Regulation of therapeutic goods
The regulation of therapeutic goods, drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia; the role of therapeutic goods regulation is designed to protect the health and safety of the population. Regulation is aimed at ensuring the safety and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered. There is some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Modern drug regulation has historical roots in the response to the proliferation of universal antidotes which appeared in the wake of Mithridates' death. Mithridates had brought together physicians and shamans to concoct a potion that would make him immune to poisons.
Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means; the first was through the Leechbook of the Bald, written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians; the resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to the development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were created in public and the process was observed and recorded, it was believed that if the concoction proved unsuccessful, it was due to the apothecaries’ process of making them and they could be held accountable because of the public nature of the creation. In the 9th century, many Muslim countries established an office of the hisba, which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines.
Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leigh weigh to ensure compliance and punishments were stringent. The first official'act', the'Apothecary Wares and Stuffs' Act was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians to appoint four people dedicated to inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there was an emergence of standard formulas for the creation of certain ‘drugs’ and ‘antidotes’ through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas; the first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618. In the United States, regulation of drugs was a state right, as opposed to federal right.
But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, increased the need for stronger federal regulation. President Roosevelt signed the Federal Food and Drug Act in 1906 which established stricter standards. A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA; this directly led to Congress passing the Sherley Amendment which established a clearer definition of ‘misbranded’. Another key catalyst for advances in drug regulation were certain catastrophes that served as calls to the government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing; this directly led to the passing of the Federal, Food and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, sold in Germany and sold around the world, led to 100,000 babies being born with various deformities.
The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world; the UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory after, the pharmaceutical industry larger complied due to the thalidomide situation; the European Economic Commission passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. The United States congress passed the Drug Amendments Act of 1962 The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards. Both the EU and US acts introduced the requirements to ensure efficacy.
Of note, increased regulations and standards for testing led to greater innovation in pharm
A hydroxy or hydroxyl group is the entity with the formula OH. It contains oxygen bonded to hydrogen. In organic chemistry and carboxylic acids contain hydroxy groups; the anion, called hydroxide, consists of a hydroxyl group. According to IUPAC rules, the term hydroxyl refers to the radical OH only, while the functional group −OH is called hydroxy group. Water, carboxylic acids, many other hydroxy-containing compounds can be deprotonated readily; this behavior is rationalized by the disparate electronegativities of hydrogen. Hydroxy-containing compounds engage in hydrogen bonding, which causes them to stick together, leading to higher boiling and melting points than found for compounds that lack this functional group. Organic compounds, which are poorly soluble in water, become water-soluble when they contain two or more hydroxy groups, as illustrated by sugars and amino acid; the hydroxy group is pervasive in biochemistry. Many inorganic compounds contain hydroxy groups, including sulfuric acid, the chemical compound produced on the largest scale industrially.
Hydroxy groups participate in the dehydration reactions that link simple biological molecules into long chains. The joining of a fatty acid to glycerol to form a triacylglycerol removes the −OH from the carboxy end of the fatty acid; the joining of two aldehyde sugars to form a disaccharide removes the −OH from the carboxy group at the aldehyde end of one sugar. The creation of a peptide bond to link two amino acids to make a protein removes the −OH from the carboxy group of one amino acid. Hydroxyl radicals are reactive and undergo chemical reactions that make them short-lived; when biological systems are exposed to hydroxyl radicals, they can cause damage to cells, including those in humans, where they can react with DNA, proteins. In 2009, India's Chandrayaan-1 satellite, NASA's Cassini spacecraft and the Deep Impact probe have each detected the presence of water by evidence of hydroxyl fragments on the Moon; as reported by Richard Kerr, "A spectrometer detected an infrared absorption at a wavelength of 3.0 micrometers that only water or hydroxyl—a hydrogen and an oxygen bound together—could have created."
NASA reported in 2009 that the LCROSS probe revealed an ultraviolet emission spectrum consistent with hydroxyl presence. The Venus Express orbiter sent back Venus science data from April 2006 until December 2014. Results from Venus Express include the detection of hydroxyl in the atmosphere. Hydronium Ion Oxide Reece, Jane. "Unit 1, Chapter 4 &5." In Campbell Biology. Berge, Susan. San Francisco: Pearson Benjamin Cummings. ISBN 978-0-321-55823-7
Alexander Theodore Shulgin was an American medicinal chemist, organic chemist, psychopharmacologist, author. He is credited with introducing MDMA to psychologists in the late 1970s for psychopharmaceutical use and for the discovery and personal bioassay of over 230 psychoactive compounds for their psychedelic and entactogenic potential. In 1991 and 1997, he and his wife Ann Shulgin authored the books PIHKAL and TIHKAL, which extensively described their work and personal experiences with these two classes of psychoactive drugs. Shulgin performed seminal work into the descriptive synthesis of many of these compounds; some of Shulgin's noteworthy discoveries include compounds of the 2C* family and compounds of the DOx family. Due in part to Shulgin's extensive work in the field of psychedelic research and the rational drug design of psychedelic drugs, he has since been dubbed the "godfather of psychedelics". Shulgin was born in California, to Theodore Stevens Shulgin and Henrietta D. Shulgin, his father was born in Russia.
Both Theodore and Henrietta were public school teachers in Alameda County. Shulgin began studying organic chemistry as a Harvard University scholarship student at the age of 16. In 1943 he dropped out of school to join the U. S. Navy. While serving on USS Pope in the Navy during World War II, Shulgin was given a glass of orange juice by a nurse prior to surgery for a thumb infection. Shulgin drank the juice and, assuming that the powder at the bottom of the glass was a sedative, fell asleep rapidly. Upon waking he learned; the experience made him aware of the influence of placebos over the human mind. After serving in the Navy, Shulgin returned to Berkeley, in 1954 earned his PhD in biochemistry from the University of California, Berkeley. Through the late 1950s Shulgin completed post-doctoral work in the fields of psychiatry and pharmacology at University of California, San Francisco. After working at Bio-Rad Laboratories as a research director for a brief period, he began work at Dow Chemical Company as a senior research chemist.
At this time he had a series of psychedelic experiences that helped to shape his further goals and research, the first of, brought on by mescaline. "I first explored mescaline in the late'50s... Three-hundred-fifty to 400 milligrams. I learned there was a great deal inside me."Shulgin reported personal revelations that "had been brought about by a fraction of a gram of a white solid, but that in no way whatsoever could it be argued that these memories had been contained within the white solid... I understood that our entire universe is contained in the spirit. We may choose not to find access to it, we may deny its existence, but it is indeed there inside us, there are chemicals that can catalyze its availability." Shulgin's professional activities continued to lean in the direction of psychopharmacology, furthered by his personal experiences with psychedelics. But during this period he was unable to do much independent research, his opportunity for further research came in 1961 after his development of Zectran, the first biodegradable pesticide, a profitable product.
In his book PIHKAL, Shulgin limits his pesticide days at Dow Chemical to one sentence in 978 pages. Dow Chemical Company, in return for Zectran's valuable patent, gave Shulgin great freedom. During this time, he created and patented drugs when Dow asked, published findings on other drugs in journals such as Nature and the Journal of Organic Chemistry. Dow Chemical requested that he no longer use their name on his publications. In late 1966, Shulgin left Dow, he first spent two years studying neurology at the University of California, San Francisco School of Medicine, leaving to work on a consulting project. He set up a home-based lab on his property, known as "the Farm", became a private consultant, he taught classes in the local universities and at the San Francisco General Hospital. Through his friend Bob Sager, head of the U. S. DEA's Western Laboratories, Shulgin formed a relationship with the DEA and began holding pharmacology seminars for the agents, supplying the DEA with samples of various compounds, serving as an expert witness in court.
In 1988, he authored a then-definitive law enforcement reference book on controlled substances, received several awards from the DEA. In order to work with scheduled psychoactive chemicals, Shulgin obtained a DEA Schedule I license for an analytical laboratory, which allowed him to synthesize and possess any otherwise illicit drug. Shulgin set up a chemical synthesis laboratory in a small building behind his house, which gave him a great deal of career autonomy. Shulgin used this freedom to synthesize and test the effects of psychoactive drugs. In 1976, Shulgin was introduced to MDMA by a student in the medicinal chemistry group he advised at San Francisco State University. MDMA had been synthesized in 1912 by Merck and patented in 1913 as an intermediate of another synthesis in order to block competitors, but was never explored in its own right. Shulgin went on to develop a new synthesis method, in 1976, introduced the chemical to Leo Zeff, a psychologist from Oakland, California. Zeff used the substance in his practice in small doses as an aid to talk therapy.
Zeff introduced the substance to hundreds of psychologists and lay therapists around the nation, including Ann, whom Alexander Shulgin met in 1979, married in 1981. It was her fo
The Riksdag is the national legislature and the supreme decision-making body of Sweden. Since 1971, the Riksdag has been a unicameral legislature with 349 members, elected proportionally and serving, from 1994 onwards, on fixed four-year terms; the constitutional functions of the Riksdag are enumerated in the Instrument of Government, its internal workings are specified in greater detail in the Riksdag Act. The seat of the Riksdag is at Parliament House, on the island of Helgeandsholmen in the central parts of Stockholm; the Riksdag has its institutional roots in the feudal Riksdag of the Estates, by tradition thought to have first assembled in Arboga in 1435, in 1866 following reforms of the 1809 Instrument of Government that body was transformed into a bicameral legislature with an upper chamber and a lower chamber. The most recent general election was held on 9 September 2018; the Swedish word riksdag, in definite form riksdagen, is a general term for "parliament" or "assembly", but it is only used for Sweden's legislature and certain related institutions.
In addition to Sweden's parliament, it is used for the Parliament of Finland and the Estonian Riigikogu, as well as the historical German Reichstag and the Danish Rigsdagen. In Swedish use, riksdagen is uncapitalized. Riksdag derives from the genitive of rike, referring to royal power, dag, meaning diet or conference; the Oxford English Dictionary traces English use of the term "Riksdag" in reference to the Swedish assembly back to 1855. The roots of the modern Riksdag can be found in a 1435 meeting of the Swedish nobility in the city of Arboga; this informal organization was modified in 1527 by the first modern Swedish king Gustav I Vasa to include representatives from all the four social estates: the nobility, the clergy, the burghers, the yeomanry. This form of Ständestaat representation lasted until 1865, when representation by estate was abolished and the modern bicameral parliament established. However, it did not become a parliament in the modern sense until parliamentary principles were established in the political system in Sweden, in 1917.
On 22 June 1866, the Riksdag decided to reconstitute itself as a bicameral legislature, consisting of Första kammaren or the First Chamber, with 155 members and Andra kammaren or the Second Chamber with 233 members. The First Chamber was indirectly elected by county and city councillors, while the Second Chamber was directly elected by universal suffrage; this reform was a result of great malcontent with the old Estates, following the changes brought by the beginnings of the industrial revolution, was no longer able to provide representation for large segments of the population. By an amendment to the 1809 Instrument of Government, the general election of 1970 was the first to a unicameral assembly with 350 seats; the following general election to the unicameral Riksdag in 1973 only gave the Government the support of 175 members, while the opposition could mobilize an equal force of 175 members. In a number of cases a tied vote ensued, the final decision had to be determined by lot. To avoid any reccurrence of this unstable situation, the number of seats in the Riksdag was reduced to 349, from 1976 onwards.
The Riksdag performs the normal functions of a legislature in a parliamentary democracy. It amends the constitution and appoints a government. In most parliamentary democracies, the head of state commissions a politician to form a government. Under the new Instrument of Government enacted in 1974, that task was removed from the Monarch of Sweden and given to the Speaker of the Riksdag. To make changes to the Constitution under the new Instrument of Government, amendments must be approved twice, in two successive electoral periods with a regular general election held in between. There are 15 parliamentary committees in the Riksdag; as of February 2013, 44.7 percent of the members of the Riksdag are women. This is the world's fourth highest proportion of females in a national legislature—behind only the Parliaments of Rwanda and Cuba – hence the second-highest in the developed world and among parliamentary democracies. Following the 2014 elections, in which the share of Liberal female members of parliament plunged and the Sweden Democrats more than doubled their seats, the figure dropped to 43,5%.
Only the Left Party has a majority of female MPs. Members of the Riksdag are full-time legislators with a salary of 66 900 SEK per month. According to a survey investigation by the sociologist Jenny Hansson, Members of the Riksdag have an average work week of 66 hours, including side responsibilities. Hansson's investigation further reports; the presidium consists of three deputy speakers. They are elected for a 4-year term. After holding talks with leaders of the various party groups in the Riksdag, the speaker of the Riksdag nominates a Prime Minister; the nomination is put to a vote. The nomination is rejected only if an absolute majority of the members vote "no"; this means the Riksdag can consent to a Prime Min
The melting point of a substance is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium; the melting point of a substance depends on pressure and is specified at a standard pressure such as 1 atmosphere or 100 kPa. When considered as the temperature of the reverse change from liquid to solid, it is referred to as the freezing point or crystallization point; because of the ability of some substances to supercool, the freezing point is not considered as a characteristic property of a substance. When the "characteristic freezing point" of a substance is determined, in fact the actual methodology is always "the principle of observing the disappearance rather than the formation of ice", that is, the melting point. For most substances and freezing points are equal. For example, the melting point and freezing point of mercury is 234.32 kelvins. However, certain substances possess differing solid-liquid transition temperatures.
For example, agar melts at 85 °C and solidifies from 31 °C. The melting point of ice at 1 atmosphere of pressure is close to 0 °C. In the presence of nucleating substances, the freezing point of water is not always the same as the melting point. In the absence of nucleators water can exist as a supercooled liquid down to −48.3 °C before freezing. The chemical element with the highest melting point is tungsten, at 3,414 °C; the often-cited carbon does not melt at ambient pressure but sublimes at about 3,726.85 °C. Tantalum hafnium carbide is a refractory compound with a high melting point of 4215 K. At the other end of the scale, helium does not freeze at all at normal pressure at temperatures arbitrarily close to absolute zero. Many laboratory techniques exist for the determination of melting points. A Kofler bench is a metal strip with a temperature gradient. Any substance can be placed on a section of the strip, revealing its thermal behaviour at the temperature at that point. Differential scanning calorimetry gives information on melting point together with its enthalpy of fusion.
A basic melting point apparatus for the analysis of crystalline solids consists of an oil bath with a transparent window and a simple magnifier. The several grains of a solid are placed in a thin glass tube and immersed in the oil bath; the oil bath is heated and with the aid of the magnifier melting of the individual crystals at a certain temperature can be observed. In large/small devices, the sample is placed in a heating block, optical detection is automated; the measurement can be made continuously with an operating process. For instance, oil refineries measure the freeze point of diesel fuel online, meaning that the sample is taken from the process and measured automatically; this allows for more frequent measurements as the sample does not have to be manually collected and taken to a remote laboratory. For refractory materials the high melting point may be determined by heating the material in a black body furnace and measuring the black-body temperature with an optical pyrometer. For the highest melting materials, this may require extrapolation by several hundred degrees.
The spectral radiance from an incandescent body is known to be a function of its temperature. An optical pyrometer matches the radiance of a body under study to the radiance of a source, calibrated as a function of temperature. In this way, the measurement of the absolute magnitude of the intensity of radiation is unnecessary. However, known temperatures must be used to determine the calibration of the pyrometer. For temperatures above the calibration range of the source, an extrapolation technique must be employed; this extrapolation is accomplished by using Planck's law of radiation. The constants in this equation are not known with sufficient accuracy, causing errors in the extrapolation to become larger at higher temperatures. However, standard techniques have been developed to perform this extrapolation. Consider the case of using gold as the source. In this technique, the current through the filament of the pyrometer is adjusted until the light intensity of the filament matches that of a black-body at the melting point of gold.
This establishes the primary calibration temperature and can be expressed in terms of current through the pyrometer lamp. With the same current setting, the pyrometer is sighted on another black-body at a higher temperature. An absorbing medium of known transmission is inserted between this black-body; the temperature of the black-body is adjusted until a match exists between its intensity and that of the pyrometer filament. The true higher temperature of the black-body is determined from Planck's Law; the absorbing medium is removed and the current through the filament is adjusted to match the filament intensity to that of the black-body. This establishes a second calibration point for the pyrometer; this step is repeated to carry the calibration to hi
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both inhibitory neurotransmission; the serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand. The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, epinephrine / norepinephrine, acetylcholine, as well as many hormones, including oxytocin, vasopressin, cortisol and substance P, among others; the serotonin receptors influence various biological and neurological processes such as aggression, appetite, learning, mood, nausea and thermoregulation. The serotonin receptors are the target of a variety of pharmaceutical and recreational drugs, including many antidepressants, anorectics, gastroprokinetic agents, antimigraine agents and entactogens. Serotonin receptors are found in all animals and are known to regulate longevity and behavioral aging in the primitive nematode, Caenorhabditis elegans.
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors are found in the central and peripheral nervous systems. They can be divided into 7 families of G protein-coupled receptors except for the 5-HT3 receptor, a ligand-gated ion channel, which activate an intracellular second messenger cascade to produce an excitatory or inhibitory response. In 2014, a novel 5-HT receptor was isolated from the small white butterfly, Pieris rapae, named pr5-HT8, it does not occur in mammals and shares low similarity to the known 5-HT receptor classes. The 7 general serotonin receptor classes include a total of 14 known serotonin receptors; the specific types have been characterized as follows: Note that there is no 5-HT1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT2 family of receptors and was redesignated as the 5-HT2C receptor. Nonselective agonists of 5-HT receptor subtypes include ergotamine, which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors.
LSD is a 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist. The genes coding for serotonin receptors are expressed across the mammalian brain. Genes coding for different receptors types follow different developmental curves. There is a developmental increase of HTR5A expression in several subregions of the human cortex, paralleled by a decreased expression of HTR1A from the embryonic period to the post-natal one. A number of receptors were classed as "5-HT1-like" - by 1998 it was being argued that, since these receptors were "a heterogeneous population of 5-HT1B, 5-HT1D and 5-HT7" receptors the classification was redundant. Serotonin+Receptors at the US National Library of Medicine Medical Subject Headings "5-Hydroxytryptamine Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Rubenstein LA, Lanzara RG. "Activation of G protein-coupled receptors entails cysteine modulation of agonist binding". Cogprints. Retrieved 2008-04-11. Paterson LM, Kornum BR, Nutt DJ, Pike VW, Knudsen GM.
"5-HT radioligands for human brain imaging with PET and SPECT". Med Res Rev. 33: 54–111. Doi:10.1002/med.20245. PMC 4188513. PMID 21674551
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.