MK-912, a new alpha 2-adrenoceptor antagonist, was assessed in six volunteers by use of antagonism of the effects of intravenous
clonidine as the main index of response. Subjects received single doses of either 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 that were observed during the placebo treatment period (p less than 0.05). The peak elevation in plasma
growth hormone that was produced by
clonidine on the day the placebo was given was inhibited an average of 87% by the 2 mg dose of
MK-912 (p less than 0.01). Although there was a trend toward antagonism of
clonidine by the 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 the
clonidine-induced peak elevation of plasma
growth hormone was observed (p less than 0.05). Oral
MK-912 almost completely inhibits the effect of 200 micrograms of intravenous
clonidine in human subjects, which is consistent with its role as a potent alpha 2-antagonist over the dose range of 0.2 to 2.0 mg.