This randomized, double-blind, crossover study in 10 healthy male volunteers compared four single oral doses of ICI 141,292 ('Visacor'), i.e. 50, 100, 200, and 300 mg, with placebo. Venous blood samples were collected pre-dose and at various times after dosing and the concentrations of ICI 141,292 in the plasma were determined by radioimmunoassay. A standardized 4-min bicycle exercise test was also performed and before this the resting haemodynamic parameters were assessed.
Peak plasma concentrations of ICI 141,292 and the area under the plasma concentration-time curve increased disproportionately with dose such that after scaling to a dose of 200 mg there remained a significant linear trend with dose. The time to peak plasma concentration displayed an increasing trend with dose and, once again, the linear component of this trend was statistically significant. The mean heart rates during exercise were all significantly reduced compared to placebo for 24 h by each of the doses (range 7.8 to 17.4 beats min-' at 24 h, p <0.01). The increase in heart rate during exercise was inversely related to the logarithm of the ICI 141,292 plasma concentration with higher plasma concentrations being associated with lower heart rate increases. The mean supine resting heart rates were slightly but significantly reduced at 2 and 6 h after dosing by each treatment and by the 300 mg dose at 24 h. Each of the doses of ICI 141,292 was well tolerated.