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This study was undertaken to evaluate a dosing time-dependent effect of temocapril, an angiotensin-converting enzyme (ACE) inhibitor, on the mortality of stroke-prone spontaneously hypertensive rats (SHRSP). Temocapril (1 mg/kg/day) prolonged the survival rate of these animals, with a maximum effect after dosing at the early resting period and a minimum effect after dosing at the early active period. The pharmacokinetics of temocaprilat, an active metabolite of temocapril, did not differ significantly between the two dosing times. However, the inhibition of ACE activity in serum and organs (brain and aorta) and the reduction of blood pressure were significantly greater after dosing at the early resting period than at the early active period. These data suggest that the effect of temocapril on the mortality of SHRSP depends on the time of dosing, with a maximum effect seen after dosing at the early resting period. Dosing time-dependent differences in the pharmacodynamics of temocapril might be involved in explaining this phenomenon.

Vasopeptidase inhibitors are a new class of cardiovascular drug that simultaneously inhibit both neutral endopeptidase and angiotensin-converting enzyme (ACE). They increase the availability of peptides that have vasodilatory and other vascular effects; they also inhibit production of angiotensin II. In animal models vasopeptidase inhibitors decrease blood pressure in low, medium, and high renin forms of hypertension, and they also appear to confer benefits in models of heart failure and ischaemic heart disease. Studies in human hypertension show that these agents are effective in decreasing blood pressure regardless of race or age. Experience with omapatrilat, the most clinically advanced of these drugs, has shown it to be more effective than currently available ACE inhibitors or other widely used antihypertensive agents. Studies with omapatrilat in congestive heart failure have shown beneficial effects on haemodynamics and symptoms. The vasopeptidase inhibitors appear to have safety profiles similar to ACE inhibitors, though the frequency of side-effects such as angio-oedema and cough remains to be established. Large trials with clinical endpoints, some already in progress, are needed to establish the place of this class of drug beside that of established therapies in conditions such as hypertension, heart failure, ischaemic heart disease, and nephropathy.

Objective: To evaluate the pharmacokinetic profiles of temocaprilat and its hypotensive effect after single and repeated dosings of temocapril in young and elderly hypertensive patients., Methods: An angiotensin-converting enzyme inhibitor, temocapril (2 mg), was given once daily for 8 days to nine young and ten elderly hypertensive patients. Pharmacokinetics of temocaprilat, an active metabolite, and its hypotensive effect were evaluated after the first and last doses., Results: The area under the plasma concentration-time curve (AUC) of temocaprilat after the first dose was significantly greater in the elderly than in the young. This parameter was elevated after the final dose in both groups. The AUC (eighth dose)/AUC (first dose) ratio in the elderly was similar to that in the young. Blood pressure (BP) tended to decrease in the young and significantly decreased in the elderly after the first dose. The hypotensive effect was not enhanced after the final dose in either group., Conclusion: These results suggest that although plasma temocaprilat concentration rises during repeated dosing, its BP-lowering effect is not enhanced in the elderly. Therefore, if a remarkable BP reduction is not detected at the initiation of treatment, the risk of hypotensive episode might be small during long-term therapy with temocapril in elderly hypertensive patients.

To investigate how the interruption of the renin-angiotensin system (RAS) and reduction of blood pressure (BP) affect the lesions of chronic focal and segmental glomerulosclerosis (FGS), we studied the effects of high and low doses of angiotensin-converting enzyme inhibitors (temocapril - TEM) a newly developed ACE inhibitor with biliary tract excretion, on the hypertensive model of FGS. A high dose of TEM significantly lowered BP and suppressed both intense proteinuria and glomerular extracapillary lesions including macrophage infiltration. On the other hand, although a low dose of TEM did not significantly lower BP throughout the experimental period, it prevented renal lesions almost in the same manner as high-dose TEM with suppression of c-myc gene expression in glomeruli. These findings suggest that in PAN-induced chronic FGS, the systemic BP elevation could not be the major factor for the progression of renal damage which TEM could prevent without significant lowering of BP.

Compared with other angiotensin-converting enzyme (ACE) inhibitors, the elimination of temocapril is less dependent on renal function. To investigate the metabolic and antihypertensive effects of temocapril in diabetic hypertensives, 30 patients with diabetes mellitus type 2 and mild to moderate hypertension [diastolic blood pressure (BP) 90-115 mm Hg] and without azotemia (plasma creatinine < 180 microM) were evaluated in a prospective randomized double-blind placebo-controlled study. After a 4-week placebo run-in, they received temocapril, 20 mg daily (n = 19), or placebo (n = 11) for 6 weeks. Insulin sensitivity index (SI), determined by the Minimal Model method of Bergman, serum lipoproteins, plasma renin activity, fibrinogen, and microalbuminuria were assessed at the end of the placebo run-in phase and the double-blind treatment phases. Temocapril but not placebo administration produced a significant decrease in supine BP (152/92+/-5/3 vs. 162/98+/-5/2 mm Hg; p < 0.01) and increase in plasma renin (p < 0.05). Variation of SI during temocapril treatment did not reach statistical significance (0.95+/-0.2 before vs. 1.44+/-0.4 x 10(-4)/min/mU/L after treatment). During administration of temocapril or placebo, no significant changes in fasting plasma glucose, insulin, and serum levels of total triglycerides, cholesterol, lipoprotein cholesterol fractions, or fibrinogen were observed. Microalbuminuria decreased significantly on temocapril treatment (49+/-10 vs. 79+/-17 mg/24 h; p < 0.01) but not on placebo. These findings demonstrate that in hypertensive patients with diabetes mellitus type 2, short-term treatment with temocapril is neutral to insulin sensitivity, lipoprotein metabolism, and fibrinogen, and significantly reduces microalbuminuria.

Aims: The aim of this study was to determine the potential impact of age on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat, in hypertensive patients., Methods: Male and female patients with mild to moderate essential hypertension (DBP 95-114 mmHg inclusive) were allocated to two age groups: young, < or = 40 years; elderly, > or = 69 years, (n = 18 per group). In Part I of the study, subjects took a single oral tablet dose of 20 mg temocapril hydrochloride following an overnight fast. In Part II they took seven once daily oral tablet doses of 20 mg temocapril hydrochloride. Pharmacokinetic profiles were determined after the single and the last dose. Trough plasma samples were taken before each dose in Part II. Urine was collected for 24 h following the single and the last dose., Results: Steady state was reached within 1 week in both groups. Statistically significant differences were detected in AUC and AUCss for temocaprilat as well as in CL(R) for temocapril and temocaprilat, respectively, after a single dose and at steady state. All other pharmacokinetic parameters for temocapril and temocaprilat did not show any significant difference., Conclusions: The pharmacokinetic differences detected in the elderly do not require a dose adjustment per se. Nonetheless, a lower starting dose may be appropriate as elderly hypertensive patients are usually considered to be at an increased risk of first dose hypotension at the onset of treatment with an ACE inhibitor.