Antimo Papa

Failure of protective effect of Captopril and Enalapril on exercise and dipyridamole-induced myocardial ischemia

Fifteen patients with angiographic evidence of significant coronary artery disease, exertional myocardial ischemia, and positive dipyridamole echocardiographic test results at basal conditions and after 7 days of placebo treatment were prospectively studied to see whether captopril (containing sulfhydryl) and enalapril (nonsulfhydryl) modify myocardial ischemia induced by exercise testing and the effects of dipyridamole echocardiographic testing on regional myocardial contractility. Patients were randomized to captopril (150 mg/day in 3 separate doses) or enalapril (20 mg/day) for 1 week. At the end of this period each patient crossed over to the alternate regimen after a washout period of 7 days. Exercise stress testing and dipyridamole echocardiographic testing were repeated at the end of each treatment period. Neither captopril nor enalapril had a significantly greater anti-ischemic effect than placebo in any patient. Exercise duration, time to onset of ST-segment depression, maximal workload, degree of ST-segment depression, and rate-pressure product were not affected by either drug. Neither captopril nor enalapril improved dipyridamole-induced mechanical dysfunction or ST-segment depression.

A randomized, double-blind comparison of lercanidipine 10 and 20 mg in patients with stable effort angina: clinical evaluation of cardiac function by ambulatory ventricular scintigraphic monitoring.

We evaluated the antiischemic action and the effects on left ventricular response to exercise of lercanidipine, a long-acting dihydropyridine calcium antagonist, in 23 patients with stable effort angina in a randomized, double-blind, parallel trial. Left ventricular function was assessed during upright bicycle exercise using an ambulatory radionuclide detector for continuous noninvasive monitoring of cardiac function. Exercise was performed under control conditions before (run-in placebo period) and after 2-week treatment with lercanidipine 10 or 20 mg once daily. During the placebo run-in period and at the study end, patients underwent clinical examination, ECG, exercise tests, ambulatory ventricular scintigraphic monitoring (VEST). Results showed that both drug doses increased time to onset of ST segment depression ≥1 mm and peak ST segment depression, with improvement of total exercise duration. Heart rate, blood pressure, and the rate-pressure product did not significantly change with respect to pretreatment value. The left ventricular ejection fraction, indicating contractility state of myocardium, was unchanged at rest and during exercise after both lercanidipine doses. In conclusion, lercanidipine is safe and effective in reducing ischemia in patients with stable effort angina without any deterioration of cardiac function.

Effects of delapril in combination with indapamide on blood pressure and left ventricular mass in elderly hypertensive patients.

We present a single-blinded, placebo-controlled trial of the effects on blood pressure and left ventricular mass and of the safety of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin-converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65–85 years (mean age, 69 ± 1) with sitting systolic/diastolic blood pressure of 160–200/95–115 mm Hg (at the end of the placebo period). After a 2-week placebo run-in, patients took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. Twenty-four-hour ambulatory blood pressure was monitored and M- and B-mode echo-cardiography were performed before and after 24 weeks of treatment. Blood pressure decreased from 156 ± 1.5/101 ± 1 mm Hg before treatment to 133 ± 1/73 ± 1 mm Hg after treatment. The total blood pressure burden also decreased; the percentage of measurements with a systolic blood pressure ≥ 140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg decreased from 48.7% ± 5%/31.5% ± 4.3% to 23.5% ± 4%/20.5% ± 2.9% (p < 0.0005 and p > 0.05). The area under the curve of the 24-hour blood pressure decreased from 250 ± 41/103 ± 21 mm Hg to 97 ± 21/37 ± 8.5 mm Hg (p < 0.001 and p < 0.005). The left ventricular mass index (LVMI) in the 15 patients with pretreatment left ventricular hypertrophy was reduced after therapy from 167.5 ± 8.5 g/m2 to 152.2 ± 7.6 g/m2 (p < 0.05). A positive correlation was observed between percent changes of the area under the curve of the 24-hour diastolic blood pressure and percent changes of LVMI (r = 0.6; p < 0.05) in the 15 patients with left ventricular hypertrophy. Only 2 patients reported side effects: 1 developed skin rash and 1 developed headache. The safety of the treatment was confirmed by laboratory tests. In elderly hypertensive patients, the combination of delapril and indapamide at low doses reduced blood pressure and had favorable effects on LVMI with few side effects.

A randomized, double-blind comparison of 10 and 20 mg lercanidipine in patients with stable effort angina: effects on myocardial ischemia and heart rate variability.

We evaluated the anti-ischemic action and the effects on autonomic function of lercanidipine, a long-acting dihydropyridine calcium antagonist, in 25 patients with stable effort angina in a randomized, double-blind, parallel trial. After a 2-week placebo run-in period, patients entered a 2-week treatment period with 10 or 20 mg of lercanidipine once daily. During the placebo run-in period and at the study end, the patients underwent clinical examination, electrocardiography, exercise tests, 24-hour Holter electrocardiography for long-term heart rate variability evaluation, and short-term spectral analysis of heart rate and systolic blood pressure variability and plasma epinephrine and norepinephrine levels at rest and during tilting. Results showed that time to onset of ST segment depression ≥1 mm was significantly increased by both drug doses. No significant change was recorded in the average hourly heart rate after treatment with both 10 and 20 mg of lercanidipine. During the 24-hour recordings, no significant change was observed in low-frequency power, high-frequency power, or low frequency/high frequency. In the standing position, there was a significant increase in plasma norepinephrine and epinephrine concentration in both groups, and no change in the supine position after 10 and 20 mg of lercanidipine. When considering short-term heart rate variability, no significant difference was observed in either treatment group in low frequency, high frequency, or their ratio on electrocardiographic R-R spectra. The blood pressure spectral component was also unchanged. In conclusion, lercanidipine is effective in reducing ischemia in patients with stable effort angina. Moreover, lercanidipine does not cause adrenergic activation, which is the main mechanism hypothesized to explain the negative effect on cardiovascular mortality assigned to short-acting dihydropyridine calcium antagonists.

Quinapril in patients with congestive heart failure: controlled trial versus captopril.

After two weeks of a wash-out run-in period with placebo, 131 patients with congestive heart failure (New York Heart Association [NYHA] class II to III) and left ventricular ejection fraction ≤ 40% were randomly assigned to a treatment period of 4 weeks with 10 mg quinapril once daily or 12.5 mg captopril twice daily. At the end of this period, doses were titrated to 20 mg quinapril once daily or 25 mg captopril twice daily on the basis of physician judgment if there were no major adverse reactions and if blood pressure was not below 110/70 mm Hg. Clinical symptoms of heart failure were significantly relieved by both drugs at the end of a 12-week treatment period. At the beginning of the study, 23 (35%) of the 65 patients taking quinapril and 27 (41%) of the 66 patients taking captopril were in NYHA functional class III, whereas, at the end of the trial, only 4 (6%) of the patients in the quinapril group and 14 (22%; p < 0.05 versus quinapril) patients in the captopril group were classified as NYHA class III. Both drugs had a positive effect on echocardiographic parameters. There was a statistically significant increase in exercise duration in both treatment groups (quinapril, 6.2 ± 1.8 versus 7.8 ± 1.9 minutes, p < 0.001; captopril, 5.9 ± 1.9 versus 7.1 ± 2.3 minutes, p < 0.001). One patient in the quinapril group died suddenly during the study and two patients in the captopril group dropped out of the study due to persistent dry cough. No patient in the quinapril group reported side effects. Three patients in the captopril group suffered from moderate dry cough, one from taste-blindness, and another from unstable angina. The safety of the tested drugs was confirmed by laboratory tests. Quinapril was as effective as captopril in reducing signs and symptoms of heart failure and in improving the left ventricular function and the exercise capacity with few side effects.

Acute dose-response, double-blind, placebo-controlled pilot study of lercanidipine in patients with angina pectoris

Abstract Objective The aim of this double-blind, placebo-controlled, parallel-group, dose-response, pilot study was to assess the acute hemodynamic and therapeutic effects of a single dose of lercanidipine in patients with angina pectoris. Background The calcium channel blocker lercanidipine is a new lipophilic, vasoselective dihydropyridine derivative with a slow onset and long duration of action that has been shown to be effective in hypertensive patients at a dosage of 10 to 20 mg/d. Methods Forty-five patients (42 males, 3 females) with chronic stable angina pectoris and angiographically documented coronary artery disease received a single oral dose of lercanidipine 5 mg (n = 7), 10 mg (n = 8), 20 mg (n = 7), 30 mg (n = 7), or 40 mg (n = 8) or of placebo (n = 8). Anti-ischemic and antianginal efficacy was assessed by a bicycle exercise test 3 and 8 hours after dosing. Systolic and diastolic blood pressures and heart rate were assessed both at rest and during exercise. Results Because of the small number of patients and high variability between the groups, no significant difference was seen compared with placebo. Nevertheless, a significant ( P Conclusions Our data indicated that the acute administration of lercanidipine 10 mg to 40 mg in patients with stable exercise-induced angina pectoris caused no unfavorable change in myocardial oxygen consumption and was well tolerated.

The effects of delapril in combination with indapamide on glomerular filtration rate in elderly hypertensive patients.

We performed a placebo-controlled trial on the effects of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin-converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65–85 years (mean age, 69 ± 1 years) who took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. In the present study (performed simultaneously with our trial on the effects of delapril/indapamide on left ventricular mass in elderly patients with hypertension and on the same patients), we report the effects of this drug combination on glomerular filtration rate. Sitting arterial pressure (mean ± SE) decreased from 156 ± 1.5/101 ± 1 mm Hg at baseline to 133 ± 1/73 ± 1 mm Hg at the end of the 24-week treatment period (p < 0.0001). No significant changes in heart rate or episodes of orthostatic hypotension were observed. Glomerular filtration rate increased from 91.8 ± 4.42 mL/min at baseline to 106.3 ± 4.5 mL/min (p < 0.001) at the end of treatment. Our results show that the combination of delapril and indapamide is effective in the elderly hypertensive patient, with a favorable effect on the prevention of deterioration of kidney function.

Randomized, placebo-controlled, crossover, double-blind comparison of immediate- and sustained-release formulations of Gallopamil in elderly patients with stable effort angina

Abstract Background The pharmacokinetics, efficacy, and safety of calcium channel blockers have rarely been investigated in the elderly. Gallopamil, a methoxy derivative of verapamil with calcium antagonistic properties, has been shown to be effective in the treatment of angina pectoris. Objective The aim of this study was to assess the anti-ischemic action of gallopamil, its effects on left ventricular and autonomic function, and its pharmacodynamics and safety in elderly patients. Methods We studied immediate-release (IR) and sustained-release (SR) formulations of gallopamil in 12 sedentary elderly patients with stable effort angina and angiographically documented coronary artery disease in a randomized, placebo-controlled, crossover, double-blind trial. Following a run-in period, patients received either IR gallopamil 50 mg TID or SR gallopamil 100 mg BID for 28 days, after which patients crossed over to the alternate regimen. A washout period of 4 days was incorporated between the 2 treatment phases. Antianginal efficacy was assessed by monitoring the number of angina episodes per week and the amount of sublingual nitroglycerin consumed per week as well as sequential cycloergometer exercise testing 2 and 6 hours postdose. Patients underwent clinical examination, electrocardiography (ECG), echocardiography, 24-hour Holter ECG monitoring, and blood testing at the beginning of the study and at the end of each phase. On the last day of the active treatment period, sequential blood samples were collected to determine plasma levels of gallopamil. Results Both IR and SR gallopamil reduced the number of angina episodes and the amount of nitroglycerin consumed per week. Gallopamil also reduced the number of ECG signs of ischemia at peak exercise testing, as well as symptomatic and asymptomatic ischemic episodes on 24-hour Holter ECG monitoring. IR and SR gallopamil did not affect left ventricular diameters, ejection fraction, and average heart rate, nor did they cause significant changes in heart rate variability. Peak plasma levels of gallopamil were reached rapidly after ingestion of the IR and SR formulations. The plasma concentrations of gallopamil and the norgallopamil metabolite were similar during the first 2 hours after administration of IR and SR gallopamil. Thereafter, patients who received the SR formulation showed significantly higher gallopamil ( P P Conclusions Our data suggest that both IR and SR gallopamil were effective in reducing signs and symptoms of ischemia in elderly patients with stable effort angina, with few adverse effects.