Showing papers in "Pharmacological Reviews in 1997"

International Union of Pharmacology. XIII. Classification of Histamine Receptors

Abstract: The classification of histamine receptors has to date been based on rigorous classical pharmacological analysis, and as yet, the classification of the three histamine receptors that have been defined by this process, (i.e., the H1-, H2-, and H 3-receptors) have not been added to because of more

Calcium Movements, Distribution, and Functions in Smooth Muscle

Abstract: Contraction of smooth muscle is regulated by the cytosolic Ca2+ level ([Ca2+]i)b, and the sensitivity to Ca2+ of the contractile elements in response to changes in the environment surrounding the cell. The first sequence of events in regulation includes the binding of endogenous substances, such as

Role of Pharmacokinetics and Metabolism in Drug Discovery and Development

Abstract: Drug research encompasses several diverse disciplines united by a common goal, namely the development of novel therapeutic agents. The search for new drugs can be divided functionally into two stages: discovery and development. The former consists of setting up a working hypothesis of the target

The Sarcoplasmic Reticulum Ca2+ Channel/Ryanodine Receptor: Modulation by Endogenous Effectors, Drugs and Disease States

Abstract: ### A. The ryanodine receptor The ryanodine receptor (RyR)c corresponds to the sarcoplasmic reticulum (SR) Ca2+ channel ([Inui et al., 1987][1]; [Imagawa et al., 1987][2]). Its structure and function have been reviewed recently ([Fleischer and Inui, 1989][3]; [Lai and Meissner, 1989][4];[McPherson

Adenosine A2B Receptors

Abstract: Adenosine is an endogenous nucleoside that modulates many physiological processes. Its actions are mediated by interaction with specific cell membrane receptors. Four subtypes of adenosine receptors have been cloned: A1, A2A, A2B, and A3. Significant advancement has been made in the understanding of

The Blood-Brain Barrier in Neuroinflammatory Diseases

Abstract: The existence of the blood-brain barrier (BBB)bwas revealed through studies by [Ehrlich (1885)][1] in the late 19th century, describing that brain tissue remained unstained after injection of a vital dye into the systemic blood circulation of rats. In contrast, the brain tissue was stained after

The D3 Dopamine Receptor: Neurobiology and Potential Clinical Relevance

Abstract: Dopamine is a major neurotransmitter in the central nervous system. Receptors for this catecholamine are of considerable interest, as they are the principal target of drugs employed in the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson’s disease. Before 1990, the

XIV. International Union of Pharmacology Nomenclature in Nitric Oxide Research

Abstract: The discovery that the biological actions of endothelium-derived relaxing factor ([Furchgott and Zawadzki, 1980][1]) are due to the endogenous release of nitric oxide (NO)c ([Palmer et al., 1987][2]; [Ignarro et al., 1987][3]; [Khan and Furchgott, 1987][4]) revealed the existence of a ubiquitous

The Pharmacology of Ryanodine and Related Compounds

Abstract: The goal of this review has been to describe the current state of the pharmacology of ryanodine and related compounds relative to the vertebrate RyRs. Resolution of questions concerning the molecular properties of RyR channel function and the contributions made by the RyR isoforms to cellular signaling in a variety of tissues will require the production of new pharmacological agents directed against these proteins. Novel naturally occurring ryanodine congeners have been identified, and significant advances have been made in developing chemical approaches that permit the structure of ryanodine to be derivatized in selective ways. Moreover, several of these changes have yielded compounds that differ in their binding affinities and in their abilities to modify the properties of the RyR channels. These advances give substance to the possibility of designing the required pharmacological agents based on rational design changes of the structure ryanodine.

Molecular Interactions Between Inhaled Anesthetics and Proteins

Abstract: The fundamental interactions of inhalational anesthetics with proteins have been considered in some detail, using specific examples where appropriate to illustrate these interactions and demonstrate progress. It is now clear that these low-affinity volatile molecules with rapid kinetics can specifically bind to discrete sites in some proteins at reasonable pharmacological concentrations, and some general features of these sites are beginning to emerge. The structural or dynamic consequences of anesthetic binding, however, are still vague at best. The remaining challenge is to define which interactions produce anesthetic binding to relevant targets and what the features of this relevant anesthetic binding site are. Finally, and most importantly, how does the occupancy of these pockets, patches, or cavities result in the subtle alterations in protein conformation and dynamics that confound their function and ultimately produce the behavioral response that we term "anesthesia"?

Red Blood Cells: A Neglected Compartment in Pharmacokinetics and Pharmacodynamics

Abstract: The significance of studying the kinetics of drug partitioning into red blood cells (RBCsb) in animals and humans is not fully appreciated, although the importance of routine determination of rate and extent of partitioning of investigational drugs has been stressed ([Lee et al., 1981b][1]; [

Chemically Reactive Intermediates and Pulmonary Xenobiotic Toxicity

Abstract: ### A. Activation of Xenobiotics to Chemically Reactive Intermediates The biochemical literature abounds with reviews of drug oxidation and conjugation by and toxic effects in liver ([Gillette, 1974a][1],[b][2]). Although it was once believed that drug-induced hepatotoxicity was the result of some

Pharmacogenetics in Biological Perspective

Abstract: What have we learned? Pharmacogenetics, heritable variation in response to xenobiotics, is present in all forms of life. Initially, human data perhaps have created the most excitement, and they provide much biochemical detail. However, if we look at pharmacogenetic variation of insects and bacteria, we see it as a characteristic of populations; individuals with inborn resistance to various toxicants can cause the survival of a population by the process of Darwinian selection. Diversity of a population and Darwinian selection are different milestones serving population survival. Variation of drug response may represent variation of drug targets, drug metabolism, and probably drug transport. Metabolic variation appears to be the most prominent; at present, it is not clear whether this prominence has historical or biological causes. It is an interesting exercise to compare pharmacogenetic resistance with intoxication and resistance to infection by invasion of disease-carrying bacteria or other pathogens. The big difference is that pathogens tend to show variabilities that drugs do not have. The immune system is made to deal with the genetic variabilities linked to the short life span of most pathogens. However, there are, besides the immune system, several cases of genetic host resistance associated with the long life span of mammalian hosts. Such genetic host resistances are factors equivalent to pharmacogenetic variation. Current data pertain to resistance against malaria, tuberculosis, cholera, and AIDS. Most pharmacogenetic variants within a population are preadaptive, that is, they are established before xenobiotic exposure. Hence, one must postulate a multiplicity of variants in a population capable of resisting a multiplicity of drugs. The persistence of this multiplicity suggests that most variants are either present in heterozygous form and are thereby advantageous for their carriers, or they are selectively neutral mutants. It means that the biological cost of pharmacogenetic diversity, measured in terms of reduced fertility, should be low in a population. The frequencies of variant genes are usually not the same in different populations. Also the nucleotide substitutions in a variable gene often differ between populations. In other words, pharmacogenetic differences between populations are typical events. Pharmacogenetics is usually thought of as the study of a situation in which a single gene product exerts control over a given drug response so that a failure to respond, or an excessive response, may result. However, one should not forget that random variation is always present, probably reflecting the randomness of mutations plus variation of any environmental factors that might contribute. This underlying randomness of variation will always affect the picture of any all-or-none variation. Future pharmacogenetics must deal with both random and monogenic variation.

Pharmacology of Lazaroids and Brain Energy Metabolism: A Review

Abstract: ### A. Background A considerable body of experimental evidence indicates that lipid peroxidation ([Komara et al., 1986][1]; [Dexter et al., 1989][2]), the presence of iron ([Riederer et al., 1989][3]; [Hirsh et al., 1991][4]) and the depletion of natural antioxidants ([Sato and Hall, 1992][5]) seem