Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.
1. Zabicipril, S9650, a new angiotensin converting enzyme inhibitor, was administered to salt-replete, normotensive males in single doses of up to 10 mg. 2. The safety, tolerance and dose-response relationship with regard to inhibition of plasma ACE activity were characterised initially in an open, pilot, dose-finding study in 12 subjects and further explored in a double-blind, parallel group, placebo controlled study in another 30 subjects. 3. The drug was generally well tolerated and produced no change in routine haematology or serum biochemistry tests. 4. Dose related (0.03 to 10 mg) inhibition of plasma converting-enzyme was observed, with 2.5 mg of zabicipril producing over 90% inhibition at 4 h and 60% at 24 h. 5. There were no significant changes in blood pressure or heart rate in normotensive subjects over the dose range studied. 6. A dose related rise in plasma renin activity and angiotensin I was observed. No dose related reduction in plasma aldosterone was observed. 7. These initial studies suggest that zabicipril is a well tolerated inhibitor of converting enzyme with near maximal inhibitory effect occurring at a dose of 2.5 mg. Further exploration of the dose range after single and multiple doses is indicated.
University Department of Medicine and Therapeutics, Stobhill General Hospital, Glasgow.
N J
NJ
MacDonald
D M
DM
Hughes
K R
KR
Lees
J L
JL
Reid
D000328:Adult; D000450:Aldosterone / Q000097:blood; D000803:Angiotensin I / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; C065499:zabicipril; D000450:Aldosterone; D000803:Angiotensin I; D012083:Renin