1.
Drug nomenclature
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Drug nomenclature is the systematic naming of drugs, especially pharmaceutical drugs. Generic names for drugs are nowadays constructed out of affixes and stems that classify the drugs into different categories, a marketed drug might also have a company code or compound code. The chemical names are the names, based on the molecular structure of the drug. There are various systems of nomenclature and thus various chemical names for any one substance. The most important is the IUPAC name, chemical names are typically very long and too complex to be commonly used in referring to a drug. Sometimes, a company that is developing a drug might give the drug a company code, for example, CDP870 is UCB’s company code for Cimzia. Many of these codes, although not all, have prefixes that correspond to the company name, during development, the company will apply for regulatory approval of the drug by the relevant national regulatory agency, and it will apply for a generic name for that country. It will also apply for an International Nonproprietary Name through the World Health Organization, nowadays the national nonproprietary names are usually the same as the INN. The generic names usually indicate via their stems what drug class the drug belongs to, for example, one can tell that aciclovir is an antiviral drug because its name ends in the -vir suffix. Otherwise the 2 names are both given, joined by hyphens or slashes. For example, suspensions combining trimethoprim and sulfamethoxazole are called either trimethoprim/sulfamethoxazole or co-trimoxazole, similarly, co-codamol is codeine-acetaminophen, and co-triamterzide is triamterene-hydrochlorothiazide. The USP ceased maintaining PENs, but the similar co-prefixed BANs are still current, for drugs that make it all the way through development, testing, and regulatory acceptance, the pharmaceutical company then gives the drug a trade name. The term trade name is a term in the pharmaceutical industry for a brand name or trademark name. For example, Lipitor is Pfizers trade name for atorvastatin, a cholesterol-lowering medication, Drug names are often subject to legal regulation, including approval for new drugs and on packaging to establish clear rules about adulterants and fraudulent or misleading labelling. A national formulary is often designated to define drug names for regulatory purposes, unbiased mentions of a drug place the nonproprietary name first and follow it with the trade name in parentheses, if relevant. This pattern is important for the literature, where conflict of interest is disclosed or avoided. The authors reporting on a study are not endorsing any particular brand of drug and they will often state which brand was used, for methodologic validity, but they do so in a way that makes clear the absence of endorsement. For example, the 2015 American Society of Hematology publication policies say, Non-proprietary names should be used and he first letter of the name of a proprietary drug should be capitalized
2.
Drugs.com
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Drugs. com is an online pharmaceutical encyclopedia which provides drug information for consumers and healthcare professionals primarily in the USA. The domain Drugs. com was registered by Bonnie Neubeck in 1994. In 1999 at the height of the boom, Eric MacIver purchased an option to buy the domain from Neubeck. com. Venture Frogs sold the drugs. com domain name to an investor in June 2001. The Drugs. com website is owned and operated by the Drugsite Trust, the Drugsite Trust is a privately held Trust administered by two New Zealand pharmacists, Karen Ann and Phillip James Thornton The Drugs. com website was officially launched in September 2001. Stedmans, AHFS, Harvard Health Publications, Mayoclinic, North American Compendiums, in March 2008, Drugs. com announced the release of Mednotes —an online personal medication record application which connected to Google Health. In May 2010, U. S. FDA announced a collaboration with Drugs. com to distribute consumer health updates on the Drugs. com website, Drugs. com is certified by the TRUSTe online privacy certification program and the HONcode Health on the Net Foundation
3.
Regulation of therapeutic goods
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The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the 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 mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc
4.
Controlled Substances Act
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The Controlled Substances Act is the statute establishing federal U. S. drug policy under which the manufacture, importation, possession, use and distribution of certain substances is regulated. It was passed by the 91st United States Congress as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, the Act also served as the national implementing legislation for the Single Convention on Narcotic Drugs. The legislation created five Schedules, with varying qualifications for a substance to be included in each, classification decisions are required to be made on criteria including potential for abuse, currently accepted medical use in treatment in the United States, and international treaties. The nation first outlawed addictive drugs in the early 1900s and the International Opium Convention helped lead international agreements regulating trade, the Food and Drugs Act of 1906 was the beginning of over 200 laws concerning public health and consumer protections. Others were the Federal Food, Drug, and Cosmetic Act, in 1969, President Richard Nixon announced that the Attorney General, John N. Shafer—to study cannabis abuse in the United States. It implies an overwhelming indictment of the behavior which we believe is not appropriate, the actual and potential harm of use of the drug is not great enough to justify intrusion by the criminal law into private behavior, a step which our society takes only with the greatest reluctance. According to David T. Courtwright, the Act was part of a reform package designed to rationalize. It eliminated mandatory minimum sentences and provided support for drug treatment, king notes that the rehabilitation clauses were added as a compromise to Senator Jim Hughes, who favored a moderate approach. The bill, as introduced by Senator Everett Dirksen, ran to 91 pages, since its enactment in 1970, the Act has been amended several times, The Medical Device Amendments of 1976. The Psychotropic Substances Act of 1978 added provisions implementing the Convention on Psychotropic Substances, the Controlled Substances Penalties Amendments Act of 1984. The Ryan Haight Online Pharmacy Consumer Protection Act of 2008 The Electronic Prescriptions for Controlled Substances 2010, the Controlled Substances Act consists of 2 subchapters. Subchapter II describes the laws for exportation and importation of controlled substances, again specifying fines, the Drug Enforcement Administration was established in 1973, combining the Bureau of Narcotics and Dangerous Drugs and Customs drug agents. When a petition is received by the DEA, the agency begins its own investigation of the drug and this request is sent to the Assistant Secretary of Health of HHS. Under certain circumstances, the Government may temporarily schedule a drug without following the normal procedure, an example is when international treaties require control of a substance. In addition,21 U. S. C. §811 allows the Attorney General to temporarily place a substance in Schedule I to avoid an imminent hazard to the public safety, in any case, once these proceedings are complete, the temporary order is automatically vacated. Unlike ordinary scheduling proceedings, such orders are not subject to judicial review. The CSA also creates a 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
5.
Convention on Psychotropic Substances
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The Single Convention on Narcotic Drugs of 1961 could not ban the many newly discovered psychotropics, since its scope was limited to drugs with cannabis, coca, and opium-like effects. The Convention, which contains import and export restrictions and other rules aimed at limiting drug use to scientific and medical purposes, as of 2013,183 member states are Parties to the treaty. Many laws have passed to implement the Convention, including the U. S. Psychotropic Substances Act, the UK Misuse of Drugs Act 1971. Adolf Lande, under the direction of the United Nations Office of Legal Affairs, the Commentary, published in 1976, is an invaluable aid to interpreting the treaty and constitutes a key part of its legislative history. This treaty, signed in 1988, regulates precursor chemicals to drugs controlled by the Single Convention and it also strengthens provisions against money laundering and other drug-related crimes. International drug control began with the 1912 International Opium Convention, a treaty which adopted import and export restrictions on the opium poppys psychoactive derivatives, after the United Nations was formed in 1945, those enforcement functions passed to the UN. During the 1960s, drug use increased in Western developed nations, young people began using hallucinogenic, stimulant, and other drugs on a widespread scale that has continued to the present. In many jurisdictions, police had no laws under which to prosecute users and traffickers of these new drugs, LSD, the language of the Single Convention and its legislative history precluded any interpretation that would allow international regulation of these drugs under that treaty. A new convention, with a scope, would be required in order to bring those substances under control. Using the Single Convention as a template, the Commission prepared a draft convention which was forwarded to all UN member states, the Secretary-General of the United Nations scheduled a conference for early 1971 to finalize the treaty. Meanwhile, countries had already begun passing legislation to implement the draft treaty, in 1969, Canada added Part IV to its Food and Drugs Act, placing a set of restricted substances, including LSD, DMT, and MDA, under federal control. In 1970, the United States completely revamped its existing drug laws by enacting the Controlled Substances Act. In 1971, the United Kingdom passed the Misuse of Drugs Act 1971, a host of other nations followed suit. The conference convened on 11 January 1971, Nations split into two rival factions, based on their interests. According to a Senate of Canada report, One group included mostly developed nations with powerful pharmaceutical industries, the other group consisted of developing states. with few psychotropic manufacturing facilities. The organic drugmaking states that had suffered economically from the Single Conventions restrictions on cannabis, coca, the synthetic drug-producing states opposed those restrictions. The Conventions adoption marked a milestone in the development of the global drug control regime. As of June 2013, there are 183 state parties to the convention and this total includes 182 member states of the United Nations and the Holy See
6.
Pharmacokinetics
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Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as, pharmaceutical drugs, pesticides, food additives, cosmetic ingredients, 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, both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Pharmacokinetic properties of chemicals are affected by the route of administration and these may affect the absorption rate. Models have been developed to simplify conceptualization of the processes that take place in the interaction between an organism and a chemical substance. The various compartments that the model is divided into are commonly referred to as the ADME scheme, absorption - the process of a substance entering the blood circulation. Distribution - the dispersion or dissemination of substances throughout the fluids, 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 also 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. All these concepts can be represented through mathematical formulas that have a graphical representation. The model outputs for a drug can be used in industry or in the application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals, in practice, it is generally 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. 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. The final outcome of the transformations that a drug undergoes in an organism, 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. However, these models do not always reflect the real situation within an organism
7.
Bioavailability
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By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes, its bioavailability generally decreases or may vary from patient to patient, Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. Bioavailability is defined differently for drugs as opposed to dietary supplements primarily due to the method of administration and Food. Bioaccessibility is a related to bioavailability in the context of biodegradation. A molecule is said to be bioaccessible when is available to cross a cellular membrane from the environment. In pharmacology, bioavailability is a measurement of the rate and extent to which a drug reaches at the site of action and it is denoted by the letter f. Therefore, bioavailability for dietary supplements can be defined as the proportion of the administered substance capable of being absorbed, in both pharmacology and nutrition sciences, bioavailability is measured by calculating the area under curve of the drug concentration time profile. Bioavailability is commonly a factor in the production of crops. Toxic materials in soil, such as lead from paint may be rendered unavailable to animals ingesting contaminated soil by supplying phosphorus fertilizers in excess and it is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be normalized, consequently, the amount absorbed is corrected by dividing the corresponding dose administered. The absolute bioavailability is the area under curve non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the route is given below. If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability, although knowing the true extent of systemic absorption is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires a reference, that is. These limitations may be overcome, however, by administering a low dose of an isotopically labelled drug concomitantly with a therapeutic non-labelled oral dose. This technique eliminates pharmacokinetic issues on non-equivalent clearance as well as enabling the intravenous dose to be administered with a minimum of toxicology, the technique was first applied using stable-isotopes such as 13C and mass-spectrometry to distinguish the isotopes by mass difference. More recently, 14C labelled drugs are administered intravenously and accelerator mass spectrometry used to measure the isotopically labelled drug along with mass spectrometry for the unlabelled drug, in all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously. Intravenous administration of a drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution
8.
Drug metabolism
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Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. These pathways are a form of biotransformation present in all groups of organisms. These reactions often act to detoxify poisonous compounds, the study of drug metabolism is called pharmacokinetics. The metabolism of drugs is an important aspect of pharmacology. For example, the rate of metabolism determines the duration and intensity of a drugs pharmacologic action, 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 conjugated to polar compounds in phase II reactions. These reactions are catalysed by enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be processed, before being recognised by efflux transporters. Drug metabolism often converts lipophilic compounds into hydrophilic products that are readily excreted. The exact compounds an organism is exposed to will be unpredictable, and may differ widely over time. The solution that has evolved to address this problem is an elegant combination of physical barriers, all organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. This selective uptake means that most hydrophilic molecules cannot enter cells, 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 and 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 one or more charged groups. However, since these compounds are few in number, specific enzymes can recognize, 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, 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 and 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
9.
Excretion
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Excretion is the process by which metabolic wastes and other non-useful materials are eliminated from an organism. In vertebrates this is carried out by the lungs, kidneys. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell, excretion is an essential process in all forms of life. For example, in urine is expelled through the urethra. In unicellular organisms, waste products are discharged directly through the surface of the cell, green plants produce carbon dioxide and water as respiratory products. In green plants, the carbon dioxide released during respiration gets utilized during photosynthesis, oxygen is a by product generated during photosynthesis, and exits through stomata, root cell walls, and other routes. Plants can get rid of water by transpiration and guttation. These latter processes do not need added energy, they act passively, however, during the pre-abscission phase, the metabolic levels of a leaf are high. Plants also excrete some waste substances into the soil around them, in animals, the main excretory products are carbon dioxide, ammonia, urea, uric acid, guanine and creatine. The liver and kidneys clear many substances from the blood, aquatic animals usually excrete ammonia directly into the external environment, as this compound has high solubility and there is ample water available for dilution. In terrestrial animals ammonia-like compounds are converted into other materials as there is less water in the environment. Birds excrete their nitrogenous wastes as uric acid in the form of a paste and this is metabolically more expensive, but allows more efficient water retention and it can be stored more easily in the egg. Many avian species, especially seabirds, can also excrete salt via specialized nasal salt glands, in insects, a system involving Malpighian tubules is utilized to excrete metabolic waste. Metabolic waste diffuses or is actively transported into the tubule, which transports the wastes to the intestines, the metabolic waste is then released from the body along with fecal matter. The excreted material may be called dejecta or ejecta, in pathology the word ejecta is more commonly used. UAlberta. ca, Animation of excretion Brian J Ford on leaf fall in Nature
10.
PubChem
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PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service
11.
DrugBank
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The DrugBank database is a comprehensive, freely accessible, online database containing information on drugs and drug targets. As both a bioinformatics and a resource, DrugBank combines detailed drug data with comprehensive drug target information. Because of its scope, comprehensive referencing and unusually detailed data descriptions. As a result, links to DrugBank are maintained for nearly all drugs listed in Wikipedia, DrugBank is widely used by the drug industry, medicinal chemists, pharmacists, physicians, students and the general public. Its extensive drug and drug-target data has enabled the discovery and repurposing of a number of existing drugs to treat rare, the latest release of the database contains 8227 drug entries including 2003 FDA-approved small molecule drugs,221 FDA-approved biotech drugs,93 nutraceuticals and over 6000 experimental drugs. Additionally,4270 non-redundant protein sequences are linked to these drug entries, each DrugCard entry contains more than 200 data fields with half of the information being devoted to drug/chemical data and the other half devoted to drug target or protein data. Four additional databases, HMDB, T3DB, SMPDB and FooDB are also part of a suite of metabolomic/cheminformatic databases. The first version of DrugBank was released in 2006 and this early release contained relatively modest information about 841 FDA-approved small molecule drugs and 113 biotech drugs. It also included information on 2133 drug targets, the second version of DrugBank was released in 2009. This greatly expanded and improved version of the database included 1344 approved small molecule drugs and 123 biotech drugs as well as 3037 unique drug targets. Version 2.0 also included, for the first time, withdrawn drugs and illicit drugs, version 3.0 was released in 2011. This version contained 1424 approved small molecule drugs and 132 biotech drugs as well as >4000 unique drug targets, version 3.0 also included drug transporter data, drug pathway data, drug pricing, patent and manufacturing data as well as data on >5000 experimental drugs. Version 4.0 was released in 2014 and this version included 1558 FDA-approved small molecule drugs,155 biotech drugs and 4200 unique drug targets. Version 4.0 also incorporated information on drug metabolites, drug taxonomy, drug spectra, drug binding constants. Table 1 provides a complete statistical summary of the history of DrugBank’s development. All data in DrugBank is non-proprietary or is derived from a non-proprietary source and it is freely accessible and available to anyone. In addition, nearly every item is fully traceable and explicitly referenced to the original source. DrugBank data is available through a web interface and downloads
12.
ChemSpider
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ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses
13.
ChEMBL
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ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties. It is maintained by the European Bioinformatics Institute, of the European Molecular Biology Laboratory, based at the Wellcome Trust Genome Campus, Hinxton, the database, originally known as StARlite, was developed by a biotechnology company called Inpharmatica Ltd. later acquired by Galapagos NV. The data was acquired for EMBL in 2008 with an award from The Wellcome Trust, resulting in the creation of the ChEMBL chemogenomics group at EMBL-EBI, the ChEMBL database contains compound bioactivity data against drug targets. Bioactivity is reported in Ki, Kd, IC50, and EC50, data can be filtered and analyzed to develop compound screening libraries for lead identification during drug discovery. ChEMBL version 2 was launched in January 2010, including 2.4 million bioassay measurements covering 622,824 compounds and this was obtained from curating over 34,000 publications across twelve medicinal chemistry journals. ChEMBLs coverage of available bioactivity data has grown to become the most comprehensive ever seen in a public database, in October 2010 ChEMBL version 8 was launched, with over 2.97 million bioassay measurements covering 636,269 compounds. ChEMBL_10 saw the addition of the PubChem confirmatory assays, in order to integrate data that is comparable to the type, ChEMBLdb can be accessed via a web interface or downloaded by File Transfer Protocol. It is formatted in a manner amenable to computerized data mining, ChEMBL is also integrated into other large-scale chemistry resources, including PubChem and the ChemSpider system of the Royal Society of Chemistry. In addition to the database, the ChEMBL group have developed tools and these include Kinase SARfari, an integrated chemogenomics workbench focussed on kinases. The system incorporates and links sequence, structure, compounds and screening data, the primary purpose of ChEMBL-NTD is to provide a freely accessible and permanent archive and distribution centre for deposited data. July 2012 saw the release of a new data service, sponsored by the Medicines for Malaria Venture. The data in this service includes compounds from the Malaria Box screening set, myChEMBL, the ChEMBL virtual machine, was released in October 2013 to allow users to access a complete and free, easy-to-install cheminformatics infrastructure. In December 2013, the operations of the SureChem patent informatics database were transferred to EMBL-EBI, in a portmanteau, SureChem was renamed SureChEMBL. 2014 saw the introduction of the new resource ADME SARfari - a tool for predicting and comparing cross-species ADME targets
14.
European Chemicals Agency
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ECHA is the driving force among regulatory authorities in implementing the EUs chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and it is located in Helsinki, Finland. The Agency, headed by Executive Director Geert Dancet, started working on 1 June 2007, the REACH Regulation requires companies to provide information on the hazards, risks 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 commonly used substances have been registered, the information is technical but gives detail on the impact of each chemical on people and the environment. This also gives European consumers the right to ask whether the goods they buy contain dangerous substances. The Classification, Labelling 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, companies need to notify ECHA of the classification and labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100000 substances, the information is freely available on their website. Consumers can check chemicals in the products they use, Biocidal products include, for example, insect repellents and disinfectants used in hospitals. The Biocidal Products Regulation ensures that there is 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 export and import of hazardous chemicals. Through this mechanism, countries due to hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have effects on human health and the environment are identified as Substances of Very High Concern 1. These are mainly substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment, other substances considered as SVHCs include, for example, endocrine disrupting chemicals. Companies manufacturing or importing articles containing these substances in a concentration above 0 and 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 officially identified in the EU as being of very 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 then move to another list
15.
Chemical formula
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These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH
16.
Jmol
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Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D
17.
Simplified molecular-input line-entry system
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The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES
18.
International Chemical Identifier
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Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure
19.
Hypnotic
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This group is related to sedatives. Whereas the term sedative describes drugs that serve to calm or relieve anxiety, because these two functions frequently overlap, and because drugs in this class generally produce dose-dependent effects they are often referred to collectively as sedative-hypnotic drugs. Hypnotic drugs are prescribed for insomnia and other sleep disorders. When prescribed, hypnotic medication should be used for the shortest period of time necessary, most hypnotics prescribed today are either benzodiazepines or nonbenzodiazepines. Among individuals with sleep disorders,13. 7% are taking or prescribed nonbenzodiazepines, while 10. 8% are taking benzodiazepines, early classes of drugs, such as barbiturates, have fallen out of use in most practices but are still prescribed for some patients. In children, prescribing hypnotics is not yet acceptable unless used to treat night terrors or somnambulism, falling outside of the above-mentioned categories, the neuro-hormone melatonin has a hypnotic function. Research about using medications to treat insomnia evolved throughout the last half of the 20th century, treatment for insomnia in psychiatry dates back to 1869 when chloral hydrate was first used as a soporific. Barbiturates emerged as the first class of drugs that emerged in the early 1900s, although the best drug family at the time they were dangerous in overdose. During the 1970s, quinazolinones and benzodiazepines were introduced as alternatives to replace barbiturates. Benzodiazepines are not without their drawbacks, substance dependence is possible, questions have been raised as to whether they disturb sleep architecture. Nonbenzodiazepines are the most recent development, although its clear that they are less toxic than their predecessors, barbiturates, comparative efficacy over benzodiazepines have not been established. Without longitudinal studies, it is hard to determine, however some psychiatrists recommend these drugs, other sleep remedies that may be considered sedative-hypnotics exist, psychiatrists will sometimes prescribe medicines off-label if they have sedating effects. Examples of these include mirtazapine, clonidine, quetiapine, and the over-the-counter sleep aid diphenhydramine, off-label sleep remedies are particularly useful when first-line treatment is unsuccessful or deemed unsafe. Barbiturates are drugs that act as central nervous system depressants, and can produce a wide spectrum of effects. They are also effective as anxiolytics, hypnotics, and anticonvulsants, barbiturates also have analgesic effects, however, these effects are somewhat weak, preventing barbiturates from being used in surgery in the absence of other analgesics. They have dependence liability, both physical and psychological, however, barbiturates are still used in general anesthesia, for epilepsy, and assisted suicide. Barbiturates are derivatives of barbituric acid, the principal mechanism of action of barbiturates is believed to be positive allosteric modulation of GABAA receptors. Examples include amobarbital, pentobarbital, phenobarbital, secobarbital, and sodium thiopental, quinazolinones are also a class of drugs which function as hypnotic/sedatives that contain a 4-quinazolinone core
20.
Benzodiazepine
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Benzodiazepines, sometimes called benzos, are a class of psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. In 1977 benzodiazepines were globally the most prescribed medications, Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid at the GABAA receptor, resulting in sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may also cause anterograde amnesia and these properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either short-, intermediate-, or long-acting, short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia, longer-acting benzodiazepines are recommended for the treatment of anxiety. Benzodiazepines are generally viewed as safe and effective for use, although cognitive impairment. A minority of people can have paradoxical reactions such as worsened agitation or panic, long-term use is controversial because of concerns about adverse psychological and physical effects, decreasing effectiveness, and physical dependence and withdrawal. As a result of adverse effects associated with the use of benzodiazepines, withdrawal from benzodiazepines, in general. There is controversy concerning the safety of benzodiazepines in pregnancy, Benzodiazepines can be taken in overdoses and can cause dangerous deep unconsciousness. However, they are less toxic than their predecessors, the barbiturates, when combined with other central nervous system depressants such as ethanol and opioids, the potential for toxicity and fatal overdose increases. Benzodiazepines are commonly misused and taken in combination with other drugs of abuse, most are administered orally, however, they can also be given intravenously, intramuscularly, or rectally. In general, benzodiazepines are well-tolerated and are safe and effective drugs in the term for a wide range of conditions. Tolerance can develop to their effects and there is also a risk of dependence and these factors, combined with other possible secondary effects after prolonged use such as psychomotor, cognitive, or memory impairments, limit their long-term applicability. The effects of use or misuse include the tendency to cause or worsen cognitive deficits, depression. The College of Physicians and Surgeons of British Columbia recommends discontinuing the usage of benzodiazepines in those on opioids, because of their effectiveness, tolerability, and rapid onset of anxiolytic action, benzodiazepines are frequently used for the treatment of anxiety associated with panic disorder. However, there is disagreement among expert bodies regarding the use of benzodiazepines for panic disorder. APA states that there is insufficient evidence to recommend any of the established panic disorder treatments over another, one advantage of benzodiazepines is that they alleviate the anxiety symptoms much faster than antidepressants, and therefore may be preferred in patients for whom rapid symptom control is critical. However, this advantage is offset by the possibility of developing benzodiazepine dependence, APA does not recommend benzodiazepines for persons with depressive symptoms or a recent history of substance abuse. Although major concerns about benzodiazepine tolerance and withdrawal have been raised, for many such patients stable doses of benzodiazepines retain their efficacy over several years
21.
Skeletal muscle relaxant
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A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, the term muscle relaxant is used to refer to two major therapeutic groups, neuromuscular blockers and spasmolytics. Neuromuscular blockers act by interfering with transmission at the end plate and have no central nervous system activity. They are often used during surgical procedures and in intensive care, spasmolytics, also known as centrally acting muscle relaxants, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxants, the term is used to refer to spasmolytics only. The earliest known use of muscle relaxant drugs was by natives of the Amazon Basin in South America who used poison-tipped arrows that produced death by skeletal muscle paralysis and this was first documented in the 16th century, when European explorers encountered it. This poison, known today as curare, led to some of the earliest scientific studies in pharmacology, by 1943, neuromuscular blocking drugs became established as muscle relaxants in the practice of anesthesia and surgery. The U. S. Food and Drug Administration approved the use of carisoprodol in 1959, metaxalone in August 1962, most neuromuscular blockers function by blocking transmission at the end plate of the neuromuscular junction. Normally, a nerve impulse arrives at the nerve terminal, initiating an influx of calcium ions. Acetylcholine then diffuses across the synaptic cleft and it may be hydrolysed by acetylcholine esterase or bind to the nicotinic receptors located on the motor end plate. The binding of two acetylcholine molecules results in a change in the receptor that opens the sodium-potassium channel of the nicotinic receptor. This allows Na+ and Ca2+ ions to enter the cell and K+ ions to leave the cell, causing a depolarization of the end plate, following depolarization, the acetylcholine molecules are then removed from the end plate region and enzymatically hydrolysed by acetylcholinesterase. Normal end plate function can be blocked by two mechanisms, nondepolarizing agents, such as tubocurarine, block the agonist, acetylcholine, from binding to nicotinic receptors and activating them, thereby preventing depolarization. The generation of the signals in motor neurons that cause muscle contractions are dependent on the balance of synaptic excitation and inhibition the motor neuron receives. Spasmolytic agents generally work by enhancing the level of inhibition. Inhibition is enhanced by mimicking or enhancing the actions of endogenous inhibitory substances, because they may act at the level of the cortex, brain stem or spinal cord, or all three areas, they have traditionally been referred to as centrally acting muscle relaxants. However, it is now known not every agent in this class has CNS activity, most sources still use the term centrally acting muscle relaxant. According to MeSH, dantrolene is usually classified as a centrally acting muscle relaxant, the World Health Organization, in its ATC, uses the term centrally acting agents, but adds a distinct category of directly acting agents, for dantrolene
22.
Anticonvulsant
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Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants suppress the rapid and excessive firing of neurons during seizures, anticonvulsants also prevent the spread of the seizure within the brain. Some investigators have observed that anticonvulsants themselves may cause reduced IQ in children, conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid function. Several antiepileptic drugs have multiple or uncertain mechanisms of action, next to the voltage-gated sodium channels and components of the GABA system, their targets include GABAA receptors, the GAT-1 GABA transporter, and GABA transaminase. Additional targets include voltage-gated calcium channels, SV2A, and α2δ, by blocking sodium or calcium channels, antiepileptic drugs reduce the release of excitatory glutamate, whose release is considered to be elevated in epilepsy, but also that of GABA. This is probably an effect or even the actual mechanism of action for some antiepileptic drugs, since GABA can itself, directly or indirectly. Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha, the drug class was the 5th-best-selling in the US in 2007. Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy and that is, they either prevent the development of epilepsy or can halt or reverse the progression of epilepsy. However, no drug has shown in human trials to prevent epileptogenesis. The usual method of achieving approval for a drug is to show it is effective when compared against placebo, in monotherapy it is considered unethical by most to conduct a trial with placebo on a new drug of uncertain efficacy. This is because untreated epilepsy leaves the patient at significant risk of death, therefore, almost all new epilepsy drugs are initially approved only as adjunctive therapies. Patients whose epilepsy is currently uncontrolled by their medication are selected to see if supplementing the medication with the new leads to an improvement in seizure control. Any reduction in the frequency of seizures is compared against a placebo, the lack of superiority over existing treatment, combined with lacking placebo-controlled trials, means that few modern drugs have earned FDA approval as initial monotherapy. In contrast, Europe only requires equivalence to existing treatments, and has approved many more, despite their lack of FDA approval, the American Academy of Neurology and the American Epilepsy Society still recommend a number of these new drugs as initial monotherapy. In the following list, the dates in parentheses are the earliest approved use of the drug and it is still used to treat status epilepticus, particularly where there are no resuscitation facilities. Indicated for the treatment of Dravet syndrome, barbiturates are drugs that act as central nervous system depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. The following are classified as anticonvulsants, Phenobarbital, see also the related drug primidone. Known as mephobarbital in the US, no longer marketed in the UK Barbexaclone
23.
Nitrazepam
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Nitrazepam is a hypnotic drug of the benzodiazepine class, indicated for the short-term relief of severe, disabling anxiety and insomnia. It also has sedative and motor-impairing properties, as well as amnestic, anticonvulsant and it is marketed under the trade names, Alodorm, Apodorm, Arem, Insoma, Insomin, Mogadon, Nitrados, Nitrazadon, Nitrosun, Ormodon, Paxadorm, Remnos, and Somnite. Nitrazepam is used to treat short-term sleeping problems, namely difficulty falling asleep, frequent awakening, early awakening, Nitrazepam is sometimes tried to treat epilepsy when other medications fail. It has been found to be effective than clonazepam in the treatment of West syndrome. In uncontrolled studies, nitrazepam has shown effectiveness in infantile spasms and is considered when other anti-seizure drugs have failed. However, drowsiness, hypotonia, and most significantly tolerance to anti-seizure effects typically develop long term treatment. Unpleasant dreams and rebound insomnia have also been reported, Nitrazepam is a long-acting benzodiazepine with an elimination half-life of 15–38 hours. Less common side effects may include, Hypotension, faintness, palpitation, rash or pruritus, gastrointestinal disturbances, very infrequently, paradoxical reactions may occur, for example, excitement, stimulation, hallucinations, hyperactivity, and insomnia. Also, depressed or increased dreaming, disorientation, severe sedation, retrograde amnesia, headache, hypothermia, severe liver toxicity has also been reported. Tolerance to nitrazepams effects occurs with regular use, increased levels of GABA in cerebral tissue and alterations in the activity state of the serotoninergic system occur as a result of nitrazepam tolerance. Tolerance to the effects of nitrazepam occurs after about seven days. Nitrazepam can cause dependence, addiction, and benzodiazepine withdrawal syndrome, withdrawal from nitrazepam may lead to withdrawal symptoms which are similar to those seen with alcohol and barbiturates. Common withdrawal symptoms include anxiety, insomnia, concentration problems, discontinuation of nitrazepam produced rebound insomnia after short-term single nightly dose therapy. Benzodiazepines require special precautions if used in alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders, Nitrazepam in doses of 5 mg or more causes significant deterioration in vigilance performance combined with increased feelings of sleepiness. Nitrazepam at doses of 5 mg or higher impairs driving skills and like other hypnotic drugs, in the elderly, nitrazepam is associated with an increased risk of falls and hip fractures due to impairments of body balance. The elimination half-life of nitrazepam is 40 hours in the elderly and 29 hours in younger adults, Nitrazepam is commonly taken in overdose by drug abusers or suicidal individuals, sometimes leading to death. Nitrazepam is teratogenic if taken in overdose during pregnancy with 30% of births showing congenital abnormalities and it is a popular drug of abuse in countries where it is available. Doses as low as 5 mg can impair driving skills, therefore, people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it altogether
24.
Flunitrazepam
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Flunitrazepam, also known as Rohypnol among others, is an intermediate acting benzodiazepine used in some countries to treat severe insomnia and in fever, early in anesthesia. Just as with other hypnotics, flunitrazepam should be used only on a short-term basis or by those with chronic insomnia on an occasional basis. Flunitrazepam has been referred to as a date rape drug even though its incidence is rare in cases that have been reported. In countries where the drug is used, it is used for treatment of insomnia, and in some countries to begin anesthesia as well. Because of the latter, flunitrazepam is commonly used in suicide, when used in pregnancy, it might cause hypotonia. Flunitrazepam as with other benzodiazepines can lead to drug dependence and benzodiazepine withdrawal syndrome, discontinuation may result in the appearance of withdrawal symptoms when the drug is discontinued. Abrupt withdrawal may lead to a withdrawal syndrome characterised by seizures, psychosis, insomnia. Rebound insomnia, worse than baseline insomnia, typically occur after discontinuation of flunitrazepam even after short-term single nightly dose therapy, flunitrazepam produces a decrease in delta wave activity. The effect of drugs on delta waves, however, may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep, thus, flunitrazepam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to benzodiazepines in the treatment of insomnia as it enhances sleep quality based on EEG studies, paradoxical adverse effects may even lead to criminal behaviour. Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes and, therefore, use of benzodiazepines including flunitrazepam in late pregnancy, especially high doses, may result in hypotonia, also known as floppy baby syndrome. This may appear as lack of concentration, confusion and anterograde amnesia and it can be described as a hangover-like effect which can persist to the next day. It also impairs psychomotor functions similar to benzodiazepines and nonbenzodiazepine hypnotic drugs, falls. The combination with alcohol increases these impairments, partial, but incomplete tolerance develops to these impairments. Impairment of driving skills with a resultant increased risk of traffic accidents is probably the most important adverse effect. This side-effect is not unique to flunitrazepam but also occurs with other hypnotic drugs, flunitrazepam seems to have a particularly high risk of road traffic accidents compared to other hypnotic drugs. Extreme caution should be exercised by drivers after taking flunitrazepam, the use of flunitrazepam in combination with alcoholic beverages synergizes the adverse effects, and can lead to toxicity and death
25.
Malaysian ringgit
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The Malaysian ringgit is the currency of Malaysia. It is divided into 100 sen, the ringgit is issued by the Bank Negara Malaysia. In modern usage ringgit is used almost solely for the currency, to differentiate between the three currencies, the Malaysian currency is referred to as Ringgit Malaysia, hence the official abbreviation and currency symbol RM. Internationally, the ISO4217 currency code for Malaysian ringgit is MYR, the Malay names ringgit and sen were officially adopted as the sole official names in August 1975. Previously they had been known officially as dollars and cents in English and ringgit and sen in Malay, in the northern states of Peninsular Malaysia, denominations of 10 sen are called kupang in Malay, e. g.50 sen is 5 kupang. On 12 June 1967, the Malaysian dollar, issued by the new bank, Bank Negara Malaysia, replaced the Malaya. The new currency retained all denominations of its predecessor except the $10,000 denomination, and also brought over the colour schemes of the old dollar. In November 1967, five months after the introduction of the Malaysian dollar and this ended on 8 May 1973, when the Malaysian government withdrew from the agreement. The Monetary Authority of Singapore and the Brunei Currency and Monetary Board still maintain the interchangeability of their two currencies, as of 2009, in 1993, the currency symbol RM was introduced to replace the use of the dollar sign $. US$130 and RM1,000 worth of US$260. Despite these measures, the ringgit lost 50% of its value against the US dollar between 1997 and 1998, and suffered general depreciation against other currencies between December 2001 and January 2005. As of 4 September 2008, the ringgit has yet to regain its value circa 2001 against the Singapore dollar, the euro, the Australian dollar, and the British pound. On 21 July 2005, Bank Negara announced the end of the peg to the US dollar immediately after Chinas announcement of the end of the peg to the US dollar. According to Bank Negara, Malaysia allows the ringgit to operate in a float against several major currencies. Following the end of the peg, the ringgit appreciated to as high as 3.16 to the US dollar in April 2008. The ringgit had also enjoyed a period of appreciation against the Hong Kong dollar, the initial stability of the ringgit in the late-2000s had led to considerations to reintroduce the currency to foreign trading. As a result, the US dollar appreciated significantly to close at 3.43 to the MYR as of 4 September 2008, while other major currencies, including the renminbi and Hong Kong dollar, followed suit. The ringgit spiked at 3.73 to the US dollar by March 2009, before recovering to 3.00 to the US dollar by mid-2011. The first series of sen coins were introduced in 1967 in denominations of 1 sen,5 sen,10 sen,20 sen,50 sen, followed by the introduction of the 1 ringgit coin in 1971
26.
Substituted amphetamine
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The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens, among others. Some of amphetamines substituted derivatives occur in nature, for example in the leaves of Ephedra and these have been used since antiquity for their pharmacological effects. Amphetamine was first produced at the end of the 19th century, by the 1930s, amphetamine and some of its derivative compounds found use as decongestants in the symptomatic treatment of colds and also occasionally as psychoactive agents. Their effects on the nervous system are diverse, but can be summarized by three overlapping types of activity, psychoanaleptic, hallucinogenic and empathogenic. Various substituted amphetamines may cause these actions either separately or in combination, amphetamines are a subgroup of the substituted phenethylamine class of compounds. Substitution of hydrogen results in a large class of compounds. Natives of Yemen and Ethiopia have a tradition of chewing khat leaves to achieve a stimulating effect. The active substances of khat are cathinone and, to a lesser extent, amphetamine was first synthesized in 1887 by Romanian chemist Lazăr Edeleanu, although its pharmacological effects remained unknown until the 1930s. MDMA was produced in 1912 as an intermediate product, however, this synthesis also went largely unnoticed. In the 1920s, both methamphetamine and the dextrorotatory optical isomer of amphetamine, dextroamphetamine, were synthesized and this synthesis was a by-product of a search for ephedrine, a bronchodilator used to treat asthma extracted exclusively from natural sources. Over-the-counter use of substituted amphetamines was initiated in the early 1930s by the pharmaceutical company Smith, Kline & French, as a medicine for colds and nasal congestion. Subsequently, amphetamine was used in the treatment of narcolepsy, obesity, hay fever, orthostatic hypotension, epilepsy, Parkinsons disease, alcoholism, the reinforcing effects of substituted amphetamines were quickly discovered, and the misuse of substituted amphetamines had been noted as far back as 1936. During World War II, amphetamines were used by the German military to keep their tank crews awake for long periods and it was noticed that extended rest was required after such artificially induced activity. The widespread use of substituted amphetamines began in postwar Japan and quickly spread to other countries, modified designer amphetamines gained popularity since the 1960s, such as MDA and PMA. In 1970, the United States adopted the Controlled Substances Act that limited non-medical use of substituted amphetamines, street use of PMA was noted in 1972. MDMA emerged as a substitute to MDA in the early 1970s, american chemist Alexander Shulgin first synthesized the drug in 1976 and through him the drug was briefly introduced into psychotherapy. Recreational use grew and in 1985 MDMA was banned by the US authorities in an emergency scheduling initiated by the Drug Enforcement Administration, since the mid-1990s, MDMA has become a popular entactogenic drug among the youth and quite often non-MDMA substances were sold as ecstasy. Ongoing trials are investigating its efficacy as an adjunct to psychotherapy in the management of treatment-resistant post-traumatic stress disorder
27.
Opioid
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Opioids are substances that act on opioid receptors to produce morphine-like effects. Opioids are most often used medically to relieve pain, and by people addicted to opioids, opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself. Other opioids are semi-synthetic and synthetic drugs such as hydrocodone, oxycodone and fentanyl, antagonist drugs such as naloxone, the terms opiate and narcotic are sometimes encountered as synonyms for opioid. Opiate is properly limited to the alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives. In some jurisdictions all controlled drugs are classified as narcotics. The term can have pejorative connotations and its use is discouraged where that is the case. Primarily used for relief, including anesthesia they are also used to suppress cough, suppress diarrhea, treat addiction, reverse opioid overdose. Extremely strong opioids are approved only for use such as immobilizing large mammals. Opioids act by binding to receptors, which are found principally in the central and peripheral nervous system. These receptors mediate both the psychoactive and the effects of opioids. The side effects of opioids may include itchiness, sedation, nausea, respiratory depression, constipation, Tolerance and dependence will develop with continuous use, requiring increasing doses and leading to a withdrawal syndrome upon abrupt discontinuation. The euphoria attracts recreational use, and frequent, escalating recreational use of opioids typically results in addiction, accidental overdose or concurrent use with other depressant drugs commonly results in death from respiratory depression. Because of opioid drugs reputation for addiction and fatal overdose, most are controlled substances, illicit production, smuggling, and addiction to opioids prompted treaties, laws and policing which have realized limited success. In 2013 between 28 and 38 million people used opioids illicitly, in 2011 an estimated 4 million people in the United States used opioids recreationally or were dependent on them. Current increased rates of use and addiction are attributed to over-prescription of opioid medications. Conversely, fears about over-prescribing, exaggerated side effects and addiction from opioids are similarly blamed for under-treatment of pain, the term opioid originated in the 1950s. It combines opium + -oid meaning opiate-like, by the late 1960s, research found that opiate effects are mediated by activation of specific molecular receptors in the nervous system, which were termed opioid receptors. The definition of opioid was later refined to refer to substances that have activities that are mediated by the activation of opioid receptors
28.
Japan
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Japan is a sovereign island nation in Eastern Asia. Located in the Pacific Ocean, it lies off the eastern coast of the Asia Mainland and stretches from the Sea of Okhotsk in the north to the East China Sea, the kanji that make up Japans name mean sun origin. 日 can be read as ni and means sun while 本 can be read as hon, or pon, Japan is often referred to by the famous epithet Land of the Rising Sun in reference to its Japanese name. Japan is an archipelago consisting of about 6,852 islands. The four largest are Honshu, Hokkaido, Kyushu and Shikoku, the country is divided into 47 prefectures in eight regions. Hokkaido being the northernmost prefecture and Okinawa being the southernmost one, the population of 127 million is the worlds tenth largest. Japanese people make up 98. 5% of Japans total population, approximately 9.1 million people live in the city of Tokyo, the capital of Japan. Archaeological research indicates that Japan was inhabited as early as the Upper Paleolithic period, the first written mention of Japan is in Chinese history texts from the 1st century AD. Influence from other regions, mainly China, followed by periods of isolation, from the 12th century until 1868, Japan was ruled by successive feudal military shoguns who ruled in the name of the Emperor. Japan entered into a period of isolation in the early 17th century. The Second Sino-Japanese War of 1937 expanded into part of World War II in 1941, which came to an end in 1945 following the bombings of Hiroshima and Nagasaki. Japan is a member of the UN, the OECD, the G7, the G8, the country has the worlds third-largest economy by nominal GDP and the worlds fourth-largest economy by purchasing power parity. It is also the worlds fourth-largest exporter and fourth-largest importer, although Japan has officially renounced its right to declare war, it maintains a modern military with the worlds eighth-largest military budget, used for self-defense and peacekeeping roles. Japan is a country with a very high standard of living. Its population enjoys the highest life expectancy and the third lowest infant mortality rate in the world, in ancient China, Japan was called Wo 倭. It was mentioned in the third century Chinese historical text Records of the Three Kingdoms in the section for the Wei kingdom, Wa became disliked because it has the connotation of the character 矮, meaning dwarf. The 倭 kanji has been replaced with the homophone Wa, meaning harmony, the Japanese word for Japan is 日本, which is pronounced Nippon or Nihon and literally means the origin of the sun. The earliest record of the name Nihon appears in the Chinese historical records of the Tang dynasty, at the start of the seventh century, a delegation from Japan introduced their country as Nihon
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