EFFECTS OF AN ORALLY ACTIVE RENIN INHIBITOR, RO 42-5892, IN PATIENTS WITH ESSENTIAL-HYPERTENSION

Ro 42-5892 (Ro) is a new renin inhibitor that has been shown to be an orally effective compound in primates and in the first exploratory stu dies in humans. However, no firm conclusions could be drawn from the h uman trials and therefore the present study was designed to evaluate t he antihypertensive efficacy of the compound in a double-blind, placeb o-controlled trial. After a 3 week wash-out period and a 1 week single -blind placebo period, 24 patients were randomized to receive once dai ly orally either placebo or 600 mg Ro 42-5892 (N = 12/group) for 8 day s. On the last day of treatment, an intravenous infusion of placebo or 100 mg Ro was given in a double-blind fashion, 4 h after the oral adm inistration. Blood pressure (BP), heart rate (HR), plasma renin activi ty (PRA), immunoreactive renin (IRR), and plasma Ro levels were measur ed repeatedly on the first and last days of treatment. After the first oral intake of Ro, sitting diastolic BP dropped significantly from 30 min to 24 h post-dose when compared to placebo (-10.2 +/- 1.2 mm Hg v -0.4 +/- 2.0 mm Hg at peak and -6.9 +/- 1.8 mm Hg v 1.7 +/- 0.9 mm Hg at trough; P < .01 respectively). The trough effects of Ro and placeb o after the 7th and 8th doses were -5.1 +/- 1.6 mm Hg v -0.2 +/- 1.0 m m Hg; P < .05 and -5.4 +/- 1.3 mm Hg v 2.3 +/- 1.2 mm Hg; P < .01, res pectively. While intravenous administration of Ro to the placebo group was associated with a rapid BP decrease, similar in magnitude to the peak effect of the oral dose on the first day, only an early transient effect was observed in the oral Ro group. Oral and intravenous admini strations of Ro were associated with a prolonged decrease in PRA and t ransient increase in IRR levels. In conclusion, Ro 42-5892 is an orall y effective antihypertensive compound which appears to produce its eff ects for 24 h. The maximal effect of this drug is probably achieved wi th the 600 mg oral dose.