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
Janssen Pharmaceutica is a pharmaceutical company headquartered in Beerse, Belgium. It was founded in 1953 by Paul Janssen. In 1961, Janssen Pharmaceutica was purchased by New Jersey-based American corporation Johnson & Johnson, became part of Johnson & Johnson Pharmaceutical Research and Development, now renamed to Janssen Research and Development, which conducts research and development activities related to a wide range of human medical disorders, including mental illness, neurological disorders and analgesia, gastrointestinal disorders, fungal infection, HIV/AIDS, allergies and cancer. Janssen and Ortho-McNeil Pharmaceutical have been placed in the Ortho-McNeil-Janssen group within Johnson & Johnson; the early roots of what would become Janssen Pharmaceutica date back to 1933. In 1933, Constant Janssen, the father of Paul Janssen, acquired the right to distribute the pharmaceutical products of Richter, a Hungarian pharmaceutical company, for Belgium, the Netherlands and Belgian Congo. On 23 October 1934, he founded the N.
V. Produkten Richter in Turnhout. In 1937, Constant Janssen acquired an old factory building in the Statiestraat 78 in Turnhout for his growing company, which he expanded during World War II into a four-storey building. Still a student, Paul Janssen assisted in the development of paracetamol under the name Perdolan, which would become well-known. After the war, the name for the company products was changed to Eupharma, although the company name Richter would remain until 1956. Paul Janssen founded his own research laboratory in 1953 on the third floor of the building in the Statiestraat, still within the Richter-Eurpharma company of his father. In 1955, he and his team developed their first drug: Neomeritine, an antispasmodic found to be effective for the relief of menstrual pain. On 5 April 1956, the name of the company was changed to NV Laboratoria Pharmaceutica C. Janssen. On 27 April 1957, the company opened a new research facility in Beerse, but the move to Beerse would not be completed until 1971-1972.
On 2 May 1958, the research department in Beerse became a separate legal entity, the N. V. Research Laboratorium C. Janssen. On 24 October 1961, the company was acquired by the American corporation Johnson; the negotiations with Johnson & Johnson were led by Frans Van den Bergh, head of the Board of Directors. On 10 February 1964, the name was changed to Janssen Pharmaceutica N. V. and the seat of the company in Turnhout was transferred to Beerse. The company was led by Bob Stouthuysen and Frans Van Den Bergh. When, in 1971-1972 the pharmaceutical production moved to Beerse, the move from Turnhout was completed. Between 1990 and 2004, Janssen Pharmaceutica expanded worldwide, the company grew in size to about 28000 employees worldwide. From the beginning, Janssen Pharmaceutica emphasized as its core activity research for the development of new drugs; the research department, established in Beerse in 1957, developed into a large research campus. In 1987, the Janssen Research Foundation was founded which performs research into new drugs at Beerse and in other laboratories around the globe.
Janssen Pharmaceutica became the Flemish company with the largest budget for research and development. Beside the headquarters in Beerse with its research departments, pharmaceutical production and the administrative departments, Janssen Pharmaceutica in Belgium still has offices in Berchem, a chemical factory in Geel, Janssen Biotech in Olen; the Chemical Production plant in Geel makes the active ingredients for the company’s medicines. In 1975, the first plant of a new chemical factory Plant I was established in Geel, Plant II was opened in 1977, Plant III' in 1984, Plant IV in 1995. In 1999 the remaining chemical production in Beerse was transferred to Geel. About 80% of its active components are manufactured here; the site in Geel manufactures about two-thirds of the worldwide chemical production of the pharmaceutical sector of Johnson & Johnson. In 1995, the Center for Molecular Design was founded by Paul Lewi. In 1999, clinical research and non-clinical development become a global organization within Johnson & Johnson.
In 2001, part of the research activities was transferred to the United States with the reorganization of research activities in the Johnson & Johnson Pharmaceutical Research Development organization. The research activities of the Janssen Research Foundation and the R. W. Johnson Pharmaceutical Research Institute were merged into the new global research organization. A new building for pharmaceutical development was completed in Beerse in 2001. In 2002, a new logistics and informatics centre was opened at a new site, Beerse 2. In 2003 two new research buildings were constructed, the Discovery Research Center, the Drug Safety Evaluation Center. On 27 October 2004, the Paul Janssen Research Center, for discovery research, was inaugurated. In March 2015, Janssen licensed tipifarnib to Kura Oncology who will assume sole responsibility for developing and commercialising the anti-cancer drug. In the same month the company announced that Galapagos Pharma and regained the rights to the anti-inflammatory drug candidate GLPG1690 as well as two other compounds including GLPG1205.
In May 2016, the company launched a collaboration MacroGenics and their preclinical cancer treatment, MGD015. The deal could net MacroGenics more than $740 million. In September 2017 it was announced that Janssen teamed up with the Biomedical Advanced Research and Development Authority (BARD
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, poison, or other substance is taken into the body. Routes of administration are classified by the location at which the substance is applied. Common examples include intravenous administration. Routes can be classified based on where the target of action is. Action may be enteral, or parenteral. Route of administration and dosage form are aspects of drug delivery. Routes of administration are classified by application location; the route or course the active substance takes from application location to the location where it has its target effect is rather a matter of pharmacokinetics. Exceptions include the transdermal or transmucosal routes, which are still referred to as routes of administration; the location of the target effect of active substances are rather a matter of pharmacodynamics. An exception is topical administration, which means that both the application location and the effect thereof is local. Topical administration is sometimes defined as both a local application location and local pharmacodynamic effect, sometimes as a local application location regardless of location of the effects.
Administration through the gastrointestinal tract is sometimes termed enteral or enteric administration. Enteral/enteric administration includes oral and rectal administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may occur in the stomach, as such gastrointestinal may be a more fitting term for this route of administration. Furthermore, some application locations classified as enteral, such as sublingual and sublabial or buccal, are taken up in the proximal part of the gastrointestinal tract without reaching the intestines. Enteral administration can be used for systemic administration, as well as local, such as in a contrast enema, whereby contrast media is infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects. Many drugs as tablets, capsules, or drops are taken orally. Administration methods directly into the stomach include those by gastric feeding tube or gastrostomy.
Substances may be placed into the small intestines, as with a duodenal feeding tube and enteral nutrition. Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet causes irritation in the stomach; the rectal route is an effective route of administration for many medications those used at the end of life. The walls of the rectum absorb many medications and effectively. Medications delivered to the distal one-third of the rectum at least avoid the "first pass effect" through the liver, which allows for greater bio-availability of many medications than that of the oral route. Rectal mucosa is vascularized tissue that allows for rapid and effective absorption of medications. A suppository is a solid dosage form. In hospice care, a specialized rectal catheter, designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the distal rectum, giving health practitioners a way to leverage the established benefits of rectal administration.
The parenteral route is any route, not enteral. Parenteral administration can be performed by injection, that is, using a needle and a syringe, or by the insertion of an indwelling catheter. Locations of application of parenteral administration include: central nervous systemepidural, e.g. epidural anesthesia intracerebral direct injection into the brain. Used in experimental research of chemicals and as a treatment for malignancies of the brain; the intracerebral route can interrupt the blood brain barrier from holding up against subsequent routes. Intracerebroventricular administration into the ventricular system of the brain. One use is as a last line of opioid treatment for terminal cancer patients with intractable cancer pain. Epicutaneous, it can be used both for local effect as in allergy testing and typical local anesthesia, as well as systemic effects when the active substance diffuses through skin in a transdermal route. Sublingual and buccal medication administration is a way of giving someone medicine orally.
Sublingual administration is. The word "sublingual" means "under the tongue." Buccal administration involves placement of the drug between the cheek. These medications can come in the form of films, or sprays. Many drugs are designed for sublingual administration, including cardiovascular drugs, barbiturates, opioid analgesics with poor gastrointestinal bioavailability and vitamins and minerals. Extra-amniotic administration, between the endometrium and fetal membranes nasal administration (th
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, food additives, etc, it attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing and adverse effects, as seen in PK/PD models. Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body, the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are affected by the route of administration and the dose of administered drug.
These may affect the absorption rate. Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. One of these, the multi-compartmental model, is the most used approximations to reality; the various compartments that the model is divided into are referred to as the ADME scheme: Liberation – the process of release of a drug from the pharmaceutical formulation. See IVIVC. Absorption – the process of a substance entering the blood circulation. Distribution – the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue; the two phases of metabolism and excretion can be grouped together under the title elimination.
The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. All these concepts can be represented through mathematical formulas that have a corresponding graphical representation; the use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant and solubility, absorption capacity and distribution in the organism. The model outputs for a drug can be used in industry or in the clinical application of pharmacokinetic concepts.
Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine. The following are the most measured pharmacokinetic metrics: In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. In practice, it is considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started; the following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics: Pharmacokinetic modelling is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model and produce accurate results acceptable for bioequivalence studies.
The final outcome of the transformations that a drug undergoes in an organism and the rules that determine this fate depend on a number of interrelated factors. A number of functional models have been developed in order to simplify the study of pharmacokinetics; these models are based on a consideration of an organism as a number of related compartments. The simplest idea is to think of an organism as only one homogenous compartment; this monocompartmental model presupposes that blood plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug's concentration in the organism. However, these models do not always reflect the real situation within an organism. For example, not all body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (s
The blood–brain barrier is a selective semipermeable border that separates the circulating blood from the brain and extracellular fluid in the central nervous system. The blood–brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, pericytes embedded in the capillary basement membrane; this system allows the passage of water, some gases, lipid-soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function. Specialized structures participating in sensory and secretory integration within neural circuits – the circumventricular organs and choroid plexus – do not have a blood–brain barrier; the blood–brain barrier restricts the passage of pathogens, the diffusion of solutes in the blood, large or hydrophilic molecules into the cerebrospinal fluid, while allowing the diffusion of hydrophobic molecules and small polar molecules. Cells of the barrier transport metabolic products such as glucose across the barrier using specific transport proteins.
The blood–brain barrier results from the selectivity of the tight junctions between endothelial cells in CNS vessels, which restricts the passage of solutes. At the interface between blood and the brain, endothelial cells are stitched together by these tight junctions, which are composed of smaller subunits biochemical dimers, that are transmembrane proteins such as occludin, junctional adhesion molecule, or ESAM, for example; each of these transmembrane proteins is anchored into the endothelial cells by another protein complex that includes ZO-1 and associated proteins. The blood–brain barrier is composed of high-density cells restricting passage of substances from the bloodstream much more than do the endothelial cells in capillaries elsewhere in the body. Astrocyte cell projections called astrocytic feet surround the endothelial cells of the BBB, providing biochemical support to those cells; the BBB is distinct from the quite similar blood–cerebrospinal fluid barrier, a function of the choroidal cells of the choroid plexus, from the blood–retinal barrier, which can be considered a part of the whole realm of such barriers.
Several areas of the human brain are not on the brain side of the BBB. Some examples of this include the circumventricular organs, the roof of the third and fourth ventricles, capillaries in the pineal gland on the roof of the diencephalon and the pineal gland; the pineal gland secretes the hormone melatonin "directly into the systemic circulation", thus melatonin is not affected by the blood–brain barrier. Experiments in the 1920s seemed to show that the blood–brain barrier was still immature in newborns; this was due to an error in methodology. It was shown in experiments with a reduced volume of the injected liquids that the markers under investigation could not pass the BBB, it was reported that those natural substances such as albumin, α-1-fetoprotein or transferrin with elevated plasma concentration in the newborn could not be detected outside of cells in the brain. The transporter P-glycoprotein exists in the embryonal endothelium; the measurement of brain uptake of acetamide, benzyl alcohol, caffeine, phenytoin, ethylene glycol, mannitol, phenobarbital, propylene glycol and urea in ether-anesthetized newborn vs. adult rabbits shows that newborn rabbit and adult rabbit brain endothelia are functionally similar with respect to lipid-mediated permeability.
These data confirmed that no differences in permeability could be detected between newborn and adult BBB capillaries. No difference in brain uptake of glucose, amino acids, organic acids, nucleosides, or choline was observed between adult and newborn rabbits; these experiments indicate that the newborn BBB has restrictive properties similar to that of the adult. In contrast to suggestions of an immature barrier in young animals, these studies indicate that a sophisticated, selective BBB is operative at birth; the blood–brain barrier acts to protect the brain from circulating pathogens. Accordingly, blood-borne infections of the brain are rare. Infections of the brain that do occur are difficult to treat. Antibodies are too large to cross the blood–brain barrier, only certain antibiotics are able to pass. In some cases, a drug has to be administered directly into the cerebrospinal fluid where it can enter the brain by crossing the blood–cerebrospinal fluid barrier; the blood–brain barrier may become leaky in select neurological diseases, such as amyotrophic lateral sclerosis, brain trauma and edema, in systemic diseases, such as liver failure.
The blood–brain barrier becomes more permeable during inflammation, allowing antibiotics and phagocytes to move across the BBB. However, this allows bacteria and viruses to infiltrate the blood–brain barrier. Examples of pathogens that can traverse the blood–brain barrier include Toxoplasma gondii which causes toxoplasmosis, spirochetes like Borrelia, Group B streptococci which causes meningitis in newborns, Treponema pallidum which causes syphilis; some of these harmful bacteria gain access by releasing cytotoxins like pneumolysin which have a direct toxic effect on brain microvascular endothelium and tight junctions. Circumventricular organs are individual structures located adjacent to the fourth ventricle or third ventricle in the brain, are characterized by dense capillary beds with permeable endothelial cells unlike those of the blood–brain barrier. I
European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website