Clinical Pharmacodynamic Studies with Cilazapril and a Combination of Cilazapril and Propranolol

Aims To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects. Methods The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. Results In the multiple-dose study, peak plasma concentrations ( C max = 10-895 ng ml -1 ; t max = 0.5-2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14-19 h), attaining steady state in 3-4 days. In the single-dose study, C max (1-1009 ng ml -1 ) and AUC(0, t ) (0.4-1891 ng ml -1 h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, C max but not AUC(0, t ) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited ( > 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 ± 4.1 ( ± SD) ng 24 h -1 in the placebo group to 60.0 ± 18.2 ng 24 h -1 in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single-and multiple-dose studies. Conclusions Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing.

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects

Liao

Vesterqvist

Delaney

et al. 2003

“…All the ACE inhibitors showed a clear dose‐dependent blockade of blood pressure response to exogenous angiotensin I [ 2, 10–19]. Maximal or close to maximal inhibition was reached for all inhibitors at the highest tested dose levels, except for CGS 13928C and ramipril which induced maximal blockade at intermediate doses (5 mg for ramipril and 0.5 mg for CGS 13928C).…”

Section: Resultsmentioning

confidence: 99%

“…Similar results were obtained with continuous infusions of increasing angiotensin I doses [ 12, 20]. Cilazapril (4 mg), captopril (25 mg), and enalapril (10 mg) demonstrated a shift to the right of the dose–response curves with an apparent elimination half‐life of about 4 h for cilazapril and 2 h for captopril.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin‐angiotensin system

Csajka¹,

Buclin²,

Brunner

et al. 1999

“…A single blood pressure measurement was made during the final 2 min of each infusion using a Datascope Accutorr 2A monitor (Datascope, Montvak, NJ, USA). This methodology is based on that of Erb et al [40] and Essig et al [41].…”

Section: Study D: In Vivo Angiotensin Pressor Testingmentioning

confidence: 99%

Evaluation of two carrier protein–angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man

Downham

Auton

Rosul

et al. 2003

Aims We aim to modulate the renin-angiotensin system (RAS) by active immunization against angiotensin I hormone (AI), potentially providing a novel conjugate vaccine treatment for hypertension in man. Methods Immunization studies in rat and human subjects compare the effectiveness of tetanus toxoid (TT) and keyhole limpet haemocyanin (KLH) vaccines for immunotherapy following conjugation with an AI peptide analogue ( AI ). Cardiovascular responses were assessed in immunized rats and human subjects (two-dose trial only), following increasing i.v. infusions of either AI or angiotensin II hormone (AII). Results The AI -TT and AI -KLH conjugate vaccines induced an equivalent immune response, and inhibition of the pressor effects to exogenous AI in rats. Single-dose clinical trials with both conjugate vaccines only resulted in an immune response to the KLH carrier protein. A two-dose clinical trial of AI -KLH conjugate vaccine resulted in a significant immune response to AI . A shift in diastolic blood pressure (DBP) dose-response was demonstrated following challenge with AI and AII for the study volunteer showing the largest anti-AI IgG induction. Conclusion KLH was shown to be a suitable alternative to TT as a carrier protein for AI , thus supporting continued evaluation of our AI -KLH conjugate vaccine for treatment of hypertension in man.