The analgesic efficacy of dexmedetomidine (DEX)--a novel alpha 2-adrenoceptor agonist--was studied in man. Single intravenous doses of fentanyl (FEN; 2 micrograms/kg), DEX (0.25, 0.50 and 1.0 micrograms/kg) and placebo were administered to 5 healthy male volunteers in a double-blind, crossover study in randomized order. The analgesic effect of the different treatments was measured by determining the time course of pain threshold with dental dolorimetry and by quantitating subjective pain induced by a standard ischemic pain stimulus on the upper arm using a visual analogue scale (VAS). The drugs were generally well tolerated. FEN and DEX both had analgesic effects on ischemic pain, which was seen as a statistically significant decrease in subjective VAS ratings. FEN appeared to be more effective than DEX; the difference was not, however, statistically significant. Neither of the drugs affected the pain threshold measurements.

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Milk-based drinks containing casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown to possess antihypertensive and vascular endothelium-protecting properties in hypertensive animal models. Furthermore in clinical intervention trials they reduce blood pressure and arterial stiffness. The exact mechanisms are not known, but inhibition of angiotensin converting enzyme 1 (ACE1) has been suggested mainly to mediate these beneficial effects. The present study investigated the in vitro effects of three tripeptides: Ile-Pro-Pro, Val-Pro-Pro and leqcine-proline-proline (Leu-Pro-Pro) on four renin-angiotensin system enzymes: ACE1, ACE2, chymase, and cathepsin G. Also their effects on arginase I, a critical enzyme in L-arginine-nitric oxide pathway, were studied. It was shown, apparently for the first time, that the inhibitory effects of Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro on ACE1 at micromolar concentrations are competitive in nature. Therefore the efficacy of inhibition is largely dependent on the amount of substrate present. Inhibition of ACE2 and arginase I was reached only at concentrations three orders of magnitude greater. No inhibition of chymase and cathepsin G was observed by the tripeptides. The findings support the hypothesis that Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro act favourably on blood pressure mainly by selective inhibition of ACE1.

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