imidapril and Kidney-Failure--Chronic

Imidapril hydrochloride (imidapril) is a long-acting, non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, which has been used clinically in the treatment of hypertension, chronic congestive heart failure (CHF), acute myocardial infarction (AMI), and diabetic nephropathy. It has the unique advantage over other ACE inhibitors in causing a lower incidence of dry cough. After oral administration, imidapril is rapidly converted in the liver to its active metabolite imidaprilat. The plasma levels of imidaprilat gradually increase in proportion to the dose, and decline slowly. The time to reach the maximum plasma concentration (T(max)) is 2.0 h for imidapril and 9.3 h for imidaprilat. The elimination half-lives (t(1/2)) of imidapril and imidaprilat is 1.7 and 14.8 h, respectively. Imidapril and its metabolites are excreted chiefly in the urine. As an ACE inhibitor, imidaprilat is as potent as enalaprilat, an active metabolite of enalapril, and about twice as potent as captopril. In patients with hypertension, blood pressure was still decreased at 24 h after imidapril administration. The antihypertensive effect of imidapril was dose-dependent. The maximal reduction of blood pressure and plasma ACE was achieved with imidapril, 10 mg once daily, and the additional effect was not prominent with higher doses. When administered to patients with AMI, imidapril improved left ventricular ejection fraction and reduced plasma brain natriuretic peptide (BNP) levels. In patients with mild-to-moderate CHF [New York Heart Association (NYHA) functional class II-III], imidapril increased exercise time and physical working capacity and decreased plasma atrial natriuretic peptide (ANP) and BNP levels in a dose-related manner. In patients with diabetic nephropathy, imidapril decreased urinary albumin excretion. Interestingly, imidapril improved asymptomatic dysphagia in patients with a history of stroke. In the same patients it increased serum substance P levels, while the angiotensin II receptor antagonist losartan was ineffective. These studies indicate that imidapril is a versatile ACE inhibitor. In addition to its effectiveness in the treatment of hypertension, CHF, and AMI, imidapril has beneficial effects in the treatment of diabetic nephropathy and asymptomatic dysphagia. Good tissue penetration and inhibition of tissue ACE by imidapril contributes to its effectiveness in preventing cardiovascular complications of hypertension. The major advantages of imidapril are

Topics: Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Cardiomegaly; Cardiovascular Diseases; Clinical Trials as Topic; Deglutition Disorders; Heart Failure; Humans; Hypertension; Imidazoles; Imidazolidines; Kidney Failure, Chronic; Myocardial Ischemia

Left ventricular hypertrophy is considered to be a major cardiovascular risk factor in hemodialysis patients. Not only high blood pressure but also humoral factors such as angiotensin II and aldosterone are thought to contribute to the increase in left ventricular mass. We examined the effects of an angiotensin converting enzyme (ACE) inhibitor, imidapril, on left ventricular mass in patients with end-stage renal diseases on maintenance hemodialysis. Thirty patients on chronic hemodialysis were randomly divided into 2 groups of 15 patients each and given placebo or 2.5 mg imidapril once daily for 6 months. Before and after the 6-month period, left ventricular mass was evaluated by echocardiography, and circulating factors of the renin-angiotensin-aldosterone system were measured. Background characteristics such as age, gender ratio, causes of renal failure, duration of hemodialysis, body mass index and pre-dialysis blood pressure were comparable between the placebo and the imidapril groups. Systolic and diastolic blood pressures were not significantly changed in either group during the study period. In the imidapril group, serum ACE was reduced (12 +/- 1 to 5 +/- 2 U/l, p < 0.01) and plasma renin activity was increased (3.3 +/- 0.8 to 8.1 +/- 3.2 ng/ml/h, p < 0.01), but plasma angiotensin II and aldosterone were not significantly changed after 6 months (13 +/- 3 to 17 +/- 3 pg/ml and 365 +/- 125 to 312 +/- 132 pg/ml, respectively). On the other hand, left ventricular mass index was significantly decreased in the imidapril group (132 +/- 10 to 109 +/- 6 g/m2, p < 0.05) but was unchanged in the placebo group (129 +/- 6 to 126 +/- 5 g/m2). These results suggest that an ACE inhibitor reduces left ventricular mass in hemodialysis patients by a mechanism that is independent of changes in blood pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Body Weight; Echocardiography; Female; Humans; Hypertension, Renal; Hypertrophy, Left Ventricular; Imidazolidines; Kidney Failure, Chronic; Male; Middle Aged; Placebos; Renal Dialysis; Treatment Outcome

An open study on the single dose and steady-state pharmacokinetics of imidapril, a novel prodrug-type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite imidaprilat was conducted in eight patients with moderate chronic renal failure [mean creatinine clearance (CL(CR)) 64 ml x min(-1); range 42-77 ml x min(-1)], eight patients with severe chronic renal failure (mean CL(CR), 18 ml x min(-1); range 11-29 ml x min(-1)) and eight healthy volunteers with normal renal function. Subjects received an oral dose of 10 mg imidapril once per day for 7 days.. No statistical differences of either maximum concentration (Cmax) or the area under the curve (AUC) were found between patients with moderate renal failure and healthy subjects. However, Cmax and AUC for both imidapril and imidaprilat were significantly higher in patients with severe renal impairment than in healthy volunteers. There were no clinically relevant differences among the three subject groups with regard to total urinary excretion of both imidapril and imidaprilat.. The smallest imidapril dose which is clinically effective should be used in patients with severe renal insufficiency.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dose-Response Relationship, Drug; Humans; Imidazoles; Imidazolidines; Kidney Failure, Chronic; Middle Aged; Prodrugs