norepinephrine is a member of the catecholamine family of neurotransmitters. It is synthesized from the amino acid tyrosine. In the peripheral nervous system, one of the primary roles of norepinephrine is to stimulate the release of the stress hormone epinephrine (i.e. adrenaline) from the adrenal glands. Norepinephrine is involved in the fight-or-flight response and is also affected in anxiety disorders and depression.
Epinephrine, a neurotransmitter and hormone is synthesized from tyrosine. It is released from the adrenal glands and also plays a role in the fight-or-flight response. Epinephrine has vasoconstrictive effects, which promote increased heart rate, blood pressure, energy mobilization. Vasoconstriction influences metabolism by promoting the breakdown of glucose released into the bloodstream. Epinephrine also has bronchodilation effects, which is the relaxing of airways.
== Types ==
There are many different ways to classify neurotransmitters. They are commonly classified into amino acids, monoamines and peptides.
Some of the major neurotransmitters are:
Amino acids: glutamate, aspartate, D-serine, gamma-Aminobutyric acid (GABA), glycine
Gasotransmitters: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S)
Monoamines:
Catecholamines: dopamine (DA), norepinephrine (noradrenaline, NE), epinephrine (adrenaline)
Indolamines: serotonin (5-HT, SER), melatonin
histamine
Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, octopamine, tryptamine, etc.
Peptides: oxytocin, somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptides
Purines: adenosine triphosphate (ATP), adenosine
Others: acetylcholine (ACh), anandamide, etc.
In addition, over 100 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are co-released along with a small-molecule transmitter. Nevertheless, in some cases, a peptide is the primary transmitter at a synapse. Beta-Endorphin is a relatively well-known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in the central nervous system.
Single ions (such as synaptically released zinc) are also considered neurotransmitters by some, as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). The gases are produced in the neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are immediately broken down, existing for only a few seconds.
The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain. The next most prevalent is gamma-Aminobutyric Acid, or GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.
=== List of neurotransmitters, peptides, and gaseous signaling molecules ===
== Neurotransmitter systems ==
Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, called volume transmission. Major neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system, among others. Trace amines have a modulatory effect on neurotransmission in monoamine pathways (i.e., dopamine, norepinephrine, and serotonin pathways) throughout the brain via signaling through trace amine-associated receptor 1. A brief comparison of these systems follows:
== Drug effects ==
Understanding the effects of drugs on neurotransmitters comprises a significant portion of research initiatives in the field of neuroscience. Most neuroscientists involved in this field of research believe that such efforts may further advance our understanding of the circuits responsible for various neurological diseases and disorders, as well as ways to effectively treat and someday possibly prevent or cure such illnesses.
Drugs can influence behavior by altering neurotransmitter activity. For instance, drugs can decrease the rate of synthesis of neurotransmitters by affecting the synthetic enzyme(s) for that neurotransmitter. When neurotransmitter syntheses are blocked, the amount of neurotransmitters available for release becomes substantially lower, resulting in a decrease in neurotransmitter activity. Some drugs block or stimulate the release of specific neurotransmitters. Alternatively, drugs can prevent neurotransmitter storage in synaptic vesicles by causing the synaptic vesicle membranes to leak. Drugs that prevent a neurotransmitter from binding to its receptor are called receptor antagonists. For example, drugs used to treat patients with schizophrenia such as haloperidol, chlorpromazine, and clozapine are antagonists at receptors in the brain for dopamine. Other drugs act by binding to a receptor and mimicking the normal neurotransmitter. Such drugs are called receptor agonists. An example of a receptor agonist is morphine, an opiate that mimics effects of the endogenous neurotransmitter β-endorphin to relieve pain. Other drugs interfere with the deactivation of a neurotransmitter after it has been released, thereby prolonging the action of a neurotransmitter. This can be accomplished by blocking re-uptake or inhibiting degradative enzymes. Lastly, drugs can also prevent an action potential from occurring, blocking neuronal activity throughout the central and peripheral nervous system. Drugs such as tetrodotoxin that block neural activity are typically lethal.
Drugs targeting the neurotransmitter of major systems affect the whole system, which can explain the complexity of action of some drugs. Cocaine, for example, blocks the re-uptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap for an extended period of time. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to the downregulation of some post-synaptic receptors. After the effects of the drug wear off, an individual can become depressed due to decreased probability of the neurotransmitter binding to a receptor. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell which increases the amount of serotonin present at the synapse and furthermore allows it to remain there longer, providing potential for the effect of naturally released serotonin. AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.
=== Agonists ===
An agonist is a chemical capable of binding to a receptor, such as a neurotransmitter receptor, and initiating the same reaction typically produced by the binding of the endogenous substance. An agonist of a neurotransmitter will thus initiate the same receptor response as the transmitter. In neurons, an agonist drug may activate neurotransmitter receptors either directly or indirectly. Direct-binding agonists can be further characterized as full agonists, partial agonists, inverse agonists.
Direct agonists act similar to a neurotransmitter by binding directly to its associated receptor site(s), which may be located on the presynaptic neuron or postsynaptic neuron, or both. Typically, neurotransmitter receptors are located on the postsynaptic neuron, while neurotransmitter autoreceptors are located on the presynaptic neuron, as is the case for monoamine neurotransmitters; in some cases, a neurotransmitter utilizes retrograde neurotransmission, a type of feedback signaling in neurons where the neurotransmitter is released postsynaptically and binds to target receptors located on the presynaptic neuron. Nicotine, a compound found in tobacco, is a direct agonist of most nicotinic acetylcholine receptors, mainly located in cholinergic neurons. Opiates, such as morphine, heroin, hydrocodone, oxycodone, codeine, and methadone, are μ-opioid receptor agonists; this action mediates their euphoriant and pain relieving properties.
Indirect agonists increase the binding of neurotransmitters at their target receptors by stimulating the release or preventing the reuptake of neurotransmitters. Some indirect agonists trigger neurotransmitter release and prevent neurotransmitter reuptake. Amphetamine, for example, is an indirect agonist of postsynaptic dopamine, norepinephrine, and serotonin receptors in each their respective neurons; it produces both neurotransmitter release into the presynaptic neuron and subsequently the synaptic cleft and prevents their reuptake from the synaptic cleft by activating TAAR1, a presynaptic G protein-coupled receptor, and binding to a site on VMAT2, a type of monoamine transporter located on synaptic vesicles within monoamine neurons.
=== Antagonists ===
An antagonist is a chemical that acts within the body to reduce the physiological activity of another chemical substance (such as an opiate); especially one that opposes the action on the nervous system of a drug or a substance occurring naturally in the body by combining with and blocking its nervous receptor.
There are two main types of antagonist: direct-acting Antagonist and indirect-acting Antagonists:
Direct-acting antagonist- which takes up space present on receptors which are otherwise taken up by neurotransmitters themselves. This results in neurotransmitters being blocked from binding to the receptors. An example of one of the most common is called Atropine.
Indirect-acting antagonist- drugs that inhibit the release/production of neurotransmitters (e.g., Reserpine).
==== Drug antagonists ====
An antagonist drug is one that attaches (or binds) to a site called a receptor without activating that receptor to produce a biological response. It is therefore said to have no intrinsic activity. An antagonist may also be called a receptor "blocker" because they block the effect of an agonist at the site. The pharmacological effects of an antagonist, therefore, result in preventing the corresponding receptor site's agonists (e.g., drugs, hormones, neurotransmitters) from binding to and activating it. Antagonists may be "competitive" or "irreversible".
A competitive antagonist competes with an agonist for binding to the receptor. As the concentration of antagonist increases, the binding of the agonist is progressively inhibited, resulting in a decrease in the physiological response. High concentration of an antagonist can completely inhibit the response. This inhibition can be reversed, however, by an increase of the concentration of the agonist, since the agonist and antagonist compete for binding to the receptor. Competitive antagonists, therefore, can be characterized as shifting the dose–response relationship for the agonist to the right. In the presence of a competitive antagonist, it takes an increased concentration of the agonist to produce the same response observed in the absence of the antagonist.
An irreversible antagonist binds so strongly to the receptor as to render the receptor unavailable for binding to the agonist. Irreversible antagonists may even form covalent chemical bonds with the receptor. In either case, if the concentration of the irreversible antagonist is high enough, the number of unbound receptors remaining for agonist binding may be so low that even high concentrations of the agonist do not produce the maximum biological response.
=== Precursors ===
While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to whether neurotransmitter release and postsynaptic receptor firing is increased. Even with increased neurotransmitter release, it is unclear whether this will result in a long-term increase in neurotransmitter signal strength, since the nervous system can adapt to changes such as increased neurotransmitter synthesis and may therefore maintain constant firing. Some neurotransmitters may have a role in depression and there is some evidence to suggest that intake of precursors of these neurotransmitters may be useful in the treatment of mild and moderate depression.
==== Catecholamine and trace amine precursors ====
L-DOPA, a precursor of dopamine that crosses the blood–brain barrier, is used in the treatment of Parkinson's disease. For depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little evidence for benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studies suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room for further research in this area.
==== Serotonin precursors ====
Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain. It is significantly more effective than a placebo in the treatment of mild and moderate depression. This conversion requires vitamin C. 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is more effective than a placebo.
== Diseases and disorders ==
The following sections describe how imbalances or dysfunction in specific neurotransmitters—dopamine, serotonin, and glutamate—have been tentatively linked to various mental or neurological disorders.
=== Dopamine ===
For example, problems in producing dopamine (mainly in the substantia nigra) can result in Parkinson's disease, a disorder that affects a person's ability to move as they want to, resulting in stiffness, tremors or shaking, and other symptoms. Some studies suggest that having too little or too much dopamine or problems using dopamine in the thinking and feeling regions of the brain may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD). Dopamine is also involved in addiction and drug use, as most recreational drugs cause an influx of dopamine in the brain (especially opioid and methamphetamines) that produces a pleasurable feeling, which is why users constantly crave drugs.
=== Serotonin ===
Similarly, after some research suggested that drugs that block the recycling, or reuptake, of serotonin seemed to help some people diagnosed with depression, it was theorized that people with depression might have lower-than-normal serotonin levels. Though widely popularized, this theory was not borne out in subsequent research. Therefore, selective serotonin reuptake inhibitors (SSRIs) are used to increase the amounts of serotonin in synapses.
=== Glutamate ===
Furthermore, problems with producing or using glutamate have been suggestively and tentatively linked to many mental disorders, including autism, obsessive–compulsive disorder (OCD), schizophrenia, and depression. Having too much glutamate has been linked to neurological diseases such as Parkinson's disease, multiple sclerosis, Alzheimer's disease, stroke, and ALS (amyotrophic lateral sclerosis).
== Neurotransmitter imbalance ==
Generally, there are no scientifically established "norms" for appropriate levels or "balances" of different neurotransmitters. In most cases, it is practically impossible to measure neurotransmitter levels in the brain or body at any given moment. Neurotransmitters regulate each other's release, and weak consistent imbalances in this mutual regulation were linked to temperament in healthy people. However, significant imbalances or disruptions in neurotransmitter systems are associated with various diseases and mental disorders, including Parkinson's disease, depression, insomnia, Attention Deficit Hyperactivity Disorder (ADHD), anxiety, memory loss, dramatic weight changes, and addictions. Some of these conditions are also related to neurotransmitter switching, a phenomenon where neurons change the type of neurotransmitters they release. Chronic physical or emotional stress can be a contributor to neurotransmitter system changes. Genetics also plays a role in neurotransmitter activities.
Apart from recreational use, medications that directly and indirectly interact with one or more transmitter or its receptor are commonly prescribed for psychiatric and psychological issues. Notably, drugs interacting with serotonin and norepinephrine are prescribed to patients with problems such as depression and anxiety—though the notion that there is much solid medical evidence to support such interventions has been widely criticized. Studies shown that dopamine imbalance has an influence on multiple sclerosis and other neurological disorders.
== See also ==
== Notes ==
== References ==
== External links ==
Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel; McNamara, James O.; Williams, S. Mark (2001). "Chapter 6. Neurotransmitters". What Defines a Neurotransmitter? (2nd ed.). Sunderland (MA): Sinauer Associates. ISBN 0-87893-742-0. {{cite book}}: |journal= ignored (help)
Holz, Ronald W.; Fisher, Stephen K. (1999). "Chapter 10. Synaptic Transmission and Cellular Signaling: An Overview". In Siegel, George J; Agranoff, Bernard W; Albers, R Wayne; Fisher, Stephen K; Uhler, Michael D (eds.). Synaptic Transmission (6th ed.). Philadelphia: Lippincott-Raven. ISBN 0-397-51820-X. {{cite book}}: |journal= ignored (help)
Neurotransmitters and Neuroactive Peptides at Neuroscience for Kids website | Wikipedia/Neurotransmitter_systems |
Mental energy may be understood as the ability or willingness to engage in cognitive work.
It is distinct from physical energy, and has mood, cognition, and motivation domains. Concepts closely related to mental energy include vigor and fatigue.
Mental energy is not well-defined, and the scientific literature on mental energy is quite limited. The philosopher and psychologist Karl F. Stifter wrote a dissertation on the "Philosophy of Mental Energy". In the Austrian Broadcasting Corporation's TV show "Vera", Stifter lifted 1000 kg with a lifting belt over his sacrum to prove that drastic increases in muscle strength can be achieved after special mental training. A variety of measures for assessing aspects of mental energy exist.
Many people complain of low mental energy, which can interfere with work and daily activities. Low mental energy and fatigue are major public health concerns. People may pursue remedies or treatment for low mental energy. Seeking to improve mental energy is a common reason that people take dietary supplements.
== Neurotransmitters ==
Many different neurotransmitters have been theoretically implicated in the control of mental energy. This has often been based on the effects of drugs acting on these neurotransmitters. These neurotransmitters include dopamine, norepinephrine, orexin, serotonin, histamine, acetylcholine, adenosine, and glutamate. Hormones, including glucocorticoids like cortisol, as well as cytokines, have also been found to regulate mental energy.
== Food, drugs, sleep, diseases ==
Mental energy can be affected by factors such as drugs, sleep, and disease.
=== Drugs ===
Drugs that may increase mental energy include caffeine, modafinil, psychostimulants like amphetamines and methylphenidate, and corticosteroids like hydrocortisone and dexamethasone.
Drugs that may decrease mental energy include sedatives and hypnotics like antihistamines, benzodiazepines, and melatonin, as well as dopamine receptor antagonists like antipsychotics.
=== Foods, beverages etc ===
There are many marketing claims of foods, beverages, and dietary supplements improving mental energy, but data to substantiate such claims are limited or absent.
=== Sleep ===
Sleep deprivation may decrease mental energy in an exposure-dependent manner.
=== Disease ===
Various disease states, such as cardiac disease, cancer, stroke, HIV/AIDS, multiple sclerosis, Parkinson's disease, and certain mental health conditions like depression, may be associated with decreased mental energy. Chronic fatigue syndrome is characterized by a lack of the energy needed for the basic activities of daily life.
== See also ==
Disorders of diminished motivation
== References == | Wikipedia/Mental_energy |
Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, memory, and physiological processes such as vomiting and vasoconstriction. In the CNS, serotonin regulates mood, appetite, and sleep.
Most of the body's serotonin—about 90%—is synthesized in the gastrointestinal tract by enterochromaffin cells, where it regulates intestinal movements. It is also produced in smaller amounts in the brainstem's raphe nuclei, the skin's Merkel cells, pulmonary neuroendocrine cells, and taste receptor cells of the tongue. Once secreted, serotonin is taken up by platelets in the blood, which release it during clotting to promote vasoconstriction and platelet aggregation. Around 8% of the body's serotonin is stored in platelets, and 1–2% is found in the CNS.
Serotonin acts as both a vasoconstrictor and vasodilator depending on concentration and context, influencing hemostasis and blood pressure regulation. It plays a role in stimulating myenteric neurons and enhancing gastrointestinal motility through uptake and release cycles in platelets and surrounding tissue. Biochemically, serotonin is an indoleamine synthesized from tryptophan and metabolized primarily in the liver to 5-hydroxyindoleacetic acid (5-HIAA).
Serotonin is targeted by several classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), which block reabsorption in the synapse to elevate its levels. It is found in nearly all bilateral animals, including insects, spiders and worms, and also occurs in fungi and plants. In plants and insect venom, it serves a defensive function by inducing pain. Serotonin released by pathogenic amoebae may cause diarrhea in the human gut, while its presence in seeds and fruits is thought to stimulate digestion and facilitate seed dispersal.
== Molecular structure ==
Biochemically, the indoleamine molecule derives from the amino acid tryptophan, via the (rate-limiting) hydroxylation of the 5 position on the ring (forming the intermediate 5-hydroxytryptophan), and then decarboxylation to produce serotonin. Preferable conformations are defined via ethylamine chain, resulting in six different conformations.
== Crystal structure ==
Serotonin crystallizes in P212121 chiral space group forming different hydrogen-bonding interactions between serotonin molecules via N-H...O and O-H...N intermolecular bonds. Serotonin also forms several salts, including pharmaceutical formulation of serotonin adipate.
== Biological role ==
Serotonin is involved in numerous physiological processes, including sleep, thermoregulation, learning and memory, pain, (social) behavior, sexual activity, feeding, motor activity, neural development, and biological rhythms. In less complex animals, such as some invertebrates, serotonin regulates feeding and other processes. In plants serotonin synthesis seems to be associated with stress signals. Despite its longstanding prominence in pharmaceutical advertising, the claim that low serotonin levels cause depression is not supported by scientific evidence.
=== Cellular effects ===
Serotonin primarily acts through its receptors and its effects depend on which cells and tissues express these receptors.
Metabolism involves first oxidation by monoamine oxidase to 5-hydroxyindoleacetaldehyde (5-HIAL). The rate-limiting step is hydride transfer from serotonin to the flavin cofactor. There follows oxidation by aldehyde dehydrogenase (ALDH) to 5-hydroxyindoleacetic acid (5-HIAA), the indole acetic-acid derivative. The latter is then excreted by the kidneys.
==== Receptors ====
The serotonin receptors are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and psychedelic drugs. There are currently 14 known serotonin receptors, including the serotonin 5-HT1 (1A, 1B, 1D, 1E, 1F), 5-HT2 (2A, 2B, 2C), 5-HT3, 5-HT4, 5-HT5 (5A, 5B), 5-HT6, and 5-HT7 receptors. Except for the serotonin 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors (also called seven-transmembrane, or heptahelical receptors) that activate an intracellular second messenger cascade. The 5-HT5B receptor is present in rodents but not in humans.
In addition to the serotonin receptors, serotonin is an agonist of the trace amine-associated receptor 1 (TAAR1) in some species. It is a weak TAAR1 partial agonist in rats, but is inactive at the TAAR1 in mice and humans.
The cryo-EM structures of the serotonin 5-HT2A receptor with serotonin, as well as with various serotonergic psychedelics, have been solved and published by Bryan L. Roth and colleagues.
==== Termination ====
Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including cocaine, dextromethorphan (an antitussive), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). A 2006 study found that a significant portion of 5-HT's synaptic clearance is due to the selective activity of the plasma membrane monoamine transporter (PMAT) which actively transports the molecule across the membrane and back into the presynaptic cell.
In contrast to the high affinity of SERT, the PMAT has been identified as a low-affinity transporter, with an apparent Km of 114 micromoles/l for serotonin, which is approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport "capacity" than SERT, "resulting in roughly comparable uptake efficiencies to SERT ... in heterologous expression systems." The study also suggests that the administration of SSRIs such as fluoxetine and sertraline may be associated with an inhibitory effect on PMAT activity when used at higher than normal dosages (IC50 test values used in trials were 3–4 fold higher than typical prescriptive dosage).
==== Serotonylation ====
Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins. This process underlies serotonin's effects upon platelet-forming cells (thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis. A similar process underlies the pancreatic release of insulin.
The effects of serotonin upon vascular smooth muscle tone – the biological function after which serotonin was originally named – depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.
=== Nervous system ===
The neurons of the raphe nuclei are the principal source of 5-HT release in the brain. There are nine raphe nuclei, designated B1–B9, which contain the majority of serotonin-containing neurons (some scientists chose to group the nuclei raphes lineares into one nucleus), all of which are located along the midline of the brainstem, and centered on the reticular formation. Axons from the neurons of the raphe nuclei form a neurotransmitter system reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain.
It is the dorsal part of the raphe nucleus that contains neurons projecting to the central nervous system. Serotonin-releasing neurons in this area receive input from a large number of areas, notably from prefrontal cortex, lateral habenula, preoptic area, substantia nigra and amygdala. These neurons are thought to communicate the expectation of rewards in the near future, a quantity called state value in reinforcement learning.
==== Ultrastructure and function ====
The serotonin nuclei may also be divided into two main groups, the rostral and caudal containing three and four nuclei respectively. The rostral group consists of the caudal linear nuclei (B8), the dorsal raphe nuclei (B6 and B7) and the median raphe nuclei (B5, B8 and B9), that project into multiple cortical and subcortical structures. The caudal group consists of the nucleus raphe magnus (B3), raphe obscurus nucleus (B2), raphe pallidus nucleus (B1), and lateral medullary reticular formation, that project into the brainstem.
The serotonergic pathway is involved in sensorimotor function, with pathways projecting both into cortical (Dorsal and Median Raphe Nuclei), subcortical, and spinal areas involved in motor activity. Pharmacological manipulation suggests that serotonergic activity increases with motor activity while firing rates of serotonergic neurons increase with intense visual stimuli. Animal models suggest that kainate signaling negatively regulates serotonin actions in the retina, with possible implications for the control of the visual system. The descending projections form a pathway that inhibits pain called the "descending inhibitory pathway" that may be relevant to a disorder such as fibromyalgia, migraine, and other pain disorders, and the efficacy of antidepressants in them.
Serotonergic projections from the caudal nuclei are involved in regulating mood and emotion, and hypo- or hyper-serotonergic states may be involved in depression and sickness behavior.
==== Microanatomy ====
Serotonin is released into the synapse, or space between neurons, and diffuses over a relatively wide gap (>20 nm) to activate 5-HT receptors located on the dendrites, cell bodies, and presynaptic terminals of adjacent neurons.
When humans smell food, dopamine is released to increase the appetite. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with weight gain, especially in people with a low number of receptors. The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm, just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.
In macaques, alpha males have twice the level of serotonin in the brain as subordinate males and females (measured by the concentration of 5-HIAA in the cerebrospinal fluid (CSF)). Dominance status and CSF serotonin levels appear to be positively correlated. When dominant males were removed from such groups, subordinate males begin competing for dominance. Once new dominance hierarchies were established, serotonin levels of the new dominant individuals also increased to double those in subordinate males and females. The reason why serotonin levels are only high in dominant males, but not dominant females has not yet been established.
In humans, levels of 5-HT1A receptor inhibition in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype. Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.
=== Outside the nervous system ===
==== Digestive tract (emetic) ====
Serotonin regulates gastrointestinal (GI) function. The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin. There are often serotonin abnormalities in gastrointestinal disorders such as constipation and irritable bowel syndrome.
If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5-HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting. Thus, drugs and toxins stimulate serotonin release from enterochromaffin cells in the gut wall can induce emesis. The enterochromaffin cells not only react to bad food but are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.
==== Lungs ====
The lung, including that of reptiles, contains specialized epithelial cells that occur as solitary cells or as clusters called neuroepithelial bodies or bronchial Kulchitsky cells or alternatively K cells. These are enterochromaffin cells that like those in the gut release serotonin. Their function is probably vasoconstriction during hypoxia.
==== Skin ====
Serotonin is also produced by Merkel cells which are part of the somatosensory system.
==== Bone metabolism ====
In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass. Mice that lack brain serotonin have osteopenia, while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be a significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through 5-HT1B receptors, it negatively regulates bone mass, while it does so positively through 5-HT2B receptors and 5-HT2C receptors. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events. Following the 2008 findings that gut serotonin regulates bone mass, the mechanistic investigations into what regulates serotonin synthesis from the gut in the regulation of bone mass have started. Piezo1 has been shown to sense RNA in the gut and relay this information through serotonin synthesis to the bone by acting as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders. Studies in 2008, 2010 and 2019 have opened the potential for serotonin research to treat bone mass disorders.
==== Organ development ====
Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, atherosclerosis, behavior, learning, and longevity. Rodent experiment shows that neonatal exposure to SSRIs makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants. By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.
Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors, mediating liver compensatory regrowth (see Liver § Regeneration and transplantation) Serotonin present in the blood then stimulates cellular growth to repair liver damage.
5-HT2B receptors also activate osteocytes, which build up bone However, serotonin also inhibits osteoblasts, through 5-HT1B receptors.
==== Cardiovascular growth factor ====
Serotonin, in addition, evokes endothelial nitric oxide synthase activation and stimulates, through a 5-HT1B receptor-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures. In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.
==== Adipose tissue ====
Serotonin also regulates white and brown adipose tissue function, and adipocytes are capable of producing 5-HT separately from the gut. Serotonin increases lipogenesis through HTR2A in white adipose tissue, and suppressed thermogenesis in brown adipose tissue via Htr3.
== Pharmacology ==
Several classes of drugs target the serotonin system, including some antidepressants, anxiolytics, antipsychotics, analgesics, antimigraine drugs, oxytocics, antiemetics, appetite suppressants, and anticonvulsants, as well as psychedelics and entactogens.
=== Mechanism of action ===
At rest, serotonin is stored within the vesicles of presynaptic neurons. When stimulated by nerve impulses, serotonin is released as a neurotransmitter into the synapse, reversibly binding to the postsynaptic receptor to induce a nerve impulse on the postsynaptic neuron. Serotonin can also bind to auto-receptors on the presynaptic neuron to regulate the synthesis and release of serotonin. Normally serotonin is taken back into the presynaptic neuron to stop its action, then reused or broken down by monoamine oxidase.
=== Antidepressants ===
Drugs that alter serotonin levels are used in treating depression, generalized anxiety disorder, and social phobia. Monoamine oxidase inhibitors (MAOIs) prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content, and certain drugs. Some drugs inhibit the re-uptake of serotonin, making it stay in the synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs.
Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. The 5-HTTLPR gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling. The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety.
Besides their use in treating depression and anxiety, certain serotonergic antidepressants are also approved and used to treat fibromyalgia, neuropathic pain, and chronic fatigue syndrome.
=== Anxiolytics ===
Azapirone anxiolytics like buspirone and tandospirone act as serotonin 5-HT1A receptor agonists.
=== Antipsychotics ===
Many antipsychotics bind to and modulate serotonin receptors, including the serotonin 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors, among others. Activation of serotonin 5-HT1A receptors and blockade of serotonin 5-HT2A receptors may contribute to the therapeutic antipsychotic effects of these agents, whereas antagonism of serotonin 5-HT2C receptors has been especially implicated in side effects of antipsychotics.
=== Antimigraine agents ===
Antimigraine agents such as the triptans like sumatriptan act as agonists of the serotonin 5-HT1B, 5-HT1D, and/or 5-HT1F receptors. Earlier antimigraine agents were the ergoline derivatives and ergot-related drugs such as ergotamine, dihydroergotamine, and methysergide, which act as non-selective serotonin receptor agonists.
=== Oxytocics ===
Certain lysergamides like ergometrine and methylergometrine are used clinically as oxytocic agents. The oxytocic effects of these drugs are thought to most likely be mediated by agonism of serotonin 5-HT2 receptors in uterine smooth muscle tissue.
=== Antiemetics ===
Some serotonin 5-HT3 receptor antagonists, such as ondansetron, granisetron, and tropisetron, are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of postoperative nausea and vomiting.
=== Appetite suppressants ===
Some serotonin releasing agents, serotonin reuptake inhibitors, and/or serotonin 5-HT2C receptor agonists, such as fenfluramine, dexfenfluramine, chlorphentermine, sibutramine, and lorcaserin, have been approved and used as appetite suppressants for purposes of weight loss in the treatment of overweightness or obesity. Several of the preceding agents have been withdrawn from the market due to toxicity, such as cardiac fibrosis or pulmonary hypertension.
=== Anticonvulsants ===
Although it was previously withdrawn from the market as an appetite suppressant, fenfluramine was reintroduced as an anticonvulsant for treatment of seizures in certain rare forms of epilepsy like Dravet syndrome and Lennox–Gastaut syndrome. Selective serotonin 5-HT2C receptor agonists, like lorcaserin, bexicaserin, and BMB-101, are also being developed for this use.
=== Psychedelics ===
Serotonergic psychedelics, including drugs like psilocybin (found in psilocybin mushrooms), dimethyltryptamine (DMT) (found in ayahuasca), lysergic acid diethylamide (LSD), mescaline (found in peyote cactus), and 5-MeO-DMT (found in Anadenanthera trees and the Bufo alvarius toad), are non-selective agonists of the serotonin receptors and mediate their hallucinogenic effects specifically by activation of the serotonin 5-HT2A receptor. This is evidenced by the fact that serotonin 5-HT2A receptor antagonists and so-called "trip killers" like ketanserin block the hallucinogenic effects of serotonergic psychedelics in humans, among many other findings. Some serotonergic psychedelics, like psilocin, DMT, and 5-MeO-DMT, are substituted tryptamines and are very similar in chemical structure to serotonin.
Serotonin itself, despite acting as a serotonin 5-HT2A receptor agonist, is thought to be non-hallucinogenic. The hallucinogenic effects of serotonergic psychedelics appear to be mediated by activation of serotonin 5-HT2A receptors expressed in a population of cortical neurons in the medial prefrontal cortex (mPFC). These serotonin 5-HT2A receptors, unlike most serotonin and related receptors, are expressed intracellularly. In addition, the neurons containing them lack expression of the serotonin transporter (SERT), which normally transports serotonin from the extracellular space to the intracellular space within neurons. Serotonin itself is too hydrophilic to enter serotonergic neurons without the SERT, and hence these serotonin 5-HT2A receptors are inaccessible to serotonin. Conversely, serotonergic psychedelics are more lipophilic than serotonin and readily enter these neurons. In addition to explaining why serotonin does not show psychedelic effects, these findings may explain why drugs that increase serotonin levels, like selective serotonin reuptake inhibitors (SSRIs) and various other types of serotonergic agents, do not produce psychedelic effects. Artificial expression of the SERT in these medial prefrontal cortex neurons resulted in the serotonin releasing agent para-chloroamphetamine (PCA), which does not normally show psychedelic-like effects, being able to produce psychedelic-like effects in animals.
Although serotonin itself is non-hallucinogenic, administration of very high doses of a serotonin precursor, like tryptophan or 5-hydroxytryptophan (5-HTP), or intracerebroventricular injection of high doses of serotonin directly into the brain, can produce psychedelic-like effects in animals. These psychedelic-like effects can be abolished by indolethylamine N-methyltransferase (INMT) inhibitors, which block conversion of serotonin and other endogenous tryptamines into N-methylated tryptamines, including N-methylserotonin (NMS; norbufotenin), bufotenin (5-hydroxy-N,N-dimethyltryptamine; 5-HO-DMT), N-methyltryptamine (NMT), and N,N-dimethyltryptamine (DMT). These N-methyltryptamines are much more lipophilic than serotonin and, in contrast, are able to diffuse into serotonergic neurons and activate intracellular serotonin 5-HT2A receptors. Another possible metabolite of serotonin with psychedelic-like effects in animals is 5-methoxytryptamine (5-MT).
DMT is a naturally occurring endogenous compound in the body. In relation to the fact that serotonin itself is unable to activate intracellular serotonin 5-HT2A receptors, it is possible that DMT might be the endogenous ligand of these receptors rather than serotonin.
=== Entactogens ===
The entactogen MDMA is a serotonin releasing agent and, while it also possesses other actions such as concomitant release of norepinephrine and dopamine and weak direct agonism of the serotonin 5-HT2 receptors, its serotonin release plays a key role in its unique entactogenic effects. Entactogens like MDMA should be distinguished from other drugs such as stimulants like amphetamine and psychedelics like LSD, although MDMA itself also has some characteristics of both of these types of agents. Coadministration of selective serotonin reuptake inhibitors (SSRIs), which block the serotonin transporter (SERT) and prevent MDMA from inducing serotonin release, markedly reduce the subjective effects of MDMA, demonstrating the key role of serotonin in the effects of the drug. Serotonin releasing agents like MDMA achieve much greater increases in serotonin levels than SSRIs and have far more robust of subjective effects. Besides MDMA, many other entactogens also exist and are known.
=== Serotonin syndrome ===
Extremely high levels of serotonin or activation of certain serotonin receptors can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents, such as an SSRI with a MAOI, which may occur in therapeutic doses. However, serotonin syndrome can occur with overdose of certain serotonin receptor agonists, like the NBOMe series of serotonergic psychedelics.
The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels. It is estimated that 14% of patients experiencing serotonin syndrome overdose on SSRIs; meanwhile the fatality rate is between 2% and 12%.
=== Cardiac fibrosis and other fibroses ===
Some serotonergic agonist drugs cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.
In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. These are the serotonergic vasoconstrictive antimigraine drugs (ergotamine and methysergide), the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.
As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was declining in use since it was reported in 2003 to be associated with cardiac fibrosis.
Two independent studies published in The New England Journal of Medicine in January 2007 implicated pergolide, along with cabergoline, in causing valvular heart disease. As a result of this, the FDA removed pergolide from the United States market in March 2007. (Since cabergoline is not approved in the United States for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).
== Comparative biology and evolution ==
=== Unicellular organisms ===
Serotonin is used by a variety of single-cell organisms for various purposes. SSRIs have been found to be toxic to algae. The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some people. Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels, which returned to normal following resolution of the infection. E. histolytica also responds to the presence of serotonin by becoming more virulent. This means serotonin secretion not only serves to increase the spread of entamoebas by giving the host diarrhea but also serves to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside the gut of a host, there is nothing that the entamoebas provoke to release serotonin, hence the serotonin concentration is very low. Low serotonin signals to the entamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the enterochromaffine cells get provoked by them and the serotonin concentration increases.
=== Edible plants and mushrooms ===
In drying seeds, serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.
However, since serotonin is a major gastrointestinal tract modulator, it may be produced in the fruits of plants as a way of speeding the passage of seeds through the digestive tract, in the same way as many well-known seed and fruit associated laxatives. Serotonin is found in mushrooms, fruits, and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantains, pineapples, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.
Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms. It is also naturally found in Paramuricea clavata, or the Red Sea Fan.
Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 μg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27–13.34 μg/g) was found in 70–85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found.
Root development in Arabidopsis thaliana is stimulated and modulated by serotonin – in various ways at various concentrations.
Serotonin serves as a plant defense chemical against fungi. When infected with Fusarium crown rot (Fusarium pseudograminearum), wheat (Triticum aestivum) greatly increases its production of tryptophan to synthesize new serotonin. The function of this is poorly understood but wheat also produces serotonin when infected by Stagonospora nodorum – in that case to retard spore production. The model cereal Brachypodium distachyon – used as a research substitute for wheat and other production cereals – also produces serotonin, coumaroyl-serotonin, and feruloyl-serotonin in response to F. graminearum. This produces a slight antimicrobial effect. B. distachyon produces more serotonin (and conjugates) in response to deoxynivalenol (DON)-producing F. graminearum than non-DON-producing. Solanum lycopersicum produces many AA conjugates – including several of serotonin – in its leaves, stems, and roots in response to Ralstonia solanacearum infection.
Serotonin occurs in several hallucinogenic mushrooms of the genus Panaeolus.
=== Invertebrates ===
Serotonin functions as a neurotransmitter in the nervous systems of most animals.
==== Nematodes ====
For example, in the roundworm Caenorhabditis elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, such as finding a new source of food or in male animals finding a female with which to mate. When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food. The released serotonin activates the muscles used for feeding, while octopamine suppresses them. Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability.
==== Decapods ====
If lobsters are injected with serotonin, they behave like dominant individuals whereas octopamine causes subordinate behavior. A crayfish that is frightened may flip its tail to flee, and the effect of serotonin on this behavior depends largely on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is social experience alters the proportion between serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response. The effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors predominates in dominants.
==== In venoms ====
Serotonin is a common component of invertebrate venoms, salivary glands, nervous tissues, and various other tissues, across molluscs, insects, crustaceans, scorpions, various kinds of worms, and jellyfish. Adult Rhodnius prolixus – hematophagous on vertebrates – secrete lipocalins into the wound during feeding. In 2003 these lipocalins were demonstrated to sequester serotonin to prevent vasoconstriction (and possibly coagulation) in the host.
==== Insects ====
Serotonin is evolutionarily conserved and appears across the animal kingdom. It is seen in insect processes in roles similar to in the human central nervous system, such as memory, appetite, sleep, and behavior. Some circuits in mushroom bodies are serotonergic. (See specific Drosophila example below, §Dipterans.)
===== Acrididae =====
Locust swarming is initiated but not maintained by serotonin, with release being triggered by tactile contact between individuals. This transforms social preference from aversion to a gregarious state that enables coherent groups. Learning in flies and honeybees is affected by the presence of serotonin.
===== Role in insecticides =====
Insect 5-HT receptors have similar sequences to the vertebrate versions, but pharmacological differences have been seen. Invertebrate drug response has been far less characterized than mammalian pharmacology and the potential for species selective insecticides has been discussed.
===== Hymenopterans =====
Wasps and hornets have serotonin in their venom, which causes pain and inflammation as do scorpions. Pheidole dentata takes on more and more tasks in the colony as it gets older, which requires it to respond to more and more olfactory cues in the course of performing them. This olfactory response broadening was demonstrated to go along with increased serotonin and dopamine, but not octopamine in 2006.
===== Dipterans =====
If flies are fed serotonin, they are more aggressive; flies depleted of serotonin still exhibit aggression, but they do so much less frequently. In their crops it plays a vital role in digestive motility produced by contraction. Serotonin that acts on the crop is exogenous to the crop itself and 2012 research suggested that it probably originated in the serotonin neural plexus in the thoracic-abdominal synganglion. In 2011 a Drosophila serotonergic mushroom body was found to work in concert with Amnesiac to form memories. In 2007 serotonin was found to promote aggression in Diptera, which was counteracted by neuropeptide F – a surprising find given that they both promote courtship, which is usually similar to aggression in most respects.
=== Vertebrates ===
Serotonin, also referred to as 5-hydroxytryptamine (5-HT), is a neurotransmitter most known for its involvement in mood disorders in humans. It is also a widely present neuromodulator among vertebrates and invertebrates. Serotonin has been found having associations with many physiological systems such as cardiovascular, thermoregulation, and behavioral functions, including: circadian rhythm, appetite, aggressive and sexual behavior, sensorimotor reactivity and learning, and pain sensitivity. Serotonin's function in neurological systems along with specific behaviors among vertebrates found to be strongly associated with serotonin will be further discussed. Two relevant case studies are also mentioned regarding serotonin development involving teleost fish and mice.
In mammals, 5-HT is highly concentrated in the substantia nigra, ventral tegmental area and raphe nuclei. Lesser concentrated areas include other brain regions and the spinal cord. 5-HT neurons are also shown to be highly branched, indicating that they are structurally prominent for influencing multiple areas of the CNS at the same time, although this trend is exclusive solely to mammals.
==== 5-HT system in vertebrates ====
Vertebrates are multicellular organisms in the phylum Chordata that possess a backbone and a nervous system. This includes mammals, fish, reptiles, birds, etc. In humans, the nervous system is composed of the central and peripheral nervous system, with little known about the specific mechanisms of neurotransmitters in most other vertebrates. However, it is known that while serotonin is involved in stress and behavioral responses, it is also important in cognitive functions. Brain organization in most vertebrates includes 5-HT cells in the hindbrain. In addition to this, 5-HT is often found in other sections of the brain in non-placental vertebrates, including the basal forebrain and pretectum. Since location of serotonin receptors contribute to behavioral responses, this suggests serotonin is part of specific pathways in non-placental vertebrates that are not present in amniotic organisms. Teleost fish and mice are organisms most often used to study the connection between serotonin and vertebrate behavior. Both organisms show similarities in the effect of serotonin on behavior, but differ in the mechanism in which the responses occur.
===== Dogs / canine species =====
There are few studies of serotonin in dogs. One study reported serotonin values were higher at dawn than at dusk. In another study, serum 5-HT levels did not seem to be associated with dogs' behavioural response to a stressful situation. Urinary serotonin/creatinine ratio in bitches tended to be higher 4 weeks after surgery. In addition, serotonin was positively correlated with both cortisol and progesterone but not with testosterone after ovariohysterectomy.
===== Teleost fish =====
Like non-placental vertebrates, teleost fish also possess 5-HT cells in other sections of the brain, including the basal forebrain. Danio rerio (zebra fish) are a species of teleost fish often used for studying serotonin within the brain. Despite much being unknown about serotonergic systems in vertebrates, the importance in moderating stress and social interaction is known. It is hypothesized that AVT and CRF cooperate with serotonin in the hypothalamic-pituitary-interrenal axis. These neuropeptides influence the plasticity of the teleost, affecting its ability to change and respond to its environment. Subordinate fish in social settings show a drastic increase in 5-HT concentrations. High levels of 5-HT long term influence the inhibition of aggression in subordinate fish.
===== Mice =====
Researchers at the Department of Pharmacology and Medical Chemistry used serotonergic drugs on male mice to study the effects of selected drugs on their behavior. Mice in isolation exhibit increased levels of agonistic behavior towards one another. Results found that serotonergic drugs reduce aggression in isolated mice while simultaneously increasing social interaction. Each of the treatments use a different mechanism for targeting aggression, but ultimately all have the same outcome. While the study shows that serotonergic drugs successfully target serotonin receptors, it does not show specifics of the mechanisms that affect behavior, as all types of drugs tended to reduce aggression in isolated male mice. Aggressive mice kept out of isolation may respond differently to changes in serotonin reuptake.
==== Behavior ====
Like in humans, serotonin is involved in regulating behavior in most other vertebrates. This includes not only response and social behaviors, but also influencing mood. Defects in serotonin pathways can lead to intense variations in mood, as well as symptoms of mood disorders, which can be present in more than just humans.
===== Social interaction =====
One of the most researched aspects of social interaction in which serotonin is involved is aggression. Aggression is regulated by the 5-HT system, as serotonin levels can both induce or inhibit aggressive behaviors, as seen in mice (see section on Mice) and crabs. While this is widely accepted, it is unknown if serotonin interacts directly or indirectly with parts of the brain influencing aggression and other behaviors. Studies of serotonin levels show that they drastically increase and decrease during social interactions, and they generally correlate with inhibiting or inciting aggressive behavior. The exact mechanism of serotonin influencing social behaviors is unknown, as pathways in the 5-HT system in various vertebrates can differ greatly.
===== Response to stimuli =====
Serotonin is important in environmental response pathways, along with other neurotransmitters. Specifically, it has been found to be involved in auditory processing in social settings, as primary sensory systems are connected to social interactions. Serotonin is found in the IC structure of the midbrain, which processes specie specific and non-specific social interactions and vocalizations. It also receives acoustic projections that convey signals to auditory processing regions. Research has proposed that serotonin shapes the auditory information being received by the IC and therefore is influential in the responses to auditory stimuli. This can influence how an organism responds to the sounds of predatory or other impactful species in their environment, as serotonin uptake can influence aggression or social interaction.
===== Mood =====
We can describe mood not as specific to an emotional status, but as associated with a relatively long-lasting emotional state. Serotonin's association with mood is most known for various forms of depression and bipolar disorders in humans. Disorders caused by serotonergic activity potentially contribute to the many symptoms of major depression, such as overall mood, activity, suicidal thoughts and sexual and cognitive dysfunction. Selective serotonin reuptake inhibitors (SSRI's) are a class of drugs demonstrated to be an effective treatment in major depressive disorder and are the most prescribed class of antidepressants. SSRI's function is to block the reuptake of serotonin, making more serotonin available to absorb by the receiving neuron. Animals have been studied for decades in order to understand depressive behavior among species. One of the most familiar studies, the forced swimming test (FST), was performed to measure potential antidepressant activity. Rats were placed in an inescapable container of water, at which point time spent immobile and number of active behaviors (such as splashing or climbing) were compared before and after a panel of anti-depressant drugs were administered. Antidepressants that selectively inhibit NE reuptake were shown to reduce immobility and selectively increase climbing without affecting swimming. However, results of the SSRI's also show reduced immobility but increased swimming without affecting climbing. This study demonstrated the importance of behavioral tests for antidepressants, as they can detect drugs with an effect on core behavior along with behavioral components of species.
=== Growth and reproduction ===
In the nematode C. elegans, artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: C. elegans becomes more active, and mating and egg-laying are suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal. Serotonin is necessary for normal nematode male mating behavior, and the inclination to leave food to search for a mate. The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway, which control long-term adaption.
In the fruit fly insulin both regulates blood sugar as well as acting as a growth factor. Thus, in the fruit fly, serotonergic neurons regulate the adult body size by affecting insulin secretion. Serotonin has also been identified as the trigger for swarm behavior in locusts. In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones, modulating insulin release from the beta cells in the pancreas through serotonylation of GTPase signaling proteins. Exposure to SSRIs during pregnancy reduces fetal growth.
Genetically altered C. elegans worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.
=== Aging and age-related phenotypes ===
Serotonin is known to regulate aging, learning, and memory. The first evidence comes from the study of longevity in C. elegans. During early phase of aging, the level of serotonin increases, which alters locomotory behaviors and associative memory. The effect is restored by mutations and drugs (including mianserin and methiothepin) that inhibit serotonin receptors. The observation does not contradict with the notion that the serotonin level goes down in mammals and humans, which is typically seen in late but not early phase of aging.
== Biochemical mechanisms ==
=== Biosynthesis ===
In animals and humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes, tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (DDC), and the coenzyme pyridoxal phosphate. The TPH-mediated reaction is the rate-limiting step in the pathway.
TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific isoform.
Serotonin can be synthesized from tryptophan in the lab using Aspergillus niger and Psilocybe coprophila as catalysts. The first phase to 5-hydroxytryptophan would require letting tryptophan sit in ethanol and water for 7 days, then mixing in enough HCl (or other acid) to bring the pH to 3, and then adding NaOH to make a pH of 13 for 1 hour. Aspergillus niger would be the catalyst for this first phase. The second phase to synthesizing tryptophan itself from the 5-hydroxytryptophan intermediate would require adding ethanol and water, and letting sit for 30 days this time. The next two steps would be the same as the first phase: adding HCl to make the pH = 3, and then adding NaOH to make the pH very basic at 13 for 1 hour. This phase uses the Psilocybe coprophila as the catalyst for the reaction.
Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system, because it does not cross the blood–brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, do cross the blood–brain barrier. These agents are available as dietary supplements and in various foods, and may be effective serotonergic agents.
One product of serotonin breakdown is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. Serotonin and 5-HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.
== Analytical chemistry ==
Indium tin oxide is recommended for the electrode material in electrochemical investigation of concentrations produced, detected, or consumed by microbes. A mass spectrometry technique was developed in 1994 to measure the molecular weight of both natural and synthetic serotonins.
== History and etymology ==
It had been known to physiologists for over a century that a vasoconstrictor material appears in serum when blood was allowed to clot. In 1935, Italian Vittorio Erspamer, working in Pavia, showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown amine, which he named "enteramine". In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin.
In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field. Synonyms of serotonin include: 5-hydroxytriptamine, enteramine, substance DS, and 3-(β-aminoethyl)-5-hydroxyindole. In 1953, Betty Twarog and Page discovered serotonin in the central nervous system. Page regarded Erspamer's work on Octopus vulgaris, Discoglossus pictus, Hexaplex trunculus, Bolinus brandaris, Sepia, Mytilus, and Ostrea as valid and fundamental to understanding this newly identified substance, but regarded his earlier results in various models – especially those from rat blood – to be too confounded by the presence of other bioactive chemicals, including some other vasoactives.
== Effects in humans ==
Serotonin, given orally at a dose of 100 mg, produced effects in humans including blood pressure changes, abdominal cramps, muscle aches, and a feeling of sedation. In contrast to psychedelic drugs like LSD, no hallucinogenic effects were reported. In other studies, serotonin, at low intravenous doses of 2 to 6 mg, had no effects on electroencephalogram (EEG) readings in humans. In accordance with the preceding findings, it has been stated that administration of serotonin in humans produces no psychoactive effects that cannot be attributed to anxiety by its profound peripheral adverse effects including circulatory disturbance, other autonomic effects, and vomiting. Intracerebroventricular injection of serotonin has been studied in patient with severe psychiatric conditions, but little information about its psychoactive effects is provided.
It is thought that exogenous serotonin is too hydrophilic to cross the blood–brain barrier and has too poor of metabolic stability due to rapid metabolism by monoamine oxidase (MAO) such that it cannot produce drug-like central effects in humans with peripheral administration. However, close analogues of serotonin that are more lipophilic and metabolically stable, like bufotenin (N,N-dimethylserotonin), 5-MeO-DMT (N,N,O-trimethylserotonin), and 5-MeO-AMT (α,O-dimethylserotonin), among many others, are active and produce pronounced centrally mediated effects in humans. These drugs are non-selective serotonin receptor agonists like serotonin and are serotonergic psychedelics due to activation of the serotonin 5-HT2A receptor. α-Methylserotonin is well-studied in preclinical research, but is not known to have been tested in humans.
== Notes ==
== References ==
== Further reading ==
== External links ==
5-Hydroxytryptamine MS Spectrum
Serotonin bound to proteins in the PDB
PsychoTropicalResearch Extensive reviews on serotonergic drugs and Serotonin Syndrome.
Molecule of the Month: Serotonin at University of Bristol
60-Second Psych: No Fair! My Serotonin Level Is Low, Scientific American
Serotonin Test Interpretation on ClinLab Navigator Archived 1 February 2010 at the Wayback Machine. | Wikipedia/Serotonergic_drug |
In behavioral psychology, reinforcement refers to consequences that increase the likelihood of an organism's future behavior, typically in the presence of a particular antecedent stimulus. For example, a rat can be trained to push a lever to receive food whenever a light is turned on; in this example, the light is the antecedent stimulus, the lever pushing is the operant behavior, and the food is the reinforcer. Likewise, a student that receives attention and praise when answering a teacher's question will be more likely to answer future questions in class; the teacher's question is the antecedent, the student's response is the behavior, and the praise and attention are the reinforcements. Punishment is the inverse to reinforcement, referring to any behavior that decreases the likelihood that a response will occur. In operant conditioning terms, punishment does not need to involve any type of pain, fear, or physical actions; even a brief spoken expression of disapproval is a type of punishment.
Consequences that lead to appetitive behavior such as subjective "wanting" and "liking" (desire and pleasure) function as rewards or positive reinforcement. There is also negative reinforcement, which involves taking away an undesirable stimulus. An example of negative reinforcement would be taking an aspirin to relieve a headache.
Reinforcement is an important component of operant conditioning and behavior modification. The concept has been applied in a variety of practical areas, including parenting, coaching, therapy, self-help, education, and management.
== Terminology ==
In the behavioral sciences, the terms "positive" and "negative" refer when used in their strict technical sense to the nature of the action performed by the conditioner rather than to the responding operant's evaluation of that action and its consequence(s). "Positive" actions are those that add a factor, be it pleasant or unpleasant, to the environment, whereas "negative" actions are those that remove or withhold from the environment a factor of either type. In turn, the strict sense of "reinforcement" refers only to reward-based conditioning; the introduction of unpleasant factors and the removal or withholding of pleasant factors are instead referred to as "punishment", which when used in its strict sense thus stands in contradistinction to "reinforcement". Thus, "positive reinforcement" refers to the addition of a pleasant factor, "positive punishment" refers to the addition of an unpleasant factor, "negative reinforcement" refers to the removal or withholding of an unpleasant factor, and "negative punishment" refers to the removal or withholding of a pleasant factor.
This usage is at odds with some non-technical usages of the four term combinations, especially in the case of the term "negative reinforcement", which is often used to denote what technical parlance would describe as "positive punishment" in that the non-technical usage interprets "reinforcement" as subsuming both reward and punishment and "negative" as referring to the responding operant's evaluation of the factor being introduced. By contrast, technical parlance would use the term "negative reinforcement" to describe encouragement of a given behavior by creating a scenario in which an unpleasant factor is or will be present but engaging in the behavior results in either escaping from that factor or preventing its occurrence, as in Martin Seligman’s experiment involving dogs learning to avoid electric shocks.
== Introduction ==
B.F. Skinner was a well-known and influential researcher who articulated many of the theoretical constructs of reinforcement and behaviorism. Skinner defined reinforcers according to the change in response strength (response rate) rather than to more subjective criteria, such as what is pleasurable or valuable to someone. Accordingly, activities, foods or items considered pleasant or enjoyable may not necessarily be reinforcing (because they produce no increase in the response preceding them). Stimuli, settings, and activities only fit the definition of reinforcers if the behavior that immediately precedes the potential reinforcer increases in similar situations in the future; for example, a child who receives a cookie when he or she asks for one. If the frequency of "cookie-requesting behavior" increases, the cookie can be seen as reinforcing "cookie-requesting behavior". If however, "cookie-requesting behavior" does not increase the cookie cannot be considered reinforcing.
The sole criterion that determines if a stimulus is reinforcing is the change in probability of a behavior after administration of that potential reinforcer. Other theories may focus on additional factors such as whether the person expected a behavior to produce a given outcome, but in the behavioral theory, reinforcement is defined by an increased probability of a response.
The study of reinforcement has produced an enormous body of reproducible experimental results. Reinforcement is the central concept and procedure in special education, applied behavior analysis, and the experimental analysis of behavior and is a core concept in some medical and psychopharmacology models, particularly addiction, dependence, and compulsion.
== History ==
Laboratory research on reinforcement is usually dated from the work of Edward Thorndike, known for his experiments with cats escaping from puzzle boxes. A number of others continued this research, notably B.F. Skinner, who published his seminal work on the topic in The Behavior of Organisms, in 1938, and elaborated this research in many subsequent publications. Notably Skinner argued that positive reinforcement is superior to punishment in shaping behavior. Though punishment may seem just the opposite of reinforcement, Skinner claimed that they differ immensely, saying that positive reinforcement results in lasting behavioral modification (long-term) whereas punishment changes behavior only temporarily (short-term) and has many detrimental side-effects.
A great many researchers subsequently expanded our understanding of reinforcement and challenged some of Skinner's conclusions. For example, Azrin and Holz defined punishment as a “consequence of behavior that reduces the future probability of that behavior,” and some studies have shown that positive reinforcement and punishment are equally effective in modifying behavior. Research on the effects of positive reinforcement, negative reinforcement and punishment continue today as those concepts are fundamental to learning theory and apply to many practical applications of that theory.
== Operant conditioning ==
The term operant conditioning was introduced by Skinner to indicate that in his experimental paradigm, the organism is free to operate on the environment. In this paradigm, the experimenter cannot trigger the desirable response; the experimenter waits for the response to occur (to be emitted by the organism) and then a potential reinforcer is delivered. In the classical conditioning paradigm, the experimenter triggers (elicits) the desirable response by presenting a reflex eliciting stimulus, the unconditional stimulus (UCS), which they pair (precede) with a neutral stimulus, the conditional stimulus (CS).
Reinforcement is a basic term in operant conditioning. For the punishment aspect of operant conditioning, see punishment (psychology).
=== Positive reinforcement ===
Positive reinforcement occurs when a desirable event or stimulus is presented as a consequence of a behavior and the chance that this behavior will manifest in similar environments increases.: 253 For example, if reading a book is fun, then experiencing the fun positively reinforces the behavior of reading fun books. The person who receives the positive reinforcement (i.e., who has fun reading the book) will read more books to have more fun.
The high probability instruction (HPI) treatment is a behaviorist treatment based on the idea of positive reinforcement.
=== Negative reinforcement ===
Negative reinforcement increases the rate of a behavior that avoids or escapes an aversive situation or stimulus.: 252–253 That is, something unpleasant is already happening, and the behavior helps the person avoid or escape the unpleasantness. In contrast to positive reinforcement, which involves adding a pleasant stimulus, in negative reinforcement, the focus is on the removal of an unpleasant situation or stimulus. For example, if someone feels unhappy, then they might engage in a behavior (e.g., reading books) to escape from the aversive situation (e.g., their unhappy feelings).: 253 The success of that avoidant or escapist behavior in removing the unpleasant situation or stimulus reinforces the behavior.
Doing something unpleasant to people to prevent or remove a behavior from happening again is punishment, not negative reinforcement.: 252 The main difference is that reinforcement always increases the likelihood of a behavior (e.g., channel surfing while bored temporarily alleviated boredom; therefore, there will be more channel surfing while bored), whereas punishment decreases it (e.g., hangovers are an unpleasant stimulus, so people learn to avoid the behavior that led to that unpleasant stimulus).
=== Extinction ===
Extinction occurs when a given behavior is ignored (i.e. followed up with no consequence). Behaviors disappear over time when they continuously receive no reinforcement. During a deliberate extinction, the targeted behavior spikes first (in an attempt to produce the expected, previously reinforced effects), and then declines over time. Neither reinforcement nor extinction need to be deliberate in order to have an effect on a subject's behavior. For example, if a child reads books because they are fun, then the parents' decision to ignore the book reading will not remove the positive reinforcement (i.e., fun) the child receives from reading books. However, if a child engages in a behavior to get attention from the parents, then the parents' decision to ignore the behavior will cause the behavior to go extinct, and the child will find a different behavior to get their parents' attention.
=== Reinforcement versus punishment ===
Reinforcers serve to increase behaviors whereas punishers serve to decrease behaviors; thus, positive reinforcers are stimuli that the subject will work to attain, and negative reinforcers are stimuli that the subject will work to be rid of or to end. The table below illustrates the adding and subtracting of stimuli (pleasant or aversive) in relation to reinforcement vs. punishment.
=== Further ideas and concepts ===
Distinguishing between positive and negative reinforcement can be difficult and may not always be necessary. Focusing on what is being removed or added and how it affects behavior can be more helpful.
An event that punishes behavior for some may reinforce behavior for others.
Some reinforcement can include both positive and negative features, such as a drug addict taking drugs for the added euphoria (positive reinforcement) and also to eliminate withdrawal symptoms (negative reinforcement).
Reinforcement in the business world is essential in driving productivity. Employees are constantly motivated by the ability to receive a positive stimulus, such as a promotion or a bonus. Employees are also driven by negative reinforcement, such as by eliminating unpleasant tasks.
Though negative reinforcement has a positive effect in the short term for a workplace (i.e. encourages a financially beneficial action), over-reliance on a negative reinforcement hinders the ability of workers to act in a creative, engaged way creating growth in the long term.
=== Primary and secondary reinforcers ===
A primary reinforcer, sometimes called an unconditioned reinforcer, is a stimulus that does not require pairing with a different stimulus in order to function as a reinforcer and most likely has obtained this function through the evolution and its role in species' survival. Examples of primary reinforcers include food, water, and sex. Some primary reinforcers, such as certain drugs, may mimic the effects of other primary reinforcers. While these primary reinforcers are fairly stable through life and across individuals, the reinforcing value of different primary reinforcers varies due to multiple factors (e.g., genetics, experience). Thus, one person may prefer one type of food while another avoids it. Or one person may eat much food while another eats very little. So even though food is a primary reinforcer for both individuals, the value of food as a reinforcer differs between them.
A secondary reinforcer, sometimes called a conditioned reinforcer, is a stimulus or situation that has acquired its function as a reinforcer after pairing with a stimulus that functions as a reinforcer. This stimulus may be a primary reinforcer or another conditioned reinforcer (such as money).
When trying to distinguish primary and secondary reinforcers in human examples, use the "caveman test." If the stimulus is something that a caveman would naturally find desirable (e.g. candy) then it is a primary reinforcer. If, on the other hand, the caveman would not react to it (e.g. a dollar bill), it is a secondary reinforcer. As with primary reinforcers, an organism can experience satisfaction and deprivation with secondary reinforcers.
=== Other reinforcement terms ===
A generalized reinforcer is a conditioned reinforcer that has obtained the reinforcing function by pairing with many other reinforcers and functions as a reinforcer under a wide-variety of motivating operations. (One example of this is money because it is paired with many other reinforcers).: 83
In reinforcer sampling, a potentially reinforcing but unfamiliar stimulus is presented to an organism without regard to any prior behavior.
Socially-mediated reinforcement involves the delivery of reinforcement that requires the behavior of another organism. For example, another person is providing the reinforcement.
The Premack principle is a special case of reinforcement elaborated by David Premack, which states that a highly preferred activity can be used effectively as a reinforcer for a less-preferred activity.: 123
Reinforcement hierarchy is a list of actions, rank-ordering the most desirable to least desirable consequences that may serve as a reinforcer. A reinforcement hierarchy can be used to determine the relative frequency and desirability of different activities, and is often employed when applying the Premack principle.
Contingent outcomes are more likely to reinforce behavior than non-contingent responses. Contingent outcomes are those directly linked to a causal behavior, such a light turning on being contingent on flipping a switch. Note that contingent outcomes are not necessary to demonstrate reinforcement, but perceived contingency may increase learning.
Contiguous stimuli are stimuli closely associated by time and space with specific behaviors. They reduce the amount of time needed to learn a behavior while increasing its resistance to extinction. Giving a dog a piece of food immediately after sitting is more contiguous with (and therefore more likely to reinforce) the behavior than a several minute delay in food delivery following the behavior.
Noncontingent reinforcement refers to response-independent delivery of stimuli identified as reinforcers for some behaviors of that organism. However, this typically entails time-based delivery of stimuli identified as maintaining aberrant behavior, which decreases the rate of the target behavior. As no measured behavior is identified as being strengthened, there is controversy surrounding the use of the term noncontingent "reinforcement".
== Natural and artificial reinforcement ==
In his 1967 paper, Arbitrary and Natural Reinforcement, Charles Ferster proposed classifying reinforcement into events that increase the frequency of an operant behavior as a natural consequence of the behavior itself, and events that affect frequency by their requirement of human mediation, such as in a token economy where subjects are rewarded for certain behavior by the therapist.
In 1970, Baer and Wolf developed the concept of "behavioral traps." A behavioral trap requires only a simple response to enter the trap, yet once entered, the trap cannot be resisted in creating general behavior change. It is the use of a behavioral trap that increases a person's repertoire, by exposing them to the naturally occurring reinforcement of that behavior. Behavioral traps have four characteristics:
They are "baited" with desirable reinforcers that "lure" the student into the trap.
Only a low-effort response already in the repertoire is necessary to enter the trap.
Interrelated contingencies of reinforcement inside the trap motivate the person to acquire, extend, and maintain targeted skills.
They can remain effective for long periods of time because the person shows few, if any, satiation effects.
Thus, artificial reinforcement can be used to build or develop generalizable skills, eventually transitioning to naturally occurring reinforcement to maintain or increase the behavior. Another example is a social situation that will generally result from a specific behavior once it has met a certain criterion.
== Intermittent reinforcement schedules ==
Behavior is not always reinforced every time it is emitted, and the pattern of reinforcement strongly affects how fast an operant response is learned, what its rate is at any given time, and how long it continues when reinforcement ceases. The simplest rules controlling reinforcement are continuous reinforcement, where every response is reinforced, and extinction, where no response is reinforced. Between these extremes, more complex schedules of reinforcement specify the rules that determine how and when a response will be followed by a reinforcer.
Specific schedules of reinforcement reliably induce specific patterns of response, and these rules apply across many different species. The varying consistency and predictability of reinforcement is an important influence on how the different schedules operate. Many simple and complex schedules were investigated at great length by B.F. Skinner using pigeons.
=== Simple schedules ===
Ratio schedule – the reinforcement depends only on the number of responses the organism has performed.
Continuous reinforcement (CRF) – a schedule of reinforcement in which every occurrence of the instrumental response (desired response) is followed by the reinforcer.: 86
Simple schedules have a single rule to determine when a single type of reinforcer is delivered for a specific response.
Fixed ratio (FR) – schedules deliver reinforcement after every nth response.: 88 An FR 1 schedule is synonymous with a CRF schedule.
(ex. Every three times a rat presses a button, that rat receives a slice of cheese)
Variable ratio schedule (VR) – reinforced on average every nth response, but not always on the nth response.: 88
(ex. Gamblers win 1 out every an 10 turns on a slot machine, however this is an average and they could hypothetically win on any given turn)
Fixed interval (FI) – reinforced after n amount of time.
(ex. Every 10 minutes, a rat receives a slice of cheese when it presses a button. Eventually, the rat will learn to ignore the button until each 10 minute interval has elapsed)
Variable interval (VI) – reinforced on an average of n amount of time, but not always exactly n amount of time.: 89
(ie. A radio host gives away concert tickets approximately every hour, but the exact minutes may vary)
Fixed time (FT) – Provides a reinforcing stimulus at a fixed time since the last reinforcement delivery, regardless of whether the subject has responded or not. In other words, it is a non-contingent schedule.
Variable time (VT) – Provides reinforcement at an average variable time since last reinforcement, regardless of whether the subject has responded or not.
Simple schedules are utilized in many differential reinforcement procedures:
Differential reinforcement of alternative behavior (DRA) - A conditioning procedure in which an undesired response is decreased by placing it on extinction or, less commonly, providing contingent punishment, while simultaneously providing reinforcement contingent on a desirable response. An example would be a teacher attending to a student only when they raise their hand, while ignoring the student when he or she calls out.
Differential reinforcement of other behavior (DRO) – Also known as omission training procedures, an instrumental conditioning procedure in which a positive reinforcer is periodically delivered only if the participant does something other than the target response. An example would be reinforcing any hand action other than nose picking.: 338
Differential reinforcement of incompatible behavior (DRI) – Used to reduce a frequent behavior without punishing it by reinforcing an incompatible response. An example would be reinforcing clapping to reduce nose picking
Differential reinforcement of low response rate (DRL) – Used to encourage low rates of responding. It is like an interval schedule, except that premature responses reset the time required between behavior.
Differential reinforcement of high rate (DRH) – Used to increase high rates of responding. It is like an interval schedule, except that a minimum number of responses are required in the interval in order to receive reinforcement.
==== Effects of different types of simple schedules ====
Fixed ratio: activity slows after reinforcer is delivered, then response rates increase until the next reinforcer delivery (post-reinforcement pause).
Variable ratio: rapid, steady rate of responding; most resistant to extinction.
Fixed interval: responding increases towards the end of the interval; poor resistance to extinction.
Variable interval: steady activity results, good resistance to extinction.
Ratio schedules produce higher rates of responding than interval schedules, when the rates of reinforcement are otherwise similar.
Variable schedules produce higher rates and greater resistance to extinction than most fixed schedules. This is also known as the Partial Reinforcement Extinction Effect (PREE).
The variable ratio schedule produces both the highest rate of responding and the greatest resistance to extinction (for example, the behavior of gamblers at slot machines).
Fixed schedules produce "post-reinforcement pauses" (PRP), where responses will briefly cease immediately following reinforcement, though the pause is a function of the upcoming response requirement rather than the prior reinforcement.
The PRP of a fixed interval schedule is frequently followed by a "scallop-shaped" accelerating rate of response, while fixed ratio schedules produce a more "angular" response.
fixed interval scallop: the pattern of responding that develops with fixed interval reinforcement schedule, performance on a fixed interval reflects subject's accuracy in telling time.
Organisms whose schedules of reinforcement are "thinned" (that is, requiring more responses or a greater wait before reinforcement) may experience "ratio strain" if thinned too quickly. This produces behavior similar to that seen during extinction.
Ratio strain: the disruption of responding that occurs when a fixed ratio response requirement is increased too rapidly.
Ratio run: high and steady rate of responding that completes each ratio requirement. Usually higher ratio requirement causes longer post-reinforcement pauses to occur.
Partial reinforcement schedules are more resistant to extinction than continuous reinforcement schedules.
Ratio schedules are more resistant than interval schedules and variable schedules more resistant than fixed ones.
Momentary changes in reinforcement value lead to dynamic changes in behavior.
=== Compound schedules ===
Compound schedules combine two or more different simple schedules in some way using the same reinforcer for the same behavior. There are many possibilities; among those most often used are:
Alternative schedules' – A type of compound schedule where two or more simple schedules are in effect and whichever schedule is completed first results in reinforcement.
Conjunctive schedules – A complex schedule of reinforcement where two or more simple schedules are in effect independently of each other, and requirements on all of the simple schedules must be met for reinforcement.
Multiple schedules – Two or more schedules alternate over time, with a stimulus indicating which is in force. Reinforcement is delivered if the response requirement is met while a schedule is in effect.
Mixed schedules – Either of two, or more, schedules may occur with no stimulus indicating which is in force. Reinforcement is delivered if the response requirement is met while a schedule is in effect.
Concurrent schedules – A complex reinforcement procedure in which the participant can choose any one of two or more simple reinforcement schedules that are available simultaneously. Organisms are free to change back and forth between the response alternatives at any time.
Concurrent-chain schedule of reinforcement' – A complex reinforcement procedure in which the participant is permitted to choose during the first link which of several simple reinforcement schedules will be in effect in the second link. Once a choice has been made, the rejected alternatives become unavailable until the start of the next trial.
Interlocking schedules – A single schedule with two components where progress in one component affects progress in the other component. In an interlocking FR 60 FI 120-s schedule, for example, each response subtracts time from the interval component such that each response is "equal" to removing two seconds from the FI schedule.
Chained schedules – Reinforcement occurs after two or more successive schedules have been completed, with a stimulus indicating when one schedule has been completed and the next has started
Tandem schedules – Reinforcement occurs when two or more successive schedule requirements have been completed, with no stimulus indicating when a schedule has been completed and the next has started.
Higher-order schedules – completion of one schedule is reinforced according to a second schedule; e.g. in FR2 (FI10 secs), two successive fixed interval schedules require completion before a response is reinforced.
=== Superimposed schedules ===
The psychology term superimposed schedules of reinforcement refers to a structure of rewards where two or more simple schedules of reinforcement operate simultaneously. Reinforcers can be positive, negative, or both. An example is a person who comes home after a long day at work. The behavior of opening the front door is rewarded by a big kiss on the lips by the person's spouse and a rip in the pants from the family dog jumping enthusiastically. Another example of superimposed schedules of reinforcement is a pigeon in an experimental cage pecking at a button. The pecks deliver a hopper of grain every 20th peck, and access to water after every 200 pecks.
Superimposed schedules of reinforcement are a type of compound schedule that evolved from the initial work on simple schedules of reinforcement by B.F. Skinner and his colleagues (Skinner and Ferster, 1957). They demonstrated that reinforcers could be delivered on schedules, and further that organisms behaved differently under different schedules. Rather than a reinforcer, such as food or water, being delivered every time as a consequence of some behavior, a reinforcer could be delivered after more than one instance of the behavior. For example, a pigeon may be required to peck a button switch ten times before food appears. This is a "ratio schedule". Also, a reinforcer could be delivered after an interval of time passed following a target behavior. An example is a rat that is given a food pellet immediately following the first response that occurs after two minutes has elapsed since the last lever press. This is called an "interval schedule".
In addition, ratio schedules can deliver reinforcement following fixed or variable number of behaviors by the individual organism. Likewise, interval schedules can deliver reinforcement following fixed or variable intervals of time following a single response by the organism. Individual behaviors tend to generate response rates that differ based upon how the reinforcement schedule is created. Much subsequent research in many labs examined the effects on behaviors of scheduling reinforcers.
If an organism is offered the opportunity to choose between or among two or more simple schedules of reinforcement at the same time, the reinforcement structure is called a "concurrent schedule of reinforcement". Brechner (1974, 1977) introduced the concept of superimposed schedules of reinforcement in an attempt to create a laboratory analogy of social traps, such as when humans overharvest their fisheries or tear down their rainforests. Brechner created a situation where simple reinforcement schedules were superimposed upon each other. In other words, a single response or group of responses by an organism led to multiple consequences. Concurrent schedules of reinforcement can be thought of as "or" schedules, and superimposed schedules of reinforcement can be thought of as "and" schedules. Brechner and Linder (1981) and Brechner (1987) expanded the concept to describe how superimposed schedules and the social trap analogy could be used to analyze the way energy flows through systems.
Superimposed schedules of reinforcement have many real-world applications in addition to generating social traps. Many different human individual and social situations can be created by superimposing simple reinforcement schedules. For example, a human being could have simultaneous tobacco and alcohol addictions. Even more complex situations can be created or simulated by superimposing two or more concurrent schedules. For example, a high school senior could have a choice between going to Stanford University or UCLA, and at the same time have the choice of going into the Army or the Air Force, and simultaneously the choice of taking a job with an internet company or a job with a software company. That is a reinforcement structure of three superimposed concurrent schedules of reinforcement.
Superimposed schedules of reinforcement can create the three classic conflict situations (approach–approach conflict, approach–avoidance conflict, and avoidance–avoidance conflict) described by Kurt Lewin (1935) and can operationalize other Lewinian situations analyzed by his force field analysis. Other examples of the use of superimposed schedules of reinforcement as an analytical tool are its application to the contingencies of rent control (Brechner, 2003) and problem of toxic waste dumping in the Los Angeles County storm drain system (Brechner, 2010).
=== Concurrent schedules ===
In operant conditioning, concurrent schedules of reinforcement are schedules of reinforcement that are simultaneously available to an animal subject or human participant, so that the subject or participant can respond on either schedule. For example, in a two-alternative forced choice task, a pigeon in a Skinner box is faced with two pecking keys; pecking responses can be made on either, and food reinforcement might follow a peck on either. The schedules of reinforcement arranged for pecks on the two keys can be different. They may be independent, or they may be linked so that behavior on one key affects the likelihood of reinforcement on the other.
It is not necessary for responses on the two schedules to be physically distinct. In an alternate way of arranging concurrent schedules, introduced by Findley in 1958, both schedules are arranged on a single key or other response device, and the subject can respond on a second key to change between the schedules. In such a "Findley concurrent" procedure, a stimulus (e.g., the color of the main key) signals which schedule is in effect.
Concurrent schedules often induce rapid alternation between the keys. To prevent this, a "changeover delay" is commonly introduced: each schedule is inactivated for a brief period after the subject switches to it.
When both the concurrent schedules are variable intervals, a quantitative relationship known as the matching law is found between relative response rates in the two schedules and the relative reinforcement rates they deliver; this was first observed by R.J. Herrnstein in 1961. Matching law is a rule for instrumental behavior which states that the relative rate of responding on a particular response alternative equals the relative rate of reinforcement for that response (rate of behavior = rate of reinforcement). Animals and humans have a tendency to prefer choice in schedules.
== Shaping ==
Shaping is the reinforcement of successive approximations to a desired instrumental response. In training a rat to press a lever, for example, simply turning toward the lever is reinforced at first. Then, only turning and stepping toward it is reinforced. Eventually the rat will be reinforced for pressing the lever. The successful attainment of one behavior starts the shaping process for the next. As training progresses, the response becomes progressively more like the desired behavior, with each subsequent behavior becoming a closer approximation of the final behavior.
The intervention of shaping is used in many training situations, and also for individuals with autism as well as other developmental disabilities. When shaping is combined with other evidence-based practices such as Functional Communication Training (FCT), it can yield positive outcomes for human behavior. Shaping typically uses continuous reinforcement, but the response can later be shifted to an intermittent reinforcement schedule.
Shaping is also used for food refusal. Food refusal is when an individual has a partial or total aversion to food items. This can be as minimal as being a picky eater to so severe that it can affect an individual's health. Shaping has been used to have a high success rate for food acceptance.
== Chaining ==
Chaining involves linking discrete behaviors together in a series, such that the consequence of each behavior is both the reinforcement for the previous behavior, and the antecedent stimulus for the next behavior. There are many ways to teach chaining, such as forward chaining (starting from the first behavior in the chain), backwards chaining (starting from the last behavior) and total task chaining (teaching each behavior in the chain simultaneously). People's morning routines are a typical chain, with a series of behaviors (e.g. showering, drying off, getting dressed) occurring in sequence as a well learned habit.
Challenging behaviors seen in individuals with autism and other related disabilities have successfully managed and maintained in studies using a scheduled of chained reinforcements. Functional communication training is an intervention that often uses chained schedules of reinforcement to effectively promote the appropriate and desired functional communication response.
== Mathematical models ==
There has been research on building a mathematical model of reinforcement. This model is known as MPR, which is short for mathematical principles of reinforcement. Peter Killeen has made key discoveries in the field with his research on pigeons.
== Applications ==
Reinforcement and punishment are ubiquitous in human social interactions, and a great many applications of operant principles have been suggested and implemented. Following are a few examples.
=== Addiction and dependence ===
Positive and negative reinforcement play central roles in the development and maintenance of addiction and drug dependence. An addictive drug is intrinsically rewarding; that is, it functions as a primary positive reinforcer of drug use. The brain's reward system assigns it incentive salience (i.e., it is "wanted" or "desired"), so as an addiction develops, deprivation of the drug leads to craving. In addition, stimuli associated with drug use – e.g., the sight of a syringe, and the location of use – become associated with the intense reinforcement induced by the drug. These previously neutral stimuli acquire several properties: their appearance can induce craving, and they can become conditioned positive reinforcers of continued use. Thus, if an addicted individual encounters one of these drug cues, a craving for the associated drug may reappear. For example, anti-drug agencies previously used posters with images of drug paraphernalia as an attempt to show the dangers of drug use. However, such posters are no longer used because of the effects of incentive salience in causing relapse upon sight of the stimuli illustrated in the posters.
In drug dependent individuals, negative reinforcement occurs when a drug is self-administered in order to alleviate or "escape" the symptoms of physical dependence (e.g., tremors and sweating) and/or psychological dependence (e.g., anhedonia, restlessness, irritability, and anxiety) that arise during the state of drug withdrawal.
=== Animal training ===
Animal trainers and pet owners were applying the principles and practices of operant conditioning long before these ideas were named and studied, and animal training still provides one of the clearest and most convincing examples of operant control. Of the concepts and procedures described in this article, a few of the most salient are: availability of immediate reinforcement (e.g. the ever-present bag of dog yummies); contingency, assuring that reinforcement follows the desired behavior and not something else; the use of secondary reinforcement, as in sounding a clicker immediately after a desired response; shaping, as in gradually getting a dog to jump higher and higher; intermittent reinforcement, reducing the frequency of those yummies to induce persistent behavior without satiation; chaining, where a complex behavior is gradually put together.
=== Child behavior – parent management training ===
Providing positive reinforcement for appropriate child behaviors is a major focus of parent management training. Typically, parents learn to reward appropriate behavior through social rewards (such as praise, smiles, and hugs) as well as concrete rewards (such as stickers or points towards a larger reward as part of an incentive system created collaboratively with the child). In addition, parents learn to select simple behaviors as an initial focus and reward each of the small steps that their child achieves towards reaching a larger goal (this concept is called "successive approximations"). They may also use indirect rewards such through progress charts. Providing positive reinforcement in the classroom can be beneficial to student success. When applying positive reinforcement to students, it's crucial to make it individualized to that student's needs. This way, the student understands why they are receiving the praise, they can accept it, and eventually learn to continue the action that was earned by positive reinforcement. For example, using rewards or extra recess time might apply to some students more, whereas others might accept the enforcement by receiving stickers or check marks indicating praise.
=== Economics ===
Both psychologists and economists have become interested in applying operant concepts and findings to the behavior of humans in the marketplace. An example
is the analysis of consumer demand, as indexed by the amount of a commodity that is purchased. In economics, the degree to which price influences consumption is called "the price elasticity of demand." Certain commodities are more elastic than others; for example, a change in price of certain foods may have a large effect on the amount bought, while gasoline and other essentials may be less affected by price changes. In terms of operant analysis, such effects may be interpreted in terms of motivations of consumers and the relative value of the commodities as reinforcers.
=== Gambling – variable ratio scheduling ===
As stated earlier in this article, a variable ratio schedule yields reinforcement after the emission of an unpredictable number of responses. This schedule typically generates rapid, persistent responding. Slot machines pay off on a variable ratio schedule, and they produce just this sort of persistent lever-pulling behavior in gamblers. Because the machines are programmed to pay out less money than they take in, the persistent slot-machine user invariably loses in the long run. Slots machines, and thus variable ratio reinforcement, have often been blamed as a factor underlying gambling addiction.
=== Praise ===
The concept of praise as a means of behavioral reinforcement in humans is rooted in B.F. Skinner's model of operant conditioning. Through this lens, praise has been viewed as a means of positive reinforcement, wherein an observed behavior is made more likely to occur by contingently praising said behavior. Hundreds of studies have demonstrated the effectiveness of praise in promoting positive behaviors, notably in the study of teacher and parent use of praise on child in promoting improved behavior and academic performance, but also in the study of work performance. Praise has also been demonstrated to reinforce positive behaviors in non-praised adjacent individuals (such as a classmate of the praise recipient) through vicarious reinforcement. Praise may be more or less effective in changing behavior depending on its form, content and delivery. In order for praise to effect positive behavior change, it must be contingent on the positive behavior (i.e., only administered after the targeted behavior is enacted), must specify the particulars of the behavior that is to be reinforced, and must be delivered sincerely and credibly.
Acknowledging the effect of praise as a positive reinforcement strategy, numerous behavioral and cognitive behavioral interventions have incorporated the use of praise in their protocols. The strategic use of praise is recognized as an evidence-based practice in both classroom management and parenting training interventions, though praise is often subsumed in intervention research into a larger category of positive reinforcement, which includes strategies such as strategic attention and behavioral rewards.
=== Traumatic bonding ===
Traumatic bonding occurs as the result of ongoing cycles of abuse in which the intermittent reinforcement of reward and punishment creates powerful emotional bonds that are resistant to change.
The other source indicated that
'The necessary conditions for traumatic bonding are that one person must dominate the other and that the level of abuse chronically spikes and then subsides. The relationship is characterized by periods of permissive, compassionate, and even affectionate behavior from the dominant person, punctuated by intermittent episodes of intense abuse. To maintain the upper hand, the victimizer manipulates the behavior of the victim and limits the victim's options so as to perpetuate the power imbalance. Any threat to the balance of dominance and submission may be met with an escalating cycle of punishment ranging from seething intimidation to intensely violent outbursts. The victimizer also isolates the victim from other sources of support, which reduces the likelihood of detection and intervention, impairs the victim's ability to receive countervailing self-referent feedback, and strengthens the sense of unilateral dependency ... The traumatic effects of these abusive relationships may include the impairment of the victim's capacity for accurate self-appraisal, leading to a sense of personal inadequacy and a subordinate sense of dependence upon the dominating person. Victims also may encounter a variety of unpleasant social and legal consequences of their emotional and behavioral affiliation with someone who perpetrated aggressive acts, even if they themselves were the recipients of the aggression.
=== Video games ===
Most video games are designed around some type of compulsion loop, adding a type of positive reinforcement through a variable rate schedule to keep the player playing the game, though this can also lead to video game addiction.
As part of a trend in the monetization of video games in the 2010s, some games offered "loot boxes" as rewards or purchasable by real-world funds that offered a random selection of in-game items, distributed by rarity. The practice has been tied to the same methods that slot machines and other gambling devices dole out rewards, as it follows a variable rate schedule. While the general perception that loot boxes are a form of gambling, the practice is only classified as such in a few countries as gambling and otherwise legal. However, methods to use those items as virtual currency for online gambling or trading for real-world money has created a skin gambling market that is under legal evaluation.
== Criticisms ==
The standard definition of behavioral reinforcement has been criticized as circular, since it appears to argue that response strength is increased by reinforcement, and defines reinforcement as something that increases response strength (i.e., response strength is increased by things that increase response strength). However, the correct usage of reinforcement is that something is a reinforcer because of its effect on behavior, and not the other way around. It becomes circular if one says that a particular stimulus strengthens behavior because it is a reinforcer, and does not explain why a stimulus is producing that effect on the behavior. Other definitions have been proposed, such as F.D. Sheffield's "consummatory behavior contingent on a response", but these are not broadly used in psychology.
Increasingly, understanding of the role reinforcers play is moving away from a "strengthening" effect to a "signalling" effect. That is, the view that reinforcers increase responding because they signal the behaviors that are likely to result in reinforcement. While in most practical applications, the effect of any given reinforcer will be the same regardless of whether the reinforcer is signalling or strengthening, this approach helps to explain a number of behavioral phenomena including patterns of responding on intermittent reinforcement schedules (fixed interval scallops) and the differential outcomes effect.
== See also ==
== References ==
== Further reading ==
== External links ==
An On-Line Positive Reinforcement Tutorial
Scholarpedia Reinforcement
scienceofbehavior.com Archived 2 October 2011 at the Wayback Machine | Wikipedia/Positive_reinforcer |
Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).
Mechanisms of peripheral selectivity include physicochemical hydrophilicity and large molecular size, which prevent drug permeation through the lipid bilayer cell membranes of the blood–brain barrier, and efflux out of the brain by blood–brain barrier transporters such as P-glycoprotein among many others. Transport out of the brain by P-glycoprotein is thought to be responsible for the peripheral selectivity of many drugs, including loperamide, domperidone, fexofenadine, bilastine, cetirizine, ivermectin, and dexamethasone, among others.
== List of peripherally selective drugs ==
α-Methylserotonin – a non-selective serotonin receptor agonist
AL-34662 – a serotonin 5-HT2A receptor agonist
Alvimopan – a μ-opioid receptor antagonist used in the treatment of postoperative ileus
Anastrozole – an aromatase inhibitor used in the treatment of breast cancer
Atenolol – a beta blocker (β-adrenergic receptor antagonist)
Benserazide – an aromatic L-amino acid decarboxylase inhibitor used in combination with levodopa in the treatment of Parkinson's disease
Bethanechol – a muscarinic acetylcholine receptor agonist used in the treatment of dry mouth and urinary retention
Bicalutamide – an antiandrogen with peripheral selectivity in animals but seemingly not in humans
Bilastine – a non-sedating antihistamine
Bisoprolol – a beta blocker (β-adrenergic receptor antagonist)
Bufotenidine (5-HTQ) – a serotonin 5-HT3 receptor antagonist
Bufotenin – a non-selective serotonin receptor agonist and serotonergic psychedelic
BW-501C67 – a serotonin 5-HT2A and 5-HT2C receptor antagonist
Carbachol – a non-selective acetylcholine receptor agonist used in the treatment of glaucoma
Carbidopa – an aromatic L-amino acid decarboxylase inhibitor used in combination with levodopa in the treatment of Parkinson's disease
Carteolol – a beta blocker (β-adrenergic receptor antagonist)
Cetirizine – a non-sedating antihistamine
Colchicine – an alkaloid and tubulin polymerization inhibitor used to treat gout
Darolutamide – an antiandrogen used in the treatment of prostate cancer
Desloratadine – a non-sedating antihistamine
Dexamethasone – a glucocorticoid with some peripheral selectivity
Digoxin – a cardiac glycoside and sodium–potassium pump inhibitor
Docarpamine – a dopamine prodrug and non-selective dopamine receptor agonist
Domperidone – a dopamine D2 receptor antagonist used as an antiemetic, gastroprokinetic agent, and galactogogue
Dopamine – a non-selective dopamine and adrenergic receptor agonist used as a cardiac stimulant and positive inotropic agent
Eluxadoline – a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist used in the treatment of diarrhea-predominant irritable bowel syndrome
Entacapone – a catechol-O-methyltransferase inhibitor used in combination with levodopa in the treatment of Parkinson's disease
Epinephrine (adrenaline) – a non-selective adrenergic receptor agonist used as a cardiac stimulant and in the treatment of anaphylaxis
Ergotamine – non-selective serotonin, adrenergic, and dopamine receptor modulator used as a vasoconstrictor to treat migraines
Esmolol – a beta blocker (β-adrenergic receptor antagonist)
Etamicastat – a dopamine β-hydroxylase inhibitor developed as an antihypertensive agent
Etilefrine – a non-selective adrenergic receptor agonist used as an antihypotensive agent
Fenoldopam – a dopamine D1 receptor agonist used as an antihypertensive agent
Fexofenadine – a non-sedating antihistamine
Fulvestrant – an antiestrogen used in the treatment of breast cancer
GABA – a GABA receptor agonist and dietary supplement
Glycopyrronium bromide – an anticholinergic (acetylcholine receptor antagonist)
Hyoscine butylbromide – an anticholinergic (acetylcholine receptor antagonist)
Isoprenaline – a β-adrenergic receptor agonist used as a sympathomimetic
Itopride – a dopamine D2 receptor antagonist and acetylcholinesterase inhibitor used as a gastroprokinetic agent
Ivermectin – an antiparasitic
Labetalol – a beta blocker (β-adrenergic receptor antagonist)
Levocetirizine – a non-sedating antihistamine
Loperamide – a μ-opioid receptor agonist used as an antidiarrheal
Loratadine – a non-sedating antihistamine
Methacholine – a choline ester and muscarinic acetylcholine receptor agonist
Methylhomatropine – an anticholinergic (acetylcholine receptor antagonist)
Methylnaltrexone – a μ-opioid receptor antagonist used in the treatment of opioid-induced constipation
Metopimazine – a dopamine D2 receptor antagonist used in the treatment of nausea, vomiting, and gastroparesis
Midodrine – an α1-adrenergic receptor agonist used in the treatment of orthostatic hypotension
Monlunabant – a cannabinoid CB1 receptor antagonist
Nadolol – a beta blocker (β-adrenergic receptor antagonist)
Naloxegol – a μ-opioid receptor antagonist used in the treatment of opioid-induced constipation
Nebicapone – a catechol-O-methyltransferase inhibitor for Parkinson's disease that was never marketed
Norepinephrine (noradrenaline) – a non-selective adrenergic receptor agonist
Ondansetron – a serotonin 5-HT3 receptor antagonist with some peripheral selectivity
Opicapone – a catechol-O-methyltransferase inhibitor used in combination with levodopa in the treatment of Parkinson's disease
Oxidopamine (6-hydroxydopamine; 6-OHDA) – a dopaminergic neurotoxin
Peptides and proteins (e.g., insulin, oxytocin, vasopressin, opioid peptides, growth factors, many others)
Phenylephrine – an α1-adrenergic receptor agonist used as a decongestant, to treat hypotension, and for other uses
Phenylpropanolamine – a norepinephrine releasing agent and indirectly acting sympathomimetic with some peripheral selectivity
Pirenzepine – an anticholinergic (acetylcholine receptor antagonist)
Pseudoephedrine – a norepinephrine releasing agent and indirectly acting sympathomimetic with some peripheral selectivity
Pyridostigmine – an acetylcholinesterase inhibitor and parasympathomimetic
Sarpogrelate a serotonin 5-HT2 receptor antagonist
Serotonin – a non-selective serotonin receptor agonist
Sotalol – a beta blocker (β-adrenergic receptor antagonist)
Terfenadine – a non-sedating antihistamine
Timepidium bromide – an anticholinergic (acetylcholine receptor antagonist)
Tolcapone – a catechol-O-methyltransferase inhibitor used in combination with levodopa in the treatment of Parkinson's disease
Trepipam – a dopamine D1 receptor agonist that was never marketed
Trimetaphan camsilate – a nicotinic acetylcholine receptor antagonist
Trospium chloride – an anticholinergic (acetylcholine receptor antagonist)
Tyramine – a norepinephrine–dopamine releasing agent and sympathomimetic agent
Vinblastine – a Vinca alkaloid and antineoplastic agent
VU0530244 – a selective serotonin 5-HT2B receptor antagonist
Xamoterol – a β1-adrenergic receptor partial agonist
Xanomeline/trospium chloride – a combination of a centrally active M1 and M4 receptor muscarinic acetylcholine receptor agonist (xanomeline) and a peripherally selective non-selective muscarinic acetylcholine receptor antagonist (trospium chloride) used to treat schizophrenia
Xylamidine – a serotonin 5-HT2A and 5-HT2C receptor antagonist
Zamicastat – a dopamine β-hydroxylase inhibitor developed as an antihypertensive agent
Zevaquenabant – a cannabinoid CB1 receptor antagonist
== References ==
== External links ==
Media related to Peripherally selective drugs at Wikimedia Commons | Wikipedia/Peripherally_selective_drug |
Ariadne, also known chemically as 4C-D or 4C-DOM, by its developmental code name BL-3912, and by its former tentative brand name Dimoxamine, is a little-known psychoactive drug of the phenethylamine, phenylisobutylamine, and 4C families. It is a homologue of the psychedelics 2C-D and DOM.
The drug is a serotonin receptor agonist, including of the serotonin 5-HT2A receptor. However, it is non-hallucinogenic in animals and humans, although it still has some psychoactive effects. It may be non-hallucinogenic due to lower-efficacy partial agonism of the serotonin 5-HT2A receptor.
Ariadne was developed by Alexander Shulgin. It was studied at Bristol Laboratories as an antidepressant and for various other uses but was never marketed. There has been renewed interest in Ariadne in the 2020s owing to increased interest in psychedelics for treatment of psychiatric disorders.
== Effects ==
In his 1991 book PiHKAL, Alexander Shulgin reported testing Ariadne on himself up to a dose of 32 mg, finding that it produced "the alert of a psychedelic, with none of the rest of the package". Very little published data exists about the human pharmacology of Ariadne apart from Shulgin's limited testing; unpublished human trials reportedly observed some psychoactive effects, but no hallucinations.
In his 2011 book The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds, Shulgin described (R)-Ariadne as increasing mental alertness and producing feelings of well-being at doses of 25 to 50 mg. It was claimed to improve symptoms of manic depression in psychotic individuals at doses of 50 to 100 mg and to improve symptoms of Parkinson's disease at a dosage of 100 mg/day. Doses of up to 300 mg resulted in an altered state of consciousness but still no psychedelic effects. For comparison, DOM shows psychoactive sub-hallucinogenic effects at doses of 1 to 3 mg and psychedelic effects at doses of more than 3 mg.
== Interactions ==
== Pharmacology ==
=== Pharmacodynamics ===
Ariadne is a potent and selective agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. However, it is less efficacious in activating the serotonin 5-HT2A receptor, including the Gq, G11, and β-arrestin2 signaling pathways, compared to the related drug DOM, and this weaker partial agonism may be responsible for its lack of psychedelic effects. In addition to the serotonin 5-HT2 receptors, Ariadne is a lower-affinity agonist of the serotonin 5-HT1 receptors. Ariadne shows essentially no activity at the monoamine transporters.
Ariadne shows a markedly attenuated head-twitch response, a behavioral proxy of psychedelic effects, in animals, although it does still significantly induce a weak head-twitch response. The drug substitutes for DOM in rodent drug discrimination tests, albeit with dramatically lower potency than DOx drugs like DOM itself, DOET, and DOB. It has also been shown to produce stimulus generalization in rats trained to respond to LSD and MDMA. Ariadne's capacity to fully substitute for MDMA is not shared with DOM and is unusual among psychedelics, but is shared with α-ethyltryptamine (αET). In monkeys, Ariadne was found to possibly increase motivation, as it caused monkeys that had stopped running mazes to begin running them again. Ariadne has also been found to be effective in an animal model of Parkinson's disease, where it reversed motor deficits similarly to levodopa.
Serotonin 5-HT2A receptor agonists have been found to increase dopamine levels in the nucleus accumbens and other mesolimbic areas and non-hallucinogenic serotonin 5-HT2A receptor agonists like Ariadne may do so without producing psychedelic effects. This action may underlie the preliminary observations of effectiveness of Ariadne in the treatment of parkinsonism in animals and humans.
It is thought that the reduced efficacy of Ariadne in activating the serotonin 5-HT2A receptor is responsible for its non-hallucinogenic nature in humans.
== Chemistry ==
Ariadne, also known as 4-methyl-2,5-dimethoxy-α-ethylphenethylamine, is a substituted phenethylamine and amphetamine derivative. It is the analogue of 2,5-dimethoxy-4-methylamphetamine (DOM) in which the α-methyl group has been replaced with an α-ethyl group and is the analogue of 2,5-dimethoxy-4-methylphenethylamine (2C-D) with an ethyl group substituted at the α carbon.
Ariadne's alternative name 4C-DOM or 4C-D stands for "four-carbon DOM", whereas the name of 2C-D stands for "two-carbon DOM". Another name of Ariadne is α-Et-2C-D, which stands for α-ethyl-2C-D. Racemic Ariadne is additionally known by the former developmental code name BL-3912, while the (R)-enantiomer of Ariadne is known by the former developmental code name BL-3912A.
Other related compounds include 4C-B (the α-ethyl homologue of 2C-B and DOB) and 4C-T-2 (the α-ethyl homologue of 2C-T-2 and Aleph-2).
== History ==
Ariadne was first synthesized by Alexander Shulgin. Shulgin reported that the drug was tested by Bristol Laboratories as an antidepressant, in an anecdote where he was explaining how human testing is invaluable (compared to animal testing) on drugs that change the state of the mind. He said, "Before they launched into a full multi-clinic study to determine whether it's going to be worth the animal studies or not, every person on the board of directors took it." In The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds (2011), he described it also being evaluated for increasing mental alertness in geriatric individuals, treating Parkinson's disease, and treating psychosis and manic depression. The tentative commercial name of Ariadne was Dimoxamine. (R)-Ariadne was said to have completed phase 2 clinical trials, but the actual clinical data were never disclosed and further development was halted due to strategic economic reasons.
== See also ==
ASR-2001
BMB-201
DOET
ITI-1549
Zalsupindole
== References ==
== External links ==
4C-D (ARIADNE) - Isomer Design
Ariadne Experience Reports - Erowid
The Small & Handy 4C-D Ariadne Thread - Bluelight
ARIADNE - PiHKAL - Erowid
ARIADNE - PiHKAL - Isomer Design | Wikipedia/Ariadne_(drug) |
Antimony potassium tartrate, also known as potassium antimonyl tartrate, potassium antimontarterate, or tartar emetic, has the formula K2Sb2(C4H2O6)2. The compound has long been known as a powerful emetic, and was used in the treatment of schistosomiasis and leishmaniasis. It is used as a resolving agent. It typically is obtained as a hydrate.
== Medical ==
The first treatment application against trypanosomiasis was tested in 1906, and the compound's use to treat other tropical diseases was researched. The treatment of leishmania with antimony potassium tartrate started in 1913. After the introduction of antimony(V) containing complexes like sodium stibogluconate and meglumine antimoniate, the use of antimony potassium tartrate was phased out. After British physician John Brian Christopherson's discovery in 1918 that antimony potassium tartrate could cure schistosomiasis, the antimonial drugs became widely used. However, the injection of antimony potassium tartrate had severe side effects such as Adams–Stokes syndrome and therefore alternative substances were under investigation. With the introduction and subsequent larger use of praziquantel in the 1970s, antimony-based treatments fell out of use.
Tartar emetic was used in the late 19th and early 20th century in patent medicine as a remedy for alcohol intoxication, and was first ruled ineffective in the United States in 1941, in United States v. 11 1/4 Dozen Packages of Articles Labeled in Part Mrs. Moffat's Shoo-Fly Powders for Drunkenness.
The New England Journal of Medicine reported a case study of a patient whose wife secretly gave him a dose of a product called "tartaro emetico" which contained trivalent antimony (antimony potassium tartrate) and is sold in Central America as an aversive treatment for alcohol use disorder. The patient, who had been out drinking the night before, developed persistent vomiting shortly after being given orange juice with the drug. When admitted to the hospital, and later in the intensive care unit, he experienced severe chest pains, cardiac abnormalities, renal and hepatic toxicity, and nearly died. The Journal reports that "Two years later, he [the patient] reports complete abstinence from alcohol."
=== Emetic ===
Antimony potassium tartrate's potential as an emetic has been known since the Middle Ages. The compound itself was considered toxic and therefore a different way to administer it was found. Cups made from pure antimony were used to store wine for 24 hours and then the resulting solution of antimony potassium tartrate in wine was consumed in small portions until the wanted emetic effect was reached.
Poisoning by "tartarised antimony" or "emetic tartar" is a plot device in the first modern detective novel, The Notting Hill Mystery (1862). The emetic tartar was kept by a character in the novel because he was "addicted to the pleasures of the table, and was in the habit of taking an occasional emetic."
The compound is still used to induce vomiting in captured animals in order to study their diets.
=== Insecticide ===
Antimony potassium tartrate is used as an insecticide against thrips. It is in IRAC class 8E.
== Preparation, structure, reactions ==
Antimony potassium tartrate is prepared by treating a solution of potassium hydrogen tartrate and antimony trioxide:
2 KOH + Sb2O3 + (HOCHCO2H)2 → K2Sb2(C4H2O6)2 + 3 H2O
With an excess of tartaric acid, the monoanionic monoantimony salt is produced:
2 KOH + Sb2O3 + 4 (HOCHCO2H)2 → 2 KSb(C4H2O6)2 + 2 H2O
Antimony potassium tartrate has been the subject of several X-ray crystallography studies.
The core complex is an anionic dimer of antimony tartrate (Sb2(C4H2O6)22-) which is arranged in a large ring with the carbonyl groups pointing outwards. The complex has D2 molecular symmetry with two Sb(III) centers bonded in distorted square pyramids. Water and potassium ions are held within the unit cell but are not tightly bound to the dimer. The anion is a well-used resolving agent.
== Further reading ==
Of historic interest:
Frederick, George Mann (1952). Practical organic chemistry. England: Longmans, Green & Co. p. 115. ISBN 0-582-44407-1. {{cite book}}: ISBN / Date incompatibility (help)
Knapp, Fr. (1839). "Zur Bildungsgeschichte des Brechweinsteins". Annalen der Pharmacie. 32: 76–85. doi:10.1002/jlac.18390320107.
== References ==
== Further reading ==
Priesner, Claus (1997). "Basilius Valentinus und die Labortechnik um 1600". Berichte zur Wissenschaftsgeschichte. 20 (2–3): 159–172. doi:10.1002/bewi.19970200205. S2CID 170226309.
Geoffroy, M.; Stack, T. (1751). "Observations on the Effects of the Vitrum Antimonii Ceratum, by Mons. Geoffroy, of the Royal Academy of Sciences, and F. R. S. Translated from the French by Tho. Stack, M. D. F. R. S". Philosophical Transactions. 47: 273–278. doi:10.1098/rstl.1751.0042. JSTOR 105054. S2CID 186212284.
Berzelius, Jöns Jacob (1824). Lehrbuch der Chemie.
Copus, Martinus (1569). Das Spißglas in ein Glas gegossen, das man Vitrum Antimonii nennt, ein wahrhafftige Gift vnd gantzgeferliche Artzney sey.
The Technologist. 1861.
"Captain Cook's Antimony Cup" (PDF). Vesalius, VII, 2: 62–64. 2001.
Schneider, R. (1859). "Ueber einige Antimon-Verbindungen". Annalen der Physik und Chemie. 184 (11): 407–415. Bibcode:1859AnP...184..407S. doi:10.1002/andp.18591841104.
Groschuff, E. (1918). "Reines Antimon". Zeitschrift für anorganische und allgemeine Chemie. 103: 164–188. doi:10.1002/zaac.19181030109.
Soubeiran, E.; Capitaine, H. (1840). "Zur Geschichte der Weinsteinsäure". Journal für Praktische Chemie. 19: 435–442. doi:10.1002/prac.18400190171.
Pfaff, C. H. (1838). "Ueber Antimon-Wasserstoffgas und die davon abhängige Unsicherheit des von James Marsh entdeckten Verfahrens zur Entdeckung des Arseniks". Archiv der Pharmazie. 64 (2): 169–174. doi:10.1002/ardp.18380640215. S2CID 84920753.
Zimmermann, E. (1930). "Das Antimon in der Chemotherapie". Klinische Wochenschrift. 9: 27–31. doi:10.1007/BF01740712. S2CID 43264526.
Gress, Mary E.; Jacobson, Robert A. (1974). "X-ray and white radiation neutron diffraction studies of optically active potassium antimony tartrate, K2Sb2(d-C4H2O6)2·3H2O (tarter emetic)". Inorganica Chimica Acta. 8: 209–217. doi:10.1016/S0020-1693(00)92617-3. | Wikipedia/Antimony_potassium_tartrate |
Translational research (also called translation research, translational science, or, when the context is clear, simply translation) is research aimed at translating (converting) results in basic research into results that directly benefit humans. The term is used in science and technology, especially in biology and medical science. As such, translational research forms a subset of applied research.
The term has been used most commonly in life sciences and biotechnology, but applies across the spectrum of science and humanities. In the context of biomedicine, translational research is also known as bench to bedside. In the field of education, it is defined as research which translates concepts to classroom practice.
Critics of translational medical research (to the exclusion of more basic research) point to examples of important drugs that arose from fortuitous discoveries in the course of basic research such as penicillin and benzodiazepines. Other problems have stemmed from the widespread irreproducibility thought to exist in translational research literature.
Although translational research is relatively new, there are now several major research centers focused on it. In the U.S., the National Institutes of Health has implemented a major national initiative to leverage existing academic health center infrastructure through the Clinical and Translational Science Awards. Furthermore, some universities acknowledge translational research as its own field in which to study for a PhD or graduate certificate.
== Definitions ==
Translational research is aimed at solving particular problems; the term has been used most commonly in life sciences and biotechnology, but applies across the spectrum of science and humanities.
In the field of education, it is defined for school-based education by the Education Futures Collaboration (www.meshguides.org) as research which translates concepts to classroom practice. Examples of translational research are commonly found in education subject association journals and in the MESHGuides which have been designed for this purpose.
In bioscience, translational research is a term often used interchangeably with translational medicine or translational science or bench to bedside. The adjective "translational" refers to the "translation" (the term derives from the Latin for "carrying over") of basic scientific findings in a laboratory setting into potential treatments for disease.
Biomedical translational research adopts a scientific investigation/enquiry into a given problem facing medical/health practices: it aims to "translate" findings in fundamental research into practice. In the field of biomedicine, it is often called "translational medicine", defined by the European Society for Translational Medicine (EUSTM) as "an interdisciplinary branch of the biomedical field supported by three main pillars: benchside, bedside and community", from laboratory experiments through clinical trials, to therapies, to point-of-care patient applications. The end point of translational research in medicine is the production of a promising new treatment that can be used clinically. Translational research is conceived due to the elongated time often taken to bring to bear discovered medical idea in practical terms in a health system. It is for these reasons that translational research is more effective in dedicated university science departments or isolated, dedicated research centers. Since 2009, the field has had specialized journals, the American Journal of Translational Research and Translational Research dedicated to translational research and its findings.
Translational research in biomedicine is broken down into different stages. In a two-stage model, T1 research, refers to the "bench-to-bedside" enterprise of translating knowledge from the basic sciences into the development of new treatments and T2 research refers to translating the findings from clinical trials into everyday practice, although this model is actually referring to the 2 "roadblocks" T1 and T2. Waldman et al. propose a scheme going from T0 to T5. T0 is laboratory (before human) research. In T1-translation, new laboratory discoveries are first translated to human application, which includes phase I & II clinical trials. In T2-translation, candidate health applications progress through clinical development to engender the evidence base for integration into clinical practice guidelines. This includes phase III clinical trials. In T3-translation, dissemination into community practices happens. T4-translation seeks to (1) advance scientific knowledge to paradigms of disease prevention, and (2) move health practices established in T3 into population health impact. Finally, T5-translation focuses on improving the wellness of populations by reforming suboptimal social structures
== Comparison to basic research or applied research ==
Basic research is the systematic study directed toward greater knowledge or understanding of the fundamental aspects of phenomena and is performed without thought of practical ends. It results in general knowledge and understanding of nature and its laws. For instance, basic biomedical research focuses on studies of disease processes using, for example, cell cultures or animal models without consideration of the potential utility of that information.
Applied research is a form of systematic inquiry involving the practical application of science. It accesses and uses the research communities' accumulated theories, knowledge, methods, and techniques, for a specific, often stated, business, or client-driven purpose. Translational research forms a subset of applied research. In life-sciences, this was evidenced by a citation pattern between the applied and basic sides in cancer research that appeared around 2000. In fields such as psychology, translational research is seen as a bridging between applied research and basic research types. The field of psychology defines translational research as the use of basic research to develop and test applications, such as treatment.
== Challenges and criticisms ==
Critics of translational medical research (to the exclusion of more basic research) point to examples of important drugs that arose from fortuitous discoveries in the course of basic research such as penicillin and benzodiazepines, and the importance of basic research in improving our understanding of basic biological facts (e.g. the function and structure of DNA) that go on to transform applied medical research. Examples of failed translational research in the pharmaceutical industry include the failure of anti-aβ therapeutics in Alzheimer's disease. Other problems have stemmed from the widespread irreproducibility thought to exist in translational research literature.
== Translational research-facilities in life-sciences ==
In U.S., the National Institutes of Health has implemented a major national initiative to leverage existing academic health center infrastructure through the Clinical and Translational Science Awards.
The National Center for Advancing Translational Sciences (NCATS) was established on December 23, 2011.
Although translational research is relatively new, it is being recognized and embraced globally. Some major centers for translational research include:
About 60 hubs of the Clinical and Translational Science Awards program.
Texas Medical Center, Houston, Texas, United States
Translational Research Institute (Australia), Brisbane, Queensland, Australia.
University of Rochester, Rochester, New York, United States has a dedicated Clinical and Translational Science Institute
Stanford University Medical Center, Stanford, California, United States.
Translational Genomics Research Institute, Phoenix, Arizona, United States.
Maine Medical Center in Portland, Maine, United States has a dedicated translational research institute.
Scripps Research Institute, Florida, United States, has a dedicated translational research institute.
UC Davis Clinical and Translational Science Center, Sacramento, California
Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
Weill Cornell Medicine has a Clinical and Translational Science Center.
Hansjörg Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, Massachusetts, United States.
Additionally, translational research is now acknowledged by some universities as a dedicated field to study a PhD or graduate certificate in, in a medical context. These institutes currently include Monash University in Victoria, Australia, the University of Queensland, Diamantina Institute in Brisbane, Australia, at Duke University in Durham, North Carolina, America, at Creighton University in Omaha, Nebraska at Emory University in Atlanta, Georgia, and at The George Washington University in Washington, D.C.
The industry and academic interactions to promote translational science initiatives has been carried out by various global centers such as European Commission, GlaxoSmithKline and Novartis Institute for Biomedical Research.
== See also ==
Biological engineering
Clinical and Translational Science (journal)
Clinical trials
Implementation research
Personalized medicine
Systems biology
Translational research informatics
Research practice gap (Knowledge transfer)
== References ==
== External links ==
Translational Research Institute
NIH Roadmap
American Journal of Translational Research
Center for Comparative Medicine and Translational Research
OSCAT2012: Conference on translational medicine | Wikipedia/Translational_science |
In a nosological sense, the term phenotype can be used in clinical medicine for speaking about the presentation of a disease. The complementary concept in this regard is endotype, which refers to the pathogenesis of the disease ignoring its presentation.
In this context, a phenotype would be any observable characteristic or trait of a disease, such as morphology, development, biochemical or physiological properties, or behavior, without any implication of a mechanism. A clinical phenotype would be the presentation of a disease in a given individual.
Some organizations have their own specialised meaning. For example, the term 'phenotype' in the field of chronic obstructive pulmonary disease (COPD) means "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes", but nearly all specialities use this meaning in some way, like in asthma research.
== Etymology ==
The word phenotype comes from Greek phainein 'to show' and typos 'type'. Normally it refers to the presentation of a trait in an individual, but in this case it means the presentation of a disease entity.
== See also ==
Clinical case definition
Clinical disease
Component causes
Heterogeneous condition
Syndrome
== References == | Wikipedia/Phenotype_(clinical_medicine) |
Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy is a monthly peer-reviewed medical journal covering human pharmacology and pharmacotherapy, published by Wiley-Blackwell on behalf of the American College of Clinical Pharmacy, of which it is an official journal. It was established in 1981 under founding editor-in-chief Russel R. Miller. The second editor was Richard T. Scheife. The third and current editor is C. Lindsay DeVane. Initially published six times a year the journal has been a monthly since 1991.
== Abstracting and indexing ==
The journal is abstracted and indexed in:
According to the Journal Citation Reports, the journal has a 2021 impact factor of 6.251, ranking it 44th out of 279 journals in the category "Pharmacology & Pharmacy".
== References ==
== Further reading ==
DeVane, CL (January 2013). "Celebrating 32 years of Pharmacotherapy". Pharmacotherapy. 33 (1): 1–2. doi:10.1002/phar.1245.
Scheife, RT (April 2009). "A ghost in the machine". Pharmacotherapy. 29 (4): 363–4. doi:10.1592/phco.29.4.363. PMID 19323615. S2CID 207884725.
Scheife, RT (February 2006). "Higher, faster, farther". Pharmacotherapy. 26 (2): 151–3. doi:10.1592/phco.26.2.151.
Miller, WA (October 2001). "The value and influence of Pharmacotherapy to the advancement of clinical pharmacology and pharmacotherapy". Pharmacotherapy. 21 (10): 1153–6. doi:10.1592/phco.21.15.1153.33887. PMID 11601659. S2CID 31657087.
Miller, RR (May–June 1983). "Status report on Pharmacotherapy". Pharmacotherapy. 3 (3): 135–6. doi:10.1002/j.1875-9114.1983.tb03236.x. S2CID 71098800.
Miller, RR (July–August 1981). "A new journal". Pharmacotherapy. 1 (1): 1–2. doi:10.1002/j.1875-9114.1981.tb03545.x.
== External links ==
Official website
American College of Clinical Pharmacy | Wikipedia/Pharmacotherapy_(journal) |
Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.
In clinical use, neuromuscular block is used adjunctively to anesthesia to produce paralysis, firstly to paralyze the vocal cords, and permit endotracheal intubation, and secondly to optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.
This class of medications helps to reduce patient movement, breathing, or ventilator dyssynchrony and allows lower insufflation pressures during laparoscopy. It has several indications for use in the intense care unit. It can help reduce hoarseness in voice as well as injury to the vocal cord during intubation. In addition, it plays an important role in facilitating mechanical ventilation in patients with poor lung function.
Patients are still aware of pain even after full conduction block has occurred; hence, general anesthetics and/or analgesics must also be given to prevent anesthesia awareness.
== Nomenclature ==
Neuromuscular blocking drugs are often classified into two broad classes:
Pachycurares, which are bulky molecules with nondepolarizing activity
Leptocurares, which are thin and flexible molecules that tend to have depolarizing activity.
It is also common to classify them based on their chemical structure.
Acetylcholine, suxamethonium, and decamethonium
Suxamethonium was synthesised by connecting two acetylcholine molecules and has the same number of heavy atoms between methonium heads as decamethonium. Just like acetylcholine, succinylcholine, decamethonium and other polymethylene chains, of the appropriate length and with two methonium, heads have small trimethyl onium heads and flexible links. They all exhibit a depolarizing block.
Aminosteroids
Pancuronium, vecuronium, rocuronium, rapacuronium, dacuronium, malouètine, dihydrochandonium, dipyrandium, pipecuronium, chandonium (HS-310), HS-342 and other HS- compounds are aminosteroidal agents. They have in common the steroid structural base, which provides a rigid and bulky body. Most of the agents in this category would also be classified as non-depolarizing.
Tetrahydroisoquinoline derivatives
Compounds based on the tetrahydroisoquinoline moiety such as atracurium, mivacurium, and doxacurium would fall in this category. They have a long and flexible chain between the onium heads, except for the double bond of mivacurium. D-tubocurarine and dimethyltubocurarine are also in this category. Most of the agents in this category would be classified as non-depolarizing.
Gallamine and other chemical classes
Gallamine is a trisquaternary ether with three ethonium heads attached to a phenyl ring through an ether linkage. Many other different structures have been used for their muscle relaxant effect such as alcuronium (alloferin), anatruxonium, diadonium, fazadinium (AH8165) and tropeinium.
Novel NMB agents
In recent years much research has been devoted to new types of quaternary ammonium muscle relaxants. These are asymmetrical diester isoquinolinium compounds and bis-benzyltropinium compounds that are bistropinium salts of various diacids. These classes have been developed to create muscle relaxants that are faster and shorter acting. Both the asymmetric structure of diester isoquinolinium compounds and the acyloxylated benzyl groups on the bisbenzyltropiniums destabilizes them and can lead to spontaneous breakdown and therefore possibly a shorter duration of action.
== Classification ==
These drugs fall into two groups:
Non-depolarizing blocking agents: These agents constitute the majority of the clinically relevant neuromuscular blockers. They act by competitively blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors.
Depolarizing blocking agents: These agents act by depolarizing the sarcolemma of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.
=== Non-depolarizing blocking agents ===
A neuromuscular non-depolarizing agent is a form of neuromuscular blocker that does not depolarize the motor end plate.
The quaternary ammonium muscle relaxants belong to this class. Quaternary ammonium muscle relaxants are quaternary ammonium salts used as drugs for muscle relaxation, most commonly in anesthesia. It is necessary to prevent spontaneous movement of muscle during surgical operations. Muscle relaxants inhibit neuron transmission to muscle by blocking the nicotinic acetylcholine receptor. What they have in common, and is necessary for their effect, is the structural presence of quaternary ammonium groups, usually two. Some of them are found in nature and others are synthesized molecules.
Below are some more common agents that act as competitive antagonists against acetylcholine at the site of postsynaptic acetylcholine receptors.
Tubocurarine, found in curare of the South American plant Pareira, Chondrodendron tomentosum, is the prototypical non-depolarizing neuromuscular blocker. It has a slow onset (<5 min) and a long duration of action (30 mins). Side-effects include hypotension, which is partially explained by its effect of increasing histamine release, a vasodilator, as well as its effect of blocking autonomic ganglia. It is excreted in the urine.
This drug needs to block about 70–80% of the ACh receptors for neuromuscular conduction to fail, and hence for effective blockade to occur. At this stage, end-plate potentials (EPPs) can still be detected, but are too small to reach the threshold potential needed for activation of muscle fiber contraction.
The speed of onset depends on the potency of the drug, greater potency is associated with slower onset of block. Rocuronium, with an ED95 of 0.3 mg/kg IV has a more rapid onset than Vecuronium with an ED95 of 0.05mg/kg. Steroidal compounds, such as rocuronium and vecuronium, are intermediate-acting drugs while Pancuronium and pipecuronium are long-acting drugs.
In larger clinical dose, some of the blocking agent can access the pore of the ion channel and cause blockage. This weakens neuromuscular transmission and diminishes the effect of acetylcholinesterase inhibitors (e.g. neostigmine). Nondepolarizing NBAs may also block prejunctional sodium channels which interfere with the mobilization of acetylcholine at the nerve ending.
=== Depolarizing blocking agents ===
A depolarizing neuromuscular blocking agent is a form of neuromuscular blocker that depolarizes the motor end plate. An example is succinylcholine. Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.
These agents have two phases of block with notably different characteristics. During phase I (depolarizing phase), succinylcholine interacts with nicotinic receptor to open the channel and cause depolarization of the end plate, which later spread to and result in depolarization of adjacent membranes. As a result, there is a disorganised contraction of muscle motor unit. This causes muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. The muscle fiber is then held in a partially depolarised state leading to relaxation.
Further administration of the agent leads to phase II block which has a similar clinical behaviour to non-depolarising blocking agents. Phase II block is characterised by complete membrane repolarisation however there is still ongoing neuromuscular blockade, the mechanism of phase II block is not fully understood. Phase I block effect is increased by cholinesterase inhibitors as increase in acetylcholine levels leads to deepening of the phase I block due to the membrane potential being pushed further away from repolarisation, however in phase II block cholinesterase inhibitors inhibit the block.
The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the only such drug used clinically. It has a rapid onset (30 seconds) but very short duration of action (5–10 minutes) because of hydrolysis by various cholinesterases (such as butyrylcholinesterase in the blood). The patient will experience fasciculation due to the depolarisation of muscle neurone fibres and seconds later, flaccid paralysis will occur. Succinylcholine was originally known as diacetylcholine because structurally it is composed of two acetylcholine molecules joined with a methyl group. Decamethonium is sometimes, but rarely, used in clinical practice.
It is indicated for rapid sequence intubation.
==== Dosing/onset of action ====
IV dose 1-1.5mg/kg or 3 to 5 x ED95
Paralysis occurs in one to two minutes.
Clinical duration of action (time from drug administration to recovery of single twich to 25% of baseline) is 7-12 minutes.
If IV access is unavailable, intramuscular administration 3-4mg/kg. Paralysis occurs at 4 minutes.
Use of succinylcholine infusion or repeated bolus administration increase the risk of Phase II block and prolonged paralysis. Phase II block occurs after large doses (>4mg/kg). This occurs when the post-synaptic membrane action potential returns to baseline in spite of the presence of succinylcholine and causes continued activation of nicotinic acetylcholine receptors.
=== Comparison of drugs ===
The main difference is in the reversal of these two types of neuromuscular-blocking drugs.
Non-depolarizing blockers are reversed by acetylcholinesterase inhibitor drugs since non-depolarizing blockers are competitive antagonists at the ACh receptor so can be reversed by increases in ACh.
The depolarizing blockers already have ACh-like actions, so these agents have prolonged effect under the influence of acetylcholinesterase inhibitors. Administration of depolarizing blockers initially produces fasciculations (a sudden twitch just before paralysis occurs). This is due to depolarization of the muscle. Also, post-operative pain is associated with depolarizing blockers.
The tetanic fade is the failure of muscles to maintain a fused tetany at sufficiently high frequencies of electrical stimulation.
Non-depolarizing blockers have this effect on patients, probably by an effect on presynaptic receptors.
Depolarizing blockers do not cause the tetanic fade. However, a clinically similar manifestation called Phase II block occurs with repeated doses of suxamethonium.
This discrepancy is diagnostically useful in case of intoxication of an unknown neuromuscular-blocking drug.
== Physiology at the Neuromuscular Junction ==
Neuromuscular blocking agents exert their effect by modulating the signal transmission in skeletal muscles. An action potential is, in other words, a depolarisation in neurone membrane due to a change in membrane potential greater than the threshold potential leads to an electrical impulse generation. The electrical impulse travels along the pre-synaptic neurone axon to synapse with the muscle at the neuromuscular junction (NMJ) to cause muscle contraction.
When the action potential reaches the axon terminal, it triggers the opening of the calcium ion gated channels, which causes the influx of Ca2+. Ca2+ will stimulate the release of neurotransmitter in the neurotransmitter containing vesicles by exocytosis (vesicle fuses with the pre-synpatic membrane).
The neurotransmitter, acetylcholine(ACh) binds to the nicotinic receptors on the motor end plate, which is a specialised area of the muscle fibre's post-synaptic membrane. This binding causes the nicotinic receptor channels to open and allow the influx of Na+ into the muscle fibre.
Fifty percent of the released ACh is hydrolysed by acetylcholinesterase (AChE) and the remaining bind to the nicotinic receptors on the motor end plate. When ACh is degraded by AChE, the receptors are no longer stimulated and the muscle cannot be depolarized.
If enough Na+ enter the muscle fibre, it causes an increase in the membrane potential from its resting potential of -95mV to -50mV (above the threshold potential -55mV) which causes an action potential to spread throughout the fibre. This potential travels along the surface of the sarcolemma. The sarcolemma is an excitable membrane that surrounds the contractile structures known as myofibrils that are located deep in the muscle fibre. For the action potential to reach the myofibrils, the action potential travels along the transverse tubules (T-tubules) that connects the sarcolemma and center of the fibre.
Later, action potential reaches the sarcoplasmic reticulum which stores the Ca2+ needed for muscle contraction and causes Ca2+ to be released from the sarcoplasmic reticulum.
== Mechanism of action ==
Quaternary muscle relaxants bind to the nicotinic acetylcholine receptor and inhibit or interfere with the binding and effect of ACh to the receptor. Each ACh-receptor has two receptive sites and activation of the receptor requires binding to both of them. Each receptor site is located at one of the two α-subunits of the receptor. Each receptive site has two subsites, an anionic site that binds to the cationic ammonium head and a site that binds to the blocking agent by donating a hydrogen bond.
Non-depolarizing agents
A decrease in binding of acetylcholine leads to a decrease in its effect and neuron transmission to the muscle is less likely to occur. It is generally accepted that non-depolarizing agents block by acting as reversible competitive inhibitors. That is, they bind to the receptor as antagonists and that leaves fewer receptors available for acetylcholine to bind.
Depolarizing agents
Depolarizing agents produce their block by binding to and activating the ACh receptor, at first causing muscle contraction, then paralysis. They bind to the receptor and cause depolarization by opening channels just like acetylcholine does. This causes repetitive excitation that lasts longer than a normal acetylcholine excitation and is most likely explained by the resistance of depolarizing agents to the enzyme acetylcholinesterase. The constant depolarization and triggering of the receptors keeps the endplate resistant to activation by acetylcholine. Therefore, a normal neuron transmission to muscle cannot cause contraction of the muscle because the endplate is depolarized and thereby the muscle paralysed.
Binding to the nicotinic receptor
Shorter molecules like acetylcholine need two molecules to activate the receptor, one at each receptive site. Decamethonium congeners, which prefer straight line conformations (their lowest energy state), usually span the two receptive sites with one molecule (binding inter-site). Longer congeners must bend when fitting receptive sites.
The greater energy a molecule needs to bend and fit usually results in lower potency.
== Structural and conformational action relationship ==
Conformational study on neuromuscular blocking drugs is relatively new and developing. Traditional SAR studies do not specify environmental factors on molecules. Computer-based conformational searches assume that the molecules are in vacuo, which is not the case in vivo. Solvation models take into account the effect of a solvent on the conformation of the molecule. However, no system of solvation can mimic the effect of the complex fluid composition of the body.
The division of muscle relaxants to rigid and non-rigid is at most qualitative. The energy required for conformational changes may give a more precise and quantitative picture. Energy required for reducing onium head distance in the longer muscle relaxant chains may quantify their ability to bend and fit its receptive sites. Using computers it is possible to calculate the lowest energy state conformer and thus most populated and best representing the molecule. This state is referred to as the global minimum. The global minimum for some simple molecules can be discovered quite easily with certainty. Such as for decamethonium the straight line conformer is clearly the lowest energy state. Some molecules, on the other hand, have many rotatable bonds and their global minimum can only be approximated.
=== Molecular length and rigidity ===
Neuromuscular blocking agents need to fit in a space close to 2 nanometres, which resembles the molecular length of decamethonium. Some molecules of decamethonium congeners may bind only to one receptive site. Flexible molecules have a greater chance of fitting receptive sites. However, the most populated conformation may not be the best-fitted one. Very flexible molecules are, in fact, weak neuromuscular inhibitors with flat dose-response curves. On the other hand, stiff or rigid molecules tend to fit well or not at all. If the lowest-energy conformation fits, the compound has high potency because there is a great concentration of molecules close to the lowest-energy conformation. Molecules can be thin but yet rigid. Decamethonium for example needs relatively high energy to change the N-N distance.
In general, molecular rigidity contributes to potency, while size affects whether a muscle relaxant shows a polarizing or a depolarizing effect. Cations must be able to flow through the trans-membrane tube of the ion-channel to depolarize the endplate. Small molecules may be rigid and potent but unable to occupy or block the area between the receptive sites. Large molecules, on the other hand, may bind to both receptive sites and hinder depolarizing cations independent of whether the ion-channel is open or closed below. Having a lipophilic surface pointed towards the synapse enhances this effect by repelling cations. The importance of this effect varies between different muscle relaxants and classifying depolarizing from non-depolarizing blocks is a complex issue. The onium heads are usually kept small and the chains connecting the heads usually keep the N-N distance at 10 N or O atoms. Keeping the distance in mind the structure of the chain can vary (double bonded, cyclohexyl, benzyl, etc.)
Succinylcholine has a 10-atom distance between its N atoms, like decamethonium. Yet it has been reported that it takes two molecules, as with acetylcholine, to open one nicotinic ion channel. The conformational explanation for this is that each acetylcholine moiety of succinylcholine prefers the gauche (bent, cis) state. The attraction between the N and O atoms is greater than the onium head repulsion. In this most populated state, the N-N distance is shorter than the optimal distance of ten carbon atoms and too short to occupy both receptive sites. This similarity between succinyl- and acetyl-choline also explains its acetylcholine-like side-effects.
Comparing molecular lengths, the pachycurares dimethyltubocurarine and d-tubocurarine both are very rigid and measure close to 1.8 nm in total length. Pancuronium and vecuronium measure 1.9 nm, whereas pipecuronium is 2.1 nm. The potency of these compounds follows the same rank of order as their length. Likewise, the leptocurares prefer a similar length. Decamethonium, which measures 2 nm, is the most potent in its category, whereas C11 is slightly too long. Gallamine despite having low bulk and rigidity is the most potent in its class, and it measures 1.9 nm. Based on this information one can conclude that the optimum length for neuromuscular blocking agents, depolarizing or not, should be 2 to 2.1 nm.
The CAR for long-chain bisquaternary tetrahydroisoquinolines like atracurium, cisatracurium, mivacurium, and doxacurium is hard to determine because of their bulky onium heads and large number of rotatable bonds and groups. These agents must follow the same receptive topology as others, which means that they do not fit between the receptive sites without bending. Mivacurium for example has a molecular length of 3.6 nm when stretched out, far from the 2 to 2.1 nm optimum. Mivacurium, atracurium, and doxacurium have greater N-N distance and molecular length than d-tubocurarine even when bent. To make them fit, they have flexible connections that give their onium heads a chance to position themselves beneficially. This bent N-N scenario probably does not apply to laudexium and decamethylene bisatropium, which prefer a straight conformation.
=== Beers and Reich's law ===
It has been concluded that acetylcholine and related compounds must be in the gauche (bent) configuration when bound to the nicotinic receptor. Beers and Reich's studies on cholinergic receptors in 1970 showed a relationship affecting whether a compound was muscarinic or nicotinic. They showed that the distance from the centre of the quaternary N atom to the van der Waals extension of the respective O atom (or an equivalent H-bond acceptor) is a determining factor. If the distance is 0.44 nm, the compound shows muscarinic properties—and if the distance is 0.59 nm, nicotinic properties dominate.)
=== Rational design ===
Pancuronium remains one of the few muscle relaxants logically and rationally designed from structure-action / effects relationship data. A steroid skeleton was chosen because of its appropriate size and rigidness. Acetylcholine moieties were inserted to increase receptor affinity. Although having many unwanted side-effects, a slow onset of action and recovery rate it was a big success and at the time the most potent neuromuscular drug available. Pancuronium and some other neuromuscular blocking agents block M2-receptors and therefore affect the vagus nerve, leading to hypotension and tachycardia. This muscarinic blocking effect is related to the acetylcholine moiety on the A ring on pancuronium. Making the N atom on the A ring tertiary, the ring loses its acetylcholine moiety, and the resulting compound, vecuronium, has nearly 100 times less affinity to muscarin receptors while maintaining its nicotinic affinity and a similar duration of action. Vecuronium is, therefore, free from cardiovascular effects. The D ring shows excellent properties validating Beers and Reich's rule with great precision. As a result, vecuronium has the greatest potency and specificity of all mono-quaternary compounds.
=== Potency ===
Two functional groups contribute significantly to aminosteroidal neuromuscular blocking potency, it is presumed to enable them to bind the receptor at two points. A bis-quaternary two point arrangement on A and D-ring (binding inter-site) or a D-ring acetylcholine moiety (binding at two points intra-site) are most likely to succeed. A third group can have variable effects. The quaternary and acetyl groups on the A and D ring of pipecuronium prevent it from binding intra-site (binding to two points at the same site). Instead, it must bind as bis-quaternary (inter-site). These structures are very dissimilar from acetylcholine and free pipecuronium from nicotinic or muscarinic side-effects linked to acetylcholine moiety. Also, they protect the molecule from hydrolysis by cholinesterases, which explain its nature of kidney excretion. The four methyl-groups on the quaternary N atoms make it less lipophilic than most aminosteroids. This also affects pipecuroniums metabolism by resisting hepatic uptake, metabolism, and biliary excretion. The length of the molecule (2.1 nm, close to ideal) and its rigidness make pipecuronium the most potent and clean one-bulk bis-quaternary. Even though the N-N distance (1.6 nm) is far away from what is considered ideal, its onium heads are well-exposed, and the quaternary groups help to bring together the onium heads to the anionic centers of the receptors without chirality issues.
Adding more than two onium heads in general does not add to potency. Though the third onium head in gallamine seems to help position the two outside heads near the optimum molecular length, it can interfere unfavorably and gallamine turns out to be a weak muscle relaxant, like all multi-quaternary compounds.
Considering acetylcholine a quaternizing group larger than methyl and an acyl group larger than acetyl would reduce the molecule's potency. The charged N and the carbonyl O atoms are distanced from structures they bind to on receptive sites and, thus, decrease potency. The carbonyl O in vecuronium for example is thrust outward to appose the H-bond donor of the receptive site. This also helps explain why gallamine, rocuronium, and rapacuronium are of relatively low potency.
In general, methyl quaternization is optimal for potency but, opposing this rule, the trimethyl derivatives of gallamine are of lower potency than gallamine. The reason for this is that gallamine has a suboptimal N-N distance. Substituting the ethyl groups with methyl groups would make the molecular length also shorter than optimal. Methoxylation of tetrahydroisoquinolinium agents seems to improve their potency. How methoxylation improves potency is still unclear.
Histamine release is a common attribute of benzylisoquinolinium muscle relaxants. This problem generally decreases with increased potency and smaller doses. The need for larger doses increases the degree of this side-effect. Conformational or structural explanations for histamine release are not clear.
== Pharmacokinetics ==
Metabolism and Hofmann elimination
Deacetylating vecuronium at position 3 results in a very active metabolite. In the case of rapacuronium the 3-deacylated metabolite is even more potent than rapacuronium. As long as the D-ring acetylcholine moiety is unchanged they retain their muscle relaxing effect. Mono-quaternary aminosteroids produced with deacylation in position 17 on the other hand are generally weak muscle relaxants. In the development of atracurium the main idea was to make use of Hofmann elimination of the muscle relaxant in vivo. When working with bisbenzyl-isoquinolinium types of molecules, inserting proper features into the molecule such as an appropriate electron withdrawing group then Hofmann elimination should occur at conditions in vivo. Atracurium, the resulting molecule, breaks down spontaneously in the body to inactive compounds and being especially useful in patients with kidney or liver failure. Cis-atracurium is very similar to atracurium except it is more potent and has a weaker tendency to cause histamine release.
Structure relations to onset time
The effect of structure on the onset of action is not very well known except that the time of onset appears inversely related to potency. In general mono-quaternary aminosteroids are faster than bis-quaternary compounds, which means they are also of lower potency. A possible explanation for this effect is that drug delivery and receptor binding are of a different timescale. Weaker muscle relaxants are given in larger doses so more molecules in the central compartment must diffuse into the effect compartment, which is the space within the mouth of the receptor, of the body. After delivery to the effect compartment then all molecules act quickly. Therapeutically this relationship is very inconvenient because low potency, often meaning low specificity can decrease the safety margin thus increasing the chances of side-effects. In addition, even though low potency usually accelerates onset of action, it does not guaranty a fast onset. Gallamine, for example, is weak and slow. When fast onset is necessary then succinylcholine or rocuronium are usually preferable.
Elimination
Muscle relaxants can have very different metabolic pathways and it is important that the drug does not accumulate if certain elimination pathways are not active, for example in kidney failure.
== Medical Use ==
=== Endotracheal intubation ===
Administration of neuromuscular blocking agents (NMBA) during anesthesia can facilitate endotracheal intubation. This can decrease the incidence of postintubation hoarseness and airway injury.
Short-acting neuromuscular blocking agents are chosen for endotracheal intubation for short procedures (< 30minutes), and neuromonitoring is required soon after intubation. Options include succinylcholine, rocuronium or vecuronium if sugammadex is available for rapid reversal block.
Any short or intermediate acting neuromuscular blocking agents can be applied for endotracheal intubation for long procedures (≥ 30 minutes). Options include succinylcholine, rocuronium, vecuronium, mivacurium, atracurium and cisatracurium. The choice among these NMBA depends on availability, cost and patient parameters that affect drug metabolism.
Intraoperative relaxation can be maintained as necessary with additional dose of nondepolarizing NMBA.
Among all NMBA, Succinylcholine establish the most stable and fastest intubating conditions, thus is considered as the preferred NMBA for rapid sequence induction and intubation (RSII). Alternatives for succinylcholine for RSII include high dose rocuronium (1.2mg/kg which is a 4 X ED95 dose), or avoidance of NMBAs with a high dose remifentanil intubation.
=== Facilitation of surgery ===
Nondepolarizing NMBAs can be used to induce muscle relaxation that improves surgical conditions, including laparoscopic, robotic, abdominal and thoracic procedures. It can reduce patient movement, muscle tone, breathing or coughing against ventilator and allow lower insufflation pressure during laparoscopy. Administration of NMBAs should be individualized according to patient’s parameters. However, many operations can be performed without the need to apply any NMBAs as adequate anesthesia during surgery can achieve many of the theoretical benefits of neuromuscular blockage.
== Adverse effects ==
Since these drugs may cause paralysis of the diaphragm, mechanical ventilation should be at hand to provide respiration.
In addition, these drugs may exhibit cardiovascular effects, since they are not fully selective for the nicotinic receptor and hence may have effects on muscarinic receptors. If nicotinic receptors of the autonomic ganglia or adrenal medulla are blocked, these drugs may cause autonomic symptoms. Also, neuromuscular blockers may facilitate histamine release, which causes hypotension, flushing, and tachycardia.
Succinylcholine may also trigger malignant hyperthermia in rare cases in patients who may be susceptible.
In depolarizing the musculature, suxamethonium may trigger a transient release of large amounts of potassium from muscle fibers. This puts the patient at risk for life-threatening complications, such as hyperkalemia and cardiac arrhythmias. Other effects include myalgia, increased intragastric pressure, increased intraocular pressure, increased intracranial pressure, cardiac dysrhythmias (bradycardia is the most common type) and allergic reactions. As a result, it is contraindicated for patients with susceptibility to malignant hyperthermia, denervating conditions, major burns after 48 hours, and severe hyperkalemia.
For nondepolarizing NMBAs except vecuronium, pipecuronium, doxacurium, cisatracurium, rocuronium and rapacuronium, they produce certain extent of cardiovascular effect. Moreover, Tubocurarine can produce hypotension effect while Pancuronium can lead to moderate increase in heart rate and small increase in cardiac output with little or no increase in systemic vascular resistance, which is unique in nondeploarizing NMBAs.
Certain drugs such as aminoglycoside antibiotics and polymyxin and some fluoroquinolones also have neuromuscular blocking action as their side-effect.
== Interactions ==
Some drugs enhance or inhibit the response to NMBAs which require the dosage adjustment guided by monitoring.
=== Combination of NMBAs ===
In some clinical circumstances, succinylcholine may be administered before and after a nondepolarising NMBA or two different nondepolarising NMBAs are administered in sequence. Combining different NMBAs can result in different degrees of neuromuscular block and management should be guided with the use of a neuromuscular function monitor.
The administration of nondepolarising neuromuscular blocking agent has an antagonistic effect on the subsequent depolarising block induced by succinylcholine. If a nondepolarising NMBA is administered prior to succinycholine, the dose of succinylcholine must be increased.
The administration of succinylcholine on the subsequent administration of a nondepolarising neuromuscular block depends on the drug used. Studies have shown that administration of succinylcholien before a nondepolarising NMBA does not affect the potency of mivacurium or rocuronium. But for vecuronium and cisatracurium, it speeds up the onset, increases the potency and prolongs the duration of action.
Combining two nondepolarising NMBAs of the same chemical class (e.g. rocuronium and vecuronium) produces an additive effect, while combining two nondepolarising NMBAs of different chemical class (e.g. rocuronium and cisatracurium) produces a synergistic response.
=== Inhaled anesthetics ===
Inhaled anesthetics inhibit nicotinic acetylcholine receptors (nAChRs) and potentiate neuromuscular blockage with nondepolarising NMBAs. It depends on the type of volatile anesthetic (desflurane > sevoflurane > isoflurane > nitrous oxide), the concentration and the duration of exposure.
=== Antibiotics ===
Tetracycline, aminoglycosides, polymyxins and clindamycin potentiate neuromuscular blockage by inhibiting ACh release or desensitisation of post-synpatic nAChRs to ACh. This interaction happens mostly during maintenance of anesthesia. As antibiotics typically are given after a dose of NMBA, this interaction needs to be considered when re-dosing NMBA.
=== Anti-seizure drugs ===
Patients receiving chronic treatment are relatively resistance to nondepolarising NMBAs due to the accelerated clearance.
=== Lithium ===
Lithium is structurally similar to other cations such as sodium, potassium, magnesium and calcium, this causes lithium to activate potassium channels which inhibit neuromuscular transmission. Patients who take lithium can have a prolonged response to both depolarising and nondepolarising NMBAs.
=== Antidepressants ===
Sertraline and amitriptyline inhibit butyrylcholinesterase and cause prolonged paralysis. Mivacurium causes prolonged paralysis for patients chronically taking sertraline.
=== Local anesthetics (LAs) ===
LAs may enhance the effects of depolarisation and nondepolarising NMBAs through pre and post-synaptic interactions at the NMJ. It may result in blood levels high enough to potentiate NMBA-induced neuromuscular block. Epidurally administered levobupivacaine and mepivacaine potentiate amino-steroidal NMBAs and delay recovery from neuromuscular blockade.
== Estimating effect ==
Methods for estimating the degree of neuromuscular block include valuation of muscular response to stimuli from surface electrodes, such as in the train-of-four test, wherein four such stimuli are given in rapid succession. With no neuromuscular blockade, the resultant muscle contractions are of equal strength, but gradually decrease in case of neuromuscular blockade. It is recommended during use of continuous-infusion neuromuscular blocking agents in intensive care.
== Reversal ==
The effect of non-depolarizing neuromuscular-blocking drugs may be reversed with acetylcholinesterase inhibitors, neostigmine, and edrophonium, as commonly used examples. Of these, edrophonium has a faster onset of action than neostigmine, but it is unreliable when used to antagonize deep neuromuscular block. Acetylcholinesterase inhibitors increase the amount of acetylcholine in the neuromuscular junction, so a prerequisite for their effect is that the neuromuscular block is not complete, because in case every acetylcholine receptor is blocked then it does not matter how much acetylcholine is present.
Sugammadex is a newer drug for reversing neuromuscular block by rocuronium and vecuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA).
== History ==
Curare is a crude extract from certain South American plants in the genera Strychnos and Chondrodendron, originally brought to Europe by explorers such as Walter Raleigh Edward Bancroft, a chemist and physician in the 16th century brought samples of crude curare from South America back to the Old-World. The effect of curare was experimented with by Sir Benjamin Brodie when he injected small animals with curare, and found that the animals stopped breathing but could be kept alive by inflating their lungs with bellows. This observation led to the conclusion that curare can paralyse the respiratory muscles. It was also experimented by Charles Waterton in 1814 when he injected three donkeys with curare. The first donkey was injected in the shoulder and died afterward. The second donkey had a tourniquet applied to the foreleg and was injected distal to the tourniquet. The donkey lived while the tourniquet was in place but died after it was removed. The third donkey after injected with curare appeared to be dead but was resuscitated using bellows. Charles Waterton's experiment confirmed the paralytic effect of curare.
It was known in the 19th century to have a paralysing effect, due in part to the studies of scientists like Claude Bernard. D-tubocurarine a mono-quaternary alkaloid was isolated from Chondrodendron tomentosum in 1942, and it was shown to be the major constituent in curare responsible for producing the paralysing effect. At that time, it was known that curare and, therefore, d-tubocurarine worked at the neuromuscular junction. The isolation of tubocurarine and its marketing as the drug Intocostrin led to more research in the field of neuromuscular-blocking drugs. Scientists figured out that the potency of tubocurarine was related to the separation distance between the two quaternary ammonium heads.
Neurologist Walter Freeman learned about curare and suggested to Richard Gill, a patient suffering from multiple sclerosis, that he try using it. Gill brought 25 pounds of raw curare from Ecuador. The raw curare was then given to Squibb and Sons to derive an effective antidote to curare. In 1942, Wintersteiner and Dutcher (two scientists working for Squibb and Sons) isolated the alkaloid d-tubocurarine. Soon after, they developed a preparation of curare called Intocostrin.
At the same time in Montreal, Harold Randall Griffith and his resident Enid Johnson at the Homeopathic Hospital administered curare to a young patient undergoing appendectomy. This was the first use of NMBA as muscle relaxant in anesthesia.
The 1940s, 1950s and 1960s saw the rapid development of several synthetic NMBA. Gallamine was the first synthetic NMBA used clinically. Further research led to the development of synthesized molecules with different curariform effects, depending on the distance between the quaternary ammonium groups. One of the synthesized bis-quaternaries was decamethonium a 10-carbon bis-quaternary compound. Following research with decamethonium, scientists developed suxamethonium, which is a double acetylcholine molecule that was connected at the acetyl end. The discovery and development of suxamethonium lead to a Nobel Prize in medicine in 1957. Suxamethonium showed different blocking effect in that its effect was achieved more quickly and augmented a response in the muscle before block. Also, tubocurarine effects were known to be reversible by acetylcholinesterase inhibitors, whereas decamethonium and suxamethonium block were not reversible.
Another compound malouétine that was a bis-quaternary steroid was isolated from the plant Malouetia bequaertiana and showed curariform activity. This led to the synthetic drug pancuronium, a bis-quaternary steroid, and subsequently other drugs that had better pharmacological properties. Research on these molecules helped improve understanding of the physiology of neurons and receptors.
=== Outdated treatment ===
Gallamine triethiodide is originally developed for preventing muscle contractions during surgical procedures. However, it is no longer marketed in the United States according to the FDA orange book.
== See also ==
Ganglionic blocker
Cholinergic blocking drugs
== References ==
== External links ==
Neuromuscular+blocking+agents at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Neuromuscular-blocking_drugs |
The sarcolemma (sarco (from sarx) from Greek; flesh, and lemma from Greek; sheath), also called the myolemma, is the cell membrane surrounding a skeletal muscle fibre or a cardiomyocyte.
It consists of a lipid bilayer and a thin outer coat of polysaccharide material (glycocalyx) that contacts the basement membrane. The basement membrane contains numerous thin collagen fibrils and specialized proteins such as laminin that provide a scaffold to which the muscle fibre can adhere. Through transmembrane proteins in the plasma membrane, the actin skeleton inside the cell is connected to the basement membrane and the cell's exterior. At each end of the muscle fibre, the surface layer of the sarcolemma fuses with a tendon fibre, and the tendon fibres, in turn, collect into bundles to form the muscle tendons that adhere to bones.
The sarcolemma generally maintains the same function in muscle cells as the plasma membrane does in other eukaryote cells. It acts as a barrier between the extracellular and intracellular compartments, defining the individual muscle fibre from its surroundings. The lipid nature of the membrane allows it to separate the fluids of the intra- and extracellular compartments, since it is only selectively permeable to water through aquaporin channels. As in other cells, this allows for the compositions of the compartments to be controlled by selective transport through the membrane. Membrane proteins, such as ion pumps, may create ion gradients with the consumption of ATP, that may later be used to drive transport of other substances through the membrane (co-transport) or generate electrical impulses such as action potentials.
A special feature of the sarcolemma is that it invaginates into the sarcoplasm of the muscle cell, forming membranous tubules radially and longitudinally within the fiber called T-tubules or transverse tubules. On either side of the transverse tubules are terminal cisternal enlargements of the sarcoplasmic reticulum (termed endoplasmic reticulum in nonmuscle cells). A transverse tubule surrounded by two SR cisternae are known as a triad, and the contact between these structures is located at the junction of the A and I bands.
== References == | Wikipedia/Sarcolemma |
Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.
These agents have broad effects due to their actions in nerves located vastly over the body. These nerves include motor nerves in somatic nervous system which innervate skeletal muscles as well as nerves in the sympathetic and parasympathetic nervous systems. Organs that receive innervations from these systems include exocrine glands, heart, eyes, gastrointestinal tract etc. Antimuscarinic and antinicotinic agents can increase heart rate, inhibit secretions, and gastrointestinal motility.
Naturally occurring antimuscarinics were found in alkaloids from Belladonna (Solanaceae) plants. They were used as deadly poison and pupil-dilating cosmetics. While curare, the naturally occurring antinicotinics derived from Chondrodendron and Strychnos, was a poison used by South American Indians for hunting.
According to their site of actions, cholinergic blocking drugs can be classified into two general types — antimuscarinic and antinicotinic agents. Antimuscarinic agents (also known as muscarinic antagonists), including atropine and hyoscine, block acetylcholine at the muscarinic acetylcholine receptors. Antinicotinic agents (also known as ganglionic blockers, neuromuscular blockers), including tubocurarine and hexamethonium, block acetylcholine action at nicotinic acetylcholine receptors. Their effects are based on the expression of corresponding receptors in different parts of the body.
There are many adverse effects, interactions and contraindications for antinicotinic and antimuscarinic agents. Adverse effects include hypotension, dry mouth, dry eyes etc. They interact with grapefruit juice and various medications, e.g. warfarin, metoclopramide. Therefore, cautions should be exercised and advice from medical professionals should be sought before using medications.
== History ==
=== Discovery of cholinergic nervous system ===
In 1900, Reid Hunt, a pharmacologist (1870-1948), realised a fall in blood pressure in rabbits after removing adrenaline (epinephrine) from adrenal glands extract. While he initially attributed this effect to choline, he later discovered acetylcholine was 100 000 times more potent in lowering blood pressure.
British physiologist Sir Henry Hallett Dale (1875-1968) observed acetylcholine for causing blood vessel dilation and slowing down heart rate. In 1914, Dale noted that the physiological effect of acetylcholine resembled the stimulation of parasympathetic nervous system and hypothesized acetylcholine as the neurotransmitter. Later, Dale named substances that mimic acetylcholine action as "cholinergics".
In 1914, Dale also distinguished two types of activities of acetylcholine, namely muscarinic and nicotinic, as they mimic the effects of injecting muscarine, extracted from poisonous mushroom Amanita muscaria, and nicotine.
=== Antimuscarinic agents ===
Naturally occurring antimuscarinics were found in alkaloids from Belladonna (Solanaceae) plants. They were used as deadly poison in Roman Empire and Middle Ages. The name Belladonna, meaning beautiful ladies, was derived from women using berry juice from the plant cosmetically to dilate their pupils.
The mydriatic effect was studied by the German chemist Friedlieb Ferdinand Runge (1795-1867), in which the active ingredient, atropine, was first discovered by Vaquelin in 1809 and was first isolated by Heinrich F. G. Mein in 1813.
In the 1850s, atropine was used as antispasmodic in asthma treatment and as morphine antidote for its mydriatic effect. Bezold and Bloebaum showed that atropine blocked the effects of vagal stimulation on the heart in 1867. Subsequently in 1872, Heidenhain found its ability to prevent salivary secretion.
=== Antinicotinic agents ===
Curare, derived from Chondrodendron and Strychnos, was used as poison by South American Indians to coat arrow tips or blow-pipe darts for hunting animals. It is first identified when Spanish soldiers were attacked by these indigenous tribes in the 16th century.
In 1906, Langley studied the actions of nicotine and curare on chicken and frog muscles. Curare was found to block the stimulant action of nicotine in both innervated and chronically denervated muscles. In 1940, Jenkinson identified tubocurarine as a competitive antagonist of acetylcholine.
Curare and tubocurarine had important roles in establishing the concept of specific cholinoceptors in the motor end plate. At right dose, they are used as general anesthetic for relaxing abdominal muscles in operations.
== General effects on body ==
=== Antimuscarinic agents ===
Muscarinic receptors are G-protein coupled receptors that present mainly in the parasympathetic system and sweat gland. Antimuscarinc agents, therefore, generally produce effects that are opposite to the stimulation of the parasympathetic system, which is responsible for "rest and digest".
=== Antinicotinic agent ===
Nicotinic receptors are ligand-gated ion channels that present in both parasympathetic and sympathetic ganglions, while the antagonistic effect of antinicotinic agents depend on which system predominates in a particular site. Nicotinic receptors are also present in neuromuscular junctions and the brain.
== Clinical uses ==
Listed below are some examples of antimuscarinic and antinicotinic agents according to the British National Formulary, including non-clinically one for better illustration of their site of actions.
=== Antimuscarinic agents ===
Antimuscarinic agents are muscarinic antagonists and they bind to muscarinic cholinergic receptors postsynaptically without activating them. They occupy and prevent acetylcholine from binding to the active sites of receptors to elicit their effect.
=== Antinicotinic agents ===
Antinicotinic agents are classified into ganglionic blockers and neuromuscular blockers.
Ganglionic blockers are of little clinical use as they act at all autonomic ganglions. They act by:
Interfering acetylcholine release
Prolonged depolarization (depolarisation block), i.e. stimulation then block stimulation
Competitive inhibition of nicotinic receptor
Neuromuscular blockers act at neuromuscular junction by:
Inhibiting acetylcholine synthesis
Inhibiting acetylcholine release
Blocking acetylcholine receptors postsynaptically
Prolonged depolarization of motor end plate
== Adverse effects ==
=== Drug reactions ===
The following are some side effects after taking either antinicotinic or anticholinergic medications. They vary from mild to severe and some of these effects depends on the duration of drug usage.
Cognitive function decline (Confusion, memory loss and difficulty in concentration) paralysis, Tachycardia, Hypotension (Anticholinergics are histamine-inducing, leading to vasodilation during anaphylactic reaction, hence a dropping in blood pressure), constipation, dry mouth, dry eyes, hypohidrosis/ anhidrosis, blurry vision, or Increase in intraocular pressure, increase in the risk of glaucoma.
=== Overdose ===
Anticholinergic overdose, both antinicotinic and antimuscarinic, can exert toxic effects on both central and peripheral systems. The following symptoms could be presented:
Mild symptoms include tachycardia, flushed face, mydriasis and blurred vision, fever, dry mouth and skin, and urinary retention. Early stage of overdose can lead to central nervous system stimulation, for instance, hyperactivity, followed by depression, such as agitation (Anxiety or nervous), delirium, disorientation, hallucinations, seizures, hypertension, or hyperthermia. In late or severe stage of overdose, it could lead to coma, medullary paralysis, death.
Supportive care is usually performed in anticholinergic toxicated patients. Intravenous benzodiazepine is used as a first-line treatment for agitation. Cooling measures are employed if there is any significant hyperthermia. Activated charcoal is only given within one hour of anticholinergic ingestion. Physostigmine is given only if presenting both peripheral and central signs and symptoms of anticholinergic poisoning. Physostigmine is a central and peripheral acting acetylcholinesterase inhibitor and generally given to patients with pure anticholinergic poisoning.
== Interactions ==
Combined use of medications with anticholinergics may cause synergistic (supra-additive), additive, or antagonistic interactions, leading to no therapeutic effect or overdosing. Below listed are some medications or food that can interact with anticholinergics.
Medications indicated for:
Irregular heartbeat, e.g. disopyramide, quinidine. Drug-induced arrhythmia worsened by anticholinergics' side effect of tachycardia.
Parkinson's disease, e.g. levodopa. Atropine decreases the absorption of levodopa.
Preventing travel sickness, relieve stomach cramps or spasms, e.g. hyoscine. Additive effect.
Nausea and vomiting, e.g. cyclizine. Additive effect.
Parasympathetic stimulation, e.g. bethanechol, pilocarpine, carbachol
Antihistamines e.g. chlorpheniramine, diphenhydramine, promethazine. They have similar structures as anticholinergics, causing additive effect.
Tricyclic antidepressants, e.g. amitriptyline, clomipramine. Additive effect.
Adrenergic decongestants, e.g. phenylephrine. Combined use with atropine increases the risk of severe hypertension.
Alzheimer's disease e.g. rivastigmine and donepezil. May reduce seizure threshold.
Muscle relaxants for surgery.
Grapefruit juice and grapefruit-based products. CYP3A4 inhibitor which may reduce or amplify drug effect, such as darifenacin.
== Contraindications ==
The followings are the common contraindications adopted from the British National Formulary.
=== Antimuscarinic agents ===
For all antimuscarinics,
Angle-closure glaucoma
Bladder outlet obstruction (BOO)
Myasthenia gravis
Gastro-intestinal obstruction
Toxic megacolon
Urinary retention
Paralytic ileus
Intestinal atony (paralysis of muscles)
Severe ulcerative colitis
Hypertension, especially M2 receptor antagonists
=== Antinicotinic agents ===
For anticholinergics, such as
Trimethoprim:
Blood dyscrasias
Suxamethonium:
Hyperkalemia
Low plasma-cholinesterase activity e.g. severe liver disease
Major trauma
Personal or family history of congenital myotonic disease
Personal or family history of malignant hyperthermia
Prolonged immobilisation
Severe burns
Skeletal muscle myopathies e.g. Duchenne muscular dystrophy
== References == | Wikipedia/Cholinergic_blocking_drugs |
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.
Barbiturates have largely been replaced by benzodiazepines and nonbenzodiazepines ("Z-drugs") in routine medical practice, particularly in the treatment of anxiety disorders and insomnia, because of the significantly lower risk of overdose, and the lack of an antidote for barbiturate overdose. Despite this, barbiturates are still in use for various purposes: in general anesthesia, epilepsy, treatment of acute migraines or cluster headaches, acute tension headaches, euthanasia, capital punishment, and assisted suicide.
== Uses ==
=== Medicine ===
Barbiturates, such as phenobarbital, were long used as anxiolytics and hypnotics. Intermediate-acting barbiturates reduce time to fall asleep, increase total sleep time, and reduce REM sleep time. Today they have been largely replaced by benzodiazepines for these purposes because the latter are less toxic in drug overdose. However, barbiturates are still used as anticonvulsants (e.g., phenobarbital and primidone) and general anesthetics (e.g., sodium thiopental).
Barbiturates in high doses are used for medical aid in dying, and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection. Barbiturates are frequently employed as euthanizing agents in small-animal veterinary medicine.
=== Interrogation ===
Sodium thiopental is an ultra-short-acting barbiturate that is marketed under the name Sodium Pentothal. It is often mistaken for "truth serum", or sodium amytal, an intermediate-acting barbiturate that is used for sedation and to treat insomnia, but was also used in so-called sodium amytal "interviews" where the person being questioned would incorrectly be thought to be more likely to provide the truth whilst under the influence of the drug. When dissolved in water, sodium amytal can be swallowed, or it can be administered by intravenous injection. The drug does not itself force people to tell the truth, but is thought to decrease inhibitions and slow creative thinking, making subjects more likely to be caught off guard when questioned, and increasing the possibility of the subject revealing information through emotional outbursts. Lying is somewhat more complex than telling the truth, especially under the influence of a sedative-hypnotic drug.
The memory-impairing effects and cognitive impairments induced by sodium thiopental are thought to reduce a subject's ability to invent and remember lies. This practice is no longer considered legally admissible in court, owing to findings that subjects undergoing such interrogations may form false memories, putting the reliability of all information obtained through such methods into question. Nonetheless, it is still employed in certain circumstances by defense and law enforcement agencies as a "humane" alternative to torture interrogation when the subject is believed to have information critical to the security of the state or agency employing the tactic.
=== Chemistry ===
In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementary hydrogen bonds was published. Since this first article, different kind of receptors were designed, as well as different barbiturates and cyanurates, not for their efficiencies as drugs but for applications in supramolecular chemistry, in the conception of materials and molecular devices.
The preferred IUPAC name of the base compound, barbituric acid, is 1,3-diazinane-2,4,6-trione. Different barbiturates have different substituents in the basic structure, mainly in position 5 on the ring. In modern chemistry the barbiturates are often presented by its Hirshfeld surface representations showing its intermolecular interactions [1] calculated with CrystalExplorer Program.
Sodium barbital and barbital have also been used as pH buffers for biological research, e.g., in immuno-electrophoresis or in fixative solutions.
== Classification ==
Barbiturates are classified based on the duration of action. Examples of each class include:
Ultra short acting (30 minutes): thiopentone, methohexitone
Short acting (2 hours): hexobarbitone, cyclobarbitone, pentobarbitone, secobarbitone
Intermediate acting (3–6 hours): amobarbitone, butabarbitone
Long acting (6 hours): phenobarbitone
== Indications ==
Indications for the use of barbiturates include:
Seizure
Neonatal withdrawal syndrome
Insomnia
Anxiety
Inducing anesthesia
== Side effects ==
There are special risks to consider for older adults, and women who are pregnant. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of 65 are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. When barbiturates are taken during pregnancy, the drug passes through the placenta to the fetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk. A rare adverse reaction to barbiturates is Stevens–Johnson syndrome, which primarily affects the mucous membranes.
=== Common side effects ===
Nausea
Hypotension
Headache
Drowsiness
Skin rash
=== Serious side effects ===
Confusion
Coma
Hallucination
Fainting
Slow breathing
=== Rare side effects ===
Agranulocytosis
Stevens–Johnson syndrome
Liver injury
Megaloblastic anemia
=== Tolerance and dependence ===
With regular use, tolerance to the effects of barbiturates develops. Research shows tolerance can develop with even one administration of a barbiturate. As with all GABAergic drugs, barbiturate withdrawal produces potentially fatal effects such as seizures, in a manner reminiscent of delirium tremens and benzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that of alcohol or benzodiazepines. It is considered one of the most dangerous withdrawals of any known addictive substance. Similarly to benzodiazepines, the longer acting barbiturates produce a less severe withdrawal syndrome than short acting and ultra-short acting barbiturates. Withdrawal symptoms are dose-dependent with heavier users being more affected than lower-dose addicts.
The pharmacological treatment of barbiturate withdrawal is an extended process often consisting of converting the patient to a long-acting benzodiazepine (i.e. Valium), followed by slowly tapering off the benzodiazepine. Mental cravings for barbiturates can last for months or years in some cases and counselling/support groups are highly encouraged by addiction specialists. Patients should never try to tackle the task of discontinuing barbiturates without consulting a doctor, owing to the high lethality and relatively sudden onset of the withdrawal. Attempting to quit "cold turkey" may result in neurological damage due to excitotoxicity, severe physical injuries received during convulsions, and even death resulting from arrhythmias during grande Mal seizures, paralleling death caused by delirium tremens.
=== Overdose ===
Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The lethal dose is highly variable among different members of the class, with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. Tolerance to the anxiolytic and sedative effects of barbiturates tends to develop faster than tolerance to their effects on smooth muscle, respiration, and heart rate, making them generally unsuitable for a long time psychiatric use. Tolerance to the anticonvulsant effects tends to correlate more with tolerance to physiological effects, however, meaning that they are still a viable option for long-term epilepsy treatment.
Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous owing to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects. (ex. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increases the channels' overall function by 900%, not 600%).
The longest-acting barbiturates have half-lives of a day or more, and subsequently result in bioaccumulation of the drug in the system. The therapeutic and recreational effects of long-acting barbiturates wear off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic or prescribed dose) despite the user feeling little or no effects from the plasma-bound concentrations of the drug. Users who consume alcohol or other sedatives after the drug's effects have worn off, but before it has cleared the system, may experience a greatly exaggerated effect from the other sedatives which can be incapacitating or even fatal.
Barbiturates induce a number of hepatic CYP enzymes (most notably CYP2C9, CYP2C19, and CYP3A4), leading to exaggerated effects from many prodrugs and decreased effects from drugs which are metabolized by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such as codeine, tramadol, and carisoprodol, which become considerably more potent after being metabolized by CYP enzymes. Although all known members of the class possess relevant enzyme induction capabilities, the degree of induction overall as well as the impact on each specific enzyme span a broad range, with phenobarbital and secobarbital being the most potent enzyme inducers and butalbital and talbutal being among the weakest enzyme inducers in the class.
People who are known to have killed themselves by barbiturate overdose include Stefan Zweig, Charles Boyer, Ruan Lingyu, Dalida, Jeannine Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, Carole Landis, C. P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven's Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalized with burns, the doctors treating her not being aware of her barbiturate addiction).
== Contraindications ==
The use of Barbiturates is contraindicated in the following conditions:
variegate porphyria (because of induction of enzymes needed for porphyria synthesis by barbiturates)
Status asthmaticus (because of respiratory depression caused by the barbiturates)
== Mechanism of action ==
Barbiturates act as positive allosteric modulators and, at higher doses, as agonists of GABAA receptors. GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABAA receptor at multiple homologous transmembrane pockets located at subunit interfaces, which are binding sites distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABAergic effect, barbiturates also block AMPA and kainate receptors, subtypes of ionotropic glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can explain the superior CNS-depressant effects of these agents to alternative GABA potentiating agents such as benzodiazepines and quinazolinones. At higher concentration, they inhibit the Ca2+-dependent release of neurotransmitters such as glutamate via an effect on P/Q-type voltage-dependent calcium channels.
Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.
Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABAA receptor channel is only one of several representatives. This Cys-loop receptor superfamily of ion channels includes the neuronal nACh receptor channel, the 5-HT3 receptor channel, and the glycine receptor channel. However, while GABAA receptor currents are increased by barbiturates (and other general anesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anesthetic concentrations of both thiopental and pentobarbital. Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates. This is the mechanism responsible for the (mild to moderate) anesthetic effect of barbiturates in high doses when used in anesthetic concentration.
== Interactions ==
Drug interactions with barbiturates are:
alcohol
opioids
benzodiazepines
anticoagulants
antihistamines
atazanavir
birth-control pills
boceprevir
== Caution ==
Caution is needed in people using:
Medications such as opioids or benzodiazepines
Alcohol
Caution is also required in patients with:
Asthma
Kidney- or liver-problems
Heart-disease
Substance use disorder
Depression
History of suicidal thoughts
== History ==
Barbituric acid was first synthesized 27 November 1864, by German chemist Adolf von Baeyer. This was done by condensing urea with diethyl malonate. There are several stories about how the substance got its name. The most likely story is that Baeyer and his colleagues went to celebrate their discovery in a tavern where the town's artillery garrison were also celebrating the feast of Saint Barbara – the patron saint of artillerymen. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea. Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara. No substance of medical value was discovered, however, until 1903 when two German scientists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Mering proposed this name because the most peaceful place he knew was the Italian city of Verona. In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative–hypnotic.
It was not until the 1950s that the behavioral disturbances and physical dependence potential of barbiturates became recognized.
Since the 1970s, most barbiturates were replaced by benzodiazepines.
Barbituric acid itself does not have any direct effect on the central nervous system and chemists have derived over 2,500 compounds from it that possess pharmacologically active qualities. The broad class of barbiturates is further broken down and classified according to speed of onset and duration of action. Ultrashort-acting barbiturates are commonly used for anesthesia because their extremely short duration of action allows for greater control. These properties allow doctors to rapidly put a patient "under" in emergency surgery situations. Doctors can also bring a patient out of anesthesia just as quickly, should complications arise during surgery. The middle two classes of barbiturates are often combined under the title "short/intermediate-acting." These barbiturates are also employed for anesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines and Z-drug such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual "hang-over" effect and feel groggy.
Barbiturates can in most cases be used either as the free acid or as salts of sodium, calcium, potassium, magnesium, lithium, etc. Codeine- and dionine-based salts of barbituric acid have been developed.
== Society and culture ==
=== Legal status ===
During World War II, military personnel in the Pacific region were given "goofballs" to improve their tolerance of the heat and humidity of daily working conditions. Goofballs reduced the demand on the respiratory system, as well as maintaining blood pressure. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent physicians prescribing high doses to unknowing patients through the 1950s and 1960s.
In the late 1950s and 1960s, an increasing number of published reports of barbiturate overdoses and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.
In the Netherlands, the Opium Law classifies all barbiturates as List II drugs, with the exception of secobarbital, which is on List I.
There is a small group of List II drugs for which physicians have to write the prescriptions according to the same, tougher guidelines as those for List I drugs (writing the prescription in full in letters, listing the patients name, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to). Among that group of drugs are the barbiturates amobarbital, butalbital, cyclobarbital, and pentobarbital.
In the United States, the Controlled Substances Act of 1970 classified most barbiturates as controlled substances—and they remain so as of August 2023. Barbital, methylphenobarbital (also known as mephobarbital), and phenobarbital are designated schedule IV drugs, and "Any substance which contains any quantity of a derivative of barbituric acid, or any salt of a derivative of barbituric acid" (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V; however, amobarbital, pentobarbital, and secobarbital are now schedule II controlled substances unless they are in a suppository dosage form.
In 1971, the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the 34th version of the treaty, as of 25 January 2014, regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and allobarbital, barbital, butobarbital, mephobarbital, phenobarbital, butabarbital, and vinylbital as schedule IV on its "Green List". The combination medication Fioricet, consisting of butalbital, caffeine, and paracetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its sibling Fiorinal, which contains aspirin instead of paracetamol and may contain codeine phosphate, remains a schedule III drug.
=== Recreational use ===
Recreational users report that a barbiturate high gives them feelings of relaxed contentment and euphoria. Physical and psychological dependence may also develop with repeated use. Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with a sedative-hypnotic misuse die by suicide. Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, and loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting benzodiazepines such as diazepam and clonazepam. Often polysubstance use occurs and barbiturates are consumed with or substituted by other available substances, most commonly alcohol.
People who use substances tend to prefer short-acting and intermediate-acting barbiturates. The most commonly used are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly used. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours.
Slang terms for barbiturates include barbs, barbies, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, 'reds & blues', and tooties.
== Examples ==
Thiopental is a barbiturate with one of the C=O double bonds (with the carbon being labelled 2 in the adjacent diagram) replaced with a C=S double bond, R1 being CH2CH3 (ethyl) and R3) being CH(CH3)CH2CH2CH3 (sec-pentyl). Thiopental is no longer available in the United States.
== See also ==
Benzodiazepine
Psycholeptic
Dille–Koppanyi reagent, Zwikker reagent, and others spot tests for barbiturates
== Explanatory notes ==
== References ==
== External links and further reading ==
López-Muñoz, F.; Ucha-Udabe, R.; Alamo, C. (2005). "The history of barbiturates a century after their clinical introduction". Neuropsychiatric Disease and Treatment. 1 (4): 329–343. PMC 2424120. PMID 18568113. | Wikipedia/Barbiturates |
Synaptosomal-Associated Protein, 25kDa (SNAP-25) is a Target Soluble NSF (N-ethylmaleimide-sensitive factor) Attachment Protein Receptor (t-SNARE) protein encoded by the SNAP25 gene found on chromosome 20p12.2 in humans. SNAP-25 is a component of the trans-SNARE complex, which accounts for membrane fusion specificity and directly executes fusion by forming a tight complex that brings the synaptic vesicle and plasma membranes together.
== Structure and function ==
SNAP-25, a Q-SNARE protein, is anchored to the cytosolic face of membranes via palmitoyl side chains covalently bound to cysteine amino acid residues in the central linker domain of the molecule. This means that SNAP-25 does not contain a trans-membrane domain.
SNAP-25 has been identified to contribute two α-helices to the SNARE complex, a four-α-helix domain complex. The SNARE complex participates in vesicle fusion, which involves the docking, priming and merging of a vesicle with the cell membrane to initiate an exocytotic event. Synaptobrevin, a protein that is a part of the vesicle-associated membrane protein (VAMP) family, and syntaxin-1 also help form the SNARE complex by each contributing a single α-helix. SNAP-25 assembles with synaptobrevin and syntaxin-1, and the selective binding of these proteins enables vesicle docking and fusion to occur at active zones on the plasma membrane. The energy needed for fusion to occur, results from the assembly of the SNARE proteins along with additional Sec1/Munc18-like (SM) proteins.
To form the SNARE complex, synaptobrevin, syntaxin-1, and SNAP-25 associate and begin to wrap around each other to form a coiled coil quaternary structure. The α-helices of both synaptobrevin and syntaxin-1 bind to those of SNAP-25. Synaptobrevin binds the α-helix near the C-terminus of SNAP-25, while syntaxin-1 binds the α-helix near the N-terminus. Dissociation of the SNARE complex is driven by ATPase N-ethylmaleimide-sensitive fusion (NSF) protein.
SNAP-25 inhibits presynaptic P-, Q-, and L-type voltage-gated calcium channels and interacts with the synaptotagmin C2B domain in a Ca2+-independent fashion. In glutamatergic synapses, SNAP-25 decreases the Ca2+ responsiveness, while it is normally absent in GABAergic synapses.
Two isoforms (mRNA splice variants) of SNAP-25 exist, which are SNAP-25a and SNAP-25b. The two isoforms differ by nine amino acid residues, including a re-localization of one of the four palmitoylated cysteine residues involved in membrane attachment. The major characteristics of these two forms are outlined in the table below.
SNAP-25 not only plays a role in synaptogenesis and the exocytotic release of neurotransmitters, but it also affects spine morphogenesis and density, post synaptic receptor trafficking and neuronal plasticity. Other non-neuronal processes such as metabolism can also be affected by SNAP-25 protein expression.
== Clinical significance ==
=== Developmental and epileptic encephalopathies (DEEs) ===
Individuals harboring pathogenic heterozygous de novo missense or loss-of-function variants in SNAP-25 often present with an early-onset developmental and epileptic encephalopathy. The core symptoms comprise intellectual disability ranging between mild to profound and early-onset seizures mostly occurring before the age of two years. Further recurrent symptoms include movement disorders, cerebral visual impairment, and brain atrophy. Electrophysiological studies identified aberrant spontaneous neurotransmission as causative and suggest that structurally clustered pathogenic variants lead to similar synaptic phenotypes.
=== Attention Deficit Hyperactivity Disorder (ADHD) ===
Consistent with the regulation of synaptic Ca2+ responsiveness, heterozygous deletion of the SNAP-25 gene in mice results in a hyperactive phenotype similar to attention deficit hyperactivity disorder (ADHD). In heterozygous mice, a decrease in hyperactivity is observed with dextroamphetamine (or Dexedrine), an active ingredient in the ADHD drug Adderall. Homozygous deletions of the SNAP-25 gene are lethal. An additional study indicated that incorporation of a SNAP-25 transgene back into the heterozygous SNAP-25 mutant mouse can rescue normal activity levels similar to wildtype mice. This suggests that low protein levels of SNAP-25 can be a cause of hyper-kinetic behavior. Subsequent studies have suggested that at least some of the SNAP-25 gene mutations in humans might predispose to ADHD. Identification of polymorphisms in the 3’ untranslated region of the SNAP-25 gene was established in linkage studies with families that had been pre-diagnosed ADHD.
=== Schizophrenia ===
Studies in the post mortem brains of patients with Schizophrenia have shown that altered protein levels of SNAP-25 are specific to regions of the brain. Reduced SNAP-25 protein expression has been observed in the hippocampus as well as an area of the frontal lobe known as Broadman's area 10 whereas SNAP-25 expression has increased in both the cingulate cortex and prefrontal lobe of Broadman's area 9. The varying levels of SNAP-25 protein found in different areas of the brain have been thought to contribute to the conflicting psychological behaviors (depressive vs. hyperactive) expressed in some Schizophrenic patients.
The blind-drunk (Bdr) mouse model which has a point mutations in the SNAP-25b protein has provided a complex phenotype involving behaviors such as an abnormal circadian rhythm, uncoordinated gait, and disinterest in new objects/toys. Another mouse model generated from Cre-LoxP recombination, showed that conditional knockout (cKO) of the SNAP-25 gene in the forebrain, showed inactive SNAP-25 gene expression in glutamatergic neurons. However, significant glutamate levels were found in the cortex of these cKO mice. These mice also exhibited deficient social skills, impaired learning and memory, enhanced kinesthetic activity, a reduced startle response, impaired self-care, nursing ability and nest-building skills. Antipsychotic drugs such as Clozapine and Riluzole have been shown to significantly reduce the schizophrenic phenotype expressed in SNAP-25 cKO mice.
=== Alzheimer's disease ===
Individuals with Alzhiemer's disease have been shown to have decreased presynaptic protein levels and impaired synaptic function in neurons. SNAP-25 can be used as a biomarker in the cerebral spinal fluid (CSF) of patients exhibiting different variations of Alzheimer's disease (prodromal Alzheimer's and overt Alzheimer's). Increased levels of SNAP-25 protein were observed in patients with Alzheimer's compared to control individuals. Additionally, the presence of truncated SNAP-25 protein can be seen in the CSF of some patients with this disease. In five distinct regions of the brain, low levels of SNAP-25 can be seen in patients with Alzheimer's.
=== Bipolar disorder ===
A single nucleotide polymorphism in the SNAP-25 gene promoter has been shown to influence the expression levels of the SNAP-25b isoform in the prefrontal cortex. Increased levels of SNAP-25b have been shown to impair synaptic transmission and maturation which could lead to early-onset bipolar disorder (EOBD).The most abundant isoform of SNAP-25 is SNAP-25a during the early weeks of development in mice however in adulthood there is a change and the SNAP-25b isoform increases in the brain. This is shown to correlate with adolescent humans being increasingly diagnosed with EOBD during puberty. It has been suggested that early-onset bipolar disorder is more closely linked to Schizophrenia than to Bipolar Disorder itself. The single nucleotide polymorphism of SNAP-25 (rs6039769) associated with EOBD has been shown to increase the risk of patients developing Schizophrenia.
=== Botulism ===
A genome wide association study pointed to the rs362584 polymorphism in the gene as possibly associated with the personality trait neuroticism. Botulinum toxins A, C and E cleave SNAP-25, leading to paralysis in clinically developed botulism.
=== Epilepsy ===
Deletion of the SNAP-25b isoform has been shown to cause developmental abnormalities and seizures in mice. High levels of SNAP-25a and the protein syntaxin appear to be linked to seizures found in infantile-epilepsy. SNAP-25 knock-in mice have distinct phenotypic behavior similar to the fits and seizures of epileptic patients, as well as anxiety.
=== Learning disabilities ===
In the coloboma hyperactive mutant mouse model where SNAP-25 protein levels are reduced to 50% of the normal level, depolarized neurotransmitter release of dopamine and serotonin were reduced as well as glutamate release. The reduction in glutamate levels can lead to deficient memory and increased learning disabilities. Certain polymorphisms of SNAP-25 (rs363043, rs353016, rs363039, rs363050) have been shown to affect the cognitive behavior, specifically the Intelligence Quotient (IQ)), of patients without pre-existing neurological diseases.
=== Neonatal development ===
SNAP-25 protein expression can be altered by sex hormone levels in neonatal rats. Male rats that received an antiestrogen drug showed a 30% decrease in SNAP-25 levels and females treated with estrogen or testosterone showed a 30% increase in SNAP-25 levels. This suggests that synaptosomal proteins, such as SNAP-25, may have a dependence on neonatal hormone levels during brain development in rats. An additional study, showed that SNAP-25 levels in the hippocampus of the brain in neonatal mice were altered if the mother had been exposed to human influenza virus during pregnancy.
== Impact in other non-humans ==
Loss is lethal to Drosophila, but can be fully substituted by overexpression of the related SNAP-24.
== Interactive pathway map ==
Click on genes, proteins and metabolites below to link to respective articles.
== Interactions ==
SNAP-25 has been shown to interact with:
== References ==
== Further reading ==
== External links ==
SNAP25+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Synaptosomal-associated_protein_25 |
Vesicle associated membrane proteins (VAMPs) are a family of SNARE proteins with similar structure, and are mostly involved in vesicle fusion.
VAMP1 and VAMP2 proteins known as synaptobrevins are expressed in brain and are constituents of the synaptic vesicles, where they participate in neurotransmitter release.
VAMP3 (known as cellubrevin) is ubiquitously expressed and participates in regulated and constitutive exocytosis as a constituent of secretory granules and secretory vesicles.
VAMP5 and VAMP7 participate in constitutive exocytosis.
VAMP5 is a constituent of secretory vesicles, myotubes and tubulovesicular structures.
VAMP7 is found both in secretory granules and endosomes.
VAMP8 (known as endobrevin) participates in endocytosis and is found in early endosomes. VAMP8 also participates the regulated exocytosis in pancreatic acinar cells.
VAMP4 is involved in transport from the Golgi.
== References ==
== External links ==
Vesicle-Associated+Membrane+Protein+1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Vesicle-associated_membrane_protein |
Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors. Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.
Clinically, neuromuscular drugs are used in anesthesia to cause paralysis of targeted skeletal muscles. It is most commonly applied in endotracheal intubation by reducing the incidence of hoarseness in vocal cords and esophageal injuries. It is also applied to improve surgical operating conditions by aiding mechanical ventilation in patients with lowered lung compliance. Other than surgical indications, neuromuscular drugs can also be indicated for the use of Alzheimer's disease, Parkinson's disease, etc. Common adverse effects of neuromuscular drugs include abnormal heart rate, blood pressure, and cardiac output.
== History ==
Curare is an alkaloid poison extracted from native South American plants in the Chondrondendron genus. They were initially used by indigenous groups as a paralyzing agent for hunting. European scientists later discovered that tubocurarine was the major constituent responsible for the paralyzing effect by acting on the neuromuscular junction.
Anasthesiologists Harold Griffith and Enid Johnson first documented the successful use of curare, in a clinical trial to facilitate muscle relaxation in a healthy patient undergoing appendicectomy in 1942. Before the use of curare, anesthesiologist required large doses of anesthetic such as chloroform to achieve similar paralyzing effects, hence increased the risk of life-threatening effects in elderly patients who had cardiac complications. Ever since, neuromuscular agents have been commonly used in practice during anesthetic procedures. The clinical trial conducted by Griffith and Johnson also paved the way for discovery of many more neuromuscular drugs for surgical use.
== Classification ==
Neuromuscular blocking agents are classified into the following two groups:
Depolarizing neuromuscular blockers: Depolarizing neuromuscular blockers directly bind to postsynaptic cholinergic receptors of the neuromuscular junction to generate a sustained action potential. This causes prolonged stimulation and desensitization of neuroreceptors, causing skeletal muscle relaxation effects such as paralysis. Depolarizing neuromuscular blockers, notably succinylcholine, tend to be preferred over non-depolarizing neuromuscular blockers due to their long-acting and rapid-onset properties.
Non-depolarizing neuromuscular blockers: Non-depolarizing neuromuscular blockers directly bind to acetylcholine receptors on the postsynaptic neuron and does not cause depolarization of the neuromuscular junction. They act as competitive inhibitors to acetylcholine, blocking their binding to acetylcholine receptors on the postsynaptic membrane to inhibit membrane depolarization. Inhibition of neurotransmitter binding in the neuromuscular junction induces paralyzing effects. Compared to depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers tend to have slower onset times and shorter duration of actions.
Aside from neuromuscular blocking agents, acetylcholinesterase inhibitors and butyrylcholinesterase inhibitors act on the neuromuscular junction to enhance neurotransmitter transmission in voluntary and involuntary muscles. Additionally, some antibiotics, such as aminoglycosides, may also exert undesired side effects on the neuromuscular junction.
Acetylcholinesterase inhibitors: Acetylcholinesterase inhibitors prevent the degradation of acetylcholine, subsequently increasing its concentration and duration of action in the neuromuscular junction. Acetylcholinesterase inhibitors are primarily used to treat symptoms of dementia, Alzheimer's disease, Parkinson's disease, and myasthenia gravis.
Butyrylcholinesterase inhibitors: Butyrylcholinesterease inhibitors prevent the degradation of butyrylcholine, which increases its concentration and duration of action in the neuromuscular junction. Like acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors are regarded as a therapeutic option for Alzheimer's disease.
Aminoglycosides: Aminoglycosides are frequently used in combinational antibacterial therapies for nosocomial respiratory tract infections, complicated intra-abdominal infections, sepsis, osteomyelitis caused by aerobic gram-negative bacilli, and complicated urinary tract infections. Seven neuromuscular drugs are approved by the US Food and Drug Administration, these drugs include: streptomycin, plazomicin, neomycin, amikacin, tobramycin, gentamicin, and paromomycin. It is clinically proven that aminoglycosides can exert neuromuscular blocking side effects. As aminoglycosides only have neuromuscular blocking side effects, they are not a major class of neuromuscular drugs.
== Mechanism of action ==
Depolarizing neuromuscular blockers: Depolarizing agents act as agonists for acetylcholine receptors. Succinylcholine is currently the only depolarizing neuromuscular blocking drug that has been placed in ongoing clinical use. Its pharmacological structure resembles two acetylcholine molecules combined through acetate methyl groups. It contains two quaternary ammonium radicals which associate with the two alpha subunits of the nicotinic receptor to cause depolarization. These nicotinic receptors respond to acetylcholine and are located in the central and peripheral nervous system, muscle, and other tissue. They act as the primary receptor in muscle for motor nerve-muscle communication which signals muscle contractions.
Under normal conditions, without the interference of depolarizing neuromuscular blockers, when depolarization is triggered, voltage-gated sodium channels are activated due to sensing the depolarization from the activation of acetylcholine receptors. This causes the rapid opening of the sodium channels, then closure after a brief period, becoming inactivated. The membrane potential is then required to be reset before the reactivation of the sodium channels. This process occurs almost instantly with acetylcholine, within one ms, as it is rapidly hydrolyzed through acetylcholinesterase.
However, when depolarizing neuromuscular blockers are applied, the modified structure of succinylcholine cannot be hydrolyzed by acetylcholinesterase. This causes the extensive activation of the nicotinic receptors and inactivation of the sodium channels, resulting in the blockage of the junctional transmission between muscles, causing the muscle to remain flaccid. Contrastingly, prolonged use of succinylcholine may cause a desensitization block to the neuromuscular junction, where acetylcholine receptors are insensitive to the channel opening effect of agonists (e.g., acetylcholine or acetylcholine-agonist drugs) (Refer to adverse reactions of depolarizing neuromuscular drugs below).
Non-depolarizing neuromuscular blockers: Non-depolarizing agents act as competitive inhibitors for acetylcholine. Upon the binding of non-depolarizing neuromuscular blockers, neurotransmission is reduced. Consequently, depolarizing and muscle-contracting effects are decreased. Non-depolarizing neuromuscular blockers are generally reversible, and hence have no permanent effects on acetylcholine receptors.
Unlike depolarizing neuromuscular blockers, non-depolarizing drugs do not produce conformational changes to the receptor. The blockers bind to acetylcholine receptors through a dynamic mechanism, with repeated association and dissociation. Thus, as the concentration of antagonists increases, the concentration of binding subsequently increases. Effective neuromuscular block by non-depolarizing neuromuscular drugs occurs only when 70-80% of acetylcholine receptors are occupied by the drug. This is because at this occupancy rate, junctional potential cannot reach the threshold value required for muscle contraction.The main difference between the two major classes of neuromuscular blocking agents is their respective reversal process of paralyzing effects. Non-depolarizing blockers are reversed through acetylcholinesterase inhibitor drugs which increase the concentration of acetylcholine. Acetylcholine behaves as competitive antagonists on acetylcholine receptors, reducing the binding of non-depolarizing blockers. Whereas, depolarizing blockers that mimic acetylcholine would have increased pharmacological effects when administered alongside acetylcholinesterase inhibitors. Therefore, inhibition reversal for depolarizing neuromuscular blockers occurs naturally within a specific period, after half-life has been achieved.
Acetylcholinesterase and butyrylcholinesterase inhibitors: Both cholinesterase inhibitors share similar mechanisms of action. The active site of cholinesterase's consists of an anionic site and an esteric site.
Phosphorylation of the anionic site by cholinesterase inhibitors prevents the binding of acetylcholine on acetylcholinesterase and butyrylcholine on butyrylcholinesterase respectively. As a result, acetylcholine and butyrylcholine will accumulate in the neuromuscular junction.
== Pharmacokinetics ==
Depolarizing drug
Succinylcholine:
The dosage of succinylcholine is patient-specific and determined based on total body weight and physical condition, thus extensive patient assessment and evaluation are required for accurate calculation. The current recommended dose of succinylcholine indicated for tracheal intubation by the FDA for adults is 1.0-1.5 mg/kg. Whereas, studies have shown that low-dose succinylcholine (0.45 mg/kg) is suitable for optimal intubation conditions in ASA 3 and 4 emergency non-prepared-patients (A patient with severe systemic disease that is a constant threat to life). This dosage can generate profound blockage within 60 seconds (short onset), quicker than other neuromuscular drugs currently available. Where neuromuscular blockage begins to recover within 3 minutes and is completely recovered within 15 minutes. Estimating the dose higher for intubation is preferred over underdosing, as reasonably higher dose produces similar paralysis with little to no known dose associated risks. Whereas under-dosing has shown inadequate paralysis, creating difficulties whilst performing intubation or other operative procedures.
Non-depolarizing drug
Non-depolarizing neuromuscular blockers are indicated in general anesthesia to facilitate endotracheal intubation, and to aid in surgeries via muscle relaxation. They can be further separated into two classes, benzylisoquinolinium compounds, and aminosteroid compounds.
Benzylisoquinolinium compounds, also known as benzylisoquinolines, have a structure of two quaternary ammonium groups linked by a chain of methyl groups. The methyl chain contains one or more chiral groups, leading to the existence of stereoisomers of benzylisoquinolinium drugs. Atracurirum, a bezylisoquinolinium drug, is commonly used in clinical settings.
Atracurium: The recommended clinical dosage of atracurium for adults is to “dose to effect” approach to ensure muscle relaxation. The drug has a relatively intermediate duration of action when compared to other non-depolarizing agents. The drug has an onset of 2 to 3 minutes in adults and an expected peak effect at 3 to 5 minutes. Recovery is expected to begin within 20 to 35 minutes of the initial dose, but it may take up to 70 minutes to achieve 95% recovery.
On the other hand, aminosteroid compounds have a structure based on androstane, with the addition of ACh-like groups. Vecuronium and pancuronium are the two most common aminosteroid compounds utilized in clinical settings.
Vecuronium and pancuronium: The recommended dosage of vecuronium and pancuronium both vary depending on interpatient variability. These drugs aim to achieve adequate muscle relaxation for surgical procedures to prevent surgical trauma. Vecuronium and pancuronium have an onset of 2 to 5 minutes in adults. The time it takes to recover 25% of neuromuscular control after vecuronium and pancuronium therapy are 25 to 40 minutes and 60 to 80 minutes respectively.
Acetylcholinesterase inhibitor
Donepezil: Donepezil is a widely used acetylcholinesterase inhibitor indicated for Alzheimer's disease. The drug can be administered orally or with a transdermal patch. However, the estimated time to peak will differ between both routes of administration. Oral donepezil has a peak concentration time of 3 to 8 hours depending on the dosage, while transdermal donepezil has an expected time to peak at 7 days.
== Adverse effects ==
Depolarizing drug
Succinylcholine: Succinylcholine presents several undesirable side effects which affect its application as it interacts with both muscarinic and nicotinic receptors, due to its acetylcholine-mimicking properties.
Firstly, hyperkalemia is the most seen adverse effect of succinylcholine due to its stimulatory effect of the drug on skeletal muscles. This results in an increase in serum potassium levels as high as 0.5 mEq/L. This increase is clinically insignificant in normal patients but can be detrimental for patients with predisposed hyperkalemia caused by up-regulation of post-junctional acetylcholine receptors. Therefore, succinylcholine use is contraindicated for this category of patients. Further consideration is also required for patients with chronically elevated potassium or traumatic injuries, as there is a high probability of acute hyperkalemia which can lead to dysrhythmia or death.
Secondly, succinylcholine causes the activation of muscarinic receptors in the SA node, causing bradycardia. This effect is especially highlighted in use with patients with high vagal tone (traumatic or young patients). In adults with a normal vagal tone, bradycardia has only been reported on repeated incremental dosages of succinylcholine. Anticholinergic drugs such as atropine and glycopyrrolate can be used as secondary therapy in treating or prophylaxis of bradycardia.
Thirdly, succinylcholine use has been associated with postoperative myalgia, where patients often experience muscle pain similar to that of post-exercise muscle pain mainly in the shoulders, neck, neck and upper abdominal muscle the following day after surgery, especially in young healthy patients with greater muscle mass, whereas reports from children, elderly and pregnant woman are less frequent. This is caused by the fasciculations (muscle twitches) that appear in sites such as intercostal muscles, and the diaphragm. These fasciculations are not relieved through analgesics, and in common practice, a sub-paralyzing dose of non-depolarizing neuromuscular blocker is administered a few minutes before succinylcholine administration to reduce visible fasciculation and postoperative myalgia. The use of succinylcholine is therefore also contraindicated in patient with muscle myopathy within 24 to 72 hours post-administration.
Non-depolarizing drug
Atracurium: Atracurium is commonly associated with histamine-related symptoms, most notably flushing and erythema. Less commonly seen adverse effects include urticaria, hypotension, wheezing, tachycardia, bronchospasm, dyspnea, bradycardia, and laryngospasm. Moreover, drops of up to 30 mmHg in mean arterial pressure was also observed within two minutes of administration in some patients. H1 and H2 receptor blocking agents can be used to attenuate the drop in mean arterial pressure. A slow injection speed between 30 and 60 seconds reduces adverse effects. Furthermore, Atracium produces a toxic metabolite called laudanosine when administered and can accumulate in patients with impaired renal function. This may lead to potential seizures and epilepsy. Thus, the dosage of the atracium should be compensated for patients with decreased renal functions.
Vecuronium: Most of vecuronium's adverse effects is correlated to the drug's extension of pharmacological effects past the desired time of use. Serious adverse effects include bronchospasm, anaphylaxis, apnea, and prolonged paralysis. In some instances, hypersensitivity-associated histamine release may occur, leading to allergy-like symptoms or severe anaphylaxis in rare cases. Vecuronium has a relatively favourable safety profile when compared to pancuronium or other aminosteroid non-depolarizing drugs.
Pancuronium: Pancuronium produces more significant adverse effects due to the blockade of muscarinic M2 receptors in the atria. Therefore, pancuronium may increase cardiac output, mean arterial pressure, and heart rate. To add on, patients with renal failure may experience a 30-50% decrease in plasma clearance, hence an increase in neuromuscular blockade duration. The use of pancuronium with insufficient anesthetic agents leads to morbidity and psychological trauma.
Acetylcholinesterase inhibitor
Donepezil: Donepezil may exhibit cardiac issues such as hypertension, cardiac arrhythmia, atrioventricular block, and bradycardia due to its vagotonia properties. Common gastrointestinal side effects such as nausea, diarrhea, and vomiting are also associated with donepezil and other acetylcholinesterase inhibitors. Studies have also shown an association of donepezil use and nightmares due to increased activation of the visual cortex during sleep. Patients can be advised to complete their drug regimen in the morning to prevent occurrences of nightmares.
== References == | Wikipedia/Neuromuscular_drug |
Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. This means of delivery is largely founded on nanomedicine, which plans to employ nanoparticle-mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue. The conventional drug delivery system is the absorption of the drug across a biological membrane, whereas the targeted release system releases the drug in a dosage form. The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side-effects, and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost, which makes productivity more difficult, and the reduced ability to adjust the dosages.
Targeted drug delivery systems have been developed to optimize regenerative techniques. The system is based on a method that delivers a certain amount of a therapeutic agent for a prolonged period of time to a targeted diseased area within the body. This helps maintain the required plasma and tissue drug levels in the body, thereby preventing any damage to the healthy tissue via the drug. The drug delivery system is highly integrated and requires various disciplines, such as chemists, biologists, and engineers, to join forces to optimize this system.
== Background ==
In traditional drug delivery systems such as oral ingestion or intravascular injection, the medication is distributed throughout the body through the systemic blood circulation. For most therapeutic agents, only a small portion of the medication reaches the organ to be affected, such as in chemotherapy where roughly 99% of the drugs administered do not reach the tumor site. Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues. For example, by avoiding the host's defense mechanisms and inhibiting non-specific distribution in the liver and spleen, a system can reach the intended site of action in higher concentrations. Targeted delivery is believed to improve efficacy while reducing side-effects.
When implementing a targeted release system, the following design criteria for the system must be taken into account: the drug properties, side-effects of the drugs, the route taken for the delivery of the drug, the targeted site, and the disease.
Increasing developments to novel treatments requires a controlled microenvironment that is accomplished only through the implementation of therapeutic agents whose side-effects can be avoided with targeted drug delivery. Advances in the field of targeted drug delivery to cardiac tissue will be an integral component to regenerate cardiac tissue.
There are two kinds of targeted drug delivery: active targeted drug delivery, such as some antibody medications, and passive targeted drug delivery, such as the enhanced permeability and retention effect (EPR-effect).
== Targeting methods ==
This ability for nanoparticles to concentrate in areas of solely diseased tissue is accomplished through either one or both means of targeting: passive or active.
=== Passive targeting ===
Passive targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. In passive targeting, the drug's success is directly related to circulation time. This is achieved by cloaking the nanoparticle with some sort of coating. Several substances can achieve this, with one of them being polyethylene glycol (PEG). By adding PEG to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic. The particles obtain this property due to the hydrophobic interactions that are natural to the reticuloendothelial system (RES), thus the drug-loaded nanoparticle is able to stay in circulation for a longer period of time. To work in conjunction with this mechanism of passive targeting, nanoparticles that are between 10 and 100 nanometers in size have been found to circulate systemically for longer periods of time.
=== Active targeting ===
Active targeting of drug-loaded nanoparticles enhances the effects of passive targeting to make the nanoparticle more specific to a target site. There are several ways that active targeting can be accomplished. One way to actively target solely diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted to. Researchers can then utilize cell-specific ligands that will allow the nanoparticle to bind specifically to the cell that has the complementary receptor. This form of active targeting was found to be successful when utilizing transferrin as the cell-specific ligand. The transferrin was conjugated to the nanoparticle to target tumor cells that possess transferrin-receptor mediated endocytosis mechanisms on their membrane. This means of targeting was found to increase uptake, as opposed to non-conjugated nanoparticles. Another cell-specific ligand is the RGD motif which binds to the integrin αvβ3. This integrin is upregulated in tumor and activated endothelial cells. Conjugation of RGD to chemotherapeutic-loaded nanoparticles has been shown to increase cancer cell uptake in vitro and therapeutic efficacy in vivo.
Active targeting can also be achieved by utilizing magnetoliposomes, which usually serves as a contrast agent in magnetic resonance imaging. Thus, by grafting these liposomes with a desired drug to deliver to a region of the body, magnetic positioning could aid with this process.
Furthermore, a nanoparticle could possess the capability to be activated by a trigger that is specific to the target site, such as utilizing materials that are pH responsive. Most of the body has a consistent, neutral pH. However, some areas of the body are naturally more acidic than others, and, thus, nanoparticles can take advantage of this ability by releasing the drug when it encounters a specific pH. Another specific triggering mechanism is based on the redox potential. One of the side effects of tumors is hypoxia, which alters the redox potential in the vicinity of the tumor. By modifying the redox potential that triggers the payload release the vesicles can be selective to different types of tumors.
By utilizing both passive and active targeting, a drug-loaded nanoparticle has a heightened advantage over a conventional drug. It is able to circulate throughout the body for an extended period of time until it is successfully attracted to its target through the use of cell-specific ligands, magnetic positioning, or pH responsive materials. Because of these advantages, side effects from conventional drugs will be largely reduced as a result of the drug-loaded nanoparticles affecting only diseased tissue. However, an emerging field known as nanotoxicology has concerns that the nanoparticles themselves could pose a threat to both the environment and human health with side effects of their own. Active targeting can also be achieved through peptide based drug targeting system.
== Delivery vehicles ==
There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc. An ideal drug delivery vehicle must be non-toxic, biocompatible, non-immunogenic, biodegradable, and must avoid recognition by the host's defense mechanisms[3].
=== Peptides ===
Cell Surface Peptides provide one way to introduce drug delivery into a target cell. This method is accomplished by the peptide binding to a target cells surface receptors, in a way that bypasses immune defenses that would otherwise compromise a slower delivery, without causing harm to the host. In particular, peptides, such as intercellular adhesion molecule-1, have shown a great deal of binding ability in a target cell. This method has shown a degree of efficacy in treating both autoimmune diseases as well as forms of cancer as a result of this binding affinity. Peptide mediated delivery is also of promise due to the low cost of creating the peptides as well as the simplicity of their structure.
=== Liposomes ===
The most common vehicle currently used for targeted drug delivery is the liposome. Liposomes are non-toxic, non-hemolytic, and non-immunogenic even upon repeated injections; they are biocompatible and biodegradable and can be designed to avoid clearance mechanisms (reticuloendothelial system (RES), renal clearance, chemical or enzymatic inactivation, etc.) Lipid-based, ligand-coated nanocarriers can store their payload in the hydrophobic shell or the hydrophilic interior depending on the nature of the drug/contrast agent being carried.
The only problem to using liposomes in vivo is their immediate uptake and clearance by the RES system and their relatively low stability in vitro. To combat this, polyethylene glycol (PEG) can be added to the surface of the liposomes. Increasing the mole percent of PEG on the surface of the liposomes by 4-10% significantly increased circulation time in vivo from 200 to 1000 minutes.
PEGylation of the liposomal nanocarrier elongates the half-life of the construct while maintaining the passive targeting mechanism that is commonly conferred to lipid-based nanocarriers. When used as a delivery system, the ability to induce instability in the construct is commonly exploited allowing the selective release of the encapsulated therapeutic agent in close proximity to the target tissue/cell in vivo. This nanocarrier system is commonly used in anti-cancer treatments as the acidity of the tumour mass caused by an over-reliance on glycolysis triggers drug release.
Additional endogenous trigger pathways have been explored through the exploitation of inner and outer tumor environments, such as reactive oxygen species, glutathione, enzymes, hypoxia, and adenosine-5’- triphosphate (ATP), all of which are generally highly present in and around tumors. External triggers are also used, such as light, low frequency ultrasound (LFUS), electrical fields, and magnetic fields. In specific, LFUS has demonstrated high efficacy in the controlled trigger of various drugs in mice, such as cisplatin and calcein.
=== Micelles and dendrimers ===
Another type of drug delivery vehicle used is polymeric micelles. They are prepared from certain amphiphilic co-polymers consisting of both hydrophilic and hydrophobic monomer units. They can be used to carry drugs that have poor solubility. This method offers little in the terms of size control or function malleability. Techniques that utilize reactive polymers along with a hydrophobic additive to produce a larger micelle that create a range of sizes have been developed.
Dendrimers are also polymer-based delivery vehicles. They have a core that branches out in regular intervals to form a small, spherical, and very dense nanocarrier.
=== Biodegradable particles ===
Biodegradable particles have the ability to target diseased tissue as well as deliver their payload as a controlled-release therapy. Biodegradable particles bearing ligands to P-selectin, endothelial selectin (E-selectin) and ICAM-1 have been found to adhere to inflamed endothelium. Therefore, the use of biodegradable particles can also be used for cardiac tissue.
=== Microalgae-based delivery ===
There are biocompatible microalgae hybrid microrobots for active drug-delivery in the lungs and the gastrointestinal tract. The microrobots proved effective in tests with mice. In the two studies, "Fluorescent dye or cell membrane–coated nanoparticle functionalized algae motors were further embedded inside a pH-sensitive capsule" and "antibiotic-loaded neutrophil membrane-coated polymeric nanoparticles [were attached] to natural microalgae".
=== Artificial DNA nanostructures ===
The success of DNA nanotechnology in constructing artificially designed nanostructures out of nucleic acids such as DNA, combined with the demonstration of systems for DNA computing, has led to speculation that artificial nucleic acid nanodevices can be used to target drug delivery based upon directly sensing its environment. These methods make use of DNA solely as a structural material and a chemical, and do not make use of its biological role as the carrier of genetic information. Nucleic acid logic circuits that could potentially be used as the core of a system that releases a drug only in response to a stimulus such as a specific mRNA have been demonstrated. In addition, a DNA "box" with a controllable lid has been synthesized using the DNA origami method. This structure could encapsulate a drug in its closed state, and open to release it only in response to a desired stimulus.
== Applications ==
Targeted drug delivery can be used to treat many diseases, such as the cardiovascular diseases and diabetes. However, the most important application of targeted drug delivery is to treat cancerous tumors. In doing so, the passive method of targeting tumors takes advantage of the enhanced permeability and retention (EPR) effect. This is a situation specific to tumors that results from rapidly forming blood vessels and poor lymphatic drainage. When the blood vessels form so rapidly, large fenestrae result that are 100 to 600 nanometers in size, which allows enhanced nanoparticle entry. Further, the poor lymphatic drainage means that the large influx of nanoparticles are rarely leaving, thus, the tumor retains more nanoparticles for successful treatment to take place.
The American Heart Association rates cardiovascular disease as the number one cause of death in the United States. Each year 1.5 million myocardial infarctions (MI), also known as heart attacks, occur in the United States, with 500,000 leading to deaths. The costs related to heart attacks exceed $60 billion per year. Therefore, there is a need to come up with an optimum recovery system. The key to solving this problem lies in the effective use of pharmaceutical drugs that can be targeted directly to the diseased tissue. This technique can help develop many more regenerative techniques to cure various diseases. The development of a number of regenerative strategies in recent years for curing heart disease represents a paradigm shift away from conventional approaches that aim to manage heart disease.
Stem cell therapy can be used to help regenerate myocardium tissue and return the contractile function of the heart by creating/supporting a microenvironment before the MI. Developments in targeted drug delivery to tumors have provided the groundwork for the burgeoning field of targeted drug delivery to cardiac tissue. Recent developments have shown that there are different endothelial surfaces in tumors, which has led to the concept of endothelial cell adhesion molecule-mediated targeted drug delivery to tumors.
Liposomes can be used as drug delivery for the treatment of tuberculosis. The traditional treatment for TB is skin to chemotherapy which is not overly effective, which may be due to the failure of chemotherapy to make a high enough concentration at the infection site. The liposome delivery system allows for better microphage penetration and better builds a concentration at the infection site. The delivery of the drugs works intravenously and by inhalation. Oral intake is not advised because the liposomes break down in the Gastrointestinal System.
3D printing is also used by doctors to investigate how to target cancerous tumors in a more efficient way. By printing a plastic 3D shape of the tumor and filling it with the drugs used in the treatment the flow of the liquid can be observed allowing the modification of the doses and targeting location of the drugs.
== See also ==
Targeted therapy
Nanomedicine
Nanobiotechnology § Nanomedicine
Antibody-drug conjugate
Retrometabolic drug design
Magnetic drug delivery
PH-responsive tumor-targeted drug delivery
== References ==
== Further reading ==
Schroeder, Avi; Honen, Reuma; Turjeman, Keren; Gabizon, Alberto; Kost, Joseph; Barenholz, Yechezkel (2009). "Ultrasound triggered release of cisplatin from liposomes in murine tumors". Journal of Controlled Release. 137 (1): 63–8. doi:10.1016/j.jconrel.2009.03.007. PMID 19303426.
Scott, Robert C.; Wang, Bin; Nallamothu, Ramakrishna; Pattillo, Christopher B.; Perez-Liz, Georgina; Issekutz, Andrew; Valle, Luis Del; Wood, George C.; Kiani, Mohammad F. (2007). "Targeted delivery of antibody conjugated liposomal drug carriers to rat myocardial infarction". Biotechnology and Bioengineering. 96 (4): 795–802. doi:10.1002/bit.21233. PMID 17051598. S2CID 30039741.
Scott, Robert C; Crabbe, Deborah; Krynska, Barbara; Ansari, Ramin; Kiani, Mohammad F (2008). "Aiming for the heart: targeted delivery of drugs to diseased cardiac tissue". Expert Opinion on Drug Delivery. 5 (4): 459–70. doi:10.1517/17425247.5.4.459. PMID 18426386. S2CID 71338475.
Wang, Bin; Rosano, Jenna M; Cheheltani, Rabe'e; Achary, Mohan P; Kiani, Mohammad F (2010). "Towards a targeted multi-drug delivery approach to improve therapeutic efficacy in breast cancer". Expert Opinion on Drug Delivery. 7 (10): 1159–73. doi:10.1517/17425247.2010.513968. PMID 20738211. S2CID 19679654.
Wang, Bin; Scott, Robert C.; Pattillo, Christopher B.; Prabhakarpandian, Balabhaskar; Sundaram, Shankar; Kiani, Mohammad F. (2008). "Modeling Oxygenation and Selective Delivery of Drug Carriers Post-Myocardial Infarction". In Kang, Kyung A.; Harrison, David K.; Bruley, Duane F. (eds.). Oxygen Transport to Tissue XXIX. Advances in Experimental Medicine and Biology. Vol. 614. Springer. pp. 333–43. doi:10.1007/978-0-387-74911-2_37. ISBN 978-0-387-74910-5. PMID 18290344.
YashRoy R.C. (1999) Targeted drug delivery.Proceedings ICAR Short Course on "Recent approaches on clinical pharmacokinetics and therapeutic monitoring of drugs in farm animals", Oct 25 to Nov 3, 1999, Div of Pharmacology and Toxicology, IVRI, Izatnagar (India), pp. 129–136. https://www.researchgate.net/publication/233426779_Targeted_drug_delivery?ev=prf_pub
== External links ==
Drug delivery right on target | Wikipedia/Targeted_drug_delivery |
The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial drug candidates proceed through the entire multi-year process of drug development, concluding with an approved NDA, if successful.
The goals of the NDA are to provide enough information to permit FDA reviewers to establish the complete history of the candidate drug. Among facts needed for the application are:
Patent and manufacturing information
Drug safety and specific effectiveness for its proposed use(s) when used as directed
Reports on the design, compliance, and conclusions of completed clinical trials by the Institutional Review Board
Drug susceptibility to abuse
Proposed labeling (package insert) and directions for use
Exceptions to this process include voter driven initiatives for medical marijuana in certain states.
== Before trials ==
To legally test the drug on human subjects in the United States, the maker must first obtain an Investigational New Drug (IND) designation from FDA. This application is based on nonclinical data, typically from a combination of in vivo and in vitro laboratory safety studies, that shows the drug is safe enough to test in humans. Often the "new" drugs that are submitted for approval include new molecular entities or old medications that have been chemically modified to elicit differential pharmacological effects or reduced side effects.
== Clinical trials ==
Since the 1962 Kefauver–Harris Amendment, new drugs are statutorily required to demonstrate both safety and effectiveness through substantial evidence for approval. The amendment defines substantial evidence as "evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof."
This standard lies at the heart of the regulatory program for drugs. Data for the submission must include those from one or more rigorous clinical trials.
Due to the plural "adequate and well-controlled investigations" in the statute, FDA has interpreted the substantial evidence requirement as requiring at least two adequate and well-controlled clinical trials, each convincing on its own. However, in 1997, Congress passed an amendment, expressly granting FDA authority to consider other types of confirmatory evidence along with one adequate and well-controlled clinical investigation for approval.
The trials are typically conducted in three phases:
Phase 1: The drug is tested in 20 to 100 healthy volunteers to determine its safety at low doses. About 70% of candidate drugs advance to Phase 2.
Phase 2: The drug is tested for both efficacy and safety in up to several hundred people with the targeted disease. Some two-thirds of candidate drugs fail in Phase 2 clinical trials due to the drug not being as effective as anticipated.
Phase 3: The drug is typically tested in several hundred to several thousand people with the targeted disease in double-blind, placebo controlled trials to demonstrate its specific efficacy. Under 30% of drug candidates succeed through Phase 3.
Phase 4: These are postmarketing surveillance trials in several thousand people taking the drug for its intended purpose to monitor efficacy and safety of the approved marketed drug.
The legal requirements for safety and effectiveness have been interpreted as requiring scientific evidence that the benefits of a drug outweigh the risks and that adequate instructions exist for use, since many drugs have adverse side effects.
== The actual application ==
The results of the testing program are codified in an FDA-approved public document that is called the product label, package insert or Full Prescribing Information. The prescribing information is widely available on the web from the FDA, drug manufacturers, and frequently inserted into drug packages. The main purpose of a drug label is to provide healthcare providers and consumers with adequate information and directions for the safe use of the drug.
The documentation required in an NDA is supposed to tell "the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged.” Once approval of an NDA is obtained, the new drug can be legally marketed starting that day in the United States.
Once the application is submitted, the FDA has 60 days to conduct a preliminary review, which assesses whether the NDA is "sufficiently complete to permit a substantive review." If the FDA finds the NDA insufficiently complete, then the FDA rejects the application by sending the applicant a Refuse to File letter, which explains where the application failed to meet requirements. Where the application cannot be granted for substantive reasons, the FDA issues a Complete Response Letter.
Assuming the FDA finds the NDA acceptable, a 74-day letter is published. A standard review implies an FDA decision within about 10 months while a priority review should complete within 6 months.
== Requirements for similar products ==
Biologics, such as vaccines and many recombinant proteins used in medical treatments are generally approved by FDA via a Biologic License Application (BLA), rather than an NDA. The manufacture of biologics is considered to differ fundamentally from that of less complex chemicals, requiring a somewhat different approval process.
Generic drugs that have already been approved via an NDA submitted by another maker are approved via an Abbreviated New Drug Application (ANDA), which does not require all of the clinical trials normally required for a new drug in an NDA. Most biological drugs, including a majority of recombinant proteins are considered ineligible for an ANDA under current US law. However, a handful of biologic medicines, including biosynthetic insulin, growth hormone, glucagon, calcitonin, and hyaluronidase are grandfathered under governance of the Federal Food Drug and Cosmetics Act, because these products were already approved when legislation to regulate biotechnology medicines later passed as part of the Public Health Services Act.
Medications intended for use in animals are submitted to a different center within FDA, the Center for Veterinary Medicine (CVM) in a New Animal Drug Application (NADA). These are also specifically evaluated for their use in food animals and their possible effect on the food from animals treated with the drug.
== See also ==
Drug development
Inverse benefit law
Investigational New Drug, FDA application to start clinical trials
Kefauver Harris Amendment, a 1962 amendment to the Federal Food, Drug, and Cosmetic Act (e.g. to also require evidence of efficacy)
Regulation of therapeutic goods, rules in different countries.
== References ==
== External links ==
Henninger, Daniel (2002). "Drug Lag". In David R. Henderson (ed.). Concise Encyclopedia of Economics (1st ed.). Library of Economics and Liberty. OCLC 317650570, 50016270, 163149563
Chapter 11: Prescription Drug Product Submissions in: Fundamentals of US Regulatory Affairs, Eighth Edition 2013 Archived March 4, 2016, at the Wayback Machine
Novel Drug Approvals for 2021 | Wikipedia/New_Drug_Application |
An orphan drug is a pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by the conditions. The conditions that orphan drugs are used to treat are referred to as orphan diseases. The assignment of orphan status to a disease and to drugs developed to treat it is a matter of public policy that depends on the legislation (if there is any) of the country.
Designation of a drug as an orphan drug has yielded medical breakthroughs that might not otherwise have been achieved, due to the economics of drug research and development. Examples of this can be that in the U.S. and the EU, it is easier to gain marketing approval for an orphan drug. There may be other financial incentives, such as an extended period of exclusivity, during which the producer has sole rights to market the drug. All are intended to encourage development of drugs which would otherwise lack sufficient profit motive to attract corporate research budgets and personnel.
== Definition ==
=== United States ===
According to the US Food and Drug Administration (FDA), an orphan drug is defined as one "intended for the treatment, prevention or diagnosis of a rare disease or condition, which is one that affects less than 200,000 persons in the US" (which equates to approximately 6 cases per 10,000 population) "or meets cost recovery provisions of the act".
=== Europe ===
In the European Union (EU), the European Medicines Agency (EMA) defines a drug as "orphan" if it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically and seriously debilitating condition affecting not more than 5 in 10,000 EU people. EMA also qualifies a drug as orphan if – without incentives – it would be unlikely that marketing the drug in the EU would generate sufficient benefit for the affected people and for the drug manufacturer to justify the investment.
=== Japan ===
In Japan, drugs and medical devices are given the designation as an orphan drug or device based on the Act of Securing Quality, Efficacy, Safety of Pharmaceuticals, Medical Devices, Regenerative or Cellular Therapy Products, Gene Therapy Products, and Cosmetics if they are intended for use in less than 50,000 patients in Japan for which there is a high medical need.
== Global statistics ==
As of 2014, there were 281 marketed orphan drugs and more than 400 orphan-designated drugs in clinical trials. More than 60% of orphan drugs were biologics. The U.S. dominated development of orphan drugs, with more than 300 trials, followed by Europe. Cancer treatment was the indication in more than 30% of orphan drug trials.
Number of orphan drugs in clinical trials: 40
Number of orphan drugs in phase 2 trial: 231
Number of orphan drugs in U.S. clinical trials: 350 in the pipeline from research until registration
== Effect on investment, sales and profit ==
According to Thomson Reuters in their 2012 publication "The Economic Power of Orphan Drugs", there has been increased investment in orphan drug research and development, partly due to the U.S. Orphan Drug Act of 1983 (ODA) and similar acts in other regions of the world driven by "high-profile philanthropic funding".
According to Drug Discovery Today, the years 2001 to 2011 were the "most productive period in the history of orphan drug development, in terms of average annual orphan drug designations and orphan drug approvals".: 660 For the same decade the compound annual growth rate (CAGR) of the orphan drugs was an "impressive 25.8%, compared to only 20.1% for a matched control group of non-orphan drugs".: 6 By 2012, the market for orphan drugs was worth US$637 million, compared with US$638 million for a control group of non-orphan drugs.
By 2012,
the revenue-generating potential of orphan drugs [was] as great as for non-orphan drugs, even though patient populations for rare diseases are significantly smaller. Moreover, we suggest that orphan drugs have greater profitability when considered in the full context of developmental drivers, including government financial incentives, smaller clinical trial sizes, shorter clinical trial times and higher rates of regulatory success.
According to a 2014 report, the orphan drug market has become increasingly lucrative for a number of reasons. The cost of clinical trials for orphan drugs is substantially lower than for other diseases because trial sizes are naturally much smaller than for more diseases with larger numbers of patients. Small clinical trials and minimal competition place orphan agents at an advantage in regulatory review.
Tax incentives reduce the cost of development. On average the cost per patient for orphan drugs is "six times that of non-orphan drugs, a clear indication of their pricing power". The cost of per-person outlays are large and are expected to increase with wider use of public subsidies.
The 2014 Orphan Drug report stated that the percentage of orphan drug sales as part of all prescription drug sales had been increasing at a rapid rate. The report projected a total of US$176 billion by 2020. Although orphan disease populations are the smallest, the cost of per-patient outlays among them are the largest and are expected to increase as more people with rare diseases become eligible for subsidies – in the U.S., for example, through the Affordable Care Act.
== Legislation ==
Orphan drugs generally follow the same regulatory development path as any other pharmaceutical product, in which testing focuses on pharmacokinetics and pharmacodynamics, dosing, stability, safety and efficacy. However, some statistical burdens are lessened to maintain development momentum. For example, orphan drug regulations generally acknowledge the fact that it may not be possible to test 1,000 patients in a phase III clinical trial if fewer than that number are affected by the disease.
Government intervention on behalf of orphan drug development takes several forms:
Tax incentives
Exclusivity (enhanced patent protection and marketing rights)
Research subsidies
Creating a government-run enterprise to engage in research and development as in a Crown corporation
A 2015 study of "34 key Canadian stakeholders, including drug regulators, funders, scientists, policy experts, pharmaceutical industry representatives, and patient advocates" investigated factors behind the pharmaceutical industry growing interest in "niche markets" such as orphan drugs.
=== United States ===
The Orphan Drug Act (ODA) of January 1983, passed in the United States, with lobbying from the National Organization for Rare Disorders and many other organizations, is meant to encourage pharmaceutical companies to develop drugs for diseases that have a small market. Under the ODA drugs, vaccines, and diagnostic agents would qualify for orphan status if they were intended to treat a disease affecting fewer than 200,000 American citizens. Under the ODA orphan drug sponsors qualify for seven-year FDA-administered market Orphan Drug Exclusivity (ODE), "tax credits of up to 50% of R&D costs, R&D grants, waived FDA fees, protocol assistance: 660 and may get clinical trial tax incentives.
In the U.S., orphan drug designation means that the sponsor qualifies for certain benefits, but it does not mean the drug is safe, effective or legal.
In 2002, the Rare Diseases Act was signed into law. It amended the Public Health Service Act to establish the Office of Rare Diseases. It also increased funding for the development of treatments for people with rare diseases.
=== European Union ===
In 2000, the European Union (EU) enacted similar legislation, Regulation(EC) No 141/2000, which refers to drugs developed to treat rare diseases to as "orphan medicinal products". The EU's definition of an orphan condition is broader than that of the US, in that it also covers some tropical diseases that are primarily found in developing nations. Orphan drug status granted by the European Commission gives marketing exclusivity in the EU for 10 years after approval. The EU's legislation is administered by the Committee on Orphan Medicinal Products of the European Medicines Agency (EMA).
In late 2007 the FDA and EMA agreed to use a common application process for both agencies to make it easier for manufacturers to apply for orphan drug status but, while continuing two separate approval processes.
=== Other countries ===
Legislation has been implemented by Japan, Singapore, and Australia that offers subsidies and other incentives to encourage the development of drugs that treat orphan diseases.
=== Numbers of new drugs ===
Under the ODA and EU legislation, many orphan drugs have been developed, including drugs to treat glioma, multiple myeloma, cystic fibrosis, phenylketonuria, snake venom poisoning, and idiopathic thrombocytopenic purpura.
The Pharmaceutical Executive opines, that the "ODA is nearly universally acknowledged to be a success".
Before the US Congress enacted the ODA in 1983, only 38 drugs were approved in the US specifically to treat orphan diseases. In the US, from January 1983 to June 2004, 249 orphan drugs received marketing authorization and 1,129 received different orphan drug designations, compared to fewer than ten such products in the decade prior to 1983. From 1983 until May 2010, the FDA approved 353 orphan drugs and granted orphan designations to 2,116 compounds. As of 2010, 200 of the roughly 7,000 officially designated orphan diseases have become treatable.
Critics have questioned whether orphan drug legislation was the real cause of this increase, claiming that many of the new drugs were for disorders which were already being researched anyway, and would have had drugs developed regardless of the legislation, and whether the ODA has truly stimulated the production of non-profitable drugs; the act also has been criticised for allowing some pharmaceutical companies to make a large profit off drugs which have a small market but sell for a high price.
While the European Medicines Agency grants orphan drugs market access in all member states, in practice, they only reach the market when a member state decides that its national health system will reimburse for the drug. For example, in 2008, 44 orphan drugs reached the market in the Netherlands, 35 in Belgium, and 28 in Sweden, while in 2007, 35 such drugs reached the market in France and 23 in Italy.
Though not technically an orphan disease, research and development into the treatment for AIDS has been heavily linked to the Orphan Drug Act. In the beginning of the AIDS epidemic the lack of treatment for the disease was often accredited to a believed lack of commercial base for a medication linked to HIV infection. This encouraged the FDA to use the Orphan Drug Act to help bolster research in this field, and by 1995 13 of the 19 drugs approved by the FDA to treat AIDS had received orphan drug designation, with 10 receiving marketing rights. These are in addition to the 70 designated orphan drugs designed to treat other HIV related illnesses.
== Examples for selected diseases ==
=== Cystic fibrosis ===
In the 1980s, people with cystic fibrosis rarely lived beyond their early teens. Drugs like Pulmozyme and tobramycin, both developed with aid from the ODA, revolutionized treatment for cystic fibrosis patients by significantly improving their quality of life and extending their life expectancies. Now, cystic fibrosis patients often survive into their thirties and some into their fifties.
=== Familial hypercholesterolemia ===
The 1985 Nobel Prize for medicine went to two researchers for their work related to familial hypercholesterolemia, which causes large and rapid increases in cholesterol levels. Their research led to the development of statin drugs which are now commonly used to treat high cholesterol.
=== Wilson's disease ===
Penicillamine was developed to treat Wilson's disease, a rare hereditary disease that can lead to a fatal accumulation of copper in the body. This drug was later found to be effective in treating arthritis. Bis-choline tetrathiomolybdate is currently under investigation as a therapy against Wilson's disease.
=== Phospholipase 2G6-associated neurodegeneration ===
In 2017, FDA granted RT001 orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN).
=== Transthyretin-related hereditary amyloidosis ===
The FDA granted Patisiran (Onpattro) orphan drug status and breakthrough therapy designation due to its novel mechanism involving RNA therapy to block the production of an abnormal form of transthyretin. Patisiran received full FDA approval in 2018 and its RNA lipid nanoparticle drug delivery system was later used in the Pfizer–BioNTech COVID-19 vaccine and Moderna RNA vaccines.
== Activism, research centers ==
The Center for Orphan Drug Research at the University of Minnesota College of Pharmacy helps small companies with insufficient in-house expertise and resources in drug synthesis, formulation, pharmacometrics, and bio-analysis.
The Keck Graduate Institute Center for Rare Disease Therapies (CRDT) in Claremont, California, supports projects to revive potential orphan drugs whose development has stalled by identifying barriers to commercialization, such as problems with formulation and bio-processing.
Numerous advocacy groups such as the National Organization for Rare Disorders, Global Genes Project, Children's Rare Disease Network, Abetalipoproteinemia Collaboration Foundation, Zellweger Baby Support Network, and the Friedreich's Ataxia Research Alliance have been founded in order to advocate on behalf of patients with rare diseases with a particular emphasis on diseases that affect children.
== Cost ==
According to a 2015 report published by EvaluatePharma, the economics of orphan drugs mirrors the economics of the pharmaceutical market as a whole but has a few very large differences. The market for orphan drugs is by definition very small, but while the customer base is drastically smaller the cost of research and development is very much the same as for non orphan drugs. This, the producers have claimed, causes them to charge extremely high amounts for treatment, sometimes as high as $700,000 a year, as in the case of Spinraza (Biogen), FDA approved in December 2016 for spinal muscular atrophy, placing a large amount of stress on insurance companies and patients. An analysis of 12 orphan drugs that were approved in the US between 1990 and 2000 estimated a price reduction of on average 50% upon loss of marketing exclusivity, with a range of price reductions from 14% to 95%.
Governments have implemented steps to reduce high research and development cost with subsidies and other forms of financial assistance. The largest assistance are tax breaks which can be as high as 50% of research and development costs. Orphan drug manufacturers are also able to take advantage of the small customer base to cut cost on clinical trials due to the small number of cases to have smaller trials which reduces cost. These smaller clinical trials also allow orphan drugs to move to market faster as the average time to receive FDA approval for an orphan drug is 10 months compared to 13 months for non-orphan drugs. This is especially true in the market for cancer drugs, as a 2011 study found that between 2004 and 2010 orphan drug trials were more likely to be smaller and less randomized than their non-orphan counterparts, but still had a higher FDA approval rate, with 15 orphan cancer drugs being approved, while only 12 non-orphan drugs were approved. This allows manufactures to get cost to the point that it is economically feasible to produce these treatments. The subsidies can total up to $30 million per fiscal year in the United States alone.
By 2015, industry analysts and academic researchers agreed, that the sky-high price of orphan drugs, such as eculizumab, was not related to research, development and manufacturing costs. Their price is arbitrary and they have become more profitable than traditional medicines.Public resources went into understanding the molecular basis of the disease, public resources went into the technology to make antibodies and finally, Alexion, to their credit, kind of picked up the pieces.
== Public funding ==
=== Evaluation criteria ===
By 2007 the use of economic evaluation methods regarding public-funding of orphan drugs, using estimates of the incremental cost-effectiveness, for example, became more established internationally. The QALY has often been used in cost-utility analysis to calculate the ratio of cost to QALYs saved for a particular health care intervention. By 2008 the National Institute for Health and Care Excellence (NICE) in England and Wales, for example, operated with a threshold range of £20,000–30,000 per quality-adjusted life year (QALY). By 2005 doubts were raised about the use of economic evaluations in orphan drugs. By 2008 most of the orphan drugs appraised had cost-effectiveness thresholds "well in excess of the 'accepted' level and would not be reimbursed according to conventional criteria". As early as 2005 McCabe et al. argued that rarity should not have a premium and orphan drugs should be treated like other pharmaceuticals in general. Drummond et al. argued that the social value of health technologies should also be included in the assessment along with the estimation of the incremental cost-effectiveness ratio.
=== Abuse potential ===
The very large incentives given to pharmaceutical companies to produce orphan drugs have led to the impression that the financial support afforded to make these drugs possible is akin to abuse. Because drugs can be used to treat multiple conditions, companies can take drugs that were filed with their government agency as orphan drugs to receive financial assistance, and then market it to a wide population to increase their profit margin. For example AstraZeneca's cholesterol drug Crestor was filed as a treatment for the rare disease pediatric familial hypercholesterolemia. After the drug was approved for orphan drug designation, and AstraZeneca had received tax breaks and other advantages, AstraZeneca later applied and received FDA approval for the drug to be used to treat cholesterol in all diabetics.
=== NICE ===
The UK's National Institute for Health and Care Excellence (NICE) can pay from £100,000 to £300,000 per QALY (Quality Adjusted Life Year) for treatments of "very rare conditions". This is compared to under £20,000 for non-orphan drugs.
In 2015, NICE held consultations with "patient groups, the Department of Health, companies, learned societies, charities and researchers" regarding the appraisal of medicines and other technologies. There was a call for more research into new processes, including:
the model of pharmaceutical research and development, the expectations that companies and patient groups have about how risk and reward is shared between the industry and a publicly funded NHS, and in the arrangements for commissioning expensive new treatments.
== See also ==
Rare disease
Drug development
European Organization for Rare Diseases
Supplementary protection certificate
== References ==
== External links ==
Drug Information Association (DIA)
EVENT: DIA/FDA Orphan Drug Designation Workshop November 2010 Archived 2010-10-28 at the Wayback Machine
European Commission - The Orphan drugs strategy
List of European Orphan Drugs
USA Food and Drug Administration: The Orphan Drug Act (as amended)
US FDA List of Orphan Designations and Approvals | Wikipedia/Orphan_drug |
In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals.
The main goals of preclinical studies are to determine a starting, safe dose for first-in-human study and assess potential toxicity of the product, which typically include new medical devices, prescription drugs, and diagnostics.
Companies use stylized statistics to illustrate the risks in preclinical research, such as that on average, only one in every 5,000 compounds that enters drug discovery to the stage of preclinical development becomes an approved drug.
== Types ==
Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics (what the drug does to the body) (PD), pharmacokinetics (what the body does to the drug) (PK), ADME, and toxicology testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to good laboratory practices (GLP) testing for safety of the device and its components. Some medical devices will also undergo biocompatibility testing which helps to show whether a component of the device or all components are sustainable in a living model. Most preclinical studies must adhere to GLPs in ICH Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in the United States.
Typically, both in vitro and in vivo tests will be performed. Studies of drug toxicity include which organs are targeted by that drug, as well as if there are any long-term carcinogenic effects or toxic effects causing illness.
== Animal testing ==
The information collected from these studies is vital so that safe human testing can begin. Typically, in drug development studies animal testing involves two species. The most commonly used models are murine and canine, although primate and porcine are also used.
=== Choice of species ===
The choice of species is based on which will give the best correlation to human trials. Differences in the gut, enzyme activity, circulatory system, or other considerations make certain models more appropriate based on the dosage form, site of activity, or noxious metabolites. For example, canines may not be good models for solid oral dosage forms because the characteristic carnivore intestine is underdeveloped compared to the omnivore's, and gastric emptying rates are increased. Also, rodents can not act as models for antibiotic drugs because the resulting alteration to their intestinal flora causes significant adverse effects. Depending on a drug's functional groups, it may be metabolized in similar or different ways between species, which will affect both efficacy and toxicology.
Medical device studies also use this basic premise. Most studies are performed in larger species such as dogs, pigs and sheep which allow for testing in a similar sized model as that of a human. In addition, some species are used for similarity in specific organs or organ system physiology (swine for dermatological and coronary stent studies; goats for mammary implant studies; dogs for gastric and cancer studies; etc.).
Importantly, the regulatory guidelines of FDA, EMA, and other similar international and regional authorities usually require safety testing in at least two mammalian species, including one non-rodent species, prior to human trials authorization.
=== Ethical issues ===
Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for ethical and cost reasons. However, most research will still involve animal based testing for the need of similarity in anatomy and physiology that is required for diverse product development.
== No observable effect levels ==
Based on preclinical trials, no-observed-adverse-effect levels (NOAELs) on drugs are established, which are used to determine initial phase 1 clinical trial dosage levels on a mass API per mass patient basis. Generally a 1/100 uncertainty factor or "safety margin" is included to account for interspecies (1/10) and inter-individual (1/10) differences.
== See also ==
Drug development
Preclinical imaging
Phases of clinical research
== References == | Wikipedia/Pre-clinical_development |
In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals.
The main goals of preclinical studies are to determine a starting, safe dose for first-in-human study and assess potential toxicity of the product, which typically include new medical devices, prescription drugs, and diagnostics.
Companies use stylized statistics to illustrate the risks in preclinical research, such as that on average, only one in every 5,000 compounds that enters drug discovery to the stage of preclinical development becomes an approved drug.
== Types ==
Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics (what the drug does to the body) (PD), pharmacokinetics (what the body does to the drug) (PK), ADME, and toxicology testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to good laboratory practices (GLP) testing for safety of the device and its components. Some medical devices will also undergo biocompatibility testing which helps to show whether a component of the device or all components are sustainable in a living model. Most preclinical studies must adhere to GLPs in ICH Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in the United States.
Typically, both in vitro and in vivo tests will be performed. Studies of drug toxicity include which organs are targeted by that drug, as well as if there are any long-term carcinogenic effects or toxic effects causing illness.
== Animal testing ==
The information collected from these studies is vital so that safe human testing can begin. Typically, in drug development studies animal testing involves two species. The most commonly used models are murine and canine, although primate and porcine are also used.
=== Choice of species ===
The choice of species is based on which will give the best correlation to human trials. Differences in the gut, enzyme activity, circulatory system, or other considerations make certain models more appropriate based on the dosage form, site of activity, or noxious metabolites. For example, canines may not be good models for solid oral dosage forms because the characteristic carnivore intestine is underdeveloped compared to the omnivore's, and gastric emptying rates are increased. Also, rodents can not act as models for antibiotic drugs because the resulting alteration to their intestinal flora causes significant adverse effects. Depending on a drug's functional groups, it may be metabolized in similar or different ways between species, which will affect both efficacy and toxicology.
Medical device studies also use this basic premise. Most studies are performed in larger species such as dogs, pigs and sheep which allow for testing in a similar sized model as that of a human. In addition, some species are used for similarity in specific organs or organ system physiology (swine for dermatological and coronary stent studies; goats for mammary implant studies; dogs for gastric and cancer studies; etc.).
Importantly, the regulatory guidelines of FDA, EMA, and other similar international and regional authorities usually require safety testing in at least two mammalian species, including one non-rodent species, prior to human trials authorization.
=== Ethical issues ===
Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for ethical and cost reasons. However, most research will still involve animal based testing for the need of similarity in anatomy and physiology that is required for diverse product development.
== No observable effect levels ==
Based on preclinical trials, no-observed-adverse-effect levels (NOAELs) on drugs are established, which are used to determine initial phase 1 clinical trial dosage levels on a mass API per mass patient basis. Generally a 1/100 uncertainty factor or "safety margin" is included to account for interspecies (1/10) and inter-individual (1/10) differences.
== See also ==
Drug development
Preclinical imaging
Phases of clinical research
== References == | Wikipedia/Preclinical_development |
Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have application as antidepressants and in the treatment of depression and other psychiatric disorders. SSRIs are therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder (also known as social phobia), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), and anorexia. There is also clinical evidence of the value of SSRIs in the treatment of the symptoms of schizophrenia and their ability to prevent cardiovascular diseases.
SSRIs primarily inhibit serotonin transporter (SERT) in the brain and have negligible effects on dopamine transporter (DAT) and norepinephrine transporter (NET). Inhibiting the binding of the neurotransmitter serotonin (5-HT) to SERT results in increased 5-HT concentration in the synaptic cleft leading to increased binding of 5-HT to postsynaptic receptors. This was once thought to be the mechanism that resulted in improvement of depression symptoms, however more recent systematic review of the academic literature has established that there is no correlation between 5-HT concentration or activity in the brain and depressive symptoms.
SSRIs have dominated the market for antidepressants and are recommended by the National Institute for Health and Clinical Excellence (NICE) as a first-line treatment of depression, because they tend to have fewer adverse effects than other type of antidepressants with the same effectiveness.
== Development history ==
Before the discovery of SSRI drugs, the treatments for mood disorders were relatively limited. Now, however, there are dozens of antidepressants on the market for the treatment of depression. Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were the first drugs to be developed for the treatment of depression, dating back to the early 1950s. Because of their undesirable adverse-effect profile and high potential for toxicity, due to their non-selective pharmacological effects, strict regimens were needed for taking the drugs, which limited their use. Because of this, researchers looked for other alternatives with similar effectiveness but fewer adverse effects e.g. drugs that did not cause cardiac conduction abnormalities in overdoses or have the tendency to cause seizures, which led to the discovery of the SSRI drugs. The SSRIs are the most significant class of antidepressants marketed in recent years and are one of the major medicinal discoveries of the last few decades. SSRIs were the first drugs to establish a theoretical pathophysiological role for 5-HT in affective illnesses and in the broad spectrum of anxiety disorders. Likewise, they were the first to confirm the inhibition of neurotransmitter re-uptake as an important therapeutic principle.
The SSRIs are the first rationally designed class of psychotropic medications. The strategy behind rational drug design is to develop a new drug that is capable of affecting a specific biological target, or in this case a special neural site of action (uptake pumps, receptors), while trying to avoid effects on other site of actions. The goal in such development is to produce pharmacological agents that are more efficacious, safer and better tolerated than older medications.
An initial success was achieved when medicinal chemists set out in search of the ideal SSRI with the chemical synthesis of zimelidine (figure 1) from the antihistamine drug brompheniramine, which exhibited selective inhibition of 5-HT re-uptake with minimal inhibition of norepinephrine (NE) re-uptake. Most importantly, zimelidine did not come with the adverse effect profile as the TCAs and therefore it became the template for the second generation SSRIs. Zimelidine was the first SSRI to be marketed, but several cases of Guillain–Barré syndrome were associated with the use of the drug which led to withdrawal from the market in 1983. Subsequently, several non-tricyclic SSRIs were discovered and marketed.
Fluoxetine, which was FDA approved in 1987, is usually thought to be the first SSRI to be marketed. The work which eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970 as a collaboration between Bryan Molloy and Ray Fuller. It was known at that time that the antihistamine diphenhydramine showed some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point. Molloy and fellow Eli Lilly chemist Klaus Schmiegel synthesized a series of dozens of its derivatives. Hoping to find a derivative inhibiting only serotonin reuptake, another Eli Lilly scientist, David T. Wong, proposed to retest the series for the in vitro reuptake of serotonin, norepinephrine and dopamine, using a technique developed by neuroscientist Solomon Snyder. This test showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.
Introduction of fluoxetine to the market is hailed as a miracle drug for the treatment of depression because it had fewer adverse effects, simpler dosing strategies and greater margin of safety when overdoses were consumed and thus it had better adherence, compared to the older antidepressants (TCAs and MAOIs). Fluoxetine paved the way for the next generation of SSRIs, serving as a prototype for them. Since then the number of drugs in the SSRI class has become bigger and there are now six (fluoxetine, paroxetine, citalopram, escitalopram, sertraline, and fluvoxamine), as demonstrated in table 1.
Table 1 SSRI drugs used to treat depression.
== Mechanism of action ==
Precise mechanism of antidepressant activity of SSRIs remains somewhat uncertain, but a number of biochemical functions associated with SSRI treatment have been established. SSRIs primarily inhibit SERT in the brain and have negligible effects on DAT and NET. The SSRIs also have less affinity for α1, α2, H1 and muscarinic receptors, which might explain the differences of adverse events between TCAs and SSRIs.
Although SSRIs arrive rapidly to the brain after administration and the effects on 5-HT re-uptake can be measured instantly, it takes about 2–4 weeks to get therapeutic effects. The SSRIs have very high and selective affinity for SERT and after administration they inhibit SERT immediately. SERT inhibition is implicated in the antidepressant activity of SSRIs. 70-80% inhibition of SERT is usually necessary to induce antidepressant effects and higher dosage does not induce greater antidepressant effects for average patients. Higher dosage does, however, increase the incidence and severity of adverse events associated with excessive 5-HT re-uptake inhibition.
SSRIs prevent 5-HT from binding to SERT which prevents absorption of 5-HT back into the presynapse terminal, where it is metabolized by monoamine oxidase or stored in secretory vesicles. As a result, the 5-HT concentration increases at the somatodendritic area of the 5-HT neuron but not so much at the axon terminal area (demonstrated in figure 2). This increase in 5-HT concentration causes desensitization of somatodendritic 5-HT1A autoreceptors. When these 5-HT1A autoreceptors have been downregulated, they will no longer restrict the impulse flow of the 5-HT neuron. The impulse flow is turned on and as a result 5-HT is released at the axon terminal. However, this increase of 5-HT does not happen quickly compared to the increase of 5-HT at the somatodendritic area of the 5-HT neuron. This delay is caused by the time it takes 5-HT to downregulate 5-HT1A autoreceptors and turn on the neuro impulse flow of the 5-HT neuron. This delay can explain the reason why antidepressants do not have effect on depression immediately. This can also be the reason why the antidepressant mechanisms can be connected to the increasing neuro impulse flow from 5-HT neurons, where as the concentration of 5-HT increases at the axon terminal before SSRIs start to work properly. When SSRIs have (1) inhibited the re-uptake pump, (2) increased somatodendritic 5-HT, (3) desensitized somatodendritic 5-HT1A autoreceptors, (4) turned on the impulse flow and (5) increased the release of 5-HT from axon terminal, the last step might be desensitization of postsynaptic 5-HT receptors. This desensitization could be the reason for reduction of adverse effects of SSRIs as tolerance develops.
== Adverse effects ==
Although generally well tolerated and numerous advantages over other antidepressants, SSRIs are not devoid of adverse effects. The adverse effects of SSRIs are usually predictable from a knowledge of their pharmacology and are dose related. Such adverse effects are gastrointestinal dysfunction (nausea, diarrhea, epigastric discomfort), effects on the central nervous system (CNS) (anxiety, fatigue, tremor), anticholinergic effects (dry mouth, blurred vision, drowsiness, difficulty in urination) and sexual dysfunction (anorgasmia,
low to no libido, erectile dysfunction, numb genitals, retrograde ejaculation, loss of erotic dreams or delayed ejaculation).
Occasionally symptoms of sexual dysfunction persist after discontinuation of SSRIs.
SSRIs adverse effects are generally mild and temporary and are more of a discomfort than a serious threat in terms of systemic toxicity. Therefore, the adverse effect profile of the SSRIs may offer certain therapeutic advantages in the management of depression.
== Pharmacology ==
SSRIs are well absorbed in the gastrointestinal tract and reach peak plasma levels within 1–8 hours. During absorption SSRIs bind to proteins and are widely distributed throughout the body, including the brain, whereas they are lipophilic.
Metabolism and elimination takes place mainly in the liver and most of the SSRIs produce pharmacologically active metabolites, as demonstrated in table 3 among with other pharmacology properties of the SSRIs.
Table 3 Comparative pharmacology of SSRIs
tmax = Time to peak plasma level after oral dose; VD = Volume of distribution; t1/2 = Elimination half-life
== Structural and mechanical differences between the SSRIs ==
It is recognized that both the position and the type of substitution on an aromatic moiety of the SSRI compounds are important for the higher specificity to SERT. Halogen substituents on the aromatic ring are found to be largely responsible for SSRIs specificity to SERT, but all SSRIs possess at specific positions halogen atoms (table 2). For the SERT protein, however, the structural basis of its specificity for SSRIs is poorly understood. Research has shown that the SSRI halogens all bind to exactly the same halogen-binding pocket (HBP) within the SERT protein and mutation at this HBP in SERT dramatically reduces the transporters affinity for SSRIs.
SSRI's are by definition selective, but they also bind to the homologous NET and DAT, although with much lower affinity than to their principal target SERT. The selectivity of SSRIs for SERT is notable in that only one or two different functional group substituents are sufficient to convert an SSRI into a norepinephrine reuptake inhibitor (NRI) with higher affinity to NE. SSRI antidepressants all have the same mechanism of action and are at least 10-fold more selective for 5-HT re-uptake inhibition than for NE re-uptake inhibition. However, despite the sharing of the same mechanism of action, SSRIs differ in their potency and selectivity in inhibiting 5-HT re-uptake and many of them have important effects on other transporters and receptors. SSRIs are structurally diverse with clear variations in their pharmacodynamic and pharmacokinetic profiles, which leads to differences among them in their half-lifes, clinical activity, adverse effects and drug interactions, which explains the differences in their efficacy and tolerability among patients. However, all SSRIs are clinically equal when it comes to their efficacy over time.
Table 2 Comparison of the chemical properties of SSRI drugs
=== Structure-activity relationship (SAR) ===
==== Phenoxyphenylpropylamine derivatives ====
Compounds containing an aryloxypropylamine motif in their structure, demonstrated in figure 3a, are known as monoamine reuptake inhibitors. Drugs containing this privileged structural motif, where R1 and R2 are aryls or heteroaryls, preferable phenyl, possess a selectivity profile for NET and SERT. While compounds containing a substituent in the 2'-position of the aroxyl ring of the structure (figure 3b) exhibits selectivity and high affinity for NET, and are therefore generally SNRIs, compounds having substituent in the 4'-position exhibits selectivity and high affinity for SERT and are therefore generally SSRIs, e.g. fluoxetine and paroxetine.
Fluoxetine is a racemic mixture of (R)- and (S)-fluoxetine where both enantiomers contribute to its biological activity. Since mono-substitution in the 4-para position of the phenoxy group (figure 4) results in selective inhibition of 5-HT re-uptake, a disubstitution i.e. 2,3- or 2,4- substitution therefore results in a loss of SERT selectivity. Fluoxetine has the widest spectrum of activity since it is the least SERT selective of all the SSRIs. Fluoxetine also has a 5-HT2C antagonist activity where it blocks the 5-HT activity of 5-HT2C receptors enhancing the release of both NE and DA. A 5-HT2C antagonist do not only help out with therapeutic effects of fluoxetine but also the tolerability of the drug. The advantage of being 5-HT2C antagonist is that it has a stimulatory effect and many patients have experienced an increase in energy, concentration and focus and a decrease in fatigue from the very first dose. The stimulant activity of 5-HT2C antagonist can however, be a disadvantage for patients with agitation, insomnia and anxiety. Another feature of fluoxetine is a weak NE re-uptake inhibition which can have clinical effect in higher doses. Fluoxetine also has a long half-life which can reduce withdrawal symptoms which are characteristic for some SSRIs after abrupt discontinuation, but it also means that it takes a long time to clear the drug and its active metabolite after discontinuing fluoxetine treatment.
Paroxetine is a constrained structural analogue of fluoxetine where the linear phenylpropylamine group of fluoxetine has been folded into a piperidine ring (figure 5). The compound has the possibility of four stereoisomers because it contains two chiral centers, but one of them, the (3S,4R)-isomer, is marketed as paroxetine. Research has shown that stereochemical factors affect affinity of the molecule for SERT where substitution into the 2-ortho-position of either aromatic rings decreases affinity for rat SERT by as much as 10–100 times, where the greatest loss occurs in the phenoxy ring.
Paroxetine is the most potent SSRI drug available, but it is less selective for SERT than fluvoxamine and sertraline. Paroxetine also has weak NET inhibition which could contribute to its efficacy in depression, especially at higher doses. As demonstrated in table 2, paroxetine also inhibits the NOSs enzyme which could be the reason for its sexual dysfunction adverse effect, especially in men. Paroxetine shows the highest affinity for muscarinic receptors of all the SSRIs which results in weak anticholinergic activity and therefore undesirable adverse effects.
While scientists were trying to create a new antidepressant to inhibit the NE re-uptake they accidentally synthesised two new compounds, named talopram and talsupram. The two compounds where not marketed in spite of being potent SNRIs because a number of suicide attempts were reported in clinical trials. With minor changes to the chemical structure of talopram (figure 6), including a single 6-cyano (CN) substitution, scientists were able to convert talopram into a potent SSRI, called citalopram. But citalopram can also be viewed as a constrained analogue of paroxetine.
Citalopram has the second most selectivity for SERT, no effects on NE or DA re-uptake and nor does it have affinity to other neuroreceptors. Citalopram is composed of two enantiomers, (R)- and (S)-, which are mirror images of each other (figure 7). Researches has shown that nearly all the activity resides in the (S)-enantiomer and that (R)-citalopram actually counteracts the action of the (S)-enantiomer. The combination of the two enantiomers is known as racemic citalopram and has weak antihistaminic properties that reside in the (R)-enantiomer. Solution to improve the properties of racemic citalopram is to remove the unwanted (R)-enantiomer. The resulting drug is better known as escitalopram, but it is composed of only the pure active (S)-(+)-isomer. This change appears to remove the antihistaminic properties of the drug. By removing the (R)-enantiomer, the lowest dose of escitalopram becomes more efficacious and faster onset than comparable dose of citalopram, where escitalopram has twice the activity of citalopram and is at least 27 times more potent than the (R)-enantiomer. Escitalopram is therefore the only SSRI drug for which pure SERT inhibition is responsible for almost all of its pharmacological action. Escitalopram is the newest and most selective inhibitor of the SSRIs and is today considered the best tolerated SSRI.
==== Aminotetraline derivatives ====
Tametraline, a compound synthesized in 1978 by Pfizer, was shown to be a potent NE and DA re-uptake inhibitor with animal studies. Later on a surprisingly substantial enhancement of blocking activity of 5-HT uptake was achieved by adding chlorine atoms at C-3 and C-4 to the structure of tametraline, resulting in (+)-trans-(1R,4S)-N-methyl-4-phenyl-1-aminotetralin, a potent but nonselective uptake blocker. The (+)-cis-(1S,4S)-isomer, one of four compounds diastereomers, however exhibited significantly more selective and potent 5-HT uptake inhibiting activity compared to the other three diastereomers, where the 4-phenyl ring favours attachments at 5-HT uptake sites. The compound was named sertraline (figure 8). Although sertraline appears to differ structurally from the other SSRIs, it has a phenylaminotetralin in its structure, in which the diphenylpropylamine nucleus has been forced into a stiff bicyclic ring system.
Sertraline is the second most potent inhibitor of 5-HT re-uptake which has two very interesting characteristics that distinguish it i.e. sertraline's (1) inhibiting effect on DAT and NET and (2) the binding to sigma-1 (σ1) receptor in CNS. The DAT and NET inhibition is controversial because of much weaker inhibition which it has, compared to SERT inhibition. Sertraline has about 60 times more potent inhibition potential on 5-HT than either NE or DA re-uptake. It is possible that only modest inhibition of DAT and NET is needed to cause an increase in energy, motivation and concentration, specially when added to other activity such as SERT inhibition. Sertraline has also been found to have high affinity for the CNS σ1 receptors. A role of the σ1 site in the pharmacological action of sertraline may exist, but the significance of sertraline affinity for σ1 receptors remains unclear.
=== Binding of SSRIs to SERT protein ===
The molecular basis for SSRIs function, including their binding mode and molecular mechanism of 5-HT re-uptake inhibition in SERT, is not fully understood and is a matter of debate. Such information is very important for the understanding of essential aspects of the drugs action, ranging from selectivity profile to therapeutic efficacy and the development of new and improved drugs that target the human SERT.
The three-dimensional (3D) structure of SERT is not known and has been the main obstacle for elucidation of the structural mechanism of the human SERT. Update: X-ray crystallography data is available as of 2017 it seems (https://www.rcsb.org/structure/6AWO)... Comparative molecular modeling have been used in research to create structural models of human SERT in complex with its ligand but has not given good results because of low phylogenetic and functional similarity between human SERT and available template proteins. However the 3D structure of some bacterial homologous transporters like the leucine transporter (LeuT) is known. The human SERT, NET and DAT are all members of the neurotransmitter:sodium symporter (NSS) protein family. SERT contains approximately 630 amino acids that are predicted to form 12 transmembrane alpha-helixes (TMs) which are connected with intra- and extracellular loops (ILs and ELs). LeuT, which is also a member of the NSS family that functions as an amino acid transporter, was crystallized from Aquifex aeolicus by Yamashita et al., and shares 20-25% identity in primary structure with the human neurotransmitter transporters. Therefore, the crystal structure of LeuT and its transport mechanism have been proven to be a good model system for the study of NSS proteins. Although detailed transport mechanism of the NSS proteins is not fully understood, it is clear that in order for transport to occur a rearrangement of large proteins needs to take place.
LeuT has been co-crystallised with sertraline and (R)- and (S)-fluoxetine where the SSRIs have been found to bind as non-competitive inhibitors in a vestibule binding site (can be looked at as a second binding site), which is separated from the drugs binding site by the site chains of the two aromatic amino acids of the extracellular gate of the transport protein. The halogens on the SSRIs chemical structure all bind to the same HBP within LeuT and interact with similar amino acids, but the amino acid sequence in the HBP is highly preserved between LeuT and SERT. That suggest that in the human SERT the SSRIs also bind both at the same position and with similar manner, which is a key feature making the SSRIs selective for SERT. Conversely, there could be differences in their binding where the other part of the drug molecule will likely bind to SERT in a different way, given the diversity in their structure. The localisation of the vestibular binding site, as the primary SSRI binding site in SERT is, is however controversial since some research has shown that the SSRIs work in competitive manner by binding to the drugs binding site, not to the second binding site.
==== Binding of fluoxetine to LeuT protein ====
Both enantiomers of fluoxetine show a similar affinity for SERT. However, NE:5HT selective ratio gives the impression that the (S)-enantiomer is 100 times more selective for SERT inhibition than the (R)-enantiomer. The (R)-(+)-stereoisomer is almost 8 times more potent an inhibitor of SERT together with a longer duration of action than the (S)-(−)-isomer. (S)-(−)-norfluoxetine metabolite is seven times more potent an inhibitor on 5-HT transporter then (R)-(+)-metabolite, with selectivity ratio almost equivalent to that of (S)-fluoxetine.
Both enantiomers of fluoxetine bind to the extracellular vestibule on the LeuT protein is such a way that the three fluorine atoms of the methylphenoxy ring bind into the HBP that is formed by Leu25, Gly26, Leu29, Arg30 and Tyr108. The halogens additionally make Van der Waals interaction with Leu29 and Tyr108, where the (S)-enantiomer additionally binds to Phe253 and makes Van der Waals contact with it among with previously mentioned amino acids. Because of the (S)-enantiomers opposite chirality to the (R)-enantiomer the rest of the molecule is reversed in the HBP, where the amine tail points towards the extracellular space and interacts with the N-terminal of Leu400, Asp401 and Ala319 (amino acids which are a part of the TM10). In this LeuT bound form the complex is rather rigid. The methylphenoxy ring rotates about the O5-C6 bond by 46 degrees for the (R)-enantiomer and 16 degrees for the (S)-enantiomer, but rigidity in the molecular structure indicates that the drug maintains its low-energy configuration upon binding to its protein target.
==== Binding of sertraline to LeuT protein ====
Sertaline binds to the same extracellular vestibule in LeuT as fluoxetine where the two chlorine atoms on the phenyl ring bind to HBP formed by Leu25, Gly26, Leu29, Arg30, Tyr108, Ile111 and Phe253. The halogens additionally make Van der Waals contact with Leu29, Tyr108 and Phe253. The tetralin (tetrahydronaphthalene) on the other end of sertraline’s structure is in contact with Leu400, Asp401 and Thr409 (which are a part of the TM10) as well as the molecule interacts with Ala319 of the EL4 hairpin loop and Arg30 and Gin34 of the TM1, where the amine tail points towards the cytoplasm. The bound sertraline molecule has its dichlorophenyl ring rotated about the C4-C13 bond by 180 degrees compared to the free drug.
==== Binding of escitalopram to human SERT protein ====
Andersen et al. were able to generate a model of the (S)-citalopram binding site in human SERT by combining mutational analysis and comparative modeling where they found out that Asn-177 and Phe-341 where key determinants for (S)-citalopram potency and high affinity inhibition in addition to Tyr-95, Asp-98, Ile-172 and Ser438 previously described, where three functional groups of the inhibitors structure bind to the transporters amino acids. (S)-citalopram is positioned as that the cyanophthalane-. fluorophenyl- and methylaminoprpyl moieties occupy three different sub-pockets within the SERT binding pocket. Ile-172 and Phe-341 are likely not in direct contact with the drug molecule, but they are very important for controlling alignment of the inhibitor.
== See also ==
Serotonin
Selective serotonin reuptake inhibitors
Monoamine reuptake inhibitors
Second-generation antidepressant
Serotonin-norepinephrine reuptake inhibitors
== References == | Wikipedia/Development_and_discovery_of_SSRI_drugs |
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops (three extracellular loops interacting with ligand molecules, three intracellular loops interacting with G proteins, an N-terminal extracellular region and a C-terminal intracellular region) of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (rhodopsin-like family). They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.
G protein-coupled receptors are found only in eukaryotes, including yeast, and choanoflagellates. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters. They vary in size from small molecules to peptides, to large proteins. G protein-coupled receptors are involved in many diseases.
There are two principal signal transduction pathways involving the G protein-coupled receptors:
the cAMP signal pathway and
the phosphatidylinositol signal pathway.
When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).: 1160
GPCRs are an important drug target, and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018. It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of the pharmaceutical research.
== History and significance ==
With the determination of the first structure of the complex between a G-protein coupled receptor (GPCR) and a G-protein trimer (Gαβγ) in 2011 a new chapter of GPCR research was opened for structural investigations of global switches with more than one protein being investigated. The previous breakthroughs involved determination of the crystal structure of the first GPCR, rhodopsin, in 2000 and the crystal structure of the first GPCR with a diffusible ligand (β2AR) in 2007. The way in which the seven transmembrane helices of a GPCR are arranged into a bundle was suspected based on the low-resolution model of frog rhodopsin from cryogenic electron microscopy studies of the two-dimensional crystals. The crystal structure of rhodopsin, that came up three years later, was not a surprise apart from the presence of an additional cytoplasmic helix H8 and a precise location of a loop covering retinal binding site. However, it provided a scaffold which was hoped to be a universal template for homology modeling and drug design for other GPCRs – a notion that proved to be too optimistic.
Results 7 years later were surprising because the crystallization of β2-adrenergic receptor (β2AR) with a diffusible ligand revealed quite a different shape of the receptor extracellular side than that of rhodopsin. This area is important because it is responsible for the ligand binding and is targeted by many drugs. Moreover, the ligand binding site was much more spacious than in the rhodopsin structure and was open to the exterior. In the other receptors crystallized shortly afterwards the binding side was even more easily accessible to the ligand. New structures complemented with biochemical investigations uncovered mechanisms of action of molecular switches which modulate the structure of the receptor leading to activation states for agonists or to complete or partial inactivation states for inverse agonists.
The 2012 Nobel Prize in Chemistry was awarded to Brian Kobilka and Robert Lefkowitz for their work that was "crucial for understanding how G protein-coupled receptors function". There have been at least seven other Nobel Prizes awarded for some aspect of G protein–mediated signaling. As of 2012, two of the top ten global best-selling drugs (Advair Diskus and Abilify) act by targeting G protein-coupled receptors.
== Classification ==
The exact size of the GPCR superfamily is unknown, but at least 831 different human genes (or about 4% of the entire protein-coding genome) have been predicted to code for them from genome sequence analysis. Although numerous classification schemes have been proposed, the superfamily was classically divided into three main classes (A, B, and C) with no detectable shared sequence homology between classes.
The largest class by far is class A, which accounts for nearly 85% of the GPCR genes. Of class A GPCRs, over half of these are predicted to encode olfactory receptors, while the remaining receptors are liganded by known endogenous compounds or are classified as orphan receptors. Despite the lack of sequence homology between classes, all GPCRs have a common structure and mechanism of signal transduction. The very large rhodopsin A group has been further subdivided into 19 subgroups (A1-A19).
According to the classical A-F system, GPCRs can be grouped into six classes based on sequence homology and functional similarity:
Class A (or 1) (Rhodopsin-like)
Class B (or 2) (Secretin receptor family)
Class C (or 3) (Metabotropic glutamate/pheromone)
Class D (or 4) (Fungal mating pheromone receptors)
Class E (or 5) (Cyclic AMP receptors)
Class F (or 6) (Frizzled/Smoothened)
More recently, an alternative classification system called GRAFS (Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin) has been proposed for vertebrate GPCRs. They correspond to classical classes C, A, B2, F, and B.
An early study based on available DNA sequence suggested that the human genome encodes roughly 750 G protein-coupled receptors, about 350 of which detect hormones, growth factors, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.
Some web-servers and bioinformatics prediction methods have been used for predicting the classification of GPCRs according to their amino acid sequence alone, by means of the pseudo amino acid composition approach.
== Physiological roles ==
GPCRs are involved in a wide variety of physiological processes. Some examples of their physiological roles include:
The visual sense: The opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose.
The gustatory sense (taste): GPCRs in taste cells mediate release of gustducin in response to bitter-, umami- and sweet-tasting substances.
The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
Behavioral and mood regulation: Receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, histamine, GABA, and glutamate
Regulation of immune system activity and inflammation: chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response. GPCRs are also involved in immune-modulation, e. g. regulating interleukin induction or suppressing TLR-induced immune responses from T cells.
Autonomic nervous system transmission: Both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
Cell density sensing: A novel GPCR role in regulating cell density sensing.
Homeostasis modulation (e.g., water balance).
Involved in growth and metastasis of some types of tumors.
Used in the endocrine system for peptide and amino-acid derivative hormones that bind to GCPRs on the cell membrane of a target cell. This activates cAMP, which in turn activates several kinases, allowing for a cellular response, such as transcription.
== Receptor structure ==
GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. Some seven-transmembrane helix proteins (channelrhodopsin) that resemble GPCRs may contain ion channels, within their protein.
In 2000, the first crystal structure of a mammalian GPCR, that of bovine rhodopsin (1F88), was solved. In 2007, the first structure of a human GPCR was solved This human β2-adrenergic receptor GPCR structure proved highly similar to the bovine rhodopsin. The structures of activated or agonist-bound GPCRs have also been determined. These structures indicate how ligand binding at the extracellular side of a receptor leads to conformational changes in the cytoplasmic side of the receptor. The biggest change is an outward movement of the cytoplasmic part of the 5th and 6th transmembrane helix (TM5 and TM6). The structure of activated beta-2 adrenergic receptor in complex with Gs confirmed that the Gα binds to a cavity created by this movement.
GPCRs exhibit a similar structure to some other proteins with seven transmembrane domains, such as microbial rhodopsins and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2). However, these 7TMH (7-transmembrane helices) receptors and channels do not associate with G proteins. In addition, ADIPOR1 and ADIPOR2 are oriented oppositely to GPCRs in the membrane (i.e. GPCRs usually have an extracellular N-terminus, cytoplasmic C-terminus, whereas ADIPORs are inverted).
== Structure–function relationships ==
In terms of structure, GPCRs are characterized by an extracellular N-terminus, followed by seven transmembrane (7-TM) α-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. The GPCR arranges itself into a tertiary structure resembling a barrel, with the seven transmembrane helices forming a cavity within the plasma membrane that serves a ligand-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is the case for bulkier ligands (e.g., proteins or large peptides), which instead interact with the extracellular loops, or, as illustrated by the class C metabotropic glutamate receptors (mGluRs), the N-terminal tail. The class C GPCRs are distinguished by their large N-terminal tail, which also contains a ligand-binding domain. Upon glutamate-binding to an mGluR, the N-terminal tail undergoes a conformational change that leads to its interaction with the residues of the extracellular loops and TM domains. The eventual effect of all three types of agonist-induced activation is a change in the relative orientations of the TM helices (likened to a twisting motion) leading to a wider intracellular surface and "revelation" of residues of the intracellular helices and TM domains crucial to signal transduction function (i.e., G-protein coupling). Inverse agonists and antagonists may also bind to a number of different sites, but the eventual effect must be prevention of this TM helix reorientation.
The structure of the N- and C-terminal tails of GPCRs may also serve important functions beyond ligand-binding. For example, The C-terminus of M3 muscarinic receptors is sufficient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary for its preassembly with Gq proteins. In particular, the C-terminus often contains serine (Ser) or threonine (Thr) residues that, when phosphorylated, increase the affinity of the intracellular surface for the binding of scaffolding proteins called β-arrestins (β-arr). Once bound, β-arrestins both sterically prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellular-signal regulated kinase (ERK) pathway activation or receptor endocytosis (internalization). As the phosphorylation of these Ser and Thr residues often occurs as a result of GPCR activation, the β-arr-mediated G-protein-decoupling and internalization of GPCRs are important mechanisms of desensitization. In addition, internalized "mega-complexes" consisting of a single GPCR, β-arr(in the tail conformation), and heterotrimeric G protein exist and may account for protein signaling from endosomes.
A final common structural theme among GPCRs is palmitoylation of one or more sites of the C-terminal tail or the intracellular loops. Palmitoylation is the covalent modification of cysteine (Cys) residues via addition of hydrophobic acyl groups, and has the effect of targeting the receptor to cholesterol- and sphingolipid-rich microdomains of the plasma membrane called lipid rafts. As many of the downstream transducer and effector molecules of GPCRs (including those involved in negative feedback pathways) are also targeted to lipid rafts, this has the effect of facilitating rapid receptor signaling.
GPCRs respond to extracellular signals mediated by a huge diversity of agonists, ranging from proteins to biogenic amines to protons, but all transduce this signal via a mechanism of G-protein coupling. This is made possible by a guanine-nucleotide exchange factor (GEF) domain primarily formed by a combination of IL-2 and IL-3 along with adjacent residues of the associated TM helices.
== Mechanism ==
The G protein-coupled receptor is activated by an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a G protein. Further effect depends on the type of G protein. G proteins are subsequently inactivated by GTPase activating proteins, known as RGS proteins.
=== Ligand binding ===
GPCRs include one or more receptors for the following ligands:
sensory signal mediators (e.g., light and olfactory stimulatory molecules);
adenosine, bombesin, bradykinin, endothelin, γ-aminobutyric acid (GABA), hepatocyte growth factor (HGF), melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, GH, tachykinins, members of the vasoactive intestinal peptide family, and vasopressin;
biogenic amines (e.g., dopamine, epinephrine, norepinephrine, histamine, serotonin, and melatonin);
glutamate (metabotropic effect);
glucagon;
acetylcholine (muscarinic effect);
chemokines;
lipid mediators of inflammation (e.g., prostaglandins, prostanoids, platelet-activating factor, and leukotrienes);
peptide hormones (e.g., calcitonin, C5a anaphylatoxin, follicle-stimulating hormone [FSH], gonadotropin-releasing hormone [GnRH], neurokinin, thyrotropin-releasing hormone [TRH], and oxytocin);
and endocannabinoids.
GPCRs that act as receptors for stimuli that have not yet been identified are known as orphan receptors.
However, in contrast to other types of receptors that have been studied, wherein ligands bind externally to the membrane, the ligands of GPCRs typically bind within the transmembrane domain. However, protease-activated receptors are activated by cleavage of part of their extracellular domain.
=== Conformational change ===
The transduction of the signal through the membrane by the receptor is not completely understood. It is known that in the inactive state, the GPCR is bound to a heterotrimeric G protein complex. Binding of an agonist to the GPCR results in a conformational change in the receptor that is transmitted to the bound Gα subunit of the heterotrimeric G protein via protein domain dynamics. The activated Gα subunit exchanges GTP in place of GDP which in turn triggers the dissociation of Gα subunit from the Gβγ dimer and from the receptor. The dissociated Gα and Gβγ subunits interact with other intracellular proteins to continue the signal transduction cascade while the freed GPCR is able to rebind to another heterotrimeric G protein to form a new complex that is ready to initiate another round of signal transduction.
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive biophysical states. The binding of ligands to the receptor may shift the equilibrium toward the active receptor states. Three types of ligands exist: Agonists are ligands that shift the equilibrium in favour of active states; inverse agonists are ligands that shift the equilibrium in favour of inactive states; and neutral antagonists are ligands that do not affect the equilibrium. It is not yet known how exactly the active and inactive states differ from each other.
=== G-protein activation/deactivation cycle ===
When the receptor is inactive, the GEF domain may be bound to an also inactive α-subunit of a heterotrimeric G-protein. These "G-proteins" are a trimer of α, β, and γ subunits (known as Gα, Gβ, and Gγ, respectively) that is rendered inactive when reversibly bound to Guanosine diphosphate (GDP) (or, alternatively, no guanine nucleotide) but active when bound to guanosine triphosphate (GTP). Upon receptor activation, the GEF domain, in turn, allosterically activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit. The cell maintains a 10:1 ratio of cytosolic GTP:GDP so exchange for GTP is ensured. At this point, the subunits of the G-protein dissociate from the receptor, as well as each other, to yield a Gα-GTP monomer and a tightly interacting Gβγ dimer, which are now free to modulate the activity of other intracellular proteins. The extent to which they may diffuse, however, is limited due to the palmitoylation of Gα and the presence of an isoprenoid moiety that has been covalently added to the C-termini of Gγ.
Because Gα also has slow GTP→GDP hydrolysis capability, the inactive form of the α-subunit (Gα-GDP) is eventually regenerated, thus allowing reassociation with a Gβγ dimer to form the "resting" G-protein, which can again bind to a GPCR and await activation. The rate of GTP hydrolysis is often accelerated due to the actions of another family of allosteric modulating proteins called regulators of G-protein signaling, or RGS proteins, which are a type of GTPase-activating protein, or GAP. In fact, many of the primary effector proteins (e.g., adenylate cyclases) that become activated/inactivated upon interaction with Gα-GTP also have GAP activity. Thus, even at this early stage in the process, GPCR-initiated signaling has the capacity for self-termination.
=== Crosstalk ===
GPCRs downstream signals have been shown to possibly interact with integrin signals, such as FAK. Integrin signaling will phosphorylate FAK, which can then decrease GPCR Gαs activity.
== Signaling ==
If a receptor in an active state encounters a G protein, it may activate it. Some evidence suggests that receptors and G proteins are actually pre-coupled. For example, binding of G proteins to receptors affects the receptor's affinity for ligands. Activated G proteins are bound to GTP.
Further signal transduction depends on the type of G protein. The enzyme adenylate cyclase is an example of a cellular protein that can be regulated by a G protein, in this case the G protein Gs. Adenylate cyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylate cyclase ends when the G protein returns to the GDP-bound state.
Adenylate cyclases (of which 9 membrane-bound and one cytosolic forms are known in humans) may also be activated or inhibited in other ways (e.g., Ca2+/calmodulin binding), which can modify the activity of these enzymes in an additive or synergistic fashion along with the G proteins.
The signaling pathways activated through a GPCR are limited by the primary sequence and tertiary structure of the GPCR itself but ultimately determined by the particular conformation stabilized by a particular ligand, as well as the availability of transducer molecules. Currently, GPCRs are considered to utilize two primary types of transducers: G-proteins and β-arrestins. Because β-arr's have high affinity only to the phosphorylated form of most GPCRs (see above or below), the majority of signaling is ultimately dependent upon G-protein activation. However, the possibility for interaction does allow for G-protein-independent signaling to occur.
=== G-protein-dependent signaling ===
There are three main G-protein-mediated signaling pathways, mediated by four sub-classes of G-proteins distinguished from each other by sequence homology (Gαs, Gαi/o, Gαq/11, and Gα12/13). Each sub-class of G-protein consists of multiple proteins, each the product of multiple genes or splice variations that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible βγ combinations do not appear to radically differ from one another, these classes are defined according to the isoform of their α-subunit.: 1163
While most GPCRs are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called functional selectivity (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular agonist may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR's GEF domain, even over the course of a single interaction. In addition, a conformation that preferably activates one isoform of Gα may activate another if the preferred is less available. Furthermore, feedback pathways may result in receptor modifications (e.g., phosphorylation) that alter the G-protein preference. Regardless of these various nuances, the GPCR's preferred coupling partner is usually defined according to the G-protein most obviously activated by the endogenous ligand under most physiological or experimental conditions.
==== Gα signaling ====
The effector of both the Gαs and Gαi/o pathways is the cyclic-adenosine monophosphate (cAMP)-generating enzyme adenylate cyclase, or AC. While there are ten different AC gene products in mammals, each with subtle differences in tissue distribution or function, all catalyze the conversion of cytosolic adenosine triphosphate (ATP) to cAMP, and all are directly stimulated by G-proteins of the Gαs class. In contrast, however, interaction with Gα subunits of the Gαi/o type inhibits AC from generating cAMP. Thus, a GPCR coupled to Gαs counteracts the actions of a GPCR coupled to Gαi/o, and vice versa. The level of cytosolic cAMP may then determine the activity of various ion channels as well as members of the ser/thr-specific protein kinase A (PKA) family. Thus cAMP is considered a second messenger and PKA a secondary effector.
The effector of the Gαq/11 pathway is phospholipase C-β (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) to elicit Ca2+ release from the ER, while DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called protein kinase C (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca2+, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca2+ also binds and allosterically activates proteins called calmodulins, which in turn tosolic small GTPase, Rho. Once bound to GTP, Rho can then go on to activate various proteins responsible for cytoskeleton regulation such as Rho-kinase (ROCK). Most GPCRs that couple to Gα12/13 also couple to other sub-classes, often Gαq/11.
==== Gβγ signaling ====
The above descriptions ignore the effects of Gβγ–signalling, which can also be important, in particular in the case of activated Gαi/o-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as G-protein-regulated inwardly rectifying K+ channels (GIRKs), P/Q- and N-type voltage-gated Ca2+ channels, as well as some isoforms of AC and PLC, along with some phosphoinositide-3-kinase (PI3K) isoforms.
=== G-protein-independent signaling ===
Although they are classically thought of working only together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteins may play functional roles independent of GPCRs. GPCRs may signal independently through many proteins already mentioned for their roles in G-protein-dependent signaling such as β-arrs, GRKs, and Srcs. Such signaling has been shown to be physiologically relevant, for example, β-arrestin signaling mediated by the chemokine receptor CXCR3 was necessary for full efficacy chemotaxis of activated T cells. In addition, further scaffolding proteins involved in subcellular localization of GPCRs (e.g., PDZ-domain-containing proteins) may also act as signal transducers. Most often the effector is a member of the MAPK family.
==== Examples ====
In the late 1990s, evidence began accumulating to suggest that some GPCRs are able to signal without G proteins. The ERK2 mitogen-activated protein kinase, a key signal transduction mediator downstream of receptor activation in many pathways, has been shown to be activated in response to cAMP-mediated receptor activation in the slime mold D. discoideum despite the absence of the associated G protein α- and β-subunits.
In mammalian cells, the much-studied β2-adrenoceptor has been demonstrated to activate the ERK2 pathway after arrestin-mediated uncoupling of G-protein-mediated signaling. Therefore, it seems likely that some mechanisms previously believed related purely to receptor desensitisation are actually examples of receptors switching their signaling pathway, rather than simply being switched off.
In kidney cells, the bradykinin receptor B2 has been shown to interact directly with a protein tyrosine phosphatase. The presence of a tyrosine-phosphorylated ITIM (immunoreceptor tyrosine-based inhibitory motif) sequence in the B2 receptor is necessary to mediate this interaction and subsequently the antiproliferative effect of bradykinin.
==== GPCR-independent signaling by heterotrimeric G-proteins ====
Although it is a relatively immature area of research, it appears that heterotrimeric G-proteins may also take part in non-GPCR signaling. There is evidence for roles as signal transducers in nearly all other types of receptor-mediated signaling, including integrins, receptor tyrosine kinases (RTKs), cytokine receptors (JAK/STATs), as well as modulation of various other "accessory" proteins such as GEFs, guanine-nucleotide dissociation inhibitors (GDIs) and protein phosphatases. There may even be specific proteins of these classes whose primary function is as part of GPCR-independent pathways, termed activators of G-protein signalling (AGS). Both the ubiquity of these interactions and the importance of Gα vs. Gβγ subunits to these processes are still unclear.
== Details of cAMP and PIP2 pathways ==
There are two principal signal transduction pathways involving the G protein-linked receptors: the cAMP signal pathway and the phosphatidylinositol signal pathway.
=== cAMP signal pathway ===
The cAMP signal transduction contains five main characters: stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri); stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi); adenylyl cyclase; protein kinase A (PKA); and cAMP phosphodiesterase.
Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules, while inhibitory hormone receptor (Ri) is a receptor that can bind with inhibitory signal molecules.
Stimulative regulative G-protein is a G-protein linked to stimulative hormone receptor (Rs), and its α subunit upon activation could stimulate the activity of an enzyme or other intracellular metabolism. On the contrary, inhibitory regulative G-protein is linked to an inhibitory hormone receptor, and its α subunit upon activation could inhibit the activity of an enzyme or other intracellular metabolism.
Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes the conversion of ATP to cAMP with the help of cofactor Mg2+ or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator of protein kinase A.
Protein kinase A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylating specific committed enzymes in the metabolic pathway. It can also regulate specific gene expression, cellular secretion, and membrane permeability. The protein enzyme contains two catalytic subunits and two regulatory subunits. When there is no cAMP, the complex is inactive. When cAMP binds to the regulatory subunits, their conformation is altered, causing the dissociation of the regulatory subunits, which activates protein kinase A and allows further biological effects.
These signals then can be terminated by cAMP phosphodiesterase, which is an enzyme that degrades cAMP to 5'-AMP and inactivates protein kinase A.
=== Phosphatidylinositol signal pathway ===
In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G-protein receptor (Gq) on the cell surface and activates phospholipase C, which is located on the plasma membrane. The lipase hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds with the IP3 receptor in the membrane of the smooth endoplasmic reticulum and mitochondria to open Ca2+ channels. DAG helps activate protein kinase C (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses.
The effects of Ca2+ are also remarkable: it cooperates with DAG in activating PKC and can activate the CaM kinase pathway, in which calcium-modulated protein calmodulin (CaM) binds Ca2+, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca2+-CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway.
== Receptor regulation ==
GPCRs become desensitized when exposed to their ligand for a long period of time. There are two recognized forms of desensitization: 1) homologous desensitization, in which the activated GPCR is downregulated; and 2) heterologous desensitization, wherein the activated GPCR causes downregulation of a different GPCR. The key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases.
=== Phosphorylation by cAMP-dependent protein kinases ===
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the receptor) via adenylate cyclase and cyclic AMP (cAMP). In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active the more kinases are activated and the more receptors are phosphorylated. In β2-adrenoceptors, this phosphorylation results in the switching of the coupling from the Gs class of G-protein to the Gi class. cAMP-dependent PKA mediated phosphorylation can cause heterologous desensitisation in receptors other than those activated.
=== Phosphorylation by GRKs ===
The G protein-coupled receptor kinases (GRKs) are protein kinases that phosphorylate only active GPCRs. G-protein-coupled receptor kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR) signaling. They constitute a family of seven mammalian serine-threonine protein kinases that phosphorylate agonist-bound receptor. GRKs-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization. Activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins.
Phosphorylation of the receptor can have two consequences:
Translocation: The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysozomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depending on the internalised vesicle's subcellular localisation.
Arrestin linking: The phosphorylated receptor can be linked to arrestin molecules that prevent it from binding (and activating) G proteins, in effect switching it off for a short period of time. This mechanism is used, for example, with rhodopsin in retina cells to compensate for exposure to bright light. In many cases, arrestin's binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β2-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus, the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β2-adrenoreceptors.
=== Mechanisms of GPCR signal termination ===
As mentioned above, G-proteins may terminate their own activation due to their intrinsic GTP→GDP hydrolysis capability. However, this reaction proceeds at a slow rate (≈0.02 times/sec) and, thus, it would take around 50 seconds for any single G-protein to deactivate if other factors did not come into play. Indeed, there are around 30 isoforms of RGS proteins that, when bound to Gα through their GAP domain, accelerate the hydrolysis rate to ≈30 times/sec. This 1500-fold increase in rate allows for the cell to respond to external signals with high speed, as well as spatial resolution due to limited amount of second messenger that can be generated and limited distance a G-protein can diffuse in 0.03 seconds. For the most part, the RGS proteins are promiscuous in their ability to deactivate G-proteins, while which RGS is involved in a given signaling pathway seems more determined by the tissue and GPCR involved than anything else. In addition, RGS proteins have the additional function of increasing the rate of GTP-GDP exchange at GPCRs, (i.e., as a sort of co-GEF) further contributing to the time resolution of GPCR signaling.
In addition, the GPCR may be desensitized itself. This can occur as:
a direct result of ligand occupation, wherein the change in conformation allows recruitment of GPCR-Regulating Kinases (GRKs), which go on to phosphorylate various serine/threonine residues of IL-3 and the C-terminal tail. Upon GRK phosphorylation, the GPCR's affinity for β-arrestin (β-arrestin-1/2 in most tissues) is increased, at which point β-arrestin may bind and act to both sterically hinder G-protein coupling as well as initiate the process of receptor internalization through clathrin-mediated endocytosis. Because only the liganded receptor is desensitized by this mechanism, it is called homologous desensitization
the affinity for β-arrestin may be increased in a ligand occupation and GRK-independent manner through phosphorylation of different ser/thr sites (but also of IL-3 and the C-terminal tail) by PKC and PKA. These phosphorylations are often sufficient to impair G-protein coupling on their own as well.
PKC/PKA may, instead, phosphorylate GRKs, which can also lead to GPCR phosphorylation and β-arrestin binding in an occupation-independent manner. These latter two mechanisms allow for desensitization of one GPCR due to the activities of others, or heterologous desensitization. GRKs may also have GAP domains and so may contribute to inactivation through non-kinase mechanisms as well. A combination of these mechanisms may also occur.
Once β-arrestin is bound to a GPCR, it undergoes a conformational change allowing it to serve as a scaffolding protein for an adaptor complex termed AP-2, which in turn recruits another protein called clathrin. If enough receptors in the local area recruit clathrin in this manner, they aggregate and the membrane buds inwardly as a result of interactions between the molecules of clathrin, in a process called opsonization. Once the pit has been pinched off the plasma membrane due to the actions of two other proteins called amphiphysin and dynamin, it is now an endocytic vesicle. At this point, the adapter molecules and clathrin have dissociated, and the receptor is either trafficked back to the plasma membrane or targeted to lysosomes for degradation.
At any point in this process, the β-arrestins may also recruit other proteins—such as the non-receptor tyrosine kinase (nRTK), c-SRC—which may activate ERK1/2, or other mitogen-activated protein kinase (MAPK) signaling through, for example, phosphorylation of the small GTPase, Ras, or recruit the proteins of the ERK cascade directly (i.e., Raf-1, MEK, ERK-1/2) at which point signaling is initiated due to their close proximity to one another. Another target of c-SRC are the dynamin molecules involved in endocytosis. Dynamins polymerize around the neck of an incoming vesicle, and their phosphorylation by c-SRC provides the energy necessary for the conformational change allowing the final "pinching off" from the membrane.
=== GPCR cellular regulation ===
Receptor desensitization is mediated through a combination phosphorylation, β-arr binding, and endocytosis as described above. Downregulation occurs when endocytosed receptor is embedded in an endosome that is trafficked to merge with an organelle called a lysosome. Because lysosomal membranes are rich in proton pumps, their interiors have low pH (≈4.8 vs. the pH≈7.2 cytosol), which acts to denature the GPCRs. In addition, lysosomes contain many degradative enzymes, including proteases, which can function only at such low pH, and so the peptide bonds joining the residues of the GPCR together may be cleaved. Whether or not a given receptor is trafficked to a lysosome, detained in endosomes, or trafficked back to the plasma membrane depends on a variety of factors, including receptor type and magnitude of the signal.
GPCR regulation is additionally mediated by gene transcription factors. These factors can increase or decrease gene transcription and thus increase or decrease the generation of new receptors (up- or down-regulation) that travel to the cell membrane.
== Receptor oligomerization ==
G-protein-coupled receptor oligomerisation is a widespread phenomenon. One of the best-studied examples is the metabotropic GABAB receptor. This so-called constitutive receptor is formed by heterodimerization of GABABR1 and GABABR2 subunits. Expression of the GABABR1 without the GABABR2 in heterologous systems leads to retention of the subunit in the endoplasmic reticulum. Expression of the GABABR2 subunit alone, meanwhile, leads to surface expression of the subunit, although with no functional activity (i.e., the receptor does not bind agonist and cannot initiate a response following exposure to agonist). Expression of the two subunits together leads to plasma membrane expression of functional receptor. It has been shown that GABABR2 binding to GABABR1 causes masking of a retention signal of functional receptors.
== Origin and diversification of the superfamily ==
Signal transduction mediated by the superfamily of GPCRs dates back to the origin of multicellularity. Mammalian-like GPCRs are found in fungi, and have been classified according to the GRAFS classification system based on GPCR fingerprints. Identification of the superfamily members across the eukaryotic domain, and comparison of the family-specific motifs, have shown that the superfamily of GPCRs have a common origin. Characteristic motifs indicate that three of the five GRAFS families, Rhodopsin, Adhesion, and Frizzled, evolved from the Dictyostelium discoideum cAMP receptors before the split of opisthokonts. Later, the Secretin family evolved from the Adhesion GPCR receptor family before the split of nematodes. Insect GPCRs appear to be in their own group and Taste2 is identified as descending from Rhodopsin. Note that the Secretin/Adhesion split is based on presumed function rather than signature, as the classical Class B (7tm_2, Pfam PF00002) is used to identify both in the studies.
== See also ==
G protein-coupled receptors database
List of MeSH codes (D12.776)
Metabotropic receptor
Orphan receptor
Pepducins, a class of drug candidates targeted at GPCRs
Receptor activated solely by a synthetic ligand, a technique for control of cell signaling through synthetic GPCRs
TOG superfamily
== References ==
== Further reading ==
Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, et al. (April 2003). "The G protein-coupled receptor repertoires of human and mouse". Proceedings of the National Academy of Sciences of the United States of America. 100 (8): 4903–8. Bibcode:2003PNAS..100.4903V. doi:10.1073/pnas.0230374100. PMC 153653. PMID 12679517.
"GPCR Reference Library". Retrieved 11 August 2008. Reference for molecular and mathematical models for the initial receptor response
"The Nobel Prize in Chemistry 2012" (PDF). Archived (PDF) from the original on 18 October 2012. Retrieved 10 October 2012.
== External links ==
G-protein-coupled+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GPCR Cell Line Archived 3 April 2015 at the Wayback Machine
"IUPHAR/BPS Guide to PHARMACOLOGY Database (GPCRs)". IUPHAR Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology. Retrieved 6 February 2019.
"GPCRdb". Data, diagrams and web tools for G protein-coupled receptors (GPCRs).; Munk C, Isberg V, Mordalski S, Harpsøe K, Rataj K, Hauser AS, et al. (July 2016). "GPCRdb: the G protein-coupled receptor database - an introduction". British Journal of Pharmacology. 173 (14): 2195–207. doi:10.1111/bph.13509. PMC 4919580. PMID 27155948.
"G Protein-Coupled Receptors on the NET". Archived from the original on 23 July 2011. Retrieved 10 November 2010. a classification of GPCRs
"PSI GPCR Network Center". Archived from the original on 25 July 2013. Retrieved 11 July 2013. a Protein Structure Initiative:Biology Network Center aimed at determining the 3D structures of representative GPCR family proteins
GPCR-HGmod Archived 1 February 2016 at the Wayback Machine, a database of 3D structural models of all human G-protein coupled receptors, built by the GPCR-I-TASSER pipeline Zhang J, Yang J, Jang R, Zhang Y (August 2015). "GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human Genome". Structure. 23 (8): 1538–1549. doi:10.1016/j.str.2015.06.007. PMC 4526412. PMID 26190572. | Wikipedia/G-protein-coupled_receptor |
In the field of drug discovery, retrometabolic drug design is a strategy for the design of safer drugs either using predictable metabolism to an inactive moiety or using targeted drug delivery approaches. The phrase retrometabolic drug design was coined by Nicholas Bodor. The method is analogous to retrosynthetic analysis where the synthesis of a target molecule is planned backwards. In retrometabolic drug design, metabolic reaction information of drugs is used to design parent drugs whose metabolism and distribution can be controlled to target and eliminate the drug to increase efficacy and minimize undesirable side effects. The new drugs thus designed achieve selective organ and/or therapeutic site drug targeting and produce safe therapeutic agents and safe environmental chemicals. These approaches represent systematic methodologies that thoroughly integrate structure-activity (SAR) and structure-metabolism (SMR) relationships and are aimed at designing safe, locally active compounds with improved therapeutic index (ratio of benefit vs. side effect).
== Classification ==
The concept of retrometabolic drug design encompasses two distinct approaches. One approach is the design of soft drugs (SDs), new, active therapeutic agents, often isosteric or isolelectronic analogs of a lead compound, with a chemical structure specifically designed to allow predictable metabolism into inactive metabolites after exerting their desired therapeutic effect(s). The other approach is the design of chemical delivery systems (CDSs). CDSs are biologically inert molecules intended to enhance drug delivery to a particular organ or site and requiring several conversion steps before releasing the active drug.
Although both retrometabolic design approaches involve chemical modifications of the molecular structure and both require enzymatic reactions to fulfill drug targeting, the principles of SD and CDS design are distinctly different. While CDSs are inactive as administered and sequential enzymatic reactions provide the differential distribution and ultimately release the active drug, SDs are active as administered and are designed to be easily metabolized into inactive species. Assuming an ideal situation, with a CDS the drug is present at the site and nowhere else in the body because enzymatic processes destroy the drug at those sites. Whereas, CDSs are designed to achieve drug targeting at a selected organ or site, SDs are designed to afford a differential distribution that can be regarded as reverse targeting.
=== Soft drugs ===
Since its introduction by Nicholas Bodor in the late 1970s, the soft drug concept generated considerable research both in academic and in industrial settings. Bodor defined soft drugs as biologically active, therapeutically useful chemical compounds characterized by a predictable and controllable in vivo metabolism to non-toxic moieties after they achieve their therapeutic role. There are several rationally designed soft drugs that have either already reached the market, such as
esmolol (Breviblock)
landiolol (Onoact)
remifentanil (Ultiva)
loteprednol etabonate (Lotemax, Alrex, Zylet)
clevidipine (Cleviprex)
remimazolam (Byfavo)
or are in late-stage development (budiodarone, celivarone, AZD3043, tecafarin). There are also compounds that can be considered as soft chemicals (e.g., malathion) or soft drugs (e.g., articaine, methylphenidate) even though they were not developed as such.
=== Chemical delivery systems ===
Since their introduction in the early 1980s, CDSs have also generated considerable research work, especially for brain and eye targeting of various therapeutic agents, including those that cannot cross the blood–brain barrier or the blood–retinal barrier on their own. Within this approach, three major general CDS classes have been identified:
Enzymatic physicochemical-based (e.g., brain-targeting) CDSs: exploit site-specific traffic properties by sequential metabolic conversions that result in considerably altered properties
Site-specific enzyme-activated (e.g., eye-targeting) CDSs: exploit specific enzymes found primarily, exclusively, or at higher activity at the site of action
Receptor-based transient anchor-type (e.g., lung-targeting) CDSs: provide enhanced selectivity and activity through transient, reversible binding at the receptor
This concept has been extended to many drugs and peptides, its importance illustrated by the fact that its first applications and uses were published in Science in 1975, 1981 and 1983. Its extension to the targeted brain-delivery of neuropeptides was included by the Harvard Health Letter as one of the top 10 medical advances of 1992. Several compounds have reached advanced clinical development phase, such as
E2-CDS (Estredox) for the brain-targeted delivery of estradiol and
betaxoxime for the eye-targeted delivery of betaxolol
In the first example above, brain-targeted CDSs employ a sequential metabolic conversion of a redox-based targetor moiety, which is closely related to the ubiquitous NAD(P)H ⇌ NAD(P)+ coenzyme system, to exploit the unique properties of the blood–brain barrier (BBB). After enzymatic oxidation of the NADH type drug conjugate to its corresponding NAD+- drug, the still inactive precursor, "locks-in" behind the BBB to provide targeted and sustained CNS-delivery of the compound of interest.
The second example involves eye-specific delivery of betaxoxime, the oxime derivative of betaxolol. The administered, inactive β-amino-ketoxime is converted to the corresponding ketone via oxime hydrolase, an enzyme recently identified with preferential activity in the eye, and then stereospecifically reduced to its alcohol form. IOP-lowering activity is demonstrated without producing the active β-blockers systemically, making them void of any cardiovascular activity, a major drawback of classical antiglaucoma agents. Because of the advantages provided by this unique eye-targeting profile, oxime-based eye-targeting CDSs could replace the β-blockers currently used for ophthalmic applications.
== History and significance ==
These retrometabolic design strategies were introduced by Nicholas Bodor, one of the first and most prominent advocates for the early integration of metabolism, pharmacokinetic and general physicochemical considerations in the drug design process. These drug design concepts recognize the importance of design-controlled metabolism and directly focus not on the increase of activity alone but on the increase of the activity/toxicity ratio (therapeutic index) in order to deliver the maximum benefit while also reducing or eliminating unwanted side effects. The importance of this field is reviewed in a book dedicated to the subject (Bodor, N.; Buchwald, P.; Retrometabolic Drug Design and Targeting, 1st ed., Wiley & Sons, 2012), as well as by a full chapter of Burger's Medicinal Chemistry and Drug Design, 7th ed. (2010) with close to 150 chemical structures and more than 450 references. At the time of its introduction, the idea of designed-in metabolism represented a significant novelty and was against mainstream thinking then in place that instead focused on minimizing or entirely eliminating drug metabolism. Bodor's work on these design concepts developed during the late 1970s and early 1980s, and came to prominence during the mid-1990s. Loteprednol etabonate, a soft corticosteroid designed and patented by Bodor received final Food and Drug Administration (FDA) approval in 1998 as the active ingredient of two ophthalmic preparations (Lotemax and Alrex), currently the only corticosteroid approved by the FDA for use in all inflammatory and allergy-related ophthalmic disorders. Its safety for long-term use further supports the soft drug concept, and in 2004, loteprednol etabonate was also approved as part of a combination product (Zylet). A second generation of soft corticosteroids such as etiprednol dicloacetate is in development for a full spectrum of other possible applications such as nasal spray for rhinitis or inhalation products for asthma.
The soft drug concept ignited research work in both academic (e.g., Aston University, Göteborg University, Okayama University, Uppsala University, University of Iceland, University of Florida, Université Louis Pasteur, Yale University) and industrial (e.g., AstraZeneca, DuPont, GlaxoSmithKline, IVAX, Janssen Pharmaceutica, Nippon Organon, Novartis, ONO Pharmaceutical, Schering AG) settings. Besides corticosteroids, various other therapeutic areas have been pursued such as soft beta-blockers, soft opioid analgetics, soft estrogens, soft beta-agonists, soft anticholinergics, soft antimicrobials, soft antiarrhythmic agents, soft angiotensin converting enzyme (ACE) inhibitors, soft dihydrofolate reductase (DHFR) inhibitors, soft cancineurin inhibitors (soft immunosuppressants), soft matrix metalloproteinase (MMP) inhibitors, soft cytokine inhibitors, soft cannabinoids, soft Ca2+ channel blockers (see for a recent review).
Following the introduction of the CDS concepts, work along those lines started in numerous pharmaceutical centers around the world, and brain-targeting CDSs were explored for many therapeutic agents such as steroids (testosterone, progestins, estradiol, dexamethasone), anti-infective agents (penicillins, sulfonamides), antivirals (acyclovir, trifluorothymidine, ribavirin), antiretrovirals (AZT, ganciclovir), anticancer agents (Lomustine, chlorambucil), neurotransmitters (dopamine, GABA), nerve growth factor (NGF) inducers, anticonvulsants (Phenytoin, valproate, stiripentol), Ca2+ antagonists (felodipine), MAO inhibitors, NSAIDs and neuropeptides (tryptophan, Leu-enkephalin analogs, TRH analogs, kyotorphin analogs). A number of new chemical entities (NCE) were developed based on these principles, such as E2-CDS (Estredox or betaxoxime are in advanced clinical development phases.
A review of ongoing research using the general retrometabolic design approaches is conducted biennially at the Retrometabolism Based Drug Design and Targeting Conference, an international series of symposia developed and organized by Nicholas Bodor. Proceedings of each conference held have been published in the international pharmaceutical journal Pharmazie. Past conferences, and their published proceedings are:
May 1997, Amelia Island, Florida; Pharmazie 52(7) S1, 1997
May 1999, Amelia Island, Florida; Pharmazie 55(3), 2000
May 2001, Amelia Island Florida; Pharmazie 57(2), 2002
May 2003, Palm Coast, Florida; Pharmazie 59(5), 2004
May 2005, Hakone, Japan; Pharmazie 61(2), 2006
June 2007, Göd, Hungary; Pharmazie 63(3), 2008
May 2009, Orlando, Florida; Pharmazie 65(6), 2010
June 2011, Graz, Austria; Pharmazie 67(5), 2012
May 2013, Orlando, Florida; Pharmazie 69(6), 2014
October 2015, Orlando, Florida.
== References == | Wikipedia/Retrometabolic_drug_design |
Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique for predicting the absorption, distribution, metabolism and excretion (ADME) of synthetic or natural chemical substances in humans and other animal species. PBPK modeling is used in pharmaceutical research and drug development, and in health risk assessment for cosmetics or general chemicals.
PBPK models strive to be mechanistic by mathematically transcribing anatomical, physiological, physical, and chemical descriptions of the phenomena involved in the complex ADME processes. A large degree of residual simplification and empiricism is still present in those models, but they have an extended domain of applicability compared to that of classical, empirical function based, pharmacokinetic models. PBPK models may have purely predictive uses, but other uses, such as statistical inference, have been made possible by the development of Bayesian statistical tools able to deal with complex models. That is true for both toxicity risk assessment and therapeutic drug development.
PBPK models try to rely a priori on the anatomical and physiological structure of the body, and to a certain extent, on biochemistry. They are usually multi-compartment models, with compartments corresponding to predefined organs or tissues, with interconnections corresponding to blood or lymph flows (more rarely to diffusions). A system of differential equations for concentration or quantity of substance on each compartment can be written, and its parameters represent blood flows, pulmonary ventilation rate, organ volumes etc., for which information is available in scientific publications. Indeed, the description they make of the body is simplified and a balance needs to be struck between complexity and simplicity. Besides the advantage of allowing the recruitment of a priori information about parameter values, these models also facilitate inter-species transpositions or extrapolation from one mode of administration to another (e.g., inhalation to oral). An example of a 7-compartment PBPK model, suitable to describe the fate of many solvents in the mammalian body, is given in the Figure on the right.
== History ==
The first pharmacokinetic model described in the scientific literature
was in fact a PBPK model. It led, however, to computations intractable at that time. The focus shifted then to simpler models,
for which analytical solutions could be obtained (such solutions were sums of exponential terms, which led to further simplifications.) The availability of computers and numerical integration algorithms marked a renewed interest in physiological models in the early 1970s.
For substances with complex kinetics, or when inter-species extrapolations were required, simple models were insufficient and research continued on physiological models.
By 2010, hundreds of scientific publications had described and used PBPK models, and at least two private companies have based their business on their expertise in this area.
== Building a PBPK model ==
The model equations follow the principles of mass transport, fluid dynamics, and biochemistry in order to simulate the fate of a substance in the body.
Compartments are usually defined by grouping organs or tissues with similar blood perfusion rate and lipid content (i.e. organs for which chemicals' concentration vs. time profiles will be similar). Ports of entry (lung, skin, intestinal tract...), ports of exit (kidney, liver...) and target organs for therapeutic effect or toxicity are often left separate. Bone can be excluded from the model if the substance of interest does not distribute to it. Connections between compartment follow physiology (e.g., blood flow in exit of the gut goes to liver, etc.)
=== Basic transport equations ===
Drug distribution into a tissue can be rate-limited by either perfusion or permeability. Perfusion-rate-limited kinetics apply when the tissue membranes present no barrier to diffusion. Blood flow, assuming that the drug is transported mainly by blood, as is often the case, is then the limiting factor to distribution in the various cells of the body. That is usually true for small lipophilic drugs. Under perfusion limitation, the instantaneous rate of entry for the quantity of drug in a compartment is simply equal to (blood) volumetric flow rate through the organ times the incoming blood concentration. In that case; for a generic compartment i, the differential equation for the quantity Qi of substance, which defines the rate of change in this quantity, is:
where Fi is blood flow (noted Q in the Figure above), Cart incoming arterial blood concentration, Pi the tissue over blood partition coefficient and Vi the volume of compartment i.
A complete set of differential equations for the 7-compartment model shown above could therefore be given by the following table:
The above equations include only transport terms and do not account for inputs or outputs.
Those can be modeled with specific terms, as in the following.
=== Modeling inputs ===
Modeling inputs is necessary to come up with a meaningful description of a chemical's pharmacokinetics. The following examples show how to write the corresponding equations.
==== Ingestion ====
When dealing with an oral bolus dose (e.g. ingestion of a tablet), first order absorption is a very common assumption. In that case the gut equation is augmented with an input term, with an absorption rate constant Ka:
That requires defining an equation for the quantity ingested and present in the gut lumen:
In the absence of a gut compartment, input can be made directly in the liver. However, in that case local metabolism in the gut may not be correctly described. The case of approximately continuous absorption (e.g. via drinking water) can be modeled by a zero-order absorption rate (here Ring in units of mass over time):
More sophisticated gut absorption model can be used. In those models, additional compartments describe the various sections of the gut lumen and tissue. Intestinal pH, transit times and presence of active transporters can be taken into account
.
==== Skin depot ====
The absorption of a chemical deposited on skin can also be modeled using first order terms. It is best in that case to separate the skin from the other tissues, to further differentiate exposed skin and non-exposed skin, and differentiate viable skin (dermis and epidermis) from the stratum corneum (the actual skin upper layer exposed). This is the approach taken in [Bois F., Diaz Ochoa J.G. Gajewska M., Kovarich S., Mauch K., Paini A., Péry A., Sala Benito J.V., Teng S., Worth A., in press, Multiscale modelling approaches for assessing cosmetic ingredients safety, Toxicology. doi: 10.1016/j.tox.2016.05.026]
Unexposed stratum corneum simply exchanges with the underlying viable skin by diffusion:
where
K
p
{\displaystyle K_{p}}
is the partition coefficient,
S
s
{\displaystyle S_{s}}
is the total skin surface area,
f
S
e
{\displaystyle f_{S_{e}}}
the fraction of skin surface area exposed, ...
For the viable skin unexposed:
For the skin stratum corneum exposed:
for the viable skin exposed:
dt(QSkin_u) and dt(QSkin_e) feed from arterial blood and back to venous blood.
More complex diffusion models have been published [reference to add].
==== Intra-venous injection ====
Intravenous injection is a common clinical route of administration. (to be completed)
==== Inhalation ====
Inhalation occurs through the lung and is hardly dissociable from exhalation (to be completed)
=== Modelling metabolism ===
There are several ways metabolism can be modeled. For some models, a linear excretion rate is preferred. This can be accomplished with a simple differential equation. Otherwise a Michaelis-Menten equation, as follows, is generally appropriate for a more accurate result.
v
=
d
[
P
]
d
t
=
V
max
[
S
]
K
m
+
[
S
]
{\displaystyle v={\frac {d[P]}{dt}}={\frac {V_{\max }{[S]}}{K_{m}+[S]}}}
.
== Uses of PBPK modeling ==
PBPK models are compartmental models like many others, but they have a few advantages over so-called "classical" pharmacokinetic models, which are less grounded in physiology. PBPK models can first be used to abstract and eventually reconcile disparate data (from physicochemical or biochemical experiments, in vitro or in vivo pharmacological or toxicological experiments, etc.) They give also access to internal body concentrations of chemicals or their metabolites, and in particular at the site of their effects, be it therapeutic or toxic. Finally they also help interpolation and extrapolation of knowledge between:
Doses: e.g., from the high concentrations typically used in laboratory experiments to those found in the environment
Exposure duration: e.g., from continuous to discontinuous, or single to multiple exposures
Routes of administration: e.g., from inhalation exposures to ingestion
Species: e.g., transpositions from rodents to human, prior to giving a drug for the first time to subjects of a clinical trial, or when experiments on humans are deemed unethical, such as when the compound is toxic without therapeutic benefit
Individuals: e.g., from males to females, from adults to children, from non-pregnant women to pregnant
From in vitro to in vivo.
Some of these extrapolations are "parametric" : only changes in input or parameter values are needed to achieve the extrapolation (this is usually the case for dose and time extrapolations). Others are "nonparametric" in the sense that a change in the model structure itself is needed (e.g., when extrapolating to a pregnant female, equations for the foetus should be added).
Owing to the mechanistic basis of PBPK models, another potential use of PBPK modeling is hypothesis testing. For example, if a drug compound showed lower-than-expected oral bioavailability, various model structures (i.e., hypotheses) and parameter values can be evaluated to determine which models and/or parameters provide the best fit to the observed data. If the hypothesis that metabolism in the intestines was responsibility for the low bioavailability yielded the best fit, then the PBPK modeling results support this hypothesis over the other hypotheses evaluated.
As such, PBPK modeling can be used, inter alia, to evaluate the involvement of carrier-mediated transport, clearance saturation, enterohepatic recirculation of the parent compound, extra-hepatic/extra-gut elimination; higher in vivo solubility than predicted in vitro; drug-induced gastric emptying delays; gut loss and regional variation in gut absorption.
== Limits and extensions of PBPK modeling ==
Each type of modeling technique has its strengths and limitations. PBPK modeling is no exception. One limitation is the potential for a large number of parameters, some of which may be correlated. This can lead to the issues of parameter identifiability and redundancy. However, it is possible (and commonly done) to model explicitly the correlations between parameters (for example, the non-linear relationships between age, body-mass, organ volumes and blood flows).
After numerical values are assigned to each PBPK model parameter, specialized or general computer software is typically used to numerically integrate a set of ordinary differential equations like those described above, in order to calculate the numerical value of each compartment at specified values of time (see Software). However, if such equations involve only linear functions of each compartmental value, or under limiting conditions (e.g., when input values remain very small) that guarantee such linearity is closely approximated, such equations may be solved analytically to yield explicit equations (or, under those limiting conditions, very accurate approximations) for the time-weighted average (TWA) value of each compartment as a function of the TWA value of each specified input (see, e.g.,).
PBPK models can rely on chemical property prediction models (QSAR models or predictive chemistry models) on one hand. For example, QSAR models can be used to estimate partition coefficients. They also extend into, but are not destined to supplant, systems biology models of metabolic pathways. They are also parallel to physiome models, but do not aim at modelling physiological functions beyond fluid circulation in detail. In fact the above four types of models can reinforce each other when integrated.
== References ==
Further references:
== Forums ==
Ecotoxmodels is a website on mathematical models in ecotoxicology.
== Software ==
Dedicated software:
BioDMET
GastroPlus
Maxsim2
PK-Sim
PKQuest
PSE: gCOAS
Simcyp Simulator
ADME Workbench
General software:
ADAPT 5
Berkeley Madonna
COPASI: Biochemical System Simulator
Ecolego
Free simulation software: GNU MCSIM
GNU Octave
Matlab PottersWheel
ModelMaker
PhysioLab
R deSolve package
SAAM II
Phoenix WinNonlin/NLME/IVIVC/Trial Simulator | Wikipedia/Physiologically-based_pharmacokinetic_modelling |
Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compounds undergo more extensive optimization in a subsequent step of drug discovery called lead optimization (LO). The drug discovery process generally follows the following path that includes a hit to lead stage:
Target validation (TV) → Assay development → High-throughput screening (HTS) → Hit to lead (H2L) → Lead optimization (LO) → Preclinical development → Clinical development
The hit to lead stage starts with confirmation and evaluation of the initial screening hits and is followed by synthesis of analogs (hit expansion). Typically the initial screening hits display binding affinities for their biological target in the micromolar (10−6 molar concentration) range. Through limited H2L optimization, the affinities of the hits are often improved by several orders of magnitude to the nanomolar (10−9 M) range. The hits also undergo limited optimization to improve metabolic half life so that the compounds can be tested in animal models of disease and also to improve selectivity against other biological targets binding that may result in undesirable side effects.
On average, only one in every 5,000 compounds that enters drug discovery to the stage of preclinical development becomes an approved drug.
== Hit confirmation ==
After hits are identified from a high throughput screen, the hits are confirmed and evaluated using the following methods:
Confirmatory testing: compounds that were found active against the selected target are re-tested using the same assay conditions used during the HTS to make sure that the activity is reproducible.
Dose response curve: the compound is tested over a range of concentrations to determine the concentration that results in half maximal binding or activity (IC50 or EC50 value respectively).
Orthogonal testing: confirmed hits are assayed using a different assay which is usually closer to the target physiological condition or using a different technology.
Secondary screening: confirmed hits are tested in a functional cellular assay to determine efficacy.
Synthetic tractability: medicinal chemists evaluate compounds according to their synthesis feasibility and other parameters such as up-scaling or cost of goods.
Biophysical testing: nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), dynamic light scattering (DLS), surface plasmon resonance (SPR), dual polarisation interferometry (DPI), microscale thermophoresis (MST) are commonly used to assess whether the compound binds effectively to the target, the kinetics, thermodynamics, and stoichiometry of binding, any associated conformational change and to rule out promiscuous binding.
Hit ranking and clustering: Confirmed hit compounds are then ranked according to the various hit confirmation experiments.
Freedom to operate evaluation: hit structures are checked in specialized databases to determine if they are patentable.
== Hit expansion ==
Following hit confirmation, several compound clusters will be chosen according to their characteristics in the previously defined tests. An Ideal compound cluster will contain members that possess:
high affinity towards the target (less than 1 μM)
selectivity versus other targets
significant efficacy in a cellular assay
druglikeness (moderate molecular weight and lipophilicity usually estimated as ClogP). Affinity, molecular weight and lipophilicity can be linked in single parameter such as ligand efficiency and lipophilic efficiency.
low to moderate binding to human serum albumin
low interference with P450 enzymes and P-glycoproteins
low cytotoxicity
metabolic stability
high cell membrane permeability
sufficient water solubility (above 10 μM)
chemical stability
synthetic tractability
patentability
The project team will usually select between three and six compound series to be further explored. The next step will allow the testing of analogous compounds to determine a quantitative structure-activity relationship (QSAR). Analogs can be quickly selected from an internal library or purchased from commercially available sources ("SAR by catalog" or "SAR by purchase"). Medicinal chemists will also start synthesizing related compounds using different methods such as combinatorial chemistry, high-throughput chemistry, or more classical organic chemistry synthesis.
== Lead optimization phase ==
The objective of this drug discovery phase is to synthesize lead compounds, new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics. This optimization is accomplished through chemical modification of the hit structure, with modifications chosen by employing knowledge of the structure–activity relationship (SAR) as well as structure-based design if structural information about the target is available.
Lead optimization is concerned with experimental testing and confirmation of the compound based on animal efficacy models and ADMET (in vitro and in situ) tools that may be followed by target identification and target validation.
== Best Practices for Hit Finding ==
For educational purposes the European Federation for Medicinal Chemistry and Chemical Biology (EFMC) shared a series of webinars including 'Best Practices for Hit Finding' as well as 'Hit Generation Case Studies'.
== See also ==
== References == | Wikipedia/Drug_discovery_hit_to_lead |
Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other blood proteins act as enzymes, complement, components, protease inhibitors or kinin precursors. Contrary to popular belief, haemoglobin is not a blood protein, as it is carried within red blood cells, rather than in the blood serum.
Serum albumin accounts for 55% of blood proteins, is a major contributor to maintaining the oncotic pressure of plasma and assists, as a carrier, in the transport of lipids and steroid hormones. Globulins make up 38% of blood proteins and transport ions, hormones, and lipids assisting in immune function. Fibrinogen comprises 7% of blood proteins; conversion of fibrinogen to insoluble fibrin is essential for blood clotting. The remainder of the plasma proteins (1%) are regulatory proteins, such as enzymes, proenzymes, and hormones. All blood proteins are synthesized in liver except for the gamma globulins.
== Families of blood proteins ==
Examples of specific blood proteins:
Prealbumin (transthyretin)
Alpha 1 antitrypsin (neutralizes trypsin that has leaked from the digestive system)
Alpha-1-acid glycoprotein
Alpha-1-fetoprotein
alpha2-macroglobulin
Gamma globulins
Beta-2 microglobulin
Haptoglobin
Human Serum Albumin
Ceruloplasmin
Complement component 3
Complement component 4
C-reactive protein (CRP)
Lipoproteins (chylomicrons, VLDL, LDL, HDL)
Transferrin
Prothrombin
MBL or MBP
== Clinical significance ==
Separating serum proteins by electrophoresis is a valuable diagnostic tool, as well as a way to monitor clinical progress. Current research regarding blood plasma proteins is centered on performing proteomics analyses of serum/plasma in the search for biomarkers. These efforts started with two-dimensional gel electrophoresis efforts in the 1970s, and in more recent times this research has been performed using LC-tandem MS based proteomics. The normal laboratory value of serum total protein is around 7 g/dL.
Scientists are able to identify blood proteins using Photo-affinity labeling, a means of using photo-reactive ligands as a labeling agent to identify targeted proteins.
== References == | Wikipedia/Plasma_protein |
Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other blood proteins act as enzymes, complement, components, protease inhibitors or kinin precursors. Contrary to popular belief, haemoglobin is not a blood protein, as it is carried within red blood cells, rather than in the blood serum.
Serum albumin accounts for 55% of blood proteins, is a major contributor to maintaining the oncotic pressure of plasma and assists, as a carrier, in the transport of lipids and steroid hormones. Globulins make up 38% of blood proteins and transport ions, hormones, and lipids assisting in immune function. Fibrinogen comprises 7% of blood proteins; conversion of fibrinogen to insoluble fibrin is essential for blood clotting. The remainder of the plasma proteins (1%) are regulatory proteins, such as enzymes, proenzymes, and hormones. All blood proteins are synthesized in liver except for the gamma globulins.
== Families of blood proteins ==
Examples of specific blood proteins:
Prealbumin (transthyretin)
Alpha 1 antitrypsin (neutralizes trypsin that has leaked from the digestive system)
Alpha-1-acid glycoprotein
Alpha-1-fetoprotein
alpha2-macroglobulin
Gamma globulins
Beta-2 microglobulin
Haptoglobin
Human Serum Albumin
Ceruloplasmin
Complement component 3
Complement component 4
C-reactive protein (CRP)
Lipoproteins (chylomicrons, VLDL, LDL, HDL)
Transferrin
Prothrombin
MBL or MBP
== Clinical significance ==
Separating serum proteins by electrophoresis is a valuable diagnostic tool, as well as a way to monitor clinical progress. Current research regarding blood plasma proteins is centered on performing proteomics analyses of serum/plasma in the search for biomarkers. These efforts started with two-dimensional gel electrophoresis efforts in the 1970s, and in more recent times this research has been performed using LC-tandem MS based proteomics. The normal laboratory value of serum total protein is around 7 g/dL.
Scientists are able to identify blood proteins using Photo-affinity labeling, a means of using photo-reactive ligands as a labeling agent to identify targeted proteins.
== References == | Wikipedia/Blood_protein |
Cell-based therapies for Parkinson's disease include various investigational procedures which transplant specific populations of cells into the brains of people with Parkinson's disease. The investigation of cell transplantation therapies followed the discovery that the death of dopaminergic neurons in the substantia nigra pars compacta resulted in the motor symptoms of the disease. Thus, cell transplantation has focused on various dopamine producing cells throughout the body.
== List of cell-based sources ==
fetal ventral mesencephalic tissue (human and porcine)
human dopamine progenitor cells derived from autologous induced pluripotent stem cells (iPSCs)
adrenal medulla
sympathetic ganglia
carotid body
retinal pigment epithelium
embryonic stem cells
induced pluripotent stem cells
mesenchymal stem cells
=== Fetal ventral mesencephalic tissue ===
==== Human ====
==== Porcine ====
=== Adrenal medulla ===
The first cell-based therapy investigated for Parkinson's disease utilized the adrenal medulla. The adrenal medulla is the innermost part of the adrenal gland and contains neural crest derived chromaffin cells which secrete norepinephrine, epinephrine and to a far lesser extent dopamine into the blood. Autotransplantation of adrenal medullary tissue into the brains of animal models of Parkinson's disease showed minimal benefits. Despite this, open-label trials were undergone in humans which showed only modest benefits. Following these initial disappointing results however, a trial in Mexico demonstrated significant motor benefits in two patients with Parkinson's disease who had undergone the procedure. This publication incited widespread interest in the field and over the next few years hundreds of patients received adrenal medulla transplants. It was only when a registry was set up to consolidate all the data was it revealed that most patients did not benefit from the procedure to any significant extent. Furthermore, postoperative complications such as psychiatric disturbances were realized. These combined findings eventually led to the abandonment of this transplant procedure, which was largely flawed from the start.
=== Sympathetic ganglia ===
=== Carotid body ===
The carotid body is a group of chemoreceptor cells located at the bifurcation of the common carotid artery. It includes two populations of cells; glomus (type I) cells and sustentacular (type II) cells. Glomus cells are derived from the neural crest and secrete dopamine in response to hypoxemia (low level of oxygen in the blood). Based on their ability to secrete dopamine and also glial cell-derived neurotrophic factor (GDNF), these cells have been investigated as an intrastriatal autograft therapy for patients with Parkinson's disease. A clinical trial exploring this initially demonstrated motor benefits, unfortunately these benefits disappeared after 6–12 months, in correlation with poor survival of the grafted cells.
=== Retinal pigment epithelium ===
The retinal pigment epithelium (RPE) is a single layer of melanin containing cells located between the neural retina and the choroid. Retinal pigment epithelial cells synthesize dopamine and secrete the neurotrophic factors glial-cell derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Initial trials of intrastriatal allografts of cultured human retinal pigment epithelial cells attached to microcarriers (Spheramine, Bayer Schering Pharma AG) demonstrated
=== Stem cells ===
Researchers have differentiated ESCs into dopamine-producing cells with the hope that these neurons could be used in the treatment of Parkinson's disease.
== References == | Wikipedia/Cell-based_therapies_for_Parkinson's_disease |
The unified Parkinson's disease rating scale (UPDRS) is used to follow the longitudinal course of Parkinson's disease. The UPD rating scale is the most commonly used scale in the clinical study of Parkinson's disease.
The UPDRS is made up of these sections:
Part I: evaluation of mentation, behavior, and mood
Part II: self-evaluation of the activities of daily life (ADLs) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food
Part III: clinician-scored monitored motor evaluation
Part IV: complications of therapy
Part V: Hoehn and Yahr staging of severity of Parkinson's disease
Part VI: Schwab and England ADL scale
These are evaluated by interview and clinical observation. Some sections require multiple grades assigned to each extremity.
Clinicians and researchers alike use the UPDRS and the motor section in particular to follow the progression of a person's Parkinson's disease. Scientific researchers use it to measure benefits from a given therapy in a more unified and accepted rating system. Neurologists also use it in clinical practice to follow the progression of their patients' symptoms in a more objective manner.
Following the UPDRS scores over time provides insight into the patient's disease progression. For instance Michael J. Fox's symptoms started with a slight tremor, so his motor score would have been less than 10. For most patients, the "mentation, behavior and mood" scores increase later in the disease, but a subset exists for whom those symptoms develop early on.
== Similar rating scales ==
Other rating scales for Parkinson's disease are the Hoehn and Yahr scale and Schwab and England activities of daily living scale, although both of these measures are currently included within the UPDRS in modified format.
== MDS-UPDRS ==
In 2007, the Movement Disorder Society (MDS) published a revision of the UPDRS, known as the MDS-UPDRS. The revision became desirable after an MDS-sponsored Task Force on Rating Scales for Parkinson's Disease highlighted the limitations of the original UPDRS. Two major limitations include the lack of consistent anchor among subscales and the low emphasis on the nonmotor features of PD. The modified UPDRS retains the four-scale structure with a reorganization of the various subscales. Score ranges from 0 to 260, with 0 indicating no disability and 260 indicating total disability. The scales are:
Part I: Nonmotor experiences of daily living: 13 items. Score range: 0–52, 10 and below is mild, 22 and above is severe.
Part II: Motor experiences of daily living: 13 items. Score range: 0–52, 12 and below is mild, 30 and above is severe.
Part III: Motor examination: 18 items. Score range: 0–132, 32 and below is mild, 59 and above is severe.
Part IV: Motor complications: 6 items. Score range: 0–24, 4 and below is mild, 13 and above is severe.
Each item has 0–4 ratings: 0 (normal), 1 (slight), 2 (mild), 3 (moderate), and 4 (severe).
== References ==
== External links ==
Unified Parkinson's Disease Rating Scale on National Parkinson Foundation site
Unified Parkinson's Disease Rating Scale on Movement Disorders Virtual University site
Free online UPDRS calculator
UPDRS online calculator Archived 2018-02-27 at the Wayback Machine | Wikipedia/Unified_Parkinson's_Disease_Rating_Scale |
The research in Parkinson's disease (also known as clinical trials, medical research, research studies, or clinical studies) refers to any study intended to help answer questions about etiology, diagnostic approaches or new treatments of Parkinson's disease (PD) by studying their effects on human subjects. Clinical trials are designed and conducted by scientists and medical experts, who invite participants to undergo testing new vaccines, therapies, or treatments.
Only a small fraction of patients with Parkinson's disease participate in clinical research and specially in clinical trials. When clinical trials lack participation, it causes a significant delay in the development of new drugs and treatments.
== Research directions ==
One of the purposes of clinical research is to test the safety and efficacy of new treatments. Clinical research may also be conducted to learn other things about medical treatments or procedures, such as how to make an earlier diagnosis or how the treatment interacts with other drugs.
Though there are many types of clinical research, the two most common are interventional and observational. For example, researchers trying to identify causes of PD may conduct an observational study to examine genetic or environmental factors that may have triggered the disease in an individual. Natural history studies that evaluate how Parkinson's affects different people and how it changes over time are another example of observational research. Diagnostic accuracy studies are used to investigate how well a test, or a series of tests, are able to correctly identify diseased patients.
Researchers conducting clinical trials test the impact of treatments. These can include changing behavior, taking medications, or performing surgery. Interventional and observational research are equally important in helping to answer questions, develop new treatments, and ultimately find a cure for Parkinson's. Clinical trials are conducted in a series of phases.
Among the interventional and observational studies for Parkinson's disease, research is ongoing in a number of specific areas.
=== Quality of life ===
Quality of life research investigates the function that physical therapy, occupational therapy, exercise or other interventions may play in the quality of life of persons with Parkinson's disease. Persons with Parkinson's disease may experience motor symptoms (tremors, rigidity, slowness of movement, postural instability and gait dysfunctions) as well as non-motor symptoms (neuropsychiatric symptoms, autonomic dysfunction, or other; see Parkinson's disease). Due to this diversity of symptoms, Parkinson's disease may impact upon an individual's physical, social and mental well-being. For example, difficulties with movement can lead to difficulties with self-care, embarrassment, social-isolation, and depression.
Research may investigate whether there is a relationship between quality of life and a symptom of Parkinson's disease. Research on Parkinson's disease has investigated the link between quality of life and axial rigidity, personality traits, and patient education.
Alternatively, a study may evaluate the effectiveness of an intervention on the mitigation of symptoms, and the subsequent impact on quality of life. For example, an ongoing clinical study exploring Vitamin D as a possible therapy to improve balance and decrease the risk of falling in people with Parkinson's expects a subsequent increase in safety and well-being. Another recent study used data mining and analysis from previous clinical research to explore improvement in motor function people with Parkinson's disease experience after treatment with levodopa. The study concluded that motor learning in the presence of levodopa may improve the body's ability to adapt to Parkinson's disease.
Quality of life measures are increasingly being incorporated into clinical trials, therefore much research has gone into validating quality of life measures for persons with Parkinson's disease.
=== Neuroprotection ===
Neuroprotection is treatment that may slow down, stop, or reverse the progression of Parkinson's. Researchers are attempting to develop neuroprotective agents for Parkinson's disease, as well as other neurodegenerative brain disorders.
Several molecules have been proposed as potential neuroprotective treatments. However, none of them has been conclusively demonstrated to reduce degeneration in clinical trials. Agents currently under investigation as neuroprotective agents include anti-apoptotic drugs (omigapil, CEP-1347), antiglutamatergic agents, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrial drugs (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF).
Researchers are also investigating vaccines for Parkinson's disease that produce cells that change the way the body's immune system responds to the loss of dopamine. This treatment has shown success in reversing Parkinson's in mice, and researchers are investigating the viability of clinical studies in people.
Exercise may be neuroprotective. Animal studies show exercise may protect against dopaminergic neurotoxins, and research conducted via prospective studies shows the risk of Parkinson's disease in humans is reduced significantly by midlife exercise. More research is needed to investigate the benefits of exercise in the early stage of Parkinson's, the most suitable type of exercise, when exercise should be implemented, and the optimal duration of exercises.
A 2009 review of 11 systematic reviews and 230 random controlled trials, showed the effectiveness of Chinese Herbal Medicine (CHM) as a paratherapy for Parkinson's disease patients.
=== Genetics ===
Of those people with PD, it is only a small percentage that inherits the disease. However, the study of genetic forms of Parkinson's can assist scientists in learning more about the non-inherited forms. Several current studies are examining the genetic factors of Parkinson's disease. An example of genetic research is a recent study that investigated the GBA gene as a suspected cause of early-onset Parkinson's.
A genetic study involving researchers from BGI Genomics reveals the genetic cause of Parkinson's disease. The study, published in Neuroscience Bulletin, discovered that a mutation in the Cysteinyl-tRNA synthetase (CARS) gene (c.2384A>T; p.Glu795Val; E795V) is responsible, offering a new path for prevention and control of the disease.
=== Surgery ===
Advances in surgical procedures and neuroimaging techniques have ensured that surgical approaches can be as effective as medication at relieving some PD symptoms. Deep brain stimulation (DBS) is a surgical technique whereby a tiny electrode is inserted deep in the brain. The electrode is connected to a battery pack implanted under the collarbone via a subcutaneous wire. DBS is effective in suppressing symptoms of PD, especially tremor. A recent clinical study led to recommendations on identifying which Parkinson's patients are most likely to benefit from DBS.
== Astrocytes ==
In an animal model, manipulating glial precursor cells produced astrocytes that repaired Parkinson's multiple types of neurological damage. The researchers implanted cells only in rats with disease signs. The astrocytes used in the study differ from other types of astrocytes present in the mature brain. When implanted into the brains of rats with the disease, the new cells acted similar to astrocytes in the developing brain, which are more effective at building connections between nerves. The implanted astrocytes restored health and stability and allowed the nerve cells to resume normal activity.
Successful long-term therapy must both protect the areas of the brain under attack and foster the repair of dopaminergic neurons damage to other brain cell populations. Astrocyte dysfunction can contribute to multiple neurological disorders.
After transplantation, dopaminergic, interneurons and synaptophysin were all rescued. Interneurons play an important role in information processing and movement control and are lost in Parkinson's. Synaptophysin is a protein that is essential for communication between nerve cells. The transplanted rats recovered motor skills to normal levels, essentially reversing all symptoms. No previous therapies rescued these cells.
== Participant groups ==
Parkinson's clinical research studies need volunteers at all stages of the disease to help solve the unanswered questions about Parkinson's and to develop new treatments. Some studies seek to enroll specific groups of people.
=== Newly diagnosed ===
A number of Parkinson's disease clinical research studies seek to enroll people newly diagnosed with PD that are not currently undergoing any treatment. These trials vary in scope, some focusing on neuroprotection in which researchers seek to determine whether a certain compound might offer protection to dopamine-producing cells, thus helping to slow or stop the progression of the disease.
=== Healthy controls ===
In addition to patients with PD, healthy controls, including friends and family members of those with Parkinson's, are also needed for clinical trials. Family members may participate in genetic studies, and healthy people can participate in trials that require a control group of participants without PD. Control groups are necessary as a means of testing the research being studied.
== Participating ==
=== Benefits ===
People with PD, their friends, and their family members all have many reasons to consider participating in clinical research. Many participants believe that their involvement benefits themselves and the future of other people with the disease. Without clinical research participants, many of the advances in treating PD would not have happened. In addition to furthering the scientific community's knowledge of Parkinson's, clinical trial participation may offer access to leading healthcare professionals and potentially useful new drugs and therapies. This care is often provided free of charge in exchange for participation in the study. Finally, by participating in clinical studies, those whose lives are impacted by PD may increase knowledge and understanding of the disease.
=== How to participate ===
It can be a challenge to find the right clinical trial, and it can be even more challenging for the trial team members to find volunteers. People with PD may consult their doctors, discuss with their family members, and speak to other clinical trials participants about their experiences. Online resources for participation can be found at www.FoxTrialFinder.org. and www.ClinicalTrials.gov.
== Clinical research resources ==
People with Parkinson's disease who are considering participating in clinical research have resources available to help them navigate the clinical research process.
=== Fox Trial Finder ===
Led by The Michael J. Fox Foundation for Parkinson's Research, the Fox Trial Finder is a matching site that connects clinical trials to potential volunteers. Since its launch in 2012, the Fox Trial Finder has registered more than 19,000 volunteers across multiple continents. Volunteers enter their information—from location to the medicines they take—into a profile on Fox Trial Finder, which then matches them to nearby trials seeking volunteers with their particular criteria. The Fox Trial Finder seeks volunteers both with and without Parkinson's disease.
=== Parkinson's Advocates in Research ===
The Parkinson's Disease Foundation's Parkinson's Advocates in Research (PAIR) program is a patient-based initiative that ensures people with Parkinson's disease have a role in shaping the clinical research process. By training advocates with Parkinson's disease to serve as patient representatives on clinical research advisory boards, the PAIR program aims to improve outcomes by helping researchers overcome and identify barriers in research that they may otherwise overlook. Participants in the PAIR program receive training through PDF's Clinical Research Learning Institute, an annual multi-day training that focuses on education via training sessions, clinical researcher led workshops, as well as interaction with study coordinators and representatives from both the government and the industry.
=== Parkinson's Disease Biomarkers Program ===
The NINDS Parkinson's Disease Biomarkers Program brings together various stakeholders to create a resource of longitudinal biofluid samples from PD patients and controls and their associated clinical assessment data for biomarker discovery research. Neuroimaging and genomic data are also available for some of the samples. All samples are stored at the NINDS Human Genetics Repository at Coriell Institute and can be requested through the PDBP Data Management Resource.
== Research organizations ==
The National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), is a major funder of Parkinson's disease research in the US. In 2012, the NINDS funded approximately $98 million out of a total of $154 million in NIH-supported PD research. The NINDS supports basic, translational, and clinical PD research programs through a variety of mechanisms, including the Morris K. Udall Centers of Excellence for Parkinson's Disease Research and the Parkinson's Disease Biomarkers Program (PDBP). NINDS has just completed a major planning effort to determine priorities for future Parkinson's disease research.
The Parkinson's Disease Foundation is a leading national presence in the United States in Parkinson's disease research, education and public advocacy. PDF works on behalf of people who live with Parkinson's disease by funding promising clinical research to find treatments and cures for Parkinson's. PDF was founded in 1957, and since then has invested more than $115 million on scientific research.
The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease. As the largest private foundation for Parkinson's disease in the US, the Michael J. Fox Foundation has spent 325 million dollars on research. In 2010, the Fox foundation launched the first large-scale clinical study on evolution biomarkers of the disease with a cost of 40 million dollars in 5 years.
The CRC for Mental Health is an Australian Federal Government funded research consortium researching biomarkers, imaging reagents and therapeutics for early diagnosis of Parkinson's Disease.
The Cure Parkinson's Trust, set up in the UK in 1968 by Tom Isaacs, was instrumental in arranging a ground-breaking clinical trial of the drug GDNF at the University of Bristol during the 2010s.
== References ==
== External links ==
Parkinson's Disease Foundation
Fox Trial Finder
NINDS Parkinson's Disease Biomarkers Program
NINDS Parkinson's Disease Research page
NINDS Human Genetics Repository at Coriell Institute | Wikipedia/Parkinson's_disease_clinical_research |
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.
== Uses ==
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.
=== In oncology ===
Combination therapy has gained momentum in oncology in recent years, with various studies demonstrating higher response rates with combinations of drugs compared to monotherapies, and the FDA recently approving therapeutic combination regimens that demonstrated superior safety and efficacy to monotherapies. 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.
Various systems biology methods must be used to discover combination therapies to overcome drug resistance in select cancer types. Recent precision medicine approaches have focused on targeting multiple biomarkers found in individual tumors by using combinations of drugs. 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. That level of complexity is one of the primary impediments to the growth of combination therapy in oncology.
The National Cancer Institute has recently highlighted combination therapy as a top research priority in oncology.
=== Bacterial infections ===
Combination therapy with two or more antibiotics are often used in an effort to treat multi-drug resistant Gram-negative bacteria.
== Contrast to monotherapy ==
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.
== See also ==
Polypill, a medication which contains a combination of multiple active ingredients
Combination drug
== References ==
== External links ==
Drug combination database. covers information on more than 1300 drug combinations in either clinical use or different testing stages.
Perturbation biology method for the discovery of anti-resistance drug combinations with network pharmacology. | Wikipedia/Monotherapy |
Parkinson's disease is the 2nd most prevalent neurological disorder within the United States and Europe, affecting around 1% of the population over the age of 60. While the link connecting the onset of Parkinson's disease to environmental factors is known, the link between dietary patterns and the disease is just beginning to be researched more fully. Additionally, other research has sought to examine the symptoms of the disease and propose methods on how to alleviate these symptoms through changes in diet. Current medications that work to alleviate the symptoms of Parkinson's disease can also be made more effective through changes in diet.
== Background ==
Parkinson's disease is a degenerative disorder of the central nervous system that results due to the death of dopamine producing cells within the central nervous system. Because of the death of these cells, less dopamine is available within the brain, resulting in tremors and other side effects within motor functions. The reason for the deaths of these cells is a topic of current research, with some theories suggesting a contribution of oxidative stress due to free radicals and inflammation. Currently, there are no treatments to cure Parkinson's disease, yet a variety of treatment options are available to alleviate the symptoms including medication and dietary changes.
== Dietary prevention and neuroprotection ==
Many theories of the cause of Parkinson's disease symptoms point to the death of dopamine-producing neurons within the central nervous system due to oxidative stress. This oxidative stress is caused by metabolism and the production of molecules known as free radicals. Accumulation of these free radicals within the brain can cause damage to neurons. Additionally, dopamine-producing neurons are particularly vulnerable to oxidative stress due to the relatively high levels of metabolism associated with the production of dopamine, resulting in comparatively higher amounts of free radicals being produced by these dopamine-producing neurons. The effects of dopamine within the brain are widespread, including voluntary motor control. With the death of these dopamine-producing cells within an area of the mid-brain known as the substantia nigra, the central nervous system has less control over the body, resulting in the tremors and rigidity seen in patients with Parkinson's disease.
Antioxidants are suggested to be useful in preventing Parkinson's disease because they scavenge free radicals such as reactive nitrogen and oxygen, preventing their build-up and the destruction of dopamine-producing neurons. Research has attempted to link dietary patterns to the likelihood of developing Parkinson's disease. The MIND and Mediterranean diets are emerging as potentially beneficial diets for people with Parkinson's. People with Parkinson's who maintained the Mediterranean diet were more likely to have symptoms appear 17.4 years earlier than those who closely followed it; while MIND diet participants functioned at a cognitive level 7.5 years younger, and they declined cognitively more slowly. Research shows that a diet consisting of foods typically associated with the Mediterranean diet may act as a preventative measure for the disease due to the high levels of antioxidants found in within these foods such as complex phenols, vitamins C and E, and carotenoids. A typical Mediterranean diet consists of a high intake of vegetables, legumes, fruits, and cereals, olive oil (unsaturated fatty acids), and fish and low to moderate intake of foods such as dairy, meats, poultry. Research by Johns Hopkins has found that a common compound in fruit, called farnesol, preserves dopaminergic neurons. However, people who consume more dairy products have an increased likelihood of developing Parkinson's disease. It is important to note that the increased risk from consumption of dairy products is slight and dairy provides different nutrients that are beneficial for people with Parkinson's. Additionally, it has been seen that the intake of animal fats may be linked to the development of the disease. It has also been suggested that a diet that results in high plasma urate can result in a reduced risk of developing Parkinson's.
== Management of symptoms through diet ==
Typical symptoms of the disease include bodily shaking, rigidity, slowness of movement, difficulty in movement, as well as other motor related symptoms. As the disease progresses, patients develop cognitive and behavior problems such as dementia, sensory impairment, sleep problems, and emotional issues. Parkinson's disease (PD) can have an effect on neurons that control the digestive process, so subjects may experience constipation and gastroparesis due to the disease. PD may also make a subject more tired in the later parts of the day, decreasing the likelihood to want to eat food and leading to further dietary problems.
No special diet is required for subjects with PD, yet a well balanced diet is beneficial due to the effects of increased energy and improved effectiveness of drugs. Additional, in research it has been shown that nutritionally healthy, balanced meals enable the most effective use of symptom reducing drugs. In order to cope with the decrease in energy that many patients express, smaller meals are recommended for such cases. A good diet includes high fiber foods (such as vegetables, dried peas, beans, whole grain foods, pasta, rice, and fresh fruit) in order to reduce constipation, low saturated fats and cholesterol, low sugar and salt intake, plenty of water, and limited alcohol intake. Although this needs to be further elucidated, recent studies have shown that curcumin, a chemical in turmeric which is highly consumed by the South Asian population, can have protective roles in PD.
== Dietary considerations with medications ==
Treatments are only effective in moderating the symptoms of the disease, mainly with drugs including levodopa (L-DOPA) and dopamine agonists. Once too many dopamine producing cells have been lost however, the effects of L-DOPA become less effective. Once this occurs, a complication known as dyskinesia commonly occurs in which subjects undergo involuntary writhing movements despite the use of L-DOPA. The effects of dyskinesia vary between periods of high symptoms and low symptoms. In order to limit the onset of dyskinesia, typical L-DOPA dosages are kept as low as possible while still achieving desired results. Lastly, in cases in which drugs are ineffective, deep brain stimulation and surgery can be used to reduce symptoms.
Levodopa is taken orally and is absorbed through the small intestines into the blood, competing for access with natural proteins. Additionally, once the drug has entered the blood stream, L-DOPA utilizes the same pathways to cross the blood–brain barrier as natural protein. Only about 5–10% of levodopa crosses the blood brain barrier, while the remaining is metabolized elsewhere in the body. The metabolism of medications elsewhere is known to cause side effects such as nausea, dyskinesias, and stiffness.
In order to improve the effectiveness of PD drugs such as L-DOPA, a diet low in excessive protein is recommended since L-DOPA competes with these dietary proteins for access to the blood and brain. It is therefore recommended that the drug be taken so that it is not affected by digestion. It is recommended to take L-DOPA ideally 30 minutes before eating or at least 1 hour afterwards. A protein redistribution diet is sometimes recommended in which most protein should be eaten in the afternoon. However, with the development of dyskinesias the protein redistribution diet need not apply because slowing the absorption of L-DOPA may be beneficial. Plenty of water with the intake of L-DOPA ensures that the drug will be absorbed more quickly. L-DOPA can cause nausea in some subjects when taken on an empty stomach. Methods to reduce nausea include taking carbidopa (Sinemet), sugary drinks to calm the stomach, and avoidance of orange and grapefruit juices due to high acidity. Some PD medications are known to cause the subject to become thirsty, and methods to reduce thirst include drinking plenty of water as well as limiting caffeine uptake because it may interfere with medication or increase thirst.
== References ==
== External links ==
https://parkinsons.co.in/diet-and-nutrition-for-a-parkinsons-disease-patient/ | Wikipedia/Dietary_management_of_Parkinson's_disease |
The Lee Silverman Voice Treatment – LOUD (LSVT LOUD) is a treatment for speech disorders associated with Parkinson's disease (PD). It focuses on increasing vocal loudness and is delivered by a speech therapist in sixteen one-hour sessions spread over four weeks. A derivative of this treatment, known as LSVT BIG, is used in treating movement aspects of Parkinson's disease.
== Background ==
Dr. Lorraine Ramig started Parkinson's Disease rehabilitation research in 1983 while serving as assistant professor on tenure track in the Department of Speech, Language and Hearing Science at the University of Colorado-Boulder. Dr. Ramig was approached by colleague Dr. Wilbur Gould who requested her assistance in treating a friend, Mrs. Lee Silverman. The Voice Treatment consisted of four weeks of rigorous therapy, entailing four one-hour sessions per week, with the goal of increasing patient's voice and speech abilities. Dr. Ramig officially founded the Lee Silverman Voice Treatment program LSVT Global in 1985 in honor of the first patient who died before research was officially published and recognized as a medical discovery.
The foundation defines the processes of LSVT LOUD treatment with specific clinical exercises in speech therapy. The initial design of the project included "medical care, physical therapy, occupational therapy, speech therapy, family support, nutrition and recreation," according to Dr. Ramig, but Silverman's family challenged Ramig to create a design based only on speech so they could communicate with her better.
== Process of treatment ==
The treatment is delivered during hour-long sessions with a speech-language pathologist, given four times a week for four weeks. These sessions stress the idea of "thinking loud in order to speak loud" and use exaggerated motions and behaviors. Through video documentation, the patient's loudness is measured through a series of voice exercises using a decibel sound meter. In the two videos cited, both patients were asked to take a breath and say "Ahh" as long as they can. Targeting the vocal chords is a way of expanding the patient's capability of speaking more fluently despite the conditions of Parkinson's. In one video, the patient says "Ahh" in many scales (ascending and descaling), then goes on to functional phrases, and finally phrases that answer questions such as "I'm fine".
== LSVT – BIG ==
A derivative of this treatment, known as LSVT BIG, is used by speech-language pathologists, physiotherapists, and occupational therapists to promote high-amplitude movements in people with Parkinson's disease. The quick, explosive movements characteristic of LSVT BIG are aimed at reversing one of four cardinal movement symptoms in PD, bradykinesia. The Berlin Big Study compared the effectiveness of three distinct exercise programs in people with mild to moderate Parkinson's disease. Subjects were randomly assigned to receive either one-on-one LSVT BIG training, group Nordic walking training, or domestic unsupervised exercises. At the conclusion of the training period, the LSVT BIG group demonstrated a significant improvement in unified Parkinson's disease rating scale (UPDRS) motor score and 10-m timed up and go test timing compared with the Nordic walking and home exercise group.
== References ==
== External links ==
LSVT Global web site | Wikipedia/Lee_Silverman_voice_treatment |
The Vaccine Damage Payment is a provision of the welfare state in the United Kingdom that provides a payment of £120,000, as of 2023, for people who can show that they have suffered a vaccine injury.
The payment can also be applied for on behalf of someone who has died after becoming severely disabled because of certain vaccinations.
Vaccine Damage Payments are not a compensation scheme, which means that legal action to claim compensation can also be taken, even if a Vaccine Damage Payment has been received.
== Description ==
The Vaccine Damage Payment programme was created in 1979 to provide significant payment to people who are severely disabled as a result of vaccinations against certain diseases. It is a UK statutory programme, and it is not necessary to demonstrate negligence in order to qualify.
Between 1997 and 2005, the government of the United Kingdom paid £3.5m, in 35 payments of £100,000 each, to patients who were left disabled by vaccinations.
An FOI (Freedom of Information application) to The Department for Work and Pensions (DWP) was made in 2019. The DWP's response states that up until May 2019 £74,690,000 has been paid out from the fund, and 941 claims have been successful.
== Qualifications ==
To qualify for the programme, a person must be severely disabled as a result of a vaccination, and the disablement must be assessed as at least 60%. The state will still pay even if the vaccination was not administered by them. Additionally, a person can still qualify if a vaccine against one of the diseases listed below was administered to the claimant's mother while the mother was pregnant. The claimant may also qualify if they have been in close physical contact with someone who had an oral vaccine against poliomyelitis.
The vaccination must have been for one of the following diseases:
diphtheria
tetanus
pertussis (whooping cough)
poliomyelitis
measles
mumps
rubella (German measles)
tuberculosis (TB)
haemophilus influenzae type B (HIB)
meningococcal group C (meningitis C)
pneumococcal infection
human papillomavirus
pandemic influenza A (H1N1) 2009 (swine flu) - up to 31 August 2010
smallpox - up to 1 August 1971
Coronavirus (COVID-19)
The vaccination must also have been administered before the claimant's 18th birthday, unless the vaccination was administered during an outbreak of disease in the United Kingdom or the Isle of Man, or if it was a vaccine for poliomyelitis, rubella, Meningococcal Group C, human papillomavirus, pandemic influenza A (H1N1) 2009 (swine flu) or COVID-19. The vaccination must have been administered in the United Kingdom or the Isle of Man, or as part of Armed Forces medical treatment.
In 2018, the Department of Health and Social Care conceded that the age restriction wrongly excluded adults from the programme.
== See also ==
National Vaccine Injury Compensation Program - the no-fault system for litigating vaccine injury claims in the USA
== References ==
== External links ==
Vaccine Damage Payment—The UK government's web page on the scheme. | Wikipedia/Vaccine_Damage_Payment |
Meningococcal disease is a serious infection caused by Neisseria meningitidis, also known as meningococcus, a gram negative diplococcus. Meningococcal disease includes meningitis, meningococcal septicemia, or a combination of both, which can be life-threatening and rapidly progressive. If left untreated, the disease has a high mortality rate; however, it is preventable through vaccination. Meningitis and meningococcal sepsis are major causes of illness, death, and disability in both developed and under-developed countries.
Meningococcal disease can be transmitted to others through saliva, close contact with an infected individual by inhaling respiratory air droplets. Initial symptoms may be subtle and similar to other bacterial infection, but can quickly progress to include fever, rash, body aches, photophobia and other complications. Neisseria meningitidis colonizes a substantial proportion of the general population without issues, but it can invade the bloodstream, affecting the entire body, most notably limbs and brain, causing serious illness in a small percentage of individuals.
The global incidence of meningococcal disease is relatively low, ranging from 0.0 to 10.2 per 100,000 however cases in the United States are rising. Serotypes of the bacteria range from various countries, with serotype B accounting for most new cases worldwide. Meningococcal vaccines have sharply reduced the incidence of the disease in developed countries.
Vaccine has also shown to lessen cases of illness and their associated complications as well as death. Current vaccinations cover most of the bacterial strains that causes meningococcal disease. This has led to a decrease of incidence and burden from the disease.Treatment include supportive care, early administration of antibiotics and management of complications associated with infection. Ongoing research continues in an effort to understand specific aspects of meningococcal biology and host interactions; however, the development of improved treatments and effective vaccines is expected to depend on novel efforts by workers in many different fields.
== Pathogenesis ==
Meningococcal disease causes life-threatening meningitis and sepsis conditions. In the case of meningitis, bacteria attack the lining between the brain and skull called the meninges. Infected fluid from the meninges then passes into the spinal cord, causing symptoms including stiff neck, fever and rashes. The meninges (and sometimes the brain itself) begin to swell, which affects the central nervous system.
Even with antibiotics, approximately 1 in 10 people who have meningococcal meningitis will die; however, about as many survivors of the disease lose a limb or their hearing, or experience permanent brain damage. The sepsis type of infection is much more deadly, and results in a severe blood poisoning called meningococcal sepsis that affects the entire body. In this case, bacterial toxins rupture blood vessels and can rapidly shut down vital organs. Within hours, patient's health can change from seemingly good to mortally ill.
The N. meningitidis bacterium is surrounded by a slimy outer coat that contains disease-causing endotoxin. While many bacteria produce endotoxin, the levels produced by meningococcal bacteria are 100 to 1,000 times greater (and accordingly more lethal) than normal. As the bacteria multiply and move through the bloodstream, it sheds concentrated amounts of toxin. The endotoxin directly affects the heart, reducing its ability to circulate blood, and also causes pressure on blood vessels throughout the body. As some blood vessels start to hemorrhage, major organs like the lungs and kidneys are damaged.
Patients with meningococcal disease are treated with a large dose of antibiotic. The systemic antibiotic flowing through the bloodstream rapidly kills the bacteria but, as the bacteria are killed, even more toxin is released. It takes up to several days for the toxin to be neutralized from the body by using continuous liquid treatment and antibiotic therapy.
== Classification ==
=== Meningococcemia ===
Meningococcemia, also known as meningococcal septicemia, is an infection of the bloodstream. Meningococcemia makes up about approximately 20% of meningococcal disease cases. Symptoms of meningoccemia may include fever, low blood pressure as well as organ failure. Like many other gram-negative blood infections it can cause disseminated intravascular coagulation (DIC), which is the inappropriate clotting of blood within the vessels. DIC can cause ischemic tissue damage when upstream thrombi obstruct blood flow and hemorrhage because clotting factors are exhausted. Small bleeds into the skin cause the characteristic petechial rash, which appears with a star-like shape and mostly appears on the extremity of the body. This is due to the release of toxins into the blood that break down the walls of blood vessels. A rash can develop under the skin due to blood leakage that may leave red or brownish pinprick spots, which can develop into purple bruising. Meningococcal rash can usually be confirmed by a glass test in which the rash does not fade away under pressure.
Meningoccemia can also lead to Waterhouse–Friderichsen syndrome, which is associated with disseminated intravascular coagulation or thrombosis of multiple organs and extremities and necrosis of adrenal glands.
=== Meningitis ===
Meningococcal meningitis is a form of bacterial meningitis caused by the Neisseria meningitidis bacteria. Meningitis is a disease caused by inflammation and irritation of the meninges, the membranes surrounding the brain and spinal cord. In meningococcal meningitis this is caused by the bacteria invading the cerebrospinal fluid and circulating through the central nervous system. The classic presentation of meningitis includes fever, neck stiffness, and altered mental status; however these symptoms are typically present in less than 50% of cases. Symptoms also differentiate between age groups, with older individuals presenting with altered mental status and localized neurological impairments and younger children showing general symptoms such as irritability, lethargy, or inability to feed.
=== Atypical types of meningococcal disease ===
N. meningitidis can also result in atypical presentations throughout the body. Atypical types of meningococcal disease include septic arthritis, meningococcal pneumonia, pericarditis and acute gastrointestinal or GI symptoms.
GI symptoms from meningococcal disease includes nausea, vomiting and abdominal pain. These symptoms are rare but can occur during the initial phases of infection. These symptoms can often be misdiagnosed as gastroenteritis, also known as a inflammation of the stomach and intestines.
Septic arthritic is also associated with meningococcal disease. Septic arthritis caused by Neisseria meningitidis can appear as joint pain, redness, warmth, and limited movement. It typically affects just one joint—most often the knee—and is more common in very young or older individuals.
Meningococcal pneumonia can appear during influenza pandemics and in military camps. This is a multi-lobar, rapidly evolving pneumonia, sometimes associated with septic shock. With prompt treatment, the prognosis is excellent. Meningococcal pneumonia typical occurs in older individuals and found to be associated with serotype W of N. meningitidis. Although rare, meningococcal pericarditis can occur.
== Signs and symptoms ==
=== Meningitis ===
The patient with meningococcal meningitis typically presents with high fever, nuchal rigidity (stiff neck), Kernig's sign, severe headache, vomiting, purpura, photophobia, and sometimes chills, altered mental status, or seizures. Diarrhea or respiratory symptoms are less common. Petechiae are often also present, but do not always occur; their absence does not negate a diagnosis of meningococcal disease. Anyone with symptoms of meningococcal meningitis should receive intravenous antibiotics prior to the results of lumbar puncture being known, as delay in treatment can greatly worsen the prognosis.
=== Meningococcemia ===
Symptoms of meningococcemia are, at least initially, similar to those of influenza. Typically, the first symptoms include fever, nausea, myalgia, headache, arthralgia, chills, diarrhea, stiff neck, and malaise. Later symptoms include septic shock, purpura, hypotension, cyanosis, petechiae, seizures, anxiety, and multiple organ dysfunction syndrome. Acute respiratory distress syndrome and altered mental status may also occur. The petechial rash appear with the 'star-like' shape. Meningococcal sepsis has a greater mortality rate than meningococcal meningitis, but the risk of neurologic sequelae is much lower.
== Diagnosis ==
Diagnosing meningococcal disease is vital; death can occur in a person within 6-12 hours with initial signs and symptoms.
Diagnosis includes clinical evaluation based on symptoms blood cultures, cerebrospinal fluid (CSF) analysis, basic metabolic panel, and possibly imaging.
Lumbar puncture is the gold standard for identifying a person has meningitis and rule out other causes of infection. This fluid covers the brain and spinal cord. This test should be completed unless a person has increased pressure in the brain such as swelling in the optic nerve or altered mental status.
Computer tomography (CT) can be used if diagnosis is unclear and if a person has depressed mental status.
== Prevention ==
The most effective method of prevention is a vaccine against N. meningitidis. Different countries have different strains of the bacteria and therefore use different vaccines. Twelve serogroups (strains) exist, with six having the potential to cause a major epidemic - A, B, C, X, Y and W135 are responsible for virtually all cases of the disease in humans. Vaccines are currently available against all six strains, including a newer vaccine against serogroup B. The first vaccine to prevent meningococcal serogroup B (meningitis B) disease was approved by the European Commission on 22 January 2013.
Vaccines offer significant protection from three to five years (plain polysaccharide vaccine Menomune, Mencevax and NmVac-4) to more than eight years (conjugate vaccine Menactra).
=== Vaccinations ===
==== Children ====
Children 2–10 years of age who are at high risk for meningococcal disease such as certain chronic medical conditions and travel to or reside in countries with hyperendemic or epidemic meningococcal disease should receive primary immunization. Although safety and efficacy of the vaccine have not been established in children younger than 2 years of age and under outbreak control, the unconjugated vaccine can be considered.
==== Adolescents ====
Primary immunization against meningococcal disease with meningitis A, C, Y and W-135 vaccines is recommended for all young adolescents at 11–12 years of age and all unvaccinated older adolescents at 15 years of age. Although conjugate vaccines are the preferred meningococcal vaccine in adolescents 11 years of age or older, polysaccharide vaccines are an acceptable alternative if the conjugated vaccine is unavailable.
==== Adults ====
Primary immunization with meningitis A, C, Y and W-135 vaccines is recommended for college students who plan to live in dormitories, although the risk for meningococcal disease for college students 18–24 years of age is similar to that of the general population of similar age.
Routine primary immunization against meningococcal disease is recommended for most adults living in areas where meningococcal disease is endemic or who are planning to travel to such areas. Although conjugate vaccines are the preferred meningococcal vaccine in adults 55 years of age or younger, polysaccharide vaccines are an acceptable alternative for adults in this age group if the conjugated vaccine is unavailable. Since safety and efficacy of conjugate vaccines in adults older than 55 years of age have not been established to date, polysaccharide vaccines should be used for primary immunization in this group.
==== Medical staff ====
Health care people should receive routine immunization against meningococcal disease for laboratory personnel who are routinely exposed to isolates of N. meningitidis. Laboratory personnel and medical staff are at risk of exposure to N. meningitides or to patients with meningococcal disease. Hospital Infection Control Practices Advisory Committee (HICPAC) recommendations regarding immunization of health-care workers that routine vaccination of health-care personnel is recommended, Any individual 11–55 years of age who wishes to reduce their risk of meningococcal disease may receive meningitis A, C, Y and W-135 vaccines and those older than 55 years of age. Under certain circumstances if unvaccinated health-care personnel cannot get vaccinated and who have intensive contact with oropharyngeal secretions of infected patients and who do not use proper precautions should receive anti-infective prophylaxis against meningococcal infection (i.e., 2-day regimen of oral rifampicin or a single dose of IM ceftriaxone or a single dose of oral ciprofloxacin).
==== USA military recruits ====
Because the risk of meningococcal disease is increased among USA's military recruits, all military recruits routinely receive primary immunization against the disease.
==== Travelers ====
Immunization against meningococcal disease is not a requirement for entry into any country, unlike yellow fever. Only Saudi Arabia requires that travelers to that country for the annual Hajj and Umrah pilgrimage have a certificate of vaccination against meningococcal disease, issued not more than 3 years and not less than 10 days before arrival in Saudi Arabia.
Travelers to or residents of areas where N. meningitidis is highly endemic or epidemic are at risk of exposure should receive primary immunization against meningococcal disease.
==== HIV-infected individuals ====
HIV-infected individuals are likely to be at increased risk for meningococcal disease; HIV-infected individuals who wish to reduce their risk of meningococcal disease may receive primary immunization against meningococcal disease. Although efficacy of meningitis A, C, Y and W-135 vaccines have not been evaluated in HIV-infected individuals to date, HIV-infected individuals 11–55 years of age may receive primary immunization with the conjugated vaccine. Vaccination against meningitis does not decrease CD4+ T-cell counts or increase viral load in HIV-infected individuals, and there has been no evidence that the vaccines adversely affect survival.
==== Close contacts ====
Protective levels of anticapsular antibodies are not achieved until 7–14 days following administration of a meningococcal vaccine, vaccination cannot prevent early onset disease in these contacts and usually is not recommended following sporadic cases of invasive meningococcal disease. Unlike developed countries, in sub-Saharan Africa and other under developed countries, entire families live in a single room of a house.
Meningococcal infection is usually introduced into a household by an asymptomatic person. Carriage then spreads through the household, reaching infants usually after one or more other household members have been infected. Disease is most likely to occur in infants and young children who lack immunity to the strain of organism circulating and who subsequently acquire carriage of an invasive strain.
Close contacts are defined as those persons who could have had intimate contact with the patient's oral secretions such as through kissing or sharing of food or drink. The importance of the carrier state in meningococcal disease is well known. In developed countries the disease transmission usually occurs in day care, schools and large gatherings where usually disease transmission could occur. Because the meningococcal organism is transmitted by respiratory droplets and is susceptible to drying, it has been postulated that close contact is necessary for transmission. Therefore, the disease transmission to other susceptible person cannot be prevented. Meningitis occurs sporadically throughout the year, and since the organism has no known reservoir outside of man, asymptomatic carriers are usually the source of transmission.
Additionally, basic hygiene measures, such as handwashing and not sharing drinking cups, can reduce the incidence of infection by limiting exposure. When a case is confirmed, all close contacts with the infected person can be offered antibiotics to reduce the likelihood of the infection spreading to other people. However, rifampin-resistant strains have been reported and the indiscriminate use of antibiotics contributes to this problem. Chemoprophylaxis is commonly used to those close contacts who are at highest risk of carrying the pathogenic strains. Since vaccine duration is unknown, mass select vaccinations may be the most cost-effective means for controlling the transmission of the meningococcal disease, rather than mass routine vaccination schedules.
==== Chronic medical conditions ====
Persons with component deficiencies in the final common complement pathway (C3, C5-C9) are more susceptible to N. meningitidis infection than complement-satisfactory persons, and it was estimated that the risk of infection is 7000 times higher in such individuals. In addition, complement component-deficient populations frequently experience frequent meningococcal disease since their immune response to natural infection may be less complete than that of complement non-deficient persons.
Inherited properdin deficiency also is related, with an increased risk of contracting meningococcal disease. Persons with functional or anatomic asplenia may not efficiently clear encapsulated Neisseria meningitidis from the bloodstream Persons with other conditions associated with immunosuppression also may be at increased risk of developing meningococcal disease.
=== Antibiotics ===
An updated 2013 Cochrane review investigated the effectiveness of different antibiotics for prophylaxis against meningococcal disease and eradication of N. meningitidis particularly in people at risk of being carriers. The systematic review included 24 studies with 6,885 participants. During follow up no cases of meningococcal disease were reported and thus true antibiotic preventative measures could not be directly assessed. However, the data suggested that rifampin, ceftriaxone, ciprofloxacin and penicillin were equally effective for the eradication of N. meningitidis in potential carriers, although rifampin was associated with resistance to the antibiotic following treatment. Eighteen studies provided data on side effects and reported they were minimal but included nausea, abdominal pain, dizziness and pain at injection site.
=== Disease outbreak control ===
Meningitis A, C, Y and W-135 vaccines can be used for large-scale vaccination programs when an outbreak of meningococcal disease occurs in Africa and other regions of the world. Whenever sporadic or cluster cases or outbreaks of meningococcal disease occur in the US, chemoprophylaxis is the principal means of preventing secondary cases in household and other close contacts of individuals with invasive disease. Meningitis A, C, Y and W-135 vaccines rarely may be used as an adjunct to chemoprophylaxis,1 but only in situations where there is an ongoing risk of exposure (e.g., when cluster cases or outbreaks occur) and when a serogroup contained in the vaccine is involved.
It is important that clinicians promptly report all cases of suspected or confirmed meningococcal disease to local public health authorities and that the serogroup of the meningococcal strain involved be identified. The effectiveness of mass vaccination programs depends on early and accurate recognition of outbreaks. When a suspected outbreak of meningococcal disease occurs, public health authorities will then determine whether mass vaccinations (with or without mass chemoprophylaxis) is indicated and delineate the target population to be vaccinated based on risk assessment.
== Treatment ==
When meningococcal disease is suspected, treatment must be started immediately and should not be delayed while waiting for investigations. Treatment in primary care usually involves prompt intramuscular administration of benzylpenicillin, and then an urgent transfer to hospital (hopefully, an academic level I medical center, or at least a hospital with round the clock neurological care, ideally with neurological intensive and critical care units) for further care. Once in the hospital, the antibiotics of choice are usually IV broad spectrum 3rd generation cephalosporins, e.g., cefotaxime or ceftriaxone. Benzylpenicillin and chloramphenicol are also effective. Supportive measures include IV fluids, oxygen, inotropic support, e.g., dopamine or dobutamine and management of raised intracranial pressure. Steroid therapy may help in some adult patients, but is unlikely to affect long term outcomes.
There is some debate on which antibiotic is most effective at treating the illness. A systematic review compared two antibiotics. There was one trial: an open label (not blinded) non-inferiority trial of 510 people comparing two different types of antibiotics; ceftriaxone (in which there were 14 deaths out of 247), and chloramphenicol (12 deaths out of 256). There were no reported side effects. Both antibiotics were considered equally effective. Antibiotic choice should be based on local antibiotic resistance information.
== Prognosis ==
=== Complications ===
Complications following meningococcal disease can be divided into early and late groups. Early complications include: raised intracranial pressure, disseminated intravascular coagulation, seizures, circulatory collapse and organ failure.
Later complications of meningococcal disease can be physical, neurological, or psychological. Physical effects, most commonly following meningococcal septicemia, may include limb malformation or amputation. These outcomes are more frequently observed in children who have experienced invasive meningococcal disease. Neurological complications, typically associated with meningococcal meningitis, can include hearing loss, cognitive impairments, and seizures. Psychological effects, observed in children, include post-traumatic stress disorder (PTSD) and increased levels of anxiety.
== Epidemiology ==
=== Africa ===
The importance of meningitis disease is as significant in Africa as HIV, TB and malaria. Cases of meningococcemia leading to severe meningoencephalitis are common among young children and the elderly. Deaths occurring in less than 24 hours are more likely during the disease epidemic seasons in Africa and Sub-Saharan Africa is hit by meningitis disease outbreaks throughout the epidemic season. It may be that climate change contributes significantly the spread of the disease in Benin, Burkina Faso, Cameroon, the Central African Republic, Chad, Côte d'Ivoire, the Democratic Republic of the Congo, Ethiopia, Ghana, Mali, Niger, Nigeria and Togo. This is an area of Africa where the disease is endemic: meningitis is "silently" present, and there are always a few cases. When the number of cases passes five per population of 100,000 in one week, teams are on alert. Epidemic levels are reached when there have been 100 cases per 100,000 populations over several weeks.
Further complicating efforts to halt the spread of meningitis in Africa is the fact that extremely dry, dusty weather conditions which characterize Niger and Burkina Faso from December to June favor the development of epidemics. Overcrowded villages are breeding grounds for bacterial transmission and lead to a high prevalence of respiratory tract infections, which leave the body more susceptible to infection, encouraging the spread of meningitis. IRIN Africa news has been providing the number of deaths for each country since 1995, and a mass vaccination campaign following a community outbreak of meningococcal disease in Florida was done by the CDC.
=== Florida ===
As of June 2022, there is an ongoing outbreak of the disease in Florida. The CDC has identified 26 cases of the disease. Seven deaths have been attributed to the disease.
== History and etymology ==
From the Greek meninx (membrane) + kokkos (berry), meningococcal disease was first described by Gaspard Vieusseux during an outbreak in Geneva in 1805. In 1884, Italian pathologists Ettore Marchiafava and Angelo Celli described intracellular micrococci in cerebrospinal fluid, and in 1887, Anton Wiechselbaum identified the meningococcus (designated as Diplococcus intracellularis meningitidis) in cerebrospinal fluid and established the connection between the organism and epidemic meningitis.
== See also ==
Endocarditis
Pathogenic bacteria
Waterhouse–Friderichsen syndrome
African meningitis belt
2009–10 West African meningitis outbreak
Meningococcal vaccine
Meningitis Vaccine Project
== References ==
== Further reading ==
Centers for Disease Control and Prevention (2012). "Ch. 13: Meningococcal Disease". In Atkinson W, Wolfe S, Hamborsky J (eds.). Epidemiology and Prevention of Vaccine-Preventable Diseases (12th ed.). Washington DC: Public Health Foundation. pp. 193–204. Archived from the original on 10 March 2017.
== External links ==
DermAtlas -1886809878 | Wikipedia/Meningococcal_disease |
A COVID-19 vaccine card is a record often given to those who have received a COVID-19 vaccine showing information such as the date(s) one has received the shot(s) and the brand of vaccine one has received, sometimes including the lot number. The card also contains information identifying the recipient and the location where the shot was given. Depending on the country, it could serve as an official document verifying one has received vaccination, which could be required by some institutions, such as a school or workplace, when boarding a cruise ship, or when crossing an international border, as proof that one has been vaccinated.
Some countries issue digital records while others issue paper records. In some European Union member states, citizens might choose to have a digital record, a piece of paper, or both.
== By country ==
=== Australia ===
In Australia, vaccine providers are required to report to the Australian Immunisation Register no later than 10 days after a vaccination is given. People who have been vaccinated can either access a digital record of vaccination on a smartphone, or request a paper copy of their vaccination record.
=== Austria ===
In October 2021, Austria has emitted 43.058.575 out of 591.728.344 EU Digital COVID Certificate emitted within the EEA.
=== Brazil ===
In December 2020, the Brazilian senate approved digital cards.
=== Canada ===
In Canada, vaccination certificates are issued by the health authorities of each province and territory. Vaccine certificate/passport systems were introduced in the provinces of British Columbia, Manitoba, and Quebec starting in September 2021.
Since October 2021, all vaccination certificates follow a single national design standard, and include a QR Code for validation in accordance with the international SMART Health Card framework.
=== China ===
China uses digital vaccine certificates for cross border travel. Launched in March 2021, the system uses QR codes that show the individual's vaccination status as well as RT-PCR test and Rapid antigen test results and is built atop Tencent's WeChat platform. Prior to this, QR health codes were required for public transport and access to public spaces in the country. The platform also allows for digital contact tracing and shows a green code for users who have not been in contact with infected people. The system has sparked concerns over government surveillance and privacy of users.
=== Egypt ===
Those who have received two doses of a vaccine receive a certificate that allows them to travel. Vaccinated users can either receive a vaccine card or register online after receiving both doses to get a certificate. In October 2021, the government announced the launch of a mobile app that would enable the verification of an individual's vaccination status using a QR code instead of carrying a certificate.
=== France ===
Vaccine certificates in France are issued with a QR code — an EU Digital COVID Certificate — scanned onto the country's contact tracing app, TousAntiCovid. The app, which can also scan the QR Code of a test result, allows those vaccinated to show their vaccination status on their smartphone.
In October 2021, France has emitted 136.901.354 out of 591.728.344 EU Digital COVID Certificate emitted within the EEA.
For vaccine certificates, there are 72 186 091 French vaccine certificate for 437 509 564 EU ones (that is 16%).
=== Germany ===
In Germany, vaccination is documented in the International Certificate of Vaccination or Prophylaxis, commonly known as "gelber Impfpass" (yellow vaccination passport) The EU Digital COVID Certificate is also available, and officially recognized. It is regularly issued since July 1, 2021 in vaccination centers for people receiving their vaccination and in pharmacies for those who were vaccinated before July.
In October 2021, Germany has emitted 123.254.466 out of 591.728.344 EU Digital COVID Certificate emitted within the EEA.
For vaccine certificates, there are 119.750.418 German vaccine certificates for 437 509 564 EU ones (that is 27%).
=== India ===
In India, once a person receives a dose of vaccine, a digital certificate is issued that can either be downloaded from the CoWIN web portal, from the UMANG mobile app, from the Aarogya Setu mobile app or it can directly be downloaded on to citizen's digital document wallet Digilocker. A provisional certificate is issued after the first dose, which contains the vaccinated person's personal details, the vaccine used, the vaccinator's name, and the window for the next dose. A final certificate is issued after the second dose. For those traveling abroad, an option to link their passport is available.
=== Iran ===
Iran made issuing digital vaccine card mandatory for full vaccine administration.
=== Indonesia ===
In Indonesia, every person who have received at least a dose of vaccine will receive a vaccine card and vaccination certificate which can be downloaded from PeduliLindungi mobile app. Vaccination card contains the vaccinated person's personal details, the vaccine used, the vaccinator's name, the batch number of the vaccine used, and the window for the next dose.
=== Ireland ===
On 12 July 2021, fully vaccinated people in Ireland began receiving their EU Digital COVID Certificates via email or post. The EU Digital COVID Certificate in Ireland was initially used for international travel as restrictions into and out of the country eased from 19 July, but was also used in restaurants, hotels and bars as proof of vaccination to gain access to indoor hospitality, as well as in nightclubs, indoor live entertainment, cinemas, theatres and gyms. Requirements on the use of vaccine certificates domestically were scrapped in January 2022.
The Health Service Executive (HSE) issues a vaccine record card to those receiving a COVID-19 vaccine in Ireland that provides reminders for a follow-up appointment. The card contains the recipient's name, the dates on which the two doses were administered, the name of the vaccine, and its batch number. The vaccine record card could also be used as proof of vaccination.
=== Israel ===
In February 2021, Israel rolled out its Green Pass system for those who had completed a week after taking their second dose of the vaccine or those who had recovered from the virus and were ineligible to take the vaccine. The Green Pass is issued by the Ministry of Health. It is a secure digital certificate that is required to enter certain crowded areas such as restaurants, gyms, theatres, and synagogues that have registered themselves as part of the system. A vaccinated person has to either download the app or use the website to download the certificate. A QR Code is provided to allow the pass to be verified. When launched, the pass was valid for six months from the date of the second dose of the vaccine. In May, the Ministry extended the validity of the Green Pass until the end of the year.
=== Italy ===
Italy uses the EU Digital COVID Certificate, which is also referred to as the Green Pass.
In October 2021, Italy has emitted 97.058.162 out of 591.728.344 EU Digital COVID Certificate emitted within the EEA.
=== New Zealand ===
Under the New Zealand Government's COVID-19 Protection Framework, a vaccine pass may be required for access to some non-essential venues such as restaurants, sports centres, and faith-based gatherings. The pass contains an individual's name, date of birth, and a QR code. Some venues may choose to check the name on the pass with the individual's photo ID, but this is not required by law.
=== Philippines ===
Upon being vaccinated with a COVID-19 vaccine, the local government unit (LGU) or recognized private healthcare providers issue a vaccine card that shall act as proof of vaccination. The Department of Information and Communications Technology (DICT) is presently working with the Inter-Agency Task Force for the Management of Emerging Infectious Diseases (IATF-EID) for a centralized registry for COVID-19 vaccinated residents under a common digital vaccine ID that shall feature a unique QR code and a person's photograph.
Since 2021, the Bureau of Quarantine of the Philippines has updated the existing International Certificate of Vaccination (ICV) that shall include information for being vaccinated from COVID-19 and currently being issued to Overseas Filipino Workers (OFW) and residents going on international travel. The new ICV contains a unique QR code, which allows the verification of the authenticity of the said certificate. At presently, the ICV can only be issued to Filipino citizens and residents who have been vaccinated with a COVID-19 vaccine listed under the Emergency Use Listing (EUL) by the World Health Organization (WHO).
=== South Africa ===
Current South African COVID-19 Vaccination Record Cards Contain Identification information and provision for 3 doses of vaccines.
The eVaccine Card or Digital Vaccine Certificates can be assessed at https://vaccine.certificate.health.gov.za/ Archived 2021-10-17 at the Wayback Machine
The Digital Certificate has the Department of Health Logo at the top with a QR Code on the right intended to be used in the future, said to be available by the end of 2021.
There 3 sections to the Certificate.
The first section contains identification data including ID Document Used, ID Number, First Name, Surname and Date Of Birth.
The second section contains vaccine dose information as in Vaccine Received, Vaccine Date and Proof of vaccination code. This will be on there twice if the individual has received more than one dose.
The final section contains a card expiration date.
=== Singapore ===
After receiving each vaccination dose, an individual will be provided a physical vaccination card that certifies an individual's vaccination status. This information is also recorded on the National Immunisation Registry and is viewable through the Ministry of Health's HealthHub application. The ability to verify one's vaccination status was also added to the TraceTogether application in version 2.11. TraceTogether is used to verify one's vaccination status when entering businesses, and for contact tracing purposes. From 26 April 2022 onwards, there is no need to verify one's vaccination status using the TraceTogether application when entering businesses, unless at large events or at certain nightlife establishments.
Outbound travellers who have been fully vaccinated in Singapore can also obtain a Vaccination HealthCert, which is a digitally verifiable proof of vaccination. When required, foreign authorities can use the QR codes in the Vaccination HealthCert to verify that it has not been tampered with.
=== Sweden ===
As of the 24th of August, the Swedish government have discussed implementing a vaccine card, restricting access to music and culture events to people with two vaccine doses.
=== Switzerland ===
Digital and hard copy versions of COVID-19 vaccine cards are issued by the respective cantons upon full vaccination. The federal government provides an app and registration site, as well as QR coded documents for immunised Swiss residents. Such certification is valid for 365 days and must be provided upon entering certain premises and/or for international travel. So far, Switzerland has fully adhered to EU protocols, and digital EU vaccine certificates are approved in Switzerland, as are some of the Asian vaccines for certain travelers.
=== Taiwan ===
After inoculation, individuals receive an official yellow card like the one above that records individuals' vaccination information.
=== United Kingdom ===
Those receiving a COVID-19 vaccine in the United Kingdom (except Scotland) are given a card the size of a credit card that provides reminders for a follow-up appointment. The card contains the recipient's name, the dates on which the two doses were administered, the name of the vaccine, and its batch number. Vaccinated people looking to travel abroad can take a printout of their certificate from the website of the National Health Service (NHS). The QR Code present on the vaccination certificate can be used to store the details on a smartphone app.
Prime Minister Boris Johnson announced in July 2021 that once all adults have received their second dose of the vaccine, vaccine cards would be mandatory to gain access to crowded places such as nightclubs.
=== United States ===
Those who receive their vaccination in the United States are given a card with the Centers for Disease Control and Prevention (CDC) and the Health and Human Services (HHS) logos that records their name, the date of each dose, and the brand of the vaccine they have received. In October 2023, the CDC announced it would no longer be issuing COVID-19 vaccine cards.
Some states provide a digital record of vaccination to their residents, using a QR code that can be verified with a scanner app. New York has the Excelsior Pass which also records the results of COVID-19 tests while California has the California Digital COVID-19 Vaccine Record.
== Issues ==
=== Posting on social media ===
Many vaccine recipients have posted pictures of their vaccine cards on social media. This risks the exposure of personal information that is unsafe to share with the public.
=== Forgery ===
Fake vaccine cards have been sold on the Internet. Sales of these cards have increased substantially since some businesses started requiring proof of vaccination to gain entry. Existing laws prohibit the sale and use of these forgeries.
In September 2021, a woman in the United States was arrested for using a fake vaccine card to bypass mandatory vaccination requirements. The arrest was made after it came to light that the card said Maderna instead of Moderna in the vaccine name. The same month, U.S. Customs and Border Protection seized more than 6,000 counterfeit vaccine cards across the country with two mail packages in Pittsburgh originating from China. Prior to this, several vendors were found selling fake vaccine cards on e-commerce platforms such as Amazon.
In Russia, a black market for fake vaccine cards emerged soon after the government started requiring them for various activities.
At a Dutch nightclub, clubgoers presenting the Q-codes of digital certificates belonging to others led to an outbreak that infected 160 people.
=== Theft of authentic cards ===
A Chicago pharmacist sold 125 authentic vaccination cards online to 11 different buyers and was charged with 12 counts of theft of government property, with a potential sentence of ten years in prison for each count. A contractor at the Pomona Fairplex in California stole 528 blank vaccination cards and was charged with felony grand theft.
== See also ==
Immunity passport
Vaccine passports during the COVID-19 pandemic
Ahnenpass
== References ==
== External links ==
Media related to COVID-19 vaccination cards at Wikimedia Commons | Wikipedia/COVID-19_vaccine_card |
A biologics license application (BLA) is defined by the U.S. Food and Drug Administration (FDA) as follows:
The biologics license application is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce (21 CFR 601.2). The BLA is regulated under 21 CFR 600 – 680. A BLA is submitted by any legal person or entity who is engaged in manufacture or an applicant for a license who takes responsibility for compliance with product and establishment standards. Form 356h specifies the requirements for a BLA. This includes:
Applicant information
Product/manufacturing information
Pre-clinical studies
Clinical studies
Labeling
Some biological products are regulated by the Center for Drug Evaluation and Research (CDER) while others are regulated by the Center for Biologics Evaluation and Research (CBER).
A BLA is submitted after the investigational new drug (IND) phase, once the clinical investigations are completed. If the Form 356h is missing information, the FDA will reply within 74 days.
A BLA asserts that the product is "safe, pure, and potent", the manufacturing facilities are inspectable, and each package of the product bears the license number. Statutory standards for BLA approval are largely the same as those for New Drug Application approval. According to 21 CFR 600.3, FDA interprets "potency" to include effectiveness of the biologic.
After approval, annual reports, reports on adverse events, manufacturing changes, and labeling changes must be submitted.
== See also ==
New drug application
Investigational new drug
== References == | Wikipedia/Biologics_License_Application |
An mRNA vaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into cells, which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen (such as a virus) or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.
Reactogenicity, the tendency of a vaccine to produce adverse reactions, is similar to that of conventional non-RNA vaccines. People susceptible to an autoimmune response may have an adverse reaction to messenger RNA vaccines. The advantages of mRNA vaccines over traditional vaccines are ease of design, speed and lower cost of production, the induction of both cellular and humoral immunity, and lack of interaction with the genomic DNA. While some messenger RNA vaccines, such as the Pfizer–BioNTech COVID-19 vaccine, have the disadvantage of requiring ultracold storage before distribution, other mRNA vaccines, such as the Moderna vaccine, do not have such requirements.
In RNA therapeutics, messenger RNA vaccines have attracted considerable interest as COVID-19 vaccines. In December 2020, Pfizer–BioNTech and Moderna obtained authorization for their mRNA-based COVID-19 vaccines. On 2 December, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first medicines regulator to approve an mRNA vaccine, authorizing the Pfizer–BioNTech vaccine for widespread use. On 11 December, the US Food and Drug Administration (FDA) issued an emergency use authorization for the Pfizer–BioNTech vaccine and a week later similarly authorized the Moderna vaccine. In 2023 the Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for their discoveries concerning modified nucleosides that enabled the development of effective mRNA vaccines against COVID-19.
== History ==
=== Early research ===
The first successful transfection of designed mRNA packaged within a liposomal nanoparticle into a cell was published in 1989. "Naked" (or unprotected) lab-made mRNA was injected a year later into the muscle of mice. These studies were the first evidence that in vitro transcribed mRNA with a chosen gene was able to deliver the genetic information to produce a desired protein within living cell tissue and led to the concept proposal of messenger RNA vaccines.
Liposome-encapsulated mRNA encoding a viral antigen was shown in 1993 to stimulate T cells in mice. The following year self-amplifying mRNA was developed by including both a viral antigen and replicase encoding gene. The method was used in mice to elicit both a humoral and cellular immune response against a viral pathogen. The next year mRNA encoding a tumor antigen was shown to elicit a similar immune response against cancer cells in mice.
=== Development ===
The first human clinical trial using ex vivo dendritic cells transfected with mRNA encoding tumor antigens (therapeutic cancer mRNA vaccine) was started in 2001. Four years later, the successful use of modified nucleosides as a method to transport mRNA inside cells without setting off the body's defense system was reported. Clinical trial results of an mRNA vaccine directly injected into the body against cancer cells were reported in 2008.
BioNTech in 2008, and Moderna in 2010, were founded to develop mRNA biotechnologies. The US research agency DARPA launched at this time the biotechnology research program ADEPT to develop emerging technologies for the US military. The agency recognized the potential of nucleic acid technology for defense against pandemics and began to invest in the field. DARPA grants were seen as a vote of confidence that in turn encouraged other government agencies and private investors to invest in mRNA technology. DARPA awarded at the time a $25 million grant to Moderna.
The first human clinical trials using an mRNA vaccine against an infectious agent (rabies) began in 2013. Over the next few years, clinical trials of mRNA vaccines for a number of other viruses were started. mRNA vaccines for human use were studied for infectious agents such as influenza, Zika virus, cytomegalovirus, and Chikungunya virus.
=== Acceleration ===
The COVID-19 pandemic, and sequencing of the causative virus SARS-CoV-2 at the beginning of 2020, led to the rapid development of the first approved mRNA vaccines. BioNTech and Moderna in December of the same year obtained approval for their mRNA-based COVID-19 vaccines. On 2 December, seven days after its final eight-week trial, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first global medicines regulator in history to approve an mRNA vaccine, granting emergency authorization for Pfizer–BioNTech's BNT162b2 COVID-19 vaccine for widespread use. On 11 December, the FDA gave emergency use authorization for the Pfizer–BioNTech COVID-19 vaccine and a week later similar approval for the Moderna COVID-19 vaccine.
== Mechanism ==
The goal of a vaccine is to stimulate the adaptive immune system to create antibodies that precisely target that particular pathogen. The markers on the pathogen that the antibodies target are called antigens.
Traditional vaccines stimulate an antibody response by injecting either antigens, an attenuated (weakened) virus, an inactivated (dead) virus, or a recombinant antigen-encoding viral vector (harmless carrier virus with an antigen transgene) into the body. These antigens and viruses are prepared and grown outside the body.
In contrast, mRNA vaccines introduce a short-lived synthetically created fragment of the RNA sequence of a virus into the individual being vaccinated. These mRNA fragments are taken up by dendritic cells through phagocytosis. The dendritic cells use their internal machinery (ribosomes) to read the mRNA and produce the viral antigens that the mRNA encodes. The body degrades the mRNA fragments within a few days of introduction. Although non-immune cells can potentially also absorb vaccine mRNA, produce antigens, and display the antigens on their surfaces, dendritic cells absorb the mRNA globules much more readily. The mRNA fragments are translated in the cytoplasm and do not affect the body's genomic DNA, located separately in the cell nucleus.
Once the viral antigens are produced by the host cell, the normal adaptive immune system processes are followed. Antigens are broken down by proteasomes. Class I and class II MHC molecules then attach to the antigen and transport it to the cellular membrane, "activating" the dendritic cell. Once activated, dendritic cells migrate to lymph nodes, where they present the antigen to T cells and B cells. This triggers the production of antibodies specifically targeted to the antigen, ultimately resulting in immunity.
== mRNA ==
The central component of a mRNA vaccine is its mRNA construct. The in vitro transcribed mRNA is generated from an engineered plasmid DNA, which has an RNA polymerase promoter and sequence which corresponds to the mRNA construct. By combining T7 phage RNA polymerase and the plasmid DNA, the mRNA can be transcribed in the lab. Efficacy of the vaccine is dependent on the stability and structure of the designed mRNA.
The in vitro transcribed mRNA has the same structural components as natural mRNA in eukaryotic cells. It has a 5' cap, a 5'-untranslated region (UTR) and 3'-UTR, an open reading frame (ORF), which encodes the relevant antigen, and a 3'-poly(A) tail. By modifying these different components of the synthetic mRNA, the stability and translational ability of the mRNA can be enhanced, and in turn, the efficacy of the vaccine improved.
The mRNA can be improved by using synthetic 5'-cap analogues which enhance the stability and increase protein translation. Similarly, regulatory elements in the 5'-untranslated region and the 3'-untranslated region can be altered, and the length of the poly(A) tail optimized, to stabilize the mRNA and increase protein production. The mRNA nucleotides can be modified to both decrease innate immune activation and increase the mRNA's half-life in the host cell. The nucleic acid sequence and codon usage impacts protein translation. Enriching the sequence with guanine-cytosine content improves mRNA stability and half-life and, in turn, protein production. Replacing rare codons with synonymous codons frequently used by the host cell also enhances protein production.
== Delivery ==
For a vaccine to be successful, sufficient mRNA must enter the host cell cytoplasm to stimulate production of the specific antigens. Entry of mRNA molecules, however, faces a number of difficulties. Not only are mRNA molecules too large to cross the cell membrane by simple diffusion, they are also negatively charged like the cell membrane, which causes a mutual electrostatic repulsion. Additionally, mRNA is easily degraded by RNAases in skin and blood.
Various methods have been developed to overcome these delivery hurdles. The method of vaccine delivery can be broadly classified by whether mRNA transfer into cells occurs within (in vivo) or outside (ex vivo) the organism.
=== Ex vivo ===
Dendritic cells display antigens on their surfaces, leading to interactions with T cells to initiate an immune response. Dendritic cells can be collected from patients and programmed with the desired mRNA, then administered back into patients to create an immune response.
The simplest way that ex vivo dendritic cells take up mRNA molecules is through endocytosis, a fairly inefficient pathway in the laboratory setting that can be significantly improved through electroporation.
=== In vivo ===
Since the discovery that the direct administration of in vitro transcribed mRNA leads to the expression of antigens in the body, in vivo approaches have been investigated. They offer some advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting dendritic cells from patients and by imitating a regular infection.
Different routes of injection, such as into the skin, blood, or muscles, result in varying levels of mRNA uptake, making the choice of administration route a critical aspect of in vivo delivery. One study showed, in comparing different routes, that lymph node injection leads to the largest T-cell response.
==== Naked mRNA injection ====
Naked mRNA injection means that the delivery of the vaccine is only done in a buffer solution. This mode of mRNA uptake has been known since the 1990s. The first worldwide clinical studies used intradermal injections of naked mRNA for vaccination. A variety of methods have been used to deliver naked mRNA, such as subcutaneous, intravenous, and intratumoral injections. Although naked mRNA delivery causes an immune response, the effect is relatively weak, and after injection the mRNA is often rapidly degraded.
==== Polymer and peptide vectors ====
Cationic polymers can be mixed with mRNA to generate protective coatings called polyplexes. These protect the recombinant mRNA from ribonucleases and assist its penetration in cells. Protamine is a natural cationic peptide and has been used to encapsulate mRNA for vaccination.
==== Lipid nanoparticle vector ====
The first time the FDA approved the use of lipid nanoparticles as a drug delivery system was in 2018, when the agency approved the first siRNA drug, Onpattro. Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key technical barriers in delivering the mRNA molecule into the host cell. Research into using lipids to deliver siRNA to cells became a foundation for similar research into using lipids to deliver mRNA. However, new lipids had to be invented to encapsulate mRNA strands, which are much longer than siRNA strands.
Principally, the lipid provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid's outer layer allows the targeting of desired cell types through ligand interactions. However, many studies have also highlighted the difficulty of studying this type of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of nanoparticles in terms of cellular intake. The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system.
One issue with lipid nanoparticles is that several of the breakthroughs leading to the practical use of that technology involve the use of microfluidics. Microfluidic reaction chambers are difficult to scale up, since the entire point of microfluidics is to exploit the microscale behaviors of liquids. The only way around this obstacle is to run an extensive number of microfluidic reaction chambers in parallel, a novel task requiring custom-built equipment. For COVID-19 mRNA vaccines, this was the main manufacturing bottleneck. Pfizer used such a parallel approach to solve the scaling problem. After verifying that impingement jet mixers could not be directly scaled up, Pfizer made about 100 of the little mixers (each about the size of a U.S. half-dollar coin), connected them together with pumps and filters with a "maze of piping," and set up a computer system to regulate flow and pressure through the mixers.
Another issue, with the large-scale use of this delivery method, is the availability of the novel lipids used to create lipid nanoparticles, especially ionizable cationic lipids. Before 2020, such lipids were manufactured in small quantities measured in grams or kilograms, and they were used for medical research and a handful of drugs for rare conditions. As the safety and efficacy of mRNA vaccines became clear in 2020, the few companies able to manufacture the requisite lipids were confronted with the challenge of scaling up production to respond to orders for several tons of lipids.
==== Viral vector ====
In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar immunological responses. Typical RNA viruses used as vectors include retroviruses, lentiviruses, alphaviruses and rhabdoviruses, each of which can differ in structure and function. Clinical studies have utilized such viruses on a range of diseases in model animals such as mice, chicken and primates.
== Advantages ==
=== Traditional vaccines ===
mRNA vaccines offer specific advantages over traditional vaccines. Because mRNA vaccines are not constructed from an active pathogen (or even an inactivated pathogen), they are non-infectious. In contrast, traditional vaccines require the production of pathogens, which, if done at high volumes, could increase the risks of localized outbreaks of the virus at the production facility. Another biological advantage of mRNA vaccines is that since the antigens are produced inside the cell, they stimulate cellular immunity, as well as humoral immunity.
mRNA vaccines have the production advantage that they can be designed swiftly. Moderna designed their mRNA-1273 vaccine for COVID-19 in 2 days. They can also be manufactured faster, more cheaply, and in a more standardized fashion (with fewer error rates in production), which can improve responsiveness to serious outbreaks.
The Pfizer–BioNTech vaccine originally required 110 days to mass-produce (before Pfizer began to optimize the manufacturing process to only 60 days), which was substantially faster than traditional flu and polio vaccines. Within that larger timeframe, the actual production time is only about 22 days: two weeks for molecular cloning of DNA plasmids and purification of DNA, four days for DNA-to-RNA transcription and purification of mRNA, and four days to encapsulate mRNA in lipid nanoparticles followed by fill and finish. The majority of the days needed for each production run are allocated to rigorous quality control at each stage.
=== DNA vaccines ===
In addition to sharing the advantages of theoretical DNA vaccines over established traditional vaccines, mRNA vaccines also have additional advantages over DNA vaccines. The mRNA is translated in the cytosol, so there is no need for the RNA to enter the cell nucleus, and the risk of being integrated into the host genome is averted. Modified nucleosides (for example, pseudouridines, 2'-O-methylated nucleosides) can be incorporated to mRNA to suppress immune response stimulation to avoid immediate degradation and produce a more persistent effect through enhanced translation capacity. The open reading frame (ORF) and untranslated regions (UTR) of mRNA can be optimized for different purposes (a process called sequence engineering of mRNA), for example through enriching the guanine-cytosine content or choosing specific UTRs known to increase translation. An additional ORF coding for a replication mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed.
== Disadvantages ==
=== Storage ===
Because mRNA is fragile, some vaccines must be kept at very low temperatures to avoid degrading and thus giving little effective immunity to the recipient. Pfizer–BioNTech's BNT162b2 mRNA vaccine has to be kept between −80 and −60 °C (−112 and −76 °F). Moderna says their mRNA-1273 vaccine can be stored between −25 and −15 °C (−13 and 5 °F), which is comparable to a home freezer, and that it remains stable between 2 and 8 °C (36 and 46 °F) for up to 30 days. In November 2020, Nature reported, "While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions." Several platforms are being studied that may allow storage at higher temperatures.
=== Recent ===
Before 2020, no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so there was a risk of unknown effects. The 2020 COVID-19 pandemic required faster production capability of mRNA vaccines, made them attractive to national health organisations, and led to debate about the type of initial authorization mRNA vaccines should get (including emergency use authorization or expanded access authorization) after the eight-week period of post-final human trials.
=== Side effects ===
Reactogenicity is similar to that of conventional, non-RNA vaccines. However, those susceptible to an autoimmune response may have an adverse reaction to mRNA vaccines. The mRNA strands in the vaccine may elicit an unintended immune reaction – this entails the body believing itself to be sick, and the person feeling as if they are as a result. To minimize this, mRNA sequences in mRNA vaccines are designed to mimic those produced by host cells.
Strong but transient reactogenic effects were reported in trials of novel COVID-19 mRNA vaccines; most people will not experience severe side effects which include fever and fatigue. Severe side effects are defined as those that prevent daily activity.
== Efficacy ==
The COVID-19 mRNA vaccines from Moderna and Pfizer–BioNTech had short-term efficacy rates of over 90 percent against the original SARS-CoV-2 virus. Prior to mRNA, drug trials on pathogens other than COVID-19 were not effective and had to be abandoned in the early phases of trials. The reason for the efficacy of the new mRNA vaccines is not clear.
Physician-scientist Margaret Liu stated that the efficacy of the new COVID-19 mRNA vaccines could be due to the "sheer volume of resources" that went into development, or that the vaccines might be "triggering a nonspecific inflammatory response to the mRNA that could be heightening its specific immune response, given that the modified nucleoside technique reduced inflammation but hasn't eliminated it completely", and that "this may also explain the intense reactions such as aches and fevers reported in some recipients of the mRNA SARS-CoV-2 vaccines". These reactions though severe were transient and another view is that they were believed to be a reaction to the lipid drug delivery molecules. In June 2021, the US FDA added a warning about the possibility of increased risk of myocarditis and pericarditis for some people.
== Hesitancy ==
There is misinformation implying that mRNA vaccines could alter DNA in the nucleus. mRNA in the cytosol is very rapidly degraded before it would have time to gain entry into the cell nucleus. In fact, mRNA vaccines must be stored at very low temperature and free from RNAses to prevent mRNA degradation. Retrovirus can be single-stranded RNA (just as many SARS-CoV-2 vaccines are single-stranded RNA) which enters the cell nucleus and uses reverse transcriptase to make DNA from the RNA in the cell nucleus. A retrovirus has mechanisms to be imported into the nucleus, but other mRNA (such as the vaccine) lack these mechanisms. Once inside the nucleus, creation of DNA from RNA cannot occur without a reverse transcriptase and appropriate primers, which both accompany a retrovirus, but which would not be present for other exogenous mRNA (such as a vaccine) even if it could enter the nucleus.
== Amplification ==
mRNA vaccines use either non-amplifying (conventional) mRNA or self-amplifying mRNA. Pfizer–BioNTech and Moderna vaccines use non-amplifying mRNA. Both mRNA types continue to be investigated as vaccine methods against other potential pathogens and cancer.
=== Non-amplifying ===
The initial mRNA vaccines use a non-amplifying mRNA construct. Non-amplifying mRNA has only one open reading frame that codes for the antigen of interest. The total amount of mRNA available to the cell is equal to the amount delivered by the vaccine. Dosage strength is limited by the amount of mRNA that can be delivered by the vaccine. Non-amplifying vaccines replace uridine with N1-Methylpseudouridine in an attempt to reduce toxicity.
=== Self-amplifying ===
Self-amplifying mRNA (saRNA) vaccines replicate their mRNA after transfection. Self-amplifying mRNA has two open reading frames. The first frame, like conventional mRNA, codes for the antigen of interest. The second frame codes for an RNA-dependent RNA polymerase (and its helper proteins) which replicates the mRNA construct in the cell. This allows smaller vaccine doses. The mechanisms and consequently the evaluation of self-amplifying mRNA may be different, as self-amplifying mRNA is a much bigger molecule.
SaRNA vaccines being researched include a malaria vaccine. The first saRNA Covid vaccine authorised was Gemcovac, in India in June 2022. The second was ARCT-154, developed by Arcturus Therapeutics. A version manufactured by Meiji Seika Pharma was authorised in Japan in November 2023.
GSK began a phase 1 trial of an saRNA COVID-19 vaccine in 2021. Gritstone bio started also started a phase 1 trial of an saRNA COVID-19 vaccine in 2021, used as a booster vaccine, with interim results published in 2023. The vaccine is designed to target both the spike protein of the SARS‑CoV‑2 virus, and viral proteins that may be less prone to genetic variation, to provide greater protection against SARS‑CoV‑2 variants. saRNA vaccines must use uridine, which is required for reproduction to occur.
== See also ==
DNA vaccine
Nucleoside-modified messenger RNA
RNA therapeutics
Timeline of human vaccines
== References ==
== Further reading ==
Dolgin E (September 2021). "The tangled history of mRNA vaccines" (PDF). Nature. 597 (9): 318–24. Bibcode:2021Natur.597..318D. doi:10.1038/d41586-021-02483-w. PMID 34522017. S2CID 237515383.
Sahin U, Karikó K, Türeci Ö (October 2014). "mRNA-based therapeutics – developing a new class of drugs". Nat Rev Drug Discov. 13 (10): 759–80. doi:10.1038/nrd4278. PMID 25233993.
== External links ==
"Five things you need to know about: mRNA vaccines". Horizon. Archived from the original on 4 April 2020. Retrieved 17 November 2020.
"RNA vaccines: an introduction". PHG Foundation. University of Cambridge.
"Understanding mRNA COVID-19 Vaccines". Centers for Disease Control and Prevention. 4 January 2022.
Kolata, Gina; Mueller, Benjamin (15 January 2022). "Halting Progress and Happy Accidents: How mRNA Vaccines Were Made". The New York Times.
M.I.T. Lecture 10: Kizzmekia Corbett, Vaccines" on YouTube | Wikipedia/RNA_vaccine |
An inverse vaccine, or reverse vaccine, is a hypothetical approach to the use of vaccines that trains the immune system to not respond to certain substances. Under laboratory conditions, an inverse vaccine has been shown to combat autoimmune diseases. An autoimmune disease attacks the body's own cells and substances, an inverse vaccine must counteract this. The current method of combating the effects of an autoimmune disease is to suppress the entire immune system, which means that infections cannot be fought.
== Approaches ==
As of 2010, human trials were underway using naked DNA that encoded specific antigens of interests, particularly for multiple sclerosis using BHT-3009, and type 1 diabetes mellitus.
== Possible applications ==
Possible applications of inverse vaccines include:
Multiple Sclerosis (MS)
Type 1 diabetes
Psoriasis
Coeliac disease
Allergic asthma
Food allergies
Chronic inflammatory diseases, such as Crohn's disease
Preventing an immune response after an organ transplant
Rheumatoid arthritis
As of 2024, a study is underway into the safety of an inverse vaccine against multiple sclerosis, with a small group of patients and volunteers; for an inverse vaccine against celiac disease, a safety and efficacy study is underway in a limited group of subjects.
== See also ==
Allergen immunotherapy, an analogous technique for the treatment of allergy
== References ==
== External links ==
What is an inverse vaccine and how can it reverse autoimmune disorders? (Video)
Inverse vaccination, the opposite of Jenner’s concept, for therapy of autoimmunity | Wikipedia/Inverse_vaccine |
An mRNA vaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into cells, which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen (such as a virus) or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.
Reactogenicity, the tendency of a vaccine to produce adverse reactions, is similar to that of conventional non-RNA vaccines. People susceptible to an autoimmune response may have an adverse reaction to messenger RNA vaccines. The advantages of mRNA vaccines over traditional vaccines are ease of design, speed and lower cost of production, the induction of both cellular and humoral immunity, and lack of interaction with the genomic DNA. While some messenger RNA vaccines, such as the Pfizer–BioNTech COVID-19 vaccine, have the disadvantage of requiring ultracold storage before distribution, other mRNA vaccines, such as the Moderna vaccine, do not have such requirements.
In RNA therapeutics, messenger RNA vaccines have attracted considerable interest as COVID-19 vaccines. In December 2020, Pfizer–BioNTech and Moderna obtained authorization for their mRNA-based COVID-19 vaccines. On 2 December, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first medicines regulator to approve an mRNA vaccine, authorizing the Pfizer–BioNTech vaccine for widespread use. On 11 December, the US Food and Drug Administration (FDA) issued an emergency use authorization for the Pfizer–BioNTech vaccine and a week later similarly authorized the Moderna vaccine. In 2023 the Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for their discoveries concerning modified nucleosides that enabled the development of effective mRNA vaccines against COVID-19.
== History ==
=== Early research ===
The first successful transfection of designed mRNA packaged within a liposomal nanoparticle into a cell was published in 1989. "Naked" (or unprotected) lab-made mRNA was injected a year later into the muscle of mice. These studies were the first evidence that in vitro transcribed mRNA with a chosen gene was able to deliver the genetic information to produce a desired protein within living cell tissue and led to the concept proposal of messenger RNA vaccines.
Liposome-encapsulated mRNA encoding a viral antigen was shown in 1993 to stimulate T cells in mice. The following year self-amplifying mRNA was developed by including both a viral antigen and replicase encoding gene. The method was used in mice to elicit both a humoral and cellular immune response against a viral pathogen. The next year mRNA encoding a tumor antigen was shown to elicit a similar immune response against cancer cells in mice.
=== Development ===
The first human clinical trial using ex vivo dendritic cells transfected with mRNA encoding tumor antigens (therapeutic cancer mRNA vaccine) was started in 2001. Four years later, the successful use of modified nucleosides as a method to transport mRNA inside cells without setting off the body's defense system was reported. Clinical trial results of an mRNA vaccine directly injected into the body against cancer cells were reported in 2008.
BioNTech in 2008, and Moderna in 2010, were founded to develop mRNA biotechnologies. The US research agency DARPA launched at this time the biotechnology research program ADEPT to develop emerging technologies for the US military. The agency recognized the potential of nucleic acid technology for defense against pandemics and began to invest in the field. DARPA grants were seen as a vote of confidence that in turn encouraged other government agencies and private investors to invest in mRNA technology. DARPA awarded at the time a $25 million grant to Moderna.
The first human clinical trials using an mRNA vaccine against an infectious agent (rabies) began in 2013. Over the next few years, clinical trials of mRNA vaccines for a number of other viruses were started. mRNA vaccines for human use were studied for infectious agents such as influenza, Zika virus, cytomegalovirus, and Chikungunya virus.
=== Acceleration ===
The COVID-19 pandemic, and sequencing of the causative virus SARS-CoV-2 at the beginning of 2020, led to the rapid development of the first approved mRNA vaccines. BioNTech and Moderna in December of the same year obtained approval for their mRNA-based COVID-19 vaccines. On 2 December, seven days after its final eight-week trial, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first global medicines regulator in history to approve an mRNA vaccine, granting emergency authorization for Pfizer–BioNTech's BNT162b2 COVID-19 vaccine for widespread use. On 11 December, the FDA gave emergency use authorization for the Pfizer–BioNTech COVID-19 vaccine and a week later similar approval for the Moderna COVID-19 vaccine.
== Mechanism ==
The goal of a vaccine is to stimulate the adaptive immune system to create antibodies that precisely target that particular pathogen. The markers on the pathogen that the antibodies target are called antigens.
Traditional vaccines stimulate an antibody response by injecting either antigens, an attenuated (weakened) virus, an inactivated (dead) virus, or a recombinant antigen-encoding viral vector (harmless carrier virus with an antigen transgene) into the body. These antigens and viruses are prepared and grown outside the body.
In contrast, mRNA vaccines introduce a short-lived synthetically created fragment of the RNA sequence of a virus into the individual being vaccinated. These mRNA fragments are taken up by dendritic cells through phagocytosis. The dendritic cells use their internal machinery (ribosomes) to read the mRNA and produce the viral antigens that the mRNA encodes. The body degrades the mRNA fragments within a few days of introduction. Although non-immune cells can potentially also absorb vaccine mRNA, produce antigens, and display the antigens on their surfaces, dendritic cells absorb the mRNA globules much more readily. The mRNA fragments are translated in the cytoplasm and do not affect the body's genomic DNA, located separately in the cell nucleus.
Once the viral antigens are produced by the host cell, the normal adaptive immune system processes are followed. Antigens are broken down by proteasomes. Class I and class II MHC molecules then attach to the antigen and transport it to the cellular membrane, "activating" the dendritic cell. Once activated, dendritic cells migrate to lymph nodes, where they present the antigen to T cells and B cells. This triggers the production of antibodies specifically targeted to the antigen, ultimately resulting in immunity.
== mRNA ==
The central component of a mRNA vaccine is its mRNA construct. The in vitro transcribed mRNA is generated from an engineered plasmid DNA, which has an RNA polymerase promoter and sequence which corresponds to the mRNA construct. By combining T7 phage RNA polymerase and the plasmid DNA, the mRNA can be transcribed in the lab. Efficacy of the vaccine is dependent on the stability and structure of the designed mRNA.
The in vitro transcribed mRNA has the same structural components as natural mRNA in eukaryotic cells. It has a 5' cap, a 5'-untranslated region (UTR) and 3'-UTR, an open reading frame (ORF), which encodes the relevant antigen, and a 3'-poly(A) tail. By modifying these different components of the synthetic mRNA, the stability and translational ability of the mRNA can be enhanced, and in turn, the efficacy of the vaccine improved.
The mRNA can be improved by using synthetic 5'-cap analogues which enhance the stability and increase protein translation. Similarly, regulatory elements in the 5'-untranslated region and the 3'-untranslated region can be altered, and the length of the poly(A) tail optimized, to stabilize the mRNA and increase protein production. The mRNA nucleotides can be modified to both decrease innate immune activation and increase the mRNA's half-life in the host cell. The nucleic acid sequence and codon usage impacts protein translation. Enriching the sequence with guanine-cytosine content improves mRNA stability and half-life and, in turn, protein production. Replacing rare codons with synonymous codons frequently used by the host cell also enhances protein production.
== Delivery ==
For a vaccine to be successful, sufficient mRNA must enter the host cell cytoplasm to stimulate production of the specific antigens. Entry of mRNA molecules, however, faces a number of difficulties. Not only are mRNA molecules too large to cross the cell membrane by simple diffusion, they are also negatively charged like the cell membrane, which causes a mutual electrostatic repulsion. Additionally, mRNA is easily degraded by RNAases in skin and blood.
Various methods have been developed to overcome these delivery hurdles. The method of vaccine delivery can be broadly classified by whether mRNA transfer into cells occurs within (in vivo) or outside (ex vivo) the organism.
=== Ex vivo ===
Dendritic cells display antigens on their surfaces, leading to interactions with T cells to initiate an immune response. Dendritic cells can be collected from patients and programmed with the desired mRNA, then administered back into patients to create an immune response.
The simplest way that ex vivo dendritic cells take up mRNA molecules is through endocytosis, a fairly inefficient pathway in the laboratory setting that can be significantly improved through electroporation.
=== In vivo ===
Since the discovery that the direct administration of in vitro transcribed mRNA leads to the expression of antigens in the body, in vivo approaches have been investigated. They offer some advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting dendritic cells from patients and by imitating a regular infection.
Different routes of injection, such as into the skin, blood, or muscles, result in varying levels of mRNA uptake, making the choice of administration route a critical aspect of in vivo delivery. One study showed, in comparing different routes, that lymph node injection leads to the largest T-cell response.
==== Naked mRNA injection ====
Naked mRNA injection means that the delivery of the vaccine is only done in a buffer solution. This mode of mRNA uptake has been known since the 1990s. The first worldwide clinical studies used intradermal injections of naked mRNA for vaccination. A variety of methods have been used to deliver naked mRNA, such as subcutaneous, intravenous, and intratumoral injections. Although naked mRNA delivery causes an immune response, the effect is relatively weak, and after injection the mRNA is often rapidly degraded.
==== Polymer and peptide vectors ====
Cationic polymers can be mixed with mRNA to generate protective coatings called polyplexes. These protect the recombinant mRNA from ribonucleases and assist its penetration in cells. Protamine is a natural cationic peptide and has been used to encapsulate mRNA for vaccination.
==== Lipid nanoparticle vector ====
The first time the FDA approved the use of lipid nanoparticles as a drug delivery system was in 2018, when the agency approved the first siRNA drug, Onpattro. Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key technical barriers in delivering the mRNA molecule into the host cell. Research into using lipids to deliver siRNA to cells became a foundation for similar research into using lipids to deliver mRNA. However, new lipids had to be invented to encapsulate mRNA strands, which are much longer than siRNA strands.
Principally, the lipid provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid's outer layer allows the targeting of desired cell types through ligand interactions. However, many studies have also highlighted the difficulty of studying this type of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of nanoparticles in terms of cellular intake. The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system.
One issue with lipid nanoparticles is that several of the breakthroughs leading to the practical use of that technology involve the use of microfluidics. Microfluidic reaction chambers are difficult to scale up, since the entire point of microfluidics is to exploit the microscale behaviors of liquids. The only way around this obstacle is to run an extensive number of microfluidic reaction chambers in parallel, a novel task requiring custom-built equipment. For COVID-19 mRNA vaccines, this was the main manufacturing bottleneck. Pfizer used such a parallel approach to solve the scaling problem. After verifying that impingement jet mixers could not be directly scaled up, Pfizer made about 100 of the little mixers (each about the size of a U.S. half-dollar coin), connected them together with pumps and filters with a "maze of piping," and set up a computer system to regulate flow and pressure through the mixers.
Another issue, with the large-scale use of this delivery method, is the availability of the novel lipids used to create lipid nanoparticles, especially ionizable cationic lipids. Before 2020, such lipids were manufactured in small quantities measured in grams or kilograms, and they were used for medical research and a handful of drugs for rare conditions. As the safety and efficacy of mRNA vaccines became clear in 2020, the few companies able to manufacture the requisite lipids were confronted with the challenge of scaling up production to respond to orders for several tons of lipids.
==== Viral vector ====
In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar immunological responses. Typical RNA viruses used as vectors include retroviruses, lentiviruses, alphaviruses and rhabdoviruses, each of which can differ in structure and function. Clinical studies have utilized such viruses on a range of diseases in model animals such as mice, chicken and primates.
== Advantages ==
=== Traditional vaccines ===
mRNA vaccines offer specific advantages over traditional vaccines. Because mRNA vaccines are not constructed from an active pathogen (or even an inactivated pathogen), they are non-infectious. In contrast, traditional vaccines require the production of pathogens, which, if done at high volumes, could increase the risks of localized outbreaks of the virus at the production facility. Another biological advantage of mRNA vaccines is that since the antigens are produced inside the cell, they stimulate cellular immunity, as well as humoral immunity.
mRNA vaccines have the production advantage that they can be designed swiftly. Moderna designed their mRNA-1273 vaccine for COVID-19 in 2 days. They can also be manufactured faster, more cheaply, and in a more standardized fashion (with fewer error rates in production), which can improve responsiveness to serious outbreaks.
The Pfizer–BioNTech vaccine originally required 110 days to mass-produce (before Pfizer began to optimize the manufacturing process to only 60 days), which was substantially faster than traditional flu and polio vaccines. Within that larger timeframe, the actual production time is only about 22 days: two weeks for molecular cloning of DNA plasmids and purification of DNA, four days for DNA-to-RNA transcription and purification of mRNA, and four days to encapsulate mRNA in lipid nanoparticles followed by fill and finish. The majority of the days needed for each production run are allocated to rigorous quality control at each stage.
=== DNA vaccines ===
In addition to sharing the advantages of theoretical DNA vaccines over established traditional vaccines, mRNA vaccines also have additional advantages over DNA vaccines. The mRNA is translated in the cytosol, so there is no need for the RNA to enter the cell nucleus, and the risk of being integrated into the host genome is averted. Modified nucleosides (for example, pseudouridines, 2'-O-methylated nucleosides) can be incorporated to mRNA to suppress immune response stimulation to avoid immediate degradation and produce a more persistent effect through enhanced translation capacity. The open reading frame (ORF) and untranslated regions (UTR) of mRNA can be optimized for different purposes (a process called sequence engineering of mRNA), for example through enriching the guanine-cytosine content or choosing specific UTRs known to increase translation. An additional ORF coding for a replication mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed.
== Disadvantages ==
=== Storage ===
Because mRNA is fragile, some vaccines must be kept at very low temperatures to avoid degrading and thus giving little effective immunity to the recipient. Pfizer–BioNTech's BNT162b2 mRNA vaccine has to be kept between −80 and −60 °C (−112 and −76 °F). Moderna says their mRNA-1273 vaccine can be stored between −25 and −15 °C (−13 and 5 °F), which is comparable to a home freezer, and that it remains stable between 2 and 8 °C (36 and 46 °F) for up to 30 days. In November 2020, Nature reported, "While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions." Several platforms are being studied that may allow storage at higher temperatures.
=== Recent ===
Before 2020, no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so there was a risk of unknown effects. The 2020 COVID-19 pandemic required faster production capability of mRNA vaccines, made them attractive to national health organisations, and led to debate about the type of initial authorization mRNA vaccines should get (including emergency use authorization or expanded access authorization) after the eight-week period of post-final human trials.
=== Side effects ===
Reactogenicity is similar to that of conventional, non-RNA vaccines. However, those susceptible to an autoimmune response may have an adverse reaction to mRNA vaccines. The mRNA strands in the vaccine may elicit an unintended immune reaction – this entails the body believing itself to be sick, and the person feeling as if they are as a result. To minimize this, mRNA sequences in mRNA vaccines are designed to mimic those produced by host cells.
Strong but transient reactogenic effects were reported in trials of novel COVID-19 mRNA vaccines; most people will not experience severe side effects which include fever and fatigue. Severe side effects are defined as those that prevent daily activity.
== Efficacy ==
The COVID-19 mRNA vaccines from Moderna and Pfizer–BioNTech had short-term efficacy rates of over 90 percent against the original SARS-CoV-2 virus. Prior to mRNA, drug trials on pathogens other than COVID-19 were not effective and had to be abandoned in the early phases of trials. The reason for the efficacy of the new mRNA vaccines is not clear.
Physician-scientist Margaret Liu stated that the efficacy of the new COVID-19 mRNA vaccines could be due to the "sheer volume of resources" that went into development, or that the vaccines might be "triggering a nonspecific inflammatory response to the mRNA that could be heightening its specific immune response, given that the modified nucleoside technique reduced inflammation but hasn't eliminated it completely", and that "this may also explain the intense reactions such as aches and fevers reported in some recipients of the mRNA SARS-CoV-2 vaccines". These reactions though severe were transient and another view is that they were believed to be a reaction to the lipid drug delivery molecules. In June 2021, the US FDA added a warning about the possibility of increased risk of myocarditis and pericarditis for some people.
== Hesitancy ==
There is misinformation implying that mRNA vaccines could alter DNA in the nucleus. mRNA in the cytosol is very rapidly degraded before it would have time to gain entry into the cell nucleus. In fact, mRNA vaccines must be stored at very low temperature and free from RNAses to prevent mRNA degradation. Retrovirus can be single-stranded RNA (just as many SARS-CoV-2 vaccines are single-stranded RNA) which enters the cell nucleus and uses reverse transcriptase to make DNA from the RNA in the cell nucleus. A retrovirus has mechanisms to be imported into the nucleus, but other mRNA (such as the vaccine) lack these mechanisms. Once inside the nucleus, creation of DNA from RNA cannot occur without a reverse transcriptase and appropriate primers, which both accompany a retrovirus, but which would not be present for other exogenous mRNA (such as a vaccine) even if it could enter the nucleus.
== Amplification ==
mRNA vaccines use either non-amplifying (conventional) mRNA or self-amplifying mRNA. Pfizer–BioNTech and Moderna vaccines use non-amplifying mRNA. Both mRNA types continue to be investigated as vaccine methods against other potential pathogens and cancer.
=== Non-amplifying ===
The initial mRNA vaccines use a non-amplifying mRNA construct. Non-amplifying mRNA has only one open reading frame that codes for the antigen of interest. The total amount of mRNA available to the cell is equal to the amount delivered by the vaccine. Dosage strength is limited by the amount of mRNA that can be delivered by the vaccine. Non-amplifying vaccines replace uridine with N1-Methylpseudouridine in an attempt to reduce toxicity.
=== Self-amplifying ===
Self-amplifying mRNA (saRNA) vaccines replicate their mRNA after transfection. Self-amplifying mRNA has two open reading frames. The first frame, like conventional mRNA, codes for the antigen of interest. The second frame codes for an RNA-dependent RNA polymerase (and its helper proteins) which replicates the mRNA construct in the cell. This allows smaller vaccine doses. The mechanisms and consequently the evaluation of self-amplifying mRNA may be different, as self-amplifying mRNA is a much bigger molecule.
SaRNA vaccines being researched include a malaria vaccine. The first saRNA Covid vaccine authorised was Gemcovac, in India in June 2022. The second was ARCT-154, developed by Arcturus Therapeutics. A version manufactured by Meiji Seika Pharma was authorised in Japan in November 2023.
GSK began a phase 1 trial of an saRNA COVID-19 vaccine in 2021. Gritstone bio started also started a phase 1 trial of an saRNA COVID-19 vaccine in 2021, used as a booster vaccine, with interim results published in 2023. The vaccine is designed to target both the spike protein of the SARS‑CoV‑2 virus, and viral proteins that may be less prone to genetic variation, to provide greater protection against SARS‑CoV‑2 variants. saRNA vaccines must use uridine, which is required for reproduction to occur.
== See also ==
DNA vaccine
Nucleoside-modified messenger RNA
RNA therapeutics
Timeline of human vaccines
== References ==
== Further reading ==
Dolgin E (September 2021). "The tangled history of mRNA vaccines" (PDF). Nature. 597 (9): 318–24. Bibcode:2021Natur.597..318D. doi:10.1038/d41586-021-02483-w. PMID 34522017. S2CID 237515383.
Sahin U, Karikó K, Türeci Ö (October 2014). "mRNA-based therapeutics – developing a new class of drugs". Nat Rev Drug Discov. 13 (10): 759–80. doi:10.1038/nrd4278. PMID 25233993.
== External links ==
"Five things you need to know about: mRNA vaccines". Horizon. Archived from the original on 4 April 2020. Retrieved 17 November 2020.
"RNA vaccines: an introduction". PHG Foundation. University of Cambridge.
"Understanding mRNA COVID-19 Vaccines". Centers for Disease Control and Prevention. 4 January 2022.
Kolata, Gina; Mueller, Benjamin (15 January 2022). "Halting Progress and Happy Accidents: How mRNA Vaccines Were Made". The New York Times.
M.I.T. Lecture 10: Kizzmekia Corbett, Vaccines" on YouTube | Wikipedia/MRNA_vaccines |
Influenza vaccines, colloquially known as flu shots or the flu jab, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies from year to year, most provide modest to high protection against influenza. Vaccination against influenza began in the 1930s, with large-scale availability in the United States beginning in 1945.
Both the World Health Organization and the US Centers for Disease Control and Prevention (CDC) recommend yearly vaccination for nearly all people over the age of six months, especially those at high risk, and the influenza vaccine is on the World Health Organization's List of Essential Medicines. The European Centre for Disease Prevention and Control (ECDC) also recommends yearly vaccination of high-risk groups, particularly pregnant women, the elderly, children between six months and five years, and those with certain health problems.
The vaccines are generally safe, including for people who have severe egg allergies. A common side effect is soreness near the site of injection. Fever occurs in five to ten percent of children vaccinated, and temporary muscle pains or feelings of tiredness may occur. In certain years, the vaccine was linked to an increase in Guillain–Barré syndrome among older people at a rate of about one case per million doses. Influenza vaccines are not recommended in those who have had a severe allergy to previous versions of the vaccine itself. The vaccine comes in inactive and weakened viral forms. The live, weakened vaccine is generally not recommended in pregnant women, children less than two years old, adults older than 50, or people with a weakened immune system. Depending on the type it can be injected into a muscle (intramuscular), sprayed into the nose (intranasal), or injected into the middle layer of the skin (intradermal). The intradermal vaccine was not available during the 2018–2019 and 2019–2020 influenza seasons.
== History ==
Vaccines are used in both humans and non-humans. The human vaccine is meant unless specifically identified as a veterinary, poultry, or livestock vaccine.
=== Origins and development ===
During the worldwide Spanish flu pandemic of 1918, "Pharmacists tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and serums (chiefly against what we call Hemophilus influenzae – a name derived from the fact that it was originally considered the etiological agent – and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."
In 1931, viral growth in embryonated hens' eggs was reported by Ernest William Goodpasture and colleagues at Vanderbilt University. The work was extended to the growth of influenza virus by several workers, including Thomas Francis, Jonas Salk, Wilson Smith, and Macfarlane Burnet, leading to the first experimental influenza vaccines. In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used during World War II. Hens' eggs continued to be used to produce virus used in influenza vaccines, but manufacturers made improvements in the purity of the virus by developing improved processes to remove egg proteins and to reduce systemic reactivity of the vaccine. In 2012, the US Food and Drug Administration (FDA) approved influenza vaccines made by growing virus in cell cultures, and influenza vaccines made from recombinant proteins were approved in 2013.
=== Acceptance ===
The egg-based technology for producing influenza vaccine was created in the 1950s. In the US swine flu scare of 1976, President Gerald Ford was confronted with a potential swine flu pandemic. The vaccination program was rushed, yet plagued by delays and public relations problems. Meanwhile, maximum military containment efforts succeeded unexpectedly in confining the new strain to the single army base where it had originated. On that base, several soldiers fell severely ill, but only one died. The program was canceled after about 24% of the population had received vaccinations. An excess in deaths of 25 over normal annual levels as well as 400 excess hospitalizations, both from Guillain–Barré syndrome, were estimated to have occurred from the vaccination program itself, demonstrating that the vaccine itself is not free of risks. In the end, however, even the maligned 1976 vaccine may have saved lives. A 2010 study found a significantly enhanced immune response against the 2009 pandemic H1N1 in study participants who had received vaccination against the swine flu in 1976. The 2009 H1N1 "swine flu" outbreak resulted in the rapid approval of pandemic influenza vaccines. Pandemrix was quickly modified to target the circulating strain and by late 2010, 70 million people had received a dose. Eight years later, the BMJ gained access to early vaccine pharmacovigilance reports compiled by GSK (GlaxoSmithKline) during the pandemic, which the BMJ reported indicated death was 5.39 fold more likely with Pandemrix vs the other pandemic vaccines. However, more thorough and robust later analyses did not establish any increase of fatalities or most other serious adverse effects, with a possible rare exception for narcolepsy.
=== Quadrivalent vaccines ===
A quadrivalent flu vaccine administered by nasal mist was approved by the FDA in March 2012. Fluarix Quadrivalent was approved by the FDA in December 2012.
In 2014, the Canadian National Advisory Committee on Immunization (NACI) published a review of quadrivalent influenza vaccines.
Starting with the 2018–2019 influenza season most of the regular-dose egg-based flu shots and all the recombinant and cell-grown flu vaccines in the United States are quadrivalent. In the 2019–2020 influenza season all regular-dose flu shots and all recombinant influenza vaccine in the United States are quadrivalent.
In November 2019, the FDA approved Fluzone High-Dose Quadrivalent for use in the United States starting with the 2020–2021 influenza season.
In February 2020, the FDA approved Fluad Quadrivalent for use in the United States. In July 2020, the FDA approved both Fluad and Fluad Quadrivalent for use in the United States for the 2020–2021 influenza season.
The B/Yamagata lineage of influenza B, one of the four lineages targeted by quadrivalent vaccines, might have become extinct in 2020/2021 due to COVID-19 pandemic measures, and there have been no naturally occurring cases confirmed since March 2020. In 2023, the World Health Organization concluded that protection against the Yamagata lineage was no longer necessary in the seasonal flu vaccine, so future vaccines are recommended to be trivalent instead of quadrivalent. For the 2024–2025 Northern Hemisphere influenza season, the FDA recommends removing B/Yamagata from all influenza vaccines.
== Medical uses ==
The influenza vaccine is indicated for active immunization for the prevention of influenza disease caused by influenza virus subtypes A and type B contained in the vaccine.
The US Centers for Disease Control and Prevention (CDC) recommends the flu vaccine as the best way to protect people against the flu and prevent its spread. The flu vaccine can also reduce the severity of the flu if a person contracts a strain that the vaccine did not contain. It takes about two weeks following vaccination for protective antibodies to form.
A 2012 meta-analysis found that flu vaccination was effective 67 percent of the time; the populations that benefited the most were HIV-positive adults aged 18 to 55 (76 percent), healthy adults aged 18 to 46 (approximately 70 percent), and healthy children aged six months to 24 months (66 percent). The influenza vaccine also appears to protect against myocardial infarction with a benefit of 15–45%.
=== Effectiveness ===
A vaccine is assessed by its efficacy – the extent to which it reduces the risk of disease under controlled conditions – and its effectiveness – the observed reduction in risk after the vaccine is put into use. In the case of influenza, effectiveness is expected to be lower than the efficacy because it is measured using the rates of influenza-like illness, which is not always caused by influenza. Studies on the effectiveness of flu vaccines in the real world are difficult; vaccines may be imperfectly matched, virus prevalence varies widely between years, and influenza is often confused with other influenza-like illnesses. However, in most years (16 of the 19 years before 2007), the flu vaccine strains have been a good match for the circulating strains, and even a mismatched vaccine can often provide cross-protection. The virus rapidly changes due to antigenic drift, a slight mutation in the virus that causes a new strain to arise.
The effectiveness of seasonal flu vaccines varies significantly, with an estimated average efficacy of 50–60% against symptomatic disease, depending on vaccine strain, age, prior immunity, and immune function, so vaccinated people can still contract influenza. The effectiveness of flu vaccines is considered to be suboptimal, particularly among the elderly, but vaccination is still beneficial in reducing the mortality rate and hospitalization rate due to influenza as well as duration of hospitalization. Vaccination of school-age children has shown to provide indirect protection for other age groups. LAIVs are recommended for children based on superior efficacy, especially for children under 6, and greater immunity against non-vaccine strains when compared to inactivated vaccines.
From 2012 to 2015 in New Zealand, vaccine effectiveness against admission to an intensive care unit was 82%. Effectiveness against hospitalized influenza illness in the 2019–2020 United States flu season was 41% overall and 54% in people aged 65 years or older. One review found 31% effectiveness against death among adults.
Repeated annual influenza vaccination generally offers consistent year-on-year protection against influenza. There is, however, suggestive evidence that repeated vaccinations may cause a reduction in vaccine effectiveness for certain influenza subtypes; this has no relevance to recommendations for yearly vaccinations but might influence future vaccination policy. As of 2019, the CDC recommends a yearly vaccine as most studies demonstrate overall effectiveness of annual influenza vaccination.
There is not enough evidence to establish significant differences in the effectiveness of different influenza vaccine types, but there are high-dose or adjuvanted products that induce a stronger immune response in the elderly.
According to a 2016 study by faculty at the University of New South Wales, getting a flu shot was as effective or better at preventing a heart attack than even quitting smoking.
A 2024 CDC study found that the 2024 flu vaccine reduced the risk of hospitalization from the flu by 35% in the Southern Hemisphere. The research, conducted across five countries—Argentina, Brazil, Chile, Paraguay, and Uruguay—showed the vaccine was less effective than the one used in the previous season.
=== Children ===
In April 2002, the US Advisory Committee on Immunization Practices (ACIP) encouraged that all children 6 to 23 months of age be vaccinated annually against influenza. In 2010, ACIP again recommended annual influenza vaccination for those 6 months of age and older. The CDC also recommends that everyone except infants under the age of six months should receive seasonal influenza vaccine.
Vaccination campaigns usually focus special attention on people who are at high risk of serious complications if they catch the flu, such as pregnant women, children under 5 years, the elderly, and people with chronic illnesses or weakened immune systems, as well as those to whom they are exposed, such as health care workers.
As the death rate is high among infants who catch influenza, the CDC and the WHO recommend that household contacts and caregivers of infants be vaccinated to reduce the risk of passing an influenza infection to the infant.
Also in healthy children, the vaccine appears to decrease the risk of influenza and possibly influenza-like illness. During the 2017–18 flu season, the CDC indicated that 85 percent of the children who died "likely will not have been vaccinated".
In children under the age of two data were limited as of 2018.
In the United States, as of January 2019, the CDC recommended that children aged six through 35 months may receive either 0.25 milliliters or 0.5 milliliters per dose of Fluzone Quadrivalent. There is no preference for one or the other dose volume of Fluzone Quadrivalent for that age group.
All persons 3 years of age and older should receive 0.5 milliliters per dose of Fluzone Quadrivalent. As of October 2018, Afluria Quadrivalent is licensed for children six months of age and older in the United States. Children six months through 35 months of age should receive 0.25 milliliters for each dose of Afluria Quadrivalent. All persons 36 months of age and older should receive 0.5 milliliters per dose of Afluria Quadrivalent. For those not previously vaccinated or an unknown influenza vaccination history 2 doses are recommended, 4 weeks apart.
As of February 2018, in Canada Afluria Tetra was only licensed for adults and children five years of age and older.
In 2014, the Canadian National Advisory Committee on Immunization (NACI)had published a review of influenza vaccination in healthy 5–18-year-olds, and in 2015, published a review of the use of pediatric Fluad in children 6–72 months of age. In one study, conducted in a tertiary referral center, the rate of influenza vaccination in children was only 31%. Higher rates were found among immunosuppressed children (46%) and in children with inflammatory bowel disease (50%).
=== Adults ===
In unvaccinated adults, 16% get symptoms similar to the flu, while about 10% of vaccinated adults do. Vaccination decreased confirmed cases of influenza from about 2.4% to 1.1%. No effect on hospitalization was found.
In working adults, a review by the Cochrane Collaboration found that vaccination resulted in a modest decrease in both influenza symptoms and working days lost, without affecting transmission or influenza-related complications. In healthy working adults, influenza vaccines can provide moderate protection against virologically confirmed influenza, though such protection is greatly reduced or absent in some seasons.
In health care workers, a 2006 review found a net benefit. Of the eighteen studies in this review, only two also assessed the relationship of patient mortality relative to staff influenza vaccine uptake; both found that higher rates of healthcare worker vaccination correlated with reduced patient deaths. A 2014 review found benefits to patients when health care workers were immunized, as supported by moderate evidence based in part on the observed reduction in all-cause deaths in patients whose health care workers were given immunization compared with comparison patients where the workers were not offered the vaccine.
=== Elderly ===
Evidence for an effect in adults over 65 is unclear. Systematic reviews examining both randomized controlled and case–control studies found a lack of high-quality evidence. Reviews of case-control studies found effects against laboratory-confirmed influenza, pneumonia, and death among the community-dwelling elderly.
The group most vulnerable to non-pandemic flu, the elderly, benefits least from the vaccine. There are multiple reasons behind this steep decline in vaccine efficacy, the most common of which are the declining immunological function and frailty associated with advanced age. In a non-pandemic year, a person in the United States aged 50–64 is nearly ten times more likely to die an influenza-associated death than a younger person, and a person over 65 is more than ten times more likely to die an influenza-associated death than the 50–64 age group.
There is a high-dose flu vaccine specifically formulated to provide a stronger immune response. Available evidence indicates that vaccinating the elderly with the high-dose vaccine leads to a stronger immune response against influenza than the regular-dose vaccine.
A flu vaccine containing an adjuvant was approved by the US Food and Drug Administration (FDA) in November 2015, for use by adults aged 65 years of age and older. The vaccine is marketed as Fluad in the US and was first available in the 2016–2017 flu season. The vaccine contains the MF59C.1 adjuvant which is an oil-in-water emulsion of squalene oil. It is the first adjuvanted seasonal flu vaccine marketed in the United States. It is not clear if there is a significant benefit for the elderly to use a flu vaccine containing the MF59C.1 adjuvant. Per Advisory Committee on Immunization Practices guidelines, Fluad can be used as an alternative to other influenza vaccines approved for people 65 years and older.
Vaccinating healthcare workers who work with elderly people is recommended in many countries, with the goal of reducing influenza outbreaks in this vulnerable population. While there is no conclusive evidence from randomized clinical trials that vaccinating health care workers helps protect elderly people from influenza, there is tentative evidence of benefit.
Fluad Quad was approved for use in Australia in September 2019, Fluad Quadrivalent was approved for use in the United States in February 2020, and Fluad Tetra was authorized for use in the European Union in May 2020.
=== Pregnancy ===
As well as protecting mother and child from the effects of an influenza infection, the immunization of pregnant women tends to increase their chances of experiencing a successful full-term pregnancy.
The trivalent inactivated influenza vaccine is protective in pregnant women infected with HIV.
== Safety ==
=== Side effects ===
Common side effects of vaccination include local injection-site reactions and cold-like symptoms. Fever, malaise, and myalgia are less common. Flu vaccines are contraindicated for people who have experienced a severe allergic reaction in response to a flu vaccine or to any component of the vaccine. LAIVs are not given to children or adolescents with severe immunodeficiency or to those who are using salicylate treatments because of the risk of developing Reye syndrome. LAIVs are also not recommended for children under the age of 2, pregnant women, and adults with immunosuppression. Inactivated flu vaccines cannot cause influenza and are regarded as safe during pregnancy.
While side effects of the flu vaccine may occur, they are usually minor, including soreness, redness, swelling around the point of injection, headache, fever, nausea, or fatigue. Side effects of a nasal spray vaccine may include runny nose, wheezing, sore throat, cough, or vomiting.
In some people, a flu vaccine may cause serious side effects, including an allergic reaction, but this is rare. Furthermore, the common side effects and risks are mild and temporary when compared to the risks and severe health effects of the annual influenza epidemic.
Contrary to a common misconception, flu shots cannot cause people to get the flu.
=== Guillain–Barré syndrome ===
Although Guillain–Barré syndrome had been feared as a complication of vaccination, the CDC states that most studies on modern influenza vaccines have seen no link with Guillain–Barré. Infection with influenza virus itself increases both the risk of death (up to one in ten thousand) and the risk of developing Guillain–Barré syndrome to a far higher level than the highest level of suspected vaccine involvement (approximately ten times higher by 2009 estimates).
Although one review gives an incidence of about one case of Guillain–Barré per million vaccinations, a large study in China, covering close to a hundred million doses of vaccine against the 2009 H1N1 "swine" flu found only eleven cases of Guillain–Barré syndrome, (0.1 per million doses) total incidence in persons vaccinated, actually lower than the normal rate of the disease in China, and no other notable side effects.
=== Egg allergy ===
Although most influenza vaccines are produced using egg-based techniques, influenza vaccines are nonetheless still recommended as safe for people with egg allergies, even if severe, as no increased risk of allergic reaction to the egg-based vaccines has been shown for people with egg allergies. Studies examining the safety of influenza vaccines in people with severe egg allergies found that anaphylaxis was very rare, occurring in 1.3 cases per million doses given.
Monitoring for symptoms from vaccination is recommended in those with more severe symptoms. A study of nearly 800 children with egg allergy, including over 250 with previous anaphylactic reactions, had zero systemic allergic reactions when given the live attenuated flu vaccine.
Vaccines produced using other technologies, notably recombinant vaccines and those based on cell culture rather than egg protein, started to become available in 2012 in the US, and later in Europe and Australia.
=== Other ===
Several studies have identified an increased incidence of narcolepsy among recipients of the pandemic H1N1 influenza AS03-adjuvanted vaccine; efforts to identify a mechanism for this suggest that narcolepsy is autoimmune, and that the AS03-adjuvanted H1N1 vaccine may mimic hypocretin, serving as a trigger.
Some injection-based flu vaccines intended for adults in the United States contain thiomersal (also known as thimerosal), a mercury-based preservative. Despite some controversy in the media, the World Health Organization's Global Advisory Committee on Vaccine Safety has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on grounds of safety to change to more-expensive single-dose administration.
Exercising before the influenza vaccine is not thought to be harmful but there is no evidence of a beneficial effect either.
== Types ==
Seasonal flu vaccines are available either as:
a trivalent or quadrivalent injection, which contains the inactivated form of the virus. This is usually an intramuscular injection, though subcutaneous and intradermal routes can also be protective.
a nasal spray of live attenuated influenza vaccine, which contains the live but attenuated (weakened) form of the virus.
Injected vaccines induce protection based on an immune response to the antigens present on the inactivated virus, while the nasal spray works by establishing short-term infection in the nasal passages.
== Annual reformulation ==
Each year, three influenza strains are chosen for inclusion in the forthcoming year's seasonal flu vaccination by the Global Influenza Surveillance and Response System of the World Health Organization (WHO). The recommendation for trivalent vaccine comprises two strains of Influenza A (one each of A/H1N1 and A/H3N2), and one strain of influenza B (B/Victoria), together representing strains thought most likely to cause significant human suffering in the coming season. Starting in 2012, WHO has also recommended a second influenza B strain (B/Yamagata) for use in quadrivalent vaccines; this was discontinued in 2024.
"The WHO Global Influenza Surveillance Network was established in 1952 (renamed "Global Influenza Surveillance and Response System" in 2011). The network comprises four WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country and perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high-level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year."
Formal WHO recommendations were first issued in 1973. Beginning in 1999 there have been two recommendations per year: one for the northern hemisphere and the other for the southern hemisphere.
Due to the widespread use of non-pharmaceutical interventions at the beginning of the COVID-19 pandemic, the B/Yamagata influenza lineage has not been isolated since March 2020 and may have been eradicated. Starting with the 2024 Southern Hemisphere influenza season, the WHO and other regulatory bodies have removed B/Yamagata from influenza vaccine recommendations.
== Recommendations ==
Various public health organizations, including the World Health Organization (WHO), recommend that yearly influenza vaccination be routinely offered, particularly to people at risk of complications of influenza and those individuals who live with or care for high-risk individuals, including:
people aged 50 years of age or older
people with chronic lung diseases, including asthma
people with chronic heart diseases
people with chronic liver diseases
people with chronic kidney diseases
people who have had their spleen removed or whose spleen is not working properly
people who are immunocompromised
residents of nursing homes and other long-term care facilities
health care workers (both to prevent sickness and to prevent spread to their patients)
women who are or will be pregnant during the influenza season
children and adolescents (aged 6 months through 18 years) who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection
American Indians/Alaska Natives
people who are extremely obese (body mass index ≥40 for adults)
The flu vaccine is contraindicated for those under six months of age and those with severe, life-threatening allergies to flu vaccine or any ingredient in the vaccine.
=== World Health Organization ===
As of 2016, the World Health Organization (WHO) recommends seasonal influenza vaccination for:
First priority:
Pregnant women
Second priority (in no particular order):
Children aged 6–59 months
Elderly
Individuals with specific chronic medical conditions
Health-care workers
=== Canada ===
The National Advisory Committee on Immunization (NACI), the group that advises the Public Health Agency of Canada, recommends that everyone over six months of age be encouraged to receive annual influenza vaccination and that children between the age of six months and 24 months, and their household contacts, should be considered a high priority for the flu vaccine.
Particularly:
People at high risk of influenza-related complications or hospitalization, including people who are morbidly obese, healthy pregnant women, children aged 6–59 months, the elderly, aboriginals, and people with one of an itemized list of chronic health conditions
People capable of transmitting influenza to those at high risk, including household contacts and healthcare workers
People who provide essential community services
Certain poultry workers
Live attenuated influenza vaccine (LAIV) was not available in Canada for the 2019–2020 season.
=== European Union ===
The European Centre for Disease Prevention and Control (ECDC) recommends vaccinating the elderly as a priority, with a secondary priority for people with chronic medical conditions and health care workers.
The influenza vaccination strategy is generally that of protecting vulnerable people, rather than limiting influenza circulation or eliminating human influenza sickness. This is in contrast with the high herd immunity strategies for other infectious diseases such as polio and measles. This is also due in part to the financial and logistics burden associated with the need of an annual injection.
=== United Kingdom ===
The National Health Service in the United Kingdom provides flu vaccination to:
people who are aged 65 or over
people who have certain long-term health conditions
people who are pregnant
people who live in a care home
people who are the main carer for an older or disabled person, or receive a carer's allowance
people who live with someone who has a weakened immune system.
This vaccination is available free of charge to people in these groups. People outside these groups aged between 18 and 65 years of age can also receive private flu vaccination for a small fee from pharmacies and some private surgeries.
=== United States ===
In the United States routine influenza vaccination is recommended for all persons aged six months and over. It takes up to two weeks after vaccination for sufficient antibodies to develop in the body. The CDC recommends vaccination before the end of October, although it considers getting a vaccine in December or even later to be still beneficial. The U.S. military also requires a flu shot annually for its active and reserve servicemembers.
According to the CDC, the live attenuated virus (LAIV4) (which comes in the form of nasal spray in the US) should be avoided by some groups.
Within its blanket recommendation for general vaccination in the United States, the CDC, which began recommending the influenza vaccine to healthcare workers in 1981, emphasizes to clinicians the special urgency of vaccination for members of certain vulnerable groups, and their caregivers:
Vaccination is especially important for people at higher risk of serious influenza complications or people who live with or care for people at higher risk for serious complications. In 2009, a new high-dose formulation of the standard influenza vaccine was approved. The Fluzone High Dose is specifically for people 65 and older; the difference is that it has four times the antigen dose of the standard Fluzone.
The US government requires hospitals to report worker vaccination rates. Some US states and hundreds of US hospitals require healthcare workers to either get vaccinations or wear masks during flu season. These requirements occasionally engender union lawsuits on narrow collective bargaining grounds, but proponents note that courts have generally endorsed forced vaccination laws affecting the general population during disease outbreaks.
Vaccination against influenza is especially considered important for members of high-risk groups who would be likely to have complications from influenza, for example pregnant women and children and teenagers from six months to 18 years of age who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection;
In raising the upper age limit to 18 years, the aim is to reduce both the time children and parents lose from visits to pediatricians and missing school and the need for antibiotics for complications
An added benefit expected from the vaccination of children is a reduction in the number of influenza cases among parents and other household members, and of possible spread to the general community.
The CDC indicated that live attenuated influenza vaccine (LAIV), also called the nasal spray vaccine, was not recommended for the 2016–2017 flu season in the United States.
Furthermore, the CDC recommends that healthcare personnel who care for severely immunocompromised persons receive injections (TIV or QIV) rather than LAIV.
=== Australia ===
The Australian Government recommends seasonal flu vaccination for everyone over the age of six months. Australia uses inactivated vaccines. Until 2021, the egg-based vaccine has been the only one available (and continues to be the only free one), but from March 2021 a new cell-based vaccine is available for those who wish to pay for it, and it is expected that this one will become the standard by 2026.
The standard flu vaccine is free for the following people:
children aged six months to five years;
people aged 65 years and over;
Aboriginal and Torres Strait Islander people aged six months and over;
pregnant women; and
anyone over six months of age with medical conditions such as severe asthma, lung disease or heart disease, low immunity, or diabetes that can lead to complications from influenza.
== Uptake ==
=== At risk groups ===
Uptake of flu vaccination, both seasonally and during pandemics, is often low. Systematic reviews of pandemic flu vaccination uptake have identified several personal factors that may influence uptake, including gender (higher uptake in men), ethnicity (higher in people from ethnic minorities), and having a chronic illness. Beliefs in the safety and effectiveness of the vaccine are also important.
Several measures are useful to increase rates of vaccination in those over sixty including patient reminders using leaflets and letters, postcard reminders, client outreach programs, vaccine home visits, group vaccinations, free vaccinations, physician payment, physician reminders, and encouraging physician competition.
=== Health care workers ===
Frontline healthcare workers are often recommended to get seasonal and any pandemic flu vaccinations. For example, in the UK all healthcare workers involved in patient care are recommended to receive the seasonal flu vaccine, and were also recommended to be vaccinated against the H1N1/09 (later renamed A(H1N1)pdm09) swine flu virus during the 2009 pandemic. However, uptake is often low. During the 2009 pandemic, low uptake by healthcare workers was seen in countries including the UK, Italy, Greece, and Hong Kong.
In a 2010 survey of United States healthcare workers, 63.5% reported that they received the flu vaccine during the 2010–11 season, an increase from 61.9% reported the previous season. US Health professionals with direct patient contact had higher vaccination uptake, such as physicians and dentists (84.2%) and nurse practitioners (82.6%).
The main reason to vaccinate health care workers is to prevent staff from spreading flu to their patients and to reduce staff absence at a time of high service demand, but the reasons health care workers state for their decisions to accept or decline vaccination may more often be to do with perceived personal benefits.
In Victoria (Australia) public hospitals, rates of healthcare worker vaccination in 2005 ranged from 34% for non-clinical staff to 42% for laboratory staff. One of the reasons for rejecting vaccines was concern over adverse reactions; in one study, 31% of resident physicians at a teaching hospital incorrectly believed Australian vaccines could cause influenza.
== Manufacturing ==
Research continues into the idea of a "universal" influenza vaccine that would not require tailoring to a particular strain, but would be effective against a broad variety of influenza viruses. No vaccine candidates had been announced by November 2007, but as of 2021, there are several universal vaccines candidates, in pre-clinical development and in clinical trials.
In a 2007 report, the global capacity of approximately 826 million seasonal influenza vaccine doses (inactivated and live) was double the production of 413 million doses. In an aggressive scenario of producing pandemic influenza vaccines by 2013, only 2.8 billion courses could be produced in a six-month time frame. If all high- and upper-middle-income countries sought vaccines for their entire populations in a pandemic, nearly two billion courses would be required. If China pursued this goal as well, more than three billion courses would be required to serve these populations. Vaccine research and development is ongoing to identify novel vaccine approaches that could produce much greater quantities of vaccine at a price that is affordable to the global population.
=== Egg-based ===
Most flu vaccines are grown by vaccine manufacturers in fertilized chicken eggs. In the Northern hemisphere, the manufacturing process begins following the announcement (typically in February) of the WHO recommended strains for the winter flu season. Three strains (representing an H1N1, an H3N2, and a B strain) of flu are selected and chicken eggs are inoculated separately. These monovalent harvests are then combined to make the trivalent vaccine.
As of November 2007, both the conventional injection and the nasal spray are manufactured using chicken eggs. The European Union also approved Optaflu, a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable and avoid problems with eggs, such as allergic reactions and incompatibility with strains that affect avians like chickens.
Influenza vaccines are produced in pathogen-free eggs that are eleven or twelve days old. The top of the egg is disinfected by wiping it with alcohol and then the egg is candled to identify a non-veinous area in the allantoic cavity where a small hole is poked to serve as a pressure release. A second hole is made at the top of the egg, where the influenza virus is injected in the allantoic cavity, past the chorioallantoic membrane. The two holes are then sealed with melted paraffin and the inoculated eggs are incubated for 48 hours at 37 degrees Celsius. During the incubation time, the virus replicates and newly replicated viruses are released into the allantoic fluid
After the 48-hour incubation period, the top of the egg is cracked and ten milliliters of allantoic fluid is removed, from which about fifteen micrograms of the flu vaccine can be obtained. At this point, the viruses have been weakened or killed and the viral antigen is purified and placed inside vials, syringes, or nasal sprayers. Up to 3 eggs are needed to produce one dose of a trivalent vaccine, and an estimated 600 million eggs are produced each year for flu vaccine production.
=== Other methods of manufacture ===
Methods of vaccine generation that bypass the need for eggs include the construction of influenza virus-like particles (VLP). VLP resemble viruses, but there is no need for inactivation, as they do not include viral coding elements, but merely present antigens in a similar manner to a virion. Some methods of producing VLP include cultures of Spodoptera frugiperda Sf9 insect cells and plant-based vaccine production (e.g., production in Nicotiana benthamiana). There is evidence that some VLPs elicit antibodies that recognize a broader panel of antigenically distinct viral isolates compared to other vaccines in the hemagglutination-inhibition assay (HIA).
A gene-based DNA vaccine, used to prime the immune system after boosting with an inactivated H5N1 vaccine, underwent clinical trials in 2011.
In November 2012, Novartis received FDA approval for the first cell-culture vaccine. In 2013, the recombinant influenza vaccine, Flublok, was approved for use in the United States.
On September 17, 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for Supemtek, a quadrivalent influenza vaccine (recombinant, prepared in cell culture). The applicant for this medicinal product is Sanofi Pasteur. Supemtek was authorized for medical use in the European Union in November 2020.
Australia authorized its first cell-based vaccine in March 2021, based on an "eternal cell line" of a dog kidney. Because of the way it is produced, it produces better-matched vaccines (to the flu strains).
=== Vaccine manufacturing countries ===
According to the WHO, as of 2019, countries where influenza vaccine is produced include:
In addition, Kazakhstan, Serbia, and Thailand had facilities in the final stages of establishing production.
== Cost-effectiveness ==
The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings. In the elderly (over 65), the majority of published studies have found that vaccination is cost-saving, with the cost savings associated with influenza vaccination (e.g. prevented health care visits) outweighing the cost of vaccination. In older adults (aged 50–64 years), several published studies have found that influenza vaccination is likely to be cost-effective, however, the results of these studies were often found to be dependent on key assumptions used in the economic evaluations. The uncertainty in influenza cost-effectiveness models can partially be explained by the complexities involved in estimating the disease burden, as well as the seasonal variability in the circulating strains and the match of the vaccine. In healthy working adults (aged 18–49 years), a 2012 review found that vaccination was generally not cost-saving, with the suitability for funding being dependent on the willingness to pay to obtain the associated health benefits. In children, the majority of studies have found that influenza vaccination was cost-effective, however many of the studies included (indirect) productivity gains, which may not be given the same weight in all settings. Several studies have attempted to predict the cost-effectiveness of interventions (including pre-pandemic vaccination) to help protect against a future pandemic, however estimating the cost-effectiveness has been complicated by uncertainty as to the severity of a potential future pandemic and the efficacy of measures against it.
== Research ==
Influenza research includes molecular virology, molecular evolution, pathogenesis, host immune responses, genomics, and epidemiology. These help in developing influenza countermeasures such as vaccines, therapies, and diagnostic tools. Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains, and induce an immune response. The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help researchers' understanding of what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves.
A different approach uses Internet content to estimate the impact of an influenza vaccination campaign. More specifically, researchers have used data from Twitter and Microsoft's Bing search engine and proposed a statistical framework that, after a series of operations, maps this information to estimates of the influenza-like illness reduction percentage in areas where vaccinations have been performed. The method has been used to quantify the impact of two flu vaccination programmes in England (2013/14 and 2014/15), where school-age children were administered a live attenuated influenza vaccine (LAIV). Notably, the impact estimates were in accordance with estimations from Public Health England based on traditional syndromic surveillance endpoints.
=== Rapid response to pandemic flu ===
The rapid development, production, and distribution of pandemic influenza vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame between the identification of a pandemic strain and the need for vaccination, researchers are looking at novel technologies for vaccine production that could provide better "real-time" access and be produced more affordably, thereby increasing access for people living in low- and moderate-income countries, where an influenza pandemic may likely originate, such as live attenuated (egg-based or cell-based) technology and recombinant technologies (proteins and virus-like particles). As of July 2009, more than seventy known clinical trials have been completed or are ongoing for pandemic influenza vaccines. In September 2009, the FDA approved four vaccines against the 2009 H1N1 influenza virus (the 2009 pandemic strain), and expected the initial vaccine lots to be available within the following month.
In January 2020, the US Food and Drug Administration (FDA) approved Audenz as a vaccine for the H5N1 flu virus. Audenz is a vaccine indicated for active immunization for the prevention of disease caused by the influenza A virus H5N1 subtype contained in the vaccine. Audenz is approved for use in persons six months of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine.
Zoonotic influenza vaccine Seqirus is authorized for use in the European Union. It is an H5N8 vaccine that is intended to provide acquired immunity against H5 subtype influenza A viruses.
=== Universal flu vaccines ===
A universal influenza vaccine that would not have to be designed and made for each flu season in each hemisphere would stabilize the supply, avoid errors in predicting the season's variants, and protect against the escape of the circulating strains by mutation. Such a vaccine has been the subject of research for decades.
One approach is to use broadly neutralizing antibodies that, unlike the annual seasonal vaccines used over the first decades of the 21st century that provoke the body to generate an immune response, instead provide a component of the immune response itself. The first neutralizing antibodies were identified in 1993, via experimentation. It was found that the flu neutralizing antibodies bound to the stalk of the Hemagglutinin protein. Antibodies that could bind to the head of those proteins were identified. The highly conserved M2 proton channel was proposed as a potential target for broadly neutralizing antibodies.
The challenges for researchers are to identify single antibodies that could neutralize many subtypes of the virus so that they could be useful in any season, and that target conserved domains that are resistant to antigenic drift.
Another approach is to take the conserved domains identified from these projects, and to deliver groups of these antigens to provoke an immune response; various approaches with different antigens, presented in different ways (as fusion proteins, mounted on virus-like particles, on non-pathogenic viruses, as DNA, and others), are under development.
Efforts have also been undertaken to develop universal vaccines that specifically activate a T-cell response, based on clinical data showing that people with a strong, early T-cell response have better outcomes when infected with influenza and because T-cells respond to conserved epitopes. The challenge for developers is that these epitopes are on internal protein domains that are only mildly immunogenic.
Along with the rest of the vaccine field, people working on universal vaccines have experimented with vaccine adjuvants to improve the ability of their vaccines to create a sufficiently powerful and enduring immune response.
=== Oral influenza vaccine ===
As of 2019, an oral flu vaccine was in clinical research. The oral vaccine candidate is based on an adenovirus type 5 vector modified to remove genes needed for replication, with an added gene that expresses a small double-stranded RNA hairpin molecule as an adjuvant. In 2020, a phase II human trial of the pill form of the vaccine showed that it was well tolerated and provided similar immunity to a licensed injectable vaccine.
=== Possible Pleiotropic Effects ===
Recent observational studies and clinical trials suggest nonspecific effects of influenza vaccination, known as pleiotropic effects, with broader impact beyond protecting against influenza infection. A meta-analysis of 9001 randomized trial participants found that influenza vaccination was associated with a 34% lower risk of major adverse cardiovasular events when compared to placebo. This risk reduction size is comparable to the cardioprotective effects seen with other guideline-recommended cardiovascular medications, including statins. Protection against stroke of all etiologies has also been suggested in a large population-based retrospective cohort study of 4 million adults in Canada. There may also be protective effects against the development of type 1 diabetes and cancer-related mortality, which are active areas of investigation.
=== COVID-19 ===
An influenza vaccine and a COVID-19 vaccine may be given safely at the same time. Preliminary research indicates that influenza vaccination does not prevent COVID-19, but may reduce the incidence and severity of COVID-19 infection.
=== Criticism ===
Tom Jefferson, who has led Cochrane Collaboration reviews of flu vaccines, has called clinical evidence concerning flu vaccines "rubbish" and has therefore declared them to be ineffective; he has called for placebo-controlled randomized clinical trials, which most in the field hold as unethical. His views on the efficacy of flu vaccines are rejected by medical institutions including the CDC and the National Institutes of Health, and by key figures in the field like Anthony Fauci.
Michael Osterholm, who led the Center for Infectious Disease Research and Policy 2012 review on flu vaccines, recommended getting the vaccine but criticized its promotion, saying, "We have overpromoted and overhyped this vaccine ... it does not protect as promoted. It's all a sales job: it's all public relations."
== Veterinary use ==
Veterinary influenza vaccination aims to achieve the following four objectives:
Protection from clinical disease
Protection from infection with virulent virus
Protection from virus excretion
Serological differentiation of infected from vaccinated animals (so-called DIVA principle).
=== Horses ===
Horses with horse flu can run a fever, have a dry hacking cough, have a runny nose, and become depressed and reluctant to eat or drink for several days but usually recover in two to three weeks. "Vaccination schedules generally require a primary course of two doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognized that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations."
It is a common requirement at shows in the United Kingdom that horses be vaccinated against equine flu and a vaccination card must be produced; the International Federation for Equestrian Sports (FEI) requires vaccination every six months.
=== Poultry ===
It is possible to vaccinate poultry against specific strains of highly pathogenic avian influenza. Vaccination should be combined with other control measures such as infection monitoring, early detection, and biosecurity.
=== Pigs ===
Swine influenza vaccines are extensively used in pig farming in Europe and North America. Most swine flu vaccines include an H1N1 and an H3N2 strain.
Swine influenza has been recognized as a major problem since the outbreak in 1976. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection. Customised (autogenous) vaccines made from the specific viruses isolated are made and used in the more difficult cases. The vaccine manufacturer Novartis claims that the H3N2 strain (first identified in 1998) has brought major losses to pig farmers. Abortion storms are a common sign and sows stop eating for a few days and run a high fever. The mortality rate can be as high as fifteen percent.
=== Dogs ===
In 2004, influenza A virus subtype H3N8 was discovered to cause canine influenza. Because of the lack of previous exposure to this virus, dogs have no natural immunity to this virus. However, a vaccine was found in 2004.
== Notes ==
== References ==
== Further reading ==
== External links ==
Inactivated Influenza Vaccine Information Statement, US Centers for Disease Control and Prevention (CDC)
Live, Intranasal Influenza Vaccine Information Statement, US Centers for Disease Control and Prevention (CDC)
Seasonal Influenza (Flu) Vaccination and Preventable Disease, US Centers for Disease Control and Prevention (CDC)
Misconceptions about Seasonal Flu and Flu Vaccines, US Centers for Disease Control and Prevention (CDC)
Influenza Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Influenza_vaccines |
Vaccine line jumping is the act of obtaining a vaccine in which the supply fails to meet the demands of the population ahead of those for whom it has been prioritized, usually via fraudulent means, the exploitation of one's social status, or some other unethical manner. Vaccine line jumping is distinct from vaccine chasing, in which one goes out of their way to seek a scarcely available vaccine to which they are legally entitled.
In some situations, an honor system is used in which the recipient declares, either verbally or in writing, if they are in a priority group, but no proof is asked. Other places require that one who is in a priority group provide documentation of belonging to such a group. For example, if prioritization is by age, a driver's license or other governmental identification can be used to verify age. If by occupation, a work ID can be used, and if a medical condition is a criterion, it could be a physician certificate.
== Methods ==
Vaccine line jumpers sometimes exaggerate a factor that could include them in a priority group, such as a category of employment or medical condition. For example, a medical administrative worker who has no contact with patients might consider themselves a "healthcare worker", or one who has had a bout of pneumonia might classify themselves as having had "lung disease", even as their condition is not chronic.
Sometimes, a glitch in the registration system can enable those who do not belong to a priority group to register and obtain a shot. Some people can obtain shots ahead of what is considered to be their turn because of their wealth or connections.
== References == | Wikipedia/Vaccine_line_jumping |
Regulatory science is the scientific and technical foundations upon which regulations are based in various industries – particularly those involving health or safety. Regulatory bodies employing such principles in the United States include, for example, the FDA for food and medical products, the EPA for the environment, and the OSHA for work safety.
"Regulatory science" is contrasted with regulatory affairs and regulatory law, which refer to the administrative or legal aspects of regulation, in that the former is focused on the regulations' scientific underpinnings and concerns – rather than the regulations' promulgation, implementation, compliance, or enforcement.
== History ==
Probably the first investigator who recognized the nature of regulatory science was Alvin Weinberg, who described the scientific process used to evaluate effects of ionizing radiation as trans science. The origin of the term regulatory science is unknown. It was probably coined sometimes in the late 1970s in an undated memorandum prepared by A. Alan Moghissi, who was describing scientific issues that the newly formed US Environmental Protection Agency (EPA) was facing . During that period the EPA was forced to meet legally mandated deadlines to make decisions that would require reliance upon science that was not meeting conventional scientific requirements. At that time the prevailing view was that there was no need to establish a new scientific discipline because "science is science" regardless of its application. In the spring of 1985, Moghissi established the Institute for Regulatory Science in the commonwealth of Virginia as a nonprofit organization with the objective to perform scientific studies "at the interface between science and the regulatory system". Moghissi et al. have provided an extensive description of history of regulatory science including various perception of regulatory science leading to the acceptance of regulatory science by the FDA.
== Definition ==
Two federal regulatory agencies have provided definitions for regulatory science. According to Food and Drug Administration: “Regulatory Science is the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products”. According to Environmental Protection Agency (EPA): “Regulatory science means scientific information including assessments, models, criteria documents, and regulatory impact analyses that provide the basis for significant regulatory decisions”.
Moghissi et al. have described the history of regulatory science and define it as:
“Regulatory science consists of an applied version of various scientific disciplines used in the regulatory process”. Based on their definition the generalized FDA definition is: Regulatory science is the science of developing new tools, standards, and approaches derived from various scientific disciplines to assess the safety, efficacy, quality, and performance of all FDA-regulated products. Similarly, the generalized EPA definition is:
Regulatory science means scientific information including assessments, models, criteria documents, and regulatory impact analyses derived from various scientific disciplines that provide the basis for EPA final significant regulatory decisions.
There have been several attempts to define regulatory science. In many cases there are claims that there is a difference between regulatory science and “normal science”, “academic science”, “research science”. or compliance with regulations. The primary problem is the lack of appreciation that many branches of science are evolving and much of the evolving science includes inherent uncertainties.
== Application of regulatory science ==
Regulatory science is included in every regulation that includes science. The regulatory science community consists of three groups of regulatory scientists:
Those who are involved in development of regulations. Typically this group is employed by regulatory agencies
Those who must comply with regulations. Typically this group consists of employees or contractors of regulated community.
Those segments of the scientific community who perform research and development in areas relevant to the relevant regulated community.
The third group is of particular significance as they consist of organizations and individuals who support the first two groups. Included in this group are members of numerous advisory panels, organizations that provide peer reviews, and members of peer review panels. An example of this group is the National Academies consisting of the National Academy of Science, National Academy of Engineering, Institute of Medicine, and National Research Council.
The application of regulatory science occurs in three phases. During the first phase the regulators must meet a legislative or court- mandated deadline and promulgate regulations using their best judgment. The second phase provides opportunity to develop regulatory science tools. These include human health and ecological risk assessment procedures and post marketing evaluation method d processes for drugs ad medical devices. The third Standard Operating phase, used tools developed during the second phase to improve the initial decision. (Moghissi et al.)
== Regulatory engineering ==
Engineering is the development of new products and processes, hence regulatory engineering encompasses principally the development of products and processes to facilitate or better examine regulations or their scientific foundations. Another related segment of regulatory science deal with the application of engineering design or analysis to operations such as the safety of nuclear and other power plants, chemical production facilities, mining operations, and air transportation.
Sometimes the term "regulatory engineer(ing)" is misused to refer to essentially administrative or regulatory roles dealing with organizing or coordinating regulatory matters for an organization; however, "engineering" refers only to functional design of products and processes, and in many jurisdictions this definition is legally enforced (see Regulation and licensure in engineering).
== Areas of focus ==
=== Regulatory pharmaceutical medicine ===
Consistent with its mission, the Food and Drug Administration (FDA) suggests, “Regulatory science is the science of developing new tools, standards and approaches to assess the safety, efficacy, quality and performance of FDA-regulated products.”
Based on several decades of experience regulatory science is logically defined as a distinct scientific discipline constituting the scientific foundation of regulatory, legislative, and judicial decisions. Much like many scientific disciplines that have evolved within the last several decades, regulatory science is both interdisciplinary and multidisciplinary and relies upon a large number of basic and applied scientific disciplines.
Regulatory science is an emerging area of interest within pharmaceutical medicine as the shaping and implementation of legislation and guidelines. One definition of “regulatory science” is the science of developing new tools, standards and approaches to evaluate the efficacy, safety, quality and performance of medical products in order to assess benefit-risk and facilitate a sound and transparent regulatory decision-making. It has been recognized as having a significant impact on the industry’s ability to bring new medicines and medical devices to patients in need. Regulatory science challenges current concepts of benefit/risk assessment, submission and approval strategies, patient’s involvement and ethical aspects. It creates the platform for launching new ideas – not only by the pharmaceutical industry and regulatory authorities, but also by, for example, academia, who wants to contribute to better use of their research activities within medical aspects. Regulatory science has the potential as an enabler for directing companies towards more efficient global development of medical products as well as more robust quality decision-making processes.
=== Human health ===
By far the predominant foci of regulatory science pertain to human health and well-being. This realm covers a broad range of scientific areas – including pollution and toxicology, work safety, food, drugs, and numerous others.
=== Ecology ===
Regulatory ecology covers the protection of various species, protection of wetlands, and numerous other regulated areas, including ecotoxicology.
For example, the US Clean Water Act is based upon an interest in protecting water quality for its own sake, in contrast with the Clean Air Act which is premised upon protecting air quality only for the sake of human health; however, these are ideological policy premises rather than scientific matters themselves.
The US Department of Agriculture regulates animal care, and the FDA regulates humaneness for animal studies.
The US Department of Interior, Fish and Wildlife Service (USFWS), and National Oceanographic and Atmospheric Administration, National Marine Fisheries Service, implement the development and enforcement of policies required by the Federal Endangered Species Act (FESA), Migratory Bird Treaty Act, and other biological resources laws. The FESA requires that the decisions to list a species as endangered or threatened are based on the best available scientific data. To that end, the USFWS and other government agencies fund research to determine the conservation status of proposed species. Regulatory scientists within the Services review, evaluate, and incorporate data from these studies of proposed species in their published regulations. Survey protocols for listed species are also developed from scientific studies of their target species. The purpose of the protocols is to reliably and accurately determine the residency of the target species in a given study area.
== Regulatory economics ==
There are numerous economic decisions in the regulatory process, including the economics part of cost-benefit analysis.
== Science in legislation and in courts ==
Although often less than fully recognized, the scientific foundation of legislative decisions is included in regulatory science and should be based on reliable science. Similarly, courts have recognized the need to rely upon information that meets scientific requirements.
== References ==
== Further reading ==
Honda, Hiroshi (2016). "Overview of Issues and Discussions in Regulatory Science and Engineering over the Past Four Years in Global Arena" (PDF). American Journal of Environmental Engineering and Science. 3 (1): 1–20. ISSN 2381-1153. | Wikipedia/Regulatory_Science |
A vaccine adverse event (VAE), sometimes referred to as a vaccine injury, is an adverse event believed to have been caused by vaccination. The World Health Organization (WHO) refers to Adverse Events Following Immunization (AEFI).
AEFIs can be related to the vaccine itself (product or quality defects), to the vaccination process (administration error or stress related reactions) or can occur independently from vaccination (coincidental).
Most vaccine adverse events are mild. Serious injuries and deaths caused by vaccines are very rare, and the idea that severe events are common has been classed as a "common misconception about immunization" by the WHO. Some claimed vaccine injuries are not, in fact, caused by vaccines; for example, there is a subculture of advocates who attribute their children's autism to vaccine injury, despite the fact that vaccines do not cause autism.
Claims of vaccine injuries appeared in litigation in the United States in the latter part of the 20th century. Some families have won substantial awards from sympathetic juries, even though many public health officials have said that the claims of injuries are unfounded. In response, several vaccine makers stopped production, threatening public health, resulting in laws being passed at several points to shield makers from liabilities stemming from vaccine injury claims.
== Adverse events ==
According to the U.S. Centers for Disease Control and Prevention, while "any vaccine can cause side effects", most side effects are minor, primarily including sore arms or a mild fever. Unlike most medical interventions vaccines are given to healthy people, where the risk of side effects is not as easily outweighed by the benefit of treating existing disease. As such, the safety of immunization interventions is taken very seriously by the scientific community, with constant monitoring of a number of data sources looking for patterns of adverse events.
As the success of immunization programs increases and the incidence of disease decreases, public attention shifts away from the risks of disease to the risk of vaccination. Concerns about immunization safety often follow a pattern. First, some investigators suggest that a medical condition of increasing prevalence or unknown cause is due to an adverse effect of vaccination. The initial study, and subsequent studies by the same investigators, have inadequate methodology, typically a poorly controlled or uncontrolled case series. A premature announcement is made of the alleged adverse effect, which resonates with individuals who have the condition and which underestimates the potential harm of not being vaccinated. The initial study is not reproduced by other investigators. Finally, it takes several years before the public regains confidence in the vaccine.
Controversies in this area revolve around the question of whether the risks of adverse events following immunization outweigh the benefits of preventing infectious disease. In rare cases immunizations can cause serious adverse effects, such as gelatin measles-mumps-rubella vaccine (MMR) causing anaphylaxis, a severe allergic reaction. Allegations particularly focus on disorders claimed to be caused by the MMR vaccine and thiomersal, a preservative used in vaccines routinely given to U.S. infants prior to 2001. Current scientific evidence does not support claims of vaccines causing various disorders.
The debate is complicated by misconceptions around the recording and reporting of adverse events by anti-vaccination activists. According to authorities, anti-vaccination websites greatly exaggerate the risk of serious adverse effects from vaccines and falsely describe conditions such as autism and shaken baby syndrome as vaccine injuries, leading to misconceptions about the safety and effectiveness of vaccines. This has had the result of stigmatizing autistic people and the parents who had them immunized.
Many countries, including Canada, Germany, Japan, and the United States have specific requirements for reporting vaccine-related adverse effects, while other countries including Australia, France, and the United Kingdom include vaccines under their general requirements for reporting injuries associated with medical treatments.: 8–11 A number of countries have programs for the compensation of injuries alleged to have been caused by a vaccination.: 9–44
=== Febrile seizures ===
Febrile seizures may occur after the administration of certain vaccines, including the MMR vaccine, and influenza vaccines. According to the Centers for Disease Control and Prevention, febrile seizures do not cause any harm or have any permanent effects.
=== Allergic reactions ===
It is thought that certain vaccines can, very rarely, cause anaphylaxis in yeast-sensitive individuals and children allergic to vaccine ingredients. The rate of anaphylaxis is estimated to be around one per million vaccine doses.
== United States ==
=== Vaccine Injury Compensation Program ===
In 1988, the National Vaccine Injury Compensation Program (VICP) went into effect to compensate individuals and families of individuals who have been injured by specified childhood vaccines. The VICP was adopted in response to an earlier scare over the pertussis portion of the DPT vaccine. These claims were later generally discredited, but some U.S. lawsuits against vaccine makers won substantial awards; most makers ceased production, and the last remaining major manufacturer threatened to do so. As of October 2019, $4.2 billion in compensation (not including attorneys fees and costs) has been awarded.
VICP uses a streamlined system for litigating vaccine injury claims under which the claimant must show that the vaccine caused the injury, but just as in litigation for injury by any other product, they are not required to establish it was anyone's fault (i.e. negligence need not be proven) Claims that are denied can be pursued through civil lawsuits, though this is rare, and the statute creating the VICP also imposes substantial limitations on the ability to pursue such lawsuits. The VICP covers all vaccines listed on the Vaccine Injury Table which is maintained by the Secretary of Health and Human Services. To win an award, a claimant is required to show a causal connection between an injury and one of the vaccines listed in the Vaccine Injury Table. Compensation is payable for "table" injuries, those listed in the Vaccine Injury Table, as well as, "non-table" injuries, injuries not listed in the table.
In addition, an award may only be given if the claimant's injury lasted for more than 6 months after the vaccine was given, resulted in a hospital stay and surgery or resulted in death. Awards are based on medical expenses, lost earnings and pain and suffering (capped at $250,000).
From 1988 until March 3, 2011, 5,636 claims relating to autism, and 8,119 non-autism claims, were made to the VICP. 2,620 of these claims, one autism-related, were compensated, with 4,463 non-autism and 814 autism claims dismissed; awards (including attorney's fees) totaled over $2 billion. The VICP also applies to claims for injuries sustained before 1988; there were 4,264 of these claims of which 1,189 were compensated with awards totaling $903 million. As of October 2019, $4.2 billion in compensation (not including attorneys fees and costs) has been awarded over the life of the program.
As part of NVICP, a table has been created which lists various vaccines, side effects that might plausibly be caused by them, and the time within which the symptoms must present in order to be eligible to apply for compensation. For example, for vaccines containing tetanus toxoid (e.g., DTaP, DTP, DT, Td, or TT), anaphylaxis within four hours or brachial neuritis between two and twenty-eight days after administration, may be compensated.
=== Countermeasures Injury Compensation Program ===
Established by PREP Act, in the case of pandemic, epidemic, or other major security threat requiring a medical countermeasures, such as vaccines and medications, the CICP provides compensation to eligible individuals for serious physical injuries or death. Covid-19 vaccines are covered under the program.
=== Vaccine Adverse Event Reporting System ===
The Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance program administered jointly by the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC).
VAERS is intended to track adverse events associated with vaccines. VAERS collects and analyzes information from reports of adverse events that occur after the administration of US licensed vaccines. VAERS has several limitations, including underreporting, unverified reports, inconsistent data quality, and inadequate data about the number of people vaccinated. Due to the program's open and accessible design and its allowance of unverified reports, incomplete VAERS data is often used in false claims regarding vaccine safety.
=== Vaccine Safety Datalink ===
The Vaccine Safety Datalink (VSD), funded by the Centers for Disease Control, is composed of databases from several organizations containing information regarding health outcomes for millions of US citizens and to enhance assessment of vaccine injuries. It was designed to allow for such things as comparisons between vaccinated and non-vaccinated populations, and for the identification of possible groups at risk for adverse events.
== United Kingdom ==
The Vaccine Damage Payment Act 1979 governs AEFIs in the UK, and sets up the Vaccine Damage Payment Scheme (VDPS).
=== Vaccine Damage Payment Scheme ===
Under the VDPS, it is thought that thousands of unsuccessful claims have been made. The maximum payment per claim is currently £120,000. The 'disability threshold' before payments are granted is 60%. The scheme covers vaccinations for illnesses such as tetanus, measles, tuberculosis, and meningitis C. As of 2005, the British government had paid out £3.5 million to vaccine injury patients since 1997.
Until the advent of COVID-19, disabled vaccine injury patients were allowed to file a claim up to the age of 21. On the 2 December 2020, government agreed under regulation secondary to the 1979 Act the statutory £120,000 blanket payout for any person provably damaged by the vaccine, and by the same addition of COVID-19 to the list, government-approved Covax manufacturers were exempted from legal pursuit. Individuals who provide the vaccine (and thus are permitted by government to do so) are also protected.
== Canada ==
Quebec has a legal process to compensate certain forms of vaccination injuries; the program was set up by statute in 1985, and its first awards were made in 1988.
On 10 December 2020, the nations was made aware via an op-ed published in the Globe and Mail that "Canada needs to prepare for rare but serious health problems resulting from [Covid-19] vaccination" by, inter alia, the Honourable Dr Jane Philpott, former cabinet member and Dean of the Faculty of Health Sciences of Queen's University. The authors observed that, outside of Quebec, "People suffering severe AEFIs are left to assume the costs of legal fees, lost wages, uninsured medical services and rehabilitation supports", and plumped for a no-fault system, in which "compensation is needs-based and not punitive." They go on to write:
In the context of the COVID-19 pandemic, we are concerned that, given the anticipated scale of the COVID-19 immunization campaign and new vaccine technologies employed, mass immunization may result in a small number of Canadians experiencing serious AEFIs, despite adherence to best practices. While AEFIs are possible with routine immunizations, pandemic situations are unique with respect to the speed and scale with which vaccine technologies are developed and distributed. Rare serious AEFIs may not be captured during phases of clinical trials because it may require very large numbers of the population to be immunized for AEFIs to manifest. The anticipated incidence of serious AEFIs can be estimated at 1 in one million immunizations... the potential health consequences of adverse events following immunization borne by the few will be for our collective benefit in stopping the deadly spread of the virus. Operating under this estimate, we anticipate 25 Canadians may suffer a serious health outcome following COVID-19 vaccination, or 0.1 per 100,000 doses.
The authors conclude that an "equitable and fair compensation system with a transparent accountability process for monitoring potential AEFIs associated with COVID-19 immunization could increase public confidence in vaccines and promote uptake."
== Germany ==
Germany has established a treatment and research centre for VAEs at Marburg University Hospital (UKGM).
== See also ==
Bundaberg tragedy
Vaccine hesitancy
COVID-19 vaccine#Adverse events
== References == | Wikipedia/Adverse_vaccine_event |
A vaccine is a biological preparation that provides immunity to an infectious disease.
Vaccine or The Vaccine(s) may also refer to:
Vaccine (journal), a medical journal
Vaccine: The Controversial Story of Medicine's Greatest Lifesaver, a 2007 book by Arthur Allen
Vaccine (instrument), a Haitian musical instrument
Vaccine (musician), Christine Clements, American dubstep record producer
"Vaccine" (song), by NoCap
"Vaccine", a song by Logic from Bobby Tarantino III
"Vaccine", a song by Mew from No More Stories..., 2009
"Vaccine", a song by Migos from Culture III
"The Vaccine" (The Outer Limits), a television episode
The Vaccines, an English rock band
COVID-19 vaccine, colloquially referred to as "The Vaccine"
== See also ==
Vaccination, the process of administering a vaccine
Vaccine hesitancy, a reluctance or refusal to be vaccinated or to have one's children vaccinated
Vaxine, a video game | Wikipedia/Vaccine_(disambiguation) |
The Central Drugs Standard Control Organisation (CDSCO) is India's national regulatory body for cosmetics, pharmaceuticals and medical devices. It serves a similar function to the Food and Drug Administration (FDA) of the United States or the European Medicines Agency of the European Union. The Indian government has announced its plan to bring all medical devices, including implants and contraceptives under a review of the Central Drugs and Standard Control Organisation (CDSCO).
Within the CDSCO, the Drug Controller General of India (DCGI) regulates pharmaceutical and medical devices and is positioning within the Ministry of Health and Family Welfare. The DCGI is advised by the Drug Technical Advisory Board (DTAB) and the Drug Consultative Committee (DCC). Divided into zonal offices, each one carries out pre-licensing and post-licensing inspections, post-market surveillance, and drug recalls (where necessary). Manufacturers who deal with the authority required to name an Authorized Indian Representative (AIR) to represent them in all dealings with the CDSCO in India.
== Divisions ==
Central Drugs Standard Control Organization has 8 divisions:
BA/BE
New Drugs
Medical Device & Diagnostics
DCC-DTAB
Import & Registration
Biological
Cosmetics
Clinical Trials
== See also ==
Healthcare in India
National Health Authority
Drugs and Cosmetics Act, 1940
Indian Council of Medical Research
Hindustan Antibiotics Limited
Drugs Controller General of India
National Pharmaceutical Pricing Authority
Indian Pharmacopoeia Commission
Pharmaceutical Export Promotion Council
Food Safety and Standards Authority of India
Pharmacy Council of India
Pharmaceutical industry in India
National Medical Commission
Ministry of Health and Family Welfare
National Commission for Indian System of Medicine
Rajasthan Right to Health Care Act 2022
Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954
== References ==
== External links ==
Official website
SUGAM Online Licensing | Wikipedia/Central_Drugs_Standard_Control_Organization |
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases start with testing for drug safety in a few human subjects, then expand to many study participants (potentially tens of thousands) to determine if the treatment is effective. Clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays.
== Description ==
Clinical trials testing potential medical products are commonly classified into four phases. The drug development process will normally proceed through all four phases over many years. When expressed specifically, a clinical trial phase is capitalized both in name and Roman numeral, such as "Phase I" clinical trial.
If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are 'post-marketing' or 'surveillance' studies conducted to monitor safety over several years.
== Preclinical studies ==
Before clinical trials are undertaken for a candidate drug, vaccine, medical device, or diagnostic assay, the product candidate is tested extensively in preclinical studies. Such studies involve in vitro (test tube or cell culture) and in vivo (animal model) experiments using wide-ranging doses of the study agent to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist the developer to decide whether a drug candidate has scientific merit for further development as an investigational new drug.
== Phase 0 ==
Phase 0 is a designation for optional exploratory trials, originally introduced by the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies, but now generally adopted as standard practice. Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (what the body does to the drugs).
A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.
== Phase I ==
Phase I trials were formerly referred to as "first-in-man studies" but the field generally moved to the gender-neutral language phrase "first-in-humans" in the 1990s; these trials are the first stage of testing in human subjects. They are designed to test the safety, side effects, best dose, and formulation method for the drug. Phase I trials are not randomized, and thus are vulnerable to selection bias.
Normally, a small group of 20–100 healthy volunteers will be recruited. These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organization (CROs) who conduct these studies on behalf of pharmaceutical companies or other research investigators.
The subject who receives the drug is usually observed until several half-lives of the drug have passed. This phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. Phase I trials normally include dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer. The tested range of doses will usually be a fraction of the dose that caused harm in animal testing.
Phase I trials most often include healthy volunteers. However, there are some circumstances when clinical patients are used, such as patients who have terminal cancer or HIV and the treatment is likely to make healthy individuals ill. These studies are usually conducted in tightly controlled clinics called Central Pharmacological Units, where participants receive 24-hour medical attention and oversight. In addition to the previously mentioned unhealthy individuals, "patients who have typically already tried and failed to improve on the existing standard therapies" may also participate in Phase I trials. Volunteers are paid a variable inconvenience fee for their time spent in the volunteer center.
Before beginning a Phase I trial, the sponsor must submit an Investigational New Drug application to the FDA detailing the preliminary data on the drug gathered from cellular models and animal studies.
Phase I trials can be further divided:
=== Phase Ia ===
Single ascending dose (Phase Ia): In single ascending dose studies, small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time to confirm safety. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. If they do not exhibit any adverse side effects, and the pharmacokinetic data are roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose.
If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)). If an additional unacceptable toxicity is observed, then the dose escalation is terminated and that dose, or perhaps the previous dose, is declared to be the maximally tolerated dose. This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity. Variations of this design exist, but most are similar.
=== Phase Ib ===
Multiple ascending dose (Phase Ib): Multiple ascending dose studies investigate the pharmacokinetics and pharmacodynamics of multiple doses of the drug, looking at safety and tolerability. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
=== Food effect ===
A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.
== Phase II ==
Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect. Phase II trials are performed on larger groups (50–300 individuals) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Genetic testing is common, particularly when there is evidence of variation in metabolic rate. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.
Phase II studies are sometimes divided into Phase IIa and Phase IIb. There is no formal definition for these two sub-categories, but generally:
Phase IIa studies are usually pilot studies designed to find an optimal dose and assess safety ('dose finding' studies).
Phase IIb studies determine how well the drug works in subjects at a given dose to assess efficacy ('proof of concept' studies).
=== Trial design ===
Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of participants. Other Phase II trials are designed as randomized controlled trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.
==== Example: cancer design ====
In the first stage, the investigator attempts to rule out drugs that have no or little biologic activity. For example, the researcher may specify that a drug must have some minimal level of activity, say, in 20% of participants. If the estimated activity level is less than 20%, the researcher chooses not to consider this drug further, at least not at that maximally tolerated dose. If the estimated activity level exceeds 20%, the researcher will add more participants to get a better estimate of the response rate. A typical study for ruling out a 20% or lower response rate enters 14 participants. If no response is observed in the first 14 participants, the drug is considered not likely to have a 20% or higher activity level. The number of additional participants added depends on the degree of precision desired, but ranges from 10 to 20. Thus, a typical cancer phase II study might include fewer than 30 people to estimate the response rate.
==== Efficacy vs effectiveness ====
When a study assesses efficacy, it is looking at whether the drug given in the specific manner described in the study is able to influence an outcome of interest (e.g. tumor size) in the chosen population (e.g. cancer patients with no other ongoing diseases). When a study is assessing effectiveness, it is determining whether a treatment will influence the disease. In an effectiveness study, it is essential that participants are treated as they would be when the treatment is prescribed in actual practice. That would mean that there should be no aspects of the study designed to increase compliance above those that would occur in routine clinical practice. The outcomes in effectiveness studies are also more generally applicable than in most efficacy studies (for example does the patient feel better, come to the hospital less or live longer in effectiveness studies as opposed to better test scores or lower cell counts in efficacy studies). There is usually less rigid control of the type of participant to be included in effectiveness studies than in efficacy studies, as the researchers are interested in whether the drug will have a broad effect in the population of patients with the disease.
=== Success rate ===
Phase II clinical programs historically have experienced the lowest success rate of the four development phases. In 2010, the percentage of Phase II trials that proceeded to Phase III was 18%, and only 31% of developmental candidates advanced from Phase II to Phase III in a study of trials over 2006–2015.
== Phase III ==
This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice. Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. Phase III trials of chronic conditions or diseases often have a short follow-up period for evaluation, relative to the period of time the intervention might be used in practice. This is sometimes called the "pre-marketing phase" because it actually measures consumer response to the drug.
It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorized as "Phase IIIB studies."
While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, to obtain approval from the appropriate regulatory agencies such as FDA (US), or the EMA (European Union).
Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries. They will review the submission, and if it is acceptable, give the sponsor approval to market the drug.
Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines through a New Drug Application (NDA) containing all manufacturing, preclinical, and clinical data. In case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.
=== Adaptive design ===
The design of individual trials may be altered during a trial – usually during Phase II or III – to accommodate interim results for the benefit of the treatment, adjust statistical analysis, or to reach early termination of an unsuccessful design, a process called an "adaptive design". Examples are the 2020 World Health Organization Solidarity trial, European Discovery trial, and UK RECOVERY Trial of hospitalized people with severe COVID-19 infection, each of which applies adaptive designs to rapidly alter trial parameters as results from the experimental therapeutic strategies emerge.
Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.
=== Success rate ===
For vaccines, the probability of success ranges from 7% for non-industry-sponsored candidates to 40% for industry-sponsored candidates.
A 2019 review of average success rates of clinical trials at different phases and diseases over the years 2005–15 found a success range of 5–14%. Separated by diseases studied, cancer drug trials were on average only 3% successful, whereas ophthalmology drugs and vaccines for infectious diseases were 33% successful. Trials using disease biomarkers, especially in cancer studies, were more successful than those not using biomarkers.
A 2010 review found about 50% of drug candidates either fail during the Phase III trial or are rejected by the national regulatory agency.
== Cost of trials by phases ==
In the early 21st century, a typical Phase I trial conducted at a single clinic in the United States ranged from $1.4 million for pain or anesthesia studies to $6.6 million for immunomodulation studies. Main expense drivers were operating and clinical monitoring costs of the Phase I site.
The amount of money spent on Phase II or III trials depends on numerous factors, with therapeutic area being studied and types of clinical procedures as key drivers. Phase II studies may cost as low as $7 million for cardiovascular projects, and as much as $20 million for hematology trials.
Phase III trials for dermatology may cost as low as $11 million, whereas a pain or anesthesia Phase III trial may cost as much as $53 million. An analysis of Phase III pivotal trials leading to 59 drug approvals by the US Food and Drug Administration over 2015–16 showed that the median cost was $19 million, but some trials involving thousands of subjects may cost 100 times more.
Across all trial phases, the main expenses for clinical trials were administrative staff (about 20% of the total), clinical procedures (about 19%), and clinical monitoring of the subjects (about 11%).
== Phase IV ==
A Phase IV trial is also known as a postmarketing surveillance trial or drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
== Overall cost ==
The entire process of developing a drug from preclinical research to marketing can take approximately 12 to 18 years and often costs well over $1 billion.
== References == | Wikipedia/Phase_IV_trial |
Vaccine equity means ensuring that everyone in the world has equal access to vaccines. The importance of vaccine equity has been emphasized by researchers and public health experts during the COVID-19 pandemic but is relevant to other illnesses and vaccines as well. Historically, world-wide immunization campaigns have led to the eradication of smallpox and significantly reduced polio, measles, tuberculosis, diphtheria, whooping cough, and tetanus.
There are important reasons to establish mechanisms for global vaccine equity. Multiple factors support the emergence and spread of pandemics, not least the ability of people to travel long distances and widely transmit viruses. A virus that remains in circulation somewhere in the world is likely to spread and recur in other areas. The more widespread a virus is, and the larger and more varied the population it affects, the more likely it is to evolve more transmissible, more virulent, and more vaccine resistant variants. Vaccine equity can be essential to stop both the spread and the evolution of a disease. Ensuring that all populations receive access to vaccines is a pragmatic means towards achieving global public health. Failing to do so increases the likelihood of further waves of a disease.
Infectious diseases are disproportionately likely to affect those in low and middle-income neighborhoods and countries (LMICs), making vaccine equity an issue for local and national public health and for foreign policy. Ethically and morally, access for all to essential medicines such as vaccines is fundamentally related to the human right to health, which is well founded in international law. Economically, vaccine inequity damages the global economy. Supply chains cross borders: areas with very high vaccination rates still depend on areas with lower vaccination rates for goods and services.
Achieving vaccine equity requires addressing inequalities and roadblocks in the production, trade, and health care delivery of vaccines. Challenges include scaling-up of technology transfer and production, costs of production, safety profiles of vaccines, and anti vaccine disinformation and aggression.
== Patterns of vaccine inequality ==
The wealthy generally have better access to vaccines than the poor, both between and within countries. Within countries, there may be lower rates of vaccination in racial and ethnic minority groups, in older adults, and among those living with disabilities or chronic conditions. The distribution and accessibility of vaccines show significant disparities between urban and rural areas especially in low- and middle-income countries. Some countries have programs to redress this inequality. Political, economic, social, and diplomatic factors can limit vaccine availability in some countries.
== Factors ==
Achieving control of a disease (such as COVID-19) requires not only developing and licensing vaccines but also producing them at scale, pricing them so that they are globally affordable, allocating them to be available where and when they are needed, and deploying them to local communities. An effective global approach to achieving vaccine equity must address challenges in the dimensions of vaccine production, allocation, affordability, and deployment.
Doctors Without Borders (MSF) lists five major obstacles to vaccine equity, taking into account that many of those to be vaccinated are children:
Vaccine prices; new vaccines are on-patent and expensive (affordability)
Getting vaccines to children; this is expensive and gets even more difficult in conflict zones and natural disasters (affordability, deployment)
Five clinic visits in the first year of life is often too many; for people in remote areas with many children, it can be much more costly and difficult to get to a clinic. (deployment)
Keeping vaccines cold; see cold chain. (deployment)
Age-out; children who don't get vaccinated on-schedule often have to pay for their shots. Disruption from natural disasters or conflict can mean that entire generations go unprotected.(affordability, deployment)
Achieving vaccine equity depends on having a sufficient supply of affordable vaccines available for global use.
Ideally, a vaccine that is suitable for global use will be based on established technology; will have multiple available suppliers of the materials and equipment needed for production; be appropriate to the regions where it is to be produced or deployed, in terms of scalability of production and storage conditions; and be supported by local infrastructure for its production, delivery and regulation.
=== Vaccine development ===
Developing a new drug and gaining regulatory approval for it is a long and expensive process that can involve a variety of stakeholders. The time to develop a new drug can be 10 to 15 years, or longer. The average cost of developing at least one successful epidemic infectious disease vaccine from preclinical to the launch phase, taking into account the cost of failed attempts, has been estimated at from 18.1 million to US$1 billion.
Decisions about what drugs to develop reflect the priorities of the companies and countries where drug development occurs. As of 2021, the United States was the country launching the highest number of new drugs, and the country with the largest expenditure overall on pharmaceutical discovery, approximately 40% of the research done globally. The United States is also the country with the highest profits for pharmaceutical companies, and the highest drug costs for patients.
Emerging and reemerging viruses substantially affect people in low and middle income countries (LMICs), a pattern that is likely to increase due to climate change. Pharmaceutical companies have few financial incentives to develop treatments for neglected tropical diseases in poor countries.
International organizations such as the World Health Organization, Unicef and the Developing Countries Vaccine Manufacturers Network support development of treatments for diseases such as West Nile virus, dengue fever; Chikungunya, Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), Ebola, enterovirus D68 and Zika virus.
=== Vaccine affordability ===
A major factor in the economics of vaccines is intellectual property law. IP currently operates by granting pharmaceutical monopolies lasting decades. The economics of monopoly power give the monopolist a strong financial incentive to use value-based pricing and set prices that many, often most, potential customers can't afford (a pricing strategy that charges what the market will bear, unlike traditional cost-plus pricing charges the cost of production plus a markup). Price discrimination attempts to charge each person the maximum they would be willing to pay, and charges every purchaser more than they would be charged in a fully-competitive market. A vaccine monopolist has no incentive to let the rich actually subsidize the poor. Medical-product monopolists may claim that the high prices charged to the rich subsidize the lower prices charged to the poor when in fact both are being charged well over independent estimates of the cost of production (see, for instance, GeneXpert cartridges and pneumococcal vaccine).
Amnesty International, Oxfam International, and Médecins Sans Frontières (MSF; Doctors without Borders) have criticized government support of some vaccine monopolies, on the grounds that the monopolies dramatically increase prices and impair vaccine equity. During the COVID-19 pandemic, there were calls for COVID-related IP to be suspended, using the TRIPS Waiver. The waiver had support from most countries, but opposition from within the EU (especially Germany), UK, Norway, and Switzerland, among others.
=== Vaccine production ===
Low and middle income countries tend to lack technological expertise and manufacturing capacity for the production of drugs and medical products. This leaves them dependent on diagnostics, treatments and vaccines from manufacturers in other countries and on availability in the global market. There are some exceptions such as China, Cuba, and India, which are actively producing pharmaceuticals to internationally accepted standards.
The COVID-19 pandemic has led to recommendations to diversify pharmaceutical production and increase the productive ability of LMICs. This could allow those countries to better ensure that their own production needs are being met, which would help to achieve global vaccine equity. For example, the African Union Commission and Africa Centres for Disease Control and Prevention has called on countries and organizations to enable the production of at least 60% of the total vaccine doses required on the continent by 2040.
Potential problems to this can involve:
Availability of capital, technology and skills
Adherence to quality standards
Inconsistent or unsupportive national and international policy frameworks
Size of markets, purchasing power, and variable demand for vaccines
Lack of national or local infrastructure (e.g. reliable energy, electricity, transportation)
Even when organizations are willing to share their information, knowledge transfer can create serious delays for the production of vaccines. This may be particularly true in the case of novel technologies. LMICs may be better situated to produce vaccines that are based on more established technologies, if those are available.
=== Vaccine allocation ===
In the absence of well-organized systems to develop and distribute vaccines,
vaccine companies and high income nations may monopolize available resources.
Organizations such as GAVI,
the Coalition for Epidemic Preparedness Innovations,
and the World Health Organization have proposed multilateral initiatives such as Covax for the improvement of vaccine allocation. The intention with Covax was to collectively pool resources to ensure vaccine development and production. The resulting vaccine supplies could be fairly distributed to reach less wealthy countries and achieve vaccine equity. Foreign aid and resources from richer countries would cover the cost of distributing doses to lower-middle and low income countries.
As an allocation mechanism, Covax has succeeded in distributing COVID-19 vaccines, beginning with a shipment to Ghana on 24 February 2021. In the next year Covax delivered 1.2 billion vaccines to 144 countries. Covax was not able to acquire doses directly from manufacturers at the levels it had hoped. An estimated that 60% of the doses it distributed in 2021 (543 million out of 910 million) were donated doses from wealthy countries, beginning with the USA (41% of all donated doses).
Covax is an unprecedented initiative, but it has not met the goal of achieving vaccine equity. Higher income nations bypassed the proposed mechanism and negotiated directly with vaccine manufacturers, leaving Covax without the resources it needed to buy and distribute vaccines in a timely fashion. Smaller and poorer countries had to wait or negotiate for themselves, with varying success. Middle income countries with finances to cover the cost of vaccines still had considerable difficulty in obtaining them.
Ideally a global vaccine hub could have been developed by the international community before it was needed, rather than under the pressures of a pandemic. Improving it is important in preparation for future health crises. Analyses of Covax' institutional design and governance structures suggest that it lacked leverage to influence the behavior of donor states and pharmaceutical companies. It has been suggested that initiatives for vaccine allocation and vaccine equity could be improved by increasing the simplicity, transparency and accountability of their mechanisms. Others argue that such a body needs high-level leadership that is able to act at political and diplomatic levels to address issues of vaccine diplomacy as well as streamlining its mechanisms.
The allocation of vaccines and the issue of wastage are related. When high income countries buy more than they use, doses go to waste. If higher income countries donate near-expiration doses to lower income countries, those doses may expire before they can be effectively reallocated and used. This type of closed vial wastage could be reduced, through the improvement of supply chain management within countries, the internationally coordinated monitoring and tracking of vaccines, and well-organized systems for the timely donation and reallocation of surplus vaccines.
Open vial wastage, which occurs when only part of a vial of vaccine is used, could also be reduced. Strategies include making less doses available in a single vial, and organizing appointments to more effectively ensure that doses are used by overbooking (since some people will not appear) or not booking (so that only those who do appear receive doses).
=== Vaccine deployment ===
Barriers to deployment may be both physical and mental. In addition to supply and demand, barriers to immunization can include systems barriers related to organization of the health care system; health care provider barriers relating to availability and education of health care staff; and patient barriers around a parent or patient's fears or beliefs about immunization.
Cheap vaccines are often not administered due to a lack of infrastructure funding.
Logistical difficulties are an obstacle to achieving global vaccine equity. Hot climates, remote regions, and low-resource settings need cheap, transportable, easy-to-use vaccines.
To achieve vaccine equity, vaccine development needs to prioritize concerns about whether a vaccine can survive outside a fridge or be administered in a single shot.
“It’s important to figure out who are the most marginalized people living in your area. ... How can you make the vaccine easy for them to get? That is what vaccine equity looks like.”
To reach communities and successfully deploy a vaccine and achieve vaccine equity, it is important to take a “human-centered” public health approach that can address and respond to the concerns of local individuals and organizations. For example, vaccines could be made available by going to where people live, and partnering with houses of worship and other community centers, rather than relying on people to travel to hospitals or doctor's offices. In Laos, measures taken included repairing roads to remote areas, buying vans with modern refrigeration to transport vaccines, and visiting residences, temples, and schools to discuss the importance of vaccination.
As part of Laos' public health campaign, President Thongloun Sisoulith was publicly vaccinated, on television, to encourage others to follow his example. Working with leaders and trusted community members within communities who can present important information and publicly identify and counter misinformation can be very successful. This type of approach was used in India, which was certified as free of poliomyelitis in 2014. In that public health campaign, 98% of the “social mobilizers” involved were women, whose involvement was critical.
=== Vaccine messaging ===
Communicating about public health risks is more effective when a message involves three or four specific talking points, which are then backed up with evidence. An initial message may focus on what is happening, what to do, and how to do it, followed up by details and how to find more information.
Part of effective communication is to avoid confusing or overwhelming people. A simple message can be followed by more complex ones. Messages should be clear about the limits of what is known: explicitly identifying the boundaries of evolving knowledge rather than speculating and sending out conflicting and confusing messages.
Often, the most useful and effective communication comes from local officials and people with expertise who know their community and the issue involved well.
It is important to be aware of and address issues such as medical disparities, abuse, neglect, and disinformation that may affect communities. Disinformation tends to thrive under conditions of confusion, distrust and disenfranchisement. Countering disinformation is not just a matter of presenting facts and figures. People need to feel heard and their concerns need to be considered.
== Geographical distributions ==
=== Migrant populations ===
Migrants and refugees arriving and living in Europe face various difficulties in getting vaccinated and many of them are not fully vaccinated. People arriving from Africa, Eastern Europe, the Eastern Mediterranean, and Asia are more likely to be under-vaccinated (partial or delayed vaccination). Also, recently arrived refugees, migrants and seekers of asylum were less likely to be fully vaccinated than other people from the same groups. Those with little contact to healthcare services, no citizenship and lower income are also more likely to be under-vaccinated.
Vaccination barriers to migrants include language/literacy barriers, lack of understanding of the need for or their entitlement to vaccines, concerns about the side-effects, health professionals lack of knowledge of vaccination guidelines for migrants, and practical/legal issues, for example, having no fixed address. Vaccines uptake of migrants can be increased by customised communications, clear policies, community-guided interventions (such as vaccine advocates), and vaccine offers in local accessible settings.
== COVID-19 ==
Priorly developed work for other coronaviruses allowed the COVID-19 vaccination development team to have a head start, speeding up development and trials. Specifically, COVID-19 vaccination development began in January 2020. On May 15, 2020, Operation Warp Speed was announced as a partnership between the United States Department of Health and Human Services and the Department of Defense. $18 Billion was contracted out to eight different companies to develop COVID-19 vaccinations intended for the US population; major companies included where Moderna, Pfizer, and Johnson & Johnson. These three companies received the earliest emergency use approval from the FDA, therefore being the most common vaccinations in the United States.
Vaccine inequality has been a major concern in the COVID-19 pandemic, with most vaccines being reserved by wealthy countries, including vaccines manufactured in developing countries. Globally, the problem has been distribution; supply is adequate. Not all countries have the ability to produce the vaccine.
In low-income countries, vaccination rates long remained almost zero. This has caused sickness and death.
Vaccine inequity during the COVID-19 pandemic showed the disparity between minority groups and countries. Based on income and rural or urban setting, vaccination rates were vastly disproportionate. As of 19 March 2022, 79% of people in high income countries had received one or more doses of a COVID-19 vaccine, compared with just 14% of people in low income countries. By April 25, 2022, 15.2% of people in low income countries had received at least one dose, while overall globally 65.1% of the global population had received at least one dose.
Throughout the data of COVID-19 vaccination records, rates have consistently been much lower for lower income groups than that of middle and higher income groups. COVID-19 vaccination rates are higher in urban settings, and lower in rural settings. In an underdeveloped country such as Nigeria, vaccination rates are under 11% nationally. Because of persistent vaccine inequity, many countries continue to not have access to free or affordable COVID-19 vaccinations.
Our World in Data provides up to date statistics of COVID-19 vaccine access between nations, socioeconomic groups, and more.
In September 2021, it was estimated that the world would have manufactured enough vaccines to vaccinate everyone on the planet by January 2022. Vaccine hoarding, booster shots, a lack of funding for vaccination infrastructure, and other forms of inequality mean that it is expected that many countries will still have inadequate vaccination.
On August 4, 2021, the United Nations called for a moratorium on booster doses in high-income countries, so that low-income countries can be vaccinated. The World Health Organization repeated these criticisms of booster shots on the 18th, saying "we're planning to hand out extra life-jackets to people who already have life-jackets while we're leaving other people to drown without a single life jacket". UNICEF supported a "Donate doses now" campaign.
On 29 January 2022, Pope Francis denounced the "distortion of reality based on fear" that has ripped across the world during the COVID-19 pandemic. He urged journalists to help those misled by coronavirus-related misinformation and fake news to better understand the scientific facts.
== See also ==
Economics of vaccines
Vaccine resistance
GAVI
COVAX
CEPI
Developing Countries Vaccine Manufacturers Network
== References == | Wikipedia/Vaccine_equity |
Plague is an infectious disease caused by the bacterium Yersinia pestis. Symptoms include fever, weakness and headache. Usually this begins one to seven days after exposure. There are three forms of plague, each affecting a different part of the body and causing associated symptoms. Pneumonic plague infects the lungs, causing shortness of breath, coughing and chest pain; bubonic plague affects the lymph nodes, making them swell; and septicemic plague infects the blood and can cause tissues to turn black and die.
The bubonic and septicemic forms are generally spread by flea bites or handling an infected animal, whereas pneumonic plague is generally spread between people through the air via infectious droplets. Diagnosis is typically by finding the bacterium in fluid from a lymph node, blood or sputum.
Those at high risk may be vaccinated. Those exposed to a case of pneumonic plague may be treated with preventive medication. If infected, treatment is with antibiotics and supportive care. Typically antibiotics include a combination of gentamicin and a fluoroquinolone. The risk of death with treatment is about 10% while without it is about 70%.
Globally, about 600 cases are reported a year. In 2017, the countries with the most cases include the Democratic Republic of the Congo, Madagascar and Peru. In the United States, infections occasionally occur in rural areas, where the bacteria are believed to circulate among rodents. It has historically occurred in large outbreaks, with the best known being the Black Death in the 14th century, which resulted in more than 50 million deaths in Europe.
== Signs and symptoms ==
There are several different clinical manifestations of plague. The most common form is bubonic plague, followed by septicemic and pneumonic plague. Other clinical manifestations include plague meningitis, plague pharyngitis, and ocular plague. General symptoms of plague include fever, chills, headaches, and nausea. Many people experience swelling in their lymph nodes if they have bubonic plague. For those with pneumonic plague, symptoms may (or may not) include a cough, pain in the chest, and haemoptysis.
=== Bubonic plague ===
When a flea bites a human and contaminates the wound with regurgitated blood, the plague-causing bacteria are passed into the tissue. Y. pestis can reproduce inside cells, so even if phagocytosed, they can still survive. Once in the body, the bacteria can enter the lymphatic system, which drains interstitial fluid. Plague bacteria secrete several toxins, one of which is known to cause beta-adrenergic blockade.
Y. pestis spreads through the lymphatic vessels of the infected human until it reaches a lymph node, where it causes acute lymphadenitis. The swollen lymph nodes form the characteristic buboes associated with the disease, and autopsies of these buboes have revealed them to be mostly hemorrhagic or necrotic.
If the lymph node is overwhelmed, the infection can pass into the bloodstream, causing secondary septicemic plague and if the lungs are seeded, it can cause secondary pneumonic plague.
=== Septicemic plague ===
Lymphatics ultimately drain into the bloodstream, so the plague bacteria may enter the blood and travel to almost any part of the body. In septicemic plague, bacterial endotoxins cause disseminated intravascular coagulation (DIC), causing tiny clots throughout the body and possibly ischemic necrosis (tissue death due to lack of circulation/perfusion to that tissue) from the clots. DIC results in depletion of the body's clotting resources so that it can no longer control bleeding. Consequently, there is bleeding into the skin and other organs, which can cause red and/or black patchy rash and hemoptysis/hematemesis (coughing up/ vomiting of blood). There are bumps on the skin that look somewhat like insect bites; these are usually red, and sometimes white in the centre. Untreated, the septicemic plague is usually fatal. Early treatment with antibiotics reduces the mortality rate to between 4 and 15 per cent.
=== Pneumonic plague ===
The pneumonic form of plague arises from infection of the lungs. It causes coughing and thereby produces airborne droplets that contain bacterial cells and are likely to infect anyone inhaling them. The incubation period for pneumonic plague is short, usually two to four days, but sometimes just a few hours. The initial signs are indistinguishable from several other respiratory illnesses; they include headache, weakness, and spitting or vomiting of blood. The course of the disease is rapid; unless diagnosed and treated soon enough, typically within a few hours, death may follow in one to six days; in untreated cases, mortality is nearly 100%.
== Cause ==
Transmission of Y. pestis to an uninfected individual is possible by any of the following means:
droplet contact – coughing or sneezing on another person
direct physical contact – touching an infected person, including sexual contact
indirect contact – usually by touching soil contamination or a contaminated surface
airborne transmission – if the microorganism can remain in the air for long periods
fecal-oral transmission – usually from contaminated food or water sources
vector borne transmission – carried by insects or other animals.
Yersinia pestis circulates in animal reservoirs, particularly in rodents, in the natural foci of infection found on all continents except Australia. The natural foci of plague are situated in a broad belt in the tropical and sub-tropical latitudes and the warmer parts of the temperate latitudes around the globe, between the parallels 55° N and 40° S.
Contrary to popular belief, rats did not directly start the spread of the bubonic plague. It is mainly a disease in the fleas (Xenopsylla cheopis) that infested the rats, making the rats themselves the first victims of the plague. Rodent-borne infection in a human occurs when a person is bitten by a flea that has been infected by biting a rodent that itself has been infected by the bite of a flea carrying the disease. The bacteria multiply inside the flea, sticking together to form a plug that blocks its stomach and causes it to starve. The flea then bites a host and continues to feed, even though it cannot quell its hunger, and consequently, the flea vomits blood tainted with the bacteria back into the bite wound. The bubonic plague bacterium then infects a new person and the flea eventually dies from starvation. Serious outbreaks of plague are usually started by other disease outbreaks in rodents or a rise in the rodent population.
A 21st-century study of a 1665 outbreak of plague in the village of Eyam in England's Derbyshire Dales – which isolated itself during the outbreak, facilitating modern study – found that three-quarters of cases are likely to have been due to human-to-human transmission, especially within families, a much larger proportion than previously thought.
== Diagnosis ==
Symptoms of plague are usually non-specific and to definitively diagnose plague, laboratory testing is required. Y. pestis can be identified through both a microscope and by culturing a sample and this is used as a reference standard to confirm that a person has a case of plague. The sample can be obtained from the blood, mucus (sputum), or aspirate extracted from inflamed lymph nodes (buboes). If a person is administered antibiotics before a sample is taken or if there is a delay in transporting the person's sample to a laboratory and/or a poorly stored sample, there is a possibility for false negative results.
Polymerase chain reaction (PCR) may also be used to diagnose plague, by detecting the presence of bacterial genes such as the pla gene (plasmogen activator) and caf1 gene, (F1 capsule antigen). PCR testing requires a very small sample and is effective for both alive and dead bacteria. For this reason, if a person receives antibiotics before a sample is collected for laboratory testing, they may have a false negative culture and a positive PCR result.
Blood tests to detect antibodies against Y. pestis can also be used to diagnose plague, however, this requires taking blood samples at different periods to detect differences between the acute and convalescent phases of F1 antibody titres.
In 2020, a study about rapid diagnostic tests that detect the F1 capsule antigen (F1RDT) by sampling sputum or bubo aspirate was released. Results show rapid diagnostic F1RDT test can be used for people who have suspected pneumonic and bubonic plague but cannot be used in asymptomatic people. F1RDT may be useful in providing a fast result for prompt treatment and fast public health response as studies suggest that F1RDT is highly sensitive for both pneumonic and bubonic plague. However, when using the rapid test, both positive and negative results need to be confirmed to establish or reject the diagnosis of a confirmed case of plague and the test result needs to be interpreted within the epidemiological context as study findings indicate that although 40 out of 40 people who had the plague in a population of 1000 were correctly diagnosed, 317 people were diagnosed falsely as positive.
== Prevention ==
=== Vaccination ===
Bacteriologist Waldemar Haffkine developed the first plague vaccine in 1897. He conducted a massive inoculation program in British India, and it is estimated that 26 million doses of Haffkine's anti-plague vaccine were sent out from Bombay between 1897 and 1925, reducing the plague mortality by 50–85%.
Since human plague is rare in most parts of the world as of 2023, routine vaccination is not needed other than for those at particularly high risk of exposure, nor for people living in areas with enzootic plague, meaning it occurs at regular, predictable rates in populations and specific areas, such as the western United States. It is not even indicated for most travellers to countries with known recent reported cases, particularly if their travel is limited to urban areas with modern hotels. The United States CDC thus only recommends vaccination for (1) all laboratory and field personnel who are working with Y. pestis organisms resistant to antimicrobials: (2) people engaged in aerosol experiments with Y. pestis; and (3) people engaged in field operations in areas with enzootic plague where preventing exposure is not possible (such as some disaster areas). A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine.
=== Early diagnosis ===
Diagnosing plague early leads to a decrease in transmission or spread of the disease.
=== Prophylaxis ===
Pre-exposure prophylaxis for first responders and health care providers who will care for patients with pneumonic plague is not considered necessary as long as standard and droplet precautions can be maintained. In cases of surgical mask shortages, patient overcrowding, poor ventilation in hospital wards, or other crises, pre-exposure prophylaxis might be warranted if sufficient supplies of antimicrobials are available.
Postexposure prophylaxis should be considered for people who had close (<6 feet), sustained contact with a patient with pneumonic plague and were not wearing adequate personal protective equipment. Antimicrobial postexposure prophylaxis also can be considered for laboratory workers accidentally exposed to infectious materials and people who had close (<6 feet) or direct contact with infected animals, such as veterinary staff, pet owners, and hunters.
Specific recommendations on pre- and post-exposure prophylaxis are available in the clinical guidelines on treatment and prophylaxis of plague published in 2021.
== Treatments ==
If diagnosed in time, the various forms of plague are usually highly responsive to antibiotic therapy. The antibiotics often used are streptomycin, chloramphenicol and tetracycline. Amongst the newer generation of antibiotics, gentamicin and doxycycline have proven effective in monotherapeutic treatment of plague. Guidelines on treatment and prophylaxis of plague were published by the Centers for Disease Control and Prevention in 2021.
The plague bacterium could develop drug resistance and again become a major health threat. One case of a drug-resistant form of the bacterium was found in Madagascar in 1995. Further outbreaks in Madagascar were reported in November 2014 and October 2017.
== Epidemiology ==
Globally about 600 cases are reported a year. In 2017, the countries with the most cases include the Democratic Republic of the Congo, Madagascar and Peru. It has historically occurred in large outbreaks, with the best known being the Black Death in the 14th century which resulted in more than 50 million dead. In recent years, cases have been distributed between small seasonal outbreaks which occur primarily in Madagascar, and sporadic outbreaks or isolated cases in endemic areas.
In 2022 the possible origin of all modern strands of Yersinia pestis DNA was found in human remains in three graves located in Kyrgyzstan, dated to 1338 and 1339. The siege of Caffa in Crimea in 1346, is known to have been the first plague outbreak with following strands, later to spread over Europe. Sequencing DNA compared to other ancient and modern strands paints a family tree of the bacteria. Bacteria today affecting marmots in Kyrgyzstan, are closest to the strand found in the graves, suggesting this is also the location where plague transferred from animals to humans.
== Biological weapon ==
The plague has a long history as a biological weapon. Historical accounts from ancient China and medieval Europe details the use of infected animal carcasses, such as cows or horses, and human carcasses, by the Xiongnu/Huns, Mongols, Turks and other groups, to contaminate enemy water supplies. Han dynasty general Huo Qubing is recorded to have died of such contamination while engaging in warfare against the Xiongnu. Plague victims were also reported to have been tossed by catapult into cities under siege.
In 1347, the Genoese possession of Caffa, a great trade emporium on the Crimean peninsula, came under siege by an army of Mongol warriors of the Golden Horde under the command of Jani Beg. After a protracted siege during which the Mongol army was reportedly withering from the disease, they decided to use the infected corpses as a biological weapon. The corpses were catapulted over the city walls, infecting the inhabitants. This event might have led to the transfer of the Black Death via their ships into the south of Europe, possibly explaining its rapid spread.
During World War II, the Japanese Army developed weaponized plague, based on the breeding and release of large numbers of fleas. During the Japanese occupation of Manchuria, Unit 731 deliberately infected Chinese, Korean and Manchurian civilians and prisoners of war with the plague bacterium. These subjects, termed "maruta" or "logs", were then studied by dissection, others by vivisection while still conscious. Members of the unit such as Shirō Ishii were exonerated from the Tokyo tribunal by Douglas MacArthur but 12 of them were prosecuted in the Khabarovsk War Crime Trials in 1949 during which some admitted having spread bubonic plague within a 36-kilometre (22 mi) radius around the city of Changde.
Ishii innovated bombs containing live mice and fleas, with very small explosive loads, to deliver the weaponized microbes, overcoming the problem of the explosive killing the infected animal and insect by the use of a ceramic, rather than metal, casing for the warhead. While no records survive of the actual usage of the ceramic shells, prototypes exist and are believed to have been used in experiments during WWII.
After World War II, both the United States and the Soviet Union developed means of weaponising pneumonic plague. Experiments included various delivery methods, vacuum drying, sizing the bacterium, developing strains resistant to antibiotics, combining the bacterium with other diseases (such as diphtheria), and genetic engineering. Scientists who worked in USSR bio-weapons programs have stated that the Soviet effort was formidable and that large stocks of weaponised plague bacteria were produced. Information on many of the Soviet and US projects is largely unavailable. Aerosolized pneumonic plague remains the most significant threat.
The plague can be easily treated with antibiotics. Some countries, such as the United States, have large supplies on hand if such an attack should occur, making the threat less severe.
== See also ==
Timeline of plague
== References ==
== Further reading ==
Nelson CA, Meaney-Delman D, Fleck-Derderian S, Cooley KM, Yu PA, Mead PS (July 2021). "Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response" (PDF). MMWR Recomm Rep. 70 (3): 1–27. doi:10.15585/mmwr.rr7003a1. PMC 8312557. PMID 34264565. Archived (PDF) from the original on 2022-10-09.
== External links ==
WHO Health topic
CDC Plague map world distribution, publications, information on bioterrorism preparedness and response regarding plague
Symptoms, causes, pictures of bubonic plague | Wikipedia/Plague_(disease) |
A marker vaccine is a vaccine which allows for immunological differentiation (or segregation) of infected from vaccinated animals, and is also referred to as a DIVA (or SIVA) vaccine [Differentiation (or Segregation) of infected from vaccinated animals] in veterinary medicine. In practical terms, this is most often achieved by omitting an immunogenic antigen present in the pathogen being vaccinated against, thus creating a negative marker of vaccination. In contrast, vaccination with traditional vaccines containing the complete pathogen, either attenuated or inactivated, precludes the use of serology (e.g. analysis of specific antibodies in body fluids) in epidemiological surveys in vaccinated populations.
Apart from the obvious advantage of allowing continued serological monitoring of vaccinated individuals, cohorts or populations; the serological difference between vaccinated individuals and individuals that were exposed to the pathogen, and were contagious, can be used to continuously monitor the efficacy and safety of the vaccine.
== References == | Wikipedia/Marker_vaccine |
Vaccine development and production is economically complex and prone to market failure. Development is unprofitable in rich and poor countries, and is done with public funding. Production is concentrated in the hands of a small number of powerful companies which acquire key legal monopolies and make very large profits.
Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great. Most vaccine development to date has therefore relied on "push" funding by government, universities and non-profit organizations. In almost all cases, pharmaceuticals including vaccines are developed with public funding, but profits and control of price and availability are legally accorded to private companies. Proposed solutions include requiring results from publicly-funded research to be public-domain. Past efforts along these lines have failed by regulatory capture.
In contrast to research and development, the vaccine production market, even for out-of-patent vaccines, is highly concentrated. 80% of global production is in the hand of five large companies, which hold key patents. This reduces competition and allows high, uncompetitive prices, often more than 100 times the cost of production.
Many vaccines have been highly cost-effective and beneficial for public health. Vaccine effort that is beneficial to society is vastly in excess of that which is beneficial to vaccine producers. The number of vaccines actually administered has risen dramatically in recent decades.
== Market concentration ==
While vaccine research and development is done by many small companies, large-scale vaccine manufacturing is done by an oligopoly of big manufacturers. A March 2020 New York Times article described the political effects of this market structure: "government and international health organizations know that any vaccine developed in a lab will ultimately be manufactured by large pharmaceutical firms. At this critical juncture with coronavirus, no health expert would publicly criticize drug companies, but privately they complain that pharma is a major speed bump in developing lifesaving vaccines."
Concentration and monopolization of the manufacture of specific drugs has also led to supply shortages, and significant healthcare costs for employing people to track down hard-to-get drugs.
This oligopoly power allows vaccine manufacturers to engage in price discrimination, and vaccine prices are often two orders of magnitude (~100x) higher than the manufacturer's stated manufacturing costs, as of 2015. Sales agreements often require that the buyer keeps the price secret and agrees to other non-competitive restrictions; the exact nature and extent of this problem is hard to characterize, due to agreements being secret. Price secrecy also disadvantages vaccine purchasers in price negotiations. It also makes market analysis difficult and hinders efforts to improve affordability.
The first decade of the 2000s saw a large number of mergers and acquisitions, and as of 2010, 80% of the global vaccine market was in the hands of five multinationals: GlaxoSmithKline, Sanofi Pasteur, Pfizer, Merck, and Novartis. Of these, Novartis does not focus on vaccine development. Patents on key manufacturing processes help maintain this oligopoly.
=== National vaccine-manufacturing facilities ===
Some countries have set up local manufacturing facilities, especially during the COVID-19 pandemic. Sometimes the government simply gives a private company money to set up a privately-owned vaccination facility locally; sometimes the facility is partly controlled or owned by the government. Facilities that produce less than 100 million doses per year face diseconomies of scale, increasing the costs of vaccines. Sequential stages in the production of a vaccine dose may also be done in different facilities and shipped across borders.
In 2017, the UK had draft plans to build a national facility, later called the UK Vaccine Manufacturing Innovation Centre (VMIC). Plans came to involve industry partners including Merck and Johnson and Johnson. The facility was delayed by negotiations between industry funders and, which did not end until the country was well into the pandemic. It was originally slated to cost the government £66m. The facility was expanded and built in a rush during the pandemic, and eventually cost the government £200 million; by December of 2021, the government was trying to sell off its share (it was still trying ot sell it nearly a year later). The decision was widely criticized. It was suggested that the government not sell, or at least retain the ability to commandeer production.
Ghana built a US$122 million vaccine manufacturing facility using funding from the International Finance Corporation of the World Bank Group, working with a consortium of three Ghanaian pharmaceutical companies. It was planned to start shipping vaccines in 2024.
Italy planned a public-private vaccine production facility. Canada built a publicly-owned production facility, which at 24 million doses per year is not expected to be cost-competitive with larger commercial facilities.
== Epidemic response ==
In the past, the market power of pharmaceutical companies has delayed responses to epidemics. Manufacturers have successfully negotiated favourable terms, including market guarantees and indemnification, from governments, as a condition of manufacturing vaccines. This has delayed responses to some epidemics by months, and prevented responses to other pandemics entirely. Some intellectual property issues also hinder vaccine development for epidemic preparedness, as in the case of rVSV-ZEBOV.
== Market incentives ==
There is also no business incentive for pharmaceutical companies to test vaccines that are only of use to poor people. Vaccines developed for rich countries may also have short expiry dates, and requirements that they be refrigerated until they are injected and given in multiple shots, all of which may be very difficult in remote areas. In some cases, it has simply never been tested whether the vaccine will still be effective if the requirements are not followed (say, if it retains potency for several days unrefrigerated).
In almost all cases, pharmaceuticals including vaccines are developed with public funding, but profits and control of price and availability are legally accorded to private companies. The profits of large pharmaceutical companies are mostly used on dividends and share buybacks, which inflate executive pay, and on lobbying and advertising. Innovation is generally bought along with the small companies that developed it, rather than produced in-house; low percentage R&D spending is sometimes touted as an attraction to investors. The financialization focus of the pharmaceutical industry, especially in the US, has been cited as an obstacle to innovation.
There have been ethical issues raised with accepting donations of generally unaffordable vaccines.
== Demand ==
While the vaccine market makes up only 2-3% of the pharmaceutical market worldwide, it is growing at 10-15% per year, much faster than other pharmaceuticals (as of 2010).
Vaccine demand is increasing with new target population in emerging markets (partly due to international vaccine funders; in 2012, UNICEF bought half of the world's vaccine doses). Vaccines are becoming the financial driver of the pharmaceutical industry, and new business models may be emerging. Vaccines are newly being marketed like pharmaceuticals.
Vaccines offer new opportunities for funding from public-private partnerships (such as CEPI and GAVI), governments, and philanthropic donors and foundations (such as GAVI and CEPI's donors). Pharmaceutical companies have representation on the boards of public-private global health funding bodies including GAVI and CEPI. Private donors often find it easier to exert influence through public-private partnerships like GAVI than through the traditional public sector and multilateral government institutions like the WHO; PPPs also appeal to public donors. Philanthropic funding means that vaccines are now rolled out to large developing markets less than 10 or 20 years after they are developed, during the patent validity term of the patent owner. Newer vaccines are much more expensive than older ones. Lower-income countries are increasingly a profitable vaccine market.
== Public domain ==
Baker (2016) observed that the vast majority of the cost of most diagnostic, preventive and treatment procedures are patent royalties: The unit costs are almost universally a tiny fraction of the price to the consumer. Moreover, in the US "the government spends more than $30 billion a year on biomedical research through the National Institutes of Health". And researchers (individuals and organizations) routinely obtain patents on products whose development was paid for by taxpayers, per the Bayh–Dole Act of 1980. Baker claims that the US population would have better health care at lower cost if the results of that research were all placed in the public domain.
Moreover, the cost of those diagnostic, preventive and treatment procedures would be lower the world over if the results of publicly-funded research were in the public domain. This would likely lead to better control of infectious diseases worldwide. That, in turn, would likely reduced the disease load in the US.
== References == | Wikipedia/Economics_of_vaccines |
A genetic vaccine (also gene-based vaccine) is a vaccine that contains nucleic acids such as DNA or RNA that lead to protein biosynthesis of antigens within a cell. Genetic vaccines thus include DNA vaccines, RNA vaccines and viral vector vaccines.
== Properties ==
Most vaccines other than live attenuated vaccines and genetic vaccines are not taken up by MHC-I-presenting cells, but act outside of these cells, producing only a strong humoral immune response via antibodies. In the case of intracellular pathogens, an exclusive humoral immune response is ineffective. Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a protein is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the pathogen or a surface protein that enables the formation of neutralizing antibodies that inhibit the infection of cells. Subsequently, the protein is broken down at the proteasome into short fragments (peptides) that are imported into the endoplasmic reticulum via the transporter associated with antigen processing, allowing them to bind to MHCI-molecules that are subsequently secreted to the cell surface. The presentation of the peptides on MHC-I complexes on the cell surface is necessary for a cellular immune response. As a result, genetic vaccines and live vaccines generate cytotoxic T-cells in addition to antibodies in the vaccinated individual. In contrast to live vaccines, only parts of the pathogen are used, which means that a reversion to an infectious pathogen cannot occur as it happened during the polio vaccinations with the Sabin vaccine.
== Administration ==
Genetic vaccines are most commonly administered by injection (intramuscular or subcutaneous) or infusion, and less commonly and for DNA, by gene gun or electroporation. While viral vectors have their own mechanisms to be taken up into cells, DNA and RNA must be introduced into cells via a method of transfection. In humans, the cationic lipids SM-102, ALC-0159 and ALC-0315 are used in conjunction with electrically neutral helper lipids. This allows the nucleic acid to be taken up by endocytosis and then released into the cytosol.
== Applications ==
Examples of genetic vaccines approved for use in humans include the RNA vaccines tozinameran and mRNA-1273, the DNA vaccine ZyCoV-D as well as the viral vectors AZD1222, Ad26.COV2.S, Ad5-nCoV, and Sputnik V. In addition, genetic vaccines are being investigated against proteins of various infectious agents, protein-based toxins, as cancer vaccines, and as tolerogenic vaccines for hyposensitization of type I allergies.
== History ==
The first use of a viral vector for vaccination – a Modified Vaccinia Ankara Virus expressing HBsAg – was published by Bernard Moss and colleagues. DNA was used as a vaccine by Jeffrey Ulmer and colleagues in 1993. The first use of RNA for vaccination purposes was described in 1993 by Frédéric Martinon, Pierre Meulien and colleagues and in 1994 by X. Zhou, Peter Liljeström, and colleagues in mice. Martinon demonstrated that a cellular immune response was induced by vaccination with an RNA vaccine. In 1995, Robert Conry and colleagues described that a humoral immune response was also elicited after vaccination with an RNA vaccine. While DNA vaccines were more frequently researched in the early years due to their ease of production, low cost, and high stability to degrading enzymes, but sometimes produced low vaccine responses despite containing immunostimulatory CpG sites, more research was later conducted on RNA vaccines, whose immunogenicity was often better due to inherent adjuvants and which, unlike DNA vaccines, cannot insert into the genome of the vaccinated. Accordingly, the first RNA- and DNA-based vaccines approved for humans were RNA and DNA vaccines used as COVID vaccines. Viral vectors had previously been approved as ebola vaccines.
== References == | Wikipedia/Genetic_vaccine |
A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA) that can be transcribed by the recipient's host cells as mRNA coding for a desired protein, or antigen, to elicit an immune response. As of April 2021, six viral vector vaccines, four COVID-19 vaccines and two Ebola vaccines, have been authorized for use in humans.
== Understanding viral vectors ==
=== History ===
The first viral vector was introduced in 1972 through genetic engineering of the SV40 virus. A recombinant viral vector was first used when a hepatitis B surface antigen gene was inserted into a vaccinia virus. Subsequently, other viruses including adenovirus, adeno-associated virus, retrovirus, cytomegalovirus, sendai virus, and lentiviruses have been designed into vaccine vectors. Vaccinia virus and adenovirus are the most commonly used viral vectors because of robust immune response it induces.
The incorporation of several viruses in vaccination schemes has been investigated since the vaccinia virus was created in 1984 as a vaccine vector. Human clinical trials were conducted for viral vector vaccines against several infectious diseases including Zika virus, influenza viruses, respiratory syncytial virus, HIV, and malaria, before the vaccines that target SARS-CoV-2, which causes COVID-19.
Two Ebola vaccines that used viral vector technology were used to combat Ebola outbreaks in West Africa (2013–2016), and in the Democratic Republic of the Congo (2018–2020). The rVSV-ZEBOV vaccine was approved for medical use in the European Union in November 2019, and in December 2019 for the United States. Zabdeno/Mvabea was approved for medical use in the European Union in July 2020.
=== Technology ===
Viral vector vaccines enable antigen expression within cells and induce a robust cytotoxic T cell response, unlike subunit vaccines which only confer humoral immunity. In order to transfer a nucleic acid coding for a specific protein to a cell, the vaccines employ a variant of a virus as its vector. This process helps to create immunity against the disease, which helps to protect people from contracting the infection. Viral vector vaccines do not cause infection with either the virus used as the vector or the source of the antigen. The genetic material it delivers does not integrate into a person's genome.
The majority of viral vectors lack the required genes, making them unable to replicate. In order to be widely accepted and approved for medical use, the development of viral vector vaccines requires a high biological safety level. Consequently, non or low-pathogenic viruses are often selected.
=== Advantages ===
Viral vector vaccines have benefits over other forms of vaccinations depending on the virus which they produced thanks to their qualities of immunogenicity, immunogenic stability, and safety. Specific immunogenicity properties include highly efficient gene transduction, highly specific delivery of genes to target cells, and the ability to induce potent immune responses. The immunogenicity is further enhanced through intrinsic vector motifs that stimulate the innate immunity pathways, so the use of an adjuvant is unnecessary. Replicating vectors imitate natural infection, which stimulates the release of cytokines and co-stimulatory molecules that produce a strong adjuvant effect. The induction of innate immunity pathways is crucial to stimulating downstream pathways and adaptive immunity responses.
Additionally, viral vectors can be produced in high quantities at relatively low costs, which enables use in low-income countries.
== Viral vectors ==
=== Adenovirus ===
Adenovirus vectors have the advantage of high transduction efficiency, transgene expression, and broad viral tropism, and can infect both dividing and non-dividing cells. A disadvantage is that many people have preexisting immunity to adenoviruses from previous exposure. The seroprevalence against Ad5 in the US population is as high as 40%–45%. Most Adenovirus vectors are replication-defective because of the deletion of the E1A and E1B viral gene region. Currently, overcoming the effects of adenovirus-specific neutralizing antibodies is being explored by vaccinologists. These studies include numerous strategies such as designing alternative Adenovirus serotypes, diversifying routes of immunization, and using prime-boost procedures. Human adenovirus serotype 5 is often used because it can be easily produced in high titers.
As of April 2021, four adenovirus vector vaccines for COVID-19 have been authorized in at least one country:
The Oxford–AstraZeneca vaccine uses the modified chimpanzee adenovirus ChAdOx1.
Sputnik V uses human adenovirus serotype 26 for the first shot, and serotype 5 for the second.
The Janssen vaccine uses serotype 26.
Convidecia uses serotype 5.
Zabdeno, the first dose of the Zabdeno/Mvabea Ebola vaccine, is derived from human adenovirus serotype 26, expressing the glycoprotein of the Ebola virus Mayinga variant. Both doses are non-replicating vectors and carry the genetic code of several Ebola virus proteins.
==== Safety ====
With the increasing prevalence of adenoviral vaccines, two vaccines, Ad26.COV2.S and ChadOx1-nCoV-19, have been linked to the rare clotting disorder, thrombosis with thrombocytopenia syndrome (TTS).
=== Vaccinia virus ===
The vaccinia virus is part of the poxvirus family. It is a large, complex, and enveloped virus that was previously used for the smallpox vaccine. The vaccinia virus's large size allows for a high potential for foreign gene insertion. Several vaccinia virus strains have been developed including replication-competent and replication-deficient strains.
==== Modified vaccinia Ankara ====
Modified vaccinia ankara (MVA) is a replication-deficient strain that has been safely used for a smallpox vaccine. The Ebola vaccine regimen approved by the European Commission was developed by Janssen Pharmaceutials and Bavarian Nordic, and utilizes MVA technology in its second vaccine dose of Mvabea (MVA-BN-Filo).
=== Vesicular stomatitis virus ===
Vesicular stomatitis virus (VSV) was introduced as a vaccine vector in the late 1990s. In most VSV vaccine vectors, attenuation provides safety against its virulence. VSV is an RNA virus and is part of the Rhabdoviridae family. The VSV genome encodes for nucleocapsid, phosphoprotein, matrix, glycoprotein, and an RNA-dependent RNA polymerase proteins.
The rVSV-ZEBOV vaccine, known as Ervebo, was approved as a prophylactic Ebola vaccine for medical use by the FDA in 2019. The vaccine is a recombinant, replication-competent vaccine consisting of genetically engineered vesicular stomatitis virus. The gene for the natural VSV envelope glycoprotein is replaced with that from the Kikwit 1995 Zaire strain Ebola virus.
== Routes of administration ==
Intramuscular injection is the commonly used route for vaccine administration. The introduction of alternate routes for immunization of viral vector vaccines can induce mucosal immunology at the site of administration, thereby limiting respiratory or gastrointestinal infections. Also, studies are being done on how these diverse routes can be used to overcome the effects of specific neutralizing antibodies limiting the use of these vaccines. These routes include intranasal, oral, intradermal, and aerosol vaccination.
== References ==
== Further reading == | Wikipedia/Viral_vector_vaccine |
Chickens (Gallus gallus domesticus) and their eggs have been used extensively as research models throughout the history of biology. Today they continue to serve as an important model for normal human biology as well as pathological disease processes.
== History ==
=== Chicken embryos as a research model ===
Human fascination with the chicken and its egg are so deeply rooted in history that it is hard to say exactly when avian exploration began. As early as 1400 BCE, ancient Egyptians artificially incubated chicken eggs to propagate their food supply. The developing chicken in the egg first appears in written history after catching the attention of the famous Greek philosopher, Aristotle, around 350 BCE. As Aristotle opened chicken eggs at various time points of incubation, he noted how the organism changed over time. Through his writing of Historia Animalium, he introduced some of the earliest studies of embryology based on his observations of the chicken in the egg.
Aristotle recognized significant similarities between human and chicken development. From his studies of the developing chick, he was able to correctly decipher the role of the placenta and umbilical cord in the human.
Chick research of the 16th century significantly modernized ideas about human physiology. European scientists, including Ulisse Aldrovandi, Volcher Cotier and William Harvey, used the chick to demonstrate tissue differentiation, disproving the widely held belief of the time that organisms are "preformed" in their adult version and only grow larger during development. Distinct tissue areas were recognized that grew and gave rise to specific structures, including the blastoderm, or chick origin. Harvey also closely watched the development of the heart and blood and was the first to note the directional flow of blood between veins and arteries. The relatively large size of the chick as a model organism allowed scientists during this time to make these significant observations without the help of a microscope.
Expanding use of the microscope coupled with a new technique in the late 18th century unveiled the developing chick for close-up examination. By cutting a hole in the eggshell and covering it with another piece of shell, scientists were able to look directly into the egg while it continued to develop without dehydration. Soon studies of the developing chick identified the three embryonic germ layers: ectoderm, mesoderm and endoderm, giving rise to the field of embryology.
Host versus graft response was first described in the chicken embryo. James Murphy (biologist) (1914) found that rat tissues that could not grow in adult chickens survived in the developing chick. In an immunocompetent animal, like the mature chicken, the host immune cells attack the foreign tissue. Since the immune system of the chick is not functional until about day 14 of incubation, foreign tissue can grow. Eventually, Murphy showed that the acceptance of tissue grafts was host-specific in immunologically competent animals.
Culturing virus was once technically difficult. In 1931, Ernest Goodpasture and Alice Miles Woodruff developed a new technique that used chicken eggs to propagate a pox virus. Building on their success, the chick was used to isolate the mumps virus for vaccine development and it is still used to culture some viruses and parasites today.
The ability of chicken embryonic nerves to infiltrate a mouse tumor suggested to Rita Levi-Montalcini that the tumor must produce a diffusible growth factor (1952). She identified Nerve Growth Factor (NGF) leading to the discovery of a large family of growth factors which are key regulators during normal development and disease processes including cancer.
=== Adult chicken as a research model ===
The adult chicken has also made significant contributions to the advancement of science. By inoculating chickens with cholera bacteria (Pasteurella multocida) from an overgrown, and thereby attenuated, culture Louis Pasteur produced the first lab-derived attenuated vaccine (1860s). Great advances in immunology and oncology continued to characterize the 20th century, for which we indebted to the chicken model.
Peyton Rous (1879-1970) won the Nobel prize for discovering that viral infection of chicken could induce sarcoma (Rous, 1911). Steve Martin followed up on this work and identified a component of a chicken retrovirus, Src, which became the first known oncogene. J. Michael Bishop and Harold Varmus with their colleagues (1976) extended these findings to humans, showing that cancer causing oncogenes in mammals are induced by mutations to proto-oncogenes.
Discoveries in the chicken ultimately divided the adaptive immune response into antibody (B-cell) and cell-mediated (T-cell) responses. Chickens missing their bursa, an organ with an unknown function at the time, could not be induced to make antibodies. Through these experiments, Bruce Glick, correctly deduced that bursa was responsible for making the cells that produced antibodies. Bursa cells were termed B-cells for Bursa to differentiate them from thymus derived T-cells.
=== Cancer ===
The chicken embryo is a unique model that overcomes many limitations to studying the biology of cancer in vivo. The chorioallantoic membrane (CAM), a well-vascularized extra-embryonic tissue located underneath the eggshell, has a successful history as a biological platform for the molecular analysis of cancer including viral oncogenesis, carcinogenesis, tumor xenografting, tumor angiogenesis, and cancer metastasis. Since the chicken embryo is naturally immunodeficient, the CAM readily supports the engraftment of both normal and tumor tissues. The avian CAM successfully supports most cancer cell characteristics including growth, invasion, angiogenesis, and remodeling of the microenvironment. The chicken egg model can be also used to evaluate various adverse effects (e.g., genotoxicity, histopathologic changes) produced by environmental chemicals, including carcinogens.
=== Genetics ===
The Gallus gallus genome was sequenced by Sanger shotgun sequencing and mapped with extensive BAC contig-based physical mapping. There are significant, fundamental similarities between the human and chicken genomes. However, differences between human and chicken genomes help to identify functional elements: the genes and their regulatory elements, which are most likely to be conserved through time. Publication of the chicken genome enables expansion of transgenic techniques for advancing research within the chick model system.
== References == | Wikipedia/Chicken_as_biological_research_model |
An approved drug is a medicinal preparation that has been validated for a therapeutic use by a ruling authority of a government. This process is usually specific by country, unless specified otherwise.
== Process by country ==
=== United States ===
In the United States, the FDA approves drugs. Before a drug can be prescribed, it must undergo the FDA's approval process. While a drug can feasibly be used off-label (for non-approved indications), it still is required to be approved for a specific disease or medical condition. Drug companies seeking to sell a drug in the United States must first test it. The company then sends the Food and Drug Administration's Center for Drug Evaluation and Research (CDER) evidence from these tests to prove the drug is safe and effective for its intended use. A fee is required to make such FDA submission. For financial year 2020, this fee was: for an application requiring clinical data ($2,942,965) and for an application not requiring clinical data ($1,471,483). A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the company's data and proposed labeling. If this independent and unbiased review establishes that a drug's health benefits outweigh its known risks, the drug is approved for sale. The center doesn't actually test drugs itself, although it does conduct limited research in the areas of drug quality, safety, and effectiveness standards.
As of the end of 2013, the FDA and its predecessors had approved 1,452 drugs, though not all are still available, and some have been withdrawn for safety reasons. Accounting for subsequent corporate acquisitions, these approvals were earned by approximately 100 different organizations.
=== European Union ===
In the European Union, it is the European Medicines Agency (EMA) that evaluates medicinal products.
=== Japan ===
In Japan, the agency regulating medicinal products is Pharmaceuticals and Medical Devices Agency (PMDA).
== Approval ==
On average, only one in every 5,000 compounds that makes it through lead development to the stage of preclinical development becomes an approved drug. Only 10% of all drugs started in human clinical trials become an approved drug.
== See also ==
Drug discovery
Drug design
Drug development
Abbreviated New Drug Application
Patent medicine
== References ==
== External links ==
ClinicalTrials.gov from US National Library of Medicine
ICH Website
FDA Website
Simple Steps for Using Medications Safely by FDA | Wikipedia/Drug_approval |
Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given intravenously or by injection into a muscle. Eye drops are also available which are used to treat uveitis and early amblyopia. The intravenous solution usually begins working within a minute and lasts half an hour to an hour. Large doses may be required to treat some poisonings.
Common side effects include dry mouth, abnormally large pupils, urinary retention, constipation, and a fast heart rate. It should generally not be used in people with closed-angle glaucoma. While there is no evidence that its use during pregnancy causes birth defects, this has not been well studied so sound clinical judgment should be used. It is likely safe during breastfeeding. It is an antimuscarinic (a type of anticholinergic) that works by inhibiting the parasympathetic nervous system.
Atropine occurs naturally in a number of plants of the nightshade family, including deadly nightshade (Atropa belladonna), jimsonweed (Datura stramonium), mandrake (Mandragora officinarum) and angel's trumpet (Brugmansia). Atropine was first isolated in 1833. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.
== Medical uses ==
=== Eyes ===
Topical atropine is used as a cycloplegic, to temporarily paralyze the accommodation reflex, and as a mydriatic, to dilate the pupils. Atropine degrades slowly, typically wearing off in 7 to 14 days, so it is generally used as a therapeutic mydriatic, whereas tropicamide (a shorter-acting cholinergic antagonist) or phenylephrine (an α-adrenergic agonist) is preferred as an aid to ophthalmic examination.
In refractive and accommodative amblyopia, when occlusion is not appropriate sometimes atropine is given to induce blur in the good eye. Evidence suggests that atropine penalization is just as effective as occlusion in improving visual acuity.
Antimuscarinic topical medication is effective in slowing myopia progression in children; accommodation difficulties and papillae and follicles are possible side effects. All doses of atropine appear similarly effective, while higher doses have greater side effects. The lower dose of 0.01% is thus generally recommended due to fewer side effects and potential less rebound worsening when the atropine is stopped.
=== Heart ===
Injections of atropine are used in the treatment of symptomatic or unstable bradycardia.
Atropine was previously included in international resuscitation guidelines for use in cardiac arrest associated with asystole and PEA but was removed from these guidelines in 2010 due to a lack of evidence for its effectiveness. For symptomatic bradycardia, the usual dosage is 0.5 to 1 mg IV push; this may be repeated every 3 to 5 minutes, up to a total dose of 3 mg (maximum 0.04 mg/kg).
Atropine is also useful in treating second-degree heart block Mobitz type 1 (Wenckebach block), and also third-degree heart block with a high Purkinje or AV-nodal escape rhythm. It is usually not effective in second-degree heart block Mobitz type 2, and in third-degree heart block with a low Purkinje or ventricular escape rhythm.
Atropine has also been used to prevent a low heart rate during intubation of children; however, the evidence does not support this use.
=== Secretions ===
Atropine's actions on the parasympathetic nervous system inhibit salivary and mucous glands. The drug may also inhibit sweating via the sympathetic nervous system. This can be useful in treating hyperhidrosis, and can prevent the death rattle of dying patients. Even though atropine has not been officially indicated for either of these purposes by the FDA, it has been used by physicians for these purposes.
=== Poisonings ===
Atropine acts as an antagonist for organophosphate poisoning by blocking the action of acetylcholine at muscarinic receptors caused by organophosphate insecticides and nerve agents, such as tabun (GA), sarin (GB), soman (GD), and VX. Troops who are likely to be attacked with chemical weapons often carry autoinjectors with atropine and oxime, for rapid injection into the muscles of the thigh. In a developed case of nerve gas poisoning, maximum atropinization is desirable. Atropine is often used in conjunction with the oxime pralidoxime chloride.
Some of the nerve agents attack and destroy acetylcholinesterase by phosphorylation, so the action of acetylcholine becomes excessive and prolonged. Pralidoxime (2-PAM) can be effective against organophosphate poisoning because it can re-cleave this phosphorylation. Atropine can be used to reduce the effect of the poisoning by blocking muscarinic acetylcholine receptors, which would otherwise be overstimulated, by excessive acetylcholine accumulation.
Atropine or diphenhydramine can be used to treat muscarine intoxication.
Atropine was added to cafeteria salt shakers in an attempt to poison the staff of Radio Free Europe during the Cold War.
=== Irinotecan-induced diarrhea ===
Atropine has been observed to prevent or treat irinotecan induced acute diarrhea.
== Side effects ==
Adverse reactions to atropine include ventricular fibrillation, supraventricular or ventricular tachycardia, dizziness, nausea, blurred vision, loss of balance, dilated pupils, photophobia, dry mouth and potentially extreme confusion, deliriant hallucinations, and excitation especially among the elderly. These latter effects are because atropine can cross the blood–brain barrier. Because of the hallucinogenic properties, some have used the drug recreationally, though this is potentially dangerous and often unpleasant.
In overdoses, atropine is poisonous. Atropine is sometimes added to potentially addictive drugs, particularly antidiarrhea opioid drugs such as diphenoxylate or difenoxin, wherein the secretion-reducing effects of the atropine can also aid the antidiarrhea effects.
Although atropine treats bradycardia (slow heart rate) in emergency settings, it can cause paradoxical heart rate slowing when given at very low doses (less than 0.5 mg), presumably as a result of central action in the CNS. One proposed mechanism for atropine's paradoxical bradycardia effect at low doses involves blockade of inhibitory presynaptic muscarinic autoreceptors, thereby blocking a system that inhibits the parasympathetic response.
Atropine is incapacitating at doses of 10 to 20 mg per person. Its LD50 is estimated to be 453 mg per person (by mouth) with a probit slope of 1.8.
The antidote to atropine is physostigmine or pilocarpine.
A common mnemonic used to describe the physiologic manifestations of atropine overdose is: "hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter". These associations reflect the specific changes of warm, dry skin from decreased sweating, blurry vision, decreased lacrimation, vasodilation, and central nervous system effects on muscarinic receptors, type 4 and 5. This set of symptoms is known as anticholinergic toxidrome, and may also be caused by other drugs with anticholinergic effects, such as hyoscine hydrobromide (scopolamine), diphenhydramine, phenothiazine antipsychotics and benztropine.
== Contraindications ==
It is generally contraindicated in people with glaucoma, pyloric stenosis, or prostatic hypertrophy, except in doses ordinarily used for preanesthesia.
== Chemistry ==
Atropine, a tropane alkaloid, is an enantiomeric mixture of d-hyoscyamine and l-hyoscyamine, with most of its physiological effects due to l-hyoscyamine, the 3(S)-endo isomer of atropine. Its pharmacological effects are due to binding to muscarinic acetylcholine receptors. It is an antimuscarinic agent. Significant levels are achieved in the CNS within 30 minutes to 1 hour and disappear rapidly from the blood with a half-life of 2 hours. About 60% is excreted unchanged in the urine, and most of the rest appears in the urine as hydrolysis and conjugation products. Noratropine (24%), atropine-N-oxide (15%), tropine (2%), and tropic acid (3%) appear to be the major metabolites, while 50% of the administered dose is excreted as apparently unchanged atropine. No conjugates were detectable. Evidence that atropine is present as (+)-hyoscyamine was found, suggesting that stereoselective metabolism of atropine probably occurs. Effects on the iris and ciliary muscle may persist for longer than 72 hours.
The most common atropine compound used in medicine is atropine sulfate (monohydrate) (C17H23NO3)2·H2SO4·H2O, the full chemical name is 1αH,5αH-tropan-3-α-ol (±)-tropate(ester), sulfate monohydrate.
== Pharmacology ==
In general, atropine counters the "rest and digest" activity of glands regulated by the parasympathetic nervous system, producing clinical effects such as increased heart rate and delayed gastric emptying. This occurs because atropine is a competitive, reversible antagonist of the muscarinic acetylcholine receptors (acetylcholine being the main neurotransmitter used by the parasympathetic nervous system).
Atropine is a competitive antagonist of the muscarinic acetylcholine receptor types M1, M2, M3, M4 and M5. It is classified as an anticholinergic drug (parasympatholytic).
In cardiac uses, it works as a nonselective muscarinic acetylcholinergic antagonist, increasing firing of the sinoatrial node (SA) and conduction through the atrioventricular node (AV) of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchial secretions.
In the eye, atropine induces mydriasis by blocking the contraction of the circular pupillary sphincter muscle, which is normally stimulated by acetylcholine release, thereby allowing the radial iris dilator muscle to contract and dilate the pupil. Atropine induces cycloplegia by paralyzing the ciliary muscles, whose action inhibits accommodation to allow accurate refraction in children, helps to relieve pain associated with iridocyclitis, and treats ciliary block (malignant) glaucoma.
The vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their primary neurotransmitter. ACh binds to muscarinic receptors (M2) that are found principally on cells comprising the sinoatrial (SA) and atrioventricular (AV) nodes. Muscarinic receptors are coupled to the Gi subunit; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation of KACh channels that increase potassium efflux and hyperpolarizes the cells.
Increases in vagal activities to the SA node decrease the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential (phase 4 of the action potential); this decreases heart rate (negative chronotropy). The change in phase 4 slope results from alterations in potassium and calcium currents, as well as the slow-inward sodium current that is thought to be responsible for the pacemaker current (If). By hyperpolarizing the cells, vagal activation increases the cell's threshold for firing, which contributes to the reduction in the firing rate. Similar electrophysiological effects also occur at the AV node; however, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node (negative dromotropy). In the resting state, there is a large degree of vagal tone in the heart, which is responsible for low resting heart rates.
There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular muscle. Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy) and even smaller decreases in ventricular contractility.
Muscarinic receptor antagonists bind to muscarinic receptors thereby preventing ACh from binding to and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very effectively block the effects of vagal nerve activity on the heart. By doing so, they increase heart rate and conduction velocity.
== History ==
The name atropine was coined in the 19th century, when pure extracts from the belladonna plant Atropa belladonna were first made. The medicinal use of preparations from plants in the nightshade family is much older however. Mandragora (mandrake) was described by Theophrastus in the fourth century BC for the treatment of wounds, gout, and sleeplessness, and as a love potion. By the first century AD Dioscorides recognized wine of mandrake as an anaesthetic for treatment of pain or sleeplessness, to be given before surgery or cautery. The use of nightshade preparations for anesthesia, often in combination with opium, persisted throughout the Roman and Islamic Empires and continued in Europe until superseded in the 19th century by modern anesthetics.
Atropine-rich extracts from the Egyptian henbane plant (another nightshade) were used by Cleopatra in the last century B.C. to dilate the pupils of her eyes, in the hope that she would appear more alluring. Likewise, it is widely claimed that in the Renaissance, women used the juice of the berries of the nightshade Atropa belladonna to enlarge their pupils for cosmetic reasons. However, primary records of this practice are not known, and the claim may have originated much later by conflating records of actual cosmetic use (for complexion) with the mydriastic properties of atropine. A source from the late 19th century claims that the practice was also current in Paris.
The pharmacological study of belladonna extracts was begun by the German chemist Friedlieb Ferdinand Runge (1795–1867). In 1831, the German pharmacist Heinrich F. G. Mein (1799-1864) succeeded in preparing a pure crystalline form of the active substance, which was named atropine. The substance was first synthesized by German chemist Richard Willstätter in 1901.
== Natural sources ==
Atropine is found in many members of the family Solanaceae. The most commonly found sources are Atropa belladonna (the deadly nightshade), Datura innoxia, D. wrightii, D. metel, and D. stramonium. Other sources include members of the genera Brugmansia (angel's trumpets) and Hyoscyamus.
== Synthesis ==
Atropine can be synthesized by the reaction of tropine with tropic acid in the presence of hydrochloric acid.
=== Biosynthesis ===
The biosynthesis of atropine starting from l-phenylalanine first undergoes a transamination forming phenylpyruvic acid which is then reduced to phenyl-lactic acid. Coenzyme A then couples phenyl-lactic acid with tropine forming littorine, which then undergoes a radical rearrangement initiated with a P450 enzyme forming hyoscyamine aldehyde. A dehydrogenase then reduces the aldehyde to a primary alcohol making (−)-hyoscyamine, which upon racemization forms atropine.
== Society and culture ==
The species name "belladonna" ('beautiful woman' in Italian) comes from the original use of deadly nightshade to dilate the pupils of the eyes for cosmetic effect. Both atropine and the genus name for deadly nightshade derive from Atropos, one of the three Fates who, according to Greek mythology, chose how a person was to die.
=== Legal status ===
In March 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ryjunea, intended for slowing the progression of myopia in children aged 3 to 14 years. The applicant for this medicinal product is Santen Oy.
== References ==
== External links ==
Media related to Atropine at Wikimedia Commons | Wikipedia/Atropine_methonitrate |
Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart rate, force of cardiac contraction, and blood pressure. The primary endogenous agonists of the sympathetic nervous system are the catecholamines (i.e., epinephrine [adrenaline], norepinephrine [noradrenaline], and dopamine), which function as both neurotransmitters and hormones. Sympathomimetic drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.
These drugs can act through several mechanisms, such as directly activating postsynaptic receptors, blocking breakdown and reuptake of certain neurotransmitters, or stimulating production and release of catecholamines.
== Mechanisms of action ==
The mechanisms of sympathomimetic drugs can be direct-acting (direct interaction between drug and receptor), such as α-adrenergic agonists, β-adrenergic agonists, and dopaminergic agonists; or indirect-acting (interaction not between drug and receptor), such as MAOIs, COMT inhibitors, release stimulants, and reuptake inhibitors that increase the levels of endogenous catecholamines.
== Structure-activity relationship ==
A primary or secondary aliphatic amine separated by 2 carbons from a substituted benzene ring is minimally required for high agonist activity. The pKa of the amine is approximately 8.5-10. The presence of hydroxy group in the benzene ring at 3rd and 4th position shows maximum alpha- and beta-adrenergic activity.
For maximum sympathomimetic activity, a drug must have:
Amine group two carbons away from an aromatic group
A hydroxyl group at the chiral beta position in the R-configuration
Hydroxyl groups in the meta and para position of the aromatic ring to form a catechol which is essential for receptor binding
The structure can be modified to alter binding. If the amine is primary or secondary, it will have direct action, but if the amine is tertiary, it will have poor direct action. Also, if the amine has bulky substituents, then it will have greater beta adrenergic receptor activity, but if the substituent is not bulky, then it will favor the alpha adrenergic receptors.
=== Direct-acting ===
==== Adrenergic receptor agonists ====
Direct stimulation of the α- and β-adrenergic receptors can produce sympathomimetic effects. Salbutamol is a widely used direct-acting β2-agonist. Other examples include phenylephrine, isoproterenol, and dobutamine.
==== Dopaminergic agonists ====
Stimulation of the D1 receptor by dopaminergic agonists such as fenoldopam is used intravenously to treat hypertensive crisis.
=== Indirect-acting ===
Dopaminergic stimulants such as amphetamine, ephedrine, and propylhexedrine work by causing the release of dopamine and norepinephrine, along with (in some cases) blocking the reuptake of these neurotransmitters.
== Abuse potential ==
Illegal drugs such as cocaine and MDMA also affect dopamine, serotonin, and norepinephrine.
Norepinephrine is synthesized by the body from the amino acid tyrosine, and is used in the synthesis of epinephrine, which is a stimulating neurotransmitter of the central nervous system. All sympathomimetic amines fall into the larger group of stimulants (see psychoactive drug chart). In addition to intended therapeutic use, many of these stimulants have abuse potential, can induce tolerance, and possibly physical dependence, although not by the same mechanism(s) as opioids or sedatives. The symptoms of physical withdrawal from stimulants can include fatigue, dysphoric mood, increased appetite, vivid or lucid dreams, hypersomnia or insomnia, increased movement or decreased movement, anxiety, and drug craving, as is apparent in the rebound withdrawal from certain substituted amphetamines.
Sympathomimetic drugs are sometimes involved in development of cerebral vasculitis and generalized polyarteritis nodosa like diseases involving immune-complex deposition. Known reports of such hypersensitivity reactions include the use of pseudoephedrine, phenylpropanolamine, methamphetamine and other drugs at prescribed doses as well as at over-doses.
== Comparison ==
"Parasympatholytic" and "sympathomimetic" have similar effects, but through completely different pathways. For example, both cause mydriasis, but parasympatholytics reduce accommodation (cycloplegia) while sympathomimetics do not.
== Examples ==
amphetamine (Evekeo)
benzphetamine (Didrex)
benzylpiperazine (BZP)
cathine (found in Catha edulis)
cathinone (found in Catha edulis, khat)
cocaine (found in Erythroxylum coca, coca)
ephedrine (found in Ephedra)
lisdexamfetamine (Vyvanse)
maprotiline (Ludiomil)
MDMA (Ecstasy, Molly)
methamphetamine (Meth, Crank, Desoxyn)
methcathinone
methylenedioxypyrovalerone (MDPV)
methylphenidate (Ritalin)
4-methylaminorex
oxymetazoline (Afrin, Vicks Sinex)
pemoline (Cylert)
phenmetrazine (Preludin)
propylhexedrine (Benzedrex)
pseudoephedrine (Sudafed, SudoGest, also found in Ephedra species)
== See also ==
Adrenergic storm
Sympathetic nervous system
Sympatholytic
== References ==
== External links ==
Amines,+Sympathomimetic at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Sympathomimetic_drug |
Riot control is a form of public order policing used by law enforcement, military, paramilitary or security forces to control, disperse, and arrest people who are involved in a riot, unlawful demonstration or unlawful protest.
If a riot is spontaneous, then actions which cause people to stop and think (e.g. loud noises or issuing instructions in a calm tone) can be enough to stop it. However, these methods usually fail when there is severe anger, or the riot was planned or organized. Riot control personnel have long used less lethal weapons such as batons and whips to disperse crowds and detain rioters. Since the 1980s, riot control officers have also used tear gas, pepper spray, rubber bullets, stun grenades, and electric tasers. In some cases, riot squads may also use Long Range Acoustic Devices, water cannons, armoured fighting vehicles, aerial surveillance, police dogs or mounted police on horses. Persons performing riot control typically wear protective equipment such as riot helmets, face visors, body armor (vests, neck protectors, knee pads, etc.), gas masks and riot shields. Even though riot tactics are effective in controlling crowds, they can also lead to significant psychological effects on both the rioters and the police. Exposure to intense fear, stress, and violence during these confrontations can result in long-term mental health issues, like anxiety, post-traumatic stress disorder (PTSD), and heightened aggression, which can impact the well-being of protesters and police officers.
There have been cases where lethal weapons are used to violently suppress a protest or riot, as in the Tbilisi Massacre, Nika Riots in the Roman Empire, Boston Massacre, Haymarket Massacre, Banana Massacre, Hungarian Revolution of 1956, Kent State Shootings, Soweto Uprising, Sharpeville massacre, Mendiola Massacre, Bloody Sunday (1905), Ponce massacre, Río Piedras massacre, Bloody Sunday (1972), 1989 Tiananmen Square protests, 2017 Venezuelan protests, 2018–2019 Gaza border protests, 2022 Sri Lankan protests, 2022 Kazakh unrest and Mahsa Amini protests.
== History ==
Maintaining order during demonstrations and quenching riots has always been a challenge for governments and administrations. Until early in the 20th century, no dedicated force really existed in most countries and the traditional response when the regular police force proved inadequate was to call upon the army, often with disastrous results: either fraternization or use of excessive violence.
The terminology arguably first arises in the Keystone Cops short "A Hash House Fraud" in 1915.
In France, for example, several revolts were fueled by poor handling by the military. The National Gendarmerie created specialized "mobile" gendarmerie forces several times during the 19th century in times of trouble but these units were disbanded soon after the end of the troubles they had been tasked to handle and there was no permanent organization in place until it was finally decided in 1921 to create "Mobile Gendarmerie platoons" within the Departmental Gendarmerie. These platoons, either horse mounted or on foot were composed of 40 gendarmes each (60 in the Paris Region). In 1926, the platoons formed the "Garde Républicaine mobile" (mobile republican guard or GRM), which became a distinct branch of the Gendarmerie in 1927, the platoons becoming part of companies and legions. By 1940, the GRM was a force 21,000 strong, composed of 14 Légions, 54 company groups and 167 companies.
Long the only large force specialized in maintaining or restoring law and order in France during demonstrations or riots, the GRM progressively developed the doctrine and skills needed in that role: exercise restraint, avoid confrontation as long as possible, always leave an "exit door" for the crowd, etc. In 1940, after the fall of France, the German authorities had the GRM disbanded but it was reinstated in 1944 and renamed Mobile Gendarmerie in 1954.
The first squad trained in modern techniques of riot control in Asia was formed in 1925 in colonial Shanghai as a response to the mismanaged riot of the May Thirtieth Movement.
New policing methods, including combat pistol shooting, hand to hand combat skills, and knife fight training, were pioneered by British Assistant Commissioner William E. Fairbairn and officer Eric Anthony Sykes of the Shanghai Municipal Police as a response to a staggering rise in armed crime in the 1920s — Shanghai had become one of the world's most dangerous cities due to a breakdown in law and order in the country and the growth of organised crime and the opium trade.
Under Fairbairn, the SMP developed a myriad of riot control measures. These riot control techniques led to the introduction of Shanghai's "Reserve Unit", used to forcibly disband riots and respond to high-level crimes such as kidnappings and armed robberies. The skills developed in Shanghai have been adopted and adapted by both international police forces and clandestine warfare units. Fairbairn was again the central figure, not only leading the Reserve Unit, but teaching his methods around the world, including in the United States, and colonial Cyprus and the Straits Settlements.
== Modern Examples ==
=== Black Lives Matter protests ===
George Floyd was a Black man who was murdered by a Minneapolis Police Officer in May of 2020 during an arrest. Subsequently, many Americans protested for Black Lives Matter. The summer of 2020 oversaw a large number of mass protests for Black Lives Matter to address systemic bias in police departments. Due to the high volume of protests, police departments and sparsely the National Guard were sent to end the long protests. Police departments often wore riot gear and used both projectiles and irritants to disperse the protesters. These incidents were widely documented through the use of social media. Documentation and support for the protests further facilitated the movement. One study, recorded by the National Institute of Health, studied the usage of social media as well as its contributions to the movement's legitimacy. Counter-protesters as well as right wing militia committed violence against the protesters in addition to police departments. Instead of irritants or other standardized tools for riot control, these counter-protesters often used more violent techniques such as ramming into protesters with their cars. Data supports that Black Lives Matter protests in particular were faced with much more state intervention. Suppression techniques that were used by both the state and right wing counter-protesters resulted in injury and death. Both during and after the protests, there were many pieces of legislation that either were passed or were written to curb these protests. Law makers and the public questioned riot control and its violations of the First Amendment including the right to assembly and the right to free speech. 45 U.S. states had considered this legislation. Concerns were raised by both political parties on the distinction between riots and protests.
=== Peru protests ===
Between 2022 and 2023, several protests in Peru erupted who were against the Congress and President Dina Bolurate. In December of 2022, the government suspended several constitutional rights. These included the right to prevent troops from entering and staying in one's home, the freedom of movement, and the freedom of assembly. The force used against the protesters resulted in at least six hundred injuries and sixty deaths. Spain had traditionally funded the government in past years and continued to do so to provide weaponry and funding to dismantle these protests. The NGO Amnesty International called on Spain to discontinue these exports citing it as "lethal repression." The security forces came in with assault weapons and in one incident opened fire on protesters. Amnesty International interpreted that the President should be held criminally responsible for the deaths and injuries that the protesters had sustained.
== Equipment ==
For protection, officers that are trained in police anti-riot schools performing riot control will often wear protective helmets and carry riot shields. These are designed to protect the wearer from those dangers that come from direct melee and hurled objects such as bottles and bricks. The gear frequently worn by riot control officers protects the entire body with no vulnerable spots to exploit. For example, the helmets worn by riot control officers have an additional outward-extending part that protects the back of the neck from assault. To provide even greater protection, the protective equipment often provides ballistic protection. If tear gas or other riot control agents are to be used, gas masks may also be worn. While the visual of police in full riot gear may be intimidating, today's riot suits are designed to minimize injuries and prevent fatalities for both officers and citizens. This evolution of riot gear signifies a move towards less-than-lethal tactics and de-escalation approaches. Contemporary riot gear incorporated innovations such as tear gas, rubber bullets, batons, pepper spray, and tasers, which contributes to minimizing injuries and casualties for all parties involved. These advancements have revolutionized crowd control by shifting from relying on lethal force to employing more less-than-lethal methods that prioritize public safety and safeguard the well-being of law enforcement officers.
One of many additional concerns is to prevent people in the crowd from snatching officers' side arms, which may be stolen or even used against the police. In a very heavy crowd, the officer may not be able to see who is responsible for snatching a weapon, and may not even notice that it has happened. For this reason, riot police may have holsters with positive locking mechanisms or other extra means of retention, if their agencies can afford such tools. However, this can be a trade-off that increases the amount of time needed to draw the sidearm in an emergency. Alternately, riot police may not carry sidearms at all.
The initial choice of tactics determines the type of offensive equipment used. The base choice is between lethal (e.g. 12 gauge shotgun) and less-than-lethal weaponry (e.g. tear gas, pepper spray, plastic bullets, tasers, batons, and other incapacitants). The decision is based on the perceived level of threat and the existing laws; in many countries it is illegal to use lethal force to control riots in all but the most extreme circumstances.
Special riot hand weapons include the wooden or rubber baton; the African sjambok, a heavy leather or plastic whip, and the Indian lathi, a 6 to 8 foot (1.8 to 2.4 m) long cane with a blunt metal tip. Vehicle-mounted water cannons may serve to augment personal weapons. Some water cannons let police add dye to mark rioters or tear gas to help disperse the crowds.
In major unrest, police in armoured vehicles may be sent in following an initial subduing with firepower. Occasionally, police dogs, fire hoses, or mounted police are deployed.
== Riot control agent (RCA) ==
Riot control agents (sometimes called RCAs) are non-lethal lachrymatory agents used for riot control. Most commonly used riot control agents are pepper spray and various kinds of tear gas. These chemicals enable to disperse a protesting or rioting crowd, or to clear a building. They can rapidly produce sensory irritation or disabling physical effects which usually disappear within 15 minutes (for tear gas) and up to 2 hours (for pepper spray) following termination of exposure. They can also be used for chemical warfare defense training, but their use in warfare itself is a violation of Article I.5 of the Chemical Weapons Convention. Article II.9 of the CWC specifically authorizes their use for domestic law enforcement.
=== Pepper spray ===
The active ingredient in pepper-spray is capsaicin, which is a chemical derived from the fruit of plants in the Capsicum genus, including chilies. Desmethyldihydrocapsaicin, a synthetic analogue of capsaicin also known as pelargonic acid vanillylamide or PAVA, is used in another version of pepper spray known as PAVA spray and used in the United Kingdom. Another synthetic counterpart of pepper spray, pelargonic acid morpholide, was developed and is widely used in Russia. Its effectiveness compared to natural pepper spray is uncertain and it reportedly has caused some injuries. When undesirables threaten an area, such as a riot after a soccer game, riot police are called in to subdue them. In these situations, the police may use pepper spray, or water cannons to neutralize the threat.
Pepper spray typically comes in canisters, which are often small enough to be carried or concealed in a pocket or purse. Pepper spray can also be bought concealed in items such as rings. There are also pepper spray projectiles available, which can be fired from a paintball gun. Having been used for years against demonstrators, it is increasingly being used by police in routine interventions.
=== Tear gas ===
Tear gas is a non-specific term for any chemical that is used to temporarily incapacitate through irritation of eyes and/or respiratory system. It is used as a hand-held spray or can be fired in canisters that heat up spewing out an aerosol cloud at a steady rate.
While the use of tear gas in warfare is prohibited by various international treaties that most countries have signed, use by police and for private self-defense is not banned by these treaties.
Popular tear gases include the eye irritants ortho-chlorobenzylidene-malononitrile (CS gas), chloroacetophenone (CN gas), and dibenz (b,f)-1,4-oxazepine (CR gas). Among a long list of substances, these three have become of greater importance than the others because of their effectiveness and low risks when used. Today, CS has largely replaced CN as the most widely used tear gas internationally.
==== Decontamination ====
At room temperature, tear gases are white solids. They are stable when heated and have low vapor pressure. Consequently, they are usually dispersed as aerosols. All of them have low solubility in water but can be dissolved in several organic solvents. Hydrolysis of CN is very slow in a water solution, especially if alkali is added. CS is rapidly hydrolyzed in water solution (half-life at pH 7 is about 15 min. at room temperature) and extremely rapid when alkali is added (half-life at pH 9 is about 1 min.). CR is hydrolyzed only to a negligible extent in water solution.
CN and CR are, thus, difficult to decompose under practical conditions, whereas CS can easily be inactivated by means of a water solution. Skin is suitably decontaminated of CS and CN gas by thorough washing with soap and water. CS is then decomposed, whereas CN is only removed via soap and water. The effects of CR gas are greatly increased by water, causing any attempt to DECON CR via soap and water to increase the severity and duration of the effects. When decontamination of CR is attempted with soap and water the effects of CR can last up to 48 hours
Decontamination of material after contamination with CR gas is not possible for up to 45 days. CS can be decontaminated l with a 5–10 percent soda solution or 2 percent alkaline solution. If this type of decontamination cannot be accomplished (e.g., contaminated rooms and furniture), then the only other means is by intensive air exchange—preferably with hot air. Exposed streets and sidewalks will have toxic and irritating CS powder that will be stirred into the air by traffic and pedestrians long after the cloud has dissipated, and should be washed away with water. In contrast to human beings, domesticated animals generally have lower sensitivity to tear gases. Dogs and horses can therefore be used by police for riot control even when tear gas is used.
=== Dispensing large quantities ===
Backpack dispensers for riot control agents, when the intent is to use a larger quantity than possible with grenades, are one type of device used by organizations that might, for example, need to cover a prison yard. Dispensers are also made for attachment to helicopters; see CBU-19.
== Tactics ==
The front-line officers in a riot control are often fully armored and carry weapons such as batons, designed to be in direct contact with the crowd. These officers subdue rioters and subsequently allow the less heavily armoured, more mobile officers to make arrests where it is deemed necessary. In face of a greater threat, the riot police will be backed up with other officers equipped with riot guns to fire tear gas, rubber bullets, plastic bullets or "beanbag" rounds.
As a less aggressive step, mounted police may first be sent into the crowd. The might and height offered by the horse are combined with its training, allowing an officer to more safely infiltrate a crowd. Usually, when front-facing a riot, officers slowly walk in a line parallel to the riot's front, extending to both its ends, as they noisily and simultaneously march and beat their shields with their batons, to cause fear and psychological effects on the crowd.
In the United Kingdom, usually when large demonstrations take place that are deemed unstable, the territorial police force responsible for the demonstration in that area will usually deploy Police Support Unit personnel who are trained in riot tactics, along with normal divisional officers. If the demonstration turns violent, police will seal roads and other exits to contain protesters in a single area (known as kettling) to prevent widespread damage and wait until the protesters tire. These tactics were seen during the 2009 G-20 London summit protests and the 2010 student protests in London. Tear gas and other more offensive tactics are used as a last resort. Throughout police will be videoing or photographing protesters for future arrests, "snatch squad" tactics might also be used where several police officers, usually in protective riot gear, rush forwards, occasionally in flying wedge formation to break through the front of a crowd, with the objective of snatching one or more individuals from a riot that are attempting to control the demonstration at which they are present; the target may be a leader or a speaker, or someone who seems to be leading the crowd. This tactic was used in the 2011 England Riots, most notably by Greater Manchester Police who deployed this tactic in Manchester city centre on 9 August 2011.
A more straightforward tactic police may use is a baton charge which involves police officers charging at a crowd of people with batons and in some cases, riot shields. They run at the crowd hitting people with their batons, and in some situations use riot shields to push them away. Baton charging is designed to cause the maximum amount of pain, in the hope that they would be compelled to move away from the scene, dispersing the crowd.
== Consequences ==
There has been public controversy when it has come to the tactics of riot control. Moral and legal questions have emerged regarding constitutional rights such as the right to assembly as well as free speech. This form of state violence is also controversial as discussions have emerged regarding the legitimacy as well as the ethics of containing protests. There are discussions on the implications of the perceived military-civilian split. For example, the United States regards its police as civilians. However, the ambiguity of the laws allows for the police to act as military in conflicts with U.S. citizens which has typically been seen as legitimate or at least legal.
There are also legitimate health and safety concerns. Some effects of riot agents include irritation, runny nose, chest tightness, coughing as well as swelling. Long term effects include blindness and respiratory failure. Death can also occur instantly due to chemical burns and respiratory failure. Different countries use different methods of riot control. Chloroacetophenone, chlorobenzylidene malononitrile (tear gas) and dibenzoxazepine are common ingredients for riot control. These are highly toxic and cancerous. Countries often have different standards for usage of chemicals like capsaicin (pepper spray) and who is allowed to own and use these chemicals for self-defense. Some scholars have called for natural alternatives to limit long term health effects like those found in the Capsicum genus and the Zingiber genus.
== Psychological toll on protesters and Police officers ==
As protests and riots rage on throughout the world, there is an ongoing concern that riot control is having an impact on individuals' mental health. This rise in protests has caused an inevitable increase in law-enforcement violence, which has profound impacts on the mental health of protesters and police officers, including PTSD, anxiety, and depression. Studies have shown that rubber bullets, water cannons, and tear gas cause not only problems like eye irritation and external and internal injuries, but can also cause individuals to develop psychological issues. This all comes after the American Public Health Association named police violence as a "public health issue," making it crucial to study the psychological effects caused by riots.
The Hong Kong anti-extradition bill protests are an example that has been studied due to its psychological health effects, stemming from the severe nature of the police response. During these protests in Hong Kong, the police reportedly used upwards of 16,000 canisters of tear gas on these protesters. A survey of the Hong Kong protesters found that 25.7% of the population experienced depression, while 9.1% had thoughts of committing suicide. There were similar findings during the Arab Spring in Egypt, where school children in schools near the Tahrir Square (the location of massive riots) were experiencing higher rates of depression. In France, it was found that Yellow Vest protesters who encountered police violence had a 1.54% higher likelihood of experiencing severe depressive symptoms and were 2.58 times more likely to exhibit signs indicative of PTSD. In the whole scheme of police violence towards protesters, it is said that people who were involved in or just living in areas affected by riots could experience an uptick in PTSD by 4% to 41%.
Risk factors that can exacerbate mental health issues from riots:
Lower socioeconomic status
Female sex
Prior exposure to violence
Excessive social media use
Lack of support from family and friends
Ongoing personal conflicts
=== Psychological Effects on Police Officers ===
When considering the psychological effects of riot control, it is important to also examine how police officers are impacted by riots. They are exposed to some of the same risks and challenges, such as having objects thrown at them, being physically assaulted, and being exposed to RCA’s. Even without considering riots, police officers already have almost double the risk of developing PTSD, depression, and anxiety than the average person. When working the frontline of a riot is added, these numbers are bound to go up. For example, during the unrest after the murders of George Floyd and Breonna Taylor, the number of recorded cases of PTSD among police officers increased upwards of 30%. With the increase in mental illness from the civil unrest and public scrutiny, many police officers resigned, resorted to substance abuse, and even suicide.
Symptoms that Police Officers may face after riots:
Increased heart rate
Nervousness or restlessness
Trembling
Sweating
Reduced Appetite
Anxiety or restlessness
Frequent or recurrent thoughts of death
=== January 6th Riots ===
On the 6th, January 2021, protestors stormed the Capitol Building in Washington D.C. In the process, they beat, trampled and sprayed police officers with chemicals, overwhelmed the police, and almost killed numerous police officers who attempted to stop them from entering the Capitol. In response to this event, members of the Capitol Police and Metropolitan Police Department suffered from PTSD, anxiety, and depression. Police Officers Bobby Tabron and DeDivine K. Carter of the Metropolitan Police Department filed a lawsuit against former President, Donald J. Trump - stating that by inciting the mob, Donald Trump caused them "severe injuries" and great "emotional distress." Both officers claimed to suffer from recurrent dreams and thoughts of the attack on the Capitol Building. Beyond this lawsuit, multiple police officers who responded to the Capitol committed suicide in the following months:
Metropolitan Police Officer Gunther Hashida
Metropolitan Police Officer Kyle DeFreytag
Capitol Police Officer Howard Liebengood
Metropolitan Police Officer Jeffrey Smith
== Research ==
Research into weapons that are more effective for riot control continues. Netguns are non-lethal weapons designed to fire a net which entangles the target. Netguns have a long history of being used to capture wildlife, without injury, for research purposes. A netgun is currently in development for non-lethal riot control. Pepper-spray projectile launchers are projectile weapons that launch a fragile ball which breaks upon impact and releases an irritant powder called PAVA (capsaicin II) pepper. The launchers are often slightly modified .68 caliber paintball guns.
Stink bombs are devices designed to create an extremely unpleasant smell for riot control and area denial purposes. Stink bombs are believed to be less dangerous than other riot control chemicals, since they are effective at low concentrations. Sticky foam weapons are being tested, which cover and immobilize rioters with a gooey foam.
Low frequency sound cannons are weapons of various types that use sound to injure or incapacitate subjects using a focused beam of sound or infrasound. Active denial systems (ADS) are a non-lethal, directed-energy weapon developed by the U.S. military. The ADS directs electromagnetic radiation, specifically, high-frequency microwave radiation, at a frequency of 95 GHz, which causes the water in the upper epidermis to boil, stimulating a "burning" sensation in the nerve endings and generating intense pain. Dazzler lasers are directed-energy weapons that use intense light to cause temporary blindness or disorientation of rioters.
== See also ==
Demoralization (warfare) – Warfare tactic used to erode morale
Free speech zone – Area set aside in public places for the purpose of political protesting
Personal armor – Protective clothing; armor worn on the bodyPages displaying short descriptions of redirect targets
Blunt trauma personal protective equipment – gear that protects the wearer against injuries caused by blunt impactsPages displaying wikidata descriptions as a fallback
Baton charge – Police tactic for crowd dispersion
Crowd control – Public security practice
Crowd manipulation – Application of crowd psychology
Crowd crush – Type of disaster that occurs due to overcrowdingPages displaying short descriptions of redirect targets
Non-military armored vehicle – Armored vehicle operated outside military organizationsPages displaying short descriptions of redirect targets
Kettling – Police tactic of containing people at a protest
Snatch squad – Tactics used by police in riot control
=== Riot control units ===
Garda Public Order Unit (Ireland)
Units for the Reinstatement of Order (Greece)
Rapid Action Force (India)
Mobile Brigade Corps (Indonesia)
Compagnies Républicaines de Sécurité (France)
Mobile Gendarmerie (France)
Police Tactical Unit (Hong Kong)
Special Tactical Squad (Hong Kong)
Territorial Support Group (London in England)
Carabinieri Mobile Units Division (Italy)
Mobile Unit (Italy)
Riot Police Unit (Japan)
Unidades de Intervención Policial (Spain)
Çevik Kuvvet (Turkey)
=== Weapons used in riot control ===
Non-lethal weapon
CS gas
Long Range Acoustic Device
Plastic bullets
Pepper spray
Rubber bullet
Water cannon
Pellet guns (pellet shotguns)
Use of bayonets for crowd control
== Notes ==
== References ==
== External links ==
Media related to Riot control at Wikimedia Commons | Wikipedia/Riot_control_agent |
Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has developed within the individual from psychoactive substance consumption that results in the experience of withdrawal and that necessitates the re-consumption of the drug. A drug addiction, a distinct concept from substance dependence, is defined as compulsive, out-of-control drug use, despite negative consequences. An addictive drug is a drug which is both rewarding and reinforcing. ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral and drug addictions, but not dependence.
The International Classification of Diseases classifies substance dependence as a mental and behavioural disorder.
Within the framework of the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), substance dependence is redefined as a drug addiction, and can be diagnosed without the occurrence of a withdrawal syndrome. It was described accordingly: "When an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed. Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped. This, along with Substance Abuse are considered Substance Use Disorders." In the DSM-5 (released in 2013), substance abuse and substance dependence were eliminated and replaced with the category of substance use disorders. This was done because "the tolerance and withdrawal that previously defined dependence are actually very normal responses to prescribed medications that affect the central nervous system and do not necessarily indicate the presence of an addiction."
== Withdrawal ==
Withdrawal is the body's reaction to abstaining from a substance upon which a person has developed a dependence syndrome. When dependence has developed, cessation of substance-use produces an unpleasant state, which promotes continued drug use through negative reinforcement; i.e., the drug is used to escape or avoid re-entering the associated withdrawal state. The withdrawal state may include physical-somatic symptoms (physical dependence), emotional-motivational symptoms (psychological dependence), or both. Chemical and hormonal imbalances may arise if the substance is not re-introduced. Psychological stress may also result if the substance is not re-introduced.
Infants also experience substance withdrawal, known as neonatal abstinence syndrome (NAS), which can have severe and life-threatening effects. Addiction to drugs such as alcohol in expectant mothers not only causes NAS, but also an array of other issues which can continually affect the infant throughout their lifetime.
== Risk factors ==
=== Dependence potential ===
The dependence potential or dependence liability of a drug varies from substance to substance, and from individual to individual. Dose, frequency, pharmacokinetics of a particular substance, route of administration, and time are critical factors for developing a drug dependence.
An article in The Lancet compared the harm and dependence liability of 20 drugs, using a scale from zero to three for physical dependence, psychological dependence, and pleasure to create a mean score for dependence. Selected results can be seen in the chart below.
=== Capture rates ===
Capture rates enumerate the percentage of users who reported that they had become dependent to their respective drug at some point.
== Biomolecular mechanisms ==
=== Psychological dependence ===
Two factors have been identified as playing pivotal roles in psychological dependence: the neuropeptide "corticotropin-releasing factor" (CRF) and the gene transcription factor "cAMP response element binding protein" (CREB). The nucleus accumbens (NAcc) is one brain structure that has been implicated in the psychological component of drug dependence. In the NAcc, CREB is activated by cyclic adenosine monophosphate (cAMP) immediately after a high and triggers changes in gene expression that affect proteins such as dynorphin; dynorphin peptides reduce dopamine release into the NAcc by temporarily inhibiting the reward pathway. A sustained activation of CREB thus forces a larger dose to be taken to reach the same effect. In addition, it leaves the user feeling generally depressed and dissatisfied, and unable to find pleasure in previously enjoyable activities, often leading to a return to the drug for another dose.
In addition to CREB, it is hypothesized that stress mechanisms play a role in dependence. Koob and Kreek have hypothesized that during drug use, CRF activates the hypothalamic–pituitary–adrenal axis (HPA axis) and other stress systems in the extended amygdala. This activation influences the dysregulated emotional state associated with psychological dependence. They found that as drug use escalates, so does the presence of CRF in human cerebrospinal fluid. In rat models, the separate use of CRF inhibitors and CRF receptor antagonists both decreased self-administration of the drug of study. Other studies in this review showed dysregulation of other neuropeptides that affect the HPA axis, including enkephalin which is an endogenous opioid peptide that regulates pain. It also appears that μ-opioid receptors, which enkephalin acts upon, is influential in the reward system and can regulate the expression of stress hormones.
Increased expression of AMPA receptors in nucleus accumbens MSNs is a potential mechanism of aversion produced by drug withdrawal.
=== Physical dependence ===
Upregulation of the cAMP signal transduction pathway in the locus coeruleus by CREB has been implicated as the mechanism responsible for certain aspects of opioid-induced physical dependence. The temporal course of withdrawal correlates with LC firing, and administration of α2 agonists into the locus coeruleus leads to a decrease in LC firing and norepinephrine release during withdrawal. A possible mechanism involves upregulation of NMDA receptors, which is supported by the attenuation of withdraw by NMDA receptor antagonists. Physical dependence on opioids has been observed to produce an elevation of extracellular glutamate, an increase in NMDA receptor subunits NR1 and NR2A, phosphorylated CaMKII, and c-fos. Expression of CaMKII and c-fos is attenuated by NMDA receptor antagonists, which is associated with blunted withdrawal in adult rats, but not neonatal rats While acute administration of opioids decreases AMPA receptor expression and depresses both NMDA and non-NMDA excitatory postsynaptic potentials in the NAC, withdrawal involves a lowered threshold for LTP and an increase in spontaneous firing in the NAc.
== Diagnosis ==
=== DSM classification ===
"Substance dependence", as defined in the DSM-IV, can be diagnosed with physiological dependence, evidence of tolerance or withdrawal, or without physiological dependence.
DSM-IV substance dependencies include:
303.90 Alcohol dependence
304.00 Opioid dependence
304.10 Sedative, hypnotic, or anxiolytic dependence (including benzodiazepine dependence and barbiturate dependence)
304.20 Cocaine dependence
304.30 Cannabis dependence
304.40 Amphetamine dependence (or amphetamine-like)
304.50 Hallucinogen dependence
304.60 Inhalant dependence
304.80 Polysubstance dependence
304.90 Phencyclidine (or phencyclidine-like) dependence
304.90 Other (or unknown) substance dependence
305.10 Nicotine dependence
== Management ==
Addiction is a complex but treatable condition. It is characterized by compulsive drug craving, seeking, and use that persists even if the user is aware of severe adverse consequences. For some people, addiction becomes chronic, with periodic relapses even after long periods of abstinence. As a chronic, relapsing disease, addiction may require continued treatments to increase the intervals between relapses and diminish their intensity. While some with substance issues recover and lead fulfilling lives, others require ongoing additional support. The ultimate goal of addiction treatment is to enable an individual to manage their substance misuse; for some this may mean abstinence. Immediate goals are often to reduce substance abuse, improve the patient's ability to function, and minimize the medical and social complications of substance abuse and their addiction; this is called "harm reduction".
Treatments for addiction vary widely according to the types of drugs involved, amount of drugs used, duration of the drug addiction, medical complications and the social needs of the individual. Determining the best type of recovery program for an addicted person depends on a number of factors, including: personality, drugs of choice, concept of spirituality or religion, mental or physical illness, and local availability and affordability of programs.
Many different ideas circulate regarding what is considered a successful outcome in the recovery from addiction. Programs that emphasize controlled drinking exist for alcohol addiction. Opiate replacement therapy has been a medical standard of treatment for opioid addiction for many years.
Treatments and attitudes toward addiction vary widely among different countries. In the US and developing countries, the goal of commissioners of treatment for drug dependence is generally total abstinence from all drugs. Other countries, particularly in Europe, argue the aims of treatment for drug dependence are more complex, with treatment aims including reduction in use to the point that drug use no longer interferes with normal activities such as work and family commitments; shifting the addict away from more dangerous routes of drug administration such as injecting to safer routes such as oral administration; reduction in crime committed by drug addicts; and treatment of other comorbid conditions such as AIDS, hepatitis and mental health disorders. These kinds of outcomes can be achieved without eliminating drug use completely. Drug treatment programs in Europe often report more favorable outcomes than those in the US because the criteria for measuring success are functional rather than abstinence-based. The supporters of programs with total abstinence from drugs as a goal believe that enabling further drug use means prolonged drug use and risks an increase in addiction and complications from addiction.
=== Residential ===
Residential drug treatment can be broadly divided into two camps: 12-step programs and therapeutic communities. 12-step programs are a nonclinical support-group and spiritual-based approach to treating addiction. Therapy typically involves the use of cognitive-behavioral therapy, an approach that looks at the relationship between thoughts, feelings and behaviors, addressing the root cause of maladaptive behavior. Cognitive-behavioral therapy treats addiction as a behavior rather than a disease, and so is subsequently curable, or rather, unlearnable. Cognitive-behavioral therapy programs recognize that, for some individuals, controlled use is a more realistic possibility.
One of many recovery methods are 12-step recovery programs, with prominent examples including Alcoholics Anonymous, Narcotics Anonymous, and Pills Anonymous. They are commonly known and used for a variety of addictions for the individual addicted and the family of the individual. Substance-abuse rehabilitation (rehab) centers offer a residential treatment program for some of the more seriously addicted, in order to isolate the patient from drugs and interactions with other users and dealers. Outpatient clinics usually offer a combination of individual counseling and group counseling. Frequently, a physician or psychiatrist will prescribe medications in order to help patients cope with the side effects of their addiction. Medications can help immensely with anxiety and insomnia, can treat underlying mental disorders (cf. self-medication hypothesis, Khantzian 1997) such as depression, and can help reduce or eliminate withdrawal symptomology when withdrawing from physiologically addictive drugs. Some examples are using benzodiazepines for alcohol detoxification, which prevents delirium tremens and complications; using a slow taper of benzodiazepines or a taper of phenobarbital, sometimes including another antiepileptic agent such as gabapentin, pregabalin, or valproate, for withdrawal from barbiturates or benzodiazepines; using drugs such as baclofen to reduce cravings and propensity for relapse amongst addicts to any drug, especially effective in stimulant users, and alcoholics (in which it is nearly as effective as benzodiazepines in preventing complications); using clonidine, an alpha-agonist, and loperamide for opioid detoxification, for first-time users or those who wish to attempt an abstinence-based recovery (90% of opioid users relapse to active addiction within eight months or are multiple relapse patients); or replacing an opioid that is interfering with or destructive to a user's life, such as illicitly-obtained heroin, dilaudid, or oxycodone, with an opioid that can be administered legally, reduces or eliminates drug cravings, and does not produce a high, such as methadone or buprenorphine – opioid replacement therapy – which is the gold standard for treatment of opioid dependence in developed countries, reducing the risk and cost to both user and society more effectively than any other treatment modality (for opioid dependence), and shows the best short-term and long-term gains for the user, with the greatest longevity, least risk of fatality, greatest quality of life, and lowest risk of relapse and legal issues including arrest and incarceration.
In a survey of treatment providers from three separate institutions, the National Association of Alcoholism and Drug Abuse Counselors, Rational Recovery Systems and the Society of Psychologists in Addictive Behaviors, measuring the treatment provider's responses on the "Spiritual Belief Scale" (a scale measuring belief in the four spiritual characteristics of AA identified by Ernest Kurtz); the scores were found to explain 41% of the variance in the treatment provider's responses on the "Addiction Belief Scale" (a scale measuring adherence to the disease model or the free-will model of addiction).
=== Behavioral programming ===
Behavioral programming is considered critical in helping those with addictions achieve abstinence. From the applied behavior analysis literature and the behavioral psychology literature, several evidence based intervention programs have emerged: (1) behavioral marital therapy; (2) community reinforcement approach; (3) cue exposure therapy; and (4) contingency management strategies. In addition, the same author suggests that social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious. Community reinforcement has both efficacy and effectiveness data. In addition, behavioral treatment such as community reinforcement and family training (CRAFT) have helped family members to get their loved ones into treatment. Motivational intervention has also shown to be an effective treatment for substance dependence.
=== Alternative therapies ===
Alternative therapies, such as acupuncture, are used by some practitioners to alleviate the symptoms of drug addiction. In 1997, the American Medical Association (AMA) adopted, as policy, the following statement after a report on a number of alternative therapies including acupuncture:
There is little evidence to confirm the safety or efficacy of most alternative therapies. Much of the information currently known about these therapies makes it clear that many have not been shown to be efficacious. Well-designed, stringently controlled research should be done to evaluate the efficacy of alternative therapies.
In addition, new research surrounding the effects of psilocybin on smokers revealed that 80% of smokers quit for six months following the treatment, and 60% remained smoking free for 5 years following the treatment.
== Treatment and issues ==
Medical professionals need to apply many techniques and approaches to help patients with substance related disorders. Using a psychodynamic approach is one of the techniques that psychologists use to solve addiction problems. In psychodynamic therapy, psychologists need to understand the conflicts and the needs of the addicted person, and also need to locate the defects of their ego and defense mechanisms. Using this approach alone has proven to be ineffective in solving addiction problems. Cognitive and behavioral techniques should be integrated with psychodynamic approaches to achieve effective treatment for substance related disorders. Cognitive treatment requires psychologists to think deeply about what is happening in the brain of an addicted person. Cognitive psychologists should zoom in to neural functions of the brain and understand that drugs have been manipulating the dopamine reward center of the brain. From this particular state of thinking, cognitive psychologists need to find ways to change the thought process of the addicted person.
=== Cognitive approach ===
There are two routes typically applied to a cognitive approach to substance abuse: tracking the thoughts that pull patients to addiction and tracking the thoughts that prevent them if so from relapsing. Behavioral techniques have the widest application in treating substance related disorders. Behavioral psychologists can use the techniques of "aversion therapy", based on the findings of Pavlov's classical conditioning. It uses the principle of pairing abused substances with unpleasant stimuli or conditions; for example, pairing pain, electrical shock, or nausea with alcohol consumption. The use of medications may also be used in this approach, such as using disulfiram to pair unpleasant effects with the thought of alcohol use. Psychologists tend to use an integration of all these approaches to produce reliable and effective treatment. With the advanced clinical use of medications, biological treatment is now considered to be one of the most efficient interventions that psychologists may use as treatment for those with substance dependence.
=== Medicinal approach ===
Another approach is to use medicines that interfere with the functions of the drugs in the brain. Similarly, one can also substitute the misused substance with a weaker, safer version to slowly taper the patient off of their dependence. Such is the case with Suboxone in the context of opioid dependence. These approaches are aimed at the process of detoxification. Medical professionals weigh the consequences of withdrawal symptoms against the risk of staying dependent on these substances. These withdrawal symptoms can be very difficult and painful at times for patients. Most will have steps in place to handle severe withdrawal symptoms, either through behavioral therapy or other medications. Biological intervention should be combined with behavioral therapy approaches and other non-pharmacological techniques. Group therapies including anonymity, teamwork and sharing concerns of daily life among people who also have substance dependence issues can have a great impact on outcomes. However, these programs proved to be more effective and influential on persons who did not reach levels of serious dependence.
==== Vaccines ====
TA-CD is an active vaccine developed by the Xenova Group which is used to negate the effects of cocaine, making it suitable for use in treatment of addiction. It is created by combining norcocaine with inactivated cholera toxin.
TA-NIC is a proprietary vaccine in development similar to TA-CD but being used to create human anti-nicotine antibodies in a person to destroy nicotine in the human body so that it is no longer effective.
== History ==
The phenomenon of drug addiction has occurred to some degree throughout recorded history (see Opium). Modern agricultural practices, improvements in access to drugs, advancements in biochemistry, and dramatic increases in the recommendation of drug usage by clinical practitioners have exacerbated the problem significantly in the 20th century. Improved means of active biological agent manufacture and the introduction of synthetic compounds, such as fentanyl and methamphetamine, are also factors contributing to drug addiction.
For the entirety of US history, drugs have been used by some members of the population. In the country's early years, most drug use by the settlers was of alcohol or tobacco.
The 19th century saw opium usage in the US become much more common and popular. Morphine was isolated in the early 19th century, and came to be prescribed commonly by doctors, both as a painkiller and as an intended cure for opium addiction. At the time, the prevailing medical opinion was that the addiction process occurred in the stomach, and thus it was hypothesized that patients would not become addicted to morphine if it was injected into them via a hypodermic needle, and it was further hypothesized that this might potentially be able to cure opium addiction. However, many people did become addicted to morphine. In particular, addiction to opium became widespread among soldiers fighting in the Civil War, who very often required painkillers and thus were very often prescribed morphine. Women were also very frequently prescribed opiates, and opiates were advertised as being able to relieve "female troubles".
Many soldiers in the Vietnam War were introduced to heroin and developed a dependency on the substance which survived even when they returned to the US. Technological advances in travel meant that this increased demand for heroin in the US could now be met. Furthermore, as technology advanced, more drugs were synthesized and discovered, opening up new avenues to substance dependency.
== Society and culture ==
=== Demographics ===
Internationally, the U.S. and Eastern Europe contain the countries with the highest substance abuse disorder occurrence (5-6%). Africa, Asia, and the Middle East contain countries with the lowest worldwide occurrence (1-2%). Across the globe, those that tended to have a higher prevalence of substance dependence were in their twenties, unemployed, and men. The National Survey on Drug Use and Health (NSDUH) reports on substance dependence/abuse rates in various population demographics across the U.S. When surveying populations based on race and ethnicity in those ages 12 and older, it was observed that American Indian/Alaskan Natives were among the highest rates and Asians were among the lowest rates in comparison to other racial/ethnic groups.
When surveying populations based on gender in those ages 12 and older, it was observed that males had a higher substance dependence rate than females. However, the difference in the rates are not apparent until after age 17.
Alcohol dependence or abuse rates were shown to have no correspondence with any person's education level when populations were surveyed in varying degrees of education from ages 26 and older. However, when it came to illicit drug use there was a correlation, in which those that graduated from college had the lowest rates. Furthermore, dependence rates were greater in unemployed populations ages 18 and older and in metropolitan-residing populations ages 12 and older.
The National Opinion Research Center at the University of Chicago reported an analysis on disparities within admissions for substance abuse treatment in the Appalachian region, which comprises 13 states and 410 counties in the Eastern part of the U.S. While their findings for most demographic categories were similar to the national findings by NSDUH, they had different results for racial/ethnic groups which varied by sub-regions. Overall, Whites were the demographic with the largest admission rate (83%), while Alaskan Native, American Indian, Pacific Islander, and Asian populations had the lowest admissions (1.8%).
=== Legislation ===
Depending on the jurisdiction, addictive drugs may be legal, legal only as part of a government sponsored study, illegal to use for any purpose, illegal to sell, or even illegal to merely possess.
Most countries have legislation which brings various drugs and drug-like substances under the control of licensing systems. Typically this legislation covers any or all of the opiates, amphetamines, cannabinoids, cocaine, barbiturates, benzodiazepines, anesthetics, hallucinogenics, derivatives and a variety of more modern synthetic drugs. Unlicensed production, supply or possession is a criminal offence.
Although the legislation may be justifiable on moral or public health grounds, it can make addiction or dependency a much more serious issue for the individual: reliable supplies of a drug become difficult to secure, and the individual becomes vulnerable to both criminal abuse and legal punishment.
It is unclear whether laws against illegal drug use do anything to stem usage and dependency. In jurisdictions where addictive drugs are illegal, they are generally supplied by drug dealers, who are often involved with organized crime. Even though the cost of producing most illegal addictive substances is very low, their illegality combined with the addict's need permits the seller to command a premium price, often hundreds of times the production cost. As a result, addicts sometimes turn to crime to support their habit.
==== United States ====
In the United States, drug policy is primarily controlled by the federal government. The Department of Justice's Drug Enforcement Administration (DEA) enforces controlled substances laws and regulations. The Department of Health and Human Services' Food and Drug Administration (FDA) serve to protect and promote public health by controlling the manufacturing, marketing, and distribution of products, like medications.
The United States' approach to substance abuse has shifted over the last decade, and is continuing to change. The federal government was minimally involved in the 19th century. The federal government transitioned from using taxation of drugs in the early 20th century to criminalizing drug abuse with legislations and agencies like the Federal Bureau of Narcotics (FBN) mid-20th century in response to the nation's growing substance abuse issue. These strict punishments for drug offenses shined light on the fact that drug abuse was a multi-faceted problem. The President's Advisory Commission on Narcotics and Drug Abuse of 1963 addressed the need for a medical solution to drug abuse. However, drug abuse continued to be enforced by the federal government through agencies such as the DEA and further legislations such as The Controlled Substances Act (CSA), the Comprehensive Crime Control Act of 1984, and Anti-Drug Abuse Acts.
In the past decade, there have been growing efforts through state and local legislations to shift from criminalizing drug abuse to treating it as a health condition requiring medical intervention. 28 states currently allow for the establishment of needle exchanges. Florida, Iowa, Missouri and Arizona all introduced bills to allow for the establishment of needle exchanges in 2019. These bills have grown in popularity across party lines since needle exchanges were first introduced in Amsterdam in 1983. In addition, AB-186 Controlled substances: overdose prevention program was introduced to operate safe injection sites in the City and County of San Francisco. The bill was vetoed on September 30, 2018, by California Governor Jerry Brown. The legality of these sites are still in discussion, so there are no such sites in the United States yet. However, there is growing international evidence for successful safe injection facilities.
== See also ==
Questionnaires
== References ==
== External links ==
American Society of Addiction Medicine website
Health-EU Portal – Drugs
people, drug addicts
Trips Beyond Addiction | Living Hero Radio Show and Podcast special. With Dimitri Mobengo Mugianis, Bovenga Na Muduma, Clare S. Wilkins, Brad Burge, Tom Kingsley Brown, Susan Thesenga, Bruce K. Alexander, PhD ~ the voices of ex-addicts, researchers from The Multidisciplinary Association for Psychedelic Studies and Ibogaine/Iboga/Ayahuasca treatment providers sharing their experiences in breaking addiction with native medicines. January 2013
A social history of America's most popular drugs.
National Institute on Drug Abuse: "NIDA for Teens: Brain and Addiction".
"WHO Expert Committee on Drug Dependence – WHO Technical Report Series, No. 915 – Thirty-third Report". apps.who.int. 2003. Archived from the original on 9 October 2012. Retrieved 26 February 2015. - pdf | Wikipedia/Drug_dependence |
In pharmacology, tolerability refers to the degree to which overt adverse effects of a drug can be tolerated by a patient. Tolerability of a particular drug can be discussed in a general sense, or it can be a quantifiable measurement as part of a clinical study. Usually, it is measured by the rate of "dropouts", or patients that forfeit participation in a study due to extreme adverse effects. Tolerability, however, is often relative to the severity of the medical condition a drug is designed to treat. For instance, cancer patients may tolerate significant pain or discomfort during a chemotherapeutic study with the hope of prolonging survival or finding a cure, whereas patients experiencing a benign condition, such as a headache, are less likely to.
As an example, tricyclic antidepressants (TCAs) are very poorly tolerated and often produce severe side effects including sedation, orthostatic hypotension, and anticholinergic effects, whereas newer antidepressants have far fewer adverse effects and are well tolerated.
Drug tolerability should not be confused with drug tolerance, which refers to subjects' reduced reaction to a drug following its repeated use.
== See also ==
Side effect
== References == | Wikipedia/Drug_tolerability |
A drug holiday (sometimes also called a drug vacation, medication vacation, structured treatment interruption, tolerance break, treatment break or strategic treatment interruption) is when a patient stops taking a medication(s) for a period of time; anywhere from a few days to many months or even years if the doctor or medical provider feels it is best for the patient. It is recommended not to discontinue any medication without the close supervision of the prescribing party as it is only for specific cases.
Planned drug holidays are used in some fields of medicine. They are perhaps best known in HIV therapy, after a study suggested that stopping medication may stimulate the immune system to attack the virus. As of 2025, there is a scientific consensus against drug holiday for HIV.
Another reason for drug holidays is to permit a drug to regain effectiveness after a period of continuous use, and to reduce the tolerance effect that may require increased dosages.
In addition to drug holidays that are intended for therapeutic effect, they are sometimes used to reduce drug side effects so that patients may enjoy a more normal life for a period of time such as a weekend or holiday, or engage in a particular activity. For example, it is common for patients using SSRI anti-depressant therapies to take a drug holiday to reduce or avoid side effects associated with sexual dysfunction.
In the treatment of mental illness, a drug holiday may be part of a progression toward treatment cessation. The holiday is also a tool to assess a drug's benefits against unwanted side effects, assuming that both will dissipate after an extended vacation.
== Evolution of the practice ==
=== As a treatment for bipolar disorder ===
One-day drug holidays in the lithium treatment of bipolar disorder, known as "lithium-free days", have been in use since the pioneering work of Noack and Trautner in 1951. This was found to reduce toxic buildup of the drug in some patients.
=== As a treatment for Parkinson's disease ===
Drug holidays from L-dopa found use in the early 1970s when Sweet et al. reported they were beneficial in terms of restoring the effectiveness of the treatment after adaptation by the brain had diminished its effectiveness.
However, later studies revealed that such drug holidays conferred only temporary benefits to L-dopa responsiveness. Furthermore, there was an increased risk of death from associated complications, namely aspiration pneumonia, depression, and thromboembolic disease. L-dopa drug holidays are thus no longer recommended.
=== As a treatment for schizophrenia ===
Drug holidays from antipsychotic medication such as chlorpromazine have been used since the early 1980s to alleviate adverse reactions associated with long-term treatment.
According to Ann Mortimer, it is acknowledged that established guidelines require long-term treatment in established schizophrenia, because the vast majority of evidence from discontinuation, "drug holiday", and ultra-low-dose studies conducted over many years points to significantly higher relapse rates when compared to maintenance treatment. If antipsychotics cannot be avoided in the near term, there is no reason to question their long-term usefulness. The same might be said of insulin in diabetes.
=== As a treatment for HIV ===
HIV selectively targets activated helper T-cells. Thus, over time, HIV will tend to selectively destroy those helper T-cells most capable of fighting the HIV infection off, effectively desensitizing the immune system to the infection. The purpose of a structured treatment interruption is to create a short interval in which the virus becomes common enough to stimulate reproduction of T-cells capable of fighting the virus.
A 2006 HIV literature review noted that "two studies suggested that so-called drug holidays were of no benefit and might actually harm patients, while a third study suggested that the idea might still have value and should be revisited." As of 2025, there is a scientific consensus against drug holiday for HIV.
== See also ==
Downregulation and upregulation
Rebound effect
Tachyphylaxis
== References == | Wikipedia/Drug_holiday |
Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs.
In order for the symptoms of withdrawal to occur, one must have first developed a form of drug dependence. This may occur as physical dependence, psychological dependence, or both. Drug dependence develops from consuming one or more substances over a period of time.
Dependence arises in a dose-dependent manner and produces withdrawal symptoms that vary with the type of drug that is consumed. For example, prolonged use of an antidepressant medication is likely to cause a rather different reaction when discontinued compared to discontinuation of an opioid, such as heroin. Withdrawal symptoms from opiates include anxiety, sweating, vomiting, and diarrhea. Alcohol withdrawal symptoms include irritability, fatigue, shaking, sweating, and nausea. Withdrawal from nicotine can cause irritability, fatigue, insomnia, headache, and difficulty concentrating. Many prescription and legal nonprescription substances can also cause withdrawal symptoms when individuals stop consuming them, even if they were taken as directed by a physician.
The route of administration, whether intravenous, intramuscular, oral, or otherwise can also play a role in determining the severity of withdrawal symptoms. There are different stages of withdrawal as well; generally, a person will start to feel bad (crash or comedown), progress to feeling worse, hit a plateau, and then the symptoms begin to dissipate. However, withdrawal from certain drugs (barbiturates, benzodiazepines, alcohol, glucocorticoids) can be fatal. While it is seldom fatal to the user, withdrawal from opiates (and some other drugs) can cause miscarriage, due to fetal withdrawal. The term "cold turkey" is used to describe the sudden cessation of use of a substance and the ensuing physiologic manifestations.
The symptoms from withdrawal may be even more dramatic when the drug has masked prolonged malnutrition, disease, chronic pain, infections (common in intravenous drug use), or sleep deprivation, conditions that drug abusers often develop as a secondary consequence of the drug. When the drug is removed, these conditions may resurface and be confused with withdrawal symptoms. Genes that encode for the alpha5 nicotinic acetylcholine receptor affect nicotine and alcohol withdrawal symptoms.
== Effect on homeostasis ==
Homeostasis is the body's ability to maintain a certain chemical equilibrium in the brain and throughout the body. For example, the function of shivering in response to cold is to produce heat maintaining internal temperature at around 37 °C (98.6 °F). Homeostasis is impacted in many ways by drug usage and withdrawal. The internal systems perpetuate homeostasis by using different counter-regulatory methods in order to create a new state of balance based on the presence of the drug in the system. These methods include adapting the body's levels of neurotransmitters, hormones, and other substances present to adjust for the addition of the drug to the body.
== Substances ==
Examples (and ICD-10 code) of withdrawal syndrome include:
F10.3 alcohol withdrawal syndrome (which can lead to delirium tremens)
F11.3 Opioid withdrawal, including methadone withdrawal
F12.3 cannabis withdrawal
F13.3 benzodiazepine withdrawal
F14.3 cocaine withdrawal
F15.3 caffeine withdrawal
F17.3 nicotine withdrawal
== Prescription medicine ==
As noted above, many drugs should not be stopped abruptly without the advice and supervision of a physician, especially if the medication induces dependence or if the condition they are being used to treat is potentially dangerous and likely to return once medication is stopped, such as diabetes, asthma, heart conditions and many psychological or neurological conditions, like epilepsy, depression, hypertension, schizophrenia and psychosis. The stopping of antipsychotics in schizophrenia and psychoses needs monitoring. The stopping of antidepressants for example, can lead to antidepressant discontinuation syndrome. With careful physician attention, however, medication prioritization and discontinuation can decrease costs, simplify prescription regimens, decrease risks of adverse drug events and poly-pharmacy, focus therapies where they are most effective, and prevent cost-related under-use of medications.
Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) warns that people with dementia are more likely to experience adverse effects, and to monitor carefully for withdrawal symptoms when ceasing medications for these people as they are both more likely to experience symptoms and less likely to be able to reliably report symptoms.
=== Anti-hypertensive drugs ===
The latest evidence does not have evidence of an effect due to discontinuing vs continuing medications used for treating elevated blood pressure or prevention of heart disease in older adults on all-case mortality and incidence of heart attack. The findings are based on low quality evidence suggesting it may be safe to stop anti-hypertensive medications. However, older adults should not stop any of their medications without talking to a healthcare professional.
== See also ==
Chemical dependency
Drug detoxification
Drug tolerance
Hangover
Neonatal withdrawal
Post-acute withdrawal syndrome (PAWS)
Rebound effect
== References == | Wikipedia/Drug_withdrawal |
The Pure Food and Drug Act of 1906, also known as the Wiley Act and Dr. Wiley's Law, was the first of a series of significant consumer protection laws enacted by the United States Congress, and led to the creation of the Food and Drug Administration (FDA). Its main purpose was to ban foreign and interstate traffic in adulterated or mislabeled food and drug products, and it directed the US Bureau of Chemistry to inspect products and refer offenders to prosecutors. It required that active ingredients be placed on the label of a drug's packaging and that drugs could not fall below purity levels established by the United States Pharmacopeia or the National Formulary.
In the late 1800s, the quality of food in the US decreased significantly as populations moved to cities and the time from farm to market increased. Many food producers turned to using dangerous preservatives, including formaldehyde, to keep food appearing fresh. Simultaneously, the quality of medicine was appalling. Quack medicine was common, and many drugs were addictive or dangerous without actually providing a curative effect. Opium and alcohol were chief ingredients, even in infant medicines. The work of muckraking journalists exposed the practices of food and drug industries and caused public outcry.
Foremost among such exposés was The Jungle by Upton Sinclair, published the same year as the act. With its graphic and revolting descriptions of unsanitary conditions and unscrupulous practices rampant in the meat-packing industry, it kept the public's attention on the extreme unhygienic conditions in meat processing plants. Sinclair quipped, "I aimed at the public's heart and by accident I hit it in the stomach," as an outraged public demanded government action, resulting in the Pure Food and Drug Act and the Federal Meat Inspection Act of 1906.
== Historical significance ==
The Pure Food and Drug Act of 1906 was a key piece of Progressive Era legislation, signed by President Theodore Roosevelt on the same day as the Federal Meat Inspection Act. Enforcement of the Pure Food and Drug Act was assigned to the Bureau of Chemistry in the U.S. Department of Agriculture which was renamed the U.S. Food and Drug Administration (FDA) in 1930. The Meat Inspection Act was assigned to what is now known as the Food Safety and Inspection Service, which remains in the U.S. Department of Agriculture. The first federal law regulating foods and drugs, the 1906 Act's reach was limited to foods and drugs moving in interstate commerce. Although the law drew upon many precedents, provisions, and legal experiments pioneered in individual states, the federal law defined "misbranding" and "adulteration" for the first time and prescribed penalties for each. The law recognized the U.S. Pharmacopeia and the National Formulary as standards authorities for drugs, but made no similar provision for federal food standards. The law was principally a "truth in labeling" law designed to raise standards in the food and drug industries and protect the reputations and pocketbooks of honest businessmen.
== Particular drugs deemed addictive ==
Under the law, drug labels, for example, had to list any of 10 ingredients that were deemed "addictive" and/or "dangerous" on the product label if they were present, and could not list them if they were not present. Alcohol, morphine, opium, and cannabis were all included on the list of these "addictive" and/or "dangerous" drugs. The law also established a federal cadre of food and drug inspectors that one Southern opponent of the legislation criticized as "a Trojan horse with a bellyful of inspectors and other employees." Penalties under the law were modest, but an under-appreciated provision of the Act proved more powerful than monetary penalties. Goods found in violation of various areas of the law were subject to seizure and destruction at the expense of the manufacturer. That, combined with a legal requirement that all convictions be published as Notices of Judgment, proved to be important tools in the enforcement of the statute and had a deterrent effect upon would-be violators.
Deficiencies in this original statute, which had become noticeable by the 1920s, led to the replacement of the 1906 statute with the Federal Food, Drug, and Cosmetic Act which was enacted in 1938 and signed by President Franklin Roosevelt. This act, along with its numerous amendments, remains the statutory basis for federal regulation of all foods, drugs, biological products, cosmetics, medical devices, tobacco, and radiation-emitting devices by the U.S. Food and Drug Administration.
== History of passage ==
An 1882 article in Scientific American describes "New Laws for Analyzing Food and Drugs" and highlights historical aspects. Part of the draft stated:"An article shall be deemed to be adulterated within the meaning of this act.A.-In the case of drugs:* If, when sold under or by a name recognized in the United States Pharmacopeia, it differs from the standard of strength, quality, or purity laid down in such work.* If when sold under or by a name not recognized in the United States Pharmacopeia, but which is found in some other pharmacopeia or ether standard work on materia medica, it differs from the standard of strength, quality, or purity laid down in such work.* If its strength or purity fall below the professed standard under which it is soldB.-In the case of food or drink:* If any substance or substances has or have been mixed with it as to reduce or lower or injuriously affect its quality of strength* If any inferior or cheaper substance or substances have been substituted wholly or in part for the article*If any valuable constituent of the article has been wholly or is part abstracted* If it be an imitation of or be sold under the name of another article* If it consists wholly or in part of a diseased or decomposed, or putrid or rotten, animal or vegetable substance, whether manufactured or not, or in the case of milk, if it is the produce of a diseased animal* If it be colored, or coated, or polished, or powdered, whereby damage is concealed, or it is made to appear better than it really is, or of greater value"―Scientific American, 7 Jan 1882
It took 27 years to adopt the 1906 statute, during which time the public was made aware of many problems with foods and drugs in the U.S. Muckraking journalists, such as Samuel Hopkins Adams, targeted the patent medicine industry with its high-alcoholic content patent medicines, soothing syrups for infants with opium derivatives, and "red clauses" in newspaper contracts providing that patent medicine ads (upon which most newspapers of the time were dependent) would be withdrawn if the paper expressed support for food and drug regulatory legislation.
The Chief Chemist of the Bureau of Chemistry, Dr. Harvey Washington Wiley, captured the country's attention with his hygienic table studies, which began with a modest Congressional appropriation in 1902. The goal of the table trial was to study the human effects of common preservatives used in foods during a period of rapid changes in the food supply brought about by the need to feed cities and support an industrializing nation increasingly dependent on immigrant labor. Wiley recruited young men to eat all their meals at a common table as he added increased "doses" of preservatives including borax, benzoate, formaldehyde, sulfites, and salicylates. The table trials captured the nation's fancy and were soon dubbed "The Poison Squad" by newspapers covering the story. The men soon adopted the motto "Only the Brave dare eat the fare" and at times the publicity given to the trials became a burden. Though many results of the trial came to be in dispute, there was no doubt that formaldehyde was dangerous and it disappeared quickly as a preservative. Wiley himself felt that he had found adverse effects from large doses of each of the preservatives and the public seemed to agree with Wiley. In many cases, most particularly with ketchup and other condiments, the use of preservatives was often used to disguise unsanitary production practices. Although the law itself did not proscribe the use of some of these preservatives, consumers increasingly turned away from many products with known preservatives.
The 1906 statute regulated food and drugs moving in interstate commerce and forbade the manufacture, sale, or transportation of poisonous patent medicines. The Act arose due to public education and exposes from public interest guardians such as Upton Sinclair and Samuel Hopkins Adams, social activist Florence Kelley, researcher Harvey W. Wiley, and President Theodore Roosevelt.
== Beginnings of the Food and Drug Administration ==
The 1906 Act paved the way for the eventual creation of the Food and Drug Administration (FDA) and is generally considered to be that agency's founding date, though the agency existed before the law was passed and was not named FDA until later. "While the Food and Drug act remains a foundational law of the FDA mission, it's not the law that created the FDA. [Initially,] the Bureau of Chemistry (the precursor to the FDA) regulated food safety. In 1927, the Bureau was reorganized into the Food, Drug, and Insecticide Administration and the Bureau of Chemistry and Soils. The FDIA was renamed the FDA in 1930."
The law itself was largely replaced by the much more comprehensive Federal Food, Drug, and Cosmetic Act of 1938.
== Enforcement of labeling and future ramifications ==
The Pure Food and Drug Act was initially concerned with ensuring products were labeled correctly. Later efforts were made to outlaw certain products that were not safe, followed by efforts to outlaw products which were safe but not effective. For example, there was an attempt to outlaw Coca-Cola in 1909 because of its excessive caffeine content; caffeine had replaced cocaine as the active ingredient in Coca-Cola in 1903. In the case United States v. Forty Barrels and Twenty Kegs of Coca-Cola, the judge found that Coca-Cola had a right to use caffeine as it saw fit, although Coca-Cola eventually lost when the government appealed to the Supreme Court. It reached a settlement with the United States government to reduce the caffeine amount.
In addition to caffeine, the Pure Food and Drug Act required that drugs such as alcohol, cocaine, heroin, morphine, and cannabis, be accurately labeled with contents and dosage. Previously many drugs had been sold as patent medicines with secret ingredients or misleading labels. Cocaine, heroin, cannabis, and other such drugs continued to be legally available without prescription as long as they were labeled. It is estimated that sale of patent medicines containing opiates decreased by 33% after labeling was mandated. The Pure Food and Drug Act of 1906 is cited by drug policy reform advocates such as Jim Gray as a successful model for re-legalization of currently prohibited drugs by requiring accurate labels, monitoring of purity and dose, and consumer education.
== References ==
=== Sources ===
== External links ==
59th U.S. Congress (December 14, 1905). "S. 88, Draft bill of the Pure Food and Drug Act". Chapter 3915, cited 34 U.S. Stats. 768. U.S. Capitol Visitor Center. Archived from the original on September 19, 2015. Retrieved April 8, 2013.{{cite web}}: CS1 maint: numeric names: authors list (link)
59th U.S. Congress (1906). "THE WILEY ACT". Public Law Number 59-384, 34 Stat. 768. U.S. Food and Drug Administration. Archived from the original on July 10, 2009. Retrieved April 8, 2013.{{cite web}}: CS1 maint: numeric names: authors list (link) | Wikipedia/Pure_Food_and_Drug_Act |
The Misuse of Drugs Act 1971 (c. 38) is an act of the Parliament of the United Kingdom. It represents action in line with treaty commitments under the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.
Offences under the act include:
Possession of a controlled drug unlawfully
Possession of a controlled drug with intent to supply it
Supplying or offering to supply a controlled drug (even where no charge is made for the drug)
Allowing premises you occupy or manage to be used unlawfully for the purpose of producing or supplying controlled drugs
The act establishes the Home Secretary as the principal authority in a drug licensing system. Therefore, for example, various opiates are available legally as prescription-only medicines, and cannabis (hemp) may be grown under licence for 'industrial purposes'. The Misuse of Drugs Regulations 2001 (SI 2001/3998), created under the 1971 Act, are about licensing of production, possession and supply of substances classified under the act.
The act creates three classes of controlled substances, A, B, and C, and ranges of penalties for illegal or unlicensed possession and possession with intent to supply are graded differently within each class. The lists of substances within each class can be amended by Order in Council, so the Home Secretary can list new drugs and upgrade, downgrade or delist previously controlled drugs with less of the bureaucracy and delay associated with passing an act through both Houses of Parliament.
Critics of the act such as David Nutt say that its classification is not based on how harmful or addictive the substances are, and that it is unscientific to omit substances like tobacco and alcohol.
== List of controlled drugs ==
These drugs are known in the UK as controlled drug, because this is the term by which the act itself refers to them. In more general terms, however, many of these drugs are also controlled by the Medicines Act 1968, there are many other drugs which are controlled by the Medicines Act but not by the Misuse of Drugs Act, and some other drugs (alcohol, for example) are controlled by other laws.
The act sets out four separate categories: Class A, Class B, Class C and temporary class drugs. Substances may be removed and added to different parts of the schedule by statutory instrument, provided a report of the Advisory Council on the Misuse of Drugs has been commissioned and has reached a conclusion, although the Secretary of State is not bound by the council's findings.
Class A includes cocaine, heroin, morphine, oxycodone, fentanyl, MDMA ("ecstasy"), methamphetamine, opium, LSD, hydrocodone, DMT, mescaline extract, and psilocybin/psilocin (magic mushrooms).
Class B includes cannabis, synthetic cannabinoids, ketamine, amphetamine, codeine, methcathinone, barbiturates, mephedrone, methaqualone, methylphenidate, GHB, and GBL. Any class B drug that is prepared for injections becomes a class A substance.
Class C includes benzodiazepines, xylazine, pregabalin, and most other non-barbiturate tranquillisers; tramadol, gabapentin; anabolic steroids, nitrous oxide, khat, piperazines, and cathinone
All other psychoactive drugs except alcohol, caffeine, and tobacco (or other nicotine preparations) are controlled under the Psychoactive Substances Act 2016 and Medicines Act 1968.
In reality the potential harm has little bearing on the class, which has led to dissatisfaction with drug laws.
Substances may be removed and added to different parts of the schedule by statutory instrument, provided a report of the Advisory Council on the Misuse of Drugs has been commissioned and has reached a conclusion, although the Secretary of State is not bound by the council's findings. This list has in practice been modified a great number of times, sometimes removing substances, but more commonly adding some; for example, many benzodiazepines became Class C drugs in 1985, and many cathinones became Class B drugs in 2010.
=== Class A drugs ===
1. The following substances, namely:—
N.B. Sub-paragraphs (b) and (c) were added in 1977, sub-paragraphs (d) and (e) were added in 1986. Sub-paragraph (ba) was subsequently added in 2001.
(b) any compound structurally derived from tryptamine or from a ring-hydroxy tryptamine by modification.
(ba) a number of phenethylamine derivatives.
(c) compounds structurally derived from phenethylamine an N-alkylphenethylamine, a methylphenethylamine, an N-alkyl-α-methylphenethylamine, an ethylphenethylamine, or an N-alkyl-α-ethylphenethylamine by certain modifications.
(d) compounds structurally derived from fentanyl by certain modifications.
(e) compounds structurally derived from pethidine by certain modifications.
(ea) any compound with a maximum molecular mass of 500 atomic mass units and structurally derived from 2-(2-benzyl-benzimidazol-1-yl)ethanamine.
(f) any compound structurally derived from mescaline, 4-bromo-2,5-dimethoxy-α-methylphenethylamine, 2,5-dimethoxy-α,4-dimethylphenethylamine, N-hydroxytenamphetamine (N-hydroxy-MDA), or a compound specified in sub-paragraph (ba) or (c) above, by substitution at the nitrogen atom of the amino group with a benzyl substituent, whether or not substituted in the phenyl ring of the benzyl group to any extent.
2. Any stereoisomeric of a class A substance, exluding dextromethorphan or dextrorphan.
3. Any ester or ether of a class A substance (that is not listed as a class B substance).
4. Any salt of a class A substance.
5. Any preparation or other product containing a class A substance
6. Any preparation of a class B substance designed for administration by injection.
=== Class B drugs ===
1. The following substances, namely:—
(a)
(aa)
Compounds structurally derived from 2–amino–1–phenyl–1–propanone by certain modifications.
(ab)
Compounds structurally derived from 2–aminopropan–1–one by certain modifications.
(b)
any 5,5 disubstituted barbituric acid.
(c)
and (ca)
A number of categories of synthetic cannabinoids.
(d)
1-Phenylcyclohexylamine or compounds structurally derived from 1-phenylcyclohexylamine or 2-amino-2-phenylcyclohexanone by certain modifications (that are not already class A substances).
(e)
Any compound structurally derived from 1-benzofuran, 2,3-dihydro-1-benzofuran, 1H-indole, indoline, 1H-indene, or indane by certain modifications.
2. Any stereoisomeric form of a class B substance.
3. Any salt of a class B substance.
4. Any preparation or other product containing a class B substance, exluding those designed for administration by injection which are class A.
=== Class C drugs ===
1. The following substances, namely:—
(a)
N.B. Sub-paragraphs (b), (c), (d) and (e) all refer to anabolic steroids that were banned in 1996 (unless referenced otherwise):
(b)
(c)
Compounds structurally derived from 17-hydroxyandrostan-3-one or from 17-hydroxyestran-3-one by certain modifications, excluding Trilostane or a compounds listed above.
(ca)
1–benzylpiperazine or compounds structurally derived from 1–benzylpiperazine or 1–phenylpiperazine by certain modifications.
(d)
any substance which is an ester and/or ether of a substance specified in (b) or (c) above.
(e)
Chorionic gonadotropin
Clenbuterol
Non-human chorionic gonadotrophin
Somatotropin
Somatrem
Somatropin
=== Derivatives and analogues ===
The act contains several references to "derivatives" of compounds but the extent of this term is not fully clarified. Where unspecified it is thought to indicate derivatives which can be made from the specified compound in a single synthetic step, although such a definition would indicate that alkyllysergamide analogues would be uncontrolled. Where the derivatives are specified to be "structural derivatives" there is precedent that the statute applies whenever the structure could be converted to the specified derivatives in any number of synthetic steps.
== Penalties ==
The penalties for drug offences depend on the class of drug involved. These penalties are enforced against those who do not have a valid prescription or licence to possess the drug in question. Thus, it is not illegal for someone to possess heroin, a Class A drug, so long as it was administered to them legally (by prescription).
Class A drugs attract the highest penalty, and imprisonment is both "proper and expedient". The maximum penalties possible are as follows:
== International cooperation ==
The act makes it a crime to assist in, incite, or induce, the commission of an offence, outside the UK, against another nation's corresponding law on drugs. A corresponding law is defined as another country's law "providing for the control and regulation in that country of the production, supply, use, export and import of drugs and other substances in accordance with the provisions of the Single Convention on Narcotic Drugs" or another drug control treaty to which the UK and the other country are parties. An example might be lending money to a United States drug dealer for the purpose of violating that country's Controlled Substances Act.
== History ==
The Drugs (Prevention of Misuse) Act 1964 controlled amphetamines in the United Kingdom in advance of international agreements and was later used to control LSD.
Before 1971, the UK had a relatively liberal drugs policy and it was not until United Nations influence had been brought to bear that controlling incidental drug activities was employed to effectively criminalise drugs use. It is noted that bar the smoking of opium and cannabis; section 8, part d, under the Misuse of Drugs Act 1971 was not an offence (relating to the prosecution of the owner of a premises/building inside of which controlled drugs were being used). Section 8 of the Misuse of Drugs Act 1971 was amended by regulation 13 of Misuse of Drugs Regulations 1985 (SI 1985/2066) and section 38 of the Criminal Justice and Police Act 2001.
These amendments were however repealed in 2005 by Schedule 1 (part 6) of the Drugs Act 2005.
The current section 8 covers:
people knowingly allowing premises they own, manage, or have responsibility for, to be used by any other person for:
administration or use of any controlled drug
supply of any controlled drug
the production or cultivation of controlled drugs, (such as growing cannabis, making crystal meth, preparing magic mushrooms).
== Criticism and controversy ==
Notable criticism of the act includes:
Drug classification: making a hash of it?, Fifth Report of Session 2005–06, House of Commons Science and Technology Committee, which said that the present system of drug classification is based on historical assumptions, not scientific assessment.
Development of a rational scale to assess the harm of drugs of potential misuse, David Nutt, Leslie A. King, William Saulsbury, Colin Blakemore, The Lancet, 24 March 2007, said the act is "not fit for purpose" and "the exclusion of alcohol and tobacco from the Misuse of Drugs Act is, from a scientific perspective, arbitrary."
The Transform Drug Policy Foundation offers rational criticism of the harms caused by the Government's current prohibitionist drug policy. The Drug Equality Alliance (DEA) has launched legal actions against the UK Government's partial and unequal administration of the Act's discretionary powers, making particular reference to the arbitrary exclusion of alcohol and tobacco on the subjective grounds of historical and cultural precedents contrary to the Act's policy and objects.
Following the release of the Cambridge Two – Ruth Wyner and John Brock – who had been convicted under Section 8 of the Act in 1999, a campaign calling for an overhaul of the Act was backed by Michael Winner, Julie Christie, and Tom Stoppard in response to the original conviction.
Classification of cannabis has become especially controversial. In 2004, cannabis was reclassified from class B to class C, in accordance with advice from the Advisory Council on the Misuse of Drugs (ACMD). In 2009, it was returned to class B, against ACMD advice.
In February 2009 the UK government was accused by its most senior expert drugs adviser Professor David Nutt of making a political decisions with regard to drug classification in rejecting the scientific advice to downgrade ecstasy from a class A drug. The Advisory Council on the Misuse of Drugs (ACMD) report on ecstasy, based on a 12-month study of 4,000 academic papers, concluded that it is nowhere near as dangerous as other class A drugs such as heroin and crack cocaine, and should be downgraded to class B. The advice was not followed. Jacqui Smith, then Home Secretary, was also widely criticised by the scientific community for bullying Professor David Nutt into apologising for his comments that, in the course of a normal year, more people died from falling off horses than died from taking ecstasy. Professor Nutt was later sacked by Alan Johnson (Jacqui Smith's successor as Home Secretary); Johnson saying "It is important that the government's messages on drugs are clear and as an advisor you do nothing to undermine public understanding of them. I cannot have public confusion between scientific advice and policy and have therefore lost confidence in your ability to advise me as Chair of the ACMD."
In May 2011, a report named Taking Drugs Seriously was released by Demos. It discusses several issues with the current system, since its enactment in 1971. It states that the constant presence of new drugs will make it difficult for the government to keep up with the latest situation - over 600 drugs are now classified under the act. Comparison levels of harm previously demonstrated by David Nutt show that alcohol and tobacco were among the most lethal, while some class A drugs, such as MDMA, LSD, and magic mushrooms, were among the least harmful.
== Use of controlled substances for research ==
A common misunderstanding amongst researchers is that most national laws (including the Misuse for Drugs Act) allows the use of small amounts of a controlled substance for non-clinical / non-in vivo research without licences. A typical use case might be having a few milligrams or microlitres of a controlled substance within larger chemical collections (often tens of thousands of chemicals) for in vitro screening. Researchers often believe that there is some form of "research exemption" for such small amounts. This incorrect view may be further re-enforced by R&D chemical suppliers often stating and asking scientists to confirm that anything bought is for research use only.
A further misconception is that the Misuse of Drugs Act simply lists a few hundred substances (e.g. MDMA, Fentanyl, Amphetamine, etc.) and compliance can be achieved via checking a CAS number, chemical name or similar identifier. However, the reality is that in most cases all ethers, esters, salts and stereo isomers are also controlled and it is impossible to simply list all of these. The act contains several "generic statements" or "chemical space" laws, which aim to control all chemicals similar to the "named" substance, these provide detailed descriptions similar to Markushes, a good example of a few of these are found in the Misuse of Drugs Act 1971 (amendment) order 2013.
Due to this complexity in legislation the identification of controlled chemicals in research is often carried out computationally, either by in house systems maintained a company's sample logistics department or by the use of commercial software solutions. Automated systems are often required as many research operations can often have chemical collections running into 10Ks of molecules at the 1–5 mg scale, which are likely to include controlled substances, especially within medicinal chemistry research, even if the core research of the company is not narcotic or psychotropic drugs. These may not have been controlled when created, but they have subsequently been declared controlled, or fall within chemical space close to known controlled substances.
There are no specific research exemptions in the Misuse of Drugs Act 1971. However, the associated Misuse of Drugs Regulations 2001 (SI 2001/3998) does exempt products containing less than 1 mg of a controlled substance (1 μg for lysergide and derivatives) so long as a number of requirements are met, including that it cannot be recovered by readily applicable means, does not pose a risk to human health and is not meant for administration to a human or animal.
Although this does at first seem to allow research use, in most circumstances the sample, by definition, is "recoverable" - in order to prepare it for use the sample is "recovered" into an assay buffer or solvent such as DMSO or water. In 2017 the Home Office also confirmed that the 1 mg limit applies to the total of all preparations across the entire container in the case of sample microtitre plates. Given this, most companies and researchers choose not to rely on this exemption.
However according to Home Office licensing, "University research departments generally do not require licences to possess and supply drugs in schedules 2, 3, 4 part I, 4 part II and schedule 5, but they do require licences to produce any of those drugs and to produce, possess and/or supply drugs in schedule 1".
== See also ==
Cannabis in the United Kingdom
Controlled Drug in the United Kingdom
Crime in the United Kingdom
Dangerous Drugs (Supply to Addicts) Regulations 1968
Drug policy of the United Kingdom
Drug-related deaths in the United Kingdom
Temporary class drug
== Notes ==
== References ==
This article incorporates text published under the British Open Government Licence v3.0: To maintain the accuracy of the article, some of the text is copied directly from the legislation.
== External links ==
The full text of Misuse of Drugs Act 1971 at Wikisource
Category:Misuse of Drugs Act 1971 at Wikinews
The text of the Misuse of Drugs Act 1971 – Office of Public Sector Information
Misuse of Drugs Regulations 2001 as amended
UK Misuse of Drugs Act, Steve Chapman website
Controlled Drugs, Patient UK website
Schedules and structures Archived 7 January 2010 at the Wayback Machine of the Misuse of Drugs Act 1971 – Isomer Design | Wikipedia/Misuse_of_Drugs_Act_1971 |
The Drug Price Competition and Patent Term Restoration Act (Public Law 98-417), informally known as the Hatch-Waxman Act, is a 1984 United States federal law that established the modern system of generic drug regulation in the United States. The Act's two main goals are to facilitate entry of generic drugs into the market and to compensate the original drug developers for regulatory delays by the Food and Drug Administration. It is generally believed that the Act accomplished both goals: encouraging development of new medications and accelerating market entry of generics.
Representative Henry Waxman of California and Senator Orrin Hatch of Utah sponsored the act.
== Background ==
Although the Federal Food, Drug, and Cosmetic Act made it possible for generic companies to get regulatory approval for drugs by filing an Abbreviated New Drug Application (ANDA), in the early 1980s it became clear that very few generics were coming to market. Congress studied the issue and realized that under patent and regulatory law it was easy for innovator companies to make it difficult for generic companies to successfully file ANDAs, and that the regulatory pathway to get ANDAs approved was lengthy, expensive, and uncertain. Part of the problem was the CAFC's decision in Roche Products, Inc. v. Bolar Pharmaceutical Co., which interpreted existing U.S. law as prohibiting generic competitors from performing tests required for FDA approval using patented methods, until the patents expired.
In response, the Hatch-Waxman Act was negotiated and enacted.
== Provisions ==
Hatch-Waxman amended the Federal Food, Drug, and Cosmetic Act. Section 505(j) of the Act, codified as 21 U.S.C. § 355(j), outlines the process for pharmaceutical manufacturers to file an Abbreviated New Drug Application (ANDA) for approval of a generic drug by the Food and Drug Administration (FDA).
The Act gives drug innovators some protection while facilitating and providing incentives for companies to file ANDAs.
Drug innovators were given protections in two ways. First, a new kind of market exclusivity was introduced, by means of a new five-year period of data exclusivity awarded when the FDA approves marketing of a drug that is a new chemical entity; during that period the FDA cannot approve a generic version of the drug. This provides market exclusivity for the drug innovator outside of any patent rights. Second, the Act allows the life of patents covering a drug to be extended by a portion of the time the drug is under regulatory review by the FDA, ensuring that regulatory review will not unduly consume patent life. The Act also requires the drug innovator to give the FDA the numbers of patents it believes cover its drug; the FDA does not evaluate whether the patents cover the drug, but publicly lists them in the Orange Book, and these are the patents the life of which is extended if there are regulatory delays.
The Act facilitates the filing of ANDAs by generic companies by preventing the FDA from asking a generic company to provide anything other than information on how it is going to manufacture the drug, quality assurance, and a study showing that the drug acts the same in a human as the innovator drug; this is called bioequivalence. This part of the Act is one of few pieces of legislation that restricts the powers and reach of a federal agency. The Act also gives generic companies safe harbor from patent infringement lawsuits during the time when the generic company is preparing its ANDA; during that time the generic company needs to learn how to manufacture the drug, manufacture a test batch, and run bioequivalence studies, all activities for which it could be sued for infringement. This protection is called the research exemption.
When a company is ready to file its ANDA, the Act requires it to declare how its activities when it begins to market the drug will relate to patents listed in the Orange Book; there are four options, or "certifications": it can state that there never were patents listed, that listed patents have expired, that it will not market the drug until all the patents listed in the Orange Book have expired, or that it believes the patents in the Orange Book are not relevant or are invalid. These four alternatives are called the Paragraph I, II, III, and IV certifications (named after Section 505(j)(2)(A)(vii)(IV)). The Act incentivizes companies to file paragraph IV certifications by rewarding the first company to file an ANDA with such a certification with 180 days of administrative exclusivity if their ANDA is approved; during that period the FDA cannot approve another generic. Because the Act also makes clear that filing an ANDA with a paragraph IV certification is an act of patent infringement, the law actually promotes litigation between private parties; the innovator is prompted to commence patent enforcement litigation against the generic infringer, and the generic company is incentivized to file a countersuit to have the patents listed in the Orange Book declared invalid.
== Consequences ==
Passage of the law prompted a gold rush into the generic industry and a crush of applications, which the FDA was not prepared to handle. A series of scandals soon arose that shook public confidence in generic drugs; there were several instances in which companies obtained bioequivalence data fraudulently, by using the branded drug in their tests instead of their own product, and a congressional investigation found corruption at the FDA, where employees were accepting bribes to approve some generic companies' applications and delaying or denying others.
With time the law became successful in promoting the introduction of generics; in 1983 only 35% of top-selling branded drugs with expired patents had generic competition, and only 13% of prescriptions were for generics but in 2012, 84% of prescriptions in the US were filled with generic drugs.
There have been issues with litigation incentivized by the Act. Once the parties are in litigation, they can choose to fight the litigation to the end, or they may choose to settle the litigation. Some of these settlements have been found to be invalid reverse payment patent settlement agreements and have been struck down in court.
The FDA has been slow to adopt regulations for the introduction of generic versions of biopharmaceutical drugs (known as "biosimilars") because proving biosimilarity and quality control for biopharmaceuticals is much more complicated than for small molecule drugs. Innovator companies have emphasized those complications while generic companies, insurance companies, and consumers have advocated for the FDA to finalize their process.
According to a 2025 paper in the Journal of Economic Perspectives, the net result of the Act is "a convoluted and expensive approach to balancing innovation and competition".
== References ==
== External links ==
FDA Glossary of Term in Relation to Drugs | Wikipedia/Drug_Price_Competition_and_Patent_Term_Restoration_Act |
Medication costs, also known as drug costs are a common health care cost for many people and health care systems. Prescription costs are the costs to the end consumer. Medication costs are influenced by multiple factors such as patents, stakeholder influence, and marketing expenses. A number of countries including Canada, parts of Europe, and Brazil use external reference pricing as a means to compare drug prices and to determine a base price for a particular medication. Other countries use pharmacoeconomics, which looks at the cost/benefit of a product in terms of quality of life, alternative treatments (drug and non-drug), and cost reduction or avoidance in other parts of the health care system (for example, a drug may reduce the need for a surgical intervention, thereby saving money). Structures like the UK's National Institute for Health and Clinical Excellence and to a lesser extent Canada's Common Drug Review (a division of the Canadian Agency for Drugs and Technologies in Health) evaluate products in this way.
Medication costs can be listed in a number of ways including cost per defined daily dose, cost per specific period of time, cost per prescribed daily dose, and cost proportional to gross national product.
A November 2020 study found that more than 1.1 million senior citizens in the U.S. Medicare program are expected to die prematurely over the next decade because they will be unable to afford their prescription medications, requiring an additional $17.7 billion to be spent annually on avoidable medical costs due to health complications.
== Definition ==
Medication costs can be the selling price from the manufacturer, that price together with shipping, the wholesale price, the retail price, and the dispensed price.
The dispensed price or prescription cost is defined as a cost which the patient has to pay to get medicines or treatments which are written as directions on prescription by a prescribers. The cost is generally influenced by a financial relationship between pharmaceutical manufacturers, wholesale distributors and pharmacies. In addition to the financial relationship, each nation has different systems to control the cost of prescriptions. In the United States, a pharmacy benefit manager, a third-party organization, such as private insurances or government-run health insurances will implement cost containment programs, such as establishing a formulary, to contain the cost. In the United Kingdom, the government negotiates an overall cap on drugs bill growth with the pharmaceutical industry. In addition a government agency, the National Institute of Health and Care Excellence (NICE) assesses cost effectiveness of individual prescription drugs pricing. The National Health Service also may negotiate direct with individual pharmaceutical companies for certain specialised medicines, as well as running competitive procurements for generic drugs and for patented medicines where there is more than one drug available for a condition. Prescription costs are a regular health care cost for the sick and may mean economic hardship for the underprivileged.
With healthcare insurance, the patient in the U.S. pays a co-pay (the amount the patient must pay for each drug or medical visit), a deductible (the amount the patient has to pay before the insurance starts sharing the cost) and co-insurance (the amount the patient has to pay after deductible) for prescription costs. After reaching the out of pocket maximum, the insurance company will pay 100% of the prescription cost. The amount the patient has to pay depends on the healthcare insurance plan the patient has.
As of 2017, prescription costs range from just more than 15% in high income countries to 25% in lower-middle income countries and low income countries.: 418
== Factors ==
Pricing any pharmaceutical drug for sale to the general public is daunting. Per Forbes, setting a high ceiling price for a new drug could be problematic as physicians could shy away from prescribing the drug, because the cost could be too great for the benefit. Setting too low of a price could imply inferiority, that the drug is too "weak" for the market. There are many different pricing strategies and factors that go into the research and evaluation of a future drug's price with whole departments within US pharmaceutical companies like Pfizer devoted to cost analysis.
This chart shows discrepancies in drug pricing in different countries.
=== Marketing expenses ===
A study has placed the amount spent on drug marketing at 2-19 times that on drug research.
=== Research and development ===
Much research, needed to create drugs is done by the public sector. In addition, pharmaceutical companies also do much research prior to producing medications. The table shows research and development statistics for pharmaceutical companies as of 2013 per Astra Zeneca.
Severin Schwan, the CEO of the Swiss company Roche, reported in 2012 that Roche's research and development costs in 2014 amounted to $8.4 billion, a quarter of the entire National Institutes of Health budget. Given the profit-driven nature of pharmaceutical companies and their research and development expenses, companies use their research and development expenses as a starting point to determine appropriate yet profitable prices.
Pharmaceutical companies spend a large amount on research and development before a drug is released to the market and costs can be further divided into three major fields: the discovery into the drug's specific medical field, clinical trials, and failed drugs.
==== Discovery ====
The process of drug discovery can involve scientists determining the germs, viruses, and bacteria that cause a specific disease or illness. The time frame can range from 3–20 years and costs can range between several million to tens of millions of dollars. Research teams attempt to break down disease components to find abnormal events/processes taking place in the body. Only then do scientists work on developing chemical compounds to treat these abnormalities with the aid of computer models.
After "discovery" and a creation of a chemical compound, pharmaceutical companies move forward with the Investigational New Drug (IND) Application from the FDA. After the investigation into the drug and given approval, pharmaceutical companies can move into pre-clinical trials and clinical trials.
==== Trials ====
Drug development and pre-clinical trials focus on non-human subjects and work on animals such as rats.
The Food and Drug Administration requires at least 3 phases of clinical trials that assess the side effects and the effectiveness of the drug. An analysis of trial costs of approved drugs by the FDA from 2015 to 2016 found that out of 138 clinical trials, 59 new therapeutic agents were approved by the FDA. These trials have a median estimated cost of $19 million US dollars.
Phase 1 lasts several months and aims to assess the safety and dosage of the drug. The purpose is to determine how the drug affects the body.
Phase 2 lasts several months to two years and aims to assess the efficacy and side effect profile of the drug.
Phase 3 lasts 1 to 4 years and aims to continue assessing and monitoring the efficacy and side effects of the drug. Phase 3 aims to determine the risks and benefits of a drug to its intended patient population.
Phase 4 trials occur after the drug is approved by the FDA and aims to continue monitoring safety and efficacy of the drug.
Of these phases, the phase 3 is the most costly process of drug development. A single phase 3 trial can cost upwards of $100 million. It accounts for about 90 percent of the cost to pharmaceutical companies to develop a medication.
==== Failed drugs ====
The processes of "discovery" and clinical trials amounts to approximately 12 years from research lab to the patient, in which about 10% of all drugs that start pre-clinical trials ever make it to actual human testing. Each pharmaceutical company (who have hundreds of drugs moving in and out of these phases) will never recuperate the costs of "failed drugs". Thus, profits made from one drug need to cover the costs of previous "failed drugs". The cost of failure in R&D constitutes about 60% of all development costs. It emphasizes the importance of success rates as a key driver of R&D productivity. The average costs for studies are estimated at $30 million, $70 million, and $310 million for Phase I, II, and III, respectively.
==== Relationship ====
Overall, research and development expenses relating to a pharmaceutical drug amount to the billions. For example, it was reported that AstraZeneca spent upwards on average of $11 billion per drug for research and developmental purposes. The average of $11 billion only comprises the "discovery" costs, pre-clinical and clinical trial costs, and other expenses. With the addition of "failed drug" costs, the $11 billion easily amounts to over $20 billion in expenses. Therefore, an appropriate figure like $60 billion would be approximate sales figure that a pharmaceutical company like AstraZeneca would aim to generate to cover these costs and make a profit at the same time.
Total research and development costs provide pharmaceutical companies a ballpark estimation of total expenses. This is important in setting projected profit goals for a particular drug and thus, is one of the most necessary steps pharmaceutical companies take in pricing a particular drug.
A 2022 study invalidated the common argument as is for high medication costs that research and development investments are reflected in and necessitate the treatment costs, finding no correlation for investments in drugs (for cases where transparency was sufficient) and their costs.
=== Stakeholders ===
Patients and doctors can also have some input in pricing, though indirectly. Customers in the United States have been protesting the high prices for recent "miracle" drugs like Daraprim and Harvoni, both of which attempt to cure or treat major diseases (HIV/AIDS and hepatitis C). Public outcry has worked in many cases to control and even decide the pricing for some drugs. For example, there was severe backlash over Daraprim, a drug that treats toxoplasmosis. Turing Pharmaceuticals under the leadership of Martin Shkreli raised the price of the drug 5,500% from $13.50 to $750 per pill. After denouncement from 2016 presidential candidates Hillary Clinton and Bernie Sanders, Martin Shkreli said he would reduce the price but later decided not to.
With the recent trend of price gouging, legislators have introduced reform to curb these hikes, effectively controlling the pricing of drugs in the United States. Hillary Clinton announced a proposal to help patients with chronic and severe health conditions by placing a nationwide monthly cap of $250 on prescription out-of-pocket drugs.
Research for a drug that is curing something no one has ever cured before will cost much more than research for the medicine of a very common disease that has known treatments. Also, there would be more patients for a more common ailment so that prices would be lower. Soliris only treats two extremely rare diseases, so the number of consumers is low, making it an orphan drug. Soliris still makes money because of its high price of over $400,000 per year per patient. The benefit of this drug is immense because it cures very rare diseases that would cost much more money to treat otherwise, which saves insurance companies and health agencies millions of dollars. Hence, insurance companies and health agencies are willing to pay these prices.
=== Public policy ===
Policy makers in some countries have placed controls on the amount pharmaceutical companies can raise the price of drugs. In 2017, Democratic party leaders proposed the creation of a new federal agency to investigate and perhaps fine drug manufacturers who make unjustified price increases. Pharmaceutical companies would be required to submit a justification for a drug with a “significant price increase” within at least 30 days of implementation. Under the terms of the proposal, Mylan's well-publicized price increase for its EpiPen product would fall below the criteria for a significant price increase, while the 5000% overnight increase of Turing Pharmaceuticals Daraprim (pyrimethamine) would be subject to regulatory action.
=== Patents and monopoly rights ===
One of the most important factors that determine the cost of a drug is the availability of competing drugs and treatments. Having two or more manufacturers producing drugs for the same disease tends to reduce costs.
Patent laws give pharmaceutical companies the exclusive right to market a drug for a period of time, allowing them to extract a high monopoly price. For example, U.S. patent law grants a monopoly for 20 years after filing. After that period, the same product from different manufacturers - known as generic drugs - can be sold, usually resulting in a substantial price reduction and possible shift in market share. Two patents that are commonly used are process patents and drug product patents. Process patents only provide developers intellectual claim to the methods in which the product was manufactured, so a competitor can make the same drug by a different method without violating the patent.
In some cases, a new treatment is more effective than an older treatment, or a given drug may work better than competitors for only some patients. The availability of an imperfect substitution erodes prices to a lesser degree than would a perfect substitute.
Some countries grant additional protections from competition for a limited period, such as test data exclusivity or supplementary protection certificates. Additional incentives are available in some jurisdictions for manufacturers of orphan drugs for rare diseases, including extended monopoly protection, tax credits, waived fees, and relaxed approval processes due to the small number of affected patients.
=== Transparency ===
The process of creating drugs to testing them to selling them is a long process. Aside from the costs for research and trials, many consumers are unaware of the process of the drug supply chain. There are many middlemen and companies that buy and sell the drugs. This includes "drug manufacturers, drug wholesalers, pharmacies, and payers." Big Pharma's influence in the policies and regulations regarding drug patents and prescription costs, protects pharmaceutical companies from having to be transparent about where the money goes and who those high prices benefit, including Pharmacy Benefit Managers. Transparency between drug manufacturers and sellers increases accountability between producers and consumers and allows for patients to know more about what they are paying for. Prescription Drug Price Locators allow for patients to learn of more cost-effective sellers and find discounts that will benefit them.
In an effort by the U.S. Department of Health and Human Services (HHS) to regulate drug price transparency in television advertising in 2019, the HHS saw a resistance to change against legislation. Although what the HHS sought to change was a step in the right direction for drug price transparency, Federal Judge Amit P. Mehta ruled in favor of the pharmaceutical industry. The ruling was based on the inability to give the HHS such power to enact such legislations. Policymakers have a lot to take into account when regarding the issue of transparency, as there are many middlemen involved in the selling and buying of prescription drugs.
== Effects on consumers ==
When the price of medicine goes up the quality of life of consumers who need the medicine decreases. Consumers who have increased costs for medicine are more likely to change their lifestyle to spend less money on groceries, entertainment, and routine family needs. They are more likely to go into debt or postpone paying their existing debts. High drug prices can prevent people from saving for retirement. It is not uncommon for typical people to have challenges paying medical bills. Some people fail to get the medical care they need due to lack of money to pay for it. In low and middle income countries up to 90% of people pay for medications out of pocket. A November 2020 study by the West Health Policy Center stated that more than 1.1 million senior citizens in the U.S. Medicare program are expected to die prematurely over the next decade because they will be unable to afford their prescription medications, requiring an additional $17.7 billion to be spent annually on avoidable medical costs due to health complications.
The effects of high prescription costs on consumers also affects their long-term health and overall life expectancy. When properly used, a medication can benefit a patient and cure their disease. When a patient cannot afford to pay for their medication, they lose out on the optimal benefits of proper and adequate dosages. High prescription costs don't just affect patients in the short run, but also deteriorates their overall quality of life, as they are exposed to chronic illnesses that could have been prevented by that first prescription. Evidence from studies indicates that insulin therapy as a treatment for patients with high glucose levels that are not yet diabetic, leads to a decrease in insulin resistance, which benefits patients.
== References ==
=== Common measures taken to reduce costs ===
Consumers commonly respond to high or increasing drug prices by doing what they can to save drug costs. The most commonly recommended course of action for consumers who seek to lower their drug costs is for them to tell their own doctor and pharmacist that they need to save money and then ask for advice. Doctors and pharmacists are professionals who know their fields and are the most likely source of information about options for reducing cost.
Depending on the country and health policies implemented, there are also options to search for the most convenient and affordable health insurance plans without having to consult a healthcare provider or obtain insurance through the employer. However, those who seek to purchase insurance individually through the individual market are most likely to be underinsured and therefore could potentially have a higher prescription cost.
There can be significant variation of prices for drugs in different pharmacies, even within a single geographical area. Because of this, some people check prices at multiple pharmacies to seek lower prices. Online pharmacies can offer low prices but many consumers using online services have experienced Internet fraud and other problems, such as long shipping times from overseas and a higher insecurity regarding quality, genuineness and safety of the ordered products.
Some consumers lower costs by asking their doctor for generic drugs when available. Because pharmaceutical companies often set prices by pills rather than by dose, consumers can sometimes buy double-dose pills, split the pills themselves with their doctor's permission, and save money in the process.
=== Not purchasing the medications / inaccessibility ===
In countries without universal healthcare, there can be unaffordable out-of-pocket costs for needed medications. Approximately 25% of Americans find it difficult to afford prescription drugs. In the case of expensive anti-obesity medications it has been noted that many people "who could most benefit from weight loss may be unable to afford such expensive drugs". This may be of higher concern for conditions that are more risky or detrimental to health and/or which, unlike obesity, don't have additional treatment options that are both widely known and effective – like further improvements in diet and physical activity in the case of obesity. A study found that among U.S. Medicare beneficiaries without subsidies, 30% of prescriptions written for anticancer drugs, 22% for hepatitis C, and more than 50% for disease-modifying therapies for either immune system disorders or hypercholesterolemia were not filled by patients.
The right to science and culture is one of the rights in the Universal Declaration of Human Rights according to which "Everyone has the right freely to participate in the cultural life of the community, to enjoy the arts and to share in scientific advancement and its benefits."
=== Effects on healthcare systems ===
While some have concluded that "drug development is likely to remain an expensive and resource-intensive process", a study found that wide range of medicines in the WHO Model List of Essential Medicines can be profitably manufactured at very low cost by pharmaceutical industries and that "Most EML medicines are sold in the UK and South Africa at prices significantly higher than those estimated from production costs".
Global spending on prescription drugs in 2020 may have been ~$1.3 trillion and "The high cost of prescription drugs threatens healthcare budgets, and limits funding available for other areas in which public investment is needed".
== By region ==
=== United States ===
Prescription drug prices in the United States have been among the highest in the world. The high cost of prescription drugs became a major topic of discussion in the new millennium, leading up to the U.S. health care reform debate of 2009, and received renewed attention in 2015. High prices have been attributed to monopolies given to manufacturers by the government and a lack of ability for organizations to negotiate prices.
Individuals are able to enroll in health insurance plans, which often include prescription medication coverage. However, insurance companies decide which drugs they will cover by creating a formulary. If a medication is not on this list, the insurance company may require people to pay more money out-of-pocket compared to other medications that are on the formulary. There are also often tiers within this approved drug list, as the insurance company may be willing to cover a portion of one drug but prefer and completely cover a cheaper alternative.
Medicare Part D is a branch of Medicare that helps to cover costs of prescription medications for patients aged 65 and up. From 2010 to 2018, the Part D plan "nearly quadrupled" its spending on the catastrophic coverage phase. This increase in spending is attributed to the rising pricing of prescription medications.
=== United Kingdom ===
It varies by region in the United Kingdom. In Wales, Scotland and Northern Ireland prescription costs have been completely abolished, however in England the current prescription cost for adults as of 1 April 2024 is £9.90 per item dispensed. There are subsidised costs for those claiming Universal Credit.
=== Canada ===
To provide context for the medication costs in Canada, the country is a member of the OECD, an international organization that consists of 38 countries which includes countries like the United States, Australia, Germany, and more. Among these 38 countries, Canada ranks number three in medication costs in the OECD. The Government of Canada found that during the 2020-2021 year, the country had spent 12.3 billion dollars on medication costs. In Canada, each province and territory publicly funds their own insurance plan rather than a national insurance plan. With differing insurance plans, the medication costs the public varies from area to area.
In Canada, the medication pricing is overseen by the Patented Medicine Prices Review Board (PMPRB), which monitors the prices set for patented drugs. One way the PMPRB evaluates whether drug pricing by patentees is excessive by considering international drug pricing. The PMPRB also compares the price of the drug to a similar market. However, the patentees do not need approval of drug pricing with the PMPRB before listing drugs for sale.
=== Developing world ===
In developing countries medications make up between 25 and 70% of health care costs. Many medications are beyond the reach of the majority of the population. There have been attempts both by international agreements and by pharmaceutical companies to provide drugs at low cost, either supplied by manufacturers who own the drugs, or manufactured locally as generic versions of drugs which are elsewhere protected by patent. Countries without manufacturing capability may import such generics.
The legal framework regarding generic versions of patented drugs is formalised in the Doha Declaration on Trade-Related Aspects of Intellectual Property Rights and later agreements.
== See also ==
== References ==
== Further information ==
== External links ==
Database of International Medication Prices
International Medical Products Price Guide
Multi-country price sources | Wikipedia/Prices_of_prescription_drugs |
The Medicaid Drug Rebate Program is a program in the United States that was created by the Omnibus Budget Reconciliation Act of 1990 (OBRA'90).
The program establishes mandatory rebates that drug manufacturers must pay state Medicaid agencies related to the dispensing of outpatient prescription drugs covered by Medicaid. To participate in the program, drug manufacturers must have a National Drug Rebate Agreement with the Secretary of the Department of Health and Human Services (HHS). As of 2020, approximately 600 pharmaceutics companies participated in the Medicaid Drug Rebate Program. Rebate amounts are confidential under section 1927(b)(3)(D) of the Social Security Act.
The Medicaid Drug Rebate Program also provides for savings in other Federal health care programs. Signing the National Drug Rebate Agreement also requires drug manufacturers to enter into agreements for the 340B Drug Pricing Program as well as the Federal Supply Schedule.
== Rebate methodology ==
The Medicaid Drug Rebate Program provides for mandatory rebates on innovator drugs (e.g., brand drugs), blood clotting factors, drugs Food and Drug Administration-approved exclusively for pediatric indications, and non-innovator drugs (e.g., generic drugs). The maximum rebate is capped at 100% of the Average Manufacturer Price (AMP).
=== Innovator drugs ===
The mandatory rebate is calculated as a base rebate plus an inflationary rebate. The base rebate is the greater of 23.1% of the AMP per unit, or the difference between the AMP and the "best price," defined as the best price given to most commercial insurers. The inflationary rebate as the difference between the AMP on the launch date compared with the current quarter and the United States Consumer Price Index-Urban.
=== Blood clotting factors and drugs FDA-approved exclusively for pediatric indications ===
The mandatory rebate is calculated as a base rebate plus an inflationary rebate. The base rebate is the greater of 17.1% of the AMP, or the difference between the AMP and the best price. The inflationary rebate, when applicable, is calculated with the same methodology as for innovator drugs.
=== Non-innovator drugs ===
The mandatory rebate is calculated as a base rebate plus an inflationary rebate. The base rebate is defined as 13% of the AMP. The inflationary rebate, when applicable, is calculated with the same methodology as for innovator drugs.
== Historical changes ==
The Medicaid Drug Rebate Program has undergone a number of changes since its inception. For example, Section 606 of the Medicare, Medicaid, and SCHIP Balanced Budget Refinement Act of 1999 (BBRA) amended Section 1927(a)(1) allowing states to have the option of different rebate effective dates. This section states that agreements to the rebate program that have been entered on or after November 29, 1999, may go into effect that day, and states option, any date after up to the first day of the quarter.
== The Medicaid Drug Rebate Program and Medicaid managed care ==
At the time the law was enacted, outpatient prescription drugs covered by Medicaid managed care organizations were excluded from access to the drug rebate program. In 1990, only 2.8 million people were enrolled in Medicaid managed care and so the savings lost by the exemption were relatively small. However, enrollment in Medicaid managed care plans has grown significantly.
The Drug Rebate Equalization Act of 2009 (DRE), introduced in the 111th United States Congress by Representative Bart Stupak as H.R. 904, and in the Senate by Senator Jeff Bingaman as S. 547, sought to equalize the treatment of prescription drug discounts between Medicaid managed care and Medicaid fee-for-service. In offering states access to rebates for drugs covered by Medicaid managed care plans, this policy was seen as a way to provide relief for federal and state budgets. The Congressional Budget Office scored the DRE as saving $11 billion over ten years. This proposal was also in President Barack Obama’s 2010 United States federal budget. The DRE passed in both the House and Senate as part of their respective comprehensive health care reform legislation, and was signed into law on March 23, 2010, by President Obama with the Patient Protection and Affordable Care Act. The DRE became effective upon enactment.
== References == | Wikipedia/Medicaid_Drug_Rebate_Program |
The Comprehensive Drug Abuse Prevention and Control Act of 1970, Pub. L. 91–513, 84 Stat. 1236, enacted October 27, 1970, is a United States federal law that, with subsequent modifications, requires the pharmaceutical industry to maintain physical security and strict record keeping for certain types of drugs. Controlled substances are divided into five schedules (or classes) on the basis of their potential for abuse, accepted medical use, and accepted safety under medical supervision. Substances in Schedule I have a high potential for abuse, no accredited medical use, and a lack of accepted safety. From Schedules II to V, substances decrease in potential for abuse. The schedule a substance is placed in determines how it must be controlled. Prescriptions for drugs in all schedules must bear the physician's federal Drug Enforcement Administration (DEA) license number, but some drugs in Schedule V do not require a prescription. State schedules may vary from federal schedules.
The Controlled Substances Act (CSA), Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, is the legal foundation of the government's fight against the abuse of drugs and other substances. This law is a consolidation of numerous laws regulating the manufacture and distribution of narcotics, stimulants, depressants, hallucinogens, anabolic steroids, and chemicals used in the illicit production of controlled substances. The act also provides a mechanism for substances to be controlled, added to a schedule, decontrolled, removed from control, rescheduled, or transferred from one schedule to another.
Proceedings to add, delete, or change the schedule of a drug or other substance may be initiated by the Drug Enforcement Administration (DEA), the Department of Health and Human Services (HHS), or by petition from any interested party, including the manufacturer of a drug, a medical society or association, a pharmacy association, a public interest group concerned with drug abuse, a state or local government agency, or an individual citizen. When a petition is received by the DEA, the agency begins its own investigation of the drug.
The DEA also may begin an investigation of a drug at any time based upon information received from law enforcement laboratories, state and local law enforcement and regulatory agencies, or other sources of information.
Once the DEA has collected the necessary data, the Administrator of the Drug Enforcement Association, by authority of the Attorney General, requests from the HHS a scientific and medical evaluation and recommendation as to whether the drug or other substance should be controlled or removed from control. This request is sent to the Assistant Secretary of Health of the HHS. Then, the HHS solicits information from the Commissioner of the Food and Drug Administration and evaluations and recommendations from the National Institute on Drug Abuse, and on occasion, from the scientific and medical community. The Assistant Secretary, by authority of the Secretary, compiles the information and transmits back to the DEA a medical and scientific evaluation regarding the drug or other substance, a recommendation as to whether the drug should be controlled, and in what schedule it should be placed.
The medical and scientific evaluations are binding to the DEA with respect to scientific and medical matters. The recommendation on scheduling is binding only to the extent that if HHS recommends that the substance not be controlled, the DEA may not control the substance.
Once the DEA has received the scientific and medical evaluation from HHS, the Administrator will evaluate all available data and make a final decision whether to propose that a drug or other substance be controlled and into which schedule it should be placed.
The CSA also creates a closed system of distribution for those authorized to handle controlled substances. The cornerstone of this system is the registration of all those authorized by the DEA to handle controlled substances. All individuals and firms that are registered are required to maintain complete and accurate inventories and records of all transactions involving controlled substances, as well as security for the storage of controlled substances.
== See also ==
Controlled Substances Act
Drug abuse
Psychotropic Substances Act of 1978
== References ==
== External links ==
Full text of CDAPCA: 1970 version | Current version
Nixon, Richard M. (October 27, 1970). "389: Remarks on Signing the Comprehensive Drug Abuse Prevention and Control Act of 1970 - October 27, 1970". Internet Archive. Washington, D.C.: National Archives and Records Service. pp. 948–949. | Wikipedia/Comprehensive_Drug_Abuse_Prevention_and_Control_Act_of_1970 |
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active chemical substance is the same, the medical profile of generics is equivalent in performance compared to their performance at the time when they were patented drugs. A generic drug has the same active pharmaceutical ingredient (API) as the original, but it may differ in some characteristics such as the manufacturing process, formulation, excipients, color, taste, and packaging.
Although they may not be associated with a particular company, generic drugs are usually subject to government regulations in the countries in which they are dispensed. They are labeled with the name of the manufacturer and a generic non-proprietary name such as the United States Adopted Name (USAN) or International Nonproprietary Name (INN) of the drug. A generic drug must contain the same active ingredients as the original brand-name formulation. The U.S. Food and Drug Administration (FDA) requires generics to be identical to or within an acceptable bioequivalent range of their brand-name counterparts, with respect to pharmacokinetic and pharmacodynamic properties.
Biopharmaceuticals, such as monoclonal antibodies, differ biologically from small-molecule drugs. Biosimilars have active pharmaceutical ingredients that are almost identical to the original product and are typically regulated under an extended set of rules, but they are not the same as generic drugs as the active ingredients are not the same as those of their reference products. In most cases, generic products become available after the patent protections afforded to the drug's original developer expire. Once generic drugs enter the market, competition often leads to substantially lower prices for both the original brand-name product and its generic equivalents. In most countries, patents give 20 years of protection. However, many countries and regions, such as the European Union and the United States, may grant up to five years of additional protection ("patent term restoration") if manufacturers meet specific goals, such as conducting clinical trials for pediatric patients.
Manufacturers, wholesalers, insurers, and drugstores can all increase prices at various stages of production and distribution. In 2014, according to an analysis by the Generic Pharmaceutical Association, generic drugs accounted for 88 percent of the 4.3 billion prescriptions filled in the United States.: 2 "Branded generics" on the other hand are defined by the FDA and National Health Service as "products that are (a) either novel dosage forms of off-patent products produced by a manufacturer that is not the originator of the molecule, or (b) a molecule copy of an off-patent product with a trade name." Since the company making branded generics can spend little on research and development, it is able to spend on marketing alone, thus earning higher profits and driving costs down. For example, the largest revenues of Ranbaxy, now owned by Sun Pharma, came from branded generics.
== Nomenclature ==
Generic drug names are constructed using standardized affixes that distinguish drugs between and within classes and suggest their action.
== Economics ==
When a pharmaceutical company first markets a drug, it is usually under a patent that, until it expires, the company can use to exclude competitors by suing them for patent infringement. Pharmaceutical companies that develop new drugs generally only invest in drug candidates with strong patent protection as a strategy to recoup their costs of drug development (including the costs of the drug candidates that fail) and to make a profit. The average cost to a brand-name company of discovering, testing, and obtaining regulatory approval for a new drug, with a new chemical entity, was estimated to be as much as US$800 million in 2003 and US$2.6 billion in 2014. Drug companies that bring new products have several product line extension strategies they use to extend their exclusivity, some of which are seen as gaming the system and labeled "evergreening" by critics, but at some point there is no patent protection available. For as long as a drug patent lasts, a brand-name company enjoys a period of market exclusivity, or monopoly, in which the company is able to set the price of the drug at a level that maximizes profit. This profit often greatly exceeds the development and production costs of the drug, allowing the company to offset the cost of research and development of other drugs that are not profitable or do not pass clinical trials. The impact of loss of patent exclusivity on pharmaceutical products varies significantly across different product classes (e.g., biologics vs. small molecules), largely due to regulatory, legal and manufacturing hurdles associated with such products. Indeed, the greater degree of 'brand-brand' competitive dynamics seen in the biologics and complex generics space allows manufacturers of originators to better protect market share following loss of patent exclusivity.
Large pharmaceutical companies often spend millions protecting their patents from generic competition. Apart from litigation, they may reformulate a drug or license a subsidiary (or another company) to sell generics under the original patent. Generics sold under license from the patent holder are known as authorized generics. Generic drugs are usually sold for significantly lower prices than their branded equivalents and at lower profit margins. One reason for this is that competition increases among producers when a drug is no longer protected by patents. Generic companies incur fewer costs in creating generic drugs—only the cost of manufacturing, without the costs of drug discovery and drug development—and are therefore able to maintain profitability at a lower price. The prices are often low enough for users in less-prosperous countries to afford them. Generic drug companies may also receive the benefit of the previous marketing efforts of the brand-name company, including advertising, presentations by drug representatives, and distribution of free samples. Many drugs introduced by generic manufacturers have already been on the market for a decade or more and may already be well known to patients and providers, although often under their branded name.
India is a leading country in the world's generic drugs market, exporting US$20.0 billion worth of drugs in the 2019–20 (April–March) year. India exports generic drugs to the United States and the European Union. Also according to the market research community the Global Generic Drugs Market was evaluated US$465.96 million in 2021 and is expected to rise with a CAGR of 5.5% from 2022- 2028 during the forecast period. In the United Kingdom, generic drug pricing is controlled by the government's reimbursement rate. The price paid by pharmacists and doctors is determined mainly by the number of license holders, the sales value of the original brand, and the ease of manufacture. A typical price decay graph will show a "scalloped" curve, which usually starts at the brand-name price on the day of generic launch and then falls as competition intensifies. After some years, the graph typically flattens out at approximately 20% of the original brand price. In about 20% of cases, the price "bounces": Some license holders withdraw from the market when the selling price dips below their cost of goods, and the price then rises for a while until the license holders re-enter the market with new stock. The NHS spent about £4.3 billion on generic medicines in 2016–17. In 2012, 84 percent of prescriptions in the US were filled with generic drugs, and in 2014, the use of generic drugs in the United States led to US$254 billion in health care savings.: 2
In the mid-2010s the generics industry began transitioning to the end of an era of giant patent cliffs in the pharmaceutical industry; patented drugs with sales of around US$28 billion were set to come off patent in 2018, but in 2019 only about US$10 billion in revenue was set to open for competition, and less the next year. Companies in the industry have responded with consolidation or turning to try to generate new drugs. Most developed nations require generic drug manufacturers to prove that their formulations are bioequivalent to their brand-name counterparts. Bioequivalence does not mean generic drugs must be exactly the same as the brand-name product ("pharmaceutical equivalent"). Chemical differences may exist; a different salt or ester may be used, for instance. Different inactive ingredients means that the generic may look different from the originator brand; however, the therapeutic effect of the drug must be the same ("pharmaceutical alternative"). Most small molecule drugs are accepted as bioequivalent if their pharmacokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) are within a 90% confidence interval of 80–125%; most approved generics in the US are well within this limit. For more complex products—such as inhalers, patch delivery systems, liposomal preparations, or biosimilar drugs—demonstrating pharmacodynamic or clinical equivalence is more challenging.
=== United States ===
Enacted in 1984, the Drug Price Competition and Patent Term Restoration Act, informally known as the Hatch–Waxman Act, standardized procedures for recognition of generic drugs. In 2007, the FDA launched the Generic Initiative for Value and Efficiency (GIVE): an effort to modernize and streamline the generic drug approval process, and to increase the number and variety of generic products available.
Before a company can market a generic drug, it needs to file an Abbreviated New Drug Application (ANDA) with the Food and Drug Administration, seeking to demonstrate therapeutic equivalence to a previously approved "reference-listed drug" and proving that it can manufacture the drug safely and consistently. For an ANDA to be approved, the FDA requires that the 90% confidence interval of the geometric mean test/reference ratios for the total drug exposure (represented by the area under the curve or AUC) and the maximum plasma concentration (Cmax) should fall within limits of 80–125%. (This range is part of a statistical calculation, and does not mean that generic drugs are allowed to differ from their brand-name counterparts by up to 25 percent.) The FDA evaluated 2,070 studies conducted between 1996 and 2007 that compared the absorption of brand-name and generic drugs into a person's body. The average difference in absorption between the generic and the brand-name drug was 3.5 percent, comparable to the difference between two batches of a brand-name drug. Non-innovator versions of biologic drugs, or biosimilars, require clinical trials for immunogenicity in addition to tests establishing bioequivalency. These products cannot be entirely identical because of batch-to-batch variability and their biological nature, and they are subject to extra rules.
When an application is approved, the FDA adds the generic drug to its Approved Drug Products with Therapeutic Equivalence Evaluations list and annotates the list to show the equivalence between the reference-listed drug and the generic. The FDA also recognizes drugs that use the same ingredients with different bioavailability and divides them into therapeutic equivalence groups. For example, as of 2006, diltiazem hydrochloride had four equivalence groups, all using the same active ingredient, but considered equivalent only within each group.
In order to start selling a drug promptly after the patent on innovator drug expires, a generic company has to file its ANDA well before the patent expires. This puts the generic company at risk of being sued for patent infringement, since the act of filing the ANDA is considered "constructive infringement" of the patent. In order to incentivize generic companies to take that risk the Hatch-Waxman act granted a 180-day administrative exclusivity period to generic drug manufacturers who are the first to file an ANDA.
When faced with patent litigation from the drug innovator or patent holder, generic companies will often counter-sue, challenging the validity of the patent. Like any litigation between private parties, the innovator and generic companies may choose to settle the litigation. Some of these settlement agreements have been struck down by courts when they took the form of reverse payment patent settlement agreements, in which the generic company basically accepts a payment to drop the litigation, delaying the introduction of the generic product and frustrating the purpose of the Hatch–Waxman Act.
Innovator companies sometimes try to maintain some of the revenue from their drug after patents expire by allowing another company to sell an authorized generic; a 2011 FTC report found that consumers benefitted from lower costs when an authorized generic was introduced during the 180 day exclusivity period, as it created competition. Innovator companies may also present arguments to the FDA that the ANDA should not be accepted by filing an FDA citizen petition. The right of individuals or organizations to petition the federal government is guaranteed by the First Amendment to the United States Constitution. For this reason, the FDA has promulgated regulations that provide, among other things, that at any time, any "interested person" can request that the FDA "issue, amend, or revoke a regulation or order," and set forth a procedure for doing so.
==== Acceptance ====
Some generic drugs are viewed with suspicion by doctors. For example, warfarin (Coumadin) has a narrow therapeutic window and requires frequent blood tests to make sure patients do not have a subtherapeutic or a toxic level. A study performed in Ontario showed that replacing Coumadin with generic warfarin was safe, but many physicians are not comfortable with their patients taking branded generic equivalents. In some countries (for example, Australia) where a drug is prescribed under more than one brand name, doctors may choose not to allow pharmacists to substitute a brand different from the one prescribed unless the consumer requests it.
==== Fraud ====
A series of scandals around the approval of generic drugs in the late 1980s shook public confidence in generic drugs; there were several instances in which companies obtained bioequivalence data fraudulently, by using the branded drug in their tests instead of their own product, and a congressional investigation found corruption at the FDA, where employees were accepting bribes to approve some generic companies' applications and delaying or denying others.
In 2007, North Carolina Public Radio's The People's Pharmacy began reporting on consumers' complaints that generic versions of bupropion (Wellbutrin) were yielding unexpected effects. Subsequently, Impax Laboratories's 300 mg extended-release tablets, marketed by Teva Pharmaceutical Industries, were withdrawn from the US market after the FDA determined in 2012 that they were not bioequivalent.
Problems with the quality of generic drugs – especially those produced outside the United States – are widespread as of 2019. The FDA does infrequent – less than annual – inspections of production sites outside the United States. The FDA normally gives advance notice of inspections, which can lead to cover-ups of problems before inspectors arrive; inspections performed with little or no advance notice have produced evidence of serious problems at a majority of generic drug manufacturing sites in India and China.
==== Litigation ====
Two women, each claiming to have suffered severe medical complications from a generic version of metoclopramide, lost their Supreme Court appeal on June 23, 2011. In a 5–4 ruling in PLIVA, Inc. v. Mensing, the court held that generic companies cannot be held liable for information, or the lack of information, on the originator's label.
=== India ===
The Indian government began encouraging more drug manufacturing by Indian companies in the early 1960s, and with the Patents Act in 1970. The Patents Act removed composition patents for foods and drugs, and though it kept process patents, these were shortened to a period of five to seven years. The resulting lack of patent protection created a niche in both the Indian and global markets that Indian companies filled by reverse-engineering new processes for manufacturing low-cost drugs. The code of ethics issued by the Medical Council of India in 2002 calls for physicians to prescribe drugs by their generic names only. India is a leading country in the world's generic drugs market, with Sun Pharmaceuticals being the largest pharmaceutical company in India. Indian generics companies exported US$17.3 billion worth of drugs in the 2017–18 (April–March) year. In 1945–2017, bioequivalence studies were only required for generics of drugs that are less than four years old. Since 2017, all generic drugs of certain classes, irrespective of age, require bioequivalence to be approved.
=== China ===
Generic drug production is a large part of the pharmaceutical industry in China. Western observers have said that China lacks administrative protection for patents. However, entry to the World Trade Organization has brought a stronger patent system. China remains the largest exporter of active pharmaceutical ingredients, accounting for 40% of the world market per a 2017 estimate.
Bioequivalence studies are required for new generic drugs starting from 2016, with older drugs planned as well. In addition, in vitro dissolution behavior is required to match. Since 2018, 44 classes of drugs are exempt from testing (requiring only a dissolution check), and 13 classes only require simplified testing.
== Industry ==
As of 2021, several major companies traditionally dominate the generic drugs market, including Viatris (merger of Mylan and Upjohn), Teva, Novartis' Sandoz, and Sun Pharma. Prices in traditional generic drugs have declined and newer companies such as India-based Sun Pharma, Aurobindo Pharma, and Dr. Reddy's Laboratories, as well as Canada-based Apotex, have taken market share, which has led to a focus on biosimilars.
== See also ==
== References ==
== Further reading ==
== External links ==
"United States Adopted Names Program, generic drug naming process, lists of adopted names". 16 August 2023.
"USFDA, Office of Generic Drugs". Food and Drug Administration. Archived from the original on 2009-05-28. Retrieved 2019-12-16.
"UK Department of Health, generic drugs". Archived from the original on 2007-03-01.
"The Medical Letter on Drugs and Therapeutics".
"GPhA Generic Pharmaceutical Association". Archived from the original on 2021-04-22. Retrieved 2008-06-16.
"Canada Generic Drugs: Government of Canada and Health Canada". 2 May 2018. | Wikipedia/Generic_drugs |
An Abbreviated New Drug Application (ANDA) is an application for a U.S. generic drug approval for an existing licensed medication or approved drug.
The ANDA is submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, which provides for the review and ultimate approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public. Electronic submissions of ANDAs have grown by 70% since November 2008. The Section IV challenge has been credited with suppressing new drug innovation.
A generic drug product is one that is comparable to a patented drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use. All approved products, both innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).
Generic drug applications are termed "abbreviated" because (in comparison with a New Drug Application or the 505(b)(2) regulatory pathway for complex generic or biosimilar medications) they are generally not required to include preclinical (animal and in vitro) and clinical (human) trial data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy volunteers. This gives them the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator drug. In cases of topically active drugs, the bioequivalence of a drug can be demonstrated by comparing drugs dissolution or transdermal drug absorption is compared with the innovator drug. In cases of systemically active drugs, active drug blood concentration of that drug is compared with the innovator drug.
Using bioequivalence as the basis for approving generic copies of drug products was established by the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act. This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA's approval process. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.
== Notes ==
This article incorporates public domain material from websites or documents of the United States Department of Health and Human Services.
== External links ==
FDA source
Henninger, Daniel (2002). "Drug Lag". In David R. Henderson (ed.). Concise Encyclopedia of Economics (1st ed.). Library of Economics and Liberty. OCLC 317650570, 50016270, 163149563 | Wikipedia/Abbreviated_New_Drug_Application |
Nitroglycerin, also known as glyceryl trinitrate (GTN), is a vasodilator used for heart failure, high blood pressure, anal fissures, painful periods, and to treat and prevent chest pain caused by decreased blood flow to the heart (angina) or due to the recreational use of cocaine. This includes chest pain from a heart attack. It is taken by mouth, under the tongue, applied to the skin, or by injection into a vein.
Common side effects include headache and low blood pressure. The low blood pressure can be severe. It is unclear if use in pregnancy is safe for the fetus. It should not be used together with medications within the PDE5 inhibitor family such as sildenafil due to the risk of low blood pressure. Nitroglycerin is in the nitrate family of medications. While it is not entirely clear how it works, it is believed to function by dilating blood vessels.
Nitroglycerin was written about as early as 1846 and came into medical use in 1878. The drug nitroglycerin is a dilute form of the same chemical used as the explosive, nitroglycerin. Dilution makes it non-explosive. In 2022, it was the 196th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
== Medical uses ==
Nitroglycerin is used for the treatment of angina, acute myocardial infarction, severe hypertension, and acute coronary artery spasms. It may be administered intravenously, as a sublingual spray/tablet, or as a patch applied to the skin.
=== Angina ===
Nitroglycerin is useful in decreasing angina attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of NO, also called endothelium-derived relaxing factor, before the structure of NO as the responsible agent was known. This led to the development of transdermal patches of nitroglycerin, providing 24-hour release. However, the effectiveness of nitroglycerin is limited by development of tolerance/tachyphylaxis within 2–3 weeks of sustained use. Continuous administration and absorption (such as provided by daily pills and especially skin patches) accelerate onset of tolerance and limit the usefulness of the agent. Thus, nitroglycerin works best when used only in short-term, pulse dosing. Nitroglycerin is useful for myocardial infarction (heart attack) and pulmonary edema, again working best if used quickly, within a few minutes of symptom onset, as a pulse dose. It may also be given as a sublingual or buccal dose in the form of a tablet placed under the tongue or a spray into the mouth for the treatment of an angina attack.
=== Other uses ===
Tentative evidence indicates efficacy of nitroglycerin in the treatment of various tendinopathies, both in pain management and acceleration of soft tissue repair.
Nitroglycerin is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment.
Nitroglycerin has been used to decrease pain associated with dysmenorrhea.
Nitroglycerin was once researched for the prevention and treatment of osteoporosis; however, the researcher Sophie Jamal was found to have falsified the findings, sparking one of the largest scientific misconduct cases in Canada.
=== Tolerance ===
After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as nitroglycerin—may develop in a patient, reducing its effectiveness. Tolerance is defined as the loss of symptomatic and hemodynamic effects of nitroglycerin or the need for higher doses of the drug to achieve the same effects, and was first described soon after the introduction of nitroglycerin in cardiovascular therapy. Studies have shown that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients' prognosis. These include endothelial and autonomic dysfunction.
The mechanisms of nitrate tolerance have been investigated over the last 30 years, and several hypotheses to explain tolerance have been offered, including:
plasma volume expansion
impaired transformation of nitroglycerin into NO or related species
counteraction of nitroglycerin vasodilation by neurohormonal activation
oxidative stress
== Adverse events ==
Nitroglycerin can cause severe hypotension, reflex tachycardia, and severe headaches that necessitate analgesic intervention for pain relief, the painful nature of which can have a marked negative effect on patient compliance.
Nitroglycerin also can cause severe hypotension, circulatory collapse, and death if used together with vasodilator drugs that are used for erectile dysfunction, such as sildenafil, tadalafil, and vardenafil.
Nitroglycerin transdermal patches should be removed before defibrillation due to the risk of explosion or burns, but investigations have concluded that nitroglycerin patch explosions during defibrillation were due to the breakdown voltage of the metal mesh in some patches.
== Mechanism of action ==
Nitroglycerin is a prodrug which must be denitrated, with the nitrite anion or a related species further reduced to produce the active metabolite nitric oxide (NO). Organic nitrates that undergo these two steps within the body are called nitrovasodilators, and the denitration and reduction occur via a variety of mechanisms. The mechanism by which such nitrates produce NO is widely disputed. Some believe that organic nitrates produce NO by reacting with sulfhydryl groups, while others believe that enzymes such as glutathione S-transferases, cytochrome P450 (CYP), and xanthine oxidoreductase are the primary source of nitroglycerin bioactivation.
The NO produced by this process is a potent activator of guanylyl cyclase (GC) by heme-dependent mechanisms; this activation results in formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). Among other roles, cGMP serves as a substrate for a cGMP-dependent protein kinase that activates myosin light chain phosphatase. Thus, production of NO from exogenous sources such as nitroglycerin increases the level of cGMP within the cell, and stimulates dephosphorylation of myosin, which initiates relaxation of smooth muscle cells in blood vessels.
== History ==
It was known almost from the time of the first synthesis of nitroglycerin by Ascanio Sobrero in 1846 that handling and tasting of nitroglycerin could cause sudden intense headaches, which suggested a vasodilation effect. Constantine Hering developed a form of nitroglycerin in 1847 and advocated for its dosing as a treatment of a number of diseases; however, its use as a specific treatment for blood pressure and chest pain was not among these. This is primarily due to his deep rooted focus in homeopathy.
Following Thomas Brunton's discovery that amyl nitrite could be used to treat chest pain, William Murrell experimented with the use of nitroglycerin to alleviate angina and reduce blood pressure, and showed that the accompanying headaches occurred as a result of overdose. Murrell began treating patients with small doses of nitroglycerin in 1878, and the substance was widely adopted after he published his results in The Lancet in 1879.
The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients, because of a general awareness that nitroglycerin was explosive.
Overdoses may generate methemoglobinemia.
== Society and culture ==
=== Brand names ===
In the United States, Nitrostat is marketed by Viatris after Upjohn was spun off from Pfizer.
== References ==
== Further reading == | Wikipedia/Glyceryl_trinitrate_(pharmacology) |
Research on Adverse Drug Events and Reports (RADAR) is a pharmacovigilance team of 25 doctors who receive calls about possible adverse drug reactions (ADR) and investigate. RADAR is based at Northwestern's Feinberg School of Medicine. RADAR is led by Dennis West. Though it was without funding for its first four years, RADAR has raised about $12 million through grants from the National Institutes of Health, the American Cancer Society and other such institutions. Its work has identified safety problems with 33 drugs. Adverse drug events are a serious health problem.
== Aims ==
The aims of RADAR are to disseminate safety reports for serious adverse drug reactions (sADRs) and to identify barriers to identification and reporting of these clinical events. Investigators have developed a well-coordinated system to accurately compile case report information on sADRs and to identify milestones associated with identification and reporting of the relevant ADR information. This ADR identification system allows us to amass pertinent sADR information from a diverse set of data sources in order to identify and report sADRs in a timely and thorough manner. With increasingly shortened review periods, postmarketing surveillance for sADRs has become very important. In some instances, initial cases are identified at hospital case conferences and reported to the U.S. Food and Drug Administration (FDA) or to the pharmaceutical manufacturer. The RADAR methodology relies on initial recognition of these “sentinel” cases that then prompts hypothesis–driven inquiries as to whether an unrecognized adverse drug event signal is present in the population of those exposed to that drug.
== Results ==
Between 1998 and 2007, 33 serious adverse drug or device reactions have been reported by RADAR investigators. The toxicities involved multiple biological system and included thrombotic thrombocytopenic purpura (TTP) (ticlopidine and clopidogrel), thromboembolism (thalidomide and lenalidomide), liver failure (gemtuzumab and nevirapine), hypersensitivity (drug eluting coronary arterial stents), pure red-cell aplasia (PRCA) (epoetin), vision changes (amiodarone, sildenafil, and tadalafil), late thrombotic events (drug eluting cardiac stents), leukemia (G-CSF), and interstitial pneumonitis (gemcitabine). For each individual ADR, the number of unique event reports collected by RADAR ranged from 0 to 96. Twenty-seven sADRs were associated with drugs and four were associated with a device.
== Methods ==
The success of the RADAR program has previously been largely based on the use of diverse data sources to identify, clarify, and verify ADRs. Databases, registries, clinical trials, referral centers, and case reports have all been utilized as sites of detection. In particular, RADAR has made use of reports submitted to MedWatch as well as more focused databases such as the Medicare-SEER database. Hypothesis-driven active surveillance of a few hundred safety reports serves as the underlying conceptual framework of RADAR pharmacovigilance. Fewer than 20 individual ADR reports led to RADAR investigators identifying safety signals for the majority of the ADRs described to date. Despite a small number of reports for each ADR, causality assessments have been supported by pathology studies, antibody studies, and autopsies. For example, the initial description of thrombotic thrombocytopenic purpura associated with clopidogrel included only 11 cases.
== Strengths ==
RADAR has also identified key barriers to timely and efficiently identifying ADRs and to comprehensively reporting these findings. In particular, we identified quality concerns with MedWatch reports (the FDA's primary source of adverse event reports) and poor quality of dissemination of adverse event findings from the FDA and the pharmaceutical sponsor. Our efforts have found that RADAR sADR identification and dissemination efforts can be as rapid as one to two years after FDA approval, in contrast to the seven years generally seen with safety efforts from the FDA and pharmaceutical sponsors. Thus, the RADAR project has developed into an important adjunct to the current pharmaceutical drug and device safety system.
== Specific ADR reports by RADAR ==
RADAR has analyzed historical data on many drugs from their initial inception, through approval by the FDA, and to the
present. These analyses synthesize the various sources of statistical information on the presence of adverse reactions to these drugs and assess whether the actual risk is in line with studies.
== References == | Wikipedia/Research_on_Adverse_Drug_Events_and_Reports |
The United States Federal Food, Drug, and Cosmetic Act (abbreviated as FFDCA, FDCA, or FD&C) is a set of laws passed by the United States Congress in 1938 giving authority to the U.S. Food and Drug Administration (FDA) to oversee the safety of food, drugs, medical devices, and cosmetics. The FDA's principal representative with members of congress during its drafting was Charles W. Crawford. A principal author of this law was Royal S. Copeland, a three-term U.S. senator from New York. In 1968, the Electronic Product Radiation Control provisions were added to the FD&C. Also in that year the FDA formed the Drug Efficacy Study Implementation (DESI) to incorporate into FD&C regulations the recommendations from a National Academy of Sciences investigation of effectiveness of previously marketed drugs. The act has been amended many times, most recently to add requirements about bioterrorism preparations.
The introduction of this act was influenced by the death of more than 100 patients due to elixir sulfanilamide, a sulfanilamide medication where the toxic solvent diethylene glycol was used to dissolve the drug and make a liquid form. It replaced the earlier Pure Food and Drug Act of 1906.
== Contents ==
The FDC Act has ten chapters:
I. Short Title
II. Definitions
201(f) is the definition for a food, which explicitly includes chewing gum
201(g) is the definition for a drug
201(h) is the definition for a medical device
201(s) is the definition of a food additive
201(ff) is the definition of a dietary supplement
III. Prohibited Acts and Penalties
This section contains both civil law and criminal law clauses. Most violations under the act are civil, though repeated, intentional, and fraudulent violations are covered as criminal law. All violations of the FD&C Act require interstate commerce because of the commerce clause, but this is often interpreted broadly and few products other than raw produce are considered outside of the scope of the act.
Notably, the FD&C Act uses strict liability due to the Dotterweich and Park Supreme Court cases. It is one of a very small number of criminal statutes that does.
IV. Food
There is a distinction in food adulteration between those that are added and those that are naturally present. Substances that are added are held to a stricter "may render (it) injurious to health" standard, whereas substances that are naturally present need only be at a level that "does not ordinarily render it injurious to health"
V. Drugs and Devices
505 is the description of the drug approval process
510(k) is the section that allows for clearance of class II medical devices
515 is the description of the (class III) device approval process
VI. Cosmetics
VII. General Authority
704 allows inspections of regulated entities. Inspection results are reported on Form 483.
VIII. Imports and Exports
IX. Tobacco Products
X. Miscellaneous
== Food coloring ==
The FD&C Act is perhaps best known to consumers because of its use in the naming of food coloring additives, such as "FD&C Yellow No. 6". The Act made the certification of some food color additives mandatory. The FDA lists nine FD&C (Food, Drugs & Cosmetics) certified color additives for use in foods in the United States, and numerous D&C (Drugs & Cosmetics) colorings allowed only in drugs for external application or cosmetics. Color additives derived from natural sources, such as vegetables, minerals or animals, and artificial counterparts of natural derivatives, are exempt from certification. Both artificial and naturally derived color additives are subject to rigorous standards of safety before their approval for use in foods.
=== Certifiable colors ===
== Food additives ==
The FFDCA requires producers of food additives to demonstrate to a reasonable certainty that no harm will result from the intended use of an additive. If the FDA finds an additive to be safe the agency issues a regulation specifying the conditions under which the additive may be safely used.
=== Definition of food additive ===
A shortened definition of "food additive" is defined by the FDA as "any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristic of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation intended for any such use); if such substance is not GRAS or sanctioned prior to 1958 or otherwise excluded from the definition of food additives." The full definition can be found in Section 201(s) of the FD&C Act, which provides for any additional exclusions.
== Homeopathic medications ==
Homeopathic preparations are regulated and protected under Sections 201(g) and 201(j), provided that such medications are formulated from substances listed in the Homeopathic Pharmacopoeia of the United States, which the Act recognizes as an official drug compendium.
However, under separate authority of FTC Act, the Federal Trade Commission declared in November 2016 that homeopathic products cannot include claims of effectiveness without "competent and reliable scientific evidence". If no such evidence exists, they must state this fact clearly on their labeling.
== Bottled water ==
Bottled water is regulated by the FDA as a food. The Agency has published identity standards for types of water (mineral water, spring water), and regulations covering water processing and bottling, water quality and product labeling.
== Cosmetics ==
This Act defines cosmetics as "articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body ... for cleansing, beautifying, promoting attractiveness, or altering the appearance." Under the Act, the FDA does not approve cosmetic products, but the Act prohibits the marketing of adulterated or misbranded cosmetics. However, the FDA does not have the authority to order recalls of cosmetics. If a company is selling a product that is adulterated or misbranded, the FDA can ask the company to recall their product or sue them. The FDA can and does inspect cosmetics manufacturing facilities to ensure that cosmetics are not adulterated.
== Medical devices ==
On May 28, 1976, the FD&C Act was amended to include regulation for medical devices. The amendment required that all medical devices be classified into one of three classes:
Class I: Devices that do not require premarket approval or clearance but must follow general controls. Dental floss is a class I device.
Class II: Devices that are cleared using the 510(k) process. Diagnostic tests, cardiac catheters, hearing aids, and dental amalgams are examples of class II devices.
Class III: Devices that are approved by the premarket approval (PMA) process, analogous to a New Drug Application. These tend to be devices that are permanently implanted into a human body or may be necessary to sustain life. An artificial heart meets both criteria. The most commonly recognized class III device is an automated external defibrillator. Devices that do not meet either criterion are generally cleared as class II devices.
For devices that were marketed prior to the amendment (preamendment devices) and were classified as Class III, the amendment obligated the FDA to review the device to either reclassify it as a Class II device subject to premarket notification, or to require the device manufacturer to undergo the premarket authorization process and prove the safety and efficacy of the device in order to continue marketing it. Notable examples of such preamendment devices are those used for electroconvulsive therapy, which the FDA started reviewing in 2011.
=== Premarket notification (510(k), PMN) ===
Section 510(k) of the Federal Food, Drug, and Cosmetic Act requires those device manufacturers who must register to notify FDA, at least 90 days in advance, of their intent to market a medical device.
This is known as premarket notification, PMN, or 510(k). It allows FDA to determine whether the device is equivalent to a device already placed into one of the three classification categories. Thus, "new" devices (not in commercial distribution prior to May 28, 1976) that have not been classified can be properly identified.
Any device that reaches market via a 510(k) notification must be "substantially equivalent" to a device on the market prior to May 28, 1976 (a "predicate device"). If a device being submitted is significantly different, relative to a pre-1976 device, in terms of design, material, chemical composition, energy source, manufacturing process, or intended use, the device nominally must go through a premarket approval, or PMA.
A device that reaches market via the 510(k) process is not considered to be "approved" by the FDA. Nevertheless, it can be marketed and sold in the United States. They are generally referred to as "cleared" or "510(k) cleared" devices.
A 2011 study by Diana Zuckerman and Paul Brown of the National Research Center for Women and Families, and Steven Nissen of the Cleveland Clinic, published in the Archives of Internal Medicine, showed that most medical devices recalled in the last five years for "serious health problems or death" had been previously cleared by the FDA using the less stringent, and cheaper, 510(k) process. In a few cases the devices had been deemed so low-risk that they did not need FDA regulation. Of the 113 devices recalled, 35 were for cardiovascular issues. This may lead to a reevaluation of FDA procedures and better oversight.
=== Premarket approval (PMA) ===
Premarket approval (PMA) is the most stringent type of device marketing application required by FDA. Unlike the 510(k) pathway, the maker of the medical device must submit an application to the FDA and must receive approval prior to marketing the device.
The PMA application contains information about how the medical device was designed and how it is manufactured, as well as preclinical and clinical studies of the device, demonstrating that it is safe and effective for its intended use. Because the PMA requires a clinical trial it is significantly more expensive than a 510(k).: 7
=== Automatic Class III designation (de novo classification) ===
The Food and Drug Administration Modernization Act of 1997 created section 513(f)(2) of the FD&C Act, which obligated the FDA to establish a risk-based regulatory system for medical devices. As a result, the FDA established a de novo pathway for devices that would automatically be classified as Class III because there was no already-existing device that could be used a predicate for a 510k submission, but for which general controls or general and special controls could provide a reasonable assurance of safety and effectiveness.
== Related legislation ==
The Wheeler-Lea Act, passed in 1938, granted the Federal Trade Commission the authority to oversee advertising of all products regulated by FDA, other than prescription drugs.
== Significant amendments and related laws ==
Descriptions of these can be found at the FDA's web site.
Amendments:
Durham-Humphrey Amendment, Public Law (PL) 82–215 (October 26, 1951) created prescription-only status for some drugs
Drug Efficacy Amendment ("Kefauver Harris Amendment") PL 87–781 (October 10, 1962)
Vitamin-Mineral Amendment ("Proxmire Amendment") (April 22, 1976) prohibited the FDA from establishing standards to limit the potency of vitamins and minerals in food supplements or regulating them as drugs based solely on their potency.
Drug Abuse Control Amendments of 1965
Medical Device Amendments of 1976 PL 94–295 (May 28, 1976)
Infant Formula Act of 1980, PL 96–359 (October 26, 1980)
Orphan Drug Act, PL 97–414 (January 4, 1983)
Drug Price Competition and Patent Term Restoration Act of 1984, PL 98–417 (aka Hatch-Waxman) (September 24, 1984)
Prescription Drug Marketing Act of 1987, PL 100–293 (August 18, 1988)
Generic Animal Drug and Patent Term Restoration Act of 1988, PL 100–670 (November 16, 1988)
Nutrition Labeling and Education Act of 1990, PL 101–535 (November 8, 1990)
Safe Medical Device Amendments of 1990, PL 101–629 (November 28, 1990)
Medical Device Amendments of 1992, PL 102–300 (June 16, 1992)
Prescription Drug User Fee Act (PDUFA) of 1992, PL 102–571 (October 29, 1992)
Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994, PL 103–396 (October 22, 1994)
Dietary Supplement Health And Education Act of 1994, PL 103–417 (October 25, 1994)
Food Quality Protection Act of 1996, PL 104–170 (August 3, 1996)
Animal Drug Availability Act of 1996, PL 104–250 (October 9, 1996)
Best Pharmaceuticals for Children Act, PL 107–109 (January 4, 2002)
Medical Device User Fee and Modernization Act (MDUFMA) of 2002, PL 107–250 (October 26, 2002)
Animal Drug User Fee Act of 2003, PL 108–130 (February 20, 2003)
Pediatric Research Equity Act of 2003, PL 108–155 (December 3, 2003)
Minor Use and Minor Species Animal Health Act of 2004 PL 108–282 (August 2, 2004)
Food Allergen Labeling and Consumer Protection Act of 2004, PL 108–282 (August 2, 2004)
FDA Food Safety Modernization Act (January 4, 2011)
Generic Drug User Fee Amendment of 2012
21st Century Cures Act, PL 114–255 (December 13, 2016)
FDA Reauthorization Act of 2017, PL 115–52 (August 18, 2017)
Other laws:
Biologics Control Act of 1902 (repealed; for historical reference)
Federal Food and Drugs Act of 1906 (repealed; for historical reference)
Federal Meat Inspection Act (March 4, 1907)
Federal Trade Commission Act (September 26, 1914)
Filled Milk Act (March 4, 1923)
Import Milk Act (February 15, 1927)
Public Health Service Act (July 1, 1944)
Trademark Act of 1946 (July 5, 1946)
Reorganization Plan 1 of 1953 (March 12, 1953)
Poultry Products Inspection Act (August 28, 1957)
Fair Packaging and Labeling Act (November 3, 1966)
The National Environmental Policy Act of 1969 (January 1, 1970)
Controlled Substances Act (October 27, 1970)
Controlled Substances Import and Export Act (October 27, 1970)
Egg Products Inspection Act (December 29, 1970)
Lead-Based Paint Poisoning Prevention Act (January 13, 1971)
Federal Advisory Committee Act (October 6, 1972)
Government in the Sunshine Act (September 13, 1976)
Government Patent Policy Act of 1980 (December 12, 1980)
Federal Anti-Tampering Act (October 13, 1983)
Sanitary Food Transportation Act (November 3, 1990)
Food and Drug Administration Revitalization Act (November 28, 1990)
Mammography Quality Standards Act (MQSA) (October 27, 1992)
Food and Drug Administration Modernization Act (November 21, 1997)
Bioterrorism Act of 2002 (June 12, 2002)
Project BioShield Act of 2004 (July 21, 2004)
Food and Drug Administration Amendments Act of 2007 (September 27, 2007)
Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (H.R. 307; 113th Congress) Pub. L. 113–5 (text) (PDF) (March 13, 2013)
== Comparison to state laws ==
Some US states have adopted the FD&C Act as an equivalent state law and will by default adopt any changes to the Federal law as changes to the state law as well.
California Safe Cosmetics Act of 2005
== See also ==
Drugs in the United States
Food Administration
Food Quality Protection Act
Kefauver Harris Amendment
List of food additives
Office of Criminal Investigations
Pure Food and Drug Act
Regulation of therapeutic goods
100,000,000 Guinea Pigs (c. 1933 book which influenced passage of this Act)
== References ==
== External links ==
As codified in 21 U.S.C. chapter 9 of the United States Code from the LII
As codified in 21 U.S.C. chapter 9 of the United States Code from the US House of Representatives
Federal Food, Drug, and Cosmetic Act (PDF/details) as amended in the GPO Statute Compilations collection
Color Additive Status List
Food Ingredients and Colors
Information on Releasable 510(k)s at the FDA | Wikipedia/Federal_Food,_Drug,_and_Cosmetic_Act |
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