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Studies of the efficacy of molsidomine, previously performed on our service, demonstrated that a clear antianginal effect in the longterm treatment of angina pectoris could only be achieved with a regimen of the standard 2 mg dose when given six times daily. Consequently, since a mode of administration with a longer duration of action was implicitly desirable, the present study, carried out in eleven patients with coronary artery disease and stable, exertional angina pectoris, was undertaken to assess the antiischemic effects of 8 mg molsidomine in sustained-release form as compared with the standard 2 mg formulation according to a double-blind, randomized, crossover, placebo-controlled protocol. Additionally, plasma concentrations of molsidomine were determined to elucidate the bioavailability as well as possible correlations between plasma concentrations and antiischemic effect. As compared with placebo, after administration of 8 mg molsidomine sustained-release there were reduction in the ST-segment depression at one, three, five and eight hours of 74% (p less than 0.001), 61% (p less than 0.001), 44% (p less than 0.025), and 31% (p less than 0.01), respectively; after 2 mg molsidomine, 74% (p less than 0.001), 37% (p less than 0.025), 7% (ns) and 6% (ns), respectively. Analysis of the response of the ST-segment in the individual patients showed an unequivocal antiischemic effect with a reduction in ST-segment depression of at least 1 mm after 8 mg molsidomine sustained-release at the specified points in time in ten, five, six and four patients, respectively, and after 2 mg molsidomine in nine, five, one and no patients, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was undertaken to determine whether an effective antianginal treatment without tolerance development can be carried out with intermittent nitrate administration on a regimen with a single daily dose of 120 mg isosorbide dinitrate (ISDN) in sustained-release form (SR), as well as whether the concomitant administration of 100 mg atenolol or 100 mg atenolol and 20 mg nifedipine renders an additive antiischemic effect. In two independently performed investigations, the duration of action of a single dose of 120 mg ISDN SR was assessed after its initial administration in addition to the anti-ischemic effect during long-term treatment, each according to a randomized, double-blind, crossover, placebo-controlled protocol in a total of 15 patients with angiographically-documented coronary artery disease, stable angina pectoris and reproducible ST-segment depression during exercise. The test phases of four weeks each were separated by one week placebo phases. After completion of the study, for a further eight weeks, 120 mg ISDN SR was given together with 100 mg atenolol in the morning. Exercise testing was carried out after four weeks of treatment in a control period before and at two hours after administration of 120 mg ISDN SR with 100 mg atenolol as well as after another four weeks in a control period before and after concomitant administration of 120 mg ISDN SR, 100 mg atenolol and 20 mg nifedipine in sustained release form.(ABSTRACT TRUNCATED AT 250 WORDS)

Within a relatively short period of time, nitroglycerin patches have come into widespread use for treatment of coronary artery disease in the absence of sufficient clinical data in support of their efficacy. Presently, there is still considerable controversy regarding the extent and duration of action as well as the dosage requirements. Accordingly, a study was carried out in six patients with angiographically-documented coronary artery disease, stable exercise-induced angina pectoris and reproducible ST-segment depression to analyze the effects of nitroglycerin patches, formulated to deliver 5 mg, 10 mg, 20 mg as well as 30 mg per 24 hours, respectively, on the extent of ST-segment depression. In a further study, the extent and duration of antianginal and anti-ischemic effects of nitroglycerin patches delivering 30 mg/24 hours were investigated in ten patients according to a randomized, double-blind, crossover placebo-controlled protocol. In seven of these patients, testing was again performed at 2.5 hours after repeated application (second application at 24 hours) (Figure 1). Nitroglycerin patches delivering 5 mg, 10 mg, 20 mg as well as 30 mg/24 hours, respectively, led to significant reductions in ST-segment depression at 2.5 hours of 59% (range 25 to 100%; p less than 0.025), 63% (0 to 100%, p less than 0.01), 77% (50 to 100%, p less than 0.001) as well as 82% (50 to 100%, p less than 0.005) as compared with control values (Figure 2).(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to compare the antihypertensive and anti-ischemic effects of the newly developed cardioselective beta-blocking agent, betaxolol, with the non-selective agent, nadolol, both of which have hydrophilic long acting properties, over a period of 48 hours. Additionally, the study was intended to determine whether betaxolol exerts a lesser influence on pulmonary function and whether beta-1- and beta-2-adrenergic blocking agents also induce a decrease in blood glucose levels during standard bicycle ergometry for three to nine minutes, similar to that reported in association with exercise of longer duration and, if so, whether this effect can be circumvented by the use of a selective agent. Ten patients with angiographically documented CAD, stable exercise angina pectoris and reproducible ST-segment depression of at least 1 mm received on day 1, in a single blind fashion, one tablet of placebo, on day 2 and day 7, in a double-blind, randomized and cross-over fashion, 20 mg betaxolol or 80 mg nadolol, respectively. Bicycle ergometry was performed before, four, 24 and 48 hours after drug with fixed work loads, blood glucose determination before and after ergometry four hours after drug and airway resistance and maximal ventilatory capacity studies were carried out five hours after drug administration. As compared with placebo, betaxolol and nadolol led to reductions of ST-segment depression of 65% (p less than 0.01) and 74% (p less than 0.005) at four hours, of 53% (p less than 0.025) and 56% (p less than 0.01) at 24 hours and 41% (p less than 0.05) and 44% (p less than 0.05) at 48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

In previous studies it had been shown that during longterm treatment of coronary artery disease with isosorbide dinitrate (ISDN) in sustained-release form, there was no reduction in exercise-induced ST-segment depression, no decrease in the rate of anginal attacks or nitrate consumption and no changes in blood pressure or heart rate [1, 4]. To determine to what extent tolerance development is a fundamental property of longterm administration of ISDN, this study, carried out according to a randomized, double-blind, cross-over, placebo-controlled protocol (Figure 1), was undertaken. The anti-ischemic effects of 40 mg ISDN were analyzed after acute administration and during longterm treatment with 40 mg four times daily in eleven patients with stable angina pectoris and reproducible ST-segment depression. Additionally, the influence of this therapy on the anti-ischemic effects of 0.8 mg sublingually-administered nitroglycerin (GTN) was assessed in ten of the eleven patients. On acute administration, 40 mg ISDN led to a reduction in ST-segment depression at one hour from 2.05 to 0.18 mm (p less than 0.01), and at six hours from 2.35 to 1.20 mm (p less than 0.01) (Figure 2, Table 1). During chronic treatment, statistically significant changes were no longer detectable. In eight of the eleven patients there was a complete loss of effects; in the remaining three, a marked attenuation was observed (Figure 3). Acute administration of 40 mg ISDN resulted in plasma concentrations of 221 ng/ml 5-ISMN, 53 ng/ml 2-ISMN and 23 ng/ml ISDN (Figure 6, Table 2).(ABSTRACT TRUNCATED AT 250 WORDS)

A number of carefully controlled studies in recent years have unequivocally documented evidence of tolerance development with respect to anti-ischemic effects during longterm treatment with nitrates [1, 3, 4, 5, 7, 8]. To determine to what extent tolerance development can be circumvented through an interval regimen, a study was performed in ten patients with stable angina pectoris and reproducible ST-segment depression according to a randomized, double-blind, cross-over, placebo-controlled protocol. Analysis of the anti-ischemic effect of 20 mg ISDN was carried out after acute administration and during chronic treatment on an interval regimen with the administration of 20 mg ISDN in the morning (at 8 a.m.) and at midday (1 p.m.) (Figure 1). On acute administration, 20 mg ISDN led to a reduction in ST-segment depression from 2.15 to 0.40 mm (p less than 0.01) and during longterm treatment from 2.25 to 0.40 mm (p less than 0.01) (Figure 2, Table 1). After acute administration the plasma concentration of ISDN was 9 ng/ml, 2-ISMN 34 ng/ml and 5-ISMN 149 ng/ml (Figure 5, Table 2). Of the control values during longterm treatment, a detectable level was found only for 5-ISMN with a concentration of 36 ng/ml while that of both 2-ISMN and ISDN was 0 ng/ml. On renewed administration, there was an increase of ISDN to 9 ng/ml, 2-ISMN to 37 ng/ml and 5-ISMN to 208 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Nisoldipine (Bay K5552), a newly-developed dehydropyridine derivative with calcium antagonistic properties, was found to have a duration of action twice as long as its parent compound, nifedipine, in laboratory experiments. To evaluate the anti-ischemic potency and duration of action, the effects of 10 mg nisoldipine after acute administration and at the end of three weeks of treatment with 10 mg twice daily were compared with those of 120 mg verapamil three times daily in a double-blind, randomized, crossover, placebo-controlled study. In twelve patients with angiographically-documented coronary artery disease and stable exertional angina pectoris, bicycle ergometry was performed before and at three and seven hours after medication on the first and 21st days of the three respective treatment phases. The control value at 8 a.m. on the 21st day corresponded with the ten-hour value on the 20th day of treatment. Between the three treatment phases, there was a one-week wash-out period during which the patients received placebo three times daily. At the time of the ergometric studies, blood was drawn for determination of verapamil plasma concentrations and, additionally, each patient recorded anginal attacks and nitrate consumption. Analysis was carried out for ST-segment depression in each patient at the highest comparable workload achieved in all treatment phases, the time to onset of 1 mm ST-segment depression as well as the response of the heart rate, systolic arterial blood pressure and the heart rate-blood pressure double-product both at rest and during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrendipine is a newly-developed calcium channel blocker derived from the dehydropyridine series which, according to experimental studies, affects marked dilation of the peripheral and coronary vessels. As compared with the parent compound nifedipine, nitrendipine exhibits a clearly more prolonged elimination half-time. This study was designed to evaluate the antihypertensive efficacy, in particular, with respect to the duration of action as well as the anti-ischemic effectiveness with a protocol encompassing as many factors as possible. In 13 patients with angiographically-documented coronary artery disease and elevated blood pressure at rest and/or during exercise, on two days separated by a three-day washout period, we investigated the effects of 20 mg nitrendipine, as compared with placebo, in a double-blind, randomized, crossover study. The systolic and diastolic arterial blood pressure as well as the heart rate were recorded prior to, at two, five, eight and twelve hours after medication and the blood pressure only at 24 hours. Blood pressure and heart rate were assessed during active standing at two hours, passive tilt at 2 1/2 hours and, together with analysis of the ST segments, before and during semisupine bicycle ergometry performed at three hours after tablet administration.(ABSTRACT TRUNCATED AT 250 WORDS)