spirapril and Hypertension

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

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

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

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

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

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

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 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

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

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

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

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 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

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

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 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

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

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

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

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

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

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

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

Topics: Enalapril; Humans; Hypertension

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

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

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

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