A controlled single-dose study of the efficacy, dose response and duration of action of nicorandil in angina pectoris.

Nicorandil is a vasodilator that acts on the venous and arterial beds of the systemic circulation. It reduces both cardiac preload and afterload, as well as improving coronary blood flow. The present study assessed the efficacy, tolerability, duration of action and optimal single dose of nicorandil in patients with stable angina pectoris. Treadmill exercise tests were undertaken by 8 patients at 2 and 6 hours after single oral doses of 20, 40, and 60 mg of nicorandil, and placebo. Doses were administered at weekly intervals in this double-blind, cross-over study. The duration of exercise to onset of angina was increased by 58, 96 and 125 seconds over baseline values (p less than 0.01) with the 20-, 40- and 60-mg doses of nicorandil, respectively. Significant improvement in exercise capacity compared with the effects of placebo was maintained at 6 hours after administration. The antianginal activity was accompanied by a marked reduction in blood pressure both at rest and during exercise, which resulted in severe dizziness and fainting in 2 of 6 patients after the 60-mg dose. However, significant reflex tachycardia occurred only at 2 hours after the 60-mg dose. Plasma concentrations of nicorandil correlated with percent reductions in blood pressure at 2 hours after administration (p less than 0.001) and with increasing total exercise work load (p less than 0.01). The incidence of adverse events appeared to be dose related. Headache and dizziness accounted for most of the reported events. The 20-mg single dose of nicorandil was considered to provide the best combination of antianginal activity and tolerability in this study.

Exercise capacity after single and twice-daily doses of nicorandil in chronic stable angina pectoris.

In a double-blind parallel group study, 46 patients with chronic stable angina were randomized, after a 2-week placebo washout period, to 1 of 3 treatment groups for an additional 2 weeks. Groups 1 and 2 received nicorandil (5 mg, n = 5; 10 mg, n = 10) twice daily, respectively, increasing to 10 and 20 mg (n = 20) twice daily after 1 week of treatment; group 3 continued to receive placebo. A symptom-limited Bruce protocol exercise test was performed before and 2 hours after the initial dose and, after 2 weeks of treatment, 2 and 12 hours after administration. The following parameters were measured: resting, peak exercise and recovery blood pressure and heart rate, exercise duration, time to onset of angina and time to 1 mm of ST-segment depression. After initial dosing, there were significant increases in exercise duration (16%--n = 5, n = 10 vs -2% [placebo]) and time to onset of angina (20%, n = 5; 26%, n = 10 vs 5% [placebo]) (p less than 0.05). Time to onset of 1 mm of ST-segment depression increased in the nicorandil-treated groups compared with that in the placebo group (27%, n = 5; 25%, n = 10 vs 8% [placebo]). Calculated total exercise work increased in both nicorandil groups compared with exercise work in the placebo group (30%, n = 5; 19%, n = 10 vs 3% [placebo]). A decrease in resting systolic blood pressure (12%) in the 10-mg group was the only significant alteration in the hemodynamic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonischemic changes in right ventricular function on exercise. Do normal volunteers differ from patients with normal coronary arteries?

Factors other than ischemia may alter right ventricular function both at rest and on exercise. Normal volunteers differ from cardiac patients with normal coronary arteries with regard to their left ventricular response to exercise. This study examined changes in right ventricular function on exercise in 21 normal volunteers and 13 patients with normal coronary arteries, using first-pass radionuclide angiography. There were large ranges of right ventricular ejection fraction in the two groups, both at rest and on exercise. Resting right ventricular ejection fraction was 40.2 +/- 10.6% (mean +/- SD) in the volunteers and 38.6 +/- 9.7% in the patients, p = not significant, and on exercise rose significantly in both groups to 46.1 +/- 9.9% and 45.8 +/- 9.7%, respectively. The difference between the groups was not significant. In both groups some subjects with high resting values showed large decreases in ejection fraction on exercise, and there were significant negative correlations between resting ejection fraction and the change on exercise, r = -0.59 (p less than 0.01) in volunteers, and r = -0.66 (p less than 0.05) in patients. Older volunteers tended to have lower rest and exercise ejection fractions, but there was no difference between normotensive and hypertensive patients in their rest or exercise values. In conclusion, changes in right ventricular function on exercise are similar in normal volunteers and in patients with normal coronary arteries. Some subjects show decreases in right ventricular ejection fraction on exercise which do not appear to be related to ischemia.

A comparison of once daily bisoprolol, 5 and 10 mg, and atenolol 100 mg in the treatment of angina pectoris.

The efficacy and safety of the new cardioselective beta-blocker bisoprolol 5 mg and 10 mg once daily in the treatment of angina pectoris was compared with atenolol 100 mg once daily. 19 patients with coronary artery disease and angina of effort completed a randomised, three-way crossover study which consisted of six-week treatment periods preceeded by a two-week placebo washout. Treadmill exercise stress tests were carried out approximately 24 hours after each dose, at the end of the placebo period and after 2 and 6 weeks of each active treatment period. Patients recorded their angina attack rate and GTN consumption on diary cards. Number of anginal attacks, GTN consumption, resting and exercise systolic blood pressure, heart rate and double product were reduced, and both exercise duration and time to 1 mm ST-segment depression during exercise were increased to a similar extent by all three treatment regimens (P less than 0.01, paired t test). The only differences between the treatments were that the reductions in heart rate, double product and exercise blood pressure tended to be smaller after 6 weeks of bisoprolol 5 mg. Generally, there was no significant difference between the improvements measured at week 2 of each phase and at week 6 (P greater than 0.05, analysis of variance). All three dosage regimens were well tolerated. The data indicate that there is no difference between the safety and efficacy of bisoprolol 10 mg and atenolol 100 mg once daily in the treatment of angina pectoris. In addition, the 10 mg dose of bisoprolol would seem to have only a small advantage over the lower 5 mg once daily dose.

Peripheral vascular effects of beta-adrenoceptor blockade: comparison of two agents.

1. The effects of atenolol (100 mg), a beta 1-adrenoceptor blocker, and bevantolol (200 mg) were compared on heart rate, blood pressure, lung function and on the peripheral circulation in normal volunteers before and after isoprenaline infusion. Recordings were obtained 2 and 24 h following a single dose and 24 h after continuous dosage for 7 days. 2. The effect of atenolol on the blockade of beta-adrenergic stimuli, as measured by the ability to reduce isoprenaline-induced tachycardia, was greater than that of bevantolol. Though both drugs achieved a similar reduction in systolic pressure there was a significantly greater reduction in diastolic pressure with bevantolol. The lung function tests gave similar results to those with other beta-adrenoceptor blockers. 3. Atenolol produced a fall in peripheral blood flow consistent with unopposed peripheral alpha-adrenoceptor stimulation. The effect of bevantolol differs from that of atenolol, an initial fall in peripheral blood flow being followed by a rapid recovery to baseline or greater. This effect may be due to partial alpha-adrenoceptor agonist activity.

Duration of action of tiapamil in stable exercise induced angina.

The duration of action of tiapamil was assessed in ten patients with stable exertional angina. Maximal symptom-limited treadmill exercise electrocardiography was performed before and at 1, 3, 6 and 9 h after therapy. Significant differences were only found at 1 h after tiapamil with increases in mean exercise duration (312 vs 399 s), the time to onset of angina (221 vs 310 s) and exercise work load (5.9 vs 7.3 METS). Tiapamil had no significant effect on the exercise heart rate but increased the resting heart rate by 6 beats/minute. The resting systolic blood pressure fell by 17 mmHg (p less than 0.01), and the diastolic blood pressure by 14 mmHg. Exercise systolic and diastolic blood pressures fell by 19 and 17 mmHg respectively. Side-effects were short-lived and attributable to vasodilatation. Tiapamil is effective for the relief of angina with minimal side-effects, but its duration of action is short. For effective chronic oral use, a sustained release preparation is required.

The effects of oral nitrendipine and propranolol, alone and in combination, on hypertensive patients with special reference to AV conduction.

The effects of oral nitrendipine and oral propranolol, alone and in combination, on AV conduction have been examined in 11 patients with essential hypertension in whom arterial pressure was not adequately controlled despite treatment with thiazide diuretics. The study was performed double-blind. After a drug free period of 1 week, the patients received two 7 day courses of drug therapy after initial control measurements. Five of the eleven patients were randomised to receive nitrendipine 20 mg daily, the other six patients received propranolol (Inderal LA 160 mg daily) for the first week of therapy. During week 2, 10 patients received combined therapy. In the 10 patients who completed the study, oral nitrendipine, given either alone or in combination with oral propranolol, had no significant effect on resting PR, QRS, QT intervals nor on AV conduction as assessed by ambulatory electrocardiography. Propranolol did not affect the resting PR interval but significantly increased PR intervals on the ambulatory ECG recordings during single and combined therapy. However the maximum PR intervals remained within normal limits.

Efficacy of incremental doses of tiapamil on exercise performance in patients with chronic stable angina pectoris.

Ten patients with chronic stable angina were treated with 4 incremental doses of tiapamil (200 mg, 400 mg, 600 mg and 800 mg) in a double-blind, placebo-controlled study. Treadmill exercise electrocardiograms were performed before and after single oral doses of tiapamil. A dose-dependent increase in exercise duration occurred after tiapamil with significant improvement after tiapamil 600 mg and 800 mg. Mean exercise duration increased from 327 +/- 41 seconds (control) to 399 +/- 49 seconds (P less than 0.01) after tiapamil 600 mg and from 314 +/- 39 seconds (control) to 416 +/- 49 seconds after tiapamil 800 mg, P less than 0.001. There was an associated improvement in mean exercise time to onset of 1 mm ST-segment depression from 240 +/- 41 seconds (control) to 300 +/- 48 seconds in 10 patients after tiapamil 600 mg, (P less than 0.02) and from 206 +/- 35 seconds (control) to 272 +/- 51 seconds in 9 patients after tiapamil 800 mg, P less than 0.01. Two patients were free of angina and 1 patient normalized his ST-segments after tiapamil 800 mg. Dose-dependent side-effects were mild and tolerable. Tiapamil is safe and highly effective in improving exercise tolerance and relieving myocardial ischaemia in patients with chronic stable angina.

Management of ventricular arrhythmias associated with mitral valve prolapse by combined alpha and beta blockade.

Ventricular arrhythmias are common in patients with mitral valve prolapse. Ten patients with echocardiographically confirmed mitral valve prolapse and documented ventricular arrhythmias were included in this study. The aim was to assess the value of combined alpha- and beta-blockade (labetalol) compared with beta-blockade alone (propranolol) in the management of ventricular arrhythmias in these patients. The study was performed using physiological stress, such as the Valsalva manoeuvre, isometric exercise and treadmill exercise, to initiate ventricular arrhythmias before and after intravenous propranolol or labetalol and to document arrhythmias during 24 hour electrocardiography before and after oral medication. Labetalol and propranolol decreased the heart rate and blood pressure response to these manoeuvres to a similar extent but labetalol was more effective in the control of the ventricular arrhythmias. These findings suggest that alpha adrenergic receptors may play a role in the pathogenesis of the ventricular arrhythmias in mitral valve prolapse syndrome and that labetalol offers an alternative treatment for the management of this condition.