Annual review of pharmacology and toxicology
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Annu. Rev. Pharmacol. Toxicol. · Jan 2008
ReviewMechanisms of placebo and placebo-related effects across diseases and treatments.
The placebo effect has evolved from being thought of as a nuisance in clinical and pharmacological research to a biological phenomenon worthy of scientific investigation in its own right. It is now clear that the term placebo effect is too restrictive and, in fact, many placebo-related effects have recently been investigated. ⋯ In recent years, placebo and placebo-related effects have been analyzed with sophisticated biological tools that have uncovered specific mechanisms at both the biochemical and cellular level. This recent research has revealed that these psychosocial-induced biochemical changes in a patient's brain and body in turn may affect the course of a disease and the response to a therapy.
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Annu. Rev. Pharmacol. Toxicol. · Jan 2008
ReviewMechanism-based concepts of size and maturity in pharmacokinetics.
Growth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. ⋯ Clearance pathways develop in the fetus before birth. The use of postnatal age as a descriptor of maturation is unsatisfactory because birth may occur prematurely; therefore postmenstrual age is a superior predictor of elimination function. A sigmoid E(max) model (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age.
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Physiological and pharmacological evidence both have demonstrated a critical role for voltage-gated sodium channels (VGSCs) in many types of chronic pain syndromes because these channels play a fundamental role in the excitability of neurons in the central and peripheral nervous systems. Alterations in function of these channels appear to be intimately linked to hyperexcitability of neurons. ⋯ This review focuses on the role of VGSCs in the hyperexcitability of sensory primary afferent neurons and their contribution to the inflammatory or neuropathic pain states. The discrete localization of the tetrodotoxin (TTX)-resistant channels, in particular NaV1.8, in the peripheral nerves may provide a novel opportunity for the development of a drug targeted at these channels to achieve efficacious pain relief with an acceptable safety profile.
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Annu. Rev. Pharmacol. Toxicol. · Jan 2001
ReviewAnesthetics and ion channels: molecular models and sites of action.
The mechanisms of general anesthesia in the central nervous system are finally yielding to molecular examination. As a result of research during the past several decades, a group of ligand-gated ion channels have emerged as plausible targets for general anesthetics. ⋯ In vivo significance of a putative anesthetic target can now be examined by targeted gene manipulations in mice. In this review, we summarize from a molecular perspective recent advances in our understanding of mechanisms of action of general anesthetics on ligand-gated ion channels.
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Annu. Rev. Pharmacol. Toxicol. · Jan 1998
Review Biography Historical ArticleA quest for erythropoietin over nine decades.
The major research accomplishments of the author are described from the time of his PhD thesis work on the mechanism of cobalt polycythemia to the present day. His early work on the quest for the cell that produces erythropoietin (Epo) to his current work on oxygen sensing and signal transduction pathways involved in erythropoietin gene expression are reported. He describes his main research interest in the mechanism of cobalt polycythemia between 1954 and 1962 and his research on how hormones such as the glucocorticoids function in the regulation of erythropoiesis (1956-1962). ⋯ He describes how he was led astray in some of his early studies on the cells in the kidney that produce erythropoietin, because of the less-developed technology available to him at that time; and how in situ hybridization and other molecular biology techniques enabled him to confirm some of the earlier work in mice by other investigators that interstitial cells in the kidney were the site of production of erythropoietin in the primate. His work in the controversial area of the mechanism of the anemia of end-stage renal disease is described in detail, as it pertains to Epo deficiency and suppressed erythroid progenitor cell response to Epo. He also discusses his recent work on signal transduction pathways (hypoxia, nitric oxide, adenosine, and C kinase) in oxygen sensing and Epo gene expression.