1.
Brazil
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Brazil, officially the Federative Republic of Brazil, is the largest country in both South America and Latin America. As the worlds fifth-largest country by area and population, it is the largest country to have Portuguese as an official language. Its Amazon River basin includes a vast tropical forest, home to wildlife, a variety of ecological systems. This unique environmental heritage makes Brazil one of 17 megadiverse countries, Brazil was inhabited by numerous tribal nations prior to the landing in 1500 of explorer Pedro Álvares Cabral, who claimed the area for the Portuguese Empire. Brazil remained a Portuguese colony until 1808, when the capital of the empire was transferred from Lisbon to Rio de Janeiro, in 1815, the colony was elevated to the rank of kingdom upon the formation of the United Kingdom of Portugal, Brazil and the Algarves. Independence was achieved in 1822 with the creation of the Empire of Brazil, a state governed under a constitutional monarchy. The ratification of the first constitution in 1824 led to the formation of a bicameral legislature, the country became a presidential republic in 1889 following a military coup détat. An authoritarian military junta came to power in 1964 and ruled until 1985, Brazils current constitution, formulated in 1988, defines it as a democratic federal republic. The federation is composed of the union of the Federal District, the 26 states, Brazils economy is the worlds ninth-largest by nominal GDP and seventh-largest by GDP as of 2015. A member of the BRICS group, Brazil until 2010 had one of the worlds fastest growing economies, with its economic reforms giving the country new international recognition. Brazils national development bank plays an important role for the economic growth. Brazil is a member of the United Nations, the G20, BRICS, Unasul, Mercosul, Organization of American States, Organization of Ibero-American States, CPLP. Brazil is a power in Latin America and a middle power in international affairs. One of the worlds major breadbaskets, Brazil has been the largest producer of coffee for the last 150 years and it is likely that the word Brazil comes from the Portuguese word for brazilwood, a tree that once grew plentifully along the Brazilian coast. In Portuguese, brazilwood is called pau-brasil, with the word brasil commonly given the etymology red like an ember, formed from Latin brasa and the suffix -il. As brazilwood produces a red dye, it was highly valued by the European cloth industry and was the earliest commercially exploited product from Brazil. The popular appellation eclipsed and eventually supplanted the official Portuguese name, early sailors sometimes also called it the Land of Parrots. In the Guarani language, a language of Paraguay, Brazil is called Pindorama
2.
France
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France, officially the French Republic, is a country with territory in western Europe and several overseas regions and territories. The European, or metropolitan, area of France extends from the Mediterranean Sea to the English Channel and the North Sea, Overseas France include French Guiana on the South American continent and several island territories in the Atlantic, Pacific and Indian oceans. France spans 643,801 square kilometres and had a population of almost 67 million people as of January 2017. It is a unitary republic with the capital in Paris. Other major urban centres include Marseille, Lyon, Lille, Nice, Toulouse, during the Iron Age, what is now metropolitan France was inhabited by the Gauls, a Celtic people. The area was annexed in 51 BC by Rome, which held Gaul until 486, France emerged as a major European power in the Late Middle Ages, with its victory in the Hundred Years War strengthening state-building and political centralisation. During the Renaissance, French culture flourished and a colonial empire was established. The 16th century was dominated by civil wars between Catholics and Protestants. France became Europes dominant cultural, political, and military power under Louis XIV, in the 19th century Napoleon took power and established the First French Empire, whose subsequent Napoleonic Wars shaped the course of continental Europe. Following the collapse of the Empire, France endured a succession of governments culminating with the establishment of the French Third Republic in 1870. Following liberation in 1944, a Fourth Republic was established and later dissolved in the course of the Algerian War, the Fifth Republic, led by Charles de Gaulle, was formed in 1958 and remains to this day. Algeria and nearly all the colonies became independent in the 1960s with minimal controversy and typically retained close economic. France has long been a centre of art, science. It hosts Europes fourth-largest number of cultural UNESCO World Heritage Sites and receives around 83 million foreign tourists annually, France is a developed country with the worlds sixth-largest economy by nominal GDP and ninth-largest by purchasing power parity. In terms of household wealth, it ranks fourth in the world. France performs well in international rankings of education, health care, life expectancy, France remains a great power in the world, being one of the five permanent members of the United Nations Security Council with the power to veto and an official nuclear-weapon state. It is a member state of the European Union and the Eurozone. It is also a member of the Group of 7, North Atlantic Treaty Organization, Organisation for Economic Co-operation and Development, the World Trade Organization, originally applied to the whole Frankish Empire, the name France comes from the Latin Francia, or country of the Franks
3.
Pharmaceutical drug
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A pharmaceutical drug is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy is an important part of the field and relies on the science of pharmacology for continual advancement. Drugs are classified in various ways, one of the key divisions is by level of control, which distinguishes prescription drugs from over-the-counter drugs. Other ways to classify medicines are by mode of action, route of administration, biological system affected, an elaborate and widely used classification system is the Anatomical Therapeutic Chemical Classification System. The World Health Organization keeps a list of essential medicines, Drug discovery and drug development are complex and expensive endeavors undertaken by pharmaceutical companies, academic scientists, and governments. Governments generally regulate what drugs can be marketed, how drugs are marketed, controversies have arisen over drug pricing and disposal of used drugs. In the US, a drug is, A substance recognized by an official pharmacopoeia or formulary, a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. A substance intended to affect the structure or any function of the body, a substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device. Pharmaceutical or a drug is classified on the basis of their origin, Drug from natural origin, Herbal or plant or mineral origin, some drug substances are of marine origin. Drug from chemical as well as origin, Derived from partial herbal and partial chemical synthesis Chemical. Drug derived from animal origin, For example, hormones, Drug derived from microbial origin, Antibiotics Drug derived by biotechnology genetic-engineering, hybridoma technique for example Drug derived from radioactive substances. An elaborate and widely used system is the Anatomical Therapeutic Chemical Classification System. The World Health Organization keeps a list of essential medicines, the main classes of painkillers are NSAIDs, opioids and Local anesthetics. For consciousness Some anesthetics include Benzodiazepines and Barbiturates, the main categories of drugs for musculoskeletal disorders are, NSAIDs, muscle relaxants, neuromuscular drugs, and anticholinesterases. Euthanasia is not permitted by law in countries, and consequently medicines will not be licensed for this use in those countries. Administration is the process by which a patient takes a medicine, there are three major categories of drug administration, enteral, parenteral, and other. It can be performed in various forms such as pills, tablets. There are many variations in the routes of administration, including intravenous and they can be administered all at once as a bolus, at frequent intervals or continuously
4.
Chemical patent
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A chemical patent, pharmaceutical patent or drug patent is a patent for an invention in the chemical or pharmaceuticals industry. A chemical patent or a patent is therefore not a sui generis right. These generic structures are used to make the patent claim as broad as possible, compulsory licensing Criticism of pharmaceutical patents Evergreening Generic drug Supplementary protection certificate European Commission, Pharmaceuticals, Sector Inquiry,2008. Patents and Pharmaceuticals, a paper given on 29 November 2008 at the Presentation of the Directorate-General of Competition’s Preliminary Report of the Pharma-sector inquiry, by the Rt
5.
United States Adopted Name
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United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association, the United States Pharmacopeial Convention, and the American Pharmacists Association. In addition to drugs, the USAN Council names agents for gene therapy and cell therapy, contact lens polymers, surgical materials, diagnostics, carriers, the USAN Council began in June 1961 after the AMA and the USP jointly formed the AMA-USP Nomenclature Committee. In 1967, a representative from the Food and Drug Administration was appointed to serve on the USAN Council. 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. Currently, the USAN Council has five members, one from each sponsoring organization, one from the FDA, one member is nominated to the USAN Council annually by each sponsoring organization, the FDA nominates one liaison member annually. The member-at-large is selected by the organizations from a list of candidates proposed by the AMA, APhA. The five nominees to the Council must be approved annually by the board of trustees of the three sponsoring organizations and this distinguishes them from the trademarked names that have been registered for private use. 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 more complex and numerous, nonproprietary names based on chemistry became long and difficult to spell, pronounce. Additionally, chemically derived names provided little information to non-chemist health practitioners. Considering the needs of health led to a system in which USANs reflect relationships between new entities and older drugs, and 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 prefixes, suffixes, or infixes in the nonproprietary name. Each stem can emphasize a specific chemical structure type, a pharmacologic property, the recommended list of USAN stems is updated regularly 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 has been approved by the FDA 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, assigning a USAN and standardizing names internationally can take anywhere from several months to a few years
6.
Food and Drug Administration
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The Food and Drug Administration is a federal agency of the United States Department of Health and Human Services, one of the United States federal executive departments. As of 2017, 3/4th of the FDA budget is funded by the pharmaceutical companies due to the Prescription drug user fee act and these include regulating lasers, cellular phones, condoms and control of disease on products ranging from certain household pets to sperm donation for assisted reproduction. The FDA is led by the Commissioner of Food and Drugs, appointed by the President with the advice, the Commissioner reports to the Secretary of Health and Human Services. Dr. Robert M. Califf, MD is the current commissioner, who took over in February 2016 for Dr. Stephen Ostroff, the FDA has its headquarters in unincorporated White Oak, Maryland. The agency also has 223 field offices and 13 laboratories located throughout the 50 states, the United States Virgin Islands, in 2008, the FDA began to post employees to foreign countries, including China, India, Costa Rica, Chile, Belgium, and the United Kingdom. The site was renamed from the White Oak Naval Surface Warfare Center to the Federal Research Center at White Oak, the first building, the Life Sciences Laboratory, was dedicated and opened with 104 employees on the campus in December 2003. Only one original building from the facility was kept. All other buildings are new construction, the project is slated to be completed by 2017, assuming future Congressional funding While most of the Centers are located in the Washington, D. C. The Office of Regulatory Affairs is considered the eyes and ears of the agency, the Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. Districts are based roughly on the divisions of the federal court system. Each district comprises a main office and a number of Resident Posts. ORA also includes the Agencys network of laboratories, which analyze any physical samples taken. Though samples are usually food-related, some laboratories are equipped to analyze drugs, cosmetics, the Office of Criminal Investigations was established in 1991 to investigate criminal cases. Unlike ORA Investigators, OCI Special Agents are armed, and dont focus on aspects of the regulated industries. In many cases, OCI pursues cases involving Title 18 violations, OCI Special Agents often come from other criminal investigations backgrounds, and work closely with the Federal Bureau of Investigation, Assistant Attorney General, and even Interpol. OCI receives cases from a variety of sources—including ORA, local agencies, OCI is a smaller branch, comprising about 200 agents nationwide. The FDA frequently works with federal agencies, including the Department of Agriculture, Drug Enforcement Administration, Customs and Border Protection. Often local and state government agencies also work with the FDA to provide regulatory inspections, the FDA regulates more than US$1 trillion worth of consumer goods, about 25% of consumer expenditures in the United States
7.
Bioequivalence
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Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same. Pharmaceutical equivalence implies the same amount of the active substance, in the same dosage form, for the same route of administration. Serum/plasma samples are obtained at intervals and assayed for parent drug concentration. Occasionally, blood levels are neither feasible or possible to compare the two products, then pharmacodynamic endpoints rather than pharmacokinetic endpoints are used for comparison. Testing should be conducted at different doses, especially when the drug displays non-linear pharmacokinetics. In addition to data from studies, other data may need to be submitted to meet regulatory requirements for bioequivalence. 80–1.25. Tmax should also be similar between the products, there are tighter requirements for drugs with a narrow therapeutic index and/or saturable metabolism – thus no generic products exist on the Australian market for digoxin or phenytoin for instance. This is considered demonstrated if the 90% confidence intervals of the ratios for AUC0–t, the FDA considers two products bioequivalent if the 90% CI of the relative mean Cmax, AUC and AUC of the test to reference should be within 80% to 125% in the fasting state. A food-effect study requires the same statistical evaluation as the fasting study, while the FDA maintains that approved generic drugs are equivalent to their branded counterparts, bioequivalence problems have been reported by physicians and patients for many drugs. Certain classes of drugs are suspected to be problematic because of their chemistry. Some of these include chiral drugs, poorly absorbed drugs, in addition, complex delivery mechanisms can cause bioequivalence variances. Physicians are cautioned to avoid switching patients from branded to generic, major issues were raised in the verification of bioequivalence when multiple generic versions of FDA-approved generic drug were found not to be equivalent in efficacy and side effect profiles. The Peoples Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, the tests showed that some generic versions of Wellbutrin XL300 mg didnt perform the same as the brand-name pill in laboratory tests. The FDA investigated these complaints and concluded that the version is equivalent to Wellbutrin XL in regard to bioavailability of bupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL. After several years of denying patient reports, in 2012 the FDA reversed this opinion, announcing that Budeprion XL300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL300 mg. The FDA did not test the bioequivalence of any of the generic versions of Wellbutrin XL300 mg
8.
Pharmacokinetics
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Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as, pharmaceutical drugs, pesticides, food additives, cosmetic ingredients, 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, both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Pharmacokinetic properties of chemicals are affected by the route of administration and these may affect the absorption rate. Models have been developed to simplify conceptualization of the processes that take place in the interaction between an organism and a chemical substance. The various compartments that the model is divided into are commonly referred to as the ADME scheme, absorption - the process of a substance entering the blood circulation. Distribution - the dispersion or dissemination of substances throughout the fluids, 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 also 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. All these concepts can be represented through mathematical formulas that have a graphical representation. The model outputs for a drug can be used in industry or in the application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals, in practice, it is generally 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. 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. The final outcome of the transformations that a drug undergoes in an organism, 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. However, these models do not always reflect the real situation within an organism
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Pharmacodynamics
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Pharmacodynamics is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms, Pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. Both together influence dosing, benefit, and adverse effects, Pharmacodynamics is sometimes abbreviated as PD and pharmacokinetics as PK, especially in combined reference. Pharmacodynamics places particular emphasis on relationships, that is, the relationships between drug concentration and effect. One dominant example is drug-receptor interactions as modeled by L + R ⇌ L ⋅ R where L, R, and LR represent ligand, receptor and this equation represents a simplified model of reaction dynamics that can be studied mathematically through tools such as free energy maps. Antacids and chelating agents combine chemically in the body, the widest class of drugs act as ligands which bind to receptors which determine cellular effects. Upon drug binding, receptors can elicit their normal action, blocked action, in principle, a pharmacologist would aim for a target plasma concentration of the drug for a desired level of response. In reality, there are factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown, genetic factors may exist which would alter metabolism or drug action itself, and a patients immediate status may also affect indicated dosage. The duration of action of a drug is the length of time that particular drug is effective, the binding of ligands to receptors is governed by the law of mass action which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the concentration of bound receptors. The equilibrium dissociation constant is defined by, L + R ↔ L ⋅ R K d = where L=ligand, R=receptor, the fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear and this explains the so-called receptor reserve phenomenon i. e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response. The simplest interpretation of receptor reserve is that it is a model that states there are excess receptors on the surface than what is necessary for full effect. Thus, the existence of receptor reserve depends on the agonist, tissue, as receptor reserve is very sensitive to agonist’s intrinsic efficacy, it is usually defined only for full agonists. Often the response is determined as a function of log to consider many orders of magnitude of concentration, however, there is no biological or physical theory which relates effects to the log of concentration. It is just convenient for graphing purposes and it is useful to note that 50% of the receptors are bound when =Kd. The graph shown represents the conc-response for two hypothetical receptor agonists, plotted in a semi-log fashion, the curve toward the left represents a higher potency since lower concentrations are needed for a given response
10.
Biopharmaceutical
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A biopharmaceutical, also known as a biologic medical product, biological, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances and they are isolated from living sources—human, animal, plant, fungal, or microbial. Terminology surrounding biopharmaceuticals varies between groups and entities, with different terms referring to different subsets of therapeutics within the general biopharmaceutical category, Specialty drugs, a recent classification of pharmaceuticals, are high-cost drugs that are often biologics. In some jurisdictions, biologics are regulated via different pathways than other small molecule drugs, the term biopharmacology is sometimes used to describe the branch of pharmacology that studies biopharmaceuticals. Some of the oldest forms of biologics are extracted from the bodies of animals, as indicated the term biologics can be used to refer to a wide range of biological products in medicine. However, in most cases, the term biologics is used more restrictively for a class of therapeutics that are produced by means of processes involving recombinant DNA technology. These medications are usually one of three types, Substances that are identical to the bodys own key signalling proteins, examples are the blood-production stimulating protein erythropoetin, or the growth-stimulating hormone named growth hormone or biosynthetic human insulin and its analogues. Receptor constructs, usually based on a naturally occurring receptor linked to the immunoglobulin frame, in this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology. Some examples are listed in the table below, the cost of treatment with a typical monoclonal antibody therapy for relatively common indications is generally in the range of €7, 000–14,000 per patient per year. The first such substance approved for use was biosynthetic human insulin made via recombinant DNA. Sometimes referred to as rHI, under the trade name Humulin, was developed by Genentech, but licensed to Eli Lilly and Company, a few examples of biologics made with recombinant DNA technology include, Many vaccines are grown in tissue cultures. Viral gene therapy involves artificially manipulating a virus to include a piece of genetic material. With the expiration of patents for blockbuster biologics between 2012 and 2019, the interest in biosimilar production, i. e. follow-on biologics, has increased. Compared to small molecules that consist of chemically identical active ingredients, biologics are vastly more complex, due to their heterogeneity and the high process sensitivity, neither originators nor follow-on manufacturers produce reliably constant quality profiles over time. The process variations are monitored by modern tools and describe a unique design space for each biologic. Thus, biosimilars require a different regulatory framework compared to small-molecule generics, legislation in the 21st century has addressed this by recognizing an intermediate ground of testing for biosimilars. The filing pathway requires more testing than for generics. In 2003, the European Medicines Agency introduced an adapted pathway for biosimilars and this pathway is based on a thorough demonstration of comparability of the similar product to an existing approved product
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Monoclonal antibody
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Monoclonal antibodies are antibodies that are made by identical immune cells that are all clones of a unique parent cell. Monoclonal antibodies can have monovalent affinity, in that they bind to the same epitope, in contrast, polyclonal antibodies bind to multiple epitopes and are usually made by several different plasma cell lineages. Bispecific monoclonal antibodies can also be engineered, by increasing the therapeutic targets of one single monoclonal antibody to two epitopes, given almost any substance, it is possible to produce monoclonal antibodies that specifically bind to that substance, they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology, when used as medications, non-proprietary drug names end in -mab and many immunotherapy specialists use the word mab anacronymically. He and Élie Metchnikoff received the 1908 Nobel Prize for Physiology or Medicine for this work, in the 1970s, the B-cell cancer multiple myeloma was known. It was understood that these cancerous B-cells all produce a type of antibody. This was used to study the structure of antibodies, but it was not yet possible to produce antibodies specific to a given antigen. They shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery, in 1988, Greg Winter and his team pioneered the techniques to humanize monoclonal antibodies, eliminating the reactions that many monoclonal antibodies caused in some patients. Monoclonal antibodies are made by cell culture that involves fusing myeloma cells with mouse spleen cells immunized with the desired antigen. Rabbit B-cells can be used to form a rabbit hybridoma, polyethylene glycol is used to fuse adjacent plasma membranes, but the success rate is low, so a selective medium in which only fused cells can grow is used. This is possible because myeloma cells have lost the ability to synthesize hypoxanthine-guanine-phosphoribosyl transferase, the absence of HGPRT is not a problem for these cells unless the de novo purine synthesis pathway is also disrupted. Exposing cells to aminopterin, makes them unable to use the de novo pathway and become fully auxotrophic for nucleic acids, the selective culture medium is called HAT medium because it contains hypoxanthine, aminopterin and thymidine. This medium is selective for fused cells, unfused myeloma cells cannot grow because they lack HGPRT and thus cannot replicate their DNA. Unfused spleen cells cannot grow indefinitely because of their life span. Only fused hybrid cells, referred to as hybridomas, are able to grow indefinitely in the media because the spleen cell partner supplies HGPRT and this mixture of cells is then diluted and clones are grown from single parent cells on microtitre wells. The antibodies secreted by the different clones are then assayed for their ability to bind to the antigen or immuno-dot blot, the most productive and stable clone is then selected for future use. The hybridomas can be grown indefinitely in a cell culture medium. They can also be injected into mice, there, they produce tumors secreting an antibody-rich fluid called ascites fluid
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Small molecule
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In molecular biology and pharmacology, a small molecule is a low molecular weight organic compound that may help regulate a biological process, with a size on the order of 1 nm. In addition, this molecular weight cutoff is a necessary but insufficient condition for oral bioavailability, Small molecules can have a variety of biological functions, serving as cell signaling molecules, as drugs in medicine, as pesticides in farming, and in many other roles. These compounds can be natural or artificial, they may have an effect against a disease or may be detrimental. Larger structures such as acids and proteins, and many polysaccharides, are not small molecules—though their constituent monomers are often considered small molecules. Very small oligomers are also usually considered small molecules, such as dinucleotides, peptides such as the antioxidant glutathione, Small molecules may also be used as research tools to probe biological function as well as leads in the development of new therapeutic agents. Some can inhibit a specific function of a protein or disrupt protein–protein interactions. Most pharmaceuticals are small molecules, although some drugs can be proteins, many proteins are degraded if administered orally and most often cannot cross cell membranes. Small molecules are likely to be absorbed, although some of them are only absorbed after oral administration if given as prodrugs. One advantage small molecule drugs have over large molecule biologics is that many SMDs can be taken orally whereas biologics generally require injection or another parenteral administration, secondary metabolites are a rich source of biologically active compounds and hence are often used as research tools and leads for drug discovery. Examples of secondary metabolites include, Alkaloids Glycosides Lipids Nonribosomal peptides, such as actinomycin-D Phenazines Natural phenols Polyketide Terpenes, including steroids Tetrapyrroles. An example is the teratogen and carcinogen phorbol 12-myristate 13-acetate, which is a plant terpene that activates protein kinase C, there is also interest in creating small molecule artificial transcription factors to regulate gene expression, examples include wrenchnolol. Small-molecule anti-genomic therapeutics, or SMAT, refers to a technology that targets DNA signatures found in many biological warfare agents. Metabolite Chemogenomics Neurotransmitter Peptidomimetic Small Molecule Libraries at the US National Library of Medicine Medical Subject Headings
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Biosimilar
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A biosimilar is a biologic medical product which is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original products, and can be manufactured when the original products patent expires. Reference to the product is an integral component of the approval. Unlike with generic drugs of the more common type, biologics generally exhibit high molecular complexity. Consequently, EMA has granted a marketing authorisation for only a few biosimilars since 2006 including a monoclonal antibody which is recently approved, meanwhile, on March 6,2015, the FDA approved the United Statess first biosimilar product, the biosimilar of filgrastim called filgrastim-sndz by Sandoz. This procedure is based on a demonstration of comparability of the similar product to an existing approved product. In the United States, the Food and Drug Administration held that new legislation was required to them to approve biosimilars to those biologics originally approved through the PHS Act pathway. Additional Congressional hearings have been held, on March 17,2009, the Pathway for Biosimilars Act was introduced in the House. See the Library of Congress website and search H. R.1548 in 111th Congress Session, since 2004 the FDA has held a series of public meetings on biosimilars. The FDA gained the authority to approve biosimilars as part of the Patient Protection, on March 6,2015, Zarxio obtained the first approval of FDA. Sandoz’s Zarxio is biosimilar to Amgen’s Neupogen, which was licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009, but Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made, gene- and cell-based therapies are emerging as new approaches. Recombinant therapeutic proteins are of a complex nature and these proteins are made in living cells. After the expiry of the patent of approved recombinant drugs any other biotech company can develop, every biological displays a certain degree of variability. Originally the complexity of biological molecules led to requests for substantial efficacy and this has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose. However, the application of biologics depends on an informed and appropriate use by healthcare professionals. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan and it is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified
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Patent
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A patent is a set of exclusive rights granted by a sovereign state to an inventor or assignee for a limited period of time in exchange for detailed public disclosure of an invention. An invention is a solution to a technological problem and is a product or a process. Patents are a form of intellectual property, the procedure for granting patents, requirements placed on the patentee, and the extent of the exclusive rights vary widely between countries according to national laws and international agreements. Typically, however, a patent application must include one or more claims that define the invention. A patent may include many claims, each of which defines a specific property right and these claims must meet relevant patentability requirements, such as novelty, usefulness, and non-obviousness. Nevertheless, there are variations on what is patentable subject matter from country to country, the word patent originates from the Latin patere, which means to lay open. More directly, it is a version of the term letters patent. Similar grants included land patents, which were land grants by early state governments in the USA, and printing patents, a precursor of modern copyright. In modern usage, the term patent usually refers to the granted to anyone who invents any new, useful. The additional qualification utility patent is used to distinguish the primary meaning from these other types of patents. Particular species of patents for inventions include biological patents, business method patents, chemical patents, the period of protection was 10 years. These were mostly in the field of glass making, as Venetians emigrated, they sought similar patent protection in their new homes. This led to the diffusion of patent systems to other countries, by the 16th century, the English Crown would habitually abuse the granting of letters patent for monopolies. After public outcry, King James I of England was forced to revoke all existing monopolies, the Statute became the foundation for later developments in patent law in England and elsewhere. Important developments in patent law emerged during the 18th century through a process of judicial interpretation of the law. During the reign of Queen Anne, patent applications were required to supply a complete specification of the principles of operation of the invention for public access. Influenced by the philosophy of John Locke, the granting of patents began to be viewed as a form of property right. The English legal system became the foundation for patent law in countries with a common law heritage, including the United States, New Zealand, in the Thirteen Colonies, inventors could obtain patents through petition to a given colonys legislature
15.
European Union
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The European Union is a political and economic union of 28 member states that are located primarily in Europe. It has an area of 4,475,757 km2, the EU has developed an internal single market through a standardised system of laws that apply in all member states. Within the Schengen Area, passport controls have been abolished, a monetary union was established in 1999 and came into full force in 2002, and is composed of 19 EU member states which use the euro currency. The EU operates through a system of supranational and intergovernmental decision-making. The EU traces its origins from the European Coal and Steel Community, the community and its successors have grown in size by the accession of new member states and in power by the addition of policy areas to its remit. While no member state has left the EU or its antecedent organisations, the Maastricht Treaty established the European Union in 1993 and introduced European citizenship. The latest major amendment to the basis of the EU. The EU as a whole is the largest economy in the world, additionally,27 out of 28 EU countries have a very high Human Development Index, according to the United Nations Development Programme. In 2012, the EU was awarded the Nobel Peace Prize, through the Common Foreign and Security Policy, the EU has developed a role in external relations and defence. The union maintains permanent diplomatic missions throughout the world and represents itself at the United Nations, the World Trade Organization, the G7, because of its global influence, the European Union has been described as an emerging superpower. After World War II, European integration was seen as an antidote to the nationalism which had devastated the continent. 1952 saw the creation of the European Coal and Steel Community, the supporters of the Community included Alcide De Gasperi, Jean Monnet, Robert Schuman, and Paul-Henri Spaak. These men and others are credited as the Founding fathers of the European Union. In 1957, Belgium, France, Italy, Luxembourg, the Netherlands and West Germany signed the Treaty of Rome and they also signed another pact creating the European Atomic Energy Community for co-operation in developing nuclear energy. Both treaties came into force in 1958, the EEC and Euratom were created separately from the ECSC, although they shared the same courts and the Common Assembly. The EEC was headed by Walter Hallstein and Euratom was headed by Louis Armand, Euratom was to integrate sectors in nuclear energy while the EEC would develop a customs union among members. During the 1960s, tensions began to show, with France seeking to limit supranational power, Jean Rey presided over the first merged Commission. In 1973, the Communities enlarged to include Denmark, Ireland, Norway had negotiated to join at the same time, but Norwegian voters rejected membership in a referendum
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United States
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Forty-eight of the fifty states and the federal district are contiguous and located in North America between Canada and Mexico. The state of Alaska is in the northwest corner of North America, bordered by Canada to the east, the state of Hawaii is an archipelago in the mid-Pacific Ocean. The U. S. territories are scattered about the Pacific Ocean, the geography, climate and wildlife of the country are extremely diverse. At 3.8 million square miles and with over 324 million people, the United States is the worlds third- or fourth-largest country by area, third-largest by land area. It is one of the worlds most ethnically diverse and multicultural nations, paleo-Indians migrated from Asia to the North American mainland at least 15,000 years ago. European colonization began in the 16th century, the United States emerged from 13 British colonies along the East Coast. Numerous disputes between Great Britain and the following the Seven Years War led to the American Revolution. On July 4,1776, during the course of the American Revolutionary War, the war ended in 1783 with recognition of the independence of the United States by Great Britain, representing the first successful war of independence against a European power. The current constitution was adopted in 1788, after the Articles of Confederation, the first ten amendments, collectively named the Bill of Rights, were ratified in 1791 and designed to guarantee many fundamental civil liberties. During the second half of the 19th century, the American Civil War led to the end of slavery in the country. By the end of century, the United States extended into the Pacific Ocean. The Spanish–American War and World War I confirmed the status as a global military power. The end of the Cold War and the dissolution of the Soviet Union in 1991 left the United States as the sole superpower. The U. S. is a member of the United Nations, World Bank, International Monetary Fund, Organization of American States. The United States is a developed country, with the worlds largest economy by nominal GDP. It ranks highly in several measures of performance, including average wage, human development, per capita GDP. While the U. S. economy is considered post-industrial, characterized by the dominance of services and knowledge economy, the United States is a prominent political and cultural force internationally, and a leader in scientific research and technological innovations. In 1507, the German cartographer Martin Waldseemüller produced a map on which he named the lands of the Western Hemisphere America after the Italian explorer and cartographer Amerigo Vespucci
17.
Clinical trial
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Clinical trials are experiments or observations done in clinical research. Clinical trials generate data on safety and efficacy and 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. Clinical trials can vary in size and cost, and they can involve a research center or multiple centers. Clinical study design aims to ensure the validity and reproducibility of the results. Trials can be costly, depending on a number of factors. The sponsor may be an 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, 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 typically remain under supervision for one to 40 nights. Usually pilot experiments are conducted to gain insights for design of the trial to follow. There are two goals to testing medical treatments, to whether they work well enough, called efficacy or effectiveness. The benefits must outweigh the risks, in the US, the elderly constitute only 14 percent of the population, while they consume over one-third of drugs. Women, children and people with unrelated medical conditions are frequently excluded. For women, a reason for exclusion is the possibility of pregnancy. 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. The researchers send the data to the sponsor, who then analyzes the pooled data using statistical tests. Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol
18.
National Health Service
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The National Health Service is the name of the public health services of England, Scotland and Wales, and is commonly used to refer to those of Northern Ireland. They were established together as one of the social reforms following the Second World War on the founding principles of being comprehensive, universal. Today, each provides a range of health services, the vast majority of which are free for people ordinarily resident in the United Kingdom. Taken together, the four National Health Services in 2015-16 employed around 1.6 million people with a budget of £136.7 billion. For non-residents, the NHS is free at the time of use, for general practitioner, the NHS began on the Appointed Day of 5 July 1948. This put into practice Westminster legislation for England and Wales from 1946 and Scotland from 1947, when Clement Attlees Labour Party won the 1945 election he appointed Aneurin Bevan as Health Minister. Bevan then embarked upon what the historian of the NHS, Charles Webster. Three years after the founding of the NHS, Bevan resigned from the Labour government in opposition to the introduction of charges for the provision of dentures and glasses, the following year, Winston Churchills Conservative government introduced prescription charges. These charges were the first of many controversies over reforms to the NHS throughout its history, each of the UKs four nations have their own separate NHS, each with its own history. From its earliest days, the history of the NHS has shown its place in British society reflected and debated in film, TV, cartoons. However, some functions might be performed by one health service on behalf of another. There have been issues about cross-border payments, taken together, the four National Health Services in 2015-16 employed around 1.6 million people with a combined budget of £136.7 billion. In 2014 the total health sector workforce across the UK was 2,165,043 and this broke down into 1,789,586 in England,198,368 in Scotland,110,292 in Wales and 66,797 in Northern Ireland. The NHS is free at the time of use, for general practitioner and emergency treatment not including admission to hospital, people with the right to medical care in European Economic Area nations are also entitled to free treatment by using the European Health Insurance Card. Those from other countries with which the UK has reciprocal arrangements also qualify for free treatment, people not ordinarily resident in the UK are in general not entitled to free hospital treatment, with some exceptions such as refugees. People not ordinarily resident may be subject to an interview to establish their eligibility, patients who do not qualify for free treatment are asked to pay in advance, or to sign a written undertaking to pay, except for emergency treatment. The provision of treatment to non-UK-residents, formerly interpreted liberally, has been increasingly restricted. As of 2016 the surcharge was £200 per year, with exemptions and reductions in some cases, the systems are 98. 8% funded from general taxation and National Insurance contributions, plus small amounts from patient charges for some services
19.
Research and development
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Research and development, also known in Europe as research and technical development, is a general term for activities in connection with corporate or governmental innovation. Research and development is situated at the front end of the life cycle. R&D differs from the vast majority of activities in that it is not intended to yield immediate profit, and generally carries greater risk. New product design and development is more often not a crucial factor in the survival of a company. In an industry that is changing fast, firms must continually revise their design and this is necessary due to continuous technology change and development as well as other competitors and the changing preference of customers. Without an R&D program, a firm must rely on strategic alliances, acquisitions, a system driven by marketing is one that puts the customer needs first, and produces goods that are known to sell. Market research is carried out, which establishes what is needed, if the development is technology driven R&D is directed toward developing products to meet the unmet need. Statistics on organizations devoted to R&D may express the state of an industry, some common measures include, budgets, numbers of patents or on rates of peer-reviewed publications. Bank ratios are one of the best measures, because they are maintained, public. In the United States, a ratio of research and development for an industrial company is about 3. 5% of revenues. A high technolog company, such as a manufacturer, might spend 7% or a pharmaceutical companies such as Merck & Co.14. 1% or Novartis 15. 1%. That is, gross profits will be as much as 90% of the sales cost, with manufacturing costing only 10% of the product price, most industrial companies get 40% revenues only. On a technical level, high tech organizations explore ways to re-purpose and they often reuse advanced manufacturing processes, expensive safety certifications, specialized embedded software, computer-aided design software, electronic designs and mechanical subsystems. Research from 2000 has shown that firms with a persistent R&D strategy outperform those with an irregular or no R&D investment program. Research and development are very difficult to manage, since the feature of research is that the researchers do not know in advance exactly how to accomplish the desired result. As a result, higher R&D spending does not guarantee more creativity, research is the most risky financing area because both the development of an invention and its successful realization carries uncertainty including the profitability of the invention. One way of reducing the uncertainty of researching know-hows is to obtain already researched know-hows, president Barack Obama requested $147.696 billion for research & development in FY2012. Much of this spending was devoted to research on the mechanisms of disease
20.
Ranbaxy Laboratories
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Ranbaxy Laboratories Limited is an Indian multinational pharmaceutical company that was incorporated in India in 1961. The company went public in 1973 and Japanese pharmaceutical company Daiichi Sankyo acquired a share in 2008. In 2014, Sun Pharma acquired the entire 63. 4% share of Ranbaxy making the conglomerate the world’s fifth largest specialty generic pharma company, as of 2013, Ranbaxy was exporting its products to 125 countries with ground operations in 43 and manufacturing facilities in eight countries. In 2011, Ranbaxy Global Consumer Health Care received the OTC Company of the year award, in the 2012,2013 and 2014 Brand Trust Reports, Ranbaxy was ranked 161st, 225th and 184th respectively among Indias most trusted brands. Ranbaxy was started by Ranbir Singh and Gurbax Singh in 1937 as a distributor for a Japanese company Shionogi, the name Ranbaxy is a portmanteau of the names of its first owners Ranbir and Gurbax. Bhai Mohan Singh bought the company in 1952 from his cousins Ranbir, after Bhai Mohan Singhs son Parvinder Singh joined the company in 1967, the company saw an increase in scale. In 1998, Ranbaxy entered the United States, the worlds largest pharmaceuticals market, for the twelve months ending on 31 December 2005, the companys global sales were US$1,178 million, with overseas markets accounting for 75% of global sales. For the twelve months ending on 31 December 2006, the global sales were US$1,300 million. The settlement also resolved other disputes in other countries. On 23 June 2006, Ranbaxy received from the United States Food & Drug Administration a 180-day exclusivity period to sell simvastatin in the US as a generic drug at 80 mg strength, Ranbaxy competes with the maker of brand-name Zocor, Merck & Co. IVAX Corporation, which has 180-day exclusivity at strengths other than 80 mg, on 1 December 2011, Ranbaxy got approval from the US Food and Drug Administration to launch the generic version of drug Lipitor in the United States of America after its patent expired. In June 2008, Daiichi-Sankyo acquired a 34. 8% stake in Ranbaxy, in November 2008, Daiichi-Sankyo completed the takeover of the company from the founding Singh family in a deal worth $4.6 billion by acquiring a 63. 92% stake in Ranbaxy. Ranbaxys Malvinder Singh remained as CEO after the transaction, the addition of Ranbaxy Laboratories extended Daiichi-Sankyos operations, with the combined company worth about US$30 billion. In 2009 it was reported that former Novartis Senior Vice-President Yugal Sikri would lead the India operations of Ranbaxy Laboratories, under these agreements, shareholders of Ranbaxy, were to receive a 0.8 share of Sun Pharmaceutical for each share of Ranbaxy. After this acquisition, the partner Daiichi-Sankyo was to hold a stake of 9% in Sun Pharmaceutical, the combination of Sun Pharma and Ranbaxy created the fifth-largest specialty generics company in the world and the largest pharmaceutical company in India. During 2004–2005, Dinesh Thakur and Rajinder Kumar, two Indian employees of Ranbaxy, blew the whistle on Ranbaxys fabrication of drug test reports, thakurs office computer was soon found tampered with. Ranbaxy then accused Thakur of visiting pornographic websites using his office computer, Thakur left India for the USA and contacted the Food and Drug Administration which started investigating his claims. On 8 February 2012, three batches of the proton-pump inhibitor Pantoprazole were recalled in the Netherlands due to the presence of impurities, on 9 November 2012, Ranbaxy halted production and recalled forty-one lots of atorvastatin due to glass particles being found in some bottles
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Sun Pharmaceutical
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The company offers formulations in various therapeutic areas, such as cardiology, psychiatry, neurology, gastroenterology and diabetology. It also provides APIs such as warfarin, carbamazepine, etodolac, and clorazepate, as well as anticancers, steroids, peptides, sex hormones, Sun Pharmaceuticals was established by Mr. Dilip Shanghvi in 1983 in Vapi with five products to treat psychiatry ailments. Cardiology products were introduced in 1987 followed by gastroenterology products in 1989, today it is the largest chronic prescription company in India and a market leader in psychiatry, neurology, cardiology, orthopedics, ophthalmology, gastroenterology and nephrology. The 2014 acquisition of Ranbaxy has made the company the largest pharma company in India, the largest Indian pharma company in the US, over 72% of Sun Pharma sales are from markets outside India, primarily in the US. The US is the single largest market, accounting for about 50% turnover, in all, formulations or finished dosage forms, manufacturing is across 26 locations, including plants in the US, Canada, Brazil, Mexico and Israel. In the US, the markets a large basket of generics, with a strong pipeline awaiting approval from the U. S. Food. Sun Pharma was listed on the exchange in 1994 in an issue oversubscribed 55 times. The founding family continues to hold a majority stake in the company, today Sun Pharma is the second largest and the most profitable pharmaceutical company in India, as well as the largest pharmaceutical company by market capitalisation on the Indian exchanges. In terms of value India still stands at number 14 in the world, in 2009 Sun Pharmas Caraco Pharmaceuticals plant in Detroit was closed due to unsanitary conditions resulting in the seizure of $20 million of drugs by the FDA for contamination issues. In December 2016 the FDA sent Sun a warning letter about nine violations at its plant in Halol. Sun Pharma requested the USFDA to withdraw approval for 28 Abbreviated New Drug Applications belonging to its wholly owned subsidiary Ranbaxy Laboratories, Sun Pharma has complemented growth with select acquisitions over the last two decades. In 1996, Sun purchased a drug manufacturing plant at Ahmednagar from Knoll Pharmaceuticals. In 1997, Sun acquired Tamil Nadu Dadha Pharmaceuticals Limited based in Chennai, also in 1997, Sun Pharma initiated their first foray into the lucrative US market with the acquisition of Caraco Pharmaceuticals, based in Detroit. In 1998, Sun acquired a number of brands from Natco Pharma. In 2010, the company acquired a stake in Taro Pharmaceuticals, amongst the largest generic derma companies in the US, with operations across Canada. The company currently owns ~ 69% stake in Taro, for about $260 million, in 2011, Sun Pharma entered into a joint venture with MSD to bring complex or differentiated generics to emerging markets. On 6 April 2014, Sun Pharma announced that it would acquire 100% of Ranbaxy Laboratories Ltd, in an all-stock transaction, valued at $4 billion. Japans Daiichi Sankyo held 63. 4% stake in Ranbaxy.2 billion bid to buy Ranbaxy Laboratories, in March 2015, Sun Pharma announced it had agreed to buy GlaxoSmithKlines opiates business in Australia to strengthen its pain management portfolio
22.
Drug nomenclature
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Drug nomenclature is the systematic naming of drugs, especially pharmaceutical drugs. Generic names for drugs are nowadays constructed out of affixes and stems that classify the drugs into different categories, a marketed drug might also have a company code or compound code. The chemical names are the names, based on the molecular structure of the drug. There are various systems of nomenclature and thus various chemical names for any one substance. The most important is the IUPAC name, chemical names are typically very long and too complex to be commonly used in referring to a drug. Sometimes, a company that is developing a drug might give the drug a company code, for example, CDP870 is UCB’s company code for Cimzia. Many of these codes, although not all, have prefixes that correspond to the company name, during development, the company will apply for regulatory approval of the drug by the relevant national regulatory agency, and it will apply for a generic name for that country. It will also apply for an International Nonproprietary Name through the World Health Organization, nowadays the national nonproprietary names are usually the same as the INN. The generic names usually indicate via their stems what drug class the drug belongs to, for example, one can tell that aciclovir is an antiviral drug because its name ends in the -vir suffix. Otherwise the 2 names are both given, joined by hyphens or slashes. For example, suspensions combining trimethoprim and sulfamethoxazole are called either trimethoprim/sulfamethoxazole or co-trimoxazole, similarly, co-codamol is codeine-acetaminophen, and co-triamterzide is triamterene-hydrochlorothiazide. The USP ceased maintaining PENs, but the similar co-prefixed BANs are still current, for drugs that make it all the way through development, testing, and regulatory acceptance, the pharmaceutical company then gives the drug a trade name. The term trade name is a term in the pharmaceutical industry for a brand name or trademark name. For example, Lipitor is Pfizers trade name for atorvastatin, a cholesterol-lowering medication, Drug names are often subject to legal regulation, including approval for new drugs and on packaging to establish clear rules about adulterants and fraudulent or misleading labelling. A national formulary is often designated to define drug names for regulatory purposes, unbiased mentions of a drug place the nonproprietary name first and follow it with the trade name in parentheses, if relevant. This pattern is important for the literature, where conflict of interest is disclosed or avoided. The authors reporting on a study are not endorsing any particular brand of drug and they will often state which brand was used, for methodologic validity, but they do so in a way that makes clear the absence of endorsement. For example, the 2015 American Society of Hematology publication policies say, Non-proprietary names should be used and he first letter of the name of a proprietary drug should be capitalized
23.
Drug development
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Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. Broadly, the process of development can be divided into pre-clinical and clinical work. New chemical entities are compounds that emerge from the process of drug discovery and these have promising activity against a particular biological target that is important in disease. However, little is known about the safety, toxicity, pharmacokinetics and it is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of development is to recommend the dose. In addition, drug development must establish the physicochemical properties of the NCE, its chemical makeup, stability, manufacturers must optimize the process they use to make the chemical so they can scale up from a medicinal chemist producing milligrams, to manufacturing on the kilogram and ton scale. They further examine the product for suitability to package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, together, these processes are known in preclinical development as chemistry, manufacturing, and control. Many aspects of development focus on satisfying the regulatory requirements of drug licensing authorities. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in humans. It is a requirement that an assessment of major organ toxicity be performed. The information is gathered from this testing, as well as information on CMC. If the IND is approved, development moves to the clinical phase, Clinical trials involve three or four steps, Phase I trials, usually in healthy volunteers, determine safety and dosing. Phase II trials are used to get a reading of efficacy. Phase III trials are large, pivotal trials to determine safety, if safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the new drug application stage. Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, the process of defining characteristics of the drug does not stop once an NCE begins human clinical trials. They must also test the compound for its potential to cause cancer, in the United States, this process is called a new drug application or NDA. Most NCEs fail during drug development, either because they have unacceptable toxicity or because they simply do not have the effect on the targeted disease as shown in clinical trials. The full cost of bringing a new drug to market – from discovery through clinical trials to approval – is complex, typically, companies spend tens to hundreds of millions of U. S. dollars
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Monopoly
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A monopoly exists when a specific person or enterprise is the only supplier of a particular commodity. The verb monopolise or monopolize refers to the process by which a company gains the ability to raise prices or exclude competitors, in economics, a monopoly is a single seller. In law, a monopoly is an entity that has significant market power, that is. Although monopolies may be big businesses, size is not a characteristic of a monopoly, a small business may still have the power to raise prices in a small industry. A monopoly is distinguished from a monopsony, in there is only one buyer of a product or service. Likewise, a monopoly should be distinguished from a cartel, in which several providers act together to coordinate services, prices or sale of goods. Monopolies, monopsonies and oligopolies are all situations in one or a few entities have market power and therefore interact with their customers. Monopolies can be established by a government, form naturally, or form by integration, in many jurisdictions, competition laws restrict monopolies. A government-granted monopoly or legal monopoly, by contrast, is sanctioned by the state, patents, copyrights, and trademarks are sometimes used as examples of government-granted monopolies. The government may also reserve the venture for itself, thus forming a government monopoly, There are four basic types of market structures in traditional economic analysis, perfect competition, monopolistic competition, oligopoly and monopoly. A monopoly is a structure in which a single supplier produces, if there is a single seller in a certain market and there are no close substitutes for the product, then the market structure is that of a pure monopoly. Sometimes, there are many sellers in an industry and/or there exist many close substitutes for the goods being produced and this is termed monopolistic competition, whereas in oligopoly the companies interact strategically. Most economic textbooks follow the practice of explaining the perfect competition model. The boundaries of what constitutes a market and what does not are relevant distinctions to make in economic analysis, in a general equilibrium context, a good is a specific concept including geographical and time-related characteristics. Most studies of market structure relax a little their definition of a good, price Maker, Decides the price of the good or product to be sold, but does so by determining the quantity in order to demand the price desired by the firm. High Barriers, Other sellers are unable to enter the market of the monopoly, single seller, In a monopoly, there is one seller of the good, who produces all the output. Therefore, the market is being served by a single company, and for practical purposes. Price Discrimination, A monopolist can change the price or quantity of the product and he or she sells higher quantities at a lower price in a very elastic market, and sells lower quantities at a higher price in a less elastic market
25.
Drug discovery
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In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered through identifying the active ingredient from traditional remedies or by serendipitous discovery, hits from these screens are then tested in cells and then in animals for efficacy. Once a compound that fulfills all of these requirements has been identified, one or more of these steps may, but not necessarily, involve computer-aided drug design. Modern drug discovery is usually a capital-intensive process that involves large investments by pharmaceutical industry corporations as well as national governments. Despite advances in technology and understanding of systems, drug discovery is still a lengthy, expensive, difficult. In 2010, the research and development cost of new molecular entity was about US$1.8 billion. Drug discovery is done by companies, with research assistance from universities. The final product of drug discovery is a patent on the potential drug, the drug requires very expensive Phase I, II and III clinical trials, and most of them fail. Small companies have a role, often then selling the rights to larger companies that have the resources to run the clinical trials. This made for the beginning of the era in pharmacology, as pure chemicals, instead of crude extracts. Examples of drug compounds isolated from crude preparations are morphine, the agent in opium, and digoxin. Organic chemistry also led to the synthesis of many of the natural products isolated from biological sources, historically substances, whether crude extracts or purified chemicals were screened for biological activity without knowledge of the biological target. Only after a substance was identified was an effort made to identify the target. This approach is known as classical pharmacology, forward pharmacology, or phenotypic drug discovery, later, small molecules were synthesized to specifically target a known physiological/pathological pathway, rather than adopt the mass screening of banks of stored compounds. Cloning of human proteins made possible the screening of large libraries of compounds against specific targets thought to be linked to specific diseases and this approach is known as reverse pharmacology and is the most frequently used approach today. The definition of target itself is something argued within the pharmaceutical industry, generally, the target is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on. However, the distinction between a new and established target can be made without an understanding of just what a target is. This distinction is made by pharmaceutical companies engaged in discovery
26.
Profit (economics)
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Profit or normal profit is a component of costs and not a component of business profit at all. It represents the opportunity cost, as the time that the owner spends running the firm could be spent on running a different firm. In other words, the cost of normal profit varies both within and across industries, it is commensurate with the associated with each type of investment. Only normal profits arise in circumstances of perfect competition when long-run economic equilibrium is reached, the same is likewise true of the long run equilibria of monopolistically competitive industries and, more generally, any market which is held to be contestable. Normally, a firm that introduces a differentiated product can initially secure a temporary power for a short while. At this stage, the price the consumer must pay for the product is high. When this finally occurs, all monopoly associated with producing and selling the product disappears. Profit can, however, occur in competitive and contestable markets in the short run, economic profit is, however, much more prevalent in uncompetitive markets such as in a perfect monopoly or oligopoly situation. This allows the firm to set a price which is higher than that which would be found in a similar but more competitive industry, allowing them economic profit in both the long and short run. In a single-goods case, an economic profit happens when the firms average cost is less than the price of the product or service at the profit-maximizing output. The economic profit is equal to the quantity of output multiplied by the difference between the average cost and the price, often, governments will try to intervene in uncompetitive markets to make them more competitive. Antitrust or competition laws were created to prevent powerful firms from using their power to artificially create the barriers to entry they need to protect their economic profits. This includes the use of predatory pricing toward smaller competitors, with lower barriers, new firms can enter the market again, making the long run equilibrium much more like that of a competitive industry, with no economic profit for firms. For example, the old AT&T monopoly, which existed before the courts ordered its breakup, had to get government approval to raise its prices. Though a regulated firm will not have a profit as large as it would in an unregulated situation. The social profit from a firms activities is the normal profit plus or minus any externalities or consumer surpluses that occur in its activity, a firm may report relatively large monetary profits, but by creating negative externalities their social profit could be relatively small. Profitability is a term of economic efficiency, mathematically it is a relative index – a fraction with profit as numerator and generating profit flows or assets as denominator. It is a standard economic assumption that, other things being equal, given that profit is defined as the difference in total revenue and total cost, a firm achieves a maximum by operating at the point where the difference between the two is at its greatest
27.
Consolidation (business)
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In business, consolidation or amalgamation is the merger and acquisition of many smaller companies into much larger ones. In the context of accounting, consolidation refers to the aggregation of financial statements of a group company as consolidated financial statements. The taxation term of consolidation refers to the treatment of a group of companies, there may be amalgamations, either by transfer of two or more undertakings to a new company, or to the transfer of one or more companies to an existing company. Consolidation is the practice, in business, of combining two or more organizations into a single new one. Upon consolidation, the original organizations cease to exist and are supplanted by a new entity, statutory Consolidation, a business combination that creates a new company in which none of the previous companies survive. Stock Acquisition, a combination in which the purchasing company acquires the majority, more than 50%, of the Common stock of the acquired company. Variable interest entity Parent-subsidiary relationship, the result of a stock acquisition where the parent is the acquiring company, controlling Interest, When the parent company owns a majority of the common stock. Non-Controlling Interest or Minority Interest, the rest of the stock that the other shareholders own. Wholly owned subsidiary, when the parent owns all the common stock of the subsidiary. In an amalgamation, the companies which merge into a new or existing company are referred to as companies or amalgamating companies. The resultant company is referred to as the transferee company, a parent company can acquire another company by purchasing its net assets or by purchasing a majority share of its common stock. Costs of issuing securities, these reduce the issuing price of the stock. Treatment to the company, The acquired company records in its books the elimination of its net assets. If the acquired company is liquidated then the needs a additional entry to distribute the remaining assets to its shareholders. Treatment to the company, The acquired company records in its books the receipt of the payment from the acquiring company. FASB141 Disclosure Requirements, FASB141 requires disclosures in the notes of the financial statements when business combinations occur, such disclosures are, The name and description of the acquired entity and the percentage of the voting equity interest acquired. The primary reasons for acquisition and descriptions of factors contributed to recognition of goodwill. The period for which results of operations of acquired entity are included in the statement of the combining entity
28.
Salt (chemistry)
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In chemistry, a salt is an ionic compound that results from the neutralization reaction of an acid and a base. Salts are composed of related numbers of cations and anions so that the product is electrically neutral and these component ions can be inorganic, such as chloride, or organic, such as acetate, and can be monatomic, such as fluoride, or polyatomic, such as sulfate. There are several varieties of salts, salts that hydrolyze to produce hydroxide ions when dissolved in water are alkali salts, whilst those that hydrolyze to produce hydronium ions in water are acidic salts. Neutral salts are those salts that are neither acidic nor basic, zwitterions contain an anionic centre and a cationic centre in the same molecule, but are not considered to be salts. Examples of zwitterions include amino acids, many metabolites, peptides, usually, non-dissolved salts at standard conditions for temperature and pressure are solid, but there are exceptions. Molten salts and solutions containing dissolved salts are called electrolytes, as they are able to conduct electricity. As observed in the cytoplasm of cells, in blood, urine, plant saps and mineral waters, therefore, their salt content is given for the respective ions. Salts can appear to be clear and transparent, opaque, and even metallic, in many cases, the apparent opacity or transparency are only related to the difference in size of the individual monocrystals. Since light reflects from the boundaries, larger crystals tend to be transparent. The color of the salt is due to the electronic structure in the d-orbitals of transition elements or in the conjugated organic dye framework. Different salts can elicit all five basic tastes, e. g. salty, sweet, sour, bitter, and umami or savory. Salts of strong acids and strong bases are non-volatile and odorless and that slow, partial decomposition is usually accelerated by the presence of water, since hydrolysis is the other half of the reversible reaction equation of formation of weak salts. Many ionic compounds can be dissolved in water or other similar solvents, the exact combination of ions involved makes each compound have a unique solubility in any solvent. The solubility is dependent on how well each ion interacts with the solvent, for example, all salts of sodium, potassium and ammonium are soluble in water, as are all nitrates and many sulfates – barium sulfate, calcium sulfate and lead sulfate are examples of exceptions. However, ions that bind tightly to each other and form highly stable lattices are less soluble, for example, most carbonate salts are not soluble in water, such as lead carbonate and barium carbonate. Some soluble carbonate salts are, sodium carbonate, potassium carbonate, solid salts do not conduct electricity. Moreover, solutions of salts also conduct electricity, the name of a salt starts with the name of the cation followed by the name of the anion. Salts are often referred to only by the name of the cation or by the name of the anion. g
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Ester
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In chemistry, esters are chemical compounds derived from an acid in which at least one –OH group is replaced by an –O–alkyl group. Usually, esters are derived from an acid and an alcohol. Glycerides, which are fatty acid esters of glycerol, are important esters in biology, being one of the classes of lipids. Esters with low weight are commonly used as fragrances and found in essential oils. Phosphoesters form the backbone of DNA molecules, nitrate esters, such as nitroglycerin, are known for their explosive properties, while polyesters are important plastics, with monomers linked by ester moieties. The word ester was coined in 1848 by German chemist Leopold Gmelin, probably as a contraction of the German Essigäther, ester names are derived from the parent alcohol and the parent acid, where the latter may be organic or inorganic. Esters derived from more complex carboxylic acids are, on the hand, more frequently named using the systematic IUPAC name. For example, the ester hexyl octanoate, also known under the trivial name hexyl caprylate, has the formula CH36CO25CH3, the chemical formulas of organic esters usually take the form RCO2R′, where R and R′ are the hydrocarbon parts of the carboxylic acid and the alcohol, respectively. For example, butyl acetate, derived from butanol and acetic acid would be written CH3CO2C4H9, alternative presentations are common including BuOAc and CH3COOC4H9. Cyclic esters are called lactones, regardless of whether they are derived from an organic or an inorganic acid, one example of a lactone is γ-valerolactone. An uncommon class of organic esters are the orthoesters, which have the formula RC3, triethylorthoformate is derived, in terms of its name from orthoformic acid and ethanol. Esters can also be derived from an acid and an alcohol. For example, triphenyl phosphate is the derived from phosphoric acid. Organic carbonates are derived from acid, for example, ethylene carbonate is derived from carbonic acid. So far an alcohol and inorganic acid are linked via oxygen atoms, in corollary, boron features borinic esters, boronic esters, and borates. As oxygen is a group 16 chemical element, sulfur atoms can replace some oxygen atoms in carbon–oxygen–central inorganic atom covalent bonds of an ester, esters contain a carbonyl center, which gives rise to 120 ° C–C–O and O–C–O angles. Unlike amides, esters are structurally flexible functional groups because rotation about the C–O–C bonds has a low barrier and their flexibility and low polarity is manifested in their physical properties, they tend to be less rigid and more volatile than the corresponding amides. The pKa of the alpha-hydrogens on esters is around 25, the preference for the Z conformation is influenced by the nature of the substituents and solvent, if present
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Confidence interval
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In statistics, a confidence interval is a type of interval estimate of a population parameter. It is an interval, in principle different from sample to sample. How frequently the observed interval contains the true parameter if the experiment is repeated is called the confidence level, whereas two-sided confidence limits form a confidence interval, and one-sided limits are referred to as lower/upper confidence bounds. Confidence intervals consist of a range of values that act as good estimates of the population parameter. However, the interval computed from a sample does not necessarily include the true value of the parameter. After any particular sample is taken, the parameter is either in the interval or not. Since the observed data are random samples from the true population, the 99% confidence level means that 99% of the intervals obtained from such samples will contain the true parameter. The desired level of confidence is set by the researcher, If a corresponding hypothesis test is performed, the confidence level is the complement of the level of significance, i. e. a 95% confidence interval reflects a significance level of 0.05. The confidence interval contains the values that, when tested. Confidence intervals of difference parameters not containing 0 imply that there is a significant difference between the populations. In applied practice, confidence intervals are typically stated at the 95% confidence level, however, when presented graphically, confidence intervals can be shown at several confidence levels, for example, 90%, 95%, and 99%. Factors affecting the width of the confidence interval include the size of the sample, the level. A larger sample size normally will lead to an estimate of the population parameter. Confidence intervals were introduced to statistics by Jerzy Neyman in a paper published in 1937, Interval estimates can be contrasted with point estimates. A point estimate is a value given as the estimate of a population parameter that is of interest, for example. An interval estimate specifies instead a range within which the parameter is estimated to lie, Confidence intervals are commonly reported in tables or graphs along with point estimates of the same parameters, to show the reliability of the estimates. For example, an interval can be used to describe how reliable survey results are. In a poll of election–voting intentions, the result might be that 40% of respondents intend to vote for a certain party, a 99% confidence interval for the proportion in the whole population having the same intention on the survey might be 30% to 50%
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Inhaler
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An inhaler is a medical device used for delivering medication into the body via the lungs. It is mainly used in the treatment of asthma and chronic pulmonary disease. Zanamivir, used to treat influenza, must be administered via inhaler, decongestant inhalers are popular over-the-counter remedies for nasal congestion in the upper respiratory tract. The most common type of inhaler is the pressurized metered-dose inhaler, in MDIs, medication is typically stored in solution in a pressurized canister that contains a propellant, although it may also be a suspension. The MDI canister is attached to a plastic, hand-operated actuator, on activation, the metered-dose inhaler releases a fixed dose of medication in aerosol form. Some inhalers are made to act instantly in case of an asthma attack, dry powder inhalers release a metered or device-measured dose of powdered medication that is inhaled through a DPI device. Nebulizers — supply the medication as a created from an aqueous formulation. Nasal inhalers contain decongestant drugs to relieve congestion in the upper respiratory tract. The active ingredient in most decongestants is either pseudoephedrine or phenylephrine, many are sold over-the-counter without a prescription. In 2009, the FDA banned the use of inhalers that use chlorofluorocarbons as propellants, in their place, inhalers now use hydrofluoroalkane. HFA is not environmentally inert as it is a greenhouse gas, while some asthma sufferers and advocacy groups contend that HFA inhalers are not as effective, published clinical studies indicate CFC and HFA inhalers are equally effective in controlling asthma. While the impact of CFCs from inhalers on the layer had been minuscule the FDA in its interpretation of the Montreal Protocol mandated the switch in propellants. Patients expressed concern about the price of the HFA inhalers as there are no generic versions. The idea of delivering medication into the lungs was based on ancient traditional cures that involved the use of aromatic. These did not involve any special devices beyond the apparatus used for burning or heating to produce fumes, early inhalation devices included one devised by John Mudge in 1778. It had a pewter mug with a hole allowing attachment of a flexible tube, Mudge used it for the treatment of coughs using opium. These devices evolved with modifications by Wolfe, Mackenzie and better mouth attachments such as by Beigel in 1866, many of these early inhalers needed heat to vapourize the active chemical ingredient. The benefits of forced expiration and inspiration to treat asthma were noted by J. S. Monell in 1865, chemicals used in inhalers included ammonia, chlorine, iodine, tar, balsams, turpentine camphor and numerous others in combinations
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Transdermal patch
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A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this healing to an injured area of the body. An advantage of a drug delivery route over other types of medication delivery such as oral, topical, intravenous, intramuscular. A wide variety of pharmaceuticals are now available in transdermal patch form, the first commercially available prescription patch was approved by the U. S. Food and Drug Administration in December 1979. These patches administered scopolamine for motion sickness, the highest selling transdermal patch in the United States is the nicotine patch, which releases nicotine in controlled doses to help with cessation of tobacco smoking. The first commercially available vapour patch to reduce smoking was approved in Europe in 2007, two opioid medications used to provide round-the-clock relief for severe pain are often prescribed in patch form, fentanyl CII and buprenorphine CIII. Hormonal patches estrogen patches are sometimes prescribed to treat menopausal symptoms, contraceptive patch and testosterone CIII patches for both men and women. Nitroglycerin patches are sometimes prescribed for the treatment of angina in lieu of sublingual pills, Transdermal scopolamine is commonly used as a treatment for motion sickness. The anti-hypertensive drug clonidine is available in transdermal patch form under the brand name Catapres-TTS, emsam, a transdermal form of the MAOI selegiline, became the first transdermal delivery agent for an antidepressant approved for use in the U. S. in March 2006. Daytrana, the first methylphenidate transdermal delivery system for the treatment of Attention Deficit Hyperactivity Disorder, was approved by the FDA in April 2006, vitamin B12 may also be administered through a transdermal patch. Cyanocobalamin, a stable form of vitamin B12, is compatible with transdermal patching. 5-Hydroxytryptophan can also be administered through a patch, which was launched in the United Kingdom in early 2014. The Duragesic product label was updated to add safety information in June 2005. Since then, no problems with either the patch or its protective packaging have been reported. In 2009, the FDA announced a public health advisory warning of the risk of burns during MRI scans from transdermal drug patches with metallic backings. Patients should be advised to remove any medicated patch prior to an MRI scan, the main components to a transdermal patch are, Liner - Protects the patch during storage. The liner is removed prior to use, matrix Filler - It provides bulk to matrix as well as some of fillers acts as matrix stiffening agent. Other components includes, Stabilizer, Preservatives etc, there are five main types of transdermal patches
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Liposome
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A liposome is a spherical vesicle having at least one lipid bilayer. The liposome can be used as a vehicle for administration of nutrients, liposomes can be prepared by disrupting biological membranes. A liposome design may employ surface ligands for attaching to unhealthy tissue, the major types of liposomes are the multilamellar vesicle, the small unilamellar liposome vesicle, the large unilamellar vesicle, and the cochleate vesicle. A less desirable form are multivesicular liposomes in which one vesicle contains one or more smaller vesicles, liposomes should not be confused with micelles and reverse micelles composed of monolayers. The word liposome derives from two Greek words, lipo and soma, it is so named because its composition is primarily of phospholipid, liposomes were first described by British haematologist Alec D Bangham in 1961, at the Babraham Institute, in Cambridge. They were discovered when Bangham and R. W. Horne were testing the new electron microscope by adding negative stain to dry phospholipids. The resemblance to the plasmalemma was obvious, and the microscope pictures served as the first evidence for the membrane being a bilayer lipid structure. Their integrity as a closed, bilayer structure, that could release its contents after detergent treatment was established by Bangham, Standish, liposomes can be easily distinguished from micelles and hexagonal lipid phases by negative staining transmission electron microscopy. Alec Douglas Bangham with colleagues Jeff Watkins and Malcolm Standish wrote the 1965 paper that effectively launched the liposome “industry”, around this time he was joined at Babraham by Gerald Weissmann, an American physician with an interest in lysosomes. This insight, they felt, was to cell function what the discovery of the double helix had been to genetics, Bangham had called his lipid structures “multilamellar smectic mesophases” or sometimes “Banghasomes”. It was Weissmann who proposed the more user-friendly term liposome, a liposome has an aqueous solution core surrounded by a hydrophobic membrane, in the form of a lipid bilayer, hydrophilic solutes dissolved in the core cannot readily pass through the bilayer. Hydrophobic chemicals associate with the bilayer, a liposome can be hence loaded with hydrophobic and/or hydrophilic molecules. By preparing liposomes in a solution of DNA or drugs they can be delivered past the lipid bilayer, liposomes are used as models for artificial cells. Liposomes can also be designed to deliver drugs in other ways, liposomes that contain low pH can be constructed such that dissolved aqueous drugs will be charged in solution. As the pH naturally neutralizes within the liposome, the drug will also be neutralized and these liposomes work to deliver drug by diffusion rather than by direct cell fusion. A similar approach can be exploited in the biodetoxification of drugs by injecting empty liposomes with a transmembrane pH gradient, in this case the vesicles act as sinks to scavenge the drug in the blood circulation and prevent its toxic effect. Another strategy for drug delivery is to target endocytosis events. Liposomes can be made in a size range that makes them viable targets for natural macrophage phagocytosis
. PMID 21814422.
