spirapril and Heart-Failure

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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