Topic
Spiraprilat
About: Spiraprilat is a research topic. Over the lifetime, 11 publications have been published within this topic receiving 225 citations. The topic is also known as: SCH-33861.
Papers
TL;DR: Repeated ACE inhibitor treatment with once-daily spirapril leads to a partial escape of ACE inhibition, as reflected by a shorter duration of angiotensin II suppression, which affects the antihypertensive response in the second half of the dosing interval.
Abstract: Objective To investigate whether the compensatory rise in renin and plasma angiotensin I in response to repeated angiotensin converting enzyme (ACE) inhibitor treatment results in a partial escape of ACE inhibition over a 24-h dosing interval Design A single-blind placebo-controlled study in two parallel groups of eight hypertensive subjects receiving a once-daily dose of the ACE inhibitor, spirapril, of either 125 or 25 mg Detailed 24-h studies were performed at the end of 2 weeks of placebo, and after the first dose and 2 weeks administration of spirapril Methods Twenty-four-hour ambulatory blood pressure was measured invasively True' angiotensins I and II were measured by radioimmunoassay after high-performance liquid chromatography separation Results Both for the lower and higher doses of spirapril, the time-course of changes of spiraprilat, the active metabolite of spirapril, and ACE activity was similar but the maximal rise in angiotensin I was twofold higher after 2 weeks administration than after the first dose Angiotensin II after the first dose of spirapril fell rapidly, with lowest values 2 to 4 h after dosing At the end of dosing interval angiotensin II had returned to values seen under placebo with the 125-mg dose, but at the end of the 24-h period it was still suppressed with the 25-mg dose Compared with these first-dose responses the initial maximal degree of angiotensin II suppression after 2 weeks administration of either dose was similar, but during the subsequent hours the degree of angiotensin II suppression tended to be less with the lower and was significantly less with the higher dose of spirapril With the lower dose of spirapril responses of 24-h ambulatory blood pressure to the first dose and to 2 weeks of administration were almost superimposable, although blood pressures in the second half of the dosing interval tended to be higher during chronic treatment With the higher dose the response of nocturnal blood pressure after 2 weeks administration was diminished by 88 mmHg systolic and 68 mmHg diastolic Conclusions Repeated ACE inhibitor treatment with once-daily spirapril leads to a partial escape of ACE inhibition, as reflected by a shorter duration of angiotensin II suppression This escape also affects the antihypertensive response in the second half of the dosing interval
142 citations
TL;DR: From this work, spirapril was selected for clinical evaluation as an antihypertensive agent and in the conscious rats, orally, 5 and enalapril showed potent and sustained activity at doses of 0.1-1 mg/kg, respectively.
Abstract: The synthesis of spirapril (5), spiraprilat (25), their RSS stereoisomers, and their glycyl (18b) and lysyl (36, 37) analogues is described. These compounds were evaluated in vivo for inhibition of angiotensin converting enzyme (ACE), and selected compounds were evaluated for in vitro ACE inhibition (spirapril ID50 16 micrograms/kg; spiraprilat IC50 0.8 nM, ID50 8 micrograms/kg). In anesthetized rats, iv, esters 5 and 36 are more potent than enalapril, and diacids 25 and 37 are more potent than enalaprilat in vitro. In the conscious rats, orally, 5 and enalapril (2) showed potent and sustained activity at doses of 0.03-1 and 0.1-1 mg/kg, respectively. From this work, spirapril was selected for clinical evaluation as an antihypertensive agent.
41 citations
TL;DR: Data from small studies suggest that spirapril can be used without dosage adjustment in patients with renal impairment, as a consequence of its dual renal and hepatic clearance mechanisms, and is an effective antihypertensive agent which is well tolerated.
Abstract: Spirapril is a non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor prodrug which is converted to the active metabolite spiraprilat following oral administration, and which has been evaluated primarily for the treatment of hypertension. In dose-finding studies of patients with mild to severe hypertension, spirapril > or = 6 mg once daily produced reductions in blood pressure of approximately 10 to 18 mm Hg (systolic) and 7 to 13 mm Hg (diastolic) [24-hour postdose trough readings at the end of the treatment period]. Blood pressure normalisation (trough diastolic blood pressure < or = 90 mm Hg) had occurred in 29 to 50% of patients at the end of these investigations. The dose-response curve for spirapril appears to be flat for doses of 6 to 24 mg once daily. Comparisons with other ACE inhibitors are limited in number, and further studies are required before the relative antihypertensive efficacy of spirapril can be fully evaluated. However, in single, well controlled clinical trials, spirapril produced similar reductions in blood pressure to those seen with enalapril or captopril. When given as monotherapy or in combination with hydrochlorothiazide, spirapril may offer potential advantages over the calcium antagonist nitrendipine. Spirapril is generally well tolerated and produces an adverse event profile similar to that of other ACE inhibitors. Data from small studies suggest that spirapril can be used without dosage adjustment in patients with renal impairment, as a consequence of its dual renal and hepatic clearance mechanisms. This is in contrast to most ACE inhibitors, which are eliminated by a predominantly renal mechanism that results in accumulation of the active metabolite when renal function is impaired. However, the utility of spirapril in this patient group has yet to be fully determined because of conflicting data regarding its effects on renal function. Thus, spirapril is an effective antihypertensive agent which is well tolerated. Further comparative trials are needed to fully determine its efficacy with respect to other ACE inhibitors, and a better understanding of its effects on renal function will clarify its role in hypertensive patients with renal failure.
22 citations
TL;DR: The pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis, however, the bioavailability of spirAPrilat and hypotensive effect of Spirapril were reduced in patients.
Abstract: The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensinconverting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n=10), in patients with chronic, non-cirrhotic liver disease (n=8) and in a control group of healthy subjects (n=16). The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 μg·h·l−1, 923 μg·h·l−1 and 1300 μg·h·l−1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively. Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h−1 in patients vs. 2.00 h−1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.
11 citations
1 Jan 1994
TL;DR: Despite the evidence of a significant influence of renal impairment upon the disposition of spiraprilat, the lack of accumulation during the translation from single to multiple doses indicates that there is a considerable margin of safety for Spirapril in renal impairment.
Abstract: The pharmacokinetics of spirapril and its active diacid metabolite spiraprilat were characterized in four groups of patients categorized on the basis of their renal function. No statistically significant effects of renal impairment upon the disposition of spirapril were detected. In contrast, there were significant perturbations in the pharmacokinetics of spiraprilat: The maximum plasma concentration (Cmax) values in the severely renally impaired group were 2-3 times those in the group of patients with normal renal function whereas the corresponding area under the curve (AUC) values were 5-6 times higher. However, there was no evidence of accumulation of spiraprilat in any of the groups as determined by the pharmacokinetic parameters derived after single and multiple doses. Thus, despite the evidence of a significant influence of renal impairment upon the disposition of spiraprilat, the lack of accumulation during the translation from single to multiple doses indicates that there is a considerable margin of safety for spirapril in renal impairment.
8 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2011 | 1 |
| 1999 | 1 |
| 1997 | 1 |
| 1995 | 1 |
| 1994 | 3 |
| 1993 | 1 |