European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, food additives, etc, it attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing and adverse effects, as seen in PK/PD models. Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body, the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are affected by the route of administration and the dose of administered drug.
These may affect the absorption rate. Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. One of these, the multi-compartmental model, is the most used approximations to reality; the various compartments that the model is divided into are referred to as the ADME scheme: Liberation – the process of release of a drug from the pharmaceutical formulation. See IVIVC. Absorption – the process of a substance entering the blood circulation. Distribution – the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue; the two phases of metabolism and excretion can be grouped together under the title elimination.
The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. All these concepts can be represented through mathematical formulas that have a corresponding graphical representation; the use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant and solubility, absorption capacity and distribution in the organism. The model outputs for a drug can be used in industry or in the clinical application of pharmacokinetic concepts.
Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine. The following are the most measured pharmacokinetic metrics: In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. In practice, it is considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started; the following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics: Pharmacokinetic modelling is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model and produce accurate results acceptable for bioequivalence studies.
The final outcome of the transformations that a drug undergoes in an organism and the rules that determine this fate depend on a number of interrelated factors. A number of functional models have been developed in order to simplify the study of pharmacokinetics; these models are based on a consideration of an organism as a number of related compartments. The simplest idea is to think of an organism as only one homogenous compartment; this monocompartmental model presupposes that blood plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug's concentration in the organism. However, these models do not always reflect the real situation within an organism. For example, not all body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (s
A prescription drug is a pharmaceutical drug that requires a medical prescription to be dispensed. In contrast, over-the-counter drugs can be obtained without a prescription; the reason for this difference in substance control is the potential scope of misuse, from drug abuse to practicing medicine without a license and without sufficient education. Different jurisdictions have different definitions of. "Rx" is used as a short form for prescription drug in North America - a contraction of the Latin word "recipe" meaning "take". Prescription drugs are dispensed together with a monograph that gives detailed information about the drug; the use of prescription drugs has been increasing since the 1960s. In the U. S. 88% of older adults use at least 1 prescription drug, while 36% take at least 5 prescription medicines concurrently. In Australia, the Standard for the Uniform Scheduling of Medicines and Poisons governs the manufacture and supply of drugs with several categories: Schedule 1 – Defunct Schedule 2 – Pharmacy Medicine Schedule 3 – Pharmacist-Only Medicine Schedule 4 – Prescription-Only Medicine/Prescription Animal Remedy Schedule 5 – Caution Schedule 6 – Poison Schedule 7 – Dangerous Poison Schedule 8 – Controlled Drug Schedule 9 – Prohibited Substance Unscheduled SubstancesLike in the UK, the patient visits a health practitioner, who may prescribe the drug.
Many prescriptions issued by health practitioners in Australia are covered by the Pharmaceutical Benefits Scheme, a scheme that provides subsidised prescription drugs to residents of Australia to ensure that all Australians have affordable and reliable access to a wide range of necessary medicines. When purchasing a drug under the PBS, the consumer pays no more than the patient co-payment contribution, which, as of January 1, 2018, is A$39.50 for general patients. Those covered by government entitlements and or under the Repatriation Pharmaceutical Benefits Scheme have a reduced co-payment, $6.40 in 2018. The co-payments are compulsory and can be discounted by pharmacies up to a maximum of A$1.00 at cost to the pharmacy. In the United Kingdom, the Medicines Act 1968 and the Prescription Only Medicines Order 1997 contain regulations that cover the supply of sale, use and production of medicines. There are three categories of medicine: Prescription-only medicines, which may be dispensed by a pharmacist if they are prescribed by a prescriber Pharmacy medicines, which may be sold by a pharmacist without a prescription General sales list medicines, which may be sold without a prescription in any shopThe possession of a prescription-only medicine without a prescription is legal unless it is covered by the Misuse of Drugs Act 1971.
A patient visits a medical practitioner or dentist, who may prescribe drugs and certain other medical items, such as blood glucose-testing equipment for diabetics. Qualified and experienced nurses and pharmacists may be independent prescribers. Both may prescribe all POMs, but may not prescribe Schedule 1 controlled drugs, 3 listed controlled drugs for the treatment of addiction. Schedule 1 drugs have little or no medical benefit, hence their limitations on prescribing. District nurses and health visitors have had limited prescribing rights since the mid-1990s. Once issued, a prescription is taken by the patient to a pharmacy. Most prescriptions are NHS prescriptions, subject to a standard charge, unrelated to what is dispensed; the NHS prescription fee was increased to £8.80 per item in England on 1 April 2018. The pharmacy charges the NHS the actual cost of the medicine, which may vary from a few pence to hundreds of pounds. A patient can consolidate prescription charges by using a prescription payment certificate capping costs at £29.10 per quarter or £104.00 per year.
Outside the NHS, private prescriptions are issued by private medical practitioner and sometimes under the NHS for medicines that are not covered by the NHS. A patient pays the pharmacy the normal price for medicine prescribed outside the NHS. Survey results published by Ipsos MORI in 2008 found that around 800,000 people in England were not collecting prescriptions or getting them dispensed because of the cost, the same as in 2001. In the United States, the Federal Food and Cosmetic Act defines what substances require a prescription for them to be dispensed by a pharmacy; the federal government authorizes physicians, physician assistants, nurse practitioners and other advanced practice nurses, veterinarians and optometrists to prescribe any controlled substance. They are issued unique Drug Enforcement Act numbers.
Drug metabolism is the metabolic breakdown of drugs by living organisms through specialized enzymatic systems. More xenobiotic metabolism 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, are considered to be of ancient origin. These reactions act to detoxify poisonous compounds; the study of drug metabolism is called pharmacokinetics. The metabolism of pharmaceutical drugs is an important aspect of medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism affects multidrug resistance in infectious diseases and in chemotherapy for cancer, 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 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 the glutathione S-transferases are 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 conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase enzymes such as glutathione S-transferases. In phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters and pumped out of cells. Drug metabolism converts lipophilic compounds into hydrophilic products that are more excreted; the exact compounds an organism is exposed to will be unpredictable, may differ over time. 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, the uptake of useful molecules is mediated through transport proteins that 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, organisms, 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 any non-polar compound.
Useful metabolites are excluded since they are polar, 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 share their polar characteristics. However, since these compounds are few in number, specific enzymes can remove them. Examples of these specific detoxification systems are the glyoxalase system, which removes the reactive aldehyde methylglyoxal, the various antioxidant systems that eliminate reactive oxygen species; the metabolism of xenobiotics is divided into three phases:- modification and excretion. These reactions act in concert to remove them from cells. In phase I, a variety of enzymes act to introduce 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 + ROHPhase I reactions may occur by oxidation, hydrolysis, cyclization and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases in the liver. These oxidative reactions involve a cytochrome P450 monooxygenase, NADPH and oxygen; the classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be excreted at this point. However, many phase I products are not eliminated and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to
Regulation of therapeutic goods
The regulation of therapeutic goods, drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia; the role of therapeutic goods regulation is designed to protect the health and safety of the population. Regulation is aimed at ensuring the safety and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered. There is some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Modern drug regulation has historical roots in the response to the proliferation of universal antidotes which appeared in the wake of Mithridates' death. Mithridates had brought together physicians and shamans to concoct a potion that would make him immune to poisons.
Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means; the first was through the Leechbook of the Bald, written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians; the resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to the development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were created in public and the process was observed and recorded, it was believed that if the concoction proved unsuccessful, it was due to the apothecaries’ process of making them and they could be held accountable because of the public nature of the creation. In the 9th century, many Muslim countries established an office of the hisba, which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines.
Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leigh weigh to ensure compliance and punishments were stringent. The first official'act', the'Apothecary Wares and Stuffs' Act was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians to appoint four people dedicated to inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there was an emergence of standard formulas for the creation of certain ‘drugs’ and ‘antidotes’ through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas; the first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618. In the United States, regulation of drugs was a state right, as opposed to federal right.
But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, increased the need for stronger federal regulation. President Roosevelt signed the Federal Food and Drug Act in 1906 which established stricter standards. A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA; this directly led to Congress passing the Sherley Amendment which established a clearer definition of ‘misbranded’. Another key catalyst for advances in drug regulation were certain catastrophes that served as calls to the government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing; this directly led to the passing of the Federal, Food and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, sold in Germany and sold around the world, led to 100,000 babies being born with various deformities.
The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world; the UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory after, the pharmaceutical industry larger complied due to the thalidomide situation; the European Economic Commission passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. The United States congress passed the Drug Amendments Act of 1962 The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards. Both the EU and US acts introduced the requirements to ensure efficacy.
Of note, increased regulations and standards for testing led to greater innovation in pharm
Curare or is a common name for various plant extract alkaloid arrow poisons originating from Central and South America. These poisons function by competitively and reversibly inhibiting the nicotinic acetylcholine receptor, a subtype of acetylcholine receptor found at the neuromuscular junction; this causes weakness of the skeletal muscles and, when administered in a sufficient dose, eventual death by asphyxiation due to paralysis of the diaphragm. According to pharmacologist Rudolf Boehm's 1895 classification scheme, the three main types of curare are: tube or bamboo curare - so named because of its packing into hollow bamboo tubes - of which the main toxin is D-tubocurarine - derived from Chondrodendron and other genera in the Menispermaceae. Pot curare - packed in terra cotta pots - of which the main alkaloid components are protocurarine and protocuridine. Comprising extracts from both Menispermaceae and Loganiaceae / Strychnaceae. Calabash or gourd curare. Comprising extracts from Loganiaceae / Strychnaceae alone.
Of these three types, some formulae referable to tube curare are the most toxic, relative to their LD50 values. Although this tripartite classification of curares into'tube','pot' and'calabash' was useful, it became outmoded: Gill found that Boehm's classification became invalid shortly after his investigations, because the Indians began to use various types of containers for their preparations.- thus Manske in The Alkaloids in 1955 - where he observes: The results of the early work were inaccurate because of the complexity and variation of the composition of the mixtures of alkaloids involved...these were impure, non-crystalline alkaloids... All curare preparations were and are complex mixtures, many of the physiological actions attributed to the early curarizing preparations were undoubtedly due to impurities to other alkaloids present; the curare preparations are now considered to be of two main types, those from Chondrodendron or other members of the Menispermaceae family and those from Strychnos, a genus of the Loganiaceae family.
Some preparations may contain alkaloids from both...and the majority have other secondary ingredients. Curare was used as a paralyzing poison by South American indigenous people; the prey was shot by arrows or blowgun darts dipped in curare, leading to asphyxiation owing to the inability of the victim's respiratory muscles to contract. The word ` curare' is derived from the Carib language of the Macusi Indians of Guyana. Curare is known among indigenous peoples as Ampi, Woorara, Wourali, Ourare, Urare and Uirary. In 1596, Sir Walter Raleigh mentioned the arrow poison in his book Discovery of the Large and Beautiful Empire of Guiana, though the poison he described was not curare. In 1780, Abbe Felix Fontana discovered that it acted on the voluntary muscles rather than the nerves and the heart. In 1832, Alexander von Humboldt gave the first western account of how the toxin was prepared from plants by Orinoco River natives. During 1811–1812 Sir Benjamin Collins Brody experimented with curare, he was the first to show that curare does not kill the animal and the recovery is complete if the animal's respiration is maintained artificially.
In 1825, Charles Waterton described a classical experiment in which he kept a curarized female donkey alive by artificial respiration with a bellows through a tracheostomy. Waterton is credited with bringing curare to Europe. Robert Hermann Schomburgk, a trained botanist, identified the vine as one of the genus Strychnos and gave it the now accepted name Strychnos toxifera. George Harley showed in 1850 that curare was effective for the treatment of tetanus and strychnine poisoning. In 1857, Claude Bernard published the results of his experiments in which he demonstrated that the mechanism of action of curare was a result of interference in the conduction of nerve impulses from the motor nerve to the skeletal muscle, that this interference occurred at the neuromuscular junction. From 1887, the Burroughs Wellcome catalogue listed under its'Tabloids' brand name, tablets of curare at 1⁄12 grain for use in preparing a solution for hypodermic injection. In 1914, Henry Hallett Dale described the physiological actions of acetylcholine.
After 25 years, he showed that acetylcholine is responsible for neuromuscular transmission, which can be blocked by curare. The best known and most important toxin is d-tubocurarine, it was isolated from the crude drug — from a museum sample of curare — in 1935 by Harold King of London, working in Sir Henry Dale's laboratory. He established its chemical structure.. Pascual Scannone, a Venezuelan anesthesiologist who trained and specialized in New York City, USA, did extensive research on curare as a possible paralyzing agent for patients during surgical procedures. In 1942, he became the first person in all of Latin America to use curare during a medical procedure when he performed a tracheal intubation in a patient to whom he administed curare for muscle paralysis at the “El Algodonal Hospital” in Caracas, Venezuela. After its introduction in 1942, curare/curare-derivatives have become a used pa
The Jmol applet, among other abilities, offers an alternative to the Chime plug-in, no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, the Sculpt mode. Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS 9. Jmol operates on a wide variety of platforms. For example, Jmol is functional in Mozilla Firefox, Internet Explorer, Google Chrome, Safari. Chemistry Development Kit Comparison of software for molecular mechanics modeling Jmol extension for MediaWiki List of molecular graphics systems Molecular graphics Molecule editor Proteopedia PyMOL SAMSON Official website Wiki with listings of websites and moodles Willighagen, Egon. "Fast and Scriptable Molecular Graphics in Web Browsers without Java3D". Doi:10.1038/npre.2007.50.1