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. The first such drug, was discovered accidentally by Leo Sternbach in 1955, made available in 1960 by Hoffmann–La Roche, since 1963, has marketed the benzodiazepine diazepam. In 1977 benzodiazepines were globally the most prescribed medications, they are in the family of drugs known as minor tranquilizers. Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid at the GABAA receptor, resulting in sedative, anxiolytic and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may cause anterograde amnesia and dissociation; these properties make benzodiazepines useful in treating anxiety, agitation, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either intermediary, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia.
Benzodiazepines are viewed as safe and effective for short-term use, although cognitive impairment and paradoxical effects such as aggression or behavioral disinhibition occur. A minority of people can have paradoxical reactions such as worsened panic. Benzodiazepines are associated with increased risk of suicide. Long-term use is controversial because of concerns about decreasing effectiveness, physical dependence, an increased risk of dementia. Stopping benzodiazepines leads to improved physical and mental health; the elderly are at an increased risk of both short- and long-term adverse effects, as a result, all benzodiazepines are listed in the Beers List of inappropriate medications for older adults. There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure. Benzodiazepines can cause dangerous deep unconsciousness.
However, they are less toxic than their predecessors, the barbiturates, death results when a benzodiazepine is the only drug taken. When combined with other central nervous system depressants such as alcoholic drinks and opioids, the potential for toxicity and fatal overdose increases. Benzodiazepines are misused and taken in combination with other drugs of abuse. Benzodiazepines possess psycholeptic, hypnotic, anticonvulsant, muscle relaxant, amnesic actions, which are useful in a variety of indications such as alcohol dependence, anxiety disorders, panic and insomnia. Most are administered orally. In general, benzodiazepines are well-tolerated and are safe and effective drugs in the short term for a wide range of conditions. Tolerance can develop to their effects and there is a risk of dependence, upon discontinuation a withdrawal syndrome may occur; 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 long-term use or misuse include the tendency to cause or worsen cognitive deficits and anxiety. The College of Physicians and Surgeons of British Columbia recommends discontinuing the usage of benzodiazepines in those on opioids and those who have used them long term. Benzodiazepines can have serious adverse health outcomes, these findings support clinical and regulatory efforts to reduce usage in combination with non-benzodiazepine receptor agonists; because of their effectiveness and rapid onset of anxiolytic action, benzodiazepines are used for the treatment of anxiety associated with panic disorder. However, there is disagreement among expert bodies regarding the long-term use of benzodiazepines for panic disorder; the views range from those that hold that benzodiazepines are not effective long-term and that they should be reserved for treatment-resistant cases to those that hold that they are as effective in the long term as selective serotonin reuptake inhibitors. The American Psychiatric Association guidelines note that, in general, benzodiazepines are well tolerated, their use for the initial treatment for panic disorder is supported by numerous controlled trials.
APA states that there is insufficient evidence to recommend any of the established panic disorder treatments over another. The choice of treatment between benzodiazepines, SSRIs, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, psychotherapy should be based on the patient's history and other individual characteristics. Selective serotonin reuptake inhibitors are to be the best choice of pharmacotherapy for many patients with panic disorder, but benzodiazepines are often used, some studies suggest that these medications are still used with greater frequency than the SSRIs. One advantage of benzodiazepines is that they alleviate the anxiety symptoms much faster than antidepressants, 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
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the 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 been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open 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 considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of 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; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is 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, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.
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
Nitrazepam is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It has sedative properties, as well as amnestic and skeletal muscle relaxant effects, it was patented in 1961 and came into medical use in 1965. Nitrazepam is used to treat short-term sleeping problems, namely difficulty falling asleep, frequent awakening, early awakening, or a combination of each. Nitrazepam is sometimes tried to treat epilepsy, it has been found to be more effective than clonazepam in the treatment of West syndrome, an age-dependent epilepsy, affecting the young. In uncontrolled studies, nitrazepam has shown effectiveness in infantile spasms and is sometimes considered when other anti-seizure drugs have failed. However, drowsiness and most tolerance to anti-seizure effects develop with long term treatment limiting Nitrazepam to acute seizure management. More common side effects may include: Central nervous system depression, including somnolence, depressed mood, ataxia, vertigo, impairment of memory, impairment of motor functions, hangover feeling in the morning, slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, double vision, inattention have been reported.
Unpleasant dreams and rebound insomnia have been reported. Nitrazepam is a long-acting benzodiazepine with an elimination half-life of 15–38 hours. Residual "hangover" effects after nighttime administration of nitrazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day, which may impair the ability of users to drive safely and increases the risk of falls and hip fractures. Less common side effects may include: Hypotension, palpitation, rash or pruritus, gastrointestinal disturbances, changes in libido are less common. Infrequently, paradoxical reactions may occur, for example, stimulation, hallucinations and insomnia. Depressed or increased dreaming, severe sedation, retrograde amnesia, headache and delirium tremens are reported. Severe liver toxicity has been reported. Benzodiazepine use for more than one to six months at prescribed doses is associated with an increased risk of the development of ovarian cancer. Fifteen epidemiologic studies have shown hypnotic drug use is associated with increased mortality due to increased cancer deaths in humans.
These were cancers of the brain, bowel and bladder, other neoplasms. Not only do these studies suggest an increased risk of cancer with benzodiazepines, but that benzodiazepine receptor agonist "Z-drugs" are associated with cancer. FDA reviewers did not want to approve Z-drugs due to concerns of cancer, but changed their minds and approved the drugs despite the concerns; the data show that trial subjects receiving hypnotic drugs had an increased risk of developing cancer. The review author concluded, "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics place patients at higher risk for cancer." The evidence did not prove carcinogenicity. Nitrazepam therapy, compared with other drug therapies, increases risk of death when used for intractable epilepsy in an analysis of 302 patients; the risk of death from nitrazepam therapy may be greater in younger patients with intractable epilepsy. In older children, the tendency appears to be reversed in this study.
Nitrazepam may cause sudden death in children. It can cause swallowing incoordination, high-peaked esophageal peristalsis, delayed cricopharyngeal relaxation, severe respiratory distress necessitating ventilatory support in children. Nitrazepam may promote the development of parasympathetic overactivity or vagotonia, leading to fatal respiratory distress in children. Nitrazepam has been associated with severe hepatic disorders, similar to other nitrobenzodiazepines. Nitrobenzodiazepines such as nitrazepam, nimetazepam and clonazepam are more toxic to the liver than other benzodiazepines as they are metabolically activated by CYP3A4 which can result in cytotoxicity; this activation can lead to the generation of free radicals and oxidation of thiol, as well as covalent binding with endogenous macromolecules. Metabolism of a nontoxic drug to reactive metabolites has been causally connected with a variety of adverse reactions. Long-term use of nitrazepam carries mental and physical health risks, such as the development of cognitive deficits.
These adverse effects show improvement after a period of abstinence. Recreational use of nitrazepam is common. A monograph for the drug says: "Treatment with nitrazepam should not exceed seven to ten consecutive days. Use for more than two to three consecutive weeks requires complete re-evaluation of the patient. Prescriptions for nitrazepam should be written for short-term use and it should not be prescribed in quantities exceeding a one-month supply. Dependence can occur in as little as four weeks." Tolerance to nitrazepam's 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 sleep-inducing effects of nitrazepam occurs after about seven days.
Hoechst AG was a German chemicals life-sciences company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S. A. in 1999. With the new company's 2004 merger with Sanofi-Synthélabo, it became a subsidiary of the resulting Sanofi-Aventis pharmaceuticals group; the company was founded in 1863 as "Teerfarbenfabrik Meister, Lucius & Co." in Höchst, near Frankfurt and changed its name some years to "Teerfarbenfabrik Meister Lucius & Brüning". In 1880 it became a stock company "Farbwerke vorm. Meister Lucius & Brüning AG". For the international market the name was simplified to "Farbwerke Hoechst AG"; until 1925 the Hoechst AG was independent. In 1916, the Hoechst AG was one of the co-founders of IG Farben, an advocacy group of Germany's chemicals industry to gain industrial power during and after World War I. In 1925, IG Farben turned from an advocacy group into the well-known conglomerate. Various Hoechst facilities were bombed during the Oil Campaign of World War II, its managers in charge were defendants, as were the other IG Farben managers, in the Nuremberg trial against the company for its role in the exploitation of enslaved laborers and for testing drugs on concentration camp prisoners.
1951 - Hoechst AG was re-founded on December 7 in Frankfurt when IG Farben was split into its founder companies. The original capitalization of the company was 100,000 Deutsche Mark. By 1953 Hoechst had acquired parts of Knapsack-Griesheim, Kalle AG, Behring Werke, Wacker Chemie and Ruhr Chemie, among others.1969 - Hoechst acquired Cassella.1987 - Hoechst acquired the American chemical company Celanese and formed a new Hoechst subsidiary in the US, Hoechst Celanese. 1995 - Hoechst merges with Marion Merrell Dow of Kansas City, Missouri forming U. S. subsidiary Hoechst Marion Roussel. 1997 - Hoechst underwent a realignment wherein its various businesses were transferred to independent companies, including Nutrinova and Clariant.1999 - Hoechst and Rhône-Poulenc settle Federal Trade Commission charges that merger would violate U. S. antitrust laws. A; the merged company was headquartered in Eastern France. As part of the merger, the company demerged many of its industrial businesses into Celanese, which became an independent company again.
2005 - The company became a wholly owned subsidiary of Sanofi-Aventis. Wilhelm Meister founded the chemical company Teerfarbenfabrik Meister, Lucius & Co. which became Hoechst AG. He was the great-grandfather of William von Meister, one of the founders of Control Video Corporation which became America Online. Pascal Soriot held positions with the organisation from 1989 up until 2006 through Aventis. Notes Archive site Sanofi Aventis site Aventis Foundation Documents and clippings about Hoechst AG in the 20th Century Press Archives of the German National Library of Economics