Assessment of MK‐912, an α 2 ‐adrenoceptor antagonist, with use of intravenous clonidine

MK‐912, a new α 2 ‐adrenoceptor antagonist, was assessed in six volunteers by use of antagonism of die effects of intravenous clonidine as the main index of response. Subjects received single doses of eidier 0.2 or 2 mg of orally administered MK‐912 or placebo in a randomized, double‐blind, balanced, crossover design. Clonidine was infused intravenously over 10 minutes, 1 hour after dosing, and observations were made for 8 hours. The 2 mg dose of MK‐912 significantly inhibited the clonidine‐induced hypotension, bradycardia, xerostomia, and increase in plasma glucose concentrations diat were observed during the placebo treatment period ( p < 0.05). The peak elevation in plasma growth hormone that was produced by clonidine on die day die placebo was given was inhibited an average of 87% by die 2 mg dose of MK‐912 ( p < 0.01). Akhough there was a trend toward antagonism of clonidine by die 0.2 mg dose of MK‐912, statistically significant differences from placebo were not consistently demonstrated for most parameters. However, a mean 59% inhibition of die clonidine‐induced peak elevation of plasma growth hormone was observed ( p < 0.05). Oral MK‐912 almost completely inhibits the effect of 200 µg of intravenous clonidine in human subjects, which is consistent with its role as a potent α 2 ‐antagonist over the dose range of 0.2 to 2.0 mg. Clinical Pharmacology and Therapeutics (1989) 46, 103–109; doi: 10.1038/clpt.1989.113