The cardiovascular, anticholinergic and central effects of single doses of 30, 45 and 60 mg of sibutramine hydrochloride (BTS 54524), a new potential antidepressant, were compared with amitriptyline (50 mg) and placebo given at weekly intervals in a randomised design to six healthy male volunteers. Sibutramine was associated with increases in both supine heart rate and systolic blood pressure at 1, 2 and 6 h after 60 mg (P < 0.05). Amitriptyline caused a significant 50-60% decrease in salivation compared with placebo at 2 and 6 h but there were no changes with sibutramine. No significant changes in pupil size were detected with either drug. Visual analogue rating scales (VARS) revealed significant drowsiness with amitriptyline but neither sedative nor stimulant effects with sibutramine. Impairments of simple auditory and visual reaction times, visual two-choice reaction time, finger tapping and trail making, measured using an automated test battery, occurred with amitriptyline compared with sibutramine. If sibutramine proves to be an effective antidepressant it should be devoid of anticholinergic or central depressant effects. Chronic dosage studies are indicated to evaluate the clinical significance of its cardiovascular effects.
on the basis of changes in prothrombin time rather than of plasma concentrations) have been interactions involving inhibition rather than induction of warfarin biotransformation. By the same token, stereoselective interactions are most likely to be recognized clinically if they involve inhibitors rather than inducers of biotransformation of one of the warfarin enantiomers.The results of this investigation suggest that there are at least two means of minimizing drug interactions with warfarin: (a) use of that enantiomer which has been shown in clinical studies to be slightly or not at all affected by a drug which is to be given concomitantly (the stereoselective approach), and (b) use of S(-)-warfarin when no information is available concerning the possible stereoselectivity of concomitantly administered drugs. Only racemic warfarin is presently available for general clinical use but if this were to change, the considerations presented here suggest that it may be desirable to market both enantiomers individually, rather than only the R(+) enantiomer. As a general principle, drug biotransformation interactions result in more pronounced changes of the pharmacologic effect when the slope of the intensity of effect vs. log plasma concentration curve is relatively steep. It may be advantageous to assess suitable enantiomeric drugs from that perspective.
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