enalapril and spirapril

The evidence from recent clinical outcome trials in arterial hypertension (AH) and the treatment guidelines from national and international authorities have placed a clear emphasis on "tight" blood pressure (BP) control. This has been particularly well illustrated in the treatment of patients with diabetes mellitus and AH where "tight" BP control clearly improves the outcome with reduced numbers of fatal and non-fatal cardiovascular events. Whilst the clinical trials in AH have identified benefits through BP reduction with a range of antihypertensive drugs there is a considerable volume of evidence to suggest that the optimal treatment for diabetic nephropathy and microalbuminuria should be based upon ACE inhibition. It is widely held that inhibition of intra-renal renin angiotensin systems leads to greater benefit than can be achieved by hemodynamic changes alone. Thus, management of AH and nephropathy in both DM and other forms of renal disease revolves around BP reduction through an ACE inhibitor-based treatment regimen. Where there is renal failure it may be prudent to administer a drug such as spirapril which has non-renal elimination mechanisms and which has been shown to have no accumulation problems or increased adverse effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetic Nephropathies; Enalapril; Humans; Hypertension; Kidney Failure, Chronic; Prognosis; Renal Circulation

Spirapril is a new angiotensin-converting enzyme (ACE) inhibitor. It is a prodrug with a resorption of about 50%. The active metabolite spiraprilat reaches maximal plasma concentration within 2-3 h after oral administration. Spirapril can be administered once daily because of its long duration of action caused by an elimination half-life of about 40 h. It undergoes renal and hepatic elimination. In contrast to other ACE inhibitors it has a narrow dose range; therefore, the recommended dose is 6 mg for most patients without the need for dose titration. Spirapril has no relevant drug interactions. In several studies, spirapril was given to patients with mild-to-moderate essential hypertension at doses of 1-24 mg/day. There was an identical blood pressure lowering effect at doses of 6-24 mg/day; doses of 1-3 mg/day were less effective. Twenty-four-hour blood pressure monitoring showed a trough:peak ratio up to 0.84. In studies comparing the effect of spirapril with enalapril, lisinopril, trandolapril or captopril, spirapril was at least as effective as the other substances. Besides treating uncomplicated mild-to-moderate essential hypertension, spirapril can be used in patients with diseases accompanying hypertension such as heart and renal diseases, diabetes mellitus, and lipid disturbances. Possible advantages of spirapril compared to other ACE inhibitors are the dual mechanism of elimination, the lack of need for dose titration and a low incidence of cough.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Drug Interactions; Enalapril; Humans; Hypertension; Prodrugs

The management of hypertension and nephropathy, in both diabetes and other forms of renal disease, is usually based on blood pressure reduction through an angiotensin-converting enzyme (ACE) inhibitor-based treatment regimen. With particular respect to the choice of ACE inhibitor drug, there are no definitive direct comparisons in the treatment of renal disease. In terms of blood pressure reduction, however, there is evidence that spirapril is at least as effective as the reference ACE inhibitor, enalapril. However, patients with diabetic nephropathy and/or chronic renal failure are at potential risk from drug accumulation if the preferred agent relies predominantly on glomerular filtration for its elimination. In this respect spirapril may have an advantage because it has been shown that there are no clinically relevant increases in the spirapril(at) concentrations (24 h post-dose) even in the setting of advanced renal failure (creatinine clearance <20 ml/min). Thus, there is no requirement to modify the dose and no concerns about drug accumulation or the potential for exaggerated therapeutic or adverse effects. In summary, an ACE inhibitor drug is seen as an integral component of the drug treatment regimen for patients with nephropathy. Where there is renal failure it may be prudent to administer a drug, such as spirapril, which also has alternative elimination mechanisms.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Clinical Trials as Topic; Diabetic Nephropathies; Enalapril; Humans; Kidney Failure, Chronic

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Clinical Trials as Topic; Enalapril; Humans; Hypertension

Left ventricular hypertrophy (LVH) is a recognized complication of, rather than a physiological response to, hypertension, being a powerful independent indicator of cardiovascular disease risk. In addition, it is reasonable to assume that the reversal of LVH is a desirable therapeutic goal in the treatment of hypertension. Furthermore, the renin-angiotensin system plays an important role in LVH and, in particular, in the development of cardiac interstitial fibrosis. Therefore, the effect of angiotensin-converting enzyme (ACE) inhibition on LVH is of particular interest. In both experimental and human studies, ACE inhibitors appear to perform better than other antihypertensive agents in reversing cardiac structural changes. A recent meta-analysis showed ACE inhibitors to be more efficacious than other first-line antihypertensives in reducing left ventricular mass. A controlled long-term study of previously untreated men showed that enalapril reversed LVH significantly better than did hydrochlorothiazide and that the regression of LVH was independently related to blockade of the renin-angiotensin system. Indeed, there have been studies showing that ACE inhibitors can affect LVH without lowering blood pressure. Moreover, ACE inhibitors have shown cardioprotective and cardioreparative properties in experimental models of hypertensive LVH. In conclusion, ACE inhibitors are effective in reversing LVH as well as interstitial fibrosis. The prognostic implications of this remain to be seen. So far, the experience with spirapril on LVH is limited, but the accumulated data are promising.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Humans; Hypertension; Hypertrophy, Left Ventricular

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Heart Failure; Humans; Hypertension; Survival Rate

To study effects of two hypotensive drugs--normodipin and spirapril--on intravascular activity of platelets in patients with metabolic syndrome (MS).. Normodipin was given to 25 patients with MS for 3 months, spirapril--to 20 patients for 3 months. The effect was evaluated by changes in lipid peroxidation in plasm and platelets, antioxidant defense of liquid blood and platelets, intravascular activity of platelets.. Administration of normodipin in MS patients had a positive effect on lipid peroxidation and normalized intravascular activity of platelets. Such pronounced positive effects on lipid peroxidation of plasm and platelets as well as on intravascular activity of the latter were not registered after use of spirapril.. Optimization of platelet function in MS patients can be achieved with long-term normodipin treatment.

Topics: Adult; Amlodipine; Antihypertensive Agents; Blood Platelets; Blood Pressure; Enalapril; Female; Humans; Lipid Peroxidation; Male; Metabolic Syndrome; Middle Aged; Platelet Activation; Venous Thrombosis

Patients (n=62) with mild and moderate arterial hypertension were examined with the help of echocardiography and Doppler echocardiography. For 12 weeks these patients received 6 mg/day of spirapril. Under influence of this therapy severity of left ventricular hypertrophy diminished, and quantity of pathological types of cardiac remodeling decreased.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Echocardiography, Doppler; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Severity of Illness Index; Ventricular Remodeling

Achievement of long-term effective control of blood pressure (BP) in patients suffering from arterial hypertension by means of elaboration of stage by stage program of antihypertensive therapy and proof of its advantage over prescription of hypotensive drugs in real clinical practice.. Effect of spirapril on parameters of vasomotor function of the endothelium were assessed. In randomized comparative prospective study with 1 year duration we included patients with mild and moderate arterial hypertension. The study group received stepwise antihypertensive therapy based on angiotensin converting enzyme inhibitor spirapril. Comparison group continued to take hypotensive drugs prescribed in conditions of outpatients clinic.. Sixty patients (79.6% women) were included in the study (30--in the study group, 30--in comparison group). Lowering of BP was observed in the process of therapy in both groups. Among patients of spirapril group lowering of BP was more pronounced and occurred more quickly with achievement of target level of systolic BP <140 mm Hg and diastolic BP <80 1 month after beginning of treatment. Under the influence of therapy with spirapril for 6 months improvement of function of the endothelium was noted.. In the process of stepwise therapy with the use of spirapril effective long-term control of BP is more quickly achieved compared with standard treatment of arterial hypertension, and improvement of vasomotor function of endothelium also occurs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Severity of Illness Index; Time Factors

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

Achievement of target blood pressure (BP) levels in subjects with metabolic syndrome (MS) by the method of stepwise antihypertensive therapy and assessment of metabolic effects of combination of spirapril and nifedipine retard.. Patients (n=20, 12 women, 8 men, mean age 54+/-3 years) with MS were first given spirapril (6 mg/day). Nifedipine retard (40 mg/day) was added if target BP was not achieved after 4 weeks. Study duration was 12 weeks. The following parameters were measured at baseline and at study end: heart rate, blood pressure, body mass, waist circumference, parameters of lipid spectrum, content of insulin including index HOMA IR, blood glucose (fasting and during oral glucose tolerance test).. Target BP levels were achieved in 18 patients (90%)--in 11 with moexipril monotherapy, in 9--after addition of nifedipine. Lowering of systolic and diastolic BP from baseline was 11 and 14%, respectively. After 3 months of combination antihypertensive therapy triglyceride levels decreased by 28% while high density lipoprotein cholesterol (CH) increased 6%. Total, low density lipoprotein CH and coefficient of atherogenecity did not change as well as fasting blood glucose after fast and oral glucose tolerance test. Concentration of fasting immunoreactive insulin significantly decreased by 34% entailing 35% decrease of insulin resistance. Therapy was well tolerated, side effects were transitory and did not cause withdrawal of treatment.. In patients with MS and mild hypertension monotherapy with spirapril and combination of spirapril with nifedipine retard caused lowering of BP to target level in 55 and 90%, respectively. Combination of spirapril and nifedipine retard exerts positive metabolic action.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cholesterol, LDL; Drug Therapy, Combination; Enalapril; Female; Glucose Intolerance; Humans; Hypertension; Male; Metabolic Syndrome; Middle Aged; Nifedipine; Severity of Illness Index

The potential influence of concomitantly administered hydrochlorothiazide (CAS 58-93-5) on the pharmacokinetics of spirapril (CAS 94841-17-5)/spiraprilat (CAS 83602-05-5) and of concomitantly administered spirapril on the pharmacokinetics of hydrochlorothiazide was investigated in an open, randomised, 3-way crossover study in 12 healthy male subjects. The test drug was a newly developed bi-layer tablet containing a fixed combination of spirapril hydrochloride monohydrate and hydrochlorothiazide (Quadroplus). The reference formulations were tablets containing solely spirapril hydrochloride monohydrate (Quadropril) or hydrochlorothiazide (produced exclusively for study medication). For spirapril, spiraprilat and hydrochlorothiazide the 90% confidence intervals of the AUC(0-infinity) as a measure for the extent of absorption were entirely included within the equivalence range of 0.8 to 1.25 and the 90% confidence intervals of the Cmax as a measure for the rate of absorption were entirely included within the extended equivalence range of 0.7 to 1.43. Therefore, bioequivalence was concluded for the test and reference formulations. The results suggest that hydrochlorothiazide does not interact in the fixed combination with the pharmacokinetics of spirapril and vice versa.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Biological Availability; Diuretics; Drug Combinations; Drug Interactions; Enalapril; Half-Life; Humans; Hydrochlorothiazide; Male; Single-Blind Method; Sodium Chloride Symporter Inhibitors; Tablets

In this open multicentre study, the effect of the ACE-inhibitor spirapril on office blood pressure and 24-hour blood pressure regulation was investigated. A total of 845 general practices recruited 2,491 patients to the 12-week study. Included were patients with newly diagnosed hypertension receiving spirapril alone, and patients who had already been taking antihypertensive agents and who were changed over to monotherapy with spirapril. Also included was a group of patients receiving spirapril in addition to other antihypertensives. Data were collected separately both from the group as a whole and also from a subgroup of patients receiving spirapril (6 mg/day) for whom 24-hour blood pressure records were available at the start and termination of the study (n=606).. The 24-hour blood pressure measurements showed a decrease of the mean diurnal systolic blood pressure from 150.9 mmHg to 134.7 mmHg, and of the mean nocturnal blood pressure from 138.1 mmHg to 123.2 mmHg. The corresponding mean diurnal diastolic blood pressure decreased from 88.8 mmHgto 81.4 mmHg, and the mean nocturnal pressure from 79.6 mmHg to 72.2 mmHg. The toterability of spirapril proved to be very good with a side effect rate of 1.3 %. No serious adverse reactions were observed.. The results show that in general practice use spirapril effectively lowers blood pressure, and is very well tolerated. The blood pressure decrease is maintained over the entire 24 hours and is still clearly evident towards the end of the period, that is, in the critical early morning hours.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Echocardiography; Enalapril; Humans; Hypertension; Hypertrophy, Left Ventricular; Middle Aged; Time Factors

This study was designed to examine changes of hemorheological parameters in essential arterial hypertension subjects following antihypertensive drug therapy. Eighty two female subjects were enrolled, and sub-divided into two groups based upon their high shear whole blood viscosity being lower (L) or higher (H) than normal controls. Equal numbers of L and H subjects were then treated for four weeks with one of four agents: angiotensin-converting enzyme inhibitor (ACE-inhibitor, Spirapril - 6 mg/day); calcium antagonist (Isradipin - 5 mg/day); beta-1-blocker (Talinolol - 100 mg/day); diuretic (Indapamide - 1.5 mg/day). Both prior to and following drug treatment for six weeks, hemorheological measurements included plasma viscosity; high and low shear whole blood viscosity, hematocrit, fibrinogen and RBC aggregation. Treatment with each of the four drugs significantly (p<0.05) reduced blood pressure in both the L and H groups. However, the hemorheological effects of antihypertensive drug therapy differed markedly between groups: plasma and whole blood viscosity were significantly elevated in the L groups whereas these parameters were significantly decreased in the H groups. Fibrinogen levels and RBC aggregation decreased in both groups, whereas hematocrit was unaffected. These results thus suggest that the rheologic effects of antihypertensive drug therapy depend strongly on the initial, pre-treatment status of the subject, and that for some subjects, such therapy can result in adverse hemorheological alterations.

Topics: Antihypertensive Agents; Blood Pressure; Blood Viscosity; Enalapril; Erythrocytes; Female; Fibrinogen; Hematocrit; Hemorheology; Humans; Hypertension; Indapamide; Isradipine; Propanolamines

Treatment of hypertension in patients with chronic renal failure has been shown to postpone the decline in renal function. Treatment with an ACE inhibitor has been shown to be superior to conventional antihypertensive treatment, but it is not known how an ACE inhibitor compares to treatment with a calcium channel blocker or to treatment with a combination of these drugs. The aim of the study was to evaluate the rate of decline in GFR in patients with chronic renal failure and hypertension treated with isradipine and spirapril as monotherapy and in combination.. Sixty patients with chronic renal failure and hypertension were enrolled in the study. After enrollment, patients were followed prospectively for 6 months in the outpatient clinic on their usual antihypertensive medication, and then randomized to a double-blinded comparison of either spirapril 6 mg daily, isradipine 5 mg daily or spirapril 3 mg and isradipine 2.5 mg daily. After randomization, patients were followed for 21 months or until the need for dialysis. Every 3 months before and 3.5 months after randomization the glomerular filtration rate was measured by 51Cr-EDTA clearance and the effective renal plasma flow evaluated using the renal clearance of paraaminohippuric acid.. Blood pressure and the decline in glomerular filtration rate did not differ between the groups before randomization. After randomization, the mean decline in the glomerular filtration rate was -0.32 ml/(min x month x 1.73 m2) in the spirapril group, -0.58 ml/(min x month x 1.73 m2) in the isradipine group and -0.14 ml/(min x month x 1.73 m2) in the combination group (p = 0.38). Twelve patients, 4 in each group, reached end-stage renal failure. No significant difference was found with respect to diastolic (p = 0.10) or systolic blood pressure (p = 0.08) during the treatment period, but a trend towards a better blood pressure control in the combination group was present. During treatment, the rate of decline in renal plasma flow did not differ significantly between the groups (p = 0.09), neither did the changes in filtration fraction (FF) (p = 0.58) nor the mean FF (p = 0.22) during the treatment.. Our study indicated differences between the 3 treatment modalities in favor of combined therapy with respect to both the rate of decline in GFR and blood pressure control, but the differences where insignificant. Thus, the treatments might differ, but we were unable to confirm this because of large variation in GFR and small sample size.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Isradipine; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Plasma Flow, Effective

The purpose of this double-blind, randomised trial with a 4-week placebo run-in period followed by an active treatment period using either spirapril 3 mg or 6 mg once a day was to clarify the existence of hypotensive episodes in elderly hypertensive patients treated by an ACE-inhibitor. Forty hypertensive patients aged 60-76 years underwent 24-h ABPM at the end of the run-in (week 4) and active treatment (week 9) periods. The mean 24-h systolic blood pressure (SBP) decreased from 161.9 (26.7) mm Hg to 150.6 (29.9) mm Hg (P < 0.001) and diastolic blood pressure (DBP) from 91.70 (14.7) mm Hg to 84.2 (17.3) mm Hg (P < 0.001). No episodes of mean arterial pressure (MAP) <50 mm Hg were seen during the placebo period. Instead 11 episodes were observed during the antihypertensive treatment (one in the 3 mg group and 10 in the 6 mg group, P < 0.01 between the two treatment groups). Fifty-four episodes of MAP <70 mm Hg were observed during the placebo period and 117 during the treatment period (P < 0.001). During the placebo period low MAPs were observed only during night time. During the treatment period they were seen also from 11 am to 4 pm. In conclusion, ACE-inhibitor therapy with spirapril significantly increased hypotensive episodes in elderly hypertensive patients which may worsen their cerebral and myocardial circulation.

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure Monitoring, Ambulatory; Chi-Square Distribution; Circadian Rhythm; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Hypotension; Male; Middle Aged; Prevalence; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Outcome

To examine effectiveness and safety of quadropril.. Changes in blood pressure (BP), heart rate (HR), levels of glucose, potassium and creatinine, creatinine clearance were studied in 120 patients (48 males and 72 females, mean age 60.6 +/- 0.7 years) with mild to moderate arterial hypertension (AH) with average duration 13.8 +/- 0.7 years. The patients were divided into 3 groups: with AH (n = 40), AH + noninsulindependent diabetes mellitus (DM) (n = 43), AH and nephropathy (n = 37). 8-week treatment was performed with a standard dose of 6 mg/day (1 tablet of quadropril). Control examinations were made 2, 4 and 8 weeks after the treatment.. After 8 weeks of treatment a decrease in systolic blood pressure in AH group was 24.0 +/- 3.0 mm Hg and in diastolic blood pressure 16.3 +/- 1.3 mm Hg (P < 0.001). In the group with DM this decrease was 22.4 +/- 2.8 mm Hg and 15.7 +/- 1.4 mm Hg (p < 0.001), respectively. In the group with nephropathy this decrease was 26.4 +/- 2.4 and 16.5 +/- 1.3 mm Hg (p < 0.001), respectively. Heart rate changed significantly only in diabetics: from 75.1 +/- 1.7 to 72.9 +/- 1.3 beats/min. Biochemical parameters in the hypertensive and diabetic patients did not change significantly. In the nephropathy group there was a significant decrease in creatinine and increase in creatinine clearance. Their level of glucose and potassium changed insignificantly.. The treatment with quadropril results in a significant decrease in blood pressure, does not influence parameters of carbohydrate metabolism, improves nitrogen eliminating function of the kidneys.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Creatinine; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Safety; Treatment Outcome

To compare in the non-blind randomised parallel study the efficiency of quadropril and amlodipine in the treatment of mild to moderate arterial hypertension.. A total of 80 patients (57.6 +/- 1.0 years) were included in this study. The patients were randomised in two groups, 40 patients each. Patients of group 1 received monotherapy with quadropril, while those of group 2 were treated with amlodipine. The treatment duration was 8 weeks in both groups. Quadropril was given in a fixed dose of 6 mg once daily. The initial dose of amlodipine was 5 mg/day. In case of insufficient effect the dose was elevated to 10 mg/day. The efficacy was evaluated by changes in blood pressure (BP) measured at rest. Moreover, in 50 randomly chosen patients 24-h monitoring of BP was performed at the start and end of the treatment.. In the quadropril group baseline systolic BP reached 158.6 +/- 2.1 mm Hg, diastolic BP--101.8 +/- 0.8 mm Hg, heart rate was 74.3 +/- 1.6 beats/min. In the amlodipine group baseline systolic BP was 159.9 +/- 2.4 mm Hg, diastolic BP--101.8 +/- 1.0 mm Hg, heart rate was 71.3 +/- 1.0 beats/min. Systolic BP decreased at the end of quadropril therapy to 138.5 +/- 2.2 mm Hg, diastolic BP to 88.1 +/- 1.4 mm Hg. No significant change of the heart rate was observed. Under 5 mg of amlodipine systolic BP decreased to 137.9 +/- 2.5 mm Hg and diastolic BP to 87.1 +/- 1.6 mm Hg. Heart rate increased to 73.3 +/- 2.2 beats/min. Under therapy with 10 mg amlodipine systolic BP decreased to 145.9 +/- 3.8 mm Hg, diastolic BP to 89.7 +/- 3.4 mm Hg. Heart rate increased to 77.3 +/- 4.0 beats/min (p < 0.01). The hypotensive effect of quadropril remained stable while the effect of amlodipine decreased by the 8th week of therapy (p < 0.01). Side effects were observed significantly more often in the amlodipine group, then in the quadropril group. The main quadropril side effect was cough. Side effects observed in the amlodipine group were edemas, tachycardia, weakness.. Both quadropril and amlodipine demonstrated a comparable antihypertensive effect although in 11 of 40 patients in the amlodipine group a dose increase was necessary and tolerability of quadropril was better.

Topics: Administration, Oral; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Prognosis; Safety; Severity of Illness Index

To examine efficacy and tolerability of a single daily dose of 6 mg quadropril (spirapril).. An open multicenter study enrolled 5000 out-door patients with hypertension. All the patients received an ACE inhibitor quadropril for 3 months with four control visits (on week 0, 4, 8 and 12).. Quadropril caused a marked decrease in systolic and diastolic blood pressure. At the end of the study 89.4% of patients had a systolic blood pressure reduction of at least 15 mm Hg and 85.4% had a diastolic blood pressure reduction of at least 10 mm Hg. There were no clinically significant heart rate changes. The overall tolerability of the drug was estimated as good or very good in 95.3% of patients. Only 2.9% of patients had side effects during treatment with once daily dose of 6 mg quadropril. No serious side effects were observed.. 6 mg daily dose of quadropril is an effective and safe therapy for arterial hypertension.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Drug Therapy, Combination; Enalapril; Germany; Humans; Hypertension; Product Surveillance, Postmarketing; Treatment Outcome

In the present study we investigated the effect of a single dose, and 3 months of treatment with spirapril on kidney function, renin-angiotensin system, renal handling of sodium and blood pressure, in patients with reduced kidney function (serum creatinine 1.5-3 mg%) and hypertension. A single dose of 6 mg spirapril given at the beginning of the study did not affect glomerular filtration rate (GFR), renal plasma flow (RPF), angiotensin converting enzyme (ACE) activity, plasma renin activity (PRA) or renal handling of sodium. When the single dose of spirapril was given after 3 months of treatment with this agent, renal hemodynamics and PRA did not change. ACE activity, which was depressed by the previous spirapril treatment, decreased further (from 9.5 +/- 3.1 to 1.4 +/- 1.0 nmol/ml/min), (p < 0.05). Administration of 6 mg spirapril o.d. for 3 months did not have any effect on GFR or RPF. Serum ACE activity decreased from 92.1 +/- 8.0 to 5.1 +/- 2.6 nmol/ml/min (p < 0.05) and PRA increased from 1.4 +/- 1.2 to 4.1 +/- 3.6 ng/ml/min (p < 0.05). Plasma aldosterone did not change. Similar results were obtained when spirapril was combined with 5 mg isradipine in the initial and final single dose, or in the 3 months' treatment (5 mg o.d.). Blood pressure was normalized in 38% of the patients who received spirapril and in 71% of the patients who received spirapril and isradipine. Thus, (a) treatment with spirapril in patients with mild to moderate chronic renal insufficiency was not associated with deleterious effects on kidney function; (b) spirapril in a dose of 6 mg alone or in combination with 5 mg isradipine is effective in reducing blood pressure in hypertensive patients with reduced kidney function.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isradipine; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Time Factors

To study the effect of antihypertensive medications on autonomic nervous system in patients with hypertension and sleep apnea syndrome using frequency domain measures of heart rate and blood pressure variabilities.. The beta-receptor blocking agent atenolol (50 mg), the calcium antagonist isradipine SRO (2.5 mg), the diuretic hydrochlorothiazide (25 mg) and the ACE inhibitor spirapril (6 mg) once daily were given in a double-blind crossover schedule for 8 weeks. Cardiovascular autonomic control was assessed using frequency domain measures of heart rate variability during the spontaneous and controlled breathing tests. During orthostatic maneuver and cold pressor test the blood pressure variability analysis also was performed.. In general, the responses of heart rate and blood pressure variabilities were abnormal in the patients with arterial hypertension and sleep apnea syndrome compared to reference data. Of the four drugs, only atenolol effected heart rate and blood pressure variabilities as it shifted the autonomic regulation to the vagal direction. Other antihypertensive drugs did not change any parameter of heart rate or blood pressure variabilities.. The short-term treatment with atenolol in patients with arterial hypertension and sleep apnea syndrome is associated with normalization of autonomic nervous control judged by heart rate and blood pressure variability. Thus, beta-receptor blockade may have adjunctive beneficial effects beyond blood pressure reduction in these patients. However, the long-term effects of blood pressure reduction on autonomic nervous control remain to be studied.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Autonomic Nervous System; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Diuretics; Double-Blind Method; Enalapril; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Isradipine; Male; Middle Aged; Sleep Apnea Syndromes; Sodium Chloride Symporter Inhibitors

The antihypertensive effects of four different antihypertensive medications (beta-blocking agent, atenolol 50 mg; calcium-antagonist, isradipine SRO [slow release] 2.5 mg; diuretic, hydrochlorothiazide [HCTZ] 25 mg; and angiotension converting enzyme-inhibitor, spirapril 6 mg) on obese patients with sleep disordered breathing and hypertension were compared by the ambulatory blood pressure measurement (ABPM). Eighteen patients were randomized in a double-blind, crossover fashion to receive each of the four different medications for 8 weeks. ABPM was performed at baseline and after an 8-week treatment with these medications. A 2- to 3-week washout period occurred both at baseline and between each of the four medications. Three patients were omitted from statistical analysis because of technical problems of ABPM. Atenolol, isradipine SRO, and spirapril decreased significantly (P < .01) the mean 24-h systolic blood pressure, whereas HCTZ did not. The mean 24-h diastolic blood pressure decreased significantly after all four medications: 12 (SD+/-14) mm Hg with atenolol, 7 (SD+/-10) mm Hg with isradipine SRO, 3 mm Hg (SD+/-14) with HCTZ, and 6 (SD+/-15) mm Hg with spirapril (P < .01). During nighttime none of the medications reduced the mean diastolic or systolic blood pressure significantly. According to the 24-h blood pressure curve the influence of these four medications during the whole measurement period was not similar. Atenolol and spirapril lost their antihypertensive effect during the early morning hours. The antihypertensive effect of HCTZ varied markedly from hour to hour. The trough-to-peak ratio of no medication was >0.50. Negative correlation was observed between the apnea time and the mean systolic 24-h (r = -0.604, P = NS) and the mean systolic nocturnal blood pressure change (r = -0.590, P = NS). Our study revealed that the daytime high blood pressure was quite easily controlled by the ordinary monotherapy in these patients with partial upper airway obstruction and hypertension. Instead none of the medications used decreased nocturnal high blood pressure markedly.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Diuretics; Double-Blind Method; Enalapril; Humans; Hydrochlorothiazide; Hypertension; Isradipine; Middle Aged; Sleep Apnea Syndromes; Sodium Chloride Symporter Inhibitors; Treatment Failure

This study was designed to evaluate in 45 hypertensive patients with left ventricular hypertrophy (LVH) the effects of a 6-month course with one of three different antihypertensive regimens (the calcium channel blocker isradipine, the angiotensin converting enzyme inhibitor spirapril in monotherapy, or a combination of the two drugs, n = 15 per group) on blood pressure, LVH regression, and various functional correlates of LVH. All three treatment modalities decreased significantly LV mass index by an average of 10%, although the combination had the greatest blood pressure-lowering effect and spirapril had the least, as assessed by office resting pressures, ambulatory monitoring, and isometric grip testing. There was no correlation between magnitude of blood pressure lowering and degree of LVH regression. The effects of treatment on pressor hormone profiles differed among groups, as spirapril tended to suppress angiotensin II and norepinephrine, whereas isradipine had opposite effects. Exercise tolerance was prolonged by all three regimens, but significantly more by the combination. All three regimens decreased significantly the double product by 10% to 15%. Indices of electrophysiologic stability calculated from analysis of ambulatory electrocardiogram exhibited significant improvement in several parameters such as QRS duration, presence of late potentials, and measures of heart rate variability, resulting in fewer episodes of simple or complex ventricular arrhythmia. We conclude that all three regimens produce significant LVH regression associated with improved functional capacity and electrical stability. These results reflect the sum of the differential hemodynamic and hormonal effects exerted by each treatment modality.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Isradipine; Male

In this cross-over, double-blind study, 12 essential hypertensive patients (stage I, II, and III) with glomerular filtration rate (GFR) between 50 to 80 mL/min/1.73 m2, were submitted to 4 weeks of placebo followed by 12 weeks with isradipine SRO (IS) 5 mg, spirapril (SP) 6 mg, and isradipine plus spirapril (IS + SP). The study evaluated the effects of these drugs on GFR ((99m)Tc DTPA), effective renal plasma flow (ERPF) ((131)I-orthoiodohippurate), urinary sodium excretion (UNaV), urinary kallikrein excretion (UKal), urinary albumin excretion (UAE), and plasma renin activity (PRA). The three protocols significantly reduced mean blood pressure (128 v 107 mm Hg; 126 v 112 mm Hg; 129 v 104 mm Hg with IS, SP and IS + SP, respectively). ERPF and GFR did not change. UNaV increased significantly after IS (0.17 v 0.22 mEq/min) and IS + SP (0.18 v 0.24 mEq/min). UKal increased significantly after IS (58.6%) and IS + SP (53.6%). UAE decreased significantly only after SP. PRA increased significantly after IS (1.31 v 2.84 ng/mL/h), SP (1.10 v 2.15 ng/mL/h), and after IS + SP (1.23 v 3.21 ng/mL/min). In conclusion, IS, SP and IS + SP were effective in reducing blood pressure while keeping renal function stable. Only SP significantly decreased UAE. Enhanced UKal may have played a role in natriuresis observed after IS and IS + SP.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Isradipine; Kallikreins; Kidney Diseases; Male; Middle Aged; Natriuresis; Renal Circulation; Renal Plasma Flow, Effective; Single-Blind Method

Thirty-seven patients with mild to moderate hypertension were randomized in a double-blind, parallell-group study to receive either 6 mg of spirapril or 50 mg of atenolol. After 6 weeks of treatment, the daily dose of spirapril was increased to 12 mg and the daily dose of atenolol to 100 mg, if the target diastolic pressure < or = 90 mmHg was not achieved. The total treatment period was 12 months for both drugs. There were no changes in the lipid levels in the spirapril treatment group whereas the concentration of apoprotein A1 decreased significantly (p < 0.05) in the group treated with atenolol when compared with baseline. There was a tendency in the levels of serum cholesterol and triglycerides to increase and in the level of HDL cholesterol to decrease in the atenolol treatment group compared with baseline. Fasting blood glucose levels did not change significantly in the treatment group when compared with baseline. The 2-hour blood glucose level in the glucose tolerance test increased significantly after the 12-month therapy with both spirapril (p < 0.05) and atenolol (p < 0.05) when compared with baseline levels. There was also a tendency in the 2-hour insulin levels to increase in both the spirapril and the atenolol treatment group after the 12-month treatment period. In conclusion, spirapril had no effect on lipid metabolism whereas atenolol had some untoward effects. In the group treated with atenolol fasting blood glucose levels increased, but both spirapril and atenolol increased the 2-hour blood glucose levels in the glucose tolerance test.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Blood Glucose; Blood Pressure; Cholesterol; Cholesterol, HDL; Double-Blind Method; Enalapril; Female; Glucose Tolerance Test; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Triglycerides

The efficacy of spirapril, 6 mg once daily, was compared with enalapril, 5-20 mg once daily, in the control of mild-to-moderate hypertension in a placebo-controlled, parallel-group study. A total of 251 patients participated in the study, all of whom underwent a 4-week washout period on placebo. Thereafter, 100 patients were randomized to spirapril, 6 mg once daily, 101 patients to enalapril, 5-20 mg once daily, and 50 patients remained on placebo. Sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were measured at 2-weekly clinic visits. Blood pressure profiles during peak and trough plasma drug concentrations (2-4 hours and 24-26 hours postdose, respectively) were determined at baseline and 4 and 8 weeks after starting the double-blind phase. Compared with placebo, treatment with both spirapril and enalapril resulted in significant reductions (p < 0.001) in DBP and SBP. DBP was reduced to a greater extent with spirapril than with enalapril both at peak (-17.4 mmHg vs. -14.8 mmHg) and trough (-14.7 mmHg vs. -12.4 mmHg). Thus, although the trough/peak DBP ratios for spirapril and enalapril were very similar (84% vs. 82%), actual reductions in DBP were different. Spirapril and enalapril treatment resulted in similar reductions in SBP at both peak and trough levels. Both drugs were well tolerated, and there were very few adverse events or changes in hematological or biochemical parameters during the study. In conclusion, spirapril, 6 mg once daily, as the initial and maintenance dose, is at least as effective and well tolerated as enalapril individually titrated.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalapril; Female; Germany; Humans; Hypertension; Italy; Male; Middle Aged; Treatment Outcome; White People

This study was done to determine whether the difference in duration of action of the long-acting angiotensin-converting enzyme (ACE) inhibitor spirapril compared with the short-acting ACE inhibitor captopril affects clinical efficacy in patients with congestive heart failure.. The effects on exercise capacity, neurohumoral status, and quality of life were studied in 20 patients with mild to moderate congestive heart failure in a double-blind, randomized, comparative study in parallel groups with a duration of 12 weeks. All assessments during the study were performed in the morning, before intake of the study medication, to avoid the expected peak effect of the ACE inhibitors used. Mean peak oxygen consumption (peak Vo2) was 17.4 mL/min/kg (range, 14.2-19.9 mL/min/kg) and mean left ventricular ejection fraction was 28% (range, 13-40%). Exercise duration in the captopril group showed a significant increase after 12 weeks (P < .05) of treatment compared with the spirapril group. Peak oxygen consumption tended only to increase in the captopril-treated patients compared with the spirapril-treated patients. Serum ACE activity was significantly different between the two treatment groups during treatment (P < .0001) and showed only a significant decrease in the spirapril group. There was no difference in improvement of quality of life between the two treatment groups.. This study showed that the effects of the ACE inhibitors spirapril and captopril on exercise capacity are not related to the degree of inhibition of serum ACE activity.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Captopril; Double-Blind Method; Enalapril; Exercise; Female; Heart Failure; Humans; Male; Middle Aged; Norepinephrine; Peptidyl-Dipeptidase A; Renin

To investigate the concept of initiating therapy with low doses of a calcium antagonist and an ACE inhibitor, a fixed combination of isradipine 2.5 mg plus the ACE inhibitor spirapril 3 mg was compared with its components, with the full-dose monotherapies (isradipine 5 mg or spirapril 6 mg), and with placebo. After a 2-week wash out phase in pretreated patients and a subsequent 2-week placebo period, 405 patients with a diastolic blood pressure (DBP) between 100 and 114 mmHg were randomly allocated to 12-week once-daily double-blind treatment in one of the six treatment arms. In patients whose blood pressure was not normalized (defined as DBP< or =90 mmHg) after 6 weeks of treatment, the dosage of either medication was doubled or, in the placebo group, was switched to the fixed combination. After week 6, the mean reductions from baseline in sitting systolic/diastolic blood pressure 24 hours after dosing (trough) for the fixed combination or the monotherapies isradipine 5 mg, isradipine 2.5 mg, spirapril 6 mg, spirapril 3 mg, and placebo were 10.4/8.7, 10.0/9.4, 6.5/6.7, 10.0/8.3, 7.0/5.8, and 2.2/4.7 mmHg, respectively. The blood pressure changes obtained with the low-dose fixed combination were essentially identical to those observed with the full-dose monotherapies, thus showing an additive effect of low-dose isradipine and spirapril. In terms of tolerability, the lowest rate of any adverse events was found in the combination group. In this group, typical adverse events of calcium antagonists, such as headache, flushing, ankle edema, or palpitations, were observed only in 5%, 2%, 1%, and 0%, respectively, dry cough, considered typical for ACE inhibitors, was observed in only 1% of the combination group. In conclusion, the low-dose components isradipine 2.5 mg and spirapril 3 mg were shown to have an additive effect when combined, exerting a blood pressure-lowering effect comparable with the full doses and a trend to a better tolerability profile in comparison with the standard doses. Thus, low-dose combination therapy with these drugs appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isradipine; Male; Middle Aged

The CASSIS study was a double-blind multicentric controlled Czech and Slovak study focused on treatment of chronic heart failure with the ACE inhibitor spirapril; it was conducted for 12 weeks. The present work analyzes the second year of the extended open part of the study when all patients (n = 168) were treated with 3 mg or 6 mg spirapril. A small proportion of the patients was treated with 12 mg spirapril. The objective of the study was to test the long-term effectiveness and tolerance of spirapril. The general mortality was analyzed throughout the whole two-year period. The results revealed an unchanging total mortality, analyzed after three-month intervals, during the whole two-year period. Also the functional improvement of the patients according to NYHA which occurred after the first three months of treatment was preserved during the second year. Spirapril proved to be a well tolerated ACE-inhibitor. The authors did not observe angioneurotic oedema in any of the patients. Hypotension and cough were recorded in 0.6% of the patients. The incidence of undesirable laboratory effects was also low and the majority was due to the basic disease. Creatinine did not rise significantly and a rise of urea was observed only in a small number of patients. Liver functions and haemogram did not change during treatment. The results of the second year of erxtension indicate that spirapril is a very effective and safe ACE-inhibitor which will extend in a significant way therapeutic means in patients with chronic heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Survival Rate

Spirapril, an ACE-inhibitor without the SH group was tested in a randomized double-blind multicentric study in patients with chronic symptomatic heart failure (NYHA II-IV). After a 1-4-week initial stage with placebo the patients were randomized into five groups: the first was given placebo, the second one spirapril 1.5 mg, the third one spirapril 3 mg, the fourth one spirapril 6 mg and the fifth one 5 and later 10 mg for a period of 12 weeks. The number of patients in different groups was in the following order: 48, 48, 53, 51 and 48. The condition for admission into the study was chronic heart failure not responding adequately to treatment with digoxin and diuretics, IHD or dilatation cardiomyopathy with the left ventricular ejection fraction (% tolerating a basic ergometric load for two minutes. The primary criterium was an increment during the period of the load, secondary criteria comprised objective and subjective cardiac symptoms, changes in the left ventricular ejection fraction, cardiothoracic index/heart size and quality of life. The load tolerance increased in all groups, however, no significant differences between groups were found. The authors also found regression of signs of pulmonary congestion during active spirapril treatment and diminution of the cardiac shadow. Moreover the authors proved a significant reduction of the mortality in the actively treated patients as compared with those receiving placebo, a lower frequency of hospital admissions and reduction of serious undesirable cardiovascular symptoms during active treatment. In patients with medium severe and severe cardiac failure with IHD, combination with short acting calcium channel blockers had an unfavourable effect on the load tolerance and clinical parameters. Sprirapril, combined with diuretics and digoxin is a suitable drug also in chronic cardiac failure. Questionable remains the importance of loading tests when verifying the effectiveness of ACE-inhibitors. Treatment with short-time acting calcium antagonists cannot be recommended in symptomatic chronic cardiac failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Survival Rate

The effects of the ACE inhibitor spirapril and of hydrochlorothiazide on left ventricular diastolic function were studied. Thirteen patients with mild to moderate essential hypertension completed this randomized, double-blinded, placebo-controlled, crossover study. After a three-week run-in period the patients entered three periods lasting four weeks each, wherein they were treated with placebo, spirapril, or hydrochlorothiazide. Blood pressure, hemodynamic variables (stroke volume, heart rate, cardiac output, index of contractility, and systemic vascular resistance), echocardiography (left ventricular mass), and Doppler-derived atrial to early (A/E)-ratio velocity time integrals (VTI) were measured at the end of each of the four periods. Spirapril lowered the A/E-ratio VTIs (0.57, 0.12-1.00) (P < 0.02) as compared with both placebo (0.80, 0.50-2.67) and hydrochlorothiazide (0.83, 0.44-1.25), and the drug normalized the A/E-ratio VTI in those patients with elevated values. The hemodynamic variables, left ventricular mass, and end-systolic wall stress were unchanged during all three treatments. There were no significant changes in mean blood pressure during the treatment periods. These results indicate that spirapril lowers A/E ratio within four weeks in patients with mild to moderate essential hypertension. It thereby seems able to improve left ventricular diastolic function. The effect is not dependent upon changes in hemodynamic variables, blood pressure, left ventricular mass, or end-systolic wall stress.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Cardiac Output; Cardiography, Impedance; Cross-Over Studies; Diastole; Double-Blind Method; Echocardiography; Enalapril; Female; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Myocardial Contraction; Rest; Stroke Volume; Vascular Resistance; Vasodilation; Ventricular Function, Left

To compare the safety, efficacy, tolerability and duration of the antihypertensive effect of an ACE-inhibitor spirapril 3 mg or 6 mg in elderly (> or = 60 y) hypertensive patients in a multicentre, observational, double-blind randomised study.. After a four-week placebo period, 39 patients were randomised to six weeks of treatment with spirapril 3 mg and 47 patients with spirapril 6 mg.. In the sitting position the mean (SD) decrease in systolic blood pressure (SBP) was 12(15) mmHg (95% confidence interval 7 to 17 mmHg) and in diastolic blood pressure (DBP) 10(7) mmHg (8 to 12 mmHg) in the 3-mg group and 10(13) mmHg (6 to 14 mmHg) and 9(7) mmHg (7 to 11 mmHg), respectively, in the 6-mg group (P < 0.001 compared to placebo period in both groups). Spirapril 3 mg and 6 mg produced DBP < or = 90 mmHg or a fall > or = 10 mmHg in 53% and 51% of the patients, respectively. DBP was < or = 90 mmHg in 36% and SBP < or = 160 mmHg in 67% of the patients taking 3 mg and in 26% and 63% of the patients taking 6 mg spirapril. The most commonly reported adverse effects were cough (13-17%), dizziness, headache and insomnia. A trend to a more frequent adverse effects was observed in patients receiving spirapril 6 mg. Spirapril was both cholesterol- and glucose-neutral.. According to our study, spirapril 3mg seems to be a suitable starting dose for the treatment of hypertension in the elderly patients.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Cholesterol; Double-Blind Method; Enalapril; Female; Headache; Humans; Hypertension; Male; Middle Aged

The effects of a single oral dose (6 mg) of the angiotensin-I converting enzyme inhibitor, spirapril, on systemic, pulmonary and regional (brachial, renal, hepato-splanchnic) hemodynamics as well as on biological parameters investigating the renin-angiotensin-aldosterone and sympathetic nervous systems were studied over a 24-hour period in eight patients with severe congestive heart failure (CHF). As compared to pretreatment values, spirapril significantly decreased mean arterial (-19%, peak effect), right atrial (-42%), mean pulmonary arterial (-38%) and pulmonary capillary wedge (-46%) pressures. Spirapril significantly decreased heart rate (-14%) and increased stroke volume index (+43%) thus resulting in a slight increase in cardiac index. All these effects were maximal between 2.5 and 4 h. Brachial artery diameter (+12%) and brachial (+41%) and renal (+36%) blood flows increased significantly whereas brachial (-41%) and renal (-36%) vascular resistances decreased significantly. All these effects were usually maximal between 1 and 2.5 h. Hepato-splanchnic hemodynamics were not drug-affected. Spirapril significantly inhibited plasma converting enzyme activity (-96% at 4 h), increased plasma renin activity (+505% at 4 h), and decreased plasma aldosterone (-46% at 24 h), norepinephrine (-31% at 24 h) and atrial natriuretic factor (-33% at 7 h). Thus, in severe CHF, acute administration of spirapril, 6 mg orally, exerts both arterial and venous vasodilating properties and improves both the systemic and regional hemodynamics and the biological status of the patients.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Brachial Artery; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Liver Circulation; Male; Middle Aged; Pulmonary Circulation; Pulmonary Wedge Pressure; Renal Circulation; Vascular Resistance; Vasodilation

Left ventricular hypertrophy is a common clinical feature in hypertensive patients and may be associated with structural changes in vessel morphology. In an open prospective trial, we evaluated 14 patients with previously untreated hypertension (163 +/- 2/104 +/- 2 mm Hg) and an echocardiographically determined left ventricular mass index of 141.6 +/- 5.2 g/m2, indicating left ventricular hypertrophy. We obtained a gluteal skin biopsy sample before starting treatment to investigate subcutaneous small-artery (approximately 200 to 400 microns diameter) morphology and function. Patients then received antihypertensive treatment with a combination of spirapril (3 or 6 mg) and isradipine (2.5 or 5 mg). Echocardiographic recordings were made after 6 months and 1 year, and a final biopsy was taken after 1 year. After 1 year, blood pressure was significantly reduced to 142 +/- 3/ 90 +/- 1 mm Hg (P < .001), and left ventricular mass index decreased significantly to 105.3 +/- 5.8 g/m2 (P < .001). Baseline media-lumen ratio (7.64 +/- 0.48%) was not markedly reduced (7.21 +/- 0.55%), although a decrease occurred in 7 of 12 evaluable patients. Norepinephrine-induced vasoconstriction was markedly reduced after 1 year. In conclusion, a significant regression of left ventricular hypertrophy was obtained after 1 year of treatment with spirapril and isradipine, whereas a similar reduction in medial thickness relative to lumen diameter of subcutaneous small arteries could not be observed in all patients. Reversal of structural changes in resistance vessels may require a longer treatment period in patients with proven left ventricular hypertrophy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteries; Blood Pressure; Drug Combinations; Echocardiography; Enalapril; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Isradipine; Male; Prospective Studies; Vascular Resistance

1. The effects of a first dose and of chronic treatment with spirapril, a novel angiotensin converting enzyme (ACE) inhibitor, on short-term blood pressure and heart rate fluctuations were assessed by fast Fourier spectral analysis. The effects on systemic haemodynamics in supine and standing position were also studied. We treated 11 patients with 3 mg and 13 patients with 12 mg spirapril for 8 weeks. 2. Overall blood pressure variability was not changed by spirapril. By spectral analysis the changes in blood pressure and heart rate variability in various frequency bands can be assessed, which may be related to changes in activity of the autonomic nervous system. The relative power in the mid-frequency band (0.08-0.12 Hz) of supine systolic pressure was 23 +/- 10% during placebo and decreased during treatment with 12 mg to 11 +/- 4% (P < 0.01 vs placebo, first dose) and to 13 +/- 6% (P < 0.01, chronic treatment). Standing systolic mid-frequency power was 38 +/- 12% during placebo and decreased to 27 +/- 9% (P < 0.01 vs placebo) after the first dose of 12 mg, but it did not decrease after chronic treatment (29 +/- 13%). Treatment with 3 mg induced no changes in mid-frequency blood pressure variability. A decrease in power of the mid-frequency band may point to a decrease in sympathetic vascular drive. The power in the high-frequency band (0.15-0.40 Hz) of heart rate did not change after treatment, suggesting that there is no change in the vagal cardiac drive. 3. Supine blood pressure decreased by a decrease in vascular resistance by 16 +/- 23% (3 mg) and 14 +/- 19% (12 mg) after 8 weeks treatment. Heart rate, stroke volume and cardiac output did not change. No orthostatic hypotension occurred after the first dose. In the 12 mg group the orthostatic induced rise in heart rate (compared with supine) increased from + 9 +/- 5 beats min-1 (placebo) to + 14 +/- 4 beats min-1 (P < 0.05) after the first dose. No changes in the orthostatic heart rate increase occurred in the 3 mg group. The orthostatic changes in stroke volume, cardiac output and vascular resistance were not influenced by spirapril. 4. In conclusion, the decrease in mid-frequency blood pressure variability may suggest an inhibitory effect of acute and chronic ACE inhibition upon sympathetic vasomotor control. Vagal activity was not influenced as high-frequency heart rate variability did not change. Acute and chronic ACE inhibition did not blunt important cardiovascular reflexes, as the haemodynamic

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Posture

Thirteen patients with mild hypertension (untreated diastolic blood pressure of 95 to 114 mmHg) received, in random order, three successive treatments of four weeks with placebo, spirapril (6 mg daily), or hydrochlorothiazide (HCT2) (24 mg daily). At the end of each treatment, blood samples for assessment of platelet aggregation and platelet release of platelet factor 4 (PF4) and for assessment of fibrinolysis, estimated by tissue plasminogen activator (t-PA), plasminogen activator inhibitor-type 1 (PAI-1), and euglobulin clot lysis time (ECLT), were taken, first at rest, then immediately after five to ten minutes of vigorous exercise, and finally after the subsequent hour of recovery rest. Platelet aggregation induced in vitro by adrenaline significantly decreased during treatment with HCT2, the threshold rising to 10 microM as compared with 1.0 with placebo (P < 0.05) at rest, and the threshold for adenosine diphosphate (ADP) aggregation also rose, from 2 microM to 4 (NS). The resting plasma PF4 value fell, although not significantly, during HCT2 treatment from the placebo value of 3.28 to 2.56 ng/mL. During spirapril treatment there was no change in the threshold of either adrenaline or ADP for aggregation of platelets sampled at rest, and the PF4 plasma levels showed no significant reductions at rest. However, during exercise PF4 showed an approximate doubling of the resting value irrespective of therapy. This exercise-induced increase in PF4 was significantly reduced by spirapril as compared with placebo (P < 0.05). ECLT and t-PA did not shift significantly from the placebo level during either therapy. PAI-1 did not change during spirapril therapy, but during HCT2 treatment it fell, although not significantly, to 9.36 IU/mL from 15.91 with placebo (NS). Spirapril and HCT2 did not produce any unwanted side effect on platelet function or fibrinolysis. HCT2 seems to decrease platelet activity at rest, whereas spirapril seems to some extent to decrease platelet activity at exercise.

Topics: Aged; Alpha-Globulins; Angiotensin-Converting Enzyme Inhibitors; Blood Platelets; Diuretics; Double-Blind Method; Enalapril; Epinephrine; Exercise; Fibrinolysis; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Sodium Chloride Symporter Inhibitors

Spirapril is a new angiotensin-converting enzyme (ACE) inhibitor with a long duration of action. To determine whether duration of inhibition of serum ACE activity may affect regional blood flow (RBF), we compared spirapril with captopril, an ACE inhibitor with a short duration of action. Both the short- and long-term effects were studied in patients with mild to moderate congestive heart failure (CHF). Calf, renal, and hepatic BF measurements were performed in the morning before intake of the study medication; 24 h after the previous dose of spirapril (n = 9 patients) and 12 h after the previous dose of captopril (n = 9 patients). Serum ACE activity after 1, 6, and 12 weeks was significantly reduced in patients receiving spirapril, but not in those receiving captopril. The decrease in mean arterial pressure (MAP) was more pronounced in the spirapril group. Calf BF showed a slight but not significant increase in both spirapril- and captopril-treated patients. Effective renal BF increased significantly only in patients treated with spirapril. Although filtration fraction (FF) tended to decrease in the spirapril group, the decrease was significant only in the captopril group. No changes were observed in hepatic BF. Cerebral BF (CBF) measurements were performed after intake of the first dose of study medication and after 12 weeks, immediately after drug intake. Significant reduction in MAP in the two treatment groups both after the first dose and after 12 weeks did not affect CBF. Despite a significantly prolonged decrease in MAP and serum ACE activity in spirapril-treated patients, no marked differences in RBF were noted between the two ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Circulation; Captopril; Cerebrovascular Circulation; Double-Blind Method; Enalapril; Exercise Test; Female; Heart Failure; Humans; Leg; Liver Circulation; Male; Middle Aged; Peptidyl-Dipeptidase A; Regional Blood Flow; Renal Circulation

A one-year open study was focused on the therapeutic effect and tolerance of spirapril in 171 patients with mild to moderate hypertension in 11 centres in the Czech and Slovak Republic. The antihypertensive effectiveness was investigated after four weeks, after 12 weeks and after 52 weeks. Only the results recorded after one year are reported. The study was completed after one year by 139 patients, incl. 120 (86.3%) with a normal diastolic pressure of 90 mmHg or less. The study was not completed by 32 patients (18.8%): because treatment was not effective--9.4%, because of undesirable effects--4.7%, 3.5% were eliminated by the investigators for various reasons (change of domicile, poor collaboration) and 1.2% because the protocol was not respected. According to the analysis "intention to treat" the diastolic pressure was normalized by monotherapy with spirapril in 25.1% of the baseline group; combination of spirapril with bopindolol led to normalization of the pressure in another 38.0% patients and in 7.0% patients normal diastolic pressure was achieved by a combination of spirapril with a hydrochlorothiazide; i.e. a total of 70.1% of the baseline group had a normal diastolic pressure after one year of treatment. In another 9.4% of the baseline group the diastolic pressure declined by 10 mmHg or more but not to normal levels. Thus normalization or effective control of pressure was achieved after one year in 79.6% patients according to the analysis "intention to treat". The combination of spirapril and bopindolol proved very effective. Patients where it was necessary to combine spirapril with bopindolol or hydrochlorothiazide had significantly higher baseline readings of blood pressure. During treatment the authors did not record in any of the groups a change of lipids, potassium, uric acid, the haemogram, liver tests or creatinine. Treatment was well tolerated and undesirable effects were rare (most frequent side effects: cough 3.5%, vertigo also 3.5%). The results of the study indicate that spirapril is an effective and well tolerated ACE inhibitor in the treatment of hypertension and its combination with bopindolol is equally suitable as the combination of spirapril with hydrochlorothiazide.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

A randomized, double-blind, placebo- and active-controlled multicentre study with spirapril, a new angiotensin-converting enzyme inhibitor (ACEI), has been conducted in patients with chronic congestive heart failure (CHF) of NYHA classes II-IV. After a placebo run-in period of 1-4 weeks, patients were randomly assigned to one of five treatment groups: placebo (n = 48), spirapril 1.5 mg (n = 48), spirapril 3 mg (n = 53), spirapril 6 mg (n = 51) or enalapril 5/10 mg (n = 48). The primary objective was to assess changes in exercise tolerance, and the secondary objective was an assessment of cardiovascular signs and symptoms, quality of life, ejection fraction and chest X-ray findings. Exercise tolerance increased in all groups; however, no statistically significant differences were found between any of the groups. There was a statistically significant reduction of mortality in the pooled spirapril groups compared with placebo, and a trend for reduction of serious cardiovascular adverse events as well as duration of hospitalization. These effects and improvements in lung congestion appeared to be dose dependent. In patients with moderate to severe heart failure, the combination with first-generation calcium channel blockers had an unfavourable effect on exercise capacity and clinical parameters. Spirapril might be an effective alternative to enalapril in the treatment of patients with CHF. The role of the exercise tolerance test in establishing efficacy of ACEIs in CHF and the widespread use of nifedipine in CHF is questioned.

Topics: Angiotensin-Converting Enzyme Inhibitors; Czech Republic; Double-Blind Method; Enalapril; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Male; Middle Aged; Prodrugs; Slovakia

The benefits of treating isolated systolic hypertension (ISH) have been established, but the most appropriate choice of drug is still uncertain. For this reason, a sustained-release formulation of isradipine was compared with spirapril in a double-blind randomized study in elderly Chinese patients with ISH. The dosage was titrated if necessary after 4 weeks of treatment. The reduction in systolic/diastolic blood pressure after 8 weeks was similar for both treatments--20/10 mm Hg with isradipine versus 24/6 mm Hg with spirapril--measured in the supine position. There were no orthostatic symptoms and both treatments were well tolerated.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Delayed-Action Preparations; Double-Blind Method; Enalapril; Female; Heart Rate; Humans; Hypertension; Isradipine; Male; Peak Expiratory Flow Rate; Systole

The antihypertensive efficacy of isradipine has been widely studied. In most studies, however, blood pressure values were assessed by causal readings (CR) only. Furthermore, whether or not such blood pressure readings are sufficient proof of efficacy is still under discussion. Thus, a multicenter study was devised wherein blood pressure were recorded by CR, self-recordings, and noninvasive ambulatory monitoring (ABM). A total of 595 patients with mild-to-moderate hypertension were treated for 6 months starting with 1.25 mg of isradipine twice daily. If, after 4 weeks of treatment, CR-determined diastolic blood pressure (DBP) was still > 90 mm Hg, this dosage was doubled (n = 327) and, at week 8, pindolol at 5 mg or spirapril at 3 mg daily was added if necessary for blood pressure control. On the basis of CR, the results confirmed that low dosages of isradipine twice daily are safe and effective in the treatment of mild-to-moderate hypertension. The mean decrease in CR-determined blood pressure was 28.5/19.0 mm Hg at week 24, and the normalization rate (DBP < or = 90 mm Hg) for all patients treated was 78.2%. However, SR-determined blood pressure reduction was 20.0/13.0 mm Hg, with a normalization rate of 42%, whereas ABM-determined blood pressure reduction was 7.0/4.2 mm Hg. On the basis of ABM recordings, 66% of the patients had a DBP < 90 mm Hg on entry into the study and their blood pressures did not decrease with treatment. Thus, it appears that CR-determined blood pressures bias study results by including normotensives and thereby overestimating efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Ambulatory Care; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Drug Therapy, Combination; Enalapril; Female; Humans; Isradipine; Male; Middle Aged; Pindolol; Self Care

Spirapril is a recent ACE inhibitor with a both renal and hepatic elimination pathway. In order to determine its tolerability, primarily the impact on renal function, Spirapril was tested in a single-blind trial with a 2-week placebo run-in phase and a 4-week active treatment period. Forty-nine patients (34 males and 15 females) with varying degrees of renal impairment were included. Their pretreatment diastolic blood pressure (DBP) ranged from 95 to 115 mm Hg. Spirapril was administered in oral doses of 6 mg once daily.. Forty-four patients completed the study. Four patients dropped out due to side effects, 1 patient was withdrawn from the study due to lack of antihypertensive efficacy. 48% of the completers with renal failure achieved a normalized diastolic blood pressure (DBP < or = 90 mm Hg) or a reduction in DBP of > or = 10 mm Hg; the corresponding figure for patients with normal renal function was 31%. Renal function was assessed in the beginning and at the end of the active Spirapril treatment period using Tc-99m-DTPA-clearance (representing glomerular filtration rate), J-131-hippuran-clearance (representing renal plasma flow) and creatinine clearance. Particularly in patients with renal impairment, Spirapril did not deteriorate renal function as given by these parameters. Regression analysis revealed a linear correlation between total plasma clearance of the active metabolite Spiraprilate and creatinine clearance. There was no evidence for drug accumulation.. In patients with renal impairment the pharmacokinetic results indicate a non-renal elimination of the drug. Spirapril 6 mg once daily is concluded to be a well tolerated antihypertensive therapy for patients with mild to moderate hypertension and varying degrees of chronic renal failure.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Kidney Function Tests; Male; Metabolic Clearance Rate; Middle Aged

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Humans; Hypertension; Kidney Diseases; Single-Blind Method

This was a multicentre randomized, double-blind, parallel-group study to compare the antihypertensive efficacy of spirapril at 3 mg with 12 mg once daily, as determined by 24-hour ambulatory blood pressure monitoring (ABPM), in patients with mild to severe essential hypertension. Following a 4-week placebo run-in phase, 52 male and female outpatients, aged 23-67 years with mild to severe essential hypertension [diastolic blood pressure (DBP) > or = 100 mmHg and < 120 mmHg] were randomized to receive spirapril at either 3 mg or 12 mg once daily for 8 weeks. At the end of active treatment and using the standard mercury sphygmomanometer, the number of responders (sitting DBP < 90 mmHg, but decrease > or = 10 mmHg) was the same in both groups (32% and 37%). There were mean decrease in both systolic blood pressure (SBP) and DBP at trough with both 3 mg and 12 mg doses: -9/-7 mmHg and -12/-7 mmHg, respectively. The rate of normalization (trough DBP < or = 90 mmHg) was 12% and 30% with the 3 mg and 12 mg doses, respectively. Of the 44 patients whose daytime ABPM could be compared, one of 20 patients taking 3 mg of spirapril, and 9 of 24 taking 12 mg of spirapril achieved a DBP < or = 90 mmHg for all time intervals while awake. The differences in blood pressure-lowering were significant with both SBP and DBP during the day and at the end of the dosing interval (p < 0.001 and p < 0.01, respectively). The changes from baseline at 24 hours postdose for SBP/DBP were -3/-6 mmHg with 3 mg and -14/-12 mmHg with 12 mg of spirapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Monitoring, Physiologic; Peptidyl-Dipeptidase A; Renin

A total of 171 male and female patients with mild-to-moderate hypertension [diastolic blood pressure (DBP) 100-115 mmHg] entered this randomized, double-blind, multicentre study. A 3-week placebo run-in period was followed by a 5-week active-treatment period during which patients received either 1, 6, 12 or 24 mg of spirpril once daily. Predose sitting blood pressure was taken in the morning by sphygmomanometer as well as by an automatic device (Tonoprint). Spirapril in doses of 6, 12 or 24 mg once daily significantly and similarly lowered systolic blood pressure (SBP) and DBP compared with 1 mg once daily. The rates of blood pressure normalization (DBP < or = 90 mmHg) were 12.5%, 37.5%, 30.8% and 28.9% with 1, 6, 12 and 24 mg, respectively. The percentage of patients experiencing a DBP reduction of at least 10 mmHg was 25.0%, 56.3%, 48.7% and 52.6% and 1, 6, 12 and 24 mg of spirapril, respectively. No serious or severe adverse events related or uncertain if related to the study medication were observed. The effective 6-mg dose was as well tolerated as the inefficacious 1-mg dose. In conclusion, in patients with mild-to-moderate essential hypertension, 6 mg of spirapril once daily is an efficacious and safe antihypertensive therapy with a favourable benefit-risk profile.

Topics: Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Drug Administration Schedule; Enalapril; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged

In this single-blind trial with a 2-week placebo run-in followed by a 4-week active-treatment period, patients were given 6 mg of spirapril once daily. Forty-nine hypertensive men and women were recruited; all had pretreatment diastolic blood pressures (DBP) of 95-115 mmHg with varying degrees of renal impairment. Regression analysis of pharmacokinetic parameters C(max)ss (the maximum steady-state drug concentration in plasma during a dosing interval), Cl/f (total plasma clearance) and k (elimination rate constant) of spirapril on creatinine clearance (Clcr) showed that the pharmacokinetics of spirapril were not significantly influenced by the degree of renal impairment. C(max)ss values of spiraprilat, however, increased with decreasing Clcr, and AUC(l)ss (area under the concentration-time curve during a dosing interval) values also increased. Regression analysis of the pharmacokinetic parameters C(max)ss, Clm/fm (total plasma clearance) and lambda 1 (rate constant of the first disposition phase) of spiraprilat on Clcr showed that Clm/fm as well as lambda 1 were linearly correlated with Clcr (p < 0.01). However, the results indicate that, even when renal elimination is completely blocked, there is significant elimination of spiraprilat through a non-renal pathway. In conclusion, the risk of drug accumulation after multiple dosing is minimal as the presence of a substantial non-renal spiraprilat elimination was consistently demonstrated.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Regression Analysis; Single-Blind Method

In a randomized, double-blind, crossover study, 20 patients with mild to severe essential hypertension received 3 weeks of treatment with each of four dosages of spirapril (3, 6, 12 and 24 mg once daily) or placebo. Standing and supine blood pressures were measured by use of both an automatic oscillometric instrument (Dinamap) and a mercury sphygmomanometer over a 24-hour period. Spirapril at 6, 12 and 24 mg once daily produced similar reductions in systolic and diastolic blood pressure. At most time points, there was a statistically significant difference between the reductions with spirapril compared with placebo. Spirapril at 3 mg once daily was less effective than the higher dosages, producing a lower mean blood pressure reduction and a shorter duration of antihypertensive action, mainly as regards systolic pressure. Spirapril was well tolerated and no patients withdrew from the study because of adverse effects. These data suggest that, although all four evaluated spirapril dosages effectively lowered supine and standing blood pressure in patients with mild to severe hypertension, the blood pressure-lowering effect of the 3 mg/day regimen was less than optimal. There were only minor variations in efficacy between dosages > or = to 6 mg/day, which may be attributable to the variability of blood pressure. Further investigations of larger numbers of patients are required to verify these results.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Drug Administration Schedule; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System

In a single-blind trial with a 2-week placebo run-in phase and a 4-week active-treatment period, spirapril at 6 mg once daily was administered to 49 consecutive hypertensive patients (34 men and 15 women). All had pretreatment diastolic blood pressures (DBP) of 95-115 mmHg and varying degrees of renal impairment. At the end of the placebo run-in and at the end of active treatment, renal function was assessed using the following procedures: technetium 99m-DTPA clearance [for glomerular filtration rate (GFR)]; radioiodine (131I)-labelled sodium iodohippurate (Hippuran) clearance [for renal plasma flow (RPF)]; creatinine clearance (Clcr). No statistically significant differences were found in GFR or Clcr during spirapril treatment. In renally impaired patients, RPF remained virtually unchanged whereas, in patients with normal Clcr, there was an increase of around 10% during active treatment. At the end of the study, 48% of the patients with renal failure achieved normalization of DBP (< or = 90 mmHg) and/or a DBP reduction of > or = 10 mmHg; the corresponding rate for patients with normal renal function was 31%. In conclusion, in patients with mild-to-moderate essential hypertension and varying degrees of renal impairment, spirapril at 6 mg once daily is an efficacious and well tolerated antihypertensive therapy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Single-Blind Method

To assess the long-term course of regression of left ventricular hypertrophy (LVH) and haemodynamic changes during spirapril treatment, 11 male hypertensive patients with a left ventricular mass (LVM) > 240 g and a mean age of 48 (range 41-60) years were followed-up with echo-Doppler examinations for 36 months. The initial spirapril dose was 6 or 12 mg once daily, which was titrated to a minimum of 3 mg and a maximum of 24 mg to keep diastolic blood pressure (DBP) < or = to 95 mmHg. Patient compliance based on tablet counts was 98% (range 95-100%). The mean spirapril dose was 9 +/- 6 mg at 3 months, 9 +/- 6 mg at 12 months, and 15 +/- 9 mg at 36 months. Blood pressure was reduced from 161 +/- 20/107 +/- 6 mmHg at baseline to 137 +/- 11/89 +/- 6 mmHg at 3 months (p < 0.001), 141 +/- 20/89 +/- 4 mmHg at 12 months and 135 +/- 11/87 +/- 6 mmHg at 36 months. The respective values for LVM at baseline and at 3, 12 and 36 months were 340 +/- 71 g, 305 +/- 61 g (p < 0.05 vs baseline), 303 +/- 88 g and 298 +/- 94 g. Cardiac output did not change whereas systemic arteriolar resistance (SAR) was significantly reduced after 3 and 36 months (p < 0.01). Thus, the regression of LVH with spirapril was 10% of LVM at 3 months, 11% at 12 months, and 12% at 36 months. These changes were mainly related to a reduction of LV posterior wall thickness and SAR.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Echocardiography, Doppler; Enalapril; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Time Factors

In a randomized double-blind, placebo-controlled, crossover trial, the potential anti-ischaemic action of the angiotensin-converting enzyme (ACE) inhibitor spirapril was studied in 19 patients with coronary artery disease (CAD) and reproducible exercise-induced ST-segment depression, but without hypertension or congestive heart failure. Measurements of blood pressure and heart rate as well as exercise-testing were performed after 2 weeks of treatment each with placebo and spirapril. Anginal attacks and consumption of short-acting nitrates were recorded in the patients' diaries. Resting blood pressure was not significantly reduced (143 +/- 20/89 +/- 10 mmHg vs 138 +/- 17/87 +/- 10 mmHg). The exercise-induced ST-segment depression, the main criterion for anti-ischaemic effect, was 2.17 +/- 1.72 mm after placebo and not significantly affected by spirapril (2.03 +/- 1.47 mm) despite a significant reduction in blood pressure x heart rate product at maximum workload (213 +/- 45.4 vs 197.5 +/- 36.8; p < 0.05). The number of anginal attacks per week and nitrate consumption remained virtually unchanged. A significant reduction of exercise-induced ischaemia in normotensive patients with CAD was not demonstrated with spirapril.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Coronary Disease; Double-Blind Method; Electrocardiography; Enalapril; Exercise Test; Heart Rate; Humans; Middle Aged

This was a randomized double-blind parallel-group study of 283 patients who had mild-to-moderate [diastolic blood pressure (DBP) > 100 mmHg and < or = 115 mmHg] hypertension. After a 3 (or 4)-week placebo wash-out period followed by 6 weeks of active treatment with spirapril at either 3, 6, 12 or 24 mg once daily (or placebo), DBP decreased by approximately 10 mmHg in the (pooled) spirapril-treated patients compared with approximately 5 mmHg with placebo. There were statistically significant differences between all active-treatment groups (except the 24-mg dose group) and placebo, but not among the spirapril groups at the end of the +24-hour dosing interval. Reported adverse events were mostly not study drug-related and were similar to those with placebo except for headache, which was more frequent with spirapril than placebo (5.8% vs 1.7%, respectively). Similarly, the number and severity of the changes in laboratory variables did not differ between placebo vs spirapril, and none of these changes were dose-related. In conclusion, the studied dosages of spirapril were equally effective in reducing DBP, and the overall good decrease in blood pressure at the end of the dosing interval indicates that once-daily administration is effective in patients with mild-to-moderate hypertension.

Topics: Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

In a double-blind, parallel-group study, 260 patients with mild to severe essential hypertension were randomized to treatment with placebo or spirapril at 6, 12 or 24 mg once daily for 6 weeks. When blood pressures were measured at the end of the dosing interval (trough), all spirapril regimens had produced similar reductions in sitting systolic and diastolic blood pressures (siSBP/siDBP) which were significantly greater than those observed in placebo-treated patients. There were no relevant changes in resting heart rate in any of the study groups. At the study endpoint, the mean reductions in siSBP/siDBP were 14.9/11.5 mmHg with spirapril at 6 mg, 15.4/12.0 mmHg with spirapril at 12 mg and 17.8/12.4 mmHg with spirapril at 24 mg/day vs. 3.1/3.6 mmHg with placebo. In a subgroup of 122 patients, blood pressure was recorded at the end of the dosing interval and during the 8 hours immediately postdose to monitor the peak effects on blood pressure. All spirapril dosages produced similar reductions at peak with a mean decrease of siDBP of approximately 20 mmHg in comparison to baseline values vs 6-7 mmHg with placebo. The trough:peak ratios for 6, 12 and 24 mg all lay between 60% and 90% for siSBP and siDBP, indicating that most of the peak effect was maintained at trough. Spirapril was well tolerated; the adverse event profile was not different from that with placebo, and no dose-related adverse events were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Humans; Hypertension; Hypertrophy, Left Ventricular; Single-Blind Method

Angiotensin-converting enzyme (ACE) inhibitors may cause a further decrease in renal function in patients who already have renal failure. The acute effects of the ACE inhibitor spirapril on renal function were investigated in 10 patients with mild-to-moderate renal failure (serum creatinine of 1.5-2.5 mg/dl). Acute oral administration of spirapril at 6 mg resulted in decreases in inulin clearance (from 53.7 +/- 12.8 to 44.6 +/- 8.8 ml/min; p < 0.02; n = 5) and in PAH clearances (from 215 +/- 141.9 to 184 +/- 37.8 ml/min; p < 0.006; n = 5). However, when the acute administration of 6 mg of spirapril was given concomitantly with isradipine at 5 mg, there were no changes in these renal function parameters.

Topics: Angiotensin-Converting Enzyme Inhibitors; Drug Combinations; Enalapril; Humans; Isradipine; Kidney; Kidney Failure, Chronic; Time Factors

The effects of spirapril and isradipine on blood pressure, urinary albumin excretion and sodium-volume homeostasis in hypertensive insulin-dependent diabetic patients with nephropathy were assessed. Fifteen Type 1 diabetic patients aged 28-53 years with a diabetes duration of 19-37 years were studied. All had hypertension and diabetic nephropathy with a urinary albumin excretion of more than 300 mg/24 h. After a single blind placebo treatment period of 4 weeks the patients were randomly assigned to treatment with the calcium antagonist isradipine SRO 5 mg once daily or the ACE inhibitor spirapril 6 mg once daily for 6 months in a double-blind design. Isradipine lowered ambulatory systolic blood pressure from 152 +/- 12 to 141 +/- 11 mmHg (p < 0.05) and ambulatory diastolic pressure from 91 +/- 9 to 86 +/- 8 mmHg (p < 0.05). The blood pressure lowering effect of spirapril was similar: 156 +/- 13 vs 143 +/- 11 mmHg (p < 0.01) and 90 +/- 4 vs 84 +/- 4 mmHg (p < 0.05). The fractional albumin clearance was unchanged on isradipine but decreased after 6 months treatment with spirapril with on average 20% (p < 0.05). Total body exchangeable sodium decreased on spirapril treatment: 2994 +/- 296 vs 2636 +/- 194 meq/1.73 m2 (p < 0.05) and extracellular volume tended to do so (p = 0.12). On isradipine treatment these parameters remained unchanged. In conclusion both isradipine and spirapril lowered blood pressure in patients with diabetic nephropathy. Only the ACE inhibitor had demonstrable beneficial effects on urinary albumin excretion rate and the sodium-volume expansion seen in these patients.

Topics: Adult; Albuminuria; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Enalapril; Endothelium, Vascular; Female; Humans; Hypertension; Isradipine; Lipoproteins; Male; Middle Aged; Potassium; Sodium

The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensin-converting 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 micrograms.h.l-1, 923 micrograms.h.l-1 and 1300 micrograms.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.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Enalapril; Female; Glycogen Storage Disease; Half-Life; Hemodynamics; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Diseases; Male; Middle Aged; Pulse

The objective of this study was to assess the safety and efficacy of 1.25 to 2.5 mg of isradipine twice daily in patients with mild-to-moderate hypertension, as seen in general practice. A total of 595 patients were treated for 6 months with an initial dose of isradipine at 1.25 mg twice daily. This dose was doubled if normotension (diastolic blood pressure [DBP] < or = 90 mm Hg) was not achieved after 4 weeks of treatment (n = 327). If, after 8 weeks, blood pressure was still not normalized, either the angiotensin-converting enzyme (ACE) inhibitor spirapril at 3 mg (n = 58) or the beta-blocker pindolol at 5 mg (n = 54) was added to the treatment. After 24 weeks, the mean blood pressure decrease with isradipine at 1.25 mg twice daily was 28.5/19.0 mm Hg for systolic blood pressure (SBP)/DBP and, with 2.5 mg isradipine twice daily, 28.4/18.5 mm Hg. There was no relevant change in heart rate. The overall normalization rate for all 595 patients was 78.2%. Side-effects that were considered related or possibly related to treatment were reported in 73 patients (12.3%). Treatment with isradipine plus either spirapril or pindolol was discontinued in 32 patients (5.4%) because of side-effects related, or possibly related, to the study treatment. Blood pressure was also self-recorded in a subgroup of 45 patients. The self-recorded values were 11/6 mm Hg (SBP/DBP) lower than the respective causal readings at the start of active treatment. However, this difference disappeared completely after 8 weeks of treatment.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure Determination; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Pindolol; Treatment Outcome

The new slow-release oral formulation (SRO) of isradipine, a dihydropyridine calcium antagonist, was evaluated in 57 patients who had moderate-to-severe hypertension following a 2-week wash-out period and a 2-week placebo period. The angiotensin-converting enzyme (ACE) inhibitor spirapril, at a dose of 6 mg/day, was added to the treatment of those not responding to 5 mg/day isradipine SRO alone. After 4 weeks of active treatment, isradipine alone normalized blood pressure (diastolic blood pressure < or = 90 mm Hg) in 38 (66.6%) patients whereas a further 4 weeks of treatment with the combination of isradipine and spirapril led to normalization in 14 of the 19 (73.7%) patients with partial or nil blood pressure responses. Side-effects were mild and transient and were observed in nine patients (15.8%). Isradipine SRO is an effective and well-tolerated antihypertensive agent and combination with spirapril appears to enhance its efficacy without an increase in side-effects.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Delayed-Action Preparations; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Treatment Outcome

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.. 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 12.5 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.. Twenty-four-hour ambulatory blood pressure was measured invasively. True' angiotensins I and II were measured by radioimmunoassay after high-performance liquid chromatography separation.. 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 12.5-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 8.8 mmHg systolic and 6.8 mmHg diastolic.. 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.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Administration Schedule; Enalapril; Female; Hemodynamics; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Single-Blind Method; Time Factors

Twenty-one subjects with known bronchial hyperreactivity were prospectively randomized in double-blind fashion to receive one of two angiotensin-converting enzyme inhibitors (ACE-I), enalapril or spirapril, for three weeks. Spirometry and methacholine provocation were performed prior to, during, and following ACE-I usage. Three of 21 subjects developed a nonproductive cough. However, only one subject wheezed slightly. Spirometry and bronchial reactivity (PD20) were unchanged throughout the study.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cough; Double-Blind Method; Drug Tolerance; Enalapril; Female; Humans; Male; Methacholine Chloride; Middle Aged; Prospective Studies; Single-Blind Method

Topics: Adult; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Blood Pressure; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Male; Natriuresis; Nicardipine; Renal Circulation; Renin; Vascular Resistance

As concurrent use of digoxin with the novel ACE inhibitor spirapril should be common, potential for spirapril to affect steady-state digoxin kinetics was studied. Fifteen healthy white male volunteers aged 22-42 and weighing 135-225 lbs took digoxin tablets 0.25 mg every 12 hours for 5 weeks. In crossover design, each also received spirapril or matching placebo capsules during weeks 1 and 2, or 4 and 5. Dosage of spirapril was increased from 12 mg to 48 mg once daily. Spirapril produced no significant effect on mean (+/- SD) serum digoxin concentration in the steady state, area under curve for 12 hours, peak digoxin level, time to peak, or urinary digoxin excretion over 12 hours. No change in renal or whole body digoxin clearance was seen. Unlike some other cardiovascular drugs, spirapril does not alter steady-state digoxin kinetics in healthy adults.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Digoxin; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Enalapril; Humans; Male; Single-Blind Method

In a double-blind, randomized parallel-group investigation, a new angiotensin-converting enzyme-inhibitor, spirapril, was compared with a calcium antagonist, nitrendipine, in 266 patients with mild to moderate hypertension (diastolic blood pressure 96-119 mmHg). The object was to reduce the diastolic blood pressure measured 24 hours after intake of medicine to less than or equal to 90 mmHg. After monotherapy for four weeks with either 20 mg nitrendipine once daily or 12 mg spirapril once daily, the dosages were doubled in the patients in whom the desired blood pressure had not been obtained. After treatment for eight weeks, 12.5 mg hydrochlorthiazide daily was employed as a supplement in patients who had not yet obtained satisfactory blood pressures. Both methods of treatment resulted a lower number of patients who responded and lesser decreases in blood pressure than anticipated. No differences were found in the decreases in blood pressure resulting from the two therapeutic methods. The effect of supplementary hydrochlorthiazide to spirapril treatment was as anticipated while the combination with nitrendipine only resulted in a marginally extra decrease in blood pressure. Nitrendipine resulted in significantly more side effects and more patients defected from the investigation on account of side effects in the nitrendipine group (27%) than in the spirapril group (7%). This investigation had documented the abilities of nitrendipine and spirapril to reduce blood pressure and the side effects associated with this but does not predict whether the preparations can be employed to prevent the complications of hypertension which constitute the indications for treatment. Supplementing nitrendipine therapy with hydrochlorthiazide is not recommended.

Topics: Double-Blind Method; Drug Evaluation; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Nitrendipine

Spirapril is a new non-sulphydryl angiotensin converting enzyme (ACE) inhibitor which is eliminated mainly through the liver. In a placebo-controlled study the acute and chronic (2 weeks) antihypertensive effects of two doses of spirapril (12.5 and 25 mg) were assessed by invasive 24-h ambulatory blood pressure monitoring in two groups of eight hypertensive subjects. After the first doses of 12.5 and 25 mg, blood pressure rapidly decreased, with a nadir after 4-6 h. At this time, mean arterial pressure was decreased by 24 +/- 2% with the 12.5 and 19 +/- 1% with the 25-mg dose. The antihypertensive response was sustained for almost the whole 24-h period with the 25-mg dose, but it was attenuated during the second half of the 24-h blood pressure monitoring with the 12.5-mg dose, leaving a residual antihypertensive effect of 6 +/- 2% 24 h after dosing. Compared with the response to the first dose, the antihypertensive response after 2 weeks of treatment was similar to that following the 12.5-mg dose, but with the 25-mg dose the response during the second half of the 24-h monitoring period, especially during the night, was attenuated. The reason for this attenuated antihypertensive response during prolonged ACE inhibition remains to be established.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitors; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Evaluation; Enalapril; Humans; Hypertension; Middle Aged; Time Factors

In this study, the potential of perfusion calorimetry in the characterization of solvates forming isomorphic desolvates was investigated. Perfusion calorimetry was used to expose different hydrates forming isomorphic desolvates (emodepside hydrates II-IV, erythromycin A dihydrate and spirapril hydrochloride monohydrate) to stepwise increasing relative vapour pressures (RVP) of water and methanol, respectively, while measuring thermal activity. Furthermore, the suitability of perfusion calorimetry to distinguish the transformation of a desolvate into an isomorphic solvate from the adsorption of solvent molecules to crystal surfaces as well as from solvate formation that is accompanied by structural rearrangement was investigated. Changes in the samples were confirmed using FT-Raman and FT-IR spectroscopy. Perfusion calorimetry indicates the transformation of a desolvate into an isomorphic solvate by a substantial exothermic, peak-shaped heat flow curve at low RVP which reflects the rapid incorporation of solvent molecules by the desolvate to fill the structural voids in the lattice. In contrast, adsorption of solvent molecules to crystal surfaces is associated with distinctly smaller heat changes whereas solvate formation accompanied by structural changes is characterized by an elongated heat flow. Hence, perfusion calorimetry is a valuable tool in the characterization of solvates forming isomorphic desolvates which represents a new field of application for the method.

Topics: Calorimetry; Chemistry, Pharmaceutical; Crystallization; Depsipeptides; Enalapril; Erythromycin; Isomerism; Methanol; Perfusion; Solubility; Solvents; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Surface Properties; Vapor Pressure; Water

The role of NO in the mechanism of quadropril modulation of the flow-dependent vasodilation was examined in normotensive (Wistar) and spontaneously hypertensive (SHR) rats. The abdominal aorta was cannulated and autoperfused at different volume rates to obtain the pressure-flow curves. In the first experimental series, the blood flow-pressure dependence was measured before and after intravenous injection of quadropril (1 mg/kg). In the next series, this dependence was obtained before and after injection of NO-synthase inhibitor L-NNA (10 mg/kg) and quadropril, respectively. Quadropril potentiated vasodilation caused by an increase in perfusion volume rate in both normo- and hypertensive rats and stabilized intravascular pressure. Inhibition of NO synthesis elevated hydraulic resistance and decreased stability of intravascular pressure in normo- and hypertensive rats. In normotensive rats, these changes were promoted by a decrease in vascular distensibility. Under these conditions, quadropril pronouncedly potentiated the flow-dependent vasodilation only in SHR rats, which was revealed methodically by an increase in perfusion rate in the posterior quarter of the body. Thus, in SHR rats the quadropril-potentiated vasodilation in response to increased perfusion rate does not depend on NO synthesis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Flow Velocity; Blood Pressure; Enalapril; Hemodynamics; Hypertension; Male; Nitric Oxide; omega-N-Methylarginine; Rats; Rats, Inbred SHR; Rats, Wistar; Vascular Resistance; Vasodilation

The administration of most angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) at bedtime results in a greater reduction of nighttime blood pressure (BP) than dosing upon awakening. It has been proposed that this effect may be a consequence of a short half-life and duration of action. However, those findings were also documented for long-acting medications, such as the ARB telmisartan. Accordingly, we investigated the administration-time-dependent effects on ambulatory BP of spirapril, an ACEI with an elimination half-life of about 40 h. We studied 165 previously untreated hypertensive subjects, 42.5 +/- 13.9 yrs of age, treated with spirapril (6 mg/day) as monotherapy for 12 weeks either upon awakening or at bedtime. BP was measured by ambulatory monitoring for 48 h before and after treatment. The BP reduction during diurnal activity was similar for both treatment times. Bedtime spirapril administration, however, was significantly more efficient than morning administration in reducing asleep BP. The awake/asleep BP ratio was decreased with the upon-awakening spirapril treatment schedule but significantly increased toward a more dipping pattern with the bedtime treatment schedule. The proportion of patients with controlled ambulatory BP increased from 23 to 59% (p < 0.001) with bedtime treatment. Sleep-time BP regulation is significantly better achieved with bedtime spirapril administration. This might be clinically important, as the sleep-time BP mean has been shown to be a more relevant marker of cardiovascular risk than the awake mean values. These administration-time-dependent effects of spirapril seem to be a class-related feature, and may be associated with the nocturnal activation of the renin-angiotensin-aldosterone system.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Enalapril; Female; Half-Life; Humans; Hypertension; Hypotension; Male; Middle Aged; Receptors, Angiotensin; Renin-Angiotensin System; Risk; Telmisartan

Pharmacological and genetic interference with the renin-angiotensin system (RAS) seems to alter voluntary ethanol consumption. However, understanding the influence of the RAS on ethanol dependence and its treatment requires modeling the neuroadaptations that occur with prolonged exposure to ethanol. Increased ethanol consumption was induced in rats through repeated cycles of intoxication and withdrawal. Expression of angiotensinogen, angiotensin-converting enzyme, and the angiotensin II receptor, AT1a, was examined by quantitative reverse transcription polymerase chain reaction. Increased ethanol consumption after a history of dependence was associated with increased angiotensinogen expression in medial prefrontal cortex but not in nucleus accumbens or amygdala. Increased angiotensinogen expression also demonstrates that the astroglia is an integral part of the plasticity underlying the development of dependence. The effects of low central RAS activity on increased ethanol consumption were investigated using either spirapril, a blood-brain barrier-penetrating inhibitor of angiotensin-converting enzyme, or transgenic rats (TGR(ASrAOGEN)680) with reduced central angiotensinogen expression. Spirapril reduced ethanol intake in dependent rats compared to controls. After induction of dependence, TGR(ASrAOGEN)680 rats had increased ethanol consumption but to a lesser degree than Wistar rats with the same history of dependence. These data suggest that the central RAS is sensitized in its modulatory control of ethanol consumption in the dependent state, but pharmacological or genetic blockade of the system appears to be insufficient to halt the progression of dependence.

Topics: Adaptation, Physiological; Alcoholism; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Animals, Genetically Modified; Central Nervous System; Disease Models, Animal; Enalapril; Ethanol; Humans; Neuronal Plasticity; Rats; Rats, Wistar; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Antisense

Moexipril (7.4-15 mg/day) was given to 34, spirapril (3-6 mg/day) -- to 18 postmenopausal women with hypertension and metabolic syndrome for 16 weeks. Hydrochlorthiazide was added when therapy was not sufficiently effective. Both angiotensin converting enzyme inhibitors had similar hypotensive activity: blood pressure normalized in 71 and 61% of moexipril and spirapril treated women, respectively. Both drugs promoted normalization of metabolism of lipid (lowering of levels of cholesterol, atherogenic lipoproteins and triglycerides) and carbohydrates (lowering of hyperinsulinemia). Patients with postmenopausal metabolic syndrome had elevation of leptin level up to 27.5+/-5.5 pg/ml. Moexipril and spirapril caused lowering of elevated levels of leptin. These drugs did not affect levels of sex hormones. They exerted vasoprotective (normalization of endothelium dependent and independent vasodilatation) and nephroprotective (attenuation and normalization of microalbuminuria) effects. Thus spirapril and moexipril are effective in treatment of hypertension in patients with postmenopausal metabolic syndrome.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Lipids; Metabolic Syndrome; Middle Aged; Postmenopause; Tetrahydroisoquinolines; Treatment Outcome

In this study quadropril (Spirapril, Pliva) was given for 2 months to patients with arterial hypertension combined with chronic obstructive pulmonary disease. The results show that quadropril (6 mg/day) is highly effective as monotherapy in patients with mild and moderate hypertensive disease. Its effects appear as significant lowering of mean 24 hour systolic and diastolic blood pressure (BP), lowering of diurnal and nocturnal BP. Therapy with quadropril for 8 weeks did not impair parameters of external respiration, produced no negative action on lipid and carbohydrate metabolism, was well tolerated, and caused no considerable side effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Follow-Up Studies; Forced Expiratory Volume; Humans; Hypertension; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Pharmacological and genetic manipulations of the renin-angiotensin system (RAS) have been found to alter the voluntary consumption of alcohol. Here we characterize the role of central angiotensin II (Ang II) in alcohol intake first by using transgenic rats that express an antisense RNA against angiotensinogen and consequently have reduced Ang II levels exclusively in the central nervous system [TGR(ASrAOGEN)680]. These rats consumed markedly less alcohol in comparison to their wild-type controls. Second, Spirapril, an inhibitor of the angiotensin-converting enzyme (ACE), which passes the blood-brain barrier, did not influence the alcohol consumption in the TGR(ASrAOGEN)680, but it significantly reduced alcohol intake in wild-type rats. Studies in knockout mice indicated that the central effect of Ang II on alcohol consumption is mediated by the angiotensin receptor AT1 whereas the AT2 receptor and the bradykinin B2 receptor are not involved. Furthermore, the dopamine concentration in the ventral tegmental area (VTA) is markedly reduced in rats with low central Ang II, strengthening our hypothesis of a role of dopaminergic transmission in Ang II-controlled alcohol preference. Our results indicate that a distinct drug-mediated control of the central RAS could be a promising therapy for alcohol disease.

Topics: 3,4-Dihydroxyphenylacetic Acid; Alcohol Drinking; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Brain; Dopamine; Enalapril; Mice; Mice, Inbred C57BL; Rats; Receptor, Angiotensin, Type 1

Different physical and mathematical models of non-stoichiometric hydrates derived form previous work in inorganic hydrates are reviewed. A theoretical link between the order of water molecules in the hydrate and the shape of the isotherm is outlined. The comparison of the models with sorption isotherms and structural data of well-known cases from the literature and one in-house case shows that the model can fit many experimental situations and is in good agreement with qualitative assessments of the order in the hydrates.

Topics: Adsorption; Celiprolol; Enalapril; Erythromycin; Models, Theoretical; Pharmaceutical Preparations; Thermodynamics; Water

A specific, sensitive and precise method for the simultaneous determination of spirapril (CAS 94841-17-5) and spiraprilat (CAS 83602-05-5) in human plasma is described. The method involves the use of enalapril as internal standard, solid-phase extraction, derivatization and capillary gas chromatography with mass sensitive detection. The working range is from 2.5 to 500 micrograms/l for spirapril and spiraprilat, respectively. Data demonstrating the precision and accuracy of the analytical method are given. Moreover, data concerning freeze-thaw stability, long-term stability of frozen samples, short-term stability of thawed samples, and stability of the extracts in the autosampler are given.

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Freezing; Gas Chromatography-Mass Spectrometry; Humans; Indicators and Reagents; Reference Standards; Reproducibility of Results; Solutions

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Enalapril; Humans; Hypertension; Multicenter Studies as Topic; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Diabetes Mellitus, Type 2; Enalapril; Evidence-Based Medicine; Humans; Hypertension; Treatment Outcome

Angiotensin-converting enzyme (ACE) inhibitors effectively reduce proteinuria; however, the optimal antiproteinuric dose is still unknown. We conducted this study to determine whether an increase in ACE-inhibitor dose above the maximal antihypertensive effect has additional antiproteinuric potential.. Twenty-three proteinuric patients were administered the ACE inhibitor spirapril at a starting dose of 3 to 6 mg/d. The dose was increased every 6 weeks until the maximal antihypertensive effect, assessed by 24-hour ambulatory blood pressure (ABP) monitoring, was achieved (spir(max)), then increased to a supramaximal dose (spir(supramax)). Renal parameters, urinary protein excretion, and systemic activity of the renin-angiotensin system were compared between baseline, spir(max), and spir(supramax). Glomerular filtration rate and renal plasma flow were determined before the administration of spirapril and after administration of the supramaximal dose.. Median ABP and proteinuria decreased significantly between baseline and spir(max) (median, 102 mm Hg; range, 82 to 122 mm Hg versus 97 mm Hg; range, 82 to 113 mm Hg; median protein, 2.56 g/d; range, 1.05 to 22.1 g/d versus 1.73 g/d; range, 0.42 to 4.7 g/d). Both creatinine level and creatinine clearance remained unchanged. Suppression of angiotensin II formation led to a significant increase in renin and angiotensin I concentrations and a nonsignificant decrease in aldosterone levels. The increase in spirapril to a supramaximal dose had no further effect on serum renin or angiotensin I levels or proteinuria. There was an additional slight decrease in aldosterone levels and, subsequently, a significantly lower level than at baseline.. Our results show that the antiproteinuric effect of spirapril is associated with its antihypertensive effect. Although high-dose ACE-inhibitor therapy has no additional influence on proteinuria, a possible beneficial long-term effect cannot be ruled out.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Proteinuria; Reference Standards

Topics: Adaptation, Physiological; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Myocardial Ischemia; Rats; Severity of Illness Index; Tachycardia

In view of the prevalence of left ventricular hypertrophy (LVH) in patients with essential hypertension, (15-30%), with an increased risk (2-4 x) of developing myocardial infarction, heart failure or malignant arrhythmia, possibly even leading to sudden cardiac death, effective reversal of LVH is a major aim of treatment. For this purpose, angiotensin-converting enzyme (ACE) inhibitors have proved to be most suitable.. In an open bicentric study involving 37 hypertensive patients with LVH confirmed by echocardiography, the effect of spirapril in reversing the left ventricular mass index (LVMI) and diastolic left ventricular wall thickness was investigated after 3 and 6 months.. The LVMI decreased by 14.7% after 3, and by 27.3% after 6 months, irrespective of whether spirapril was given alone or in addition to other antihypertensive pre-medication. The results may be due to the proven 24-hour effect of spirapril in conjunction with the very long half-life.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Echocardiography; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Time Factors

Topics: Antihypertensive Agents; Blood Pressure; Cerebral Infarction; Circadian Rhythm; Delayed-Action Preparations; Enalapril; Half-Life; Humans; Hypertension; Myocardial Infarction

Topics: Angiotensin-Converting Enzyme Inhibitors; Delayed-Action Preparations; Drug Administration Schedule; Enalapril; Half-Life; Humans; Hypertension

To compare the efficacy of monotherapy with quadropril (spirapril) vs captopril in essential hypertension.. 20 female patients aged 55 +/- 2 years with moderate hypertension (WHO classification) were included in the study. 16 patients had congestive heart failure stage II NYHA and 4 patients stage III NYHA. ECG and echocardiography were performed in all the patients. Two patient groups of 10 patients were treated for 6 weeks. Group 1 received 6 mg quadropril once daily. Group 2 received 25 mg captopril 3 times daily. The therapy was considered to be efficient if diastolic pressure (BP) was reduced to 90 +/- 5 mm Hg and systolic BP to 140 +/- 10 mm Hg from baseline values in the range of 210/120-170/100 mm Hg.. The hypotensive effect of quadropril resulted in stabilisation of BP during the second week of therapy. A significant BP decrease was achieved at the end of 6 week therapy. Systolic BP fell from 178.8 +/- 3.2 to 145 +/- 5.6 mm Hd and diastolic BP from 109.7 +/- 1.2 to 92.4 +/- 1.7 mm Hg. Central and cardiac hemodynamic parameters improved. In one patient the condition improved from CHF stage III to stage II NYHA. No adverse effects were observed. A hypotensive effect of captopril reduced significantly systolic blood pressure from 182.1 +/- 2.7 to 150 +/- 4.6 mm Hg and diastolic BP from 110.4 +/- 1.1 to 100.1 +/- 1.9 mm Hg. Two patients developed adverse effects: cough and chest dyscomfort.. Quadropril monotherapy showed to be more effective in diastolic BP decrease compared with captopril monotherapy and had advantages in one daily dose regimen, absence of the first dose effect and side effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Enalapril; Female; Heart Ventricles; Humans; Hypertension; Middle Aged; Myocardial Contraction; Prognosis; Severity of Illness Index; Ultrasonography; Vascular Resistance

The efficacy and tolerability of spirapril were evaluated in a prospective, multicentre, post-marketing surveillance study on the treatment of arterial hypertension in 5000 patients, most of whom had received a single daily dose of 6 mg spirapril. The study was carried out by internists and general practitioners. In accordance with placebo-controlled clinical trials, spirapril was proven to be a very effective antihypertensive drug, in respect of both the mean reduction in systolic and diastolic blood pressure achieved as well as the responder rate of 89.4% and 85.4% for systolic and diastolic blood pressure, respectively. Efficacy was equally good in single drug treatment and combination treatment. Differentiated evaluation of blood pressure values in respect of the severity of hypertension on the basis of the World Health Organization classification showed a clear relationship between the baseline blood pressure and the reduction in blood pressure. The higher the baseline blood pressure, the more pronounced was the antihypertensive efficacy; a particular reduction in diastolic blood pressure being observed. Tolerability was also good, with an incidence of side effects of only 2.9%. Coughing was observed in only 0.88% of patients. Thus spirapril is seen to be an effective and well-tolerated antihypertensive drug whose efficacy is clearly related to baseline blood pressure and thus is also very effective in the treatment of severe forms of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Cough; Enalapril; Hemodynamics; Humans; Hypertension; Polypharmacy; Product Surveillance, Postmarketing

Glomerular hyperfiltration and renal hypertrophy are both considered important in the progression of diabetic nephropathy. The aim of this study was to compare the effects of an equivalent reduction in blood pressure produced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPI) and an antihypertensive triple drug combination of hydralazine, reserpine and hydrochlorothiazide (HRH) on kidney function, proteinuria and renal structure in hypertensive diabetic rats.. Four groups of animals were evaluated in short-term and long-term studies. In both studies one group served as a non-diabetic hypertensive control (H). The other three groups were rendered diabetic and were allocated to one of the following groups: the first diabetic group received no specific therapy (HD), the second diabetic group was treated with SPI (HD-SPI) and the third diabetic group was treated with HRH (HD-HRH). In each of the two studies the systolic blood pressure (SBP), 24 h urinary total protein, glomerular filtration rate (GFR), glomerular area, proximal tubular area and glomerular sclerosis were evaluated.. The blood pressure reduction was equal in rats receiving either SPI or HRH. The GFR, proteinuria, glomerular area and tubular area were significantly increased in the HD group, both in the short-term and the long-term study. In the HD-SPI group the diabetic hyperfiltration and renal hypertrophy responses were prevented. In the HD-HRH group the GFR and proteinuria were slightly reduced in the later phases of diabetes, while the glomerular area and tubular area were not affected. Semiquantitative analysis of renal lesions showed that SPI was more effective than HRH in the prevention of the development of glomerulosclerosis.. The results of this study suggest that the control of early adaptive hyperfiltration and renal hypertrophy by SPI may be relevant in the prevention of glomerulosclerosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Diuretics; Drug Therapy, Combination; Enalapril; Glomerular Filtration Rate; Hydralazine; Hydrochlorothiazide; Hypertension; Hypertrophy; Kidney; Male; Proteinuria; Rats; Rats, Inbred SHR; Reserpine; Sodium Chloride Symporter Inhibitors

The objective of this work was to investigate a common but poorly understood category of crystalline organic substances: isomorphic desolvates. When solvent is lost from a crystal lattice but the lattice retains its three-dimensional order, a lattice is created which is in a high-energy state relative to the original solvate structure. The desolvated lattice can reduce its internal energy by either resorbing solvent or by relaxation processes which increase the packing efficiency of the solid by reducing the unit cell volume. In the following paper, solid-state properties of isomorphic desolvates of cephalexin, cefaclor, erythromycin A, and spirapril hydrochloride hydrates are investigated. The hygroscopicity of the compounds are evaluated using a vacuum moisture balance, and structural relaxation is measured using a combination of X-ray powder diffraction and isothermal microcalorimetry. The study results are explained in terms of Kitaigorodski's close packing principle.

Topics: Absorption; Calorimetry; Cefaclor; Cephalexin; Enalapril; Erythromycin; Models, Molecular; Molecular Structure; Powders; Solubility; Water; X-Ray Diffraction

Present investigation was undertaken to study the effects of 6 week treatment with spirapril (2 mg/kg po) on insulin sensitivity, and serum lipid levels in streptozotocin (STZ)-diabetic and spontaneously hypertensive (SH) rats. Treatment of rats with spirapril in diabetic and diabetic with hypertensive animals significantly prevented STZ-induced loss of body weight, hypertension, and bradycardia. It also partially but significantly prevented STZ-induced hyperglycaemia in both diabetic Wistar and SH animals. Insulin level was not altered by spirapril treatment. There was significant reduction in cholesterol levels in the diabetic rats. In conclusion, the present investigation presents a number of beneficial effects of spirapril treatment in diabetic and/or hypertensive rats. Spirapril may be considered as one of the drugs of choice in treatment of hypertension when associated with diabetes

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Enalapril; Female; Hypertension; Insulin Resistance; Rats; Rats, Inbred SHR; Rats, Wistar

Potential involvement of brain endogenous angiotensin II in the nociception was investigated in mice by using ACE inhibitors and an angiotensin II antagonist. The mice were allocated to the groups which were orally treated with spirapril (5 mg/kg), trandolapril (5 mg/kg), enalapril (30 mg/kg), losartan (10 mg/kg), or vehicle for 1 day (single dose groups) and 7 days (repeated doses groups). Significantly longer jump latencies were obtained for the groups repeatedly treated with spirapril, trandolapril and losartan, while the group with enalapril gained no effect. In contrast, the single dosing of all agents failed to show antinociceptive effect. The brain ACE activity was determined ex vivo immediately after the hot-plate test, and showed to be suppressed for the groups repeatedly treated with spirapril or trandolapril. In the group repeatedly treated with losartan, ex vivo autoradiography depicted the marked decrease in angiotensin II-binding capacity to the sites containing exclusively AT1 receptors within the blood-brain barrier. The antinociceptive effects of repeated doses of spirapril and losartan were reversed by naloxone. These results suggest that brain endogenous angiotensin II is likely to be involved in central nociceptive mechanisms by its antagonistic interaction with endogenous opioid system.

Topics: Administration, Oral; Analgesics; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Brain; Enalapril; Imidazoles; Indoles; Losartan; Male; Mice; Naloxone; Pain Measurement; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Tetrazoles

Blockade of atrial natriuretic factor (ANF) degradation by specific neutral endopeptidase (NEP) inhibitors may be useful in treatment of hypertension because of the potential diuretic, natriuretic, and arterial pressure (AP)-lowering effects. To test this possibility, we examined the effects of chronic oral treatment with the NEP inhibitor SCH 42495 on BP, diuresis, natriuresis, plasma ANF, cyclic GMP, and the renin-angiotensin system (RAS) in conscious unrestrained spontaneously hypertensive rats (SHR) and compared them with the effects induced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPIR). Four groups of adult SHR were treated orally for 4 weeks with placebo, SCH 42495 3 mg/kg twice daily (b.i.d.), SCH 42495 30 mg/kg b.i.d., and spirapril 1 mg/kg b.i.d. Systolic BP (SBP) was measured weekly, and 24-h urine was collected every week for measurement of urinary volume, sodium, potassium, and cyclic GMP excretion. Plasma ANF, cyclic GMP, renin activity (PRA), and aldosterone (ALDO) were determined from blood collected when the rats were killed. After 4-week treatment with SCH 42495, circulating levels of ANF were similar in both SCH 42495- and placebo-treated SHR; plasma cyclic GMP was higher, however, in the treated rats than in controls and urinary cyclic GMP increased only with the higher dose of SCH 42495. PRA and plasma ALDO tended to be lower in both SCH 42495-treated groups than in controls, yet BP, diuresis, and natriuresis throughout the study were not different from controls. In contrast, spirapril decreased BP; this effect was associated with significant increments in renin and decrements in ALDO and ANF, without changes in plasma and urinary cyclic GMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Analysis of Variance; Animals; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Enalapril; Hemodynamics; Hypertension; Male; Methionine; Natriuresis; Neprilysin; Rats; Rats, Inbred SHR; Renin-Angiotensin System

The role of calcium regarding the origin of irreversible impairment of the myocardial tissue is being intensively studied. An important role in this process is played by mitochondria which by means of the active Ca2+ uptake stimulate its oxidative metabolism and intervene into the Ca2+ homeostasis in mitochondrial cells. The study investigates the influence of cardioprotective substances with distinct mechanisms of the mitochondrial Ca2+ uptake effect. The experiments were performed on chinchilla buck rabbits of 2500-3000 g of body weight. Isolated hearts were perfused according to the method of Langendorff, ischemia was evoked by a 60-minute stoppage of the coronary blood flow. The cardioprotective substances were added into the perfusion solution prior to ischemia inducement. We investigated the following cardioprotective substances: Spirapril (ACE inhibitor), magnesium (Mg2+), and MDL 73,404 (antioxidant, synthetic analogue of alpha-tocopherol). After the 60-minute ischemy the mitochondrial Ca2+ uptake decreased by 43% in comparison with the control group (p < 0.01), Spirapril caused its accretion by 35% in comparison with the ischemic group (p < 0.05), and magnesium increased the uptake even by 52% (p < 0.001). The MDL 73,404 substance had no effect on the mitochondrial Ca2+ uptake. On the basis of experimental results we assume that the cardioprotective effects of Spirapril and magnesium can be besides other factors intermediated also by the increase of intramitochondrial enzymatic activity in consequence of augmented transport of Ca2+ into mitochondria. The cardioprotective effect of the MDL 73,404 substance is assumedly caused by its antioxidant properties. (Fig. 4, Ref. 21.)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Biological Transport; Calcium; Enalapril; In Vitro Techniques; Magnesium; Male; Mitochondria, Heart; Myocardial Reperfusion Injury; Rabbits; Vitamin E

Topics: Enalapril; Humans; Hypertension

Spirapril is a prodrug that is converted by esterolysis to the active (but poorly absorbed) diacid spiraprilat. After intravenous infusion, the disposition of spirapril is monophasic with a terminal half-life of 20-50 minutes. Plasma clearance was 56 l/h and renal clearance was 11 l/h; the volume of distribution was 28 litres. After intravenous infusion of spiraprilat, the disposition was biphasic with half-lives of 2 hours and 35 hours, respectively. Plasma clearance of spiraprilat was 10 l/h, of which 7.6 l/h was cleared by the kidneys. The volume of distribution was 43 litres. The bioavailability of orally administered spirapril was 50% whereas the bioavailability of orally administered spiraprilat was virtually zero. There was a significant first-pass metabolism of spirapril after oral administration. The pharmacokinetics of spirapril were linear within the dose range of 6-50 mg whereas the disposition of spiraprilat was non-linear with respect to the terminal phase. Variability of the pharmacokinetic parameters of spiraprilat were significantly less than that of spirapril. Plasma concentrations of both spirapril and spiraprilat were increased by 30% in the elderly. Similarly, in patients with impaired liver function, plasma concentrations of spiraprilat were reduced by 30%. In patients with severe renal impairment, spiraprilat concentrations were significantly increased by a factor of 3-4. Spirapril showed no clinically relevant drug interactions with either glibenclamide, diclophenac, cimetidine, rifampicin, hydrochlorothiazide or nicardipine.

Topics: Adult; Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enalapril; Humans; Kidney Diseases; Liver Diseases; Reference Values

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Autonomic Nervous System; Enalapril; Hemodynamics; Humans; Middle Aged; Vasomotor System

Both calcium antagonists and angiotensin converting enzyme (ACE) inhibitors are known to diminish the development of intimal thickening after a balloon catheter lesion. It was previously shown that narrowing of carotid artery lumen induced by balloon injury was not influenced by treatment, even though the two ACE inhibitors used inhibited neointimal thickening. The aim of the present study was to include a calcium antagonist as well, in order to investigate whether vasospasm contributes to the persistence of lumen narrowing in ACE inhibitor treated rats after a balloon lesion.. Six groups of 10 rats were subject to balloon lesion of the left carotid artery. They received spirapril (10 mg.kg-1 x d-1) or isradipine (30 or 100 mg.kg-1 x d-1) or both, given throughout the study in the food. Controls received no drug. Neointimal thickening was measured histologically two weeks after injury. The cross sectional carotid lumen area was measured in vivo by nuclear magnetic resonance imaging, both before and two weeks after balloon injury, and also postmortem by histological techniques.. Two weeks after injury, the lumen area of the left carotid artery was significantly reduced following balloon injury, as measured by both techniques. Treatment did not modify the stenosis process as assessed by either method for measuring lumen size. Neointimal thickening, however, was inhibited by between 4% (low dose isradipine) and 59% (combined spirapril + high dose isradipine) in the various treatment groups.. Since calcium antagonist treatment was not able to influence the reduction of lumen size, it is unlikely that the narrowing is due to reversible spasm of the carotid artery in the first two weeks after inducing a balloon lesion. Alternatively, chronic vasospasm of neointimal smooth muscle might not be very sensitive to calcium antagonists.

Topics: Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Carotid Artery Injuries; Carotid Artery, Common; Carotid Stenosis; Catheterization; Enalapril; Isradipine; Magnetic Resonance Spectroscopy; Rats; Rats, Wistar

The antihypertensive effect of isradipine was studied in 45 patients with mild-to-moderate hypertension (mean age 59 years) using casual and ambulatory 24-h blood pressure measurement. Patients were included into the study according to their casual blood pressure. Isradipine was started at a dose of 1.25 mg twice daily for 4 weeks, and increased to 2.5 mg twice daily if casual blood pressure was not normalized. If necessary, 3 mg of spirapril, a new angiotensin-converting enzyme (ACE) inhibitor, (n = 1) or 5 mg of pindolol (n = 1) was added. The active-treatment period lasted 24 weeks. At the end of the therapy, casual blood pressure was significantly decreased (p < 0.001) from 173/103 to 150/86 mmHg, and mean ambulatory blood pressure, from 146/87 to 140/83 mmHg (p < 0.05). When patients were divided into three groups according to initial whole-day ambulatory blood pressure values (group I: < 140/90 mmHg; group II: > or = 140/90 mmHg; group III: > or = 140/<90 mmHg), no effect of treatment was detected in group I. However, whole-day blood pressure fell significantly (p < 0.001) in group II (155/96 vs 143/88 mmHg) as did systolic blood pressure (p < 0.01) in group III (150/83 vs 142/81 mmHg), whereas diastolic blood pressure remained unchanged. Thus, ambulatory blood pressure measurement may be superior to casual measurement in the decision-making process to treat hypertension, avoiding not only the phenomenon of 'white-coat hypertension', but also ineffective treatment. This conclusion, however, should be confirmed by prospective studies.

Topics: Adult; Aged; Ambulatory Care; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure Determination; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Pindolol

To test whether angiotensin-converting enzyme (ACE) inhibition may prevent myocardial damage and may affect coronary microvasculature in spontaneously hypertensive rats (SHR), young 5-week-old SHR were treated for 3 months with spirapril and changes in blood pressure (BP) were monitored. Untreated SHR were used as controls. The rats were killed; left ventricular (LV) shape, weight, and wall thickness were examined and the ventricular myocardium was analyzed morphometrically to determine the effect of the drug on the relative amount, number per unit area of myocardium, and average dimension of foci of myocardial scarring. Moreover, volume fraction, surface, numerical density, and diffusion distance for oxygen of the coronary capillaries were analyzed. BP remained 20-30% lower in treated SHR with respect to controls, and LV weight and thickness decreased 20 and 21%, respectively. The number and dimension of the foci of fibrosis were reduced, resulting in an overall 68% decrement in the amount of myocardial damage. Finally, a 28% increment in numerical density of capillary profiles associated with a 13% reduction in their cross-sectional area decreased the diffusion distance for oxygen from the capillary wall to the myocytes by 14% in treated SHR. Spirapril decreases BP and LV weight and thickness in the SHR model of hypertension and substantially improves coronary capillary microvasculature, decreasing hypertensive myocardial damage. These results may be attributed to inhibition of the systemic effects of angiotensin II (AII) as well as to a local protective action of the drug against possible intramyocardial AII production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Capillaries; Coronary Vessels; Enalapril; Fibrosis; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Rats; Rats, Inbred SHR

Structural alterations after myocardial infarction (MI) in rats are usually examined only after death of the experimental animal. Magnetic resonance imaging (MRI) allows repeated and noninvasive measurements of important structural [left ventricular (LV) mass, LV wall thickness, LV chamber radius] as well as function [LV end-systolic and LV end-diastolic volume, stroke volume (SV), ejection fraction (EF)] parameters for a prolonged period. We describe our experience in a series of experiments in rats. Three weeks after MI, infarct size (IS) was determined by MRI and the rats were divided into two groups with equal IS. Three weeks later, treatment with the angiotensin-converting enzyme (ACE) inhibitor spirapril (10 mg/kg in food) or placebo was started. In both groups, the first MRI scan taken before the treatment showed moderately dilated left ventricles and signs of impaired LV function, i.e., an increase in LV end-systolic and end-diastolic volume and decreased EF. After 3-week treatment, no significant differences with respect to heart structure and function were detected as compared with those of untreated animals. Prolonged treatment for 10 weeks with spirapril resulted in significant reduction of LV dilatation, LV mass, and LV end-systolic and end-diastolic volume, which was accompanied by improved EF. Hemodynamic examinations after treatment for 6 months showed, in contrast to control animals, no increase in right ventricular systolic pressure in animals receiving spirapril. Furthermore, histologic examination of perfusion-fixed hearts at the end of the study demonstrated more pronounced LV dilatation in control animals, thus confirming the in vivo MRI data. Delayed treatment with spirapril proved to have beneficial effects on structure and function of infarcted hearts within 10 weeks. Spirapril limited LV dilatation, reduced LV weight and LV end-systolic and end-diastolic volumes, and improved EF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Enalapril; Hemodynamics; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Myocardial Infarction; Peptidyl-Dipeptidase A; Perfusion; Rats; Rats, Wistar; Stroke Volume; Ventricular Function, Left

1. We examined the effect of spirapril, a potent angiotensin converting enzyme (ACE) inhibitor, on the number of capsaicin-induced coughs in rats and compared with that of enalapril. 2. Chronic treatment with enalapril, at doses of 1 and 3 mg/kg, p.o., significantly and dose-dependently enhanced the number of capsaicin-induced coughs. 3. Chronic treatment with higher dose of spirapril (3 mg/kg, p.o.) also significantly enhanced the number of capsaicin-induced coughs. However, lower dose (1 mg/kg, p.o.) of spirapril had no significant effect on the number of capsaicin-induced coughs. 4. These results suggest that cough induced activity, one of the most serious side effects associated with chronic treatment with ACE inhibitors, of spirapril is relatively lower than that of enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cough; Enalapril; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Reflex

Five groups of 12 rats were subject to balloon lesion of the left carotid artery and neointimal thickening was measured histologically 2 weeks after injury. Rat groups received either spirapril (3, 10 or 30 mg/kg/day, administered throughout the study in the food), cilazapril (10 mg/kg/day) or placebo. Spirapril caused a dose-dependent inhibition of the neointimal thickening of the rat carotid artery. The degree of inhibition with 10 mg/kg/d spirapril and cilazapril was similar (-44% and -42% respectively). The carotid lumen area was measured in vivo by nuclear magnetic resonance (NMR) imaging both before and 2 weeks after balloon injury and also postmortem by histological techniques. Two weeks after injury, the lumen area of the left carotid artery was significantly reduced following balloon injury, as measured by both techniques. Treatment did not detectably modify this stenosis process despite the use of two independent methods for assessing lumen size, even though neointimal thickening was strongly attenuated by both angiotensin converting enzyme inhibitors. This dissociation between inhibition of neointimal lesion development and decrease of lumen size provides a new view of the role of angiotensin converting enzyme inhibitors in vascular damage situations. Our results suggest that the focus, particularly in clinical studies, on lumen size, may mean that potentially beneficial effects of these drugs on other parts of the vascular wall be overlooked.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Carotid Arteries; Carotid Artery Injuries; Catheterization; Cilazapril; Enalapril; Heart Rate; Histocytochemistry; Magnetic Resonance Imaging; Rats; Rats, Wistar; Tissue Fixation

The aim was to assess the influence of the renin-angiotensin system on the geometrical and elastic properties of the aorta in conscious dogs, using a model of renovascular hypertension, and to examine the effects of inhibition of the system by the angiotensin converting enzyme inhibitor spirapril.. The aortic elastic behaviour in response to renovascular hypertension was studied in 15 conscious dogs instrumented with a pressure microtransducer and a pair of ultrasonic diameter dimension gauges in the upper descending thoracic aorta. Renovascular hypertension was induced by surgical occlusion of one renal artery and stenosis of the other. One day after renal surgery, dogs were randomly assigned to two groups receiving for two months either the new angiotensin converting enzyme inhibitor spirapril (n = 8) or a placebo capsule (n = 7). The two groups of dogs were compared to a control group of normotensive dogs (n = 7). After two months of treatment the elastic properties of the aorta were studied by computation of the beat to beat pressure-diameter hysteresis loops obtained during transient increase of pressure induced by bolus doses of angiotensin. The aortic pressure-diameter (P-D) relationship, obtained over a wide range, was fitted by an exponential fit (P = alpha.e beta D), where beta is the stiffness index. A decomposition of the P-D curve according to a biphasic model of the parallel arrangement of elastin and collagen enabled two pressure-diameter elastic moduli to be obtained, one representing the resistance to stretch at low pressure levels (elastic fibres and smooth muscle), and the other representing the resistance to stretch at the highest pressures (collagen fibres).. The pressure-diameter curve of the placebo group was shifted to the left compared to the curves of the control and spirapril groups, showing that renovascular hypertension was associated with isobaric reduction of aortic diameter. The stiffness index beta was higher (p < 0.05) in the placebo group [0.605(SD 0.304) mm-1] than in either the control group [0.362(0.126) mm-1] or the spirapril group [0.348(0.083) mm-1], suggesting that renovascular hypertension was associated with aortic stiffening. The biphasic analysis showed that the collagen pressure-diameter elastic modulus was unaffected by spirapril, whereas the elastin pressure-diameter elastic modulus was significantly reduced by converting enzyme inhibitor with respect to the placebo (p < 0.05).. Chronic converting enzyme inhibition by spirapril prevents the isobaric aortic diameter reduction induced by renovascular hypertension in conscious dogs and decreases aortic stiffness, in particular by changing the elastic behaviour of the elastin fibres rather than of the collagen fibres.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Dogs; Elasticity; Elastin; Enalapril; Hemodynamics; Hypertension, Renovascular; Male

1. To investigate the role of transcriptional and post-transcriptional factors in increasing renin synthesis secondary to angiotensin-converting enzyme (ACE) inhibitors, we studied the changes in levels of renal renin mRNA, plasma renin and other hormonal factors. 2. Spontaneously hypertensive rats were orally administered 10 mg/kg spirapril or vehicle daily for 3, 14 or 28 days. 3. Plasma renin activity in the spirapril-treated group was significantly elevated compared with that in the vehicle group at any time (P < 0.01). However, there was no significant change in plasma angiotensin II concentration between the two groups. The ratio of renal renin mRNA to beta-actin mRNA in the spirapril-treated group was higher than that in the control group (P < 0.01). 4. At 28 days, plasma renin activity in the spirapril-treated group was significantly elevated compared with that at 14 days (P < 0.05). However, there was no change in renin mRNA between 14 and 28 days after ACE inhibitor administration. 5. Plasma ACE activity in the treatment group was less than that in the control group at any time (P < 0.01). 6. Our study demonstrated a non-proportional change in plasma renin and renal renin mRNA levels. It is suggested that the main determinant of the rate of renin synthesis after administration of an ACE inhibitor may be post-transcriptional factors, and that unknown mechanisms may be involved in the increase in plasma renin level after long-term administration of ACE inhibitor in addition to the short feedback mechanism brought about by the decrease in angiotensin II.

Topics: Actins; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; RNA, Messenger

Sixteen essential hypertensive patients were entered into a protocol assessing the effect of Spirapril, an angiotensin-converting enzyme (ACE) inhibitor, on blood pressure, the renin-aldosterone system, and renal function. Specifically monitored before, during 6 weeks, and 6 months of Spirapril therapy were plasma renin activity, plasma aldosterone, serum ACE, the renal clearances of creatinine, inulin, and para-aminohippurate, and urinary albumin excretion. Blood pressure was well controlled. Spirapril stimulated plasma renin activity and suppressed ACE throughout the entire protocol. Renal clearances were unchanged. Renal vascular resistance was decreased. Urinary albumin excretion was decreased. The authors conclude that the ACE inhibitor, Spirapril, when used as an effective antihypertensive agent, preserves renal function, lowers renal vascular resistance, and decreases urinary albumin excretion.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Renal Circulation; Renin-Angiotensin System; Time Factors

The effect of the angiotensin-converting enzyme (ACE) inhibitor spirapril on structural and functional parameters of volume-overloaded rat hearts was evaluated in a time-course study. Left ventricular hypertrophy (LVH) was induced by graded disruption of the aortic valve in male Wistar rats. Four weeks later, structural (LV mass and LV wall thickness) as well as functional parameters [LV end-systolic and end-diastolic volumes, stroke volume (SV), ejection fraction (EF)] were determined in anesthetized animals by magnetic resonance imaging (MRI). The rats were then divided into two groups, one of them receiving spirapril (10 mg/kg/day) in food. LV parameters were evaluated by MRI at 4, 18, 25, and 32 days after treatment was started. MRI analysis before the start of treatment showed that both groups had developed a similar degree of eccentric LV hypertrophy. Similarly, LV wall thickness, end-systolic and end-diastolic volumes, SV, and EF did not differ between the groups. Treatment with spirapril resulted in stable LV weight during the follow-up period of 32 days, whereas the untreated group showed a significant steady increase in heart weight. LV end-diastolic volume, LV end-systolic volume, and SV were smaller in the spirapril group when measured after 25 and 32 days, but only the difference in end-diastolic volume reached statistical significance. LV wall thickness and EF were not affected by spirapril. After the last MRI determinations, blood pressure (BP) and the response to angiotensin I (ANGI) were measured in conscious animals. Systolic BP (SBP) and mean arterial pressure (MAP) were significantly lower in spirapril-treated rats, and the dose-response curve to ANGI was shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Enalapril; Heart Ventricles; Magnetic Resonance Imaging; Male; Rats; Rats, Inbred Strains; Stroke Volume; Ventricular Function, Left

Blunted cardiac responses to sympathetic and vagal activation are key features of heart failure. Since the modulation of drug effects by a selective autonomic dysfunction is little known, we developed an acute rabbit model imitating these defects. Anesthetized rabbits were subject to cervical vagotomy and propranolol (1 mg/kg i.v.) pretreatment, thus eliminating vagally and sympathetically mediated cardiac responses, while maintaining the responsiveness of the peripheral circulation to these reflexes ("V-B" animals). Responses to drugs were altered in V-B compared with normal animals: Ouabain (5-50 micrograms/kg) increased myocardial contractile force more and milrinone (30-300 micrograms/kg) less, yet it increased the heart rate more; the reflex tachycardia to nitroprusside (1-10 micrograms/kg/min) was blunted and spirapril (0.1 and 1 mg/kg, all i.v.) decreased the central venous pressure only in V-B animals. Several drug effects were thus strongly modulated by autonomic dysfunction and responses of V-B animals were closer to those of heart failure patients than the responses of the normal animals, especially for milrinone.

Topics: Animals; Autonomic Nervous System; Cardiovascular Agents; Disease Models, Animal; Enalapril; Heart Failure; Heart Rate; Milrinone; Myocardial Contraction; Nitroprusside; Ouabain; Propranolol; Pyridones; Rabbits; Vagotomy; Vasodilator Agents

Radioimmunoassays for a nonsulfhydryl angiotensin converting enzyme inhibitor prodrug--spirapril--and its active metabolite--spiraprilate--are described. Nonextraction equilibrium assays using antibodies with a high specificity for spirapril or spiraprilate were used, with charcoal separation of bound and free tracer. Within-assay reproducibility (CV%) was less than 20% in the concentration range 0.5-40 micrograms/L for both analytes and the comparable value for between-assay reproducibility was less than 25%. Results for external quality control samples were in good agreement with the expected values of 0-250 micrograms/L (spirapril, r = 0.997) and 0-300 micrograms/L (spiraprilate, r = 0.999). Overall, samples circulated to four laboratories gave good agreement for measured values, including one center using gas chromatography-mass spectrometry analysis for the two compounds. Data are presented to show the suitability of these two assays to the measurement of spirapril and spiraprilate in clinical samples from assays to the measurement of spirapril and spiraprilate in clinical samples from dose-ranging and bioequivalence studies. Results are also shown relating drug plasma concentration data to a measurement of the pharmacodynamic effects of spiraprilate, namely inhibition of angiotensin converting enzyme activity. It is concluded that these assays have the sensitivity for use in studies to model the relationship between the pharmacokinetics and pharmacodynamics of the two compounds.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antibody Specificity; Buffers; Charcoal; Cross Reactions; Dextrans; Enalapril; Humans; Quality Control; Radioimmunoassay; Reference Standards; Serum Albumin, Bovine

1. This study was undertaken to examine the possibility that the level of angiotensin-converting enzyme (ACE) increases in vascular tissue, and that this may participate in the pathogenesis of hypertension in spontaneously hypertensive rat (SHR). 2. In SHR, at the established hypertensive stage, the prolonged antihypertensive effect induced by a single oral dose of spirapril was closely correlated to the long-lasting inhibition of ACE in aortae and mesenteric arteries. In contrast, ACE in plasma, lung, heart and kidney recovered from inhibition faster than in vessels. 3. Prolonged daily oral treatment of SHR with spirapril, initiated at the age of 8 weeks and continued for 8 weeks, prevented the development of hypertension with concomitant decrease in aortic ACE activity. Blood pressure continued to be suppressed after the drug was withdrawn, as did the aortic ACE activity. 4. Spontaneously hypertensive rats developed hypertension with age as well as with the increase in aortic ACE activity which became higher with age than that of Wistar-Kyoto (WKY) normotensive control rats. On the contrary, ACE activity in plasma and lung of SHR was substantially lower than that of WKY at any age from 4 to 20 weeks old. Brain ACE activity of SHR did not differ from that of WKY at any age. Aged SHR showed the lower enzyme activity in the kidney compared with that of age-matched WKY. 5. Our results support the hypothesis that increased vascular ACE may play an essential role in the development and maintenance of hypertension in SHR.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Enalapril; Heart Rate; Hypertension; Lisinopril; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The acute hemodynamic, hormonal, and pharmacokinetic responses to the oral angiotensin-converting enzyme (ACE) inhibitor spirapril were studied in 15 patients with moderate to severe congestive heart failure in a baseline controlled dose-ranging study. Doses of 0.3, 1.0, 1.5, 3.125, and 6.25 mg were investigated for 24 h in three groups of five patients each. All doses demonstrated a significant reduction in serum ACE, even after 24 h. Significant reductions in mean arterial pressure, systemic vascular resistance, and pulmonary capillary wedge pressure were observed with doses greater than 1.0 mg spirapril. Maximal significant hemodynamic effects occurred approximately 4-6 h after drug administration. The plasma concentrations of spirapril and its metabolite spiraprilate were dose-dependent. After administration of spirapril, the quick rise to the peak level of spiraprilate suggests rapid metabolism of spirapril into spiraprilate and a slow elimination of this metabolite. No severe hypotension or other serious side effects occurred in the patients studied. The results indicate that spirapril may be expected to be an effective drug in the treatment of congestive heart failure. From our findings we conclude that 1.5 mg spirapril is an optimal starting dose in patients with moderate to severe congestive heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dose-Response Relationship, Drug; Enalapril; Female; Heart Failure; Heart Rate; Hemodynamics; Hormones; Humans; Male; Middle Aged; Norepinephrine; Renin

1. To obtain information on regulation of the brain renin-angiotensin system, the effect of long-term administration of angiotensin-converting enzyme (ACE) inhibitor on brain renin and angiotensinogen mRNA was studied. 2. Spirapril (3 mg/kg) was orally administered daily for 8 weeks to spontaneously hypertensive rats (SHR) from 12 weeks after birth. Renin and angiotensinogen mRNA in the brain and kidney were then quantitated by Northern blot analyses with [32P]-labelled rat renin and angiotensinogen cDNA as hybridization probes. Plasma renin activity (PRA), angiotensin II (AII) concentration, plasma ACE activity and brain tissue ACE activity were also measured. 3. Compared with the control group, the Spirapril-treated group had significantly lower blood pressure (P less than 0.01), significantly higher PRA (P less than 0.01), a not significantly different plasma AII concentration, and lower plasma and brain ACE activities (P less than 0.01). Interestingly, the brain renin and angiotensinogen mRNA levels of the two groups were similar, but the renal renin mRNA level was significantly higher in the Spirapril-treated group (P less than 0.01). 4. These results indicate that the mRNA levels of brain renin and angiotensinogen were not affected by chronic ACE inhibition in the circulation and suggest that AII in the brain might not be affected by systemic ACE inhibition.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Brain; Enalapril; Gene Expression; Male; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; RNA, Messenger; Time Factors

The aim was to compare the effects of two novel angiotensin converting enzyme (ACE) inhibitors, spirapril and zofenopril, on cardiac remodelling in rats with congestive heart failure after myocardial infarction. Spirapril contains no sulphydryl group, whereas zofenopril is a sulphydryl containing ACE inhibitor.. Experimental myocardial infarction was induced by ligation of the left coronary artery. Sham operated animals served as controls. Treatment with spirapril (2-2.5 mg.kg-1.d-1) or zofenopril (12-15 mg.kg-1.d-1) added to the drinking water was started immediately after myocardial infarction or sham operation and continued for six weeks. After the treatment period, all rats were killed. The heart was rapidly removed and perfused as described by Langendorff. Heart rate and left ventricular pressure were measured both at baseline and during stimulation with isoprenaline (6 nM). Heart and lung weights were determined.. Normotensive male Wistar rats (220-240 g) were used.. Experimental myocardial infarction considerably increased left ventricular cavity volume. Chronic treatment with either spirapril or zofenopril significantly attenuated this increase in volume. In infarcted rats, the increase in total heart and lung weight was also significantly reduced by chronic treatment with spirapril and zofenopril, indicating that these compounds reduce cardiac mass and pulmonary congestion in congestive heart failure due to myocardial infarction. There were no significant differences between treatment with spirapril and zofenopril. In the isolated and perfused rat heart, myocardial infarction significantly decreased both heart rate and left ventricular pressure. Converting enzyme inhibition only affected heart rate. Heart rate was significantly higher in infarcted animals treated with spirapril and zofenopril than in untreated infarcted animals.. Both spirapril and zofenopril attenuated ventricular enlargement and cardiac hypertrophy in rats with congestive heart failure after myocardial infarction when treatment was started in the acute phase of myocardial infarction. No additional role could be attributed to the sulphydryl moiety of zofenopril. It is also suggested that these two ACE inhibitors modify cardiac sympathetic activity in rats with congestive heart failure, but more studies are needed to confirm these findings.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Disease Models, Animal; Enalapril; Heart; Heart Rate; Isoproterenol; Male; Myocardial Infarction; Myocardium; Rats; Rats, Inbred Strains

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Dioxolanes; Dipeptides; Enalapril; Hypertension; Methionine; Myocardium; Neprilysin; Rats; Rats, Inbred SHR

The cardiac and hemodynamic effects of 3 doses (0.1, 0.3 and 1 mg/kg, iv) of spiraprilat, the diacid active metabolite of the new angiotensin I converting enzyme inhibitor spirapril, have been investigated and compared to those of saline in chronically implanted conscious dogs at rest. Under a normal sodium diet, spiraprilat, 1 mg/kg, induced significant (at least P less than 0.05) decreases in mean arterial pressure (MAP, -11%), total peripheral resistance (TPR, -21%), left ventricular end diastolic pressure (LVEDP, -15%) and increases in heart rate (HR, +12%) and cardiac output (CO, +16%) whereas dP/dtmax remained unchanged. Spiraprilat-induced tachycardia was not modified by propranolol pre-treatment but was abolished by previous administration of the propranolol-N-methylatropine combination. Spiraprilat, 0.1 mg/kg, did not affect any parameter, but spiraprilat, 0.3 mg/kg, showed intermediate effects. Finally, sodium depletion strongly potentiated spiraprilat effects on MAP, TPR, LVEDP, HR and CO. We conclude that: a), in conscious dogs under normal sodium diet, spiraprilat reduces TPR and MAP through peripheral vasodilating properties; b), spiraprilat-induced tachycardia is mainly related to parasympathetic tone withdrawal, possibly in relation with high and low pressure baroreceptors deactivation; and c), sodium depletion considerably potentiates spiraprilat cardiac and hemodynamic effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiac Output; Dogs; Enalapril; Female; Heart; Heart Rate; Hemodynamics; Male; Sodium; Sodium Chloride

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Chemical Phenomena; Chemistry; Dogs; Enalapril; Male; Phenylbutyrates; Rats; Rats, Inbred Strains; Spiro Compounds

The antihypertensive activity of spirapril given alone or in combination with felodipine was investigated in spontaneously hypertensive rats (SHR) during a 3-week treatment regimen and for one week after drug withdrawal. Systolic blood pressure and heart rate were recorded once a week just before dosing and at varying time intervals up to 6 hr thereafter. Recordings were continued for one week after drug withdrawal. Spirapril alone at 1 and 5 mg/kg p.o. was found to produce dose-related antihypertensive effects throughout the treatment period. Felodipine alone at 5 mg/kg p.o. reduced blood pressure slightly more than did the low dose of spirapril. The combination of spirapril and felodipine induced a marked antihypertensive response which was greater than that observed in rats treated with either drug alone. One week after treatment withdrawal, blood pressure was at initial levels with no evidence of rebound phenomena. No significant heart rate changes were observed in the treated groups, as compared with the controls, except for an increase on the 1st day of treatment in rats given felodipine. These findings indicate that the combination of an angiotensin converting enzyme (ACE) inhibitor with a calcium antagonist leads to an effective control of hypertension over a prolonged period of treatment. Since the combination allows effectiveness with lower doses of ACE inhibitor, it is expected that the antihypertensive efficacy might be associated with a lower liability to untoward effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Felodipine; Heart Rate; Male; Nitrendipine; Random Allocation; Rats; Rats, Inbred SHR; Vasodilator Agents

The new angiotensin converting enzyme inhibitor, spirapril, was found to inhibit the pressor effects of angiotensin I about 10 times more potently than captopril in conscious rabbits. Its effects on systemic hemodynamics and regional blood flows were studied in two groups of 8 normotensive anaesthetized rabbits pretreated 24 h before the acute experiment either by substituting 0.45% NaCl for drinking water or with a subcutaneous injection of 20 mg kg-1 furosemide. Under barbiturate anaesthesia, regional blood flows were then measured with microspheres before and after i.v. administration of two doses of spirapril. With anaesthesia and surgery, plasma renin activity (PRA) was elevated in the salt-replete group and very high in the salt-depleted group (37 and 152 ng ml-1 h-1, respectively). Spirapril lowered blood pressure more in salt-depleted animals and increased only cardiac output and renal blood flow in salt-replete ones. Weak cardiodepression, associated with a small fall of cardiac output, was found in salt-depleted rabbits, indicating that very high angiotensin II levels may contribute to maintain cardiac function in volume-depleted animals with an activated sympathetic system. Coronary and skin blood flow decreased, and pancreatic and hepatic artery flow increased only in this group. A change in the salt balance can thus cause major differences in the responses of the peripheral circulation to angiotensin converting enzyme inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Dose-Response Relationship, Drug; Enalapril; Female; Hemodynamics; Male; Prodrugs; Rabbits; Regional Blood Flow; Sodium

Spirapril (SCH 33844; 7-N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl-1,4-dithia- 7-azaspiro[4,4]-nonane-8(S)-carboxylic acid) is a new angiotensin-converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of hip-his-leu by rabbit lung ACE in a potent (Ki = 0.74 nM), selective, and noncompetitive fashion. SCH 33844 (0.03-1 mg/kg p.o.) produced dose-related inhibition of angiotensin I (AI) pressor responses in conscious rats with a duration of 24 h at the higher dose. SCH 33844 (0.3-30 mg/kg p.o.) reduced blood pressure in a dose-related manner in conscious SHR with a 24-h duration. Antihypertensive activity was enhanced in the presence of hydrochlorothiazide. The drug (1-10 mg/kg p.o.) also lowered blood pressure in conscious hydrochlorothiazide-treated normotensive dogs. In anesthetized dogs, SCH 33844 (1 mg/kg i.v.) reduced blood pressure and total peripheral vascular resistance and slightly increased cardiac output and stroke volume. These results suggest that peripheral vasodilation is the primary mechanism of the antihypertensive action. The metabolic profile of SCH 33844 was evaluated in dogs and rats. The compound was absorbed in a dose-proportional manner and excreted primarily as the diacid form. In contrast to captopril and enalapril, most of the drug (67%) was excreted into the feces following i.v. dosing. Chronic toxicological evaluation in dogs and rats demonstrated that the drug was relatively devoid of toxicity at oral doses as high as 400 and 450 mg/kg/day, respectively. Slight decreases in heart weight (rats) and increases in granularity of the juxtaglomerular apparatus were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Dogs; Enalapril; Hemodynamics; In Vitro Techniques; Mice; Rats; Tissue Distribution

SCH 33844 is a new, potent and long-acting inhibitor of angiotensin converting enzyme (ACE). Antihypertensive, hemodynamic and autonomic actions of SCH 33844 were examined in the present series of experiments. Oral administration of 0.3-30 mg/kg reduced blood pressure of spontaneously hypertensive rats. The magnitude of the response was significantly enhanced by pretreatment of the animals with hydrochlorothiazide. Blood pressure remained significantly depressed 24 hr following doses of 3 and 10 mg/kg. Administration of SCH 33844 (3 mg/kg) twice daily to nonpretreated rats or once daily to diuretic-pretreated animals for 5 days resulted in a progressive decrease in blood pressure. The compound did not reduce blood pressure in nephrectomized rats demonstrating the dependence of its action on renal renin. SCH 33844 (1-10 mg/kg orally) also produced dose-related decreases in pressure in diuretic-pretreated conscious normotensive dogs. However, only a small fall in pressure occurred in non-pretreated dogs. Hemodynamic actions were examined in anesthetized dogs. SCH 33844 (1 mg/kg i.v.) reduced blood pressure, increased cardiac output and caused a large fall in peripheral resistance. Autonomic actions were assessed in pithed rats. The compound (10 mg/kg orally) tended to decrease pressor responses to sympathetic activation and to i.v. norepinephrine. This profile is probably due, at least in part, to vasorelaxation following suppression of angiotensin II generation. In conclusion, SCH 33844 is a potent, long-lasting antihypertensive agent which reduces peripheral vascular resistance and possesses only slight autonomic effects.

Topics: Adrenergic Agonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Dogs; Enalapril; Female; Hemodynamics; Hydrochlorothiazide; Male; Nephrectomy; Rats; Rats, Inbred SHR; Renin

SCH 33844 is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of the synthetic substrate hippuryl-histidyl-leucine by rabbit lung ACE in vitro with an IC50 (concentration inhibiting enzyme by 50%) of 0.81 nM. The ester was 83 times less active. Intravenous administration of SCH 33844 and its diacid inhibited pressor responses to angiotensin I (AI) in anesthetized rats with calculated ID50's of 16 and 8 micrograms/kg, respectively. Oral administration of SCH 33844 (0.03-1 mg/kg) inhibited AI pressor responses in conscious rats with a duration of 24 hr at the highest dose. The diacid was inactive. Intravenous administration of SCH 33844 (100-1000 micrograms/kg) or its diacid (30 micrograms/kg) to anesthetized dogs inhibited AI pressor activity and potentiated the depressor response to bradykinin. SCH 33844 inhibited AI responses in conscious dogs following oral administration of 0.3-3 mg/kg. Oral administration of SCH 33844 (1 mg/kg) to conscious monkeys inhibited AI pressor responses for the 4 hr duration of study. In conclusion, SCH 33844 is a potent, orally effective ACE inhibitor in rats, dogs and monkeys.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Brain; Chemical Phenomena; Chemistry; Dogs; Drug Administration Routes; Drug Synergism; Enalapril; Female; Macaca fascicularis; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains

The antihypertensive activity of SCH 33844, a new angiotensin converting enzyme inhibitor, was investigated in conscious spontaneously hypertensive rats during a 3-week treatment regimen and for 1 week following drug withdrawal. SCH 33844 was given once daily at 2 dose levels (1 and 5 mg/kg orally) and its effects were compared with those of captopril (60 mg/kg orally). Systolic blood pressure was recorded twice weekly just before administration and at varying time intervals up to 6 hr after dosing; recordings were continued for 1 week after drug withdrawal. SCH 33844 was found to produce dose-related antihypertensive effects. Given at 1 mg/kg, the compound elicited small but significant blood pressure changes during the treatment. After drug withdrawal, systolic blood pressure returned to pre-drug levels within 1 week. SCH 33844 at 5 mg/kg, and captopril at 60 mg/kg, both reduced blood pressure markedly and to a similar extent. After each administration the effect was rapid in onset, lasted for over 6 hr and was not subject to tolerance. Drug withdrawal resulted in a gradual return of systolic blood pressure toward pre-treatment levels within 1 week, with no evidence of rebound phenomena. These results indicate that SCH 33844, like captopril, produces an effective antihypertensive action throughout a repeated dosing.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Dose-Response Relationship, Drug; Enalapril; Male; Rats; Rats, Inbred SHR; Substance Withdrawal Syndrome