A drug is any substance that, when inhaled, smoked, absorbed via a patch on the skin, or dissolved under the tongue causes a physiological change in the body. In pharmacology, a drug is a chemical substance of known structure, other than a nutrient of an essential dietary ingredient, when administered to a living organism, produces a biological effect. A pharmaceutical drug called a medication or medicine, is a chemical substance used to treat, prevent, or diagnose a disease or to promote well-being. Traditionally drugs were obtained through extraction from medicinal plants, but more also by organic synthesis. Pharmaceutical drugs may be used for a limited duration, or on a regular basis for chronic disorders. Pharmaceutical drugs are classified into drug classes—groups of related drugs that have similar chemical structures, the same mechanism of action, a related mode of action, that are used to treat the same disease; the Anatomical Therapeutic Chemical Classification System, the most used drug classification system, assigns drugs a unique ATC code, an alphanumeric code that assigns it to specific drug classes within the ATC system.
Another major classification system is the Biopharmaceutics Classification System. This classifies drugs according to their permeability or absorption properties. Psychoactive drugs are chemical substances that affect the function of the central nervous system, altering perception, mood or consciousness, they include alcohol, a depressant, the stimulants nicotine and caffeine. These three are the most consumed psychoactive drugs worldwide and are considered recreational drugs since they are used for pleasure rather than medicinal purposes. Other recreational drugs include hallucinogens and amphetamines and some of these are used in spiritual or religious settings; some drugs can cause addiction and all drugs can have side effects. Excessive use of stimulants can promote stimulant psychosis. Many recreational drugs are illicit and international treaties such as the Single Convention on Narcotic Drugs exist for the purpose of their prohibition. In English, the noun "drug" is thought to originate from Old French "drogue" deriving into "droge-vate" from Middle Dutch meaning "dry barrels", referring to medicinal plants preserved in them.
The transitive verb "to drug" arose and invokes the psychoactive rather than medicinal properties of a substance. A medication or medicine is a drug taken to cure or ameliorate any symptoms of an illness or medical condition; the use may be as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. Dispensing of medication is regulated by governments into three categories—over-the-counter medications, which are available in pharmacies and supermarkets without special restrictions. In the United Kingdom, behind-the-counter medicines are called pharmacy medicines which can only be sold in registered pharmacies, by or under the supervision of a pharmacist; these medications are designated by the letter P on the label. The range of medicines available without a prescription varies from country to country. Medications are produced by pharmaceutical companies and are patented to give the developer exclusive rights to produce them; those that are not patented are called generic drugs since they can be produced by other companies without restrictions or licenses from the patent holder.
Pharmaceutical drugs are categorised into drug classes. A group of drugs will share a similar chemical structure, or have the same mechanism of action, the same related mode of action or target the same illness or related illnesses; the Anatomical Therapeutic Chemical Classification System, the most used drug classification system, assigns drugs a unique ATC code, an alphanumeric code that assigns it to specific drug classes within the ATC system. Another major classification system is the Biopharmaceutics Classification System; this groups drugs according to their permeability or absorption properties. Some religions ethnic religions are based on the use of certain drugs, known as entheogens, which are hallucinogens,—psychedelics, dissociatives, or deliriants; some drugs used as entheogens include kava which can act as a stimulant, a sedative, a euphoriant and an anesthetic. The roots of the kava plant are used to produce a drink, consumed throughout the cultures of the Pacific Ocean; some shamans from different cultures use entheogens, defined as "generating the divine within" to achieve religious ecstasy.
Amazonian shamans use ayahuasca a hallucinogenic brew for this purpose. Mazatec shamans have a long and continuous tradition of religious use of Salvia divinorum a psychoactive plant, its use is to facilitate visionary states of consciousness during spiritual healing sessions. Silene undulata is used as an entheogen, its root is traditionally used to induce vivid lucid dreams during the initiation process of shamans, classifying it a occurring oneirogen similar to the more well-known dream herb Calea ternifolia. Peyote a small spineless cactus has been a
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
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding; the majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors. The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, villain, rival", derived from anti- and agonizesthai.
Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly; the activity of receptors can be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses; this may be accomplished by binding to the allosteric site. In addition, antagonists may interact at unique binding sites not involved in the biological regulation of the receptor's activity to exert their effects.
The term antagonist was coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s; the current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by'blocking' the receptor from the agonist; this definition remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.
Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states; the discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug. By definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, antagonists inhibit the function of agonists, inverse agonists, partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist.
The potency of an antagonist is defined by its half maximal inhibitory concentration. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC50 value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar; the lower the IC50 the greater the potency of the antagonist, the lower the concentration of drug, required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects; the affinity of an antagonist for its binding site, i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and Ki determination is independent of the affinity, efficacy or concentration of the agonist used.
However, it is important. The effects of receptor desensitization on reaching equilibrium must als
Pfizer Inc. is an American multinational pharmaceutical corporation headquartered in New York City, with its research headquarters in Groton, Connecticut. It is one of the world's largest pharmaceutical companies, it is listed on the New York Stock Exchange, its shares have been a component of the Dow Jones Industrial Average since 2004. Pfizer ranked No. 57 on the 2018 Fortune 500 list of the largest United States corporations by total revenue. On December 19, 2018, Pfizer announced a joint merger of their consumer healthcare division with UK pharma giant GlaxoSmithKline; the company develops and produces medicines and vaccines for a wide range of medical disciplines, including immunology, cardiology and neurology. Its products include the blockbuster drug Lipitor, used to lower LDL blood cholesterol. In 2016, Pfizer Inc. was expected to merge with Allergan, Plc to create the Ireland-based "Pfizer plc" in a deal that would have been worth $160 billion. The merger was called off in April 2016, because of new rules from the United States Treasury against tax inversions, a method of avoiding taxes by merging with a foreign company.
The company has made the second-largest pharmaceutical settlement with the United States Department of Justice. Pfizer was founded in 1849 by German-American Charles Pfizer and his cousin Charles F. Erhart from Ludwigsburg, Germany, they launched the chemicals business Charles Pfizer and Company from a building at the intersection of Harrison Avenue and Bartlett Street in Williamsburg, where they produced an antiparasitic called santonin. This was an immediate success, although it was the production of citric acid that kick-started Pfizer's growth in the 1880s. Pfizer continued to buy property to expand its lab and factory on the block bounded by Bartlett Street, Harrison Avenue, Gerry Street, Flushing Avenue. Pfizer's original administrative headquarters was at 81 Maiden Lane in Manhattan. By 1906, sales totaled $3.4 million. World War I caused a shortage of calcium citrate which Pfizer imported from Italy for the manufacture of citric acid, the company began a search for an alternative supply.
Pfizer chemists learned of a fungus that ferments sugar to citric acid, they were able to commercialize production of citric acid from this source in 1919, the company developed expertise in fermentation technology as a result. These skills were applied to the mass production of the antibiotic penicillin during World War II in response to the need to treat injured Allied soldiers. Penicillin became inexpensive in the 1940s, Pfizer searched for new antibiotics with greater profit potential, they discovered Terramycin in 1950, this changed the company from a manufacturer of fine chemicals to a research-based pharmaceutical company. Pfizer developed a drug discovery program focusing on in vitro synthesis in order to augment its research in fermentation technology; the company established an animal health division in 1959 with an 700-acre farm and research facility in Terre Haute, Indiana. By the 1950s, Pfizer had established offices in Belgium, Canada, Mexico, Puerto Rico, the United Kingdom. In 1960, the company moved its medical research laboratory operations out of New York City to a new facility in Groton, Connecticut.
In 1980, they launched Feldene, a prescription anti-inflammatory medication that became Pfizer's first product to reach one billion dollars in total sales. During the 1980s and 1990s, Pfizer Corporation growth was sustained by the discovery and marketing of Zoloft, Norvasc, Aricept and Viagra. In this decade, Pfizer grew by mergers, including those with Warner–Lambert and Wyeth. In 2003, the company acquired Esperion Therapeutics for $1.3 billion, protecting Lipitor from ETC-216. In 2004, Pfizer announced. In 2005, the company made a number of acquisitions: Vicuron Pharmaceuticals for $1.9 billion, Idun for just less than $300 million and Angiosyn for $527 million. On June 26, 2006, Pfizer announced it would sell its Consumer Healthcare unit to Johnson & Johnson for $16.6 billion. Development of torcetrapib, a drug that increases production of HDL, or "good cholesterol", which reduces LDL thought to be correlated to heart disease, was cancelled in December 2006. During a Phase III clinical trial involving 15,000 patients, more deaths occurred in the group that took the medicine than expected, a sixty percent increase in mortality was seen among patients taking the combination of torcetrapib and Lipitor versus Lipitor alone.
Lipitor alone was not implicated in the results, but Pfizer lost nearly $1 billion developing the failed drug and the market value of the company plummeted afterwards. The company announced it would acquire Powermed and Rivax. In September 2009, Pfizer pleaded guilty to the illegal marketing of the arthritis drug Bextra for uses unapproved by the U. S. Food and Drug Administration, agreed to a $2.3 billion settlement, the largest health care fraud settlement at that time. A July 2010 article in BusinessWeek reported that Pfizer was seeing more success in its battle against makers of counterfeit prescription drugs by pursuing c
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
Beta-secretase 1 known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, ASP2, is an enzyme that in humans is encoded by the BACE1 gene. BACE1 is an aspartic-acid protease important in the formation of myelin sheaths in peripheral nerve cells; the transmembrane protein contains two active site aspartate residues in its extracellular protein domain and may function as a dimer. Generation of the 40 or 42 amino acid-long amyloid-β peptides that aggregate in the brain of Alzheimer's patients requires two sequential cleavages of the amyloid precursor protein. Extracellular cleavage of APP by BACE1 creates a soluble extracellular fragment and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by γ-secretase releases the intracellular domain of APP and produces amyloid-β. Since gamma-secretase cleaves APP closer to the cell membrane than BACE1 does, it removes a fragment of the amyloid-β peptide.
Initial cleavage of APP by α-secretase rather than BACE1 prevents eventual generation of amyloid-β. Unlike APP and the presenilin proteins important in γ-secretase, no known mutations in the gene encoding BACE1 cause early-onset, familial Alzheimer's disease, a rare form of the disorder. However, levels of this enzyme have been shown to be elevated in the far more common late-onset sporadic Alzheimer's; the physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown. BACE2 is a close homolog of BACE1 with no reported APP cleavage in vivo; however a single residue mutation in APP reduces the ability of BACE1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimer's disease and other cognitive declines. Drugs to block this enzyme in theory would prevent the buildup of beta-amyloid and may help slow or stop Alzheimer's disease. Several companies are in the early stages of development and testing of this potential class of treatment. In March 2008 phase I results were reported for CoMentis Inc's candidate CTS-21166.
In April 2012 Merck & Co. Inc reported phase I results for its candidate verubecestat. Merck began a Phase II/III trial of MK-8931 in December, 2012 estimated to be completed in July 2019. In February 2017, Merck halted its late-stage trial of verubecestat for mild to moderate Alzheimer's disease after it was reported as having "virtually no chance" of working according to an independent panel of experts; this came just three months after Eli Co. announced its own setback with solanezumab. The results of Merck's trial of verubecestat on patients with early stage Alzheimer's are still expected in February 2019. In September 2014 AstraZeneca and Eli Lilly and Company announced an agreement to codevelop lanabecestat. A pivotal Phase II/III clinical trial of lanabecestat started in late 2014, but was halted in 2018 before its planned conclusion due to poor results. Another BACE1 inhibitor that has reached phase II trials is the Eli Lilly’s inhibitor LY2886721; the data on phase I trial were first presented at the Alzheimer’s Association International conference in 2012.
Daily dosing during 2 weeks, reduced BACE1 activity by 50–75% and CSF Aβ42 by 72%. Lilly reported that the phase II trial of LY2886721 was terminated due to liver abnormalities that were found in 4 out of 45 patients; this toxicity, does not have to be related to the working mechanism of the inhibitor, but can represent off-target effects as the livers of BACE1 knockout mice are normal. Tests in mice have indicated that BACE proteases BACE1, are necessary for the proper function of muscle spindles; these results raise the possibility that BACE inhibiting drugs being investigated for the treatment of Alzheimer's may have significant side effects related to impaired motor coordination, though BACE1 knockout mice are healthy. BACE1 is distantly related to the pathogenic aspartic-acid protease plasmepsin, a potential target for future anti-malarial drugs; the MEROPS online database for peptidases and their inhibitors: A01.004 beta-Secretase: Molecule of the Month, by David Goodsell, RCSB Protein Data Bank Human BACE1 genome location and BACE1 gene details page in the UCSC Genome Browser
In medicine, a side effect is an effect, whether therapeutic or adverse, secondary to the one intended. Developing drugs is a complicated process, because no two people are the same, so drugs that have no side effects, might be difficult for some people, it is difficult to make a drug that targets one part of the body but that doesn’t affect other parts, the fact that increases the risk of side effects in the untargeted parts. Drugs are prescribed or procedures performed for their side effects. For instance, X-rays were used as an imaging technique; the probability or chance of experiencing side effects are characterised as: Very common, ≥ 1⁄10 Common, 1⁄10 to 1⁄100 Uncommon, 1⁄100 to 1⁄1000 Rare, 1⁄1000 to 1⁄10000 Very rare, < 1⁄10000 Bevacizumab, used to slow the growth of blood vessels, has been used against dry age-related macular degeneration, as well as macular edema from diseases such as diabetic retinopathy and central retinal vein occlusion. Buprenorphine has been shown experimentally to be effective against refractory depression.
Bupropion, an anti-depressant, is used as a smoking cessation aid. In Ontario, smoking cessation drugs are not covered by provincial drug plans. Therefore, some physicians prescribe Wellbutrin for both indications. Carbamazepine is an approved treatment for bipolar disorder and epileptic seizures, but it has side effects useful in treating attention-deficit hyperactivity disorder, phantom limb syndrome, paroxysmal extreme pain disorder and post-traumatic stress disorder. Dexamethasone and betamethasone in premature labor, to enhance pulmonary maturation of the fetus. Doxepin has been used to treat angiodema and severe allergic reactions due to its strong antihistamine properties. Gabapentin, approved for treatment of seizures and postherpetic neuralgia in adults, has side-effects which are useful in treating bipolar disorder1, essential tremor, hot flashes, migraine prophylaxis, neuropathic pain syndromes, phantom limb syndrome, restless leg syndrome. Hydroxyzine, an antihistamine, is used as an anxiolytic.
Magnesium sulfate in obstetrics for premature preeclampsia. Methotrexate, approved for the treatment of choriocarcinoma, is used for the medical treatment of an unruptured ectopic pregnancy; the SSRI medication sertraline is approved as an antidepressant but delays conjugal climax in men, thus may be supplied to those in which climax is premature. Sildenafil was intended for pulmonary hypertension. Terazosin, an α1-adrenergic antagonist approved to treat benign prostatic hyperplasia and hypertension, is used off-label to treat drug induced diaphoresis and hyperhidrosis. Echinacea – more than 20 different types of reactions have been reported, including asthma attacks, loss of pregnancy, swelling, aching muscles and gastrointestinal upsets. Feverfew – pregnant women should avoid using this herb, as it can trigger uterine contractions which could lead to premature labour or miscarriage. Asteraceae plants – which include feverfew, echinacea and chamomile. Side effects include hay fever. Pharmacogenetics: the use of genetic information to determine which type of drugs will work best for a patient MedEffect Canada definitions.pdf