enalaprilat-anhydrous and perindoprilat

There is little information on the processes affecting selective tissue ACE inhibition and the implications in human subjects. We compared intravenously administered ACE inhibitors, perindoprilat and enalaprilat, for myocardial drug uptake and effects on angiotensin and bradykinin peptides versus hemodynamic effects in 25 patients with stable angina and well-preserved left ventricular systolic function. Myocardial uptake was rapid and more efficient for perindoprilat than for enalaprilat (peak content at 26+/-3 and 30+/-4 seconds, 0.58+/-0.12% and 0.27+/-0.07% of the administered dose for perindoprilat and enalaprilat, respectively, P=0.04 for difference). Both drugs caused a decrease in angiotensin (Ang) II level, an increase in Ang I level, and reduction in Ang II/Ang I ratio in arterial and coronary sinus blood. Bradykinin (BK)-(1-9) and BK-(1-8) levels increased in arterial blood and BK-(1-8) levels increased in coronary sinus blood after drug administration. Perindoprilat and enalaprilat caused a small decrease in mean arterial pressure (-3+/-1%, P<0.05; and -4+/-1%, P<0.01, respectively) and LV+dP/dt (-5.8+/-1.7%, P<0.01 and -4.2+/-2.8%, P<0.05, respectively), whereas systemic vascular resistance index was unchanged. Despite relatively cardioselective uptake of perindoprilat, both drugs had similar effects on the cardiac metabolism of angiotensin and bradykinin and on cardiac function. Under resting conditions, both drugs exerted small negative inotropic effects.

Topics: Adult; Aged; Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Blood Pressure; Bradykinin; Electrocardiography; Enalaprilat; Female; Hemodynamics; Humans; Indoles; Injections, Intravenous; Kinetics; Male; Middle Aged; Myocardium

Comparison of the first dose responses to low dose constant rate infusions of diacid angiotensin converting enzyme (ACE) inhibitors.. Double blind, randomised, placebo controlled, parallel group prospective study.. General hospital inpatient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of ACE inhibitor treatment.. 36 unselected elderly (aged 60-87 years) patients with symptomatic but stable chronic cardiac failure (New York Heart Association grades II-IV). ACE inhibitor started under double blind conditions with blood pressure monitoring.. Patients were randomly allocated to receive intravenous placebo (saline), enalaprilat (1.5 mg over six hours) or perindoprilat (1 mg over six hours) by constant rate intravenous infusion (5 ml/hour). The protocol allowed for discontinuation of infusion if mean arterial blood pressure fell by 30% from the value before treatment.. Blood pressure and heart rate responses, drug concentration, plasma renin, and ACE activities.. The three groups had similar age, severity of heart failure, diuretic dose before treatment, plasma renin activity, and serum electrolyte state. All patients remained symptom free throughout the study. Infusions were only ended early with active treatment: 5/12 perindoprilat cases, (mean (SD) dose 0.88 (0.18) mg, and 5/12 enalaprilat cases (mean (SD) dose 1.2 (0.4) mg. Both active treatments lowered mean arterial pressure until discontinuation of infusion. Heart rate was not altered. Two patients (one perindoprilat, one enalaprilat) showed transient and symptom free renal impairment.. Slow intravenous infusion of diacid ACE inhibitors may allow safe initiation of treatment in patients with heart failure and with activated renin angiotensin systems. The similar effects of intravenous perindoprilat and enalaprilat on blood pressure contrast with previously reported differences when perindopril and enalapril were given orally.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalaprilat; Female; Heart Failure; Heart Rate; Humans; Indoles; Male; Middle Aged; Prospective Studies; Renin

Angiotensin-converting enzyme (ACE) inhibitors improve survival in heart failure and delay progression to clinical heart failure in patients with left ventricular dysfunction after myocardial infarction. Increasing numbers of older patients are being considered for such treatment. However, there are reports of excessive and prolonged decreases in blood pressure (BP) after the first dose of some ACE inhibitors. We have studied the hemodynamics, pharmacokinetics, and neurohumoral responses to the first dose of oral captopril 6.25 mg, enalapril 2.5 mg, perindopril 2.0 mg, intravenous enalaprilat 1.5 mg, and perindoprilat 1.0 mg, compared with oral or intravenous placebo in 6 parallel groups of 12 elderly patients each with moderate-to-severe (New York Heart Association classes II-IV) heart failure. Oral dosing with active drugs led to different temporal responses. After captopril, there was an early short-lived decrease in BP. Enalapril led to a later long-lasting decrease, but perindopril was not different from placebo. Intravenous enalaprilat and intravenous perindoprilat each lowered BP to a similar extent. The doses of drugs used appeared to be comparable because plasma ACE inhibition was similar following perindopril or enalapril and also comparing perindoprilat and enalaprilat. These studies indicate that oral ACE inhibitors have different profiles of acute BP changes after the first dose. The explanation is not clear, but could include physicochemical differences in the interaction between prodrug ester and diacid metabolites leading to differences in tissue distribution and local enzyme inhibition.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Double-Blind Method; Enalapril; Enalaprilat; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Perindopril; Prodrugs

Angiotensin-converting enzyme (ACE) inhibitors prevent the formation of angiotensin II in the circulation and a range of tissues. ACE inhibitors not only are effective, well-tolerated antihypertensive drugs but also improve symptoms and signs in patients with congestive cardiac failure. In addition, they improve long-term survival in these latter patients. Although ACE inhibitors are relatively free of side effects in patients with heart failure, hypotension after the first dose has been reported that may lead to symptomatic renal, cardiac, or cerebral hypoperfusion. Most reports have been uncontrolled and anecdotal. We report a double-blind placebo-controlled study in a parallel group of patients with cardiac failure (New York Heart Association classes II through IV). In total, 72 patients (6 groups of 12) were studied after either placebo, captopril, 6.25 mg, enalapril, 2.5, or perindopril, 2 mg orally, enalaprilat 1.5 mg, or perindoprilat, 1.0 mg intravenously. The blood pressure responses differed between the groups, with a short-lived early fall after captopril and a long-lasting fall after enalapril, whereas perindopril was no different from placebo. There was no significant difference between the two active intravenous regimens. Plasma ACE measurements suggested that the relative doses used were at least comparable. Further studies are in progress to investigate the mechanisms underlying the differential hemodynamic responses and also to explore the clinical relevance to safety and efficacy in the management of heart failure.

Topics: Acetylcholinesterase; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Double-Blind Method; Enalapril; Enalaprilat; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Perindopril

To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cardiac Output; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Enalaprilat; Heart Failure; Indoles; Norepinephrine; Peptide Fragments; Ventricular Function, Left

The conformation of perindoprilat, an antihypertensive drug, is studied in the solid state by X-ray analysis. The resolution of its structure reveals important analogies between its observed conformation and that of several ACE inhibitors of the same family. This comparison points out a constant relative orientation of the functional groups, regardless of the molecular environment. This angular constancy appears to us as not being accidental and is a good argument for the spatial design of the ACE binding site. Although ACE is a carboxydipeptidase, the binding site may not contain two but one unique hydrophobic pocket receiving the C-terminal end of the inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Binding Sites; Crystallography; Indoles; Molecular Conformation; Structure-Activity Relationship