Pharmacology: The study of the origin, nature, properties, and actions of drugs and their effects on living organisms.Pharmacology, Clinical: The branch of pharmacology that deals directly with the effectiveness and safety of drugs in humans.Drug Discovery: The process of finding chemicals for potential therapeutic use.International Agencies: International organizations which provide health-related or other cooperative services.Pharmacokinetics: Dynamic and kinetic mechanisms of exogenous chemical and DRUG LIBERATION; ABSORPTION; BIOLOGICAL TRANSPORT; TISSUE DISTRIBUTION; BIOTRANSFORMATION; elimination; and DRUG TOXICITY as a function of dosage, and rate of METABOLISM. LADMER, ADME and ADMET are abbreviations for liberation, absorption, distribution, metabolism, elimination, and toxicology.Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Receptors, G-Protein-Coupled: The largest family of cell surface receptors involved in SIGNAL TRANSDUCTION. They share a common structure and signal through HETEROTRIMERIC G-PROTEINS.Terminology as Topic: The terms, expressions, designations, or symbols used in a particular science, discipline, or specialized subject area.Ligands: A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)Radioligand Assay: Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders).Societies, Pharmaceutical: Societies whose membership is limited to pharmacists.Drug Design: The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis.Therapeutics: Procedures concerned with the remedial treatment or prevention of diseases.Webcasts as Topic: Transmission of live or pre-recorded audio or video content via connection or download from the INTERNET.Education, Pharmacy, Continuing: Educational programs designed to inform graduate pharmacists of recent advances in their particular field.Drug Evaluation, Preclinical: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.History, 20th Century: Time period from 1901 through 2000 of the common era.Psychopharmacology: The study of the effects of drugs on mental and behavioral activity.Pharmacy Administration: The business and managerial aspects of pharmacy in its broadest sense.Drug-Related Side Effects and Adverse Reactions: Disorders that result from the intended use of PHARMACEUTICAL PREPARATIONS. Included in this heading are a broad variety of chemically-induced adverse conditions due to toxicity, DRUG INTERACTIONS, and metabolic effects of pharmaceuticals.Pharmacogenetics: A branch of genetics which deals with the genetic variability in individual responses to drugs and drug metabolism (BIOTRANSFORMATION).Psychology, Experimental: The branch of psychology which seeks to learn more about the fundamental causes of behavior by studying various psychologic phenomena in controlled experimental situations.Receptors, GABA: Cell-surface proteins that bind GAMMA-AMINOBUTYRIC ACID with high affinity and trigger changes that influence the behavior of cells. GABA-A receptors control chloride channels formed by the receptor complex itself. They are blocked by bicuculline and usually have modulatory sites sensitive to benzodiazepines and barbiturates. GABA-B receptors act through G-proteins on several effector systems, are insensitive to bicuculline, and have a high affinity for L-baclofen.Neuropharmacology: The branch of pharmacology dealing especially with the action of drugs upon various parts of the nervous system.Receptors, GABA-A: Cell surface proteins which bind GAMMA-AMINOBUTYRIC ACID and contain an integral membrane chloride channel. Each receptor is assembled as a pentamer from a pool of at least 19 different possible subunits. The receptors belong to a superfamily that share a common CYSTEINE loop.Binding, Competitive: The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.CHO Cells: CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals.Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.Education, Pharmacy: Formal instruction, learning, or training in the preparation, dispensing, and proper utilization of drugs in the field of medicine.Receptors, Nicotinic: One of the two major classes of cholinergic receptors. Nicotinic receptors were originally distinguished by their preference for NICOTINE over MUSCARINE. They are generally divided into muscle-type and neuronal-type (previously ganglionic) based on pharmacology, and subunit composition of the receptors.Receptors, Serotonin: Cell-surface proteins that bind SEROTONIN and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action.Education, Medical, Undergraduate: The period of medical education in a medical school. In the United States it follows the baccalaureate degree and precedes the granting of the M.D.Clinical Trials as Topic: Works about pre-planned studies of the safety, efficacy, or optimum dosage schedule (if appropriate) of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques selected according to predetermined criteria of eligibility and observed for predefined evidence of favorable and unfavorable effects. This concept includes clinical trials conducted both in the U.S. and in other countries.Benzodiazepines: A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Problem-Based Learning: Instructional use of examples or cases to teach using problem-solving skills and critical thinking.Cardiovascular System: The HEART and the BLOOD VESSELS by which BLOOD is pumped and circulated through the body.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Curriculum: A course of study offered by an educational institution.Piperidines: A family of hexahydropyridines.Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Allergy and Immunology: A medical specialty concerned with the hypersensitivity of the individual to foreign substances and protection from the resultant infection or disorder.Cannabinoids: Compounds having the cannabinoid structure. They were originally extracted from Cannabis sativa L. The most pharmacologically active constituents are TETRAHYDROCANNABINOL; CANNABINOL; and CANNABIDIOL.Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug.Education, Pharmacy, Graduate: Educational programs for pharmacists who have a bachelor's degree or a Doctor of Pharmacy degree entering a specific field of pharmacy. They may lead to an advanced degree.Patch-Clamp Techniques: An electrophysiologic technique for studying cells, cell membranes, and occasionally isolated organelles. All patch-clamp methods rely on a very high-resistance seal between a micropipette and a membrane; the seal is usually attained by gentle suction. The four most common variants include on-cell patch, inside-out patch, outside-out patch, and whole-cell clamp. Patch-clamp methods are commonly used to voltage clamp, that is control the voltage across the membrane and measure current flow, but current-clamp methods, in which the current is controlled and the voltage is measured, are also used.Pharmacological Processes: The metabolism of drugs and their mechanisms of action.Receptors, Drug: Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified.Allosteric Regulation: The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES.Piperoxan: A benzodioxane alpha-adrenergic blocking agent with considerable stimulatory action. It has been used to diagnose PHEOCHROMOCYTOMA and as an antihypertensive agent.Teaching: The educational process of instructing.Analgesics, Opioid: Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.gamma-Aminobutyric Acid: The most common inhibitory neurotransmitter in the central nervous system.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Guinea Pigs: A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research.Toxicology: The science concerned with the detection, chemical composition, and biological action of toxic substances or poisons and the treatment and prevention of toxic manifestations.Drug Therapy: The use of DRUGS to treat a DISEASE or its symptoms. One example is the use of ANTINEOPLASTIC AGENTS to treat CANCER.Membrane Potentials: The voltage differences across a membrane. For cellular membranes they are computed by subtracting the voltage measured outside the membrane from the voltage measured inside the membrane. They result from differences of inside versus outside concentration of potassium, sodium, chloride, and other ions across cells' or ORGANELLES membranes. For excitable cells, the resting membrane potentials range between -30 and -100 millivolts. Physical, chemical, or electrical stimuli can make a membrane potential more negative (hyperpolarization), or less negative (depolarization).Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.Pyridines: Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.GABA Agonists: Endogenous compounds and drugs that bind to and activate GAMMA-AMINOBUTYRIC ACID receptors (RECEPTORS, GABA).Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.Nobel PrizeIon Channel Gating: The opening and closing of ion channels due to a stimulus. The stimulus can be a change in membrane potential (voltage-gated), drugs or chemical transmitters (ligand-gated), or a mechanical deformation. Gating is thought to involve conformational changes of the ion channel which alters selective permeability.Mitragyna: A plant genus of the family RUBIACEAE. Members contain antimalarial (ANTIMALARIALS) and analgesic (ANALGESICS) indole alkaloids.Education, Professional: Formal education and training in preparation for the practice of a profession.Prostaglandins I: A class of cyclic prostaglandins that contain the 6,9-epoxy bond. Endogenous members of this family are biosynthesized enzymatically from PROSTAGLANDIN ENDOPEROXIDES.Kinetics: The rate dynamics in chemical or physical systems.Injections, Intravenous: Injections made into a vein for therapeutic or experimental purposes.Administration, Oral: The giving of drugs, chemicals, or other substances by mouth.Electrophysiology: The study of the generation and behavior of electrical charges in living organisms particularly the nervous system and the effects of electricity on living organisms.Nicotinic Antagonists: Drugs that bind to nicotinic cholinergic receptors (RECEPTORS, NICOTINIC) and block the actions of acetylcholine or cholinergic agonists. Nicotinic antagonists block synaptic transmission at autonomic ganglia, the skeletal neuromuscular junction, and at central nervous system nicotinic synapses.Receptors, Histamine H3: A class of histamine receptors discriminated by their pharmacology and mode of action. Histamine H3 receptors were first recognized as inhibitory autoreceptors on histamine-containing nerve terminals and have since been shown to regulate the release of several neurotransmitters in the central and peripheral nervous systems. (From Biochem Soc Trans 1992 Feb;20(1):122-5)History, 21st Century: Time period from 2001 through 2100 of the common era.History, 19th Century: Time period from 1801 through 1900 of the common era.Drug Delivery Systems: Systems for the delivery of drugs to target sites of pharmacological actions. Technologies employed include those concerning drug preparation, route of administration, site targeting, metabolism, and toxicity.Designer Drugs: Drugs designed and synthesized, often for illegal street use, by modification of existing drug structures (e.g., amphetamines). Of special interest are MPTP (a reverse ester of meperidine), MDA (3,4-methylenedioxyamphetamine), and MDMA (3,4-methylenedioxymethamphetamine). Many drugs act on the aminergic system, the physiologically active biogenic amines.GABA Modulators: Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.History, 18th Century: Time period from 1701 through 1800 of the common era.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Hypnotics and Sedatives: Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety.Serotonin Antagonists: Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS.Receptors, Islet Amyloid Polypeptide: G-protein coupled receptors that are formed through the dimerization of the CALCITONIN RECEPTOR with a RECEPTOR ACTIVITY-MODIFYING PROTEIN. Their affinity for ISLET AMYLOID POLYPEPTIDE is dependent upon which of several receptor activity-modifying protein subtypes they are bound to.Cricetulus: A genus of the family Muridae consisting of eleven species. C. migratorius, the grey or Armenian hamster, and C. griseus, the Chinese hamster, are the two species used in biomedical research.Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke.Adrenergic alpha-1 Receptor Antagonists: Drugs that bind to and block the activation of ADRENERGIC ALPHA-1 RECEPTORS.GABA Antagonists: Drugs that bind to but do not activate GABA RECEPTORS, thereby blocking the actions of endogenous GAMMA-AMINOBUTYRIC ACID and GABA RECEPTOR AGONISTS.Education, Graduate: Studies beyond the bachelor's degree at an institution having graduate programs for the purpose of preparing for entrance into a specific field, and obtaining a higher degree.Dequalinium: A topical bacteriostat that is available as various salts. It is used in wound dressings and mouth infections and may also have antifungal action, but may cause skin ulceration.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Drug Partial Agonism: Drug agonism involving selective binding but reduced effect. This can result in some degree of DRUG ANTAGONISM.Brain: The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.Drug Industry: That segment of commercial enterprise devoted to the design, development, and manufacture of chemical products for use in the diagnosis and treatment of disease, disability, or other dysfunction, or to improve function.Receptors, Cannabinoid: A class of G-protein-coupled receptors that are specific for CANNABINOIDS such as those derived from CANNABIS. They also bind a structurally distinct class of endogenous factors referred to as ENDOCANNABINOIDS. The receptor class may play a role in modulating the release of signaling molecules such as NEUROTRANSMITTERS and CYTOKINES.Strychnine: An alkaloid found in the seeds of STRYCHNOS NUX-VOMICA. It is a competitive antagonist at glycine receptors and thus a convulsant. It has been used as an analeptic, in the treatment of nonketotic hyperglycinemia and sleep apnea, and as a rat poison.Dogs: The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)Bicyclo Compounds, Heterocyclic: A class of saturated compounds consisting of two rings only, having two or more atoms in common, containing at least one hetero atom, and that take the name of an open chain hydrocarbon containing the same total number of atoms. (From Riguady et al., Nomenclature of Organic Chemistry, 1979, p31)Potassium Channels: Cell membrane glycoproteins that are selectively permeable to potassium ions. At least eight major groups of K channels exist and they are made up of dozens of different subunits.Analgesics: Compounds capable of relieving pain without the loss of CONSCIOUSNESS.Picrotoxin: A noncompetitive antagonist at GABA-A receptors and thus a convulsant. Picrotoxin blocks the GAMMA-AMINOBUTYRIC ACID-activated chloride ionophore. Although it is most often used as a research tool, it has been used as a CNS stimulant and an antidote in poisoning by CNS depressants, especially the barbiturates.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.PyridazinesReceptors, Histamine: Cell-surface proteins that bind histamine and trigger intracellular changes influencing the behavior of cells. Histamine receptors are widespread in the central nervous system and in peripheral tissues. Three types have been recognized and designated H1, H2, and H3. They differ in pharmacology, distribution, and mode of action.Pregnanediones: Pregnane derivatives in which two side-chain methyl groups or two methylene groups in the ring skeleton (or a combination thereof) have been oxidized to keto groups.Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.Histamine Antagonists: Drugs that bind to but do not activate histamine receptors, thereby blocking the actions of histamine or histamine agonists. Classical antihistaminics block the histamine H1 receptors only.HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Nicotinic Agonists: Drugs that bind to and activate nicotinic cholinergic receptors (RECEPTORS, NICOTINIC). Nicotinic agonists act at postganglionic nicotinic receptors, at neuroeffector junctions in the peripheral nervous system, and at nicotinic receptors in the central nervous system. Agents that function as neuromuscular depolarizing blocking agents are included here because they activate nicotinic receptors, although they are used clinically to block nicotinic transmission.Research Personnel: Those individuals engaged in research.Xenopus laevis: The commonest and widest ranging species of the clawed "frog" (Xenopus) in Africa. This species is used extensively in research. There is now a significant population in California derived from escaped laboratory animals.Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-TRYPTOPHAN. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (RECEPTORS, SEROTONIN) explain the broad physiological actions and distribution of this biochemical mediator.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Receptors, Opioid: Cell membrane proteins that bind opioids and trigger intracellular changes which influence the behavior of cells. The endogenous ligands for opioid receptors in mammals include three families of peptides, the enkephalins, endorphins, and dynorphins. The receptor classes include mu, delta, and kappa receptors. Sigma receptors bind several psychoactive substances, including certain opioids, but their endogenous ligands are not known.Sulfonamides: A group of compounds that contain the structure SO2NH2.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Membrane Transport Modulators: Agents that affect ION PUMPS; ION CHANNELS; ABC TRANSPORTERS; and other MEMBRANE TRANSPORT PROTEINS.Protein Subunits: Single chains of amino acids that are the units of multimeric PROTEINS. Multimeric proteins can be composed of identical or non-identical subunits. One or more monomeric subunits may compose a protomer which itself is a subunit structure of a larger assembly.Pain: An unpleasant sensation induced by noxious stimuli which are detected by NERVE ENDINGS of NOCICEPTIVE NEURONS.Receptors, Calcitonin: Cell surface proteins that bind calcitonin and trigger intracellular changes which influence the behavior of cells. Calcitonin receptors outside the nervous system mediate the role of calcitonin in calcium homeostasis. The role of calcitonin receptors in the brain is not well understood.Acetylcholine: A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system.Potassium Channel Blockers: A class of drugs that act by inhibition of potassium efflux through cell membranes. Blockade of potassium channels prolongs the duration of ACTION POTENTIALS. They are used as ANTI-ARRHYTHMIA AGENTS and VASODILATOR AGENTS.Systems Biology: Comprehensive, methodical analysis of complex biological systems by monitoring responses to perturbations of biological processes. Large scale, computerized collection and analysis of the data are used to develop and test models of biological systems.Nerium: A plant genus of the family APOCYNACEAE. It is a very poisonous plant that contains cardioactive agents.Behavior, Animal: The observable response an animal makes to any situation.Biological Availability: The extent to which the active ingredient of a drug dosage form becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action.Serotonin Receptor Agonists: Endogenous compounds and drugs that bind to and activate SEROTONIN RECEPTORS. Many serotonin receptor agonists are used as ANTIDEPRESSANTS; ANXIOLYTICS; and in the treatment of MIGRAINE DISORDERS.Neuromuscular Blocking Agents: Drugs that interrupt transmission of nerve impulses at the skeletal neuromuscular junction. They can be of two types, competitive, stabilizing blockers (NEUROMUSCULAR NONDEPOLARIZING AGENTS) or noncompetitive, depolarizing agents (NEUROMUSCULAR DEPOLARIZING AGENTS). Both prevent acetylcholine from triggering the muscle contraction and they are used as anesthesia adjuvants, as relaxants during electroshock, in convulsive states, etc.Biomedical Research: Research that involves the application of the natural sciences, especially biology and physiology, to medicine.Inhibitory Concentration 50: The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Central Nervous System Agents: A class of drugs producing both physiological and psychological effects through a variety of mechanisms. They can be divided into "specific" agents, e.g., affecting an identifiable molecular mechanism unique to target cells bearing receptors for that agent, and "nonspecific" agents, those producing effects on different target cells and acting by diverse molecular mechanisms. Those with nonspecific mechanisms are generally further classed according to whether they produce behavioral depression or stimulation. Those with specific mechanisms are classed by locus of action or specific therapeutic use. (From Gilman AG, et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p252)QuinolizinesMecamylamine: A nicotinic antagonist that is well absorbed from the gastrointestinal tract and crosses the blood-brain barrier. Mecamylamine has been used as a ganglionic blocker in treating hypertension, but, like most ganglionic blockers, is more often used now as a research tool.Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cellular membranes.Species Specificity: The restriction of a characteristic behavior, anatomical structure or physical system, such as immune response; metabolic response, or gene or gene variant to the members of one species. It refers to that property which differentiates one species from another but it is also used for phylogenetic levels higher or lower than the species.Synaptic Transmission: The communication from a NEURON to a target (neuron, muscle, or secretory cell) across a SYNAPSE. In chemical synaptic transmission, the presynaptic neuron releases a NEUROTRANSMITTER that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across ELECTRICAL SYNAPSES.Synephrine: Sympathetic alpha-adrenergic agonist with actions like PHENYLEPHRINE. It is used as a vasoconstrictor in circulatory failure, asthma, nasal congestion, and glaucoma.Ascaris suum: A species of parasitic nematode usually found in domestic pigs and a few other animals. Human infection can also occur, presumably as result of handling pig manure, and can lead to intestinal obstruction.Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios.Receptors, Adrenergic, alpha-1: A subclass of alpha-adrenergic receptors that mediate contraction of SMOOTH MUSCLE in a variety of tissues such as ARTERIOLES; VEINS; and the UTERUS. They are usually found on postsynaptic membranes and signal through GQ-G11 G-PROTEINS.Conotoxins: Peptide neurotoxins from the marine fish-hunting snails of the genus CONUS. They contain 13 to 29 amino acids which are strongly basic and are highly cross-linked by disulfide bonds. There are three types of conotoxins, omega-, alpha-, and mu-. OMEGA-CONOTOXINS inhibit voltage-activated entry of calcium into the presynaptic membrane and therefore the release of ACETYLCHOLINE. Alpha-conotoxins inhibit the postsynaptic acetylcholine receptor. Mu-conotoxins prevent the generation of muscle action potentials. (From Concise Encyclopedia Biochemistry and Molecular Biology, 3rd ed)Hallucinogens: Drugs capable of inducing illusions, hallucinations, delusions, paranoid ideations, and other alterations of mood and thinking. Despite the name, the feature that distinguishes these agents from other classes of drugs is their capacity to induce states of altered perception, thought, and feeling that are not experienced otherwise.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Dopamine: One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action.Organizational Affiliation: Formal relationships established between otherwise independent organizations. These include affiliation agreements, interlocking boards, common controls, hospital medical school affiliations, etc.Oocytes: Female germ cells derived from OOGONIA and termed OOCYTES when they enter MEIOSIS. The primary oocytes begin meiosis but are arrested at the diplotene state until OVULATION at PUBERTY to give rise to haploid secondary oocytes or ova (OVUM).Receptor, Cannabinoid, CB1: A subclass of cannabinoid receptor found primarily on central and peripheral NEURONS where it may play a role modulating NEUROTRANSMITTER release.Cholinergic Agents: Any drug used for its actions on cholinergic systems. Included here are agonists and antagonists, drugs that affect the life cycle of ACETYLCHOLINE, and drugs that affect the survival of cholinergic neurons. The term cholinergic agents is sometimes still used in the narrower sense of MUSCARINIC AGONISTS, although most modern texts discourage that usage.Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid is the most common excitatory neurotransmitter in the CENTRAL NERVOUS SYSTEM.Animal Rights: The moral and ethical bases of the protection of animals from cruelty and abuse. The rights are extended to domestic animals, laboratory animals, and wild animals.Receptors, Opioid, mu: A class of opioid receptors recognized by its pharmacological profile. Mu opioid receptors bind, in decreasing order of affinity, endorphins, dynorphins, met-enkephalin, and leu-enkephalin. They have also been shown to be molecular receptors for morphine.Computer-Assisted Instruction: A self-learning technique, usually online, involving interaction of the student with programmed instructional materials.Adrenergic beta-3 Receptor Antagonists: Drugs that bind to and block the activation of ADRENERGIC BETA-3 RECEPTORS.Adrenergic alpha-1 Receptor Agonists: Compounds that bind to and activate ADRENERGIC ALPHA-1 RECEPTORS.Receptors, Dopamine: Cell-surface proteins that bind dopamine with high affinity and trigger intracellular changes influencing the behavior of cells.Pharmaceutical Preparations, Dental: Drugs intended for DENTISTRY.Leukemia L1210Receptors, Bombesin: Cell surface proteins that bind bombesin or closely related peptides with high affinity and trigger intracellular changes influencing the behavior of cells. Gastrin- releasing peptide (GRP); GRP 18-27 (neuromedin C), and neuromedin B are endogenous ligands of bombesin receptors in mammals.Crotonates: Derivatives of BUTYRIC ACID that include a double bond between carbon 2 and 3 of the aliphatic structure. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include the aminobutryrate structure.Neurosciences: The scientific disciplines concerned with the embryology, anatomy, physiology, biochemistry, pharmacology, etc., of the nervous system.Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.Receptors, Dopamine D2: A subfamily of G-PROTEIN-COUPLED RECEPTORS that bind the neurotransmitter DOPAMINE and modulate its effects. D2-class receptor genes contain INTRONS, and the receptors inhibit ADENYLYL CYCLASES.IndianaTransfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.GABA-A Receptor Agonists: Endogenous compounds and drugs that bind to and activate GABA-A RECEPTORS.Great BritainCarubicin: A very toxic anthracycline-type antineoplastic related to DAUNORUBICIN, obtained from Actinomadura carminata.Stereoisomerism: The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Molecular Targeted Therapy: Treatments with drugs which interact with or block synthesis of specific cellular components characteristic of the individual's disease in order to stop or interrupt the specific biochemical dysfunction involved in progression of the disease.Tubocurarine: A neuromuscular blocker and active ingredient in CURARE; plant based alkaloid of Menispermaceae.Biological Science Disciplines: All of the divisions of the natural sciences dealing with the various aspects of the phenomena of life and vital processes. The concept includes anatomy and physiology, biochemistry and biophysics, and the biology of animals, plants, and microorganisms. It should be differentiated from BIOLOGY, one of its subdivisions, concerned specifically with the origin and life processes of living organisms.PiperazinesStudents, Nursing: Individuals enrolled in a school of nursing or a formal educational program leading to a degree in nursing.Trientine: An ethylenediamine derivative used as stabilizer for EPOXY RESINS, as ampholyte for ISOELECTRIC FOCUSING and as chelating agent for copper in HEPATOLENTICULAR DEGENERATION.Spider Venoms: Venoms of arthropods of the order Araneida of the ARACHNIDA. The venoms usually contain several protein fractions, including ENZYMES, hemolytic, neurolytic, and other TOXINS, BIOLOGICAL.Phenethylamines: A group of compounds that are derivatives of beta- aminoethylbenzene which is structurally and pharmacologically related to amphetamine. (From Merck Index, 11th ed)OxadiazolesHerb-Drug Interactions: The effect of herbs, other PLANTS, or PLANT EXTRACTS on the activity, metabolism, or toxicity of drugs.Geriatrics: The branch of medicine concerned with the physiological and pathological aspects of the aged, including the clinical problems of senescence and senility.Adrenergic alpha-Antagonists: Drugs that bind to but do not activate alpha-adrenergic receptors thereby blocking the actions of endogenous or exogenous adrenergic agonists. Adrenergic alpha-antagonists are used in the treatment of hypertension, vasospasm, peripheral vascular disease, shock, and pheochromocytoma.ThiadiazolesEducational Measurement: The assessing of academic or educational achievement. It includes all aspects of testing and test construction.Rats, Wistar: A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.Histamine Agonists: Drugs that bind to and activate histamine receptors. Although they have been suggested for a variety of clinical applications histamine agonists have so far been more widely used in research than therapeutically.Receptors, Neuropeptide: Cell surface receptors that bind specific neuropeptides with high affinity and trigger intracellular changes influencing the behavior of cells. Many neuropeptides are also hormones outside of the nervous system.Adrenergic Antagonists: Drugs that bind to but do not activate ADRENERGIC RECEPTORS. Adrenergic antagonists block the actions of the endogenous adrenergic transmitters EPINEPHRINE and NOREPINEPHRINE.Atropine: An alkaloid, originally from Atropa belladonna, but found in other plants, mainly SOLANACEAE. Hyoscyamine is the 3(S)-endo isomer of atropine.Lysergic Acid Diethylamide: Semisynthetic derivative of ergot (Claviceps purpurea). It has complex effects on serotonergic systems including antagonism at some peripheral serotonin receptors, both agonist and antagonist actions at central nervous system serotonin receptors, and possibly effects on serotonin turnover. It is a potent hallucinogen, but the mechanisms of that effect are not well understood.Sisomicin: Antibiotic produced by Micromonospora inyoensis. It is closely related to gentamicin C1A, one of the components of the gentamicin complex (GENTAMICINS).Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Parasympathomimetics: Drugs that mimic the effects of parasympathetic nervous system activity. Included here are drugs that directly stimulate muscarinic receptors and drugs that potentiate cholinergic activity, usually by slowing the breakdown of acetylcholine (CHOLINESTERASE INHIBITORS). Drugs that stimulate both sympathetic and parasympathetic postganglionic neurons (GANGLIONIC STIMULANTS) are not included here.Cannabinoid Receptor Agonists: Compounds that interact with and stimulate the activity of CANNABINOID RECEPTORS.Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue.Isoquinolines: A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)Pyrazoles: Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.

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European Association for Clinical Pharmacology and TherapeuticsFragment-based lead discovery: Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. It is based on identifying small chemical fragments, which may bind only weakly to the biological target, and then growing them or combining them to produce a lead with a higher affinity.Timeline of the nuclear program of Iran: This is the timeline of the nuclear program of Iran.Drug action: The action of drugs on the human body is called pharmacodynamics, and what the body does with the drug is called pharmacokinetics. The drugs that enter the human tend to stimulate certain receptors, ion channels, act on enzymes or transporter proteins.List of pharmaceutical compound number prefixes: This list of pharmaceutical compound number prefixes details a pharmaceutical drug labeling standard. Pharmaceutical companies produce a large number of compounds, which cannot all be given names.Concentration effect: In the study of inhaled anesthetics, the concentration effect is the increase in the rate that the Fa(alveolar concentration)/Fi(inspired concentration) ratio rises as the alveolar concentration of that gas is increased. In simple terms, the higher the concentration of gas administered, the faster the alveolar concentration of that gas approaches the inspired concentration.Proton-sensing G protein-coupled receptorsInternational Committee on Aeronautical Fatigue and Structural IntegrityLigand (biochemistry): In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a signal-triggering molecule binding to a site on a target protein.International Society for Traumatic Stress Studies: International Society for Traumatic Stress Studies (ISTSS) was established on March 2, 1985 in Washington, D.C.John Killaly: John Killaly (1776–1832) was the most significant Irish canal engineer working originally for the Grand Canal company and later, as an engineer, under the Directors-General of Inland Navigation.List of podcasting companies: This is a list of notable podcast production and distribution companies. This includes both audio and video podcasts.The Flash ChroniclesInternational Psychopharmacology Algorithm Project: The International Psychopharmacology Algorithm Project (IPAP) is a non-profit corporation whose purpose is to "enable, enhance, and propagate" use of algorithms for the treatment of some Axis I psychiatric disorders.Idiosyncratic drug reactionPharmacogenetics: Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behavior through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.Loftus, North YorkshireGABAA-rho receptor: The GABAA-rho receptor (previously known as the GABAC receptor) is a subclass of GABAA receptors composed entirely of rho (ρ) subunits. GABAA receptors including those of the ρ-subclass are ligand-gated ion channels responsible for mediating the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain.Neuropharmacology: Neuropharmacology is the study of how drugs affect cellular function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular.Org 20599WIN 56,098: WIN 56,098 is a chemical that is considered to be an aminoalkylindole derivative. It is a tricyclic aryl derivative that acts as a competitive antagonist at the CB2 cannabinoid receptor.Acetylcholine receptorBRL-15,572Community-based clinical trial: Community-based clinical trials are clinical trials conducted directly through doctors and clinics rather than academic research facilities. They are designed to be administered through primary care physicians, community health centers and local outpatient facilities.Benzodiazepine misuse: The non-medical use of Benzodiazepine drugs (called misuse or abuse in public health journals) is the use of benzodiazepines without a prescription, often for recreational purposes, which poses risks of dependence, withdrawal and other long-term effects. Benzodiazepines are one of the more common prescription drugs used recreationally.Ethyl groupGraphic facilitation: Graphic Facilitation is the use of large scale imagery to lead groups and individuals towards a goal. The method is used in various processes such as meetings, seminars, workshops and conferences.Baby hamster kidney cell: Baby Hamster Kidney fibroblasts (aka BHK cells) are an adherent cell line used in molecular biology.Syllabus: A syllabus (pl. syllabi) is an outline and summary of topics to be covered in an education or training course.Phenylpiperidine: Phenylpiperidine is a chemical compound with a phenyl moiety directly attached to piperidine. There are a variety of pharmacological effects associated some phenylpiperidines including morphine-like activity or other central nervous system effects.BentazepamDavid Steinman: You may also be looking for David B. Steinman, builder of bridges.JWH-196: JWH-196 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the indole 2-methyl derivative of related compound JWH-175, and the carbonyl reduced analog of JWH-007.Drug interaction: A drug interaction is a situation in which a substance (usually another drug) affects the activity of a drug when both are administered together. This action can be synergistic (when the drug's effect is increased) or antagonistic (when the drug's effect is decreased) or a new effect can be produced that neither produces on its own.Patch clamp: The patch clamp technique is a laboratory technique in electrophysiology that allows the study of single or multiple ion channels in cells. The technique can be applied to a wide variety of cells, but is especially useful in the study of excitable cells such as neurons, cardiomyocytes, muscle fibers, and pancreatic beta cells.BioSimMolecular modificationAllosteric regulationPiperoxanOpioid: Opioids are substances that act on the nervous system in a similar way to opiates such as morphine and codeine. In a medical context the term usually indicates medications that are artificially made rather than extracted from opium.PivagabineAntileukemic drug: Antileukemic drugs, anticancer drugs that are used to treat one or more types of leukemia, include:A. N. Hartley: Annie Norah Hartley (1902 – 1994), usually known simply as Norah Hartley, was a dog breeder and the first female board member of the Kennel Club.Journal of Medical Toxicology: The Journal of Medical Toxicology is a peer-reviewed medical journal on medical toxicology and the official journal of the American College of Medical Toxicology. It publishes original articles, illustrative cases, review articles, and other special features that are related to the clinical diagnosis and management of patients with exposure to various poisons.Reversal potential: In a biological membrane, the reversal potential (also known as the Nernst potential) of an ion is the membrane potential at which there is no net (overall) flow of that particular ion from one side of the membrane to the other. In the case of post-synaptic neurons, the reversal potential is the membrane potential at which a given neurotransmitter causes no net current flow of ions through that neurotransmitter receptor's ion channel.TerpyridineHSD2 neurons: HSD2 neurons are a small group of neurons in the brainstem which are uniquely sensitive to the mineralocorticosteroid hormone aldosterone, through expression of HSD11B2. They are located within the caudal medulla oblongata, in the nucleus of the solitary tract (NTS).Rosalyn Sussman YalowMitragyna: Mitragyna is a genus of trees in the Rubiaceae family. Members of this genus contain antimalarial and analgesic indole alkaloids.Burst kinetics: Burst kinetics is a form of enzyme kinetics that refers to an initial high velocity of enzymatic turnover when adding enzyme to substrate. This initial period of high velocity product formation is referred to as the "Burst Phase".Osmotic controlled-release oral delivery system: OROS (Osmotic [Controlled] Release Oral [Delivery] System) is a controlled release oral drug delivery system in the form of a tablet. The tablet has a rigid water-permeable jacket with one or more laser drilled small holes.Periodic current reversalCiproxifanNewington Green Unitarian ChurchNeural drug delivery systems: Neural drug delivery is the next step beyond the basic addition of growth factors to nerve guidance conduits. Drug delivery systems allow the rate of growth factor release to be regulated over time, which is critical for creating an environment more closely representative of in vivo development environments.Bath salts (drug): Bath salts is a term used in North America to describe a number of recreational designer drugs. The name derives from instances in which the drugs were sold disguised as true bath salts.Enlightenment Intensive: An Enlightenment Intensive is a group retreat designed to enable a spiritual enlightenment experience within a relatively short time. Devised by Americans Charles (1929–2007) and Ava Berner in the 1960s,http://www.Temporal analysis of products: Temporal Analysis of Products (TAP), (TAP-2), (TAP-3) is an experimental technique for studyingNonbenzodiazepine: Nonbenzodiazepines (sometimes referred to colloquially as "Z-drugs") are a class of psychoactive drugs that are very benzodiazepine-like in nature. Nonbenzodiazepines pharmacodynamics are almost entirely the same as benzodiazepine drugs and therefore employ similar benefits, side-effects, and risks.Calcium signaling: Calcium ions are important for cellular signalling, as once they enter the cytosol of the cytoplasm they exert allosteric regulatory effects on many enzymes and proteins. Calcium can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.Nicotine replacement therapyNihon UniversityCyclophane: 300px|right|Scheme 1. CyclophanesA cyclophane is a hydrocarbon consisting of an aromatic unit (typically a benzene ring) and an aliphatic chain that forms a bridge between two non-adjacent positions of the aromatic ring.CariprazinePharmaceutical manufacturing: Drug manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs by pharmaceutical companies. The process of drug manufacturing can be broken down into a series of unit operations, such as milling, granulation, coating, tablet pressing, and others.Cannabinoid receptor antagonist: The discovery of the endogenous cannabinoid system led to the development of CB1 receptor antagonists. The first cannabinoid receptor antagonist, rimonabant, was described in 1994.Strychnine poisoning

(1/926) The pathologist and toxicologist in pharmaceutical product discovery.

Significant change is occurring in the drug discovery paradigm; many companies are utilizing dedicated groups from the toxicology/ pathology disciplines to support early stage activities. The goal is to improve the efficiency of the discovery process for selecting a successful clinical candidate. Toxicity can be predicted by leveraging molecular techniques via rapid high-throughput, low-resource in vitro and in vivo test systems. Several important activities help create a platform to support rapid development of a new molecular entity. The proceedings of this symposium provide excellent examples of these applied concepts in pharmaceutical research and development. Leading biopharmaceutical companies recognize that a competitive advantage can be maintained via rapid characterization of animal models, the cellular identification of therapeutic targets, and improved sensitivity of efficacy assessment. The participation of the molecular pathologist in this quest is evolving rapidly, as evidenced by the growing number of pathologists that interact with drug discovery organizations.  (+info)

(2/926) PET and drug research and development.

The use of PET to examine the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. PET provides a new perspective on drug research by virtue of its ability to directly assess both pharmacokinetic and pharmacodynamic events in humans and in animals. These parameters can be assessed directly in the human body both in healthy volunteers and in patients. Moreover, the new generation of high-resolution, small-animal cameras hold the promise of introducing imaging in the early stages of drug development and make it possible to carry out longitudinal studies in animals and to study genetically altered animals. This places PET in a unique position to contribute significantly to the process of drug development through understanding the molecular mechanisms underlying drug action while addressing some very practical questions such as determining effective drug doses for clinical trials for new drugs, determining the duration of drug action and examining potential drug interactions.  (+info)

(3/926) The pharmacology of gene therapy.

The objective for human gene therapy is to express exogenous DNA at a site in vivo for long enough, and at sufficient levels to produce a therapeutic response. The obstacles to this objective are numerous and include the formulation or packaging of the DNA, in vivo delivery, penetration of biological barriers, DNA elimination within the cell and from the tissue compartments of the whole body, control of product expression and overt toxicity. The current challenge is to resolve each of these obstacles to produce a practical and efficient gene therapy. In doing so, it is vital to understand the disposition of DNA vectors in vivo, and to know how conventional medicines may be used to modulate this disposition and to enhance the therapeutic effect of these vectors. Many of the general concepts of human gene therapy have been reviewed extensively in the literature. This review discusses some of the pharmacological aspects of gene delivery and the fate of vectors in vivo, and then highlights how drugs are being used to modulate gene therapy.  (+info)

(4/926) Is orphan drug status beneficial to tropical disease control? Comparison of the American and future European orphan drug acts.

OBJECTIVES To quantify past outcomes of tropical pharmacology research and development (R & D) and to assess past benefits of the American orphan drug act and potential benefits of the future European orphan drug regulation on tropical diseases. METHODS: This paper presents two analyses: a 1983-97 retrospective study of the United States Orphan Drug Act concerning rare diseases and a prospective study of the European Proposal for a Regulation Concerning Orphan Drugs and its possible impact on tropical diseases. RESULTS: Different programmes have in the past tried to stimulate R & D in this area, but results remain limited. Of 1450 new chemical entities marketed between 1972 and 1997, 13 were specifically for tropical diseases and considered as essential drugs. Between 1983 & 1997, the US Orphan Drug Act approved 837 drugs and marketing of 152 new molecular entities (NMEs). Three NMEs have been designated for malaria and human African trypanosomiasis. Seven others, already commonly used in tropical diseases, received either orphan designation or an orphan approval for another indication. Pharmaceutical companies benefit from the US framework only when the US market exclusivity clause was applicable. Future European orphan drug regulation appears to be similar to the US Orphan Drug Act. CONCLUSION The orphan drug programmes relating to rare diseases have met with some success. Considering tropical diseases rare diseases seems inadequate to boost pharmaceutical R & D. However, some provisions of the European text may be relevant to tropical diseases, admitting the need for a more specific rule for evaluations of this kind of drug and recognizing the existence of 'diseases of exception'.  (+info)

(5/926) A comparison of the direct and reporter antigen popliteal lymph node assay for the detection of immunomodulation by low molecular weight compounds.

The direct popliteal lymph node assay (PLNA) is a predictive test used to detect the immune-stimulating potential of pharmaceuticals and other low molecular weight compounds (LMWCs) with known autoimmunogenic or sensitizing properties. Two limitations in the PLNA are the existence of false negatives and the inability of the assay to provide mechanistic information. Recently the direct PLNA was modified by incorporating reporter antigens (RA), either TNP-Ficoll or TNP-OVA. In the RA-PLNA, immune stimulation is detected by measuring IgM or IgG TNP-specific antibody-forming cells (AFC) using an enzyme-linked immunospot (ELISPOT) assay. The RA-PLNA, when using potent, known autoimmunogenic compounds, may provide greater sensitivity compared to the direct PLNA and might distinguish LMWCs that have intrinsic adjuvant activity from those that create neo-antigens, using TNP-OVA and TNP-Ficoll, respectively. The purpose of this study was to rigorously compare the two assays. Our first objective was to investigate the interlaboratory reproducibility of the RA-PLNA using four autoimmunogenic LMWC models, plus one negative control LMWC. Subsequently, we tested seven LMWCs with known sensitizing properties and compared the results from the direct and modified assay. The test group included LMWCs thought to be mechanistically distinct and similar to compounds typically encountered in preclinical safety assessment. All control and treatment AFC plaques were collected (76 total), pooled, coded to conceal their source, and counted. The interlaboratory reproducibility of the RA-PLNA was demonstrated with the model autoimmunogenic compounds HgCl2, diphenylhydantoin, D-penicillamine, and the negative control compound phenobarbital, by detecting TNP-specific IgM and polyclonal IgG production to both reporter antigens. Additionally, the sensitizing effects of streptozotocin were identified using an IgG2a ELISPOT with both TNP-OVA and TNP-Ficoll. With the extended test group, the sensitizing effects of aniline, a false negative LMWC in the direct PLNA, was not detected in this study when using the direct PLNA. However, there was an increase of IgG1 AFCs using TNP-OVA, when compared to control (508 +/- 113 vs. 12 +/- 4 respectively). Glafenine, diclofenac, and ibuprofen, all associated with drug-induced anaphylaxis in humans, produced significant increases in IgG1 production to TNP-OVA. Of these three LMWCs, only diclofenac, which has been documented to induce neo-antigen formation, was detected with TNP-Ficoll. Hydralazine immunomodulation could be detected only with the direct PLNA although significant increases in IgM were identified with the co-injection of either reporter antigen. Isoniazid and methyldopa consistently produced negative responses in both assays. In summary, this study has demonstrated acceptable interlaboratory reproducibility of the RA-PLNA, using model autoimmunogenic LMWCs. Additionally, it demonstrated that an advantage of the RA-PLNA was that it identified all anaphylactic-associated LMWCs tested, detected the false negative compound aniline, and revealed what is thought to be the mechanism(s) associated with diclofenac-induced immunostimulation.  (+info)

(6/926) Effects of drugs on glucose measurements with handheld glucose meters and a portable glucose analyzer.

Thirty drugs used primarily in critical care and hospital settings were tested in vitro to observe interference on glucose measurements with 6 hand-held glucose meters and a portable glucose analyzer. Paired differences of glucose measurements between drug-spiked samples and unspiked control samples were calculated to determine bias. A criterion of +/- 6 mg/dL was used as the cutoff for interference. Ascorbic acid interfered with the measurements on all glucose devices evaluated. Acetaminophen, dopamine, and mannitol interfered with glucose measurements on some devices. Dose-response relationships help assessment of drug interference in clinical use. High dosages of these drugs may be given to critically ill patients or self-administered by patients without medical supervision. Package inserts for the glucose devices may not provide adequate warning information. Hence, we recommend that clinicians choose glucose devices carefully and interpret results cautiously when glucose measurements are performed during or after drug interventions.  (+info)

(7/926) International union of pharmacology. XXII. Nomenclature for chemokine receptors.

Chemokine receptors comprise a large family of seven transmembrane domain G protein-coupled receptors differentially expressed in diverse cell types. Biological activities have been most clearly defined in leukocytes, where chemokines coordinate development, differentiation, anatomic distribution, trafficking, and effector functions and thereby regulate innate and adaptive immune responses. Pharmacological analysis of chemokine receptors is at an early stage of development. Disease indications have been established in human immunodeficiency virus/acquired immune deficiency syndrome and in Plasmodium vivax malaria, due to exploitation of CCR5 and Duffy, respectively, by the pathogen for cell entry. Additional indications are emerging among inflammatory and immunologically mediated diseases, but selection of targets in this area still remains somewhat speculative. Small molecule antagonists with nanomolar affinity have been reported for 7 of the 18 known chemokine receptors but have not yet been studied in clinical trials. Virally encoded chemokine receptors, as well as chemokine agonists and antagonists, and chemokine scavengers have been identified in medically important poxviruses and herpesviruses, again underscoring the importance of the chemokine system in microbial pathogenesis and possibly identifying specific strategies for modulating chemokine action therapeutically. The purpose of this review is to update current concepts of the biology and pharmacology of the chemokine system, to summarize key information about each chemokine receptor, and to describe a widely accepted receptor nomenclature system, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area.  (+info)

(8/926) Mechanisms mediating substance P-induced contraction in the rat iris in vitro.

PURPOSE: To determine some of the mechanisms by which substance P (SP) induces contraction in the isolated rat iris. METHODS: Rings of rat iris were mounted in a 5-ml organ chamber containing Krebs solution at 37 degrees C under basal tension of 75 mg, and isometric tension was recorded. RESULTS: Substance P produced graded contraction in the rat iris, being approximately 40-fold more potent than carbachol. Peptidase inhibitors (captopril, phosphoramidon, thiorphan) did not affect the SP response. The SP contraction was dependent on external Ca2+ by a mechanism resistant to both nifedipine and omega-conotoxin GVIA. Atropine and tetrodotoxin significantly shifted the SP response to the right (three- and fivefold, respectively). Neither phorbol nor genistein altered the SP-induced contraction, whereas staurosporine caused a weak inhibition. Indomethacin, pyrilamine, guanethidine, 8-37 calcitonin gene-related peptide (CGRP) fragment, and NG-nitro-L-arginine methyl ester had no effect on SP response. All the natural tachykinin agonists caused concentration-dependent contraction in rat iris with similar maximal responses. The NK3 selective agonist senktide caused graded contraction, being approximately 150-fold more active than the NK2 selective agonist [beta-ala] NKA. The NK1 selective agonist SP methyl ester induced a small contraction. The NK3 and NK2 antagonists SR 142801 and SR 48968 shifted the SP response to the right. Schilds plots gave pA2 (negative logarithm of the molar concentration of antagonist causing a twofold rightward displacement of the concentration response curves) values of 9.37 and 7.97 and slopes of 0.70 and 1.02, respectively. CONCLUSIONS: Substance P produces a potent contraction in the isolated rat iris that seems to depend on the neural release of acetylcholine by tetrodotoxin-sensitive mechanisms. Its response relies largely on external Ca2+, through mechanisms independent of activation of L- or N-type Ca2+ channels, and is probably mediated via activation of NK3 and NK2 receptors.  (+info)


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