Administration Of Molsidomine Research Articles

Hemodynamic effects of molsidomine, isosorbide dinitrate, and nifedipine at rest and during exercise

In the first study the hemodynamic effects of standard doses of molsidomine (2 mg intravenously), isosorbide dinitrate (ISDN) (5 mg sublingually), and nifedipine (20 mg sublingually) were assessed at rest and under exercise conditions in a group of 30 patients with coronary heart disease. With the patients at rest both molsidomine and ISDN were associated with prompt reductions in left ventricular end-diastolic pressure and mean pulmonary artery pressure, whereas nifedipine was associated with slight reductions in left ventricular end-diastolic pressure and mean pulmonary artery pressure that did not attain statistical significance. Nifedipine and ISDN caused a decrease in mean aortic blood pressure, which resulted in a reactive increase in heart rate that was only significant with nifedipine. After administration of molsidomine, there was no significant change in mean aortic pressure at rest. There were reductions in stroke volume index and cardiac index after administration of molsidomine and ISDN. Nifedipine, however, was associated with significant increases in stroke volume index and cardiac index. None of the three test substances caused changes of contractility parameters. Under exercise conditions reductions in left ventricular end-diastolic pressure, mean pulmonary pressure, and mean aortic pressure were documented following administration of molsidomine, ISDN, and nifedipine. There were no major changes in maximum heart rate or stroke volume index during exercise with any of the three drugs. However, nifedipine was associated with a significant increase in cardiac index, whereas molsidomine and ISDN produced no major changes. In a second clinical study the short-term effects of oral administration of 2 mg of molsidomine before and after a 2-week course of therapy with 2 mg of molsidomine four times daily were determined in 10 patients with the diagnosis of coronary artery disease. There was no significant difference in hemodynamic parameters at rest and during exercise between initial findings on the first and fourteenth days of the study. Comparisons of the results with the first study show that oral and intravenous administration of molsidomine is followed by comparable changes in hemodynamic parameters. Our results demonstrate that molsidomine, ISDN, and nifedipine influence preload and afterload but that their effects on venous and arterial resistance differ in degree. At standard therapeutic doses molsidomine and ISDN reduce the hemodynamic parameters of preload, whereas nifedipine is associated primarily with afterload reduction. These effects are also demonstrable under exercise conditions. All three substances limit the increase in pulmonary artery pressure caused by exercise-induced ischemia. There was no significant loss of hemodynamic effects after a 2-week course of treatment with molsidomine.

Hemodynamic effects of molsidomine in patients with heart failure following acute myocardial infarction

The short-term hemodynamic effects of molsidomine (4 mg sublingually) were evaluated in 13 patients with congestive heart failure following acute myocardial infarction. Right heart catheterization was performed by means of a Swan-Ganz thermodilution catheter. Hemodynamic measurements were made 30, 60, 120, and 180 minutes after the administration of the drug. Molsidomine significantly reduced systolic blood pressure from 121.5 ± 3.3 (mean ± SEM) to 111.1 ± 2.9 mm Hg ( p < 0.001) after 60 minutes, mean right atrial pressure from 6.1 ± 1 to 2.6 ± 0.6 mm Hg ( p < 0.0001), mean pulmonary arterial pressure from 29.8 ± 1.9 to 20.1 ± 1.3 mm Hg ( p < 0.0001), and left ventricular filling pressure from 20.3 ± 0.6 to 12.2 ± 0.7 mm Hg ( p < 0.0001). No significant change occurred in heart rate, diastolic and mean blood pressure, cardiac index, stroke volume index, left ventricular stroke work index, systemic vascular resistance, and pulmonary vascular resistance. No side effects were seen after the administration of molsidomine.

Hemodynamic and coronary effects of molsidomine at basal state, during atrial pacing, and during cold pressor test in patients with stable angina pectoris

Heart rate (HR), cardiac output (CO), coronary sinus blood flow (CSF), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), mean arterial (MAP), and coronary arteriovenous difference for oxygen (AVDcO 2) were measured in patients with stable angina pectoris without cardiac failure before and 40 to 60 minutes after administration of 2 or 3 mg of molsidomine. In 20 patients these measurements were made in basal state during spontaneous rhythm. In eight of these patients (including three receiving beta blockers) the measurements were made during atrial pacing. In eight other patients, all receiving long-term beta-blocker therapy, the measurements were made during cold pressor test. At the basal state in spontaneous rhythm, a gradual reduction in the LVSP to 70% or less of its initial value was observed in four patients receiving 3 mg of molsidomine (two of whom received beta-blocker treatment). The LVSP was immediately restored by vascular filling. In the 16 other patients molsidomine decreased LVSP, LVEDP, MAP, CO, and double product (DP = LVSP × HR). The AVDcO 2 was unchanged. CSF and myocardial oxygen uptake index (MV̇O 2 = CSF × AVDcO 2) were decreased. During atrial pacing, hemodynamic and coronary effects were similar to those seen in the basal state. During the cold pressor test, the increases in LVSP, MAP, and LVEDP were significantly reduced by molsidomine. The variations in CSF and coronary resistance ( MAP CSF ) were also significantly different after administration of molsidomine, with better metabolic regulation of the coronary circulation. These results suggest that in patients with stable coronary insufficiency without cardiac failure the improvement in ventricular load induced by molsidomine may reduce the metabolic requirements of the myocardium both in spontaneous rhythm and during atrial pacing. There is a risk of hypotension that does not appear to be related to the association with beta blockers. Molsidomine can help to preserve the predominance of physiologic regulation of the coronary circulation in conditions in which it is threatened.

Effects of molsidomine on left ventricular dimensions and cardiac function in patients with chronic heart failure

The effects of molsidomine were studied in seven patients with refractory congestive heart failure by means of two-dimensional echocardiography. Four milligrams of molsidomine or placebo was sublingually administered in a double-blind crossover manner. End-diastolic dimension, end-systolic dimension, and mean velocity of circumferential fiber shortening were measured just below the mitral valve before drug or placebo administration and 1 hour later. No significant changes were observed with placebo. Heart rate and mean arterial pressure were not significantly modified with Molsidomine (80 to 83 bpm and 100 to 97 mm Hg, respectively). The reduction in end-diastolic dimension (67 to 61 mm; 9%; p < 0.01) was slightly greater than the decline in end-systolic dimension (59 to 54 mm; 8%; p < 0.01). The mean velocity of circumferential fiber shortening increased from 0.4 to 0.5 sec −1 but did not achieve statistical significance. Thus sublingual administration of molsidomine in patients with chronic heart failure reduces end-diastolic more than end-systolic dimension without effect on blood pressure, suggesting a predominant action on cardiac preload.

The effect of molsidomine on intramyocardial pressure and regional myocardial blood flow in the canine ischemic myocardium.

Molsidomine was administered intraduodenally to anesthetized dogs which were instrumented for measurements of aortic and left ventricular (LV) pressures, coronary perfusion pressure, intramyocardial pressure in the subendocardium, and subendocardial and subepicardial myocardial blood flow in the ischemic and non-ischemic regions. The dogs were divided into two groups: group M (n = 9) was administered molsidomine (0.2 mg/kg), group S (n = 10), saline only. Maximum LV systolic pressure decline was 20% in group M and 3% in group S (p less than 0.05). Maximum LV end-diastolic pressure decline was 63% and 35% in groups M and S, respectively (p less than 0.05). There was no difference between mean aortic pressure and coronary perfusion pressure between the two groups. The subepicardial blood flow in the ischemic region was decreased (-23% in group M vs 5% in group S; p less than 0.05), but subendocardial blood flow in the ischemic region increased only slightly in group M. The ratio of subendocardial to subepicardial blood flow increased at 15 and 30 min after administration of molsidomine in the ischemic area (67% in group M vs -10% in group S; p less than 0.05), but did not show any change in the non-ischemic region. Intramyocardial pressure at systole did not show any change but it decreased at end-diastole, (-32% in group M vs -7% in group S; p less than 0.05). Thus molsidomine redistributed the myocardial blood flow from the subepicardium to the subendocardium and from the non-ischemic to the ischemic region. This redistribution was associated with a reduction in both LV end-diastolic pressure and intramyocardial pressure at end-diastole.

The Influence of Molsidomine and Its Active Metabolite SIN-1 on Fibrinolysis and Platelet Aggregation

Molsidomine and its active metabolite SIN-1 were examined in humans and animals for platelet suppressant and fibrinolytic activities. Following oral administration of molsidomine at doses of 6 or 15 mg/kg to rabbits, their blood platelets in PRP ex vivo required higher threshold concentrations of ADP, AA and thrombin to be aggregated. Unlike molsidomine, SIN-1 when infused (10 and 20 micrograms/kg i.v.) into anaesthetized cats caused a release of a substance disaggregating platelet clumps which had adhered to blood superfused collagen strip. The appearance of this unstable disaggregating substance was prevented by the pretreatment of cats with aspirin (50 mg/kg i.v.). It is suggested that SIN-1 may promote formation of a PGI2-like substance. In humans shortening of euglobulin clot lysis time was observed 60 min after a single ingestion of 2 mg of molsidomine. This fibrinolytic effect of molsidomine was not abolished by the pretreatment of patients with aspirin. Neither molsidomine nor SIN-1 activated fibrinolysis in preformed euglobulin clots in vitro.

Intravenous and oral administration of molsidomine, a pharmacodynamic and pharmacokinetic study.

In 12 healthy male volunteers, molsidomine 1, 2 and 4 mg i.v. increased resting heart rate and decreased systolic blood pressure, the latter still being affected after 8 hours. After single oral doses of 1 and 2 mg, systolic pressure tended to be reduced for 90 minutes and exercise heart rate tended to be increased. After oral treatment with 2 mg molsidomine three times daily for 1 week, the pharmacokinetic parameters and the effects on heart rate and blood pressure after the final dose were not different from those after the first dose. The terminal half-life was independent of dose and route of administration. Clearance and distribution volume were not dose-dependent. The bioavailability of a 2 mg oral dose of molsidomine was 44%. Inter-individual variation in heart rate, blood pressure and pharmacokinetics was observed.

The effect of repeated intravenous and oral doses of molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester) on plasma renin activity and plasma catecholamine levels in conscious dogs.

The responses of plasma renin activity (PRA) and plasma catecholamine levels to molsidomine, administered both intravenously and orally, were investigated in conscious trained dogs. Intravenous administration of molsidomine at increasing dosage up to 0.4 mg/kg with a constant dose interval of 4 hours did not lead to a sustained increase in PRA. By contrast, a significant increase in PRA was still present after 4 hours on administration of 0.4 mg/kg molsidomine by the oral route. This longer-lasting increase in PRA following oral administration is discussed in relation to the conversion of molsidomine to an active metabolite in the liver. A reduction of dose interval to 3 hours or less led to a marked cumulative increase in PRA. It appears that substances acting via venous pooling lead to persistent activation of the renin angiotensin aldosterone system (RAA system), which counteracts its primary therapeutic effect. A slight increase in plasma noradrenaline levels was observed in response to repeated oral administration of 0.4 mg/kg molsidomine at a dose interval of 2 hours, indicating participation of the sympathetic nervous system in the counterregulatory process.