The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · May 2005
Comparative StudyThe role of mitochondrial uncoupling in 3,4-methylenedioxymethamphetamine-mediated skeletal muscle hyperthermia and rhabdomyolysis.
Use of the popular club drug ecstasy (3,4-methylenedioxymethamphetamine, MDMA) can result in life-threatening hyperthermia and rhabdomyolysis. Recent studies show a link between skeletal muscle uncoupling proteins in MDMA-mediated hyperthermia. The mechanisms by which MDMA interacts with skeletal muscle mitochondria are largely unknown. ⋯ Clark electrode experiments on isolated skeletal muscle mitochondria in vitro (1-5 mM MDMA) and ex vivo in MDMA-treated animals demonstrated no evidence of uncoupling of oxidative phosphorylation. In vitro experiments using L6 myotubules cocultured with primary hepatocytes demonstrated the presence of uncoupling protein-3 in the L6 myotubules, but no evidence of a direct effect of MDMA or its potential metabolites on cellular creatine kinase concentrations. These findings suggest that MDMA uncouples skeletal muscle mitochondria in vivo but that this uncoupling is the result of indirect mechanisms.
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J. Pharmacol. Exp. Ther. · May 2005
Comparative StudyMechanistic pharmacokinetic and pharmacodynamic modeling of CHF3381 (2-[(2,3-dihydro-1H-inden-2-yl)amino]acetamide monohydrochloride), a novel N-methyl-D-aspartate antagonist and monoamine oxidase-A inhibitor in healthy subjects.
CHF3381 (2-[(2,3-dihydro-1H-inden-2-yl)amino]acetamide monohydrochloride) is a new N-methyl-D-aspartate antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor in development for the treatment of neuropathic pain. This study developed a mechanistic model to describe the pharmacokinetics of CHF3381 and of its two metabolites, the relationship with MAO-A activity and heart rate. Doses of 100, 200, and 400 mg twice daily for 2 weeks were administered orally to 36 subjects. ⋯ EC(50) was 1670 mug/l, not significantly different from the in vitro IC(50). The increase in heart rate due to CHF3381 was 0.0055 bpm/micro(g l-1). CHF3381 produces a concentration-dependent decrease in DHPG plasma concentrations, whose magnitude increased after multiple twice-a-day regimens for 14 days.
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J. Pharmacol. Exp. Ther. · May 2005
Comparative StudyAcetazolamide, a carbonic anhydrase inhibitor, reverses inflammation-induced thermal hyperalgesia in rats.
Inflammatory pain is linked to reduction in tissue pH. Tissue proton generation is mainly mediated by carbonic anhydrases (CAs). We therefore hypothesized that inhibition of CAs with acetazolamide (ACTZ) increases the tissue pH and reverses inflammation-induced pain. ⋯ Thus, the current data do not support our hypothesis that ACTZ reduces inflammatory hyperalgesia by raising the reduced pH in muscle. Although the possibility of pH changes and the role of CAs in the microenvironment cannot be ruled out, the mechanism of ACTZ-induced antihyperalgesia is not clear from this study. It is possible that the inhibition of ion channels and/or the inhibition of spinally located CAs contribute to the observed antihyperalgesia.