Modified-release dosage is a mechanism that delivers a drug with a delay after its administration or for a prolonged period of time or to a specific target in the body. Sustained-release dosage forms are dosage forms designed to release a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects; this can be achieved through a variety of formulations, including liposomes and drug-polymer conjugates. Sustained release's definition is more akin to a "controlled release" rather than "sustained". Extended-release dosage consists of sustained-release and controlled-release dosage. SR maintains drug release over a sustained period but not at a constant rate. CR maintains drug release over a sustained period at a nearly constant rate. Sometimes these and other terms are treated as synonyms, but the United States Food and Drug Administration has in fact defined most of these as different concepts. Sometimes the term "depot tablet" is used by non-native speakers, but this is not found in any English dictionaries and is a literal translation of the term used in Swedish and some other languages.
Modified-release dosage and its variants are mechanisms used in tablets and capsules to dissolve a drug over time in order to be released slower and steadier into the bloodstream while having the advantage of being taken at less frequent intervals than immediate-release formulations of the same drug. For example, extended-release morphine enables people with chronic pain to only take one or two tablets per day. Most it refers to time dependent release in oral dose formulations. Timed release has several distinct variants such as sustained release where prolonged release is intended, pulse release, delayed release etc. A distinction of controlled release is that not only it prolongs action but it attempts to maintain drug levels within the therapeutic window to avoid hazardous peaks in drug concentration following ingestion or injection and to maximize therapeutic efficiency. In addition to pills and injectable drug carriers, forms of controlled release medicines include gels and devices and transdermal patches.
Examples of cosmetics, personal care and food science applications centre on odour or flavour release. The release technology scientific and industrial community is represented by the Controlled Release Society; the CRS is the worldwide society for delivery science and technologies. CRS serves more than 1,600 members from more than 50 countries. Two-thirds of CRS membership is represented by industry and one-third represents academia and government. CRS is affiliated with the Journal of Controlled Release and Drug Delivery and Translational Research scientific journals; the earliest SR drugs are associated with a patent in 1938 by Israel Lipowski, who coated pellets which led to coating particles. The science of controlled release developed further with more oral sustained-release products in the late 1940s and early 1950s, the development of controlled release of marine anti-foulants in the 1950s and controlled release fertilizer in the 1970s where sustained and controlled delivery of nutrients following a single application to the soil.
Delivery is effected by dissolution, degradation or disintegration of an excipient in which the active compound is formulated. Enteric coating and other encapsulation technologies can further modify release profiles. There is no industry standard for these abbreviations, confusion and misreading have sometimes caused prescribing errors. Clear handwriting is necessary. For some drugs with multiple formulations, putting the meaning in parentheses is advisable. A few other abbreviations refer to dose rather than release rate, they include ES and XS. Today, most time-release drugs are formulated so that the active ingredient is embedded in a matrix of insoluble substance such that the dissolving drug must find its way out through the holes. In some SR formulations, the drug dissolves into the matrix, the matrix physically swells to form a gel, allowing the drug to exit through the gel's outer surface. Micro-encapsulation is regarded as a more complete technology to produce complex dissolution profiles.
Through coating an active pharmaceutical ingredient around an inert core, layering it with insoluble substances to form a microsphere one can obtain more consistent and replicable dissolution rates in a convenient format that can be mixed and matched with other instant release pharmaceutical ingredients in to any two piece gelatin capsule. There are certain considerations for the formation of sustained-release formulation: If the pharmacological activity of the active compound is not related to its blood levels, time releasing has no purpose except in some cases, such as bupropion, to reduce possible side effects. If the absorption of the active compound involves an active transport, the development of a time-release product may be problematic; the half-life of the drug refers to the drug's elimination from the bloodstream which can be caused by metabolism and other forms of excretion. If the active compound has a long half-life, it is sustained on its own. If the active compound has a short half-life, it would require a large amount to maintain a prolonged effective dose.
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In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A potent drug evokes a given response at low concentrations, while a drug of lower potency evokes the same response only at higher concentrations. Higher potency does not mean more side effects; the IUPHAR has stated that'potency' is "an imprecise term that should always be further defined", for instance as EC 50, IC 50, ED50, LD50 and so on. Harris, Robert. "Formulating High Potency Drugs". Contract Pharma. Retrieved 2013-11-13. Walker MG, Page CP, Hoffman BF, Curtis M. Integrated Pharmacology. St. Louis: Mosby. ISBN 978-0-323-04080-8
Bristol-Myers Squibb Company is an American pharmaceutical company, headquartered in New York City. Bristol-Myers Squibb manufactures prescription pharmaceuticals and biologics in several therapeutic areas, including cancer, HIV/AIDS, cardiovascular disease, hepatitis, rheumatoid arthritis and psychiatric disorders. BMS' primary R&D sites are located in Lawrence, New Jersey, Hopewell Township and New Brunswick, New Jersey. BMS had an R&D site in Wallingford, Connecticut; the Squibb corporation was founded in 1858 by Edward Robinson Squibb in New York. Squibb was known as a vigorous advocate of quality control and high purity standards within the fledgling pharmaceutical industry of his time, at one point self-publishing an alternative to the U. S. Pharmacopeia after failing to convince the American Medical Association to incorporate higher purity standards. Mentions of the Materia Medica, Squibb products, Edward Squibb's opinion on the utility and best method of preparation for various medicants are found in many medical papers of the late 1800s.
Squibb Corporation served as a major supplier of medical goods to the Union Army during the American Civil War, providing portable medical kits containing morphine, surgical anesthetics, quinine for the treatment of malaria. In 1887, Hamilton College graduates William McLaren Bristol and John Ripley Myers purchased the Clinton Pharmaceutical company of Clinton, New York. In 1898, they decided to rename it Bristol and Company. Following Myers' death in 1899, Bristol changed the name to the Bristol-Myers Corporation; the first nationally recognized product was Sal Hepatica, a laxative mineral salt in 1903. Its second national success was Ipana toothpaste, from 1901 through the 1960s. Other divisions were Drackett. In 1943, Bristol-Myers acquired Cheplin Biological Laboratories, a producer of acidophilus milk in East Syracuse, New York, converted the plant to produce penicillin for the World War II Allied forces. After the war, the company renamed the plant Bristol Laboratories in 1945 and entered the civilian antibiotics market, where it faced competition from Squibb, which had opened the world's largest penicillin plant in 1944 in New Brunswick, New Jersey.
Penicillin production at the East Syracuse plant was ended in 2005, when it became less expensive to produce overseas, but the facility continues to be used for the manufacturing process development and production of other biologic medicines for clinical trials and commercial use. Bristol-Myers and Squibb merged with Bristol-Myers as the nominal survivor; the merged company became Bristol-Myers Squibb. In 1999, President Clinton awarded Bristol-Myers Squibb the National Medal of Technology, the nation's highest recognition for technological achievement, "for extending and enhancing human life through innovative pharmaceutical research and development and for redefining the science of clinical study through groundbreaking and hugely complex clinical trials that are recognized models in the industry." In 2002, the company was involved in a lawsuit of maintaining illegally a monopoly on Taxol, its cancer treatment, it was again sued for the antitrust lawsuit 5 years which cost the company $125 million for settlement.
The company was involved in an accounting scandal in 2002 that resulted in a significant restatement of revenues from 1999 to 2001. The restatement was the result of an improper booking of sales related to "channel stuffing" as the practice of offering excess inventory to customers to create higher sales numbers; the company has since settled with the United States Department of Justice and Securities and Exchange Commission, agreeing to pay $150 million while neither admitting nor denying guilt. On October 24, 2002, Bristol-Myers Squibb Co. restated earnings downward for parts of 2000 and 2001 while revising this year's earnings upward because of its massive inventory backlog imbroglio that spurred two government investigations. On March 15, 2004, Bristol-Myers Squibb Co. adjusted upward its fourth-quarter and full-year 2003 results after reversing an earlier decision about how to deal with accounting errors made in prior years. As part of a Deferred Prosecution Agreement, the company was placed under the oversight of a monitor appointed by the U.
S. Attorney in New Jersey. In addition, the former head of the Pharma group, Richard Lane, the ex-CFO, Fred Schiff, were indicted for federal securities violations. An investigation of the company was made public in July 2006, the FBI raided the company's corporate offices; the investigation centered on charges of collusion. On September 12, 2006, the monitor, former Federal Judge Frederick B. Lacey, urged the company to remove CEO Peter Dolan over the Plavix dispute; that day, BMS announced that Dolan would indeed step down. The Deferred Prosecution Agreement expired in June 2007 and the Department of Justice did not take any further legal action against the company for matters covered by the DPA. Under CEO Jim Cornelius, CEO following Dolan until May 2010, all executives involved in the "channel-stuffing" and generic competition scandals have since left the company. In 2009, a major restructuring began focusing on the pharmaceutical business and biologic products, along with productivity initiatives and cost-cutting and streamlining business operations through a multi-year program of on-going layoffs.
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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.
Clinical trials are experiments or observations done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on efficacy, they are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial – their approval does not mean that the therapy is'safe' or effective, only that the trial may be conducted. Depending on product type and development stage, investigators enroll volunteers or patients into small pilot studies, subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, they can involve a single research center or multiple centers, in one country or in multiple countries.
Clinical study design aims to ensure the scientific reproducibility of the results. Costs for clinical trials can range into the billions of dollars per approved drug; the sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory. Only 10 percent of all drugs started in human clinical trials become an approved drug; some clinical trials involve healthy subjects with no pre-existing medical conditions. Other clinical trials pertain to patients with specific health conditions who are willing to try an experimental treatment; when participants are healthy volunteers who receive financial incentives, the goals are different than when the participants are sick. During dosing periods, study subjects remain under supervision for one to 40 nights. Pilot experiments are conducted to gain insights for design of the clinical trial to follow.
There are two goals to testing medical treatments: to learn whether they work well enough, called "efficacy" or "effectiveness". Neither is an absolute criterion; the benefits must outweigh the risks. For example, many drugs to treat cancer have severe side effects that would not be acceptable for an over-the-counter pain medication, yet the cancer drugs have been approved since they are used under a physician's care, are used for a life-threatening condition. In the US, the elderly constitute 14 % of the population. People over 55 are excluded from trials because their greater health issues and drug use complicate data interpretation, because they have different physiological capacity than younger people. Children and people with unrelated medical conditions are frequently excluded. Pregnant women are excluded due to potential risks to the fetus; the sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type of patients might benefit.
If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study. During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment and collect data on the subjects' health for a defined time period. Data include measurements such as vital signs, concentration of the study drug in the blood or tissues, changes to symptoms, whether improvement or worsening of the condition targeted by the study drug occurs; the researchers send the data to the trial sponsor, who analyzes the pooled data using statistical tests. Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device: On a specific kind of patient, for example, a patient, diagnosed with Alzheimer's disease At varying dosages, for example, a 10 milligram dose instead of a 5 milligram dose For a new indication Evaluation for improved efficacy in treating a patient's condition as compared to the standard therapy for that condition Evaluation of the study drug or device relative to two or more approved/common interventions for that condition, for example, device A versus device B, or therapy A versus therapy B)While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a placebo.
Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol. The protocol is the trial's "operating manual" and ensures that all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects; as a trial is designed to test hypotheses and rigorously monitor and assess outcomes, it can be seen as an application of the scientific method the experimental step. The most common clinical trials evaluate new pharmaceutical products, medical devices, psychological therapies, or other interventions. Clinical trials may be required before a national regulatory authority approves marketing of the innovation. To drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for premarket appr
Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, a measure of the ability of the drug to bind to its molecular target, the EC50, a measure of the potency of the drug and, proportional to both efficacy and affinity; this use of the word "efficacy" was introduced by Stephenson to describe the way in which agonists vary in the response they produce when they occupy the same number of receptors. High efficacy agonists can produce the maximal response of the receptor system while occupying a low proportion of the receptors in that system. Agonists of lower efficacy are not as efficient at producing a response from the drug-bound receptor, by stabilizing the active form of the drug-bound receptor. Therefore, they may not be able to produce the same maximal response when they occupy the entire receptor population, as the efficiency of transformation of the inactive form of the drug-receptor complex to the active drug-receptor complex may not be high enough to evoke a maximal response.
Since the observed response may be less than maximal in systems with no spare receptor reserve, some low efficacy agonists are referred to as partial agonists. However, it is worth bearing in mind that these terms are relative - partial agonists may appear as full agonists in a different system/experimental setup, as when the number of receptors increases, there may be enough drug-receptor complexes for a maximum response to be produced with individually low efficacy of transducing the response. There are relatively few true full agonists or silent antagonists. Many antagonists are in fact partial agonists or inverse agonists, but with low efficacy. Compounds considered. Another case is represented by silent agonists, which are ligands that can place a receptor an ion channel, into a desensitized state with little or no apparent activation of it, forming a complex that can subsequently generate currents when treated with an allosteric modulator. There is a distinction between intrinsic activity.
Efficacy has been treated as a proportionality constant between the binding of the drug and the generation of the biological response. Stephenson defined efficacy as: S = e p where p is the proportion of agonist-bound receptors and S is the stimulus to the biological system; the response is generated by an unknown function f, assumed to be hyperbolic. This model was arguably flawed in that it did not incorporate the equilibrium between the inactivated agonist-bound-receptor and the activated agonist-bound-receptor, shown in the del Castillo Katz model. Furchgott improved on Stephenson's model with the definition of efficacy, e, as S = ε T o t ⏟ e ⋅ p where ε is the intrinsic efficacy and T o t is the total concentration of receptors; these models of efficacy have been criticised and many more. The models of efficacy are shown in. Intrinsic activity of a test agonist is defined as: I A = maximal response to the test agonist maximal response to full agonist
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, co-sponsored by the American Medical Association, the United States Pharmacopeial Convention, the American Pharmacists Association; the USAN Program states that its goal is to select simple and unique nonproprietary names for drugs by establishing logical nomenclature classifications based on pharmacological or chemical relationships. In addition to drugs, the USAN Council names agents for gene therapy and cell therapy, contact lens polymers, surgical materials, diagnostics and substances used as an excipient; the USAN Council works in conjunction with the World Health Organization International Nonproprietary Name Expert Committee and national nomenclature groups to standardize drug nomenclature and establish rules governing the classification of new substances. The USAN Council began in June 1961 after the AMA and the USP jointly formed the AMA-USP Nomenclature Committee.
The American Pharmacists Association became the third sponsoring organization in 1964, at which point the name of the committee was changed to the USAN Council, United States Adopted Name became the official term to describe any nonproprietary name negotiated and formally adopted by the Council. In 1967, a liaison representative from the Food and Drug Administration was appointed to serve on the USAN Council; the FDA announced in 1984 that it would discontinue adding drug names to its official list and use the USAN as the established name for labeling and advertising new single-entity drugs marketed in the United States. The AMA Council on Drugs no longer exists as a separate entity. FDA now has a representative on the USAN Council, which has moved away from chemically derived names; the USAN Council has five members, one from each sponsoring organization, one from the FDA, a member-at-large. One member is nominated to the USAN Council annually by each sponsoring organization; the member-at-large is selected by the sponsoring organizations from a list of candidates proposed by the AMA, APhA, the USP.
The five nominees to the Council must be approved annually by the board of trustees of the three sponsoring organizations. Judith Jones Thomas P. Reinders David Lewis Peter Rheinstein, Chair Armen Melikian By definition, nonproprietary names are not subject to proprietary trademark rights but are in the public domain; this distinguishes them from the trademarked names. Assignment of a USAN takes into account practical considerations, such as the existence of trademarks, international harmonization of drug nomenclature, the development of new classes of drugs, the fact that the intended uses of substances for which names are being selected may change. USANs assigned today reflect both present nomenclature practices and older methods used to name drug entities. Early drug nomenclature was based on the chemical structure; as newer drugs became chemically more complex and numerous, nonproprietary names based on chemistry became long and difficult to spell, pronounce, or remember. Additionally, chemically derived names provided little useful information to non-chemist health practitioners.
Considering the needs of health professionals led to a system in which USANs reflect relationships between new entities and older drugs, avoid names that might suggest non-existent relationships. Current nomenclature practices involve the adoption of standardized syllables called "stems" that relate new chemical entities to existing drug families. Stems may be suffixes, or infixes in the nonproprietary name; each stem can emphasize a specific chemical structure type, a pharmacologic property, or a combination of these attributes. The recommended list of USAN stems is updated to keep pace to accommodate drugs with new chemical and pharmacologic properties; as a general rule, the application for a USAN should be forwarded to the USAN Council after the Investigational New Drug is active and clinical trials have begun. Many drug manufacturers seeking a USAN are multinational companies with subsidiaries in various parts of the world or contractual agreements with drug firms outside the United States.
Therefore, it is desirable to the pharmaceutical company, the various nomenclature committees, the medical community in general that a global name be established for each new single-entity compound introduced. Assigning a USAN and standardizing names internationally can take anywhere from several months to a few years. Examples of drugs for which the USAN differs from the INN include: British Approved Name International Nonproprietary Name Nomenclature of monoclonal antibodies United States Pharmacopeia US Adopted Names Program