A dose‐response study of HOE 498, a new non‐sulphydryl converting enzyme inhibitor, on blood pressure, pulse rate and the renin‐ angiotensin‐aldosterone system in normal man.

Abstract

1 The effect of different oral doses of HOE 498, a new non-sulphydryl containing converting enzyme inhibitor, was investigated in a double-blind, placebo-controlled study in normotensive volunteers. 2 Dose-related reductions in serum converting enzyme activity, plasma angiotensin II and aldosterone were seen, greater at 4 h than at 12 h after drug ingestion. Converse doserelated increases in blood angiotensin I and plasma active renin concentration occurred. 3 Falls of angiotensin II were as great with 20 mg as with 50 mg of HOE 498, although the effect was more prolonged with 50 mg. 4 The reductions in concentrations of plasma angiotensin II and serum converting enzyme activity and the increases in plasma renin concentration were correlated with the concentration of HOE 498 -diacid in plasma. 5 Dose-related falls in both supine and erect blood pressure were maximal 2-3.5 h after dosing. Pulse rate increased marginally but insignificantly in the supine; slightly and significantly in the upright position, concomitantly with the blood pressure reduction at all doses of active drug. 6 We conclude that effects of single doses of HOE 498 on the renin-angiotensin system are maximal within 4 h, but are still apparent after 24 h. Thus it is likely that once daily administration will be adequate for treatment of high blood pressure in patients.

Determinants of angiotensin II generation during converting enzyme inhibition.

“…The high-performance liquid chromatography separation used for the Ang II measurements excludes angiotensin fragments that would cross-react with the assay antiserum. The results obtained with this very accurate method nevertheless confirm previous observations made with enalapril, lisinopril, 20 and ramipril 21 where only immunoreactive Ang II was quantitated. The time course of plasma and urinary aldosterone was similar to that of plasma Ang II.…”

“…Clearly, Ang II is the pivotal parameter in the closed loop, and the system works to compensate any interference by adjusting renin secretion to restore as rapidly and completely as possible normal Ang II levels. Although they did not perform such calculations, Manhem et al 21 observed that the administration to normal volunteers of ramipril at doses varying from 5 to 50 mg did not influence plasma Ang II 24 hours after drug intake, whereas a dose-dependent rise in plasma renin and Ang I was described. A dose-dependent increase in Ang I levels and plasma active renin was also found during a 10-day administration of trandolapril to normal volunteers: on day 10, plasma immunoreactive Ang II was equally reduced over the 16-fold dose range of drug.…”

Frusemide, ACE inhibition, renal dopamine and prostaglandins: acute interactions in normal man.

“…data (Bussien et al, 1985;Witte et al, 1984;Manhem et al, 1985) and confirm that ACE was significantly inhibited.…”

Clinical Pharmacokinetics of Ramipril

“…The parent drug, ramipril, which is a dicarboxylic acid monoethyl ester, must be converted in the liver to its active metabolite, ramiprilat. The extent of ramipril absorption and hydrolysis to ramiprilat appears to be similar over the dose range 5 to 50mg as the maximal plasma concentration (Cmax) of ramiprilat was linearly related to the dose of ramipril over this range (Manhem et al 1985).…”