Food and Drug Administration
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. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, dietary supplements and over-the-counter pharmaceutical drugs, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices, animal foods & feed and veterinary products; as of 2017, 3/4th of the FDA budget is paid by people who consume pharmaceutical products, due to the Prescription Drug User Fee Act. The FDA was empowered by the United States Congress to enforce the Federal Food and Cosmetic Act, which serves as the primary focus for the Agency; these include regulating lasers, cellular phones 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 and consent of the Senate.
The Commissioner reports to the Secretary of Human Services. Scott Gottlieb, M. D. is the current commissioner, who took over in May 2017. The FDA has its headquarters in Maryland; the agency has 223 field offices and 13 laboratories located throughout the 50 states, the United States Virgin Islands, Puerto Rico. In 2008, the FDA began to post employees to foreign countries, including China, Costa Rica, Chile and the United Kingdom. In recent years, the agency began undertaking a large-scale effort to consolidate its 25 operations in the Washington metropolitan area, moving from its main headquarters in Rockville and several fragmented office buildings to the former site of the Naval Ordnance Laboratory in the White Oak area of Silver Spring, Maryland; 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 naval facility was kept.
All other buildings are new construction. The project is slated to be completed by 2021, assuming future Congressional funding While most of the Centers are located in the Washington, D. C. area as part of the Headquarters divisions, two offices – the Office of Regulatory Affairs and the Office of Criminal Investigations – are field offices with a workforce spread across the country. The Office of Regulatory Affairs is considered the "eyes and ears" of the agency, conducting the vast majority of the FDA's work in the field. Consumer Safety Officers, more called Investigators, are the individuals who inspect production and warehousing facilities, investigate complaints, illnesses, or outbreaks, review documentation in the case of medical devices, biological products, other items where it may be difficult to conduct a physical examination or take a physical sample of the product; the Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. Districts are based on the geographic divisions of the federal court system.
Each district comprises a main district office and a number of Resident Posts, which are FDA remote offices that serve a particular geographic area. ORA includes the Agency's network of regulatory laboratories, which analyze any physical samples taken. Though samples are food-related, some laboratories are equipped to analyze drugs and radiation-emitting devices; the Office of Criminal Investigations was established in 1991 to investigate criminal cases. Unlike ORA Investigators, OCI Special Agents are armed, don't focus on technical aspects of the regulated industries. OCI agents pursue and develop cases where individuals and companies have committed criminal actions, such as fraudulent claims, or knowingly and willfully shipping known adulterated goods in interstate commerce. In many cases, OCI pursues cases involving Title 18 violations, in addition to prohibited acts as defined in Chapter III of the FD&C Act. OCI Special Agents come from other criminal investigations backgrounds, work with the Federal Bureau of Investigation, Assistant Attorney General, Interpol.
OCI receives cases from a variety of sources—including ORA, local agencies, the FBI—and works with ORA Investigators to help develop the technical and science-based aspects of a case. OCI is a smaller branch; the FDA works with other federal agencies, including the Department of Agriculture, Drug Enforcement Administration and Border Protection, Consumer Product Safety Commission. Local and state government agencies work with the FDA to provide regulatory inspections and enforcement action; the FDA regulates more than US$2.4 trillion worth of consumer goods, about 25% of consumer expenditures in the United States. This includes $466 billion in food sales, $275 billion in drugs, $60 billion in cosmetics and $18 billion in vitamin supplements. Much of these expenditures are for goods imported into the United States; the FDA's federal budget request for fiscal year 2012 totaled $4.36 billion, while the proposed 2014 budget is $4.7 billion. About $2 billion of this budget is generated by user fees.
Pharmaceutical firms pay th
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, food additives, etc, it attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing and adverse effects, as seen in PK/PD models. Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body, the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are affected by the route of administration and the dose of administered drug.
These may affect the absorption rate. Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. One of these, the multi-compartmental model, is the most used approximations to reality; the various compartments that the model is divided into are referred to as the ADME scheme: Liberation – the process of release of a drug from the pharmaceutical formulation. See IVIVC. Absorption – the process of a substance entering the blood circulation. Distribution – the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue; the two phases of metabolism and excretion can be grouped together under the title elimination.
The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. All these concepts can be represented through mathematical formulas that have a corresponding graphical representation; the use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant and solubility, absorption capacity and distribution in the organism. The model outputs for a drug can be used in industry or in the clinical application of pharmacokinetic concepts.
Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine. The following are the most measured pharmacokinetic metrics: In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. In practice, it is considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started; the following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics: Pharmacokinetic modelling is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model and produce accurate results acceptable for bioequivalence studies.
The final outcome of the transformations that a drug undergoes in an organism and the rules that determine this fate depend on a number of interrelated factors. A number of functional models have been developed in order to simplify the study of pharmacokinetics; these models are based on a consideration of an organism as a number of related compartments. The simplest idea is to think of an organism as only one homogenous compartment; this monocompartmental model presupposes that blood plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug's concentration in the organism. However, these models do not always reflect the real situation within an organism. For example, not all body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (s
Pharmacology
Pharmacology is the branch of biology concerned with the study of drug action, where a drug can be broadly defined as any man-made, natural, or endogenous molecule which exerts a biochemical or physiological effect on the cell, organ, or organism. More it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals; the field encompasses drug composition and properties and drug design and cellular mechanisms, organ/systems mechanisms, signal transduction/cellular communication, molecular diagnostics, toxicology, chemical biology and medical applications and antipathogenic capabilities. The two main areas of pharmacology are pharmacokinetics. Pharmacodynamics studies the effects of a drug on biological systems, Pharmacokinetics studies the effects of biological systems on a drug. In broad terms, pharmacodynamics discusses the chemicals with biological receptors, pharmacokinetics discusses the absorption, distribution and excretion of chemicals from the biological systems.
Pharmacology is not synonymous with pharmacy and the two terms are confused. Pharmacology, a biomedical science, deals with the research and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals. In contrast, pharmacy, a health services profession, is concerned with application of the principles learned from pharmacology in its clinical settings. In either field, the primary contrast between the two are their distinctions between direct-patient care, for pharmacy practice, the science-oriented research field, driven by pharmacology; the origins of clinical pharmacology date back to the Middle Ages in Avicenna's The Canon of Medicine, Peter of Spain's Commentary on Isaac, John of St Amand's Commentary on the Antedotary of Nicholas. Clinical pharmacology owes much of its foundation to the work of William Withering. Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period.
Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such as morphine and digitalis were explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues. The first pharmacology department was set up by Rudolf Buchheim in 1847, in recognition of the need to understand how therapeutic drugs and poisons produced their effects. Early pharmacologists focused on natural substances plant extracts. Pharmacology developed in the 19th century as a biomedical science that applied the principles of scientific experimentation to therapeutic contexts. Today pharmacologists use genetics, molecular biology and other advanced tools to transform information about molecular mechanisms and targets into therapies directed against disease, defects or pathogens, create methods for preventative care and personalized medicine; the word "pharmacology" is derived from Greek φάρμακον, pharmakon, "drug, spell" and -λογία, -logia "study of", "knowledge of".
The discipline of pharmacology can be divided into many sub disciplines each with a specific focus. Clinical pharmacology is the basic science of pharmacology with an added focus on the application of pharmacological principles and methods in the medical clinic and towards patient care and outcomes. Neuropharmacology is the study of the effects of medication on central and peripheral nervous system functioning. Psychopharmacology known as behavioral pharmacology, is the study of the effects of medication on the psyche, observing changed behaviors of the body and mind, how molecular events are manifest in a measurable behavioral form. Psychopharmacology is an interdisciplinary field which studies behavioral effects of psychoactive drugs, it incorporates approaches and techniques from neuropharmacology, animal behavior and behavioral neuroscience, is interested in the behavioral and neurobiological mechanisms of action of psychoactive drugs. Another goal of behavioral pharmacology is to develop animal behavioral models to screen chemical compounds with therapeutic potentials.
People in this field use small animals to study psychotherapeutic drugs such as antipsychotics and anxiolytics, drugs of abuse such as nicotine and methamphetamine. Ethopharmacology is a term, in use since the 1960s and derives from the Greek word ἦθος ethos meaning character and "pharmacology" the study of drug actions and mechanism. Cardiovascular pharmacology is the study of the effects of drugs on the entire cardiovascular system, including the heart and blood vessels. Pharmacogenetics is clinical testing of genetic variation that gives rise to differing response to drugs. Pharmacogenomics is the application of genomic technologies to drug discovery and further characterization of older drugs. Pharmacoepidemiology is the study of the effects of drugs in large numbers of people. Safety pharmacology specialises in detecting and investigating potential undesirable pharmacodynamic effects of new chemical entities on physiological functions in relation to exposure in the therapeutic range and above.
Systems pharmacology is
Drug
A drug is any substance that, when inhaled, smoked, absorbed via a patch on the skin, or dissolved under the tongue causes a physiological change in the body. In pharmacology, a drug is a chemical substance of known structure, other than a nutrient of an essential dietary ingredient, when administered to a living organism, produces a biological effect. A pharmaceutical drug called a medication or medicine, is a chemical substance used to treat, prevent, or diagnose a disease or to promote well-being. Traditionally drugs were obtained through extraction from medicinal plants, but more also by organic synthesis. Pharmaceutical drugs may be used for a limited duration, or on a regular basis for chronic disorders. Pharmaceutical drugs are classified into drug classes—groups of related drugs that have similar chemical structures, the same mechanism of action, a related mode of action, that are used to treat the same disease; the Anatomical Therapeutic Chemical Classification System, the most used drug classification system, assigns drugs a unique ATC code, an alphanumeric code that assigns it to specific drug classes within the ATC system.
Another major classification system is the Biopharmaceutics Classification System. This classifies drugs according to their permeability or absorption properties. Psychoactive drugs are chemical substances that affect the function of the central nervous system, altering perception, mood or consciousness, they include alcohol, a depressant, the stimulants nicotine and caffeine. These three are the most consumed psychoactive drugs worldwide and are considered recreational drugs since they are used for pleasure rather than medicinal purposes. Other recreational drugs include hallucinogens and amphetamines and some of these are used in spiritual or religious settings; some drugs can cause addiction and all drugs can have side effects. Excessive use of stimulants can promote stimulant psychosis. Many recreational drugs are illicit and international treaties such as the Single Convention on Narcotic Drugs exist for the purpose of their prohibition. In English, the noun "drug" is thought to originate from Old French "drogue" deriving into "droge-vate" from Middle Dutch meaning "dry barrels", referring to medicinal plants preserved in them.
The transitive verb "to drug" arose and invokes the psychoactive rather than medicinal properties of a substance. A medication or medicine is a drug taken to cure or ameliorate any symptoms of an illness or medical condition; the use may be as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. Dispensing of medication is regulated by governments into three categories—over-the-counter medications, which are available in pharmacies and supermarkets without special restrictions. In the United Kingdom, behind-the-counter medicines are called pharmacy medicines which can only be sold in registered pharmacies, by or under the supervision of a pharmacist; these medications are designated by the letter P on the label. The range of medicines available without a prescription varies from country to country. Medications are produced by pharmaceutical companies and are patented to give the developer exclusive rights to produce them; those that are not patented are called generic drugs since they can be produced by other companies without restrictions or licenses from the patent holder.
Pharmaceutical drugs are categorised into drug classes. A group of drugs will share a similar chemical structure, or have the same mechanism of action, the same related mode of action or target the same illness or related illnesses; the Anatomical Therapeutic Chemical Classification System, the most used drug classification system, assigns drugs a unique ATC code, an alphanumeric code that assigns it to specific drug classes within the ATC system. Another major classification system is the Biopharmaceutics Classification System; this groups drugs according to their permeability or absorption properties. Some religions ethnic religions are based on the use of certain drugs, known as entheogens, which are hallucinogens,—psychedelics, dissociatives, or deliriants; some drugs used as entheogens include kava which can act as a stimulant, a sedative, a euphoriant and an anesthetic. The roots of the kava plant are used to produce a drink, consumed throughout the cultures of the Pacific Ocean; some shamans from different cultures use entheogens, defined as "generating the divine within" to achieve religious ecstasy.
Amazonian shamans use ayahuasca a hallucinogenic brew for this purpose. Mazatec shamans have a long and continuous tradition of religious use of Salvia divinorum a psychoactive plant, its use is to facilitate visionary states of consciousness during spiritual healing sessions. Silene undulata is used as an entheogen, its root is traditionally used to induce vivid lucid dreams during the initiation process of shamans, classifying it a occurring oneirogen similar to the more well-known dream herb Calea ternifolia. Peyote a small spineless cactus has been a
Intrinsic activity
Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, a measure of the ability of the drug to bind to its molecular target, the EC50, a measure of the potency of the drug and, proportional to both efficacy and affinity; this use of the word "efficacy" was introduced by Stephenson to describe the way in which agonists vary in the response they produce when they occupy the same number of receptors. High efficacy agonists can produce the maximal response of the receptor system while occupying a low proportion of the receptors in that system. Agonists of lower efficacy are not as efficient at producing a response from the drug-bound receptor, by stabilizing the active form of the drug-bound receptor. Therefore, they may not be able to produce the same maximal response when they occupy the entire receptor population, as the efficiency of transformation of the inactive form of the drug-receptor complex to the active drug-receptor complex may not be high enough to evoke a maximal response.
Since the observed response may be less than maximal in systems with no spare receptor reserve, some low efficacy agonists are referred to as partial agonists. However, it is worth bearing in mind that these terms are relative - partial agonists may appear as full agonists in a different system/experimental setup, as when the number of receptors increases, there may be enough drug-receptor complexes for a maximum response to be produced with individually low efficacy of transducing the response. There are relatively few true full agonists or silent antagonists. Many antagonists are in fact partial agonists or inverse agonists, but with low efficacy. Compounds considered. Another case is represented by silent agonists, which are ligands that can place a receptor an ion channel, into a desensitized state with little or no apparent activation of it, forming a complex that can subsequently generate currents when treated with an allosteric modulator. There is a distinction between intrinsic activity.
Efficacy has been treated as a proportionality constant between the binding of the drug and the generation of the biological response. Stephenson defined efficacy as: S = e p where p is the proportion of agonist-bound receptors and S is the stimulus to the biological system; the response is generated by an unknown function f, assumed to be hyperbolic. This model was arguably flawed in that it did not incorporate the equilibrium between the inactivated agonist-bound-receptor and the activated agonist-bound-receptor, shown in the del Castillo Katz model. Furchgott improved on Stephenson's model with the definition of efficacy, e, as S = ε T o t ⏟ e ⋅ p where ε is the intrinsic efficacy and T o t is the total concentration of receptors; these models of efficacy have been criticised and many more. The models of efficacy are shown in. Intrinsic activity of a test agonist is defined as: I A = maximal response to the test agonist maximal response to full agonist
International Standard Serial Number
An International Standard Serial Number is an eight-digit serial number used to uniquely identify a serial publication, such as a magazine. The ISSN is helpful in distinguishing between serials with the same title. ISSN are used in ordering, interlibrary loans, other practices in connection with serial literature; the ISSN system was first drafted as an International Organization for Standardization international standard in 1971 and published as ISO 3297 in 1975. ISO subcommittee TC 46/SC 9 is responsible for maintaining the standard; when a serial with the same content is published in more than one media type, a different ISSN is assigned to each media type. For example, many serials are published both in electronic media; the ISSN system refers to these types as electronic ISSN, respectively. Conversely, as defined in ISO 3297:2007, every serial in the ISSN system is assigned a linking ISSN the same as the ISSN assigned to the serial in its first published medium, which links together all ISSNs assigned to the serial in every medium.
The format of the ISSN is an eight digit code, divided by a hyphen into two four-digit numbers. As an integer number, it can be represented by the first seven digits; the last code digit, which may be 0-9 or an X, is a check digit. Formally, the general form of the ISSN code can be expressed as follows: NNNN-NNNC where N is in the set, a digit character, C is in; the ISSN of the journal Hearing Research, for example, is 0378-5955, where the final 5 is the check digit, C=5. To calculate the check digit, the following algorithm may be used: Calculate the sum of the first seven digits of the ISSN multiplied by its position in the number, counting from the right—that is, 8, 7, 6, 5, 4, 3, 2, respectively: 0 ⋅ 8 + 3 ⋅ 7 + 7 ⋅ 6 + 8 ⋅ 5 + 5 ⋅ 4 + 9 ⋅ 3 + 5 ⋅ 2 = 0 + 21 + 42 + 40 + 20 + 27 + 10 = 160 The modulus 11 of this sum is calculated. For calculations, an upper case X in the check digit position indicates a check digit of 10. To confirm the check digit, calculate the sum of all eight digits of the ISSN multiplied by its position in the number, counting from the right.
The modulus 11 of the sum must be 0. There is an online ISSN checker. ISSN codes are assigned by a network of ISSN National Centres located at national libraries and coordinated by the ISSN International Centre based in Paris; the International Centre is an intergovernmental organization created in 1974 through an agreement between UNESCO and the French government. The International Centre maintains a database of all ISSNs assigned worldwide, the ISDS Register otherwise known as the ISSN Register. At the end of 2016, the ISSN Register contained records for 1,943,572 items. ISSN and ISBN codes are similar in concept. An ISBN might be assigned for particular issues of a serial, in addition to the ISSN code for the serial as a whole. An ISSN, unlike the ISBN code, is an anonymous identifier associated with a serial title, containing no information as to the publisher or its location. For this reason a new ISSN is assigned to a serial each time it undergoes a major title change. Since the ISSN applies to an entire serial a new identifier, the Serial Item and Contribution Identifier, was built on top of it to allow references to specific volumes, articles, or other identifiable components.
Separate ISSNs are needed for serials in different media. Thus, the print and electronic media versions of a serial need separate ISSNs. A CD-ROM version and a web version of a serial require different ISSNs since two different media are involved. However, the same ISSN can be used for different file formats of the same online serial; this "media-oriented identification" of serials made sense in the 1970s. In the 1990s and onward, with personal computers, better screens, the Web, it makes sense to consider only content, independent of media; this "content-oriented identification" of serials was a repressed demand during a decade, but no ISSN update or initiative occurred. A natural extension for ISSN, the unique-identification of the articles in the serials, was the main demand application. An alternative serials' contents model arrived with the indecs Content Model and its application, the digital object identifier, as ISSN-independent initiative, consolidated in the 2000s. Only in 2007, ISSN-L was defined in the
Linear regression
In statistics, linear regression is a linear approach to modelling the relationship between a scalar response and one or more explanatory variables. The case of one explanatory variable is called simple linear regression. For more than one explanatory variable, the process is called multiple linear regression; this term is distinct from multivariate linear regression, where multiple correlated dependent variables are predicted, rather than a single scalar variable. In linear regression, the relationships are modeled using linear predictor functions whose unknown model parameters are estimated from the data; such models are called linear models. Most the conditional mean of the response given the values of the explanatory variables is assumed to be an affine function of those values. Like all forms of regression analysis, linear regression focuses on the conditional probability distribution of the response given the values of the predictors, rather than on the joint probability distribution of all of these variables, the domain of multivariate analysis.
Linear regression was the first type of regression analysis to be studied rigorously, to be used extensively in practical applications. This is because models which depend linearly on their unknown parameters are easier to fit than models which are non-linearly related to their parameters and because the statistical properties of the resulting estimators are easier to determine. Linear regression has many practical uses. Most applications fall into one of the following two broad categories: If the goal is prediction, or forecasting, or error reduction, linear regression can be used to fit a predictive model to an observed data set of values of the response and explanatory variables. After developing such a model, if additional values of the explanatory variables are collected without an accompanying response value, the fitted model can be used to make a prediction of the response. If the goal is to explain variation in the response variable that can be attributed to variation in the explanatory variables, linear regression analysis can be applied to quantify the strength of the relationship between the response and the explanatory variables, in particular to determine whether some explanatory variables may have no linear relationship with the response at all, or to identify which subsets of explanatory variables may contain redundant information about the response.
Linear regression models are fitted using the least squares approach, but they may be fitted in other ways, such as by minimizing the "lack of fit" in some other norm, or by minimizing a penalized version of the least squares cost function as in ridge regression and lasso. Conversely, the least squares approach can be used to fit models. Thus, although the terms "least squares" and "linear model" are linked, they are not synonymous. Given a data set i = 1 n of n statistical units, a linear regression model assumes that the relationship between the dependent variable y and the p-vector of regressors x is linear; this relationship is modeled through a disturbance term or error variable ε — an unobserved random variable that adds "noise" to the linear relationship between the dependent variable and regressors. Thus the model takes the form y i = β 0 1 + β 1 x i 1 + ⋯ + β p x i p + ε i = x i T β + ε i, i = 1, …, n, where T denotes the transpose, so that xiTβ is the inner product between vectors xi and β.
These n equations are stacked together and written in matrix notation as y = X β + ε, where y =, X = = ( 1 x 11 ⋯ x 1 p 1 x 21 ⋯ x 2 p ⋮ ⋮ ⋱ ⋮ 1 x n
