Trends in pharmacological sciences
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Trends Pharmacol. Sci. · Oct 2005
ReviewEmerging molecular mechanisms of general anesthetic action.
General anesthetics are essential to modern medicine, and yet a detailed understanding of their mechanisms of action is lacking. General anesthetics were once believed to be "drugs without receptors" but this view has been largely abandoned. ⋯ Neurotransmitter-gated ion channels, particularly receptors for GABA and glutamate, are modulated by most anesthetics, at both synaptic and extrasynaptic sites, and additional ion channels and receptors are also being recognized as important targets for general anesthetics. In this article, these developments, which have important implications for the development of more-selective anesthetics, are reviewed in the context of recent advances in ion channel structure and function.
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Trends Pharmacol. Sci. · Aug 2005
ReviewReduction of blood pressure variability: a new strategy for the treatment of hypertension.
The main aims of the treatment of hypertension are to prevent end-organ damage (EOD) and to avoid consequent lethal complications associated with hypertension. Blood pressure level is a well-known determinant of EOD. ⋯ The reduction of BPV is an important contributory factor of the organ protection provided by some antihypertensive drugs. Thus, reduction of BPV might represent a new strategy for the treatment of hypertension.
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Trends Pharmacol. Sci. · Mar 2005
Review Comparative StudyIndividual responder analyses for pain: does one pain scale fit all?
The outcomes of clinical trials are based on the mean responses of large numbers of subjects but fail to address inter-individual differences. The molecular mechanisms that underlie pain vary among individuals over time and among different types of pain to produce wide inter-individual variations in pain perception and response. ⋯ Pain measurement scales can be used differently across individuals based on the past pain experiences of individuals. We propose that individual responder analyses could be used in clinical trials to better detect analgesic activity across patient groups and within sub-groups, and to identify molecular-genetic mechanisms that contribute to individual variation.
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Trends Pharmacol. Sci. · Feb 2005
ReviewWhy does the rapid delivery of drugs to the brain promote addiction?
It is widely accepted that the more rapidly drugs of abuse reach the brain the greater their potential for addiction. This might be one reason why cocaine and nicotine are more addictive when they are smoked than when they are administered by other routes. Traditionally, rapidly administered drugs are thought to be more addictive because they are more euphorigenic and/or more reinforcing. ⋯ We propose an alternative (although not mutually exclusive) explanation based on the idea that the transition to addiction involves drug-induced plasticity in mesocorticolimbic systems, changes that are manifested behaviourally as psychomotor and incentive sensitization. Recent evidence suggests that rapidly administered cocaine or nicotine preferentially engage mesocorticolimbic circuits, and more readily induce psychomotor sensitization. We conclude that rapidly delivered drugs might promote addiction by promoting forms of neurobehavioural plasticity that contribute to the compulsive pursuit of drugs.
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The fuel-sensing enzyme 5'-AMP-activated protein kinase (AMPK) has a major role in the regulation of cellular lipid and protein metabolism in response to stimuli such as exercise, changes in fuel availability and the adipocyte-derived hormones leptin and adiponectin. Recent studies indicate that abnormalities in cellular lipid metabolism are involved in the pathogenesis of the metabolic syndrome, possibly because of dysregulation of AMPK and malonyl-CoA, a closely related molecule. ⋯ Thus, it has been demonstrated recently that the tumor suppressor LKB1 is a kinase that has a major role in phosphorylating and activating AMPK, and that another tumor suppressor, tuberous sclerosis complex 2, is phosphorylated and activated by AMPK. In addition, other studies indicate that mammalian homolog of target of rapamycin (mTOR), which has been implicated in the pathogenesis of insulin resistance and many types of cancer, is inhibited by AMPK.