oxadiazoles and Coronary-Disease

The cardioprotective and antithrombotic activity of molsidomine, a novel therapeutic agent for the treatment of coronary heart disease, was investigated in a series of animal models of myocardial ischemia. Molsidomine given to dogs with marked ST segment elevation (epicardial electrogram), induced by a reduction of left descending coronary artery (LAD) flow to 20% to 30% of the original value, resulted within 40 minutes in complete normalization of ECG changes. In another animal model molsidomine given either before or after occlusion of the LAD significantly reduced infarct size. All these molsidomine effects were accompanied by a marked lowering of preload, resulting in a reduction of extravascular coronary artery resistance and in increased blood flow toward the ischemic zones. In a model of myocardial ischemia and reperfusion in the anesthetized dog, molsidomine had a marked protective effect against the incidence of spontaneous ventricular fibrillation. This effect could also be attributed to the anti-ischemic activity of molsidomine, which would reduce the disparity between the refractory periods in normal and ischemic areas and thus increase ventricular stability. The antithrombotic activity of molsidomine was investigated in dogs in which the left circumflex coronary artery was electrically stimulated, a procedure that leads to thrombotic occlusion. Molsidomine in a dose-dependent manner prevented coronary thrombotic occlusion and reduced thrombus wet weight and the size of the resulting infarction. These effects of molsidomine were not related to its hemodynamic activity, since nitroglycerin and isosorbide dinitrate had similar hemodynamic effects but did not prevent coronary thrombosis. The antithrombotic activity of molsidomine is probably related to its ability to lower coronary venous blood thromboxane levels.

Topics: Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Dogs; Electric Stimulation; Molsidomine; Nitroglycerin; Oxadiazoles; Sydnones; Thromboxane B2; Vasodilator Agents; Ventricular Fibrillation

Topics: Animals; Biological Availability; Coronary Disease; Heart; Liver; Molsidomine; Oxadiazoles; Sydnones; Vasoconstriction; Vasodilation

Topics: Adrenergic beta-Antagonists; Aged; Calcium; Coronary Disease; Drug Evaluation; Female; Humans; Isosorbide Dinitrate; Male; Middle Aged; Morpholines; Nitrates; Nitroglycerin; Oxadiazoles; Sydnones

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Coronary Disease; Heart Rate; Hemodynamics; Humans; Isosorbide Dinitrate; Middle Aged; Molsidomine; Nifedipine; Oxadiazoles; Physical Exertion; Stroke Volume; Sydnones; Time Factors; Vasodilator Agents

Using a randomized, double-blind, crossover protocol, we compared the effects of oral molsidomine (Corvaton, 6 mg/day) and placebo, administered alternately for two 14-day periods, on the exercise tolerance of 25 outpatients with coronary heart disease. Resting heart rate and oxygen consumption increased by 6.8% (p less than 0.005) and 12.6% (p less than 0.01), while peripheral systolic blood pressure was reduced by 5.1% (p less than 0.05). At submaximal workloads, systolic and diastolic blood pressures were reduced by 5.6% (p less than 0.001) and 6.1% (p less than 0.001), the pressure-rate product was reduced by 8.5% (p less than 0.05), and ST segment depression was reduced by 40.0% (p less than 0.005). At maximal exercise level, mechanical power increased by 32.4% (p less than 0.001) and oxygen consumption by 15.5% (p less than 0.005), while ST segment depression was reduced by 30.6% (p less than 0.001). No alteration was found in postexercise lung function tests. It is concluded that molsidomine reduces myocardial ischemia at both submaximal and maximal work levels and increases exercise tolerance significantly. These effects could be related to reduced myocardial oxygen requirements, reflected in a lower pressure-rate product at submaximal exercise and perhaps enhanced by a lower preload, which, moreover, would favor coronary flow in subendocardial layers. The drug has no adverse bronchopulmonary effects.

Topics: Adult; Aged; Clinical Trials as Topic; Coronary Disease; Double-Blind Method; Exercise Test; Female; Hemodynamics; Humans; Lung Volume Measurements; Male; Middle Aged; Molsidomine; Oxadiazoles; Random Allocation; Respiration; Sydnones; Vasodilator Agents

Molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester; Cassella-Riedel Pharma GmbH, Frankfurt/M. FRG) has an antianginal effect for up to 3-5 h after oral administration of 2 mg Corvaton [1]. Plasma levels of the parent drug can be measured during this interval. A new galenic formulation (Corvaton retard) has been developed to prolong the duration of the therapeutic action and to improve patient compliance. The present study was carried out to establish whether the in vitro dissolution profile of the tablet was reflected in vivo, thus permitting prediction of plasma molsidomine levels in patients with coronary heart disease.

Topics: Aged; Angina Pectoris; Biological Availability; Clinical Trials as Topic; Coronary Disease; Double-Blind Method; Humans; Kinetics; Middle Aged; Molsidomine; Oxadiazoles; Sydnones; Time Factors

Topics: Adult; Clinical Trials as Topic; Coronary Disease; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones

Topics: Aged; Arterial Occlusive Diseases; Clinical Trials as Topic; Coronary Disease; Female; Hemodynamics; Humans; Isosorbide Dinitrate; Male; Molsidomine; Oxadiazoles; Random Allocation; Sydnones; Vasodilator Agents

The safety, tolerability and efficacy of PN 200-110, a new calcium antagonist with minimal negative inotropic effects, were studied in twelve patients with stable angina pectoris and coronary artery disease. The study design was single-blind and placebo-controlled and increasing doses of the drug were used on consecutive days to investigate a dose response relationship. Eleven patients completed the trial. Response to the drug was evaluated using symptom limited cycle ergometric exercise. PN 200-110 in all three tested doses of 2.5 mg, 5.0 mg and 10.0 mg significantly increased the resting heart rate (p less than 0.02) and the exercise time to the onset of angina pectoris (p less than 0.02). Doses above 2.5 mg did not appear to improve the exercise parameters evaluated. Four patients had side effects probably due to PN 200-110 but these were mild and included dizziness, headache and flushing. There were no abnormal results from haematological and biochemical screening or from urine testing. We conclude that PN 220-110 can be given safely to patients with coronary artery disease without producing deleterious effects on blood pressure either at rest or during exercise.

Topics: Angina Pectoris; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Coronary Disease; Heart Rate; Hemodynamics; Humans; Isradipine; Male; Oxadiazoles

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)

Topics: Angina Pectoris; Blood Pressure; Clinical Trials as Topic; Coronary Circulation; Coronary Disease; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Heart Rate; Humans; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

The dose-effect relation and duration of action of 2 mg, 4 mg and 6 mg molsidomine on ischemic ST-segment depression in the exercise-ECG were determined in a randomized and double-blind acute study of 12 patients with confirmed coronary artery disease. With 2 mg molsidomine a significant reduction in the amount of ischemic ST-depression from 18.0 mm to 8.1 mm, 45% of the baseline-figure, resulted. With 6 mg molsidomine a diminuation of the ST-segment depression from 16.2 mm to 6 mm, approximately 40%, was noted. The significant antianginal effect of 2 mg molsidomine lasted at least 3 hours. After 5 hours an effect was seen only in some patients. 4 mg and 6 mg molsidomine still showed a significant reduction of ST-segment depression after 5 hours. A sufficient antianginal efect over 24 hours is only achieved with a 2-mg dose administered 5-6 times or with a 4-6 mg dose applied 4-5 times daily. The most marked fall in blood pressure was noticed after 6 mg molsidomine. On average, the systolic blood pressure fell 41 mm Hg (22%). Orthostatic reactions were not seen. The maximal dose-dependent plasma levels were 15.8 ng/ml, 30.1 ng/ml and 50.0 ng/ml. A definite, reliable clinical effect was seen in some cases from plasma levels above 2 ng/ml.

Topics: Angina Pectoris; Blood Pressure; Clinical Trials as Topic; Coronary Circulation; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Exercise Test; Heart Rate; Humans; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

A single-blind study (n = 59) was performed to assess the effect of long-term (4 week) orally administered molsidomine (2 mg 4 X daily), isosorbide dinitrate (10 mg 4 X daily), and placebo on exercise tolerance performed on the bicycle ergometer by patients with stable angina on effort and with significant coronary artery disease. Isosorbide dinitrate had similar effects to placebo, both failed to modify the pressure-rate product, the sustained work load, and the ST segment depression, but slightly decreased, although not significantly, the incidence of angina. Although not affecting the pressure-rate product and the mean blood pressure, molsidomine decreased significantly the ST segment depression (p less than .05). In conclusion, by markedly reducing preload and because of its long-lasting effect (up to 6 h), the new vasodilator drug molsidomine plays a useful role in the long-term management of stable angina on effort.

Topics: Angina Pectoris; Coronary Disease; Electrocardiography; Exercise Test; Female; Hemodynamics; Humans; Isosorbide Dinitrate; Long-Term Care; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

Topics: Antihypertensive Agents; Coronary Disease; Hemodynamics; Humans; Long-Term Care; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones

The vasodilating effects of intracoronary injections of 0.4 mg SIN 1, the active metabolite of molsidomine, on epicardial coronary arteries and coronary stenoses were evaluated in 14 patients with coronary artery disease in a double-blind randomized fashion versus placebo. 9 additional patients with well-definable coronary stenoses received 0.4 mg SIN 1 as well. Diameter changes of nonstenotic coronary arteries in proximal, medial and distal coronary segments as well as changes of the residual luminal diameters within coronary stenoses were determined before (K), immediately after (M1) and 10 minutes after (M2) intracoronary application of SIN 1; in addition, aortic pressure and heart rate were monitored continuously. Aortic pressure and heart rate did not change after SIN 1 or placebo. After SIN 1, the diameter of nonstenotic coronary arteries increased in proximal segments by + 9% (M1) and + 11.7% (M2), in medial segments by + 17.6% (M1) and + 17.6% (M2), in distal segments by + 26.4% (M1) and + 28.8% (M2). Within coronary stenoses, the residual luminal diameters showed a mean increase by 31.5% (M1) and 48.3% (M2). Placebo did not alter coronary diameters significantly. SIN 1 effectively dilates nonstenotic and especially stenotic epicardial coronary arteries, as it is already known for nitrates and calcium-channel blockers. By intracoronary injections, the direct effects on coronary vessels can be detected without interference with systemic effects. The increase in residual luminal diameters within dynamic coronary stenoses after SIN 1 is most likely an important antianginal mechanism also for molsidomine.

Topics: Coronary Disease; Coronary Vessels; Double-Blind Method; Humans; Injections, Intra-Arterial; Molsidomine; Oxadiazoles; Random Allocation; Sydnones; Vasodilator Agents

1. After initial acute administration of 20 or 60 mg ISDN, 2 mg molsidomine and 20 mg nifedipine, a clear effect on the circulation and an increase in work tolerance is detectable. 2. Following 4 weeks' treatment with 3 X 20 mg ISDN, there is no essential loss of action in the venous branch or with respect to working capacity. 3. After 4 weeks' treatment with 3 X 60 mg ISDN, the improvement in working capacity is partially retained, but the action on the venous branch is significantly poorer. 4. During 4 weeks' treatment with 3 X 20 mg nifedipine, there is no essential loss of action in the arterial or venous branches, or with respect to working capacity. 5. Our results with continuous high doses of ISDN indicate that high doses should be used only in monitored exceptions.

Topics: Adult; Blood Pressure; Coronary Disease; Drug Administration Schedule; Drug Tolerance; Hemodynamics; Humans; Isosorbide Dinitrate; Middle Aged; Molsidomine; Nifedipine; Oxadiazoles; Physical Exertion; Sydnones; Vasodilator Agents

The results of treatment of 103 patients suffering from ischemic heart disease with irrigor for 7--25 days are discussed. The drug was given in a daily dose of 30 to 150 mg in tablets, intramuscularly, and intravenously. Ergometry, study of the values of central hemodynamics and lipid metabolism, and recording of the rheoencephalo-, rheovaso-, and electroencephalogram were conducted before and after the treatment. The efficacy of irrigor was appraised in treatment applied in courses, in a single intravenous infusion, and under conditions of the double blind method. A relatively stable clinical effect was noted on the 9th--12th day. A good effect was produced in 49.3% of patients. The efficacy of irrigor was the highest in patients with grade I and II chronic coronary insufficiency, with no history of circulatory insufficiency or myocardial infarction, and in intramuscular and intravenous administration. Treatment with irrigor improved the indices of central hemodynamics and cerebral and peripheral blood flow. No side effects of the treatment were noted. The study showed irrigor to be an effective agent in the treatment of ischemic heart disease.

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Nitroglycerin; Oxadiazoles; Placebos; Risk; Time Factors; Vasodilator Agents

Molsidomine is a new agent in coronary therapy. It does not influence the intra-ocular pressure in healthy volunteers or in glaucoma patients. This was tested in double-blind studies in short trials and in a long term study of 3 months. The outflow facility or the visual fields were also unchanged. These results correspond closely to those obtained previously with other coronary therapeutics. Molsidomine is not dangerous for glaucoma patients.

Topics: Coronary Disease; Drug Evaluation; Humans; Intraocular Pressure; Long-Term Care; Morpholines; Oxadiazoles; Sydnones; Vasodilator Agents

Topics: Adult; Aged; Benzyl Compounds; Clinical Trials as Topic; Coronary Disease; Drug Evaluation; Female; Humans; In Vitro Techniques; Microcirculation; Middle Aged; Oxadiazoles

Topics: Aged; Angina Pectoris; Clinical Trials as Topic; Coronary Disease; Diethylamines; Female; Follow-Up Studies; Humans; Imines; Male; Middle Aged; Oxadiazoles; Vasodilator Agents

Topics: Coronary Disease; Humans; Oxadiazoles; Sydnones

Topics: Coronary Disease; Drug Therapy, Combination; Humans; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.

Topics: Adenosine Diphosphate; Animals; Arrhythmias, Cardiac; Cardiac Output; Coronary Disease; Dogs; Electrocardiography; Heart Rate; Heart Ventricles; Molsidomine; Oxadiazoles; Platelet Aggregation; Sydnones; Thromboxane B2; Vascular Resistance

The globally-ischaemic Langendorff rabbit heart model has been used to study the cardioprotective effects of the dihydropyridine PN 200-110 (PN) at two doses, one having no negative inotropic effect and a higher dose causing a 62 +/- 5% reduction in contractility. Following 45 min no-flow global ischaemia, recovery was monitored for a period of 90 min reperfusion. Hearts were paced at a constant rate throughout experiments. Contractile force and coronary flow were recorded continuously. Tracer microspheres were injected at regular intervals to assess regional flow distributions, drill biopsies were taken to determine tissue high energy phosphate content, and enzyme leakage in the coronary effluent measured during the first 15 min of reperfusion. Untreated hearts recovered 21 +/- 2% of their initial contractile force and flow to all heart regions was reduced. In particular, endocardial flow fell to 20% of its pre-ischaemic level, with the ratio of flow to the endocardium (endo)/epicardium (epi) decreasing from ca. 1.0 to 0.4. Hearts treated with 2 X 10(-8)M PN (included in the perfusate from 30 min before ischaemia until 30 min after ischaemia) recovered 49 +/- 2% of their initial, pretreatment contractile force, and following the ischaemia the endo/epi ratio was not significantly changed from the pre-ischaemic value. The lower PN dose (3 X 10(-10)M) afforded a lesser degree of protection, contractility recovering to 29 +/- 4% of the initial level, with an endo/epi ratio of 0.7 after 90 min reperfusion. 6 The two PN doses afforded a similar degree ofprotection against enzyme leakage which was in both cases significantly less than in untreated hearts. 7 Myocardial ATP and creatine phosphate content was markedly reduced by the ischaemic episode. Neither PN dose modified this depletion. 8 These results suggest that whilst cardiodepression may well offer protection against ischaemic damage, this is not the sole mechanism wherby PN (and possibly other calcium antagonists) can protect the heart. Preservation of blood flow to the inner layers of the left ventricular wall is likely to be one of the major factors underlying the enhanced recovery shown by PN.

Topics: Animals; Calcium Channel Blockers; Coronary Circulation; Coronary Disease; Diltiazem; In Vitro Techniques; Isradipine; Myocardial Contraction; Myocardium; Oxadiazoles; Rabbits; Time Factors; Verapamil

Some aspects of hemodynamic effects and distribution of coronary flow of molsidomine were evaluated in anesthetized dogs with open chest. Three experimental groups were performed: In groups I and II 100 micrograms/kg and 200 micrograms/kg of molsidomine were administered respectively. Cardiac output (CO), end diastolic pressure (EDP), mean arterial pressure (MAP), heart rate (HR), systolic left ventricular pressure (SLVP), their maximal rates of development and fall (+P and -P, respectively), developed tension (DT), their maximal contraction (+T) and relaxation (-T) rates, were measured. Peripheral resistance (PR) and the ratios +P/-P and +T/-T were calculated. In group III 100 micrograms/kg of molsidomine were administered after the ligature of the anterior descendent artery (AD) was performed. In this group the distribution of coronary flow was measured through radioactive microspheres injection in the circumflex area (CX) (normal area) and in the AD area (ischemic area). After injecting the microspheres and following its effects for one hour, the maximum effect was determined in 30 minutes. Heart rate did not show any statistically significant variation at any of the doses used. MAP fell from 92 +/- 3 mmHg to 77 +/- 5 mmHg (P less than 0.05) in group I and from 87 +/- 3 mmHg to 69 +/- 4 mmHg in group II. Cardiac output fell from 1.63 +/- 0.13 1/min to 1.22 +/- 0.12 1/min (P less than 0.05) in group I and from 1.60 +/- 0.19 1/min to 1.13 +/- 0.18 1/min (P less than 0.05) in group II. PR did not show any significant change in any of the groups. +P decreased 13 +/- 6% (P less than 0.05) in group I and 13 +/- 5% (P less than 0.05) in group II. The decrease of -P was of 17 +/- 5% (P less than 0.05) in both groups. EDP decreased from 6.0 +/- 1.0 mmHg to 3.9 +/- 0.9 mmHg (P less than 0.05) and from 5.5 +/- 0.5 mmHg to 2.9 +/- 0.8 mmHg (P less than 0.05) in groups I and II, respectively. DT, +T, -T, +T/-T and +P/-P did not show any significant change. EDP fell from 8 +/- 1 mmHg to 4.1 +/- 1.3 mmHg (P less than 0.05); MAP fell from 82 +/- 4 mmHg to 62 +/- 6 mmHg (P less than 0.05) and CO fell from 2.05 +/- 0.27 1/min to 1.30 +/- 0.14 1/min in group III. HR and PR did not show any significant change in group III.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Blood Pressure; Cardiac Output; Coronary Circulation; Coronary Disease; Depression, Chemical; Dogs; Hemodynamics; Molsidomine; Myocardial Contraction; Oxadiazoles; Sydnones; Vasodilator Agents

Topics: Coronary Disease; Heart Failure; Humans; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

The pharmacokinetics of molsidomine were investigated in the plasma and urine of healthy male volunteers and patients with coronary heart disease after intravenous and/or oral administration of different galenic dosage forms of molsidomine. Following the rapid attainment of mean peak concentration (15 +/- 7 mg/ml) 0.5 to 1.0 hour after single oral dosing of 2 mg of molsidomine, the plasma levels of the unchanged drug decline monoexponentially with a mean half-life of 1.6 +/- 0.8 hours. Molsidomine is absorbed almost completely. Its absolute bioavailability (44 +/- 15%) and a 14C-labeled triale give evidence of quick biotransformation of molsidomine to active metabolites. Less than 2% of the unchanged drug appear in the urine, but renal excretion is the main route of elimination of the metabolites in humans (90% to 95%). The kinetics parameters after administration of multiple dosages of 4 mg of molsidomine over 29 days do not account for accumulation of or enzyme induction by molsidomine. The finding of obvious good correlations between plasma levels of the predrug molsidomine and corresponding pharmacodynamic data can be made plausible by the time course of concentration values of the active metabolite SIN-1 in plasma.

Topics: Animals; Biological Availability; Coronary Disease; Dogs; Half-Life; Humans; Kinetics; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

Fifteen consecutive patients (mean age 54 years) with proven coronary heart disease were studied with radionuclide ventriculography. After resting and exercise control studies, repeat studies were performed after administration of 4 mg of molsidomine sublingually and again after administration of 10 mg of metoprolol intravenously. Rest to exercise ejection fraction (EF) decreased significantly. This was significantly attenuated by molsidomine and by metoprolol. In a subset of nine patients with exercise ischemia, EF showed significant (p less than 0.05) improvement after molsidomine administration (46.7 +/- 13.7% to 57.1 +/- 16.7%), which was diminished to 54.4 +/- 10.5% after metoprolol administration. In the subgroup without exercise ischemia, molsidomine increased the EF to a lesser extent (47.3 +/- 12.7% to 52.6 +/- 13.4%, p less than 0.05). After administration of metoprolol the EF decreased below the control level (44.4 +/- 10.6%). Regional Fourier amplitudes accentuated the differences between the two groups. We conclude that molsidomine and metoprolol improve left ventricular function in patients with coronary heart disease and ischemia during exercise. In patients with reduced left ventricular function without signs of ischemia, molsidomine improves function as well and should be used additionally, if beta blockers are indicated for other reasons.

Topics: Adult; Coronary Disease; Exercise Test; Female; Heart Ventricles; Humans; Male; Metoprolol; Middle Aged; Molsidomine; Myocardial Contraction; Oxadiazoles; Radionuclide Imaging; Stroke Volume; Sydnones; Vasodilator Agents

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.

Topics: Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Dogs; Heart; Kinetics; Molsidomine; Oxadiazoles; Regional Blood Flow; Sydnones

The haemodynamic effects of a single dose of intravenous molsidomine were assessed in 12 patients with severe coronary disease. The investigation was carried out at rest during angina induced by pacing and after molsidomine during pacing at the rate at which angina had been produced. During angina, left ventricular systolic and end-diastolic pressure rose, left ventricular stroke work fell and coronary flow and myocardial oxygen consumption increased by 58.3% above the control levels. After the administration of molsidomine, atrial stimulation was not followed by angina and there were no significant changes in systolic blood pressure. Left ventricular end-diastolic pressure fell sharply and coronary flow and myocardial oxygen consumption were only 38% and 33% higher, respectively, than the control levels. The beneficial effects of molsidomine in ischaemic heart disease, therefore, are the result of peripheral vasodilation which, by reducing the preload and afterload, lowers the oxygen requirements of the myocardium and thus increase the threshold for angina. A direct action on the coronary network can not be excluded but if such an action does exist it must be very small in the light of the marked systemic effect.

Topics: Adult; Aged; Angina Pectoris; Blood Pressure; Coronary Circulation; Coronary Disease; Electric Stimulation; Heart Rate; Hemodynamics; Humans; Infusions, Parenteral; Male; Middle Aged; Molsidomine; Myocardium; Oxadiazoles; Oxygen Consumption; Stroke Volume; Sydnones; Vasodilator Agents

Hemodynamic effects of 2 mg of sublingual molsidomine were evaluated in 11 patients with ischemic heart disease using a weight-sustaining isometric exercise (WSIE) that we developed. Left ventricular end diastolic pressure (LVEDP), mean pulmonary pressure, mean systemic arterial pressure (mAP), cardiac index and stroke work index increased significantly during WSIE before and after molsidomine. Although WSIE resulted in a similar rise of mAP before and after molsidomine, the increment value of LVEDP during WSIE was significantly lower after molsidomine. The recovery time to the resting state of all parameters was shorter and the left ventricular function curves showed a leftward deviation with molsidomine. In conclusion, the results suggest that molsidomine will produce a preload reduction and improve the left ventricular function during WSIE in patients with ischemic heart disease.

Topics: Adult; Aged; Blood Pressure; Coronary Disease; Female; Heart Rate; Hemodynamics; Humans; Isometric Contraction; Male; Middle Aged; Molsidomine; Muscle Contraction; Oxadiazoles; Stroke Volume; Sydnones; Vasodilator Agents

The effects of a variety of currently-used anti-anginal drugs on major hemorheologic parameters (blood viscosity in the 0.692-2348 s-1 variation rates range, plasma viscosity, erythrocyte and platelet function) and also the hemostatic system were examined in 100 chronic coronary patients during specific treatment courses. The nitrates, beta-blockers (alone or in combinations), cordaron and molsidomin were shown to produce positive effects on blood rheology. A relationship was demonstrated between physical stress tolerance and blood viscosity pattern in propranolol-treated coronary patients. It is suggested that positive hemorheologic effects of anti-anginal drugs may be an important constituent of their therapeutic action and, as such, provide an additional marker of their efficiency in coronary heart disease.

Topics: Adult; Amiodarone; Benzofurans; Blood Coagulation; Blood Viscosity; Coronary Disease; Erythrocyte Aggregation; Humans; Isosorbide Dinitrate; Male; Middle Aged; Molsidomine; Nitroglycerin; Oxadiazoles; Platelet Adhesiveness; Platelet Aggregation; Propranolol; Sydnones; Vasodilator Agents

The heart rate, cardiac output, coronary sinus blood flow, systolic and end diastolic left ventricular pressures, femoral arterial pressure and coronary oxygen arterio-venous difference were measured in 12 patients with stable coronary artery disease without cardiac failure on long-term betablocker therapy, before and 45 minutes after 2 or 3 mg sublingual molsidomine. The measurements were repeated in 8 patients during a cold pressor test. Under basal conditions, molsidomine decreased the systolic and end diastolic left ventricular pressures, mean femoral arterial pressure, cardiac output and double product. The coronary oxygen arterio-venous difference was unchanged. Coronary sinus flow and myocardial oxygen consumption decreased. In the 2 patients who were given 3 mg molsidomine, a progressive reduction in systolic left ventricular pressure to 70% or less than its initial value, necessitated immediate treatment with volume expanders. During the cold pressor test before molsidomine the systolic and end diastolic left ventricular pressures, mean femoral arterial pressure and the double product increased. Coronary sinus flow was unchanged overall: it decreased in 6 patients, increased in 2 patients and remained the same in 1 patient. Coronary resistance increased in 6 patients and decreased in only one patient. During the cold pressor test after molsidomine there was a significant reduction in the increase of systolic left ventricular pressure, mean femoral artery pressure and double product. Coronary sinus blood flow increased in 5 patients and decreased in only one case. Coronary resistance decreased in half the cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Antagonists; Adult; Aged; Cold Temperature; Coronary Disease; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

Topics: Aged; Coronary Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

Topics: Angina Pectoris; Arrhythmias, Cardiac; Chronic Disease; Coronary Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

Myocardial metabolism was examined in 114 patients with ischaemic heart disease. In selected subgroups, possibilities were detected of using this method in clinical cardiological diagnostics for determining or defining more precisely the diagnosis of ischaemic heart disease, and for objective evaluation of conservative or surgical therapeutic approach in ischaemic heart disease.

Topics: Adult; Angina Pectoris; Cardiac Catheterization; Coronary Circulation; Coronary Disease; Female; Humans; Lactates; Male; Middle Aged; Myocardial Revascularization; Myocardium; Oxadiazoles; Pyruvates; Pyruvic Acid; Vasodilator Agents

Molsidomine is able to restore a better balance between myocardial oxygen supply and demand during myocardial ischaemia, by inducing a prolonged decrease in the left ventricular wall pressure, by reducing the venous return to the heart and by dilating the large coronary trunks. Molsidomine is also able to redistribute the coronary blood towards the deep sub-endocardial layers during a transient or permanent coronary occlusion, by complex changes in the metabolic autoregulation, by dilatation of the transmural coronary arteries and by reduction of the extravascular compression forces. Finally, by inhibiting platelet aggregation and by a possible action thromboxane A2/prostacyclin synthesis, molsidomine exerts a real anti-thrombotic effect which helps reduce ventricular arrhythmia, improve segmental contractility and reduce the size of the post-stenotic infarct.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Epoprostenol; Molsidomine; Oxadiazoles; Oxygen Consumption; Platelet Aggregation; Sydnones; Thromboxane A2

Topics: Administration, Oral; Adult; Angina Pectoris; Coronary Disease; Double-Blind Method; Humans; Kinetics; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

Prostacyclin belongs to the family of prostaglandins, which are derived from arachidonic acid. It is secreted by vascular endothelium and possesses vasodilator and platelet anti-aggregant properties. This paper shows that molsidomine, a new anti-angina agent with vasodilator effects, is able to induce the secretion of prostacyclin by vascular endothelial cells in the aorta of the piglet. Molsidomine, via its stable metabolite SIN 1, induces very rapid and early secretion of prostacyclin followed by a refractory effect on vascular endothelium. At the same time, SIN 1 inhibits the platelet synthesis of thromboxane A2, which suggests that part of the action of molsidomine is related to an improvement in the prostacyclin/thromboxane A2 equilibrium, which has been shown to be disturbed in the course of certain cardiovascular diseases.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cells, Cultured; Coronary Disease; Epoprostenol; Molsidomine; Nitroglycerin; Oxadiazoles; Radioimmunoassay; Swine; Sydnones

The effect of molsidomine, a novel antianginal agent, on the epicardial electrographic changes induced by reduced perfusion of the left anterior descending coronary artery (LAD) was investigated in the anesthetized dog. The LAD was cannulated and perfused at a constant volume with blood taken from a carotid artery. The perfusion volume was than reduced by approximately 75%. The sum of the ST-segment changes obtained from six unipolar epicardial leads was taken as a measure of myocardial hypoxia. Simultaneously, heart rate, blood pressure, left ventricular end-diastolic pressure, pulmonary arterial pressure, and heart contractility were also recorded. In control animals, reduction of the perfusion volume of the LAD resulted in a dramatic elevation of the ST segments lasting more than 4 hr. Molsidomine administered after the induction of the ischemia at a dose of 0.05 mg/kg i.v. resulted within 40 min in a complete normalization of the electrographic changes. This effect was evident for over 4 hr in spite of the continuous reduced perfusion of the LAD. The beneficial effect of molsidomine on the electrical changes paralleled the reduction of the left ventricular end-diastolic pressure. It is suggested that the effect of molsidomine on the ischemic electrographic changes is brought about by a reduction of the preload, resulting in a better perfusion of the ischemic zones.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Disease; Dogs; Electrocardiography; Female; Heart Rate; Male; Molsidomine; Myocardial Contraction; Myocardial Infarction; Oxadiazoles; Sydnones

We performed a double-blind crossover study with molsidomine in 10 patients with coronary heart disease. A single dose of molsidomine and placebo were given sublingually 1 hour before an exercise tolerance test. Molsidomine significantly reduced systolic blood pressure at rest and at all work-loads. There was also a significant reduction in electrocardiographic ST-segment depression at submaximal exercise. At maximal exercise the drug significantly increased symptom-limited oxygen consumption and total mechanical work. Molsidomine could prove useful in the treatment of angina pectoris. It has no adverse effects on pulmonary function.

Topics: Aged; Coronary Disease; Double-Blind Method; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Oxygen Consumption; Physical Exertion; Respiratory Function Tests; Sydnones

The heart rate (HR), the cardiac output (Qc) and the coronary sinus flow rate (Qcs), the left ventricular systolic and end-diastolic pressures (LVSP, LVEDP), the femoral artery pressure (FAP) and the difference between the coronary arterial and coronary venous oxygen tension (DAVcO2) were measured in patients with stable coronary insufficiency without cardiac failure, before and 40 to 60 minutes after 2 or 3 mg of molsidomine (M). In 20 patients, these measurements were made in the basal state, in spontaneous rhythm (SP). In 8 of these patient, (including 3 receiving beta-blockers) the measurements were made during an atrial stimulation test (ST) and in 8 other patients, all receiving long-term beta-blocker therapy, the measurements were made during a cold test (CT). At the basal state in SR, a gradual reduction in the LVSP to 70% or less of its initial value was observed in the patients receiving 3 mg of M (2 of whom received beta-blocker treatment). The LVSP was immediately restored by vascular filling. In 16 patients, M decreased the LVSP, the LVEDP, the FAP, the Qc and the double product (DP = LVSP X HR). The DAVcO2 was unchanged. Qcs and MVO2 (MVO2 = Qcs X DAVcO2) were decreased. In the course of ST, the haemodynamic and coronary changes are similar to those seen in the basal state. During the Ct, the increase in the LVSP, FAP and DP was significantly reduced by M. The variations in Qcs and coronary resistance (FAP/Qcs) were also significantly different after M., with better metabolic regulation of the coronary circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Function; Cold Temperature; Coronary Circulation; Coronary Disease; Electric Stimulation; Female; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones

The influence of molsidomin (4 mg i.v.) on platelet function, on the plasma concentrations of 6-oxo-PGF1 alpha, the stable metabolite of prostaglandin I2, and thromboxane B2, the stable metabolite of thromboxine A2 was determined in ten patients with coronary heart disease. Prostaglandin I2 is generated in the vessel wall and is a potent vasodilator and inhibitor of platelet aggregation, whereas thromboxane A2 is a vasoconstrictor and a proaggregatory substance. In addition, in-vitro tests were performed, too. 60 min after bolus injection a decrease of systolic and diastolic blood pressure was observed, whereas heart rate remained nearly constant. Platelet aggregation decreased significantly; the addition of PGI2 in vitro had an additive effect. The plasma concentrations of 6-oxo-PGF1 alpha increased after 60 minutes, whereas thromboxane B2 concentrations remained unchanged. In vitro, SIN1, a metabolite of molsidomin generated in the liver, led to a dose-dependent inhibition of ADP-induced platelet aggregation, whereas molsidomin was nearly inactive. Thus molsidomin shows an inhibition of platelet function besides the known antianginal properties. The vasodilatatory and platelet inhibiting effects of this compound may be due partly to a stimulation of the prostaglandin I2 synthesis in the vessel wall.

Topics: Angina Pectoris; Blood Pressure; Coronary Disease; Epoprostenol; Female; Humans; Male; Molsidomine; Muscle, Smooth, Vascular; Oxadiazoles; Platelet Aggregation; Prostaglandins F; Sydnones; Thromboxane A2; Thromboxane B2

The effect of molsidomine on hemodynamics and myocardial ischemia were studied in 48 patients with acute myocardial infarction. Between 8 and 12 mg of orally and intravenously administered molsidomine led to a significant reduction in left ventricular filling pressure. In response to 2 x 4 mg p.o., diastolic pulmonary arterial pressure fell from 12.1 to 8.8 mm Hg in patients with filling pressure below 20 mm Hg. Patients with left heart failure and left ventricular filling pressure above 20 mm Hg (Group 2) displayed a decline in filling pressure from 23.8 to 17.4 mm Hg following 12 mg i.v. In addition, right atrial pressure dropped significantly across the entire range of dosages. Although patients without left ventricular failure (Group I) showed a decline in cardiac output (5.7 to 4.7 l/min), this parameter remained unchanged in Group 2. Heart rate in Group 2 fell from 85 to 81 per min. Arterial blood pressure was reduced by a mean of only 10 mm Hg at high dosages and remained unchanged at lower dosages. No change was observed in peripheral resistance. The maximum effect was seen 30 min after oral administration. Three hours later, the effect was reduced by half. Only minimal activity could be observed after 8 h. The incidence of side effects was low, with transient headaches occurring in 8% of the patients. An intraindividual comparison with 1.6 mg of sublingually administered nitroglycerin demonstrated no significant difference in hemodynamic effectiveness (n = 11). Molsidomine, not unlike nitroglycerin, exerts a favorable effect on hemodynamics and myocardial ischemia. It acts primarily to reduce preload. The additional moderate effect on afterload with a slight decline in arterial pressure at high dosages may also be considered advantageous.

Topics: Administration, Oral; Blood Pressure; Cardiac Output; Coronary Disease; Heart Rate; Hemodynamics; Humans; Injections, Intravenous; Molsidomine; Myocardial Infarction; Oxadiazoles; Sydnones

The antianginal drug molsidomine was evaluated for its in vivo antithrombotic effects in barbiturate-anesthetized open-chest dogs by inducing left circumflex (LCX) coronary artery thrombosis with low-amperage stimulation (150 microA for 6 h) of the intimal surface of the vessel. Intravenous bolus administration of 0.10 mg/kg molsidomine 10 min prior to onset of electrical stimulation partially prevented occlusive LCX thrombosis and prolonged time to complete vessel occlusion by 45 min (p less than 0.05). Intracoronary thrombus mass was reduced (14 +/- 0.8 vs. 32 +/- 4 mg in controls, p less than 0.05). Final 6-h infarcts after complete LCX coronary artery thrombosis were measured by triphenyltetrazolium chloride (TTC) staining and were smaller after molsidomine pretreatment when related to left ventricular mass (14 +/- 3 vs. 28 +/- 2%, p less than 0.02) or to the LCX vessel area at risk for infarction (18 +/- 3 vs. 58 +/- 4%, p less than 0.01). Molsidomine did not induce hemodynamic alterations during time to complete thrombotic LCX coronary artery occlusion. In saline controls, heart rate and end-diastolic pressure increased whereas blood pressure and contractility decreased significantly. The percentage of ventricular ectopic beats concomitant to thrombus formation and myocardial ischemia was significantly reduced in the drug-treated dogs. Molsidomine also partially prevented the reduction in myocardial function parallel to blood flow diminution as measured with an ultrasonic technique. The drug further exerted significant ex vivo inhibition of collagen-induced platelet aggregation (p less than 0.01 vs. control from 4 h after onset of LCX stimulation). In addition to established hemodynamic effects of molsidomine there may also be a direct effect on platelet aggregation and thrombus formation in vivo which delays coronary artery narrowing and occlusion as one primary cause for myocardial ischemia.

Topics: Animals; Blood Pressure; Coronary Disease; Dogs; Electric Stimulation; Electrocardiography; Female; Heart Rate; Hemodynamics; Male; Molsidomine; Oxadiazoles; Platelet Aggregation; Sydnones

Topics: Angina Pectoris; Coronary Disease; Electrocardiography; Humans; Male; Middle Aged; Molsidomine; Morpholines; Oxadiazoles; Physical Exertion; Sydnones

To analyze the mechanisms of action of molsidomine, a new antianginal drug, 10 patients with coronary artery disease and exertional angina pectoris were studied. Hemodynamic measurements were made at rest, during submaximal exercise and during angina-limited exercise before and 1 hour after intravenous administration of 2 mg of molsidomine. When angina pectoris was prevented after the drug was given (6 of 10 patients), the exercise intensity was increased until the recurrence of angina (3 patients) or until exhaustion (3 patients), and hemodynamic data were recorded at this higher exercise capacity. At rest and during submaximal exercise, molsidomine increased heart rate and decreased cardiac output and mean systemic and pulmonary arterial pressures. The prevention of angina pectoris was attended by lower mean systemic and pulmonary arterial pressures and pressure-rate product; cardiac output and heart rate were unchanged. The greater exercise capacity (+26 percent) after molsidomine was attended by increases in maximal cardiac output (+19 percent) and in arteriovenous oxygen difference (+6 percent); the maximal pressure-rate product was unchanged and systemic vascular resistance was lower. The mechanisms of action of molsidomine are very similar to those of nitrates and imply a decrease in venous and arterial tone. Molsidomine deserves further study in patients with angina or congestive heart failure.

Topics: Adult; Angina Pectoris; Cardiac Output; Coronary Disease; Exercise Test; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Morpholines; Oxadiazoles; Oxygen Consumption; Rest; Stroke Volume; Sydnones

Increased resistance of the heart to acute transitory coronary insufficiency under conditions of prophylactic use of molsidomin was demonstrated in experiments on dogs and rats. The agent prevents electric destabilization of the heart. Reduction of pre- and postexertion of the heart is one of the main factors of the protective action of molsidomin. It is suggested that the drug may be included in the complex of measures used in the treatment of patients suffering from anginal and anginal-arrhythmic forms of stable and unstable angina pectoris.

Topics: Acute Disease; Animals; Coronary Disease; Dogs; Drug Evaluation, Preclinical; Female; Heart; Male; Molsidomine; Morpholines; Myocardial Contraction; Oxadiazoles; Rats; Sydnones; Time Factors

Antithrombotic and hemodynamic properties of molsidomine (0.10 mg/kg i.v.) were evaluated in an in-vivo model of coronary artery thrombosis initiated by electrical stimulation for 6 h. Molsidomine prolonged time to vessel occlusion and prevented heart rate and end-diastolic pressure increase and contractility decrease. Infarct size was smaller after drug treatment related either to left ventricle (P less than 0.02) or to vessel area-at-risk (P less than 0.01). It is suggested that molsidomine has antithrombotic effects which might prevent acute coronary infarction.

Topics: Animals; Blood Coagulation; Coronary Disease; Disease Models, Animal; Dogs; Female; Hemodynamics; Male; Molsidomine; Morpholines; Myocardial Infarction; Oxadiazoles; Sydnones

The actions of molsidomine, a new antianginal agent, on coronary collateral blood flow and myocardial oxygen consumption were studied in anesthetized dogs with acute ligation of the distal third of the left anterior descending coronary artery. Molsidomine (50 and 100 microgram/kg, i.v.) produced a significant decrease in myocardial oxygen consumption, however no change occurred in collateral blood flow. These results suggest that the beneficial actions of molsidomine in myocardial ischemia are primarily due to a decrease in oxygen demand.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Female; Hemodynamics; Male; Molsidomine; Morpholines; Oxadiazoles; Oxygen Consumption; Sydnones; Vasodilator Agents

Topics: Adult; Angina Pectoris; Blood Pressure; Cardiac Volume; Computers; Coronary Disease; Female; Heart; Heart Ventricles; Humans; Male; Middle Aged; Molsidomine; Morpholines; Myocardial Contraction; Oxadiazoles; Oxygen Consumption; Sydnones; Time Factors

Topics: Angina Pectoris; Blood Pressure; Coronary Disease; Drug Evaluation; Humans; Oxadiazoles; Stroke Volume; Sydnones

Topics: Adult; Coronary Disease; Female; Humans; Male; Middle Aged; Oxadiazoles; Platelet Aggregation

Topics: Coronary Artery Bypass; Coronary Disease; Echocardiography; Female; Humans; Male; Middle Aged; Morpholines; Nitroglycerin; Oxadiazoles; Sydnones

Topics: Blood Pressure; Cardiac Output; Coronary Disease; Heart Rate; Heart Ventricles; Humans; Middle Aged; Morpholines; Myocardial Contraction; Oxadiazoles; Pulmonary Circulation; Stroke Volume; Sydnones; Vascular Resistance

Topics: Blood Pressure; Cardiac Output; Coronary Circulation; Coronary Disease; Heart Rate; Hemodynamics; Humans; Morpholines; Myocardial Contraction; Oxadiazoles; Pulmonary Artery; Sydnones

Topics: Adult; Aged; Coronary Disease; Electrocardiography; Female; Humans; Male; Middle Aged; Oxadiazoles; Oxygen Consumption

In anaesthetized dogs regional myocardial blood flow (radioactive particle distribution technique) and several haemodynamic parameters were measured before and after acute ligation of left descending coronary artery. By injection of N-carboxy-3-morpholino-sydnonimine ethylester (molsidomine, Corvaton) or infusion of nitroglycerin it was tried to influence blood flow of the infarcted areas of the myocardium. 1. Ligation of the coronary artery induces myocardial infarction of anterior wall, predominantly restricted to the endocardial portions of the heart muscle. 2. Molsidomine and also nitroglycerin do not change overall blood flow of the heart in the sense of vasodilation. 3. In the infarcted area the ratio: blood flow of endocardial layers to blood flow of epicardial layers, is improved by molsidomine. 4. The positive effect of molsidomine becomes clearer in the border zone of infarction. Nitroglycerin remains without effect. 5. The effects of the compound molsidomine are explained by stronger action on extravascular factors of colonary vascular resistance (decrease in enddiastolic pressure).

Topics: Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Morpholines; Nitroglycerin; Oxadiazoles; Sydnones; Time Factors; Vascular Resistance

In ten patients with coronary heart disease molsidomine achieved a clear-cut decrease in pre- and after-load of the heart at rest. Due to decreased venous return at rest there was a fall in stroke volume resulting in a fall of systolic and diastolic aortic pressure. But at the same level of standardised exercise, systolic and diastolic arterial pressure and cardiac output were similar with or without molsidomine. Without changing after-load, there was a fall in pulmonary artery mean pressure (P less than 0.005), probably due to an increase in left-ventricular compliance and (or) a fall in pulmonary vascular resistance. A rise in venous capacity or a decrease in venous return during exercise was excluded as a possible mechanism of molsidomine action.

Topics: Adult; Blood Pressure; Cardiac Output; Coronary Disease; Female; Heart Rate; Humans; Male; Middle Aged; Morpholines; Oxadiazoles; Physical Exertion; Pulmonary Artery; Pulmonary Circulation; Sydnones; Vascular Resistance

Hemodynamic changes for 30 min after intravenous administration of molsidomin 4 mg were studied in 10 patients. Pulmonary artery pressure, pulmonary wedge pressure, right atrial pressure and aortic pressure decreased significantly after 15 min, and after 30 min they were still below the control level. Heart rate increased significantly (by 15%) 15 min after injection, and after 30 min it was still 8% above the control value. Cardiac index decreased significantly from 3.37 +/- 0.12 to 2.95 +/- 0.15 1/min/m2. Peripheral and pulmonary resistance showed no significant change. Both stroke work index and minute work decreased significantly 15 min after administration of molsidomin and after 30 min both were still below the control level. The results suggest that molsidomin decreases preload without influencing afterload. By decreasing preload, molsidomin improves the oxygen supply/demand ratio of the myocardium.

Topics: Adult; Airway Resistance; Blood Pressure; Cardiac Output; Coronary Disease; Heart Rate; Hemodynamics; Humans; Middle Aged; Morpholines; Oxadiazoles; Sydnones; Time Factors

In 15 patients with coronary heart disease and typical ST-segment depression during and/or after increasing physical effort in supine cycloergometry the normalizing effect of different dosages of Molsidomine on the electrocardiogram under effort was investigated in 74 exercise tolerance tests. Already after application of 0,5 mg Molsidomine there was observed a significant positive effect in comparison to an identical workload without drug. The normalizing effect was further increased by raising the dosage ot 1 mg or 2 mg respectively. To the administration of 3 mg only 1 out of 10 patients in the trial responded with an additional normalizing effect on the ECG since the rest of the patients showed already normal ECGs on 2 mg. This dose relationship also was observed in the pressure-rate-product. There was a dose-dependent decrease from which we can conclude a relief of the working myocardium. Under effort without drug 13 of 15 patients complained about stenocardia. Under the same effort and under Molsidomine however there were no more of these complaints. Because of these results it is recommended to use 2 mg of Molsidomine as a dosage in daily routine. It is needed 2 or 3 times dialy since in previous investigations there was shown a long-lasting effect over more than 5 hours. 3 out of 15 patients showed side effects which were only weak headache or weak congestion in the head.

Topics: Aged; Blood Pressure; Coronary Disease; Electrocardiography; Exercise Test; Heart Rate; Humans; Male; Middle Aged; Morpholines; Oxadiazoles; Sydnones

The protective effect of molsidomin (N-ethoxycarbonyl-3-morpholinosydnonimine) during ergometric exercise was tested on 40 patients with coronary insufficiency proven by preliminary exercise tests or coronary arteriography. Changes in arterial blood pressure, heart rate, pulmonary artery pressure, ischaemic S-T depression and maximal working capacity were used as criteria. The drug increased maximal working capacity and decreased S-T segment depression. In addition it caused a fall in systolic and diastolic blood pressure and pulmonary artery pressure, at rest and during exercise. Resting heart rate increased slightly but during exercise the heart rate was reduced at comparable load stages. The results suggest that molsidomon may be an effective drug in the treatment of angina pectoris.

Topics: Adult; Aged; Angina Pectoris; Blood Pressure; Coronary Disease; Electrocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Morpholines; Oxadiazoles; Physical Exertion; Pulmonary Artery; Sydnones

Topics: Aged; Coronary Disease; Drug Evaluation; Humans; Middle Aged; Oxadiazoles; Vasodilator Agents

Topics: Adult; Aged; Analgesics; Angina Pectoris; Coronary Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Myocardial Infarction; Oxadiazoles; Vasodilator Agents

Molsidomine was shown to have a strong pain-relieving action in 22 coronary patients investigated one hour after oral intake of 2 mg of the substance. During comparable maximal exercise load the ST interval lowering was reduced from an average of 0.22 mV to 0.09 mV (P less than 0.0005). At the termination of exercise it was still reduced from 0.23 mV to 0.12 mV (P less than 0.0005). At the same time the exercise tolerance increased from 570 to 717 Watt-minutes (P less than 0.0025). Pectanginal complaints were clearly reduced at the same exercise loads, 11 patients became symptom-free at the same load. Even when exercise loading was stopped at higher loads a decrease of the severity of angina pectoris could be shown. Seven patients became symptom-free at that stage. The heart rate was not influenced markedly at rest and during exercise. Systolic blood pressure was reduced from 135 mm Hg to 118 mm Hg (P less than 0.0005), and in comparable submaximal loads from 177 to 165 mm Hg (P less than 0.005).

Topics: Administration, Oral; Angina Pectoris; Blood Pressure; Coronary Disease; Electrocardiography; Exercise Test; Heart Rate; Humans; Male; Middle Aged; Morpholines; Oxadiazoles; Sydnones

Topics: Animals; Blood Pressure; Chronic Disease; Collateral Circulation; Coronary Disease; Coronary Vessels; Dogs; Electrocardiography; Heart Rate; Imines; Injections, Intravenous; Male; Morpholines; Oxadiazoles; Regional Blood Flow; Vasodilator Agents

Topics: Adult; Aged; Coronary Disease; Female; Humans; Male; Middle Aged; Oxadiazoles; Vasodilator Agents

Topics: Administration, Oral; Adult; Aged; Coronary Disease; Coronary Vessels; Ethylamines; Female; Humans; Male; Middle Aged; Oxadiazoles; Time Factors; Vasodilator Agents

Topics: Coronary Disease; Female; Humans; Male; Oxadiazoles; Vasodilator Agents

Topics: Constipation; Coronary Disease; Humans; Oxadiazoles; Sodium; Sulfuric Acids

Topics: Anti-Inflammatory Agents; Coronary Disease; Gastrointestinal Diseases; Humans; Lung Diseases; Muscles; Oxadiazoles; Urologic Diseases