Roger Messin

Comparative response to isometric (static) and dynamic exercise tests in coronary disease

Abstract Forty-six patients with arteriosclerotic heart disease manifested significant electrocardiographic changes (accompanied by angina in 35) during maximal exercise testing. These patients subsequently performed isometric exercise at levels representing various percentages of maximal voluntary contraction. Twenty-two patients also performed combined isometric and submaximal dynamic exercise. The prevalence rate of S-T segment changes during isolated isometric exercise depended on the percent of maximal voluntary contraction applied but was far lower than the rate observed during maximal dynamic exercise. Angina seldom occurred. Manifestations of coronary insufficiency appeared more often during combined submaximal dynamic and isometric exercise than during isolated isometric testing. Aortic pressure was measured in eight cases. Tension-time index and pressure-heart rate product were lower when maximal dynamic exercise was stopped owing to coronary insufficiency than at the end of isolated isometric exercise or combined submaximal dynamic and isometric exercise. However, the latter two tests produced fewer ischemic manifestations. The reasons for these discrepancies are discussed. We conclude that isometric exercise tests are unsuitable for diagnosing coronary insufficiency.

Acute and chronic effect of molsidomine extended release on exercise capacity in patients with stable angina, a double-blind cross-over clinical trial versus placebo

A double-blind, placebo-controlled, cross-over study was performed in 50 patients with ischemic heart disease and stable angina to determine the duration of efficacy of 8 mg molsidomine in extended-release form. Exercise testing was performed at baseline and 2, 4, 6, 8, and 10 h after intake of either the medication or the placebo. Total duration of exercise (in minutes) and total work performance (workload x min) was significantly improved in the molsidomine retard group, not only compared with baseline but also with placebo for all time-points. ST segment depression at 60 W and at maximal exercise improved similarly until 10 h after molsidomine retard treatment. The rate-pressure product (heart rate x systolic blood pressure) showed significant improvement only at 60 W. No attenuation of the obtained effects was observed after 14 days of treatment. The number of anginal attacks and the consumption of sublingual nitroderivates were significantly reduced with molsidomine retard 8 mg as compared with placebo. Molsidomine retard 8 mg is effective until at least 10 h after oral (p.o.) intake. A dose schedule of molsidomine retard 8 mg twice daily definitely reduces anginal symptoms.

Clinical Pharmacokinetics of Once-Daily Molsidomine: From Immediate-Release to Prolonged-Release Once-Daily Formulations

BackgroundMolsidomine is a direct nitric oxide donor routinely used in the oral treatment of stable angina pectoris. It was initially available as 4mg immediate-release tablets to be taken three to four times a day. New galenic formulations have been developed: prolonged-release molsidomine 8mg to be administered twice daily and, more recently, prolonged-release molsidomine 16mg to be taken once daily, the latter being based on the patented and US FDA-approved Geomatrix® technology.ObjectivesThis study has four objectives: (i) to compare and differentiate the pharmacokinetics of the different molsidomine formulations after single- and repeated-dose administrations; (ii) to put the new formulations in perspective with the literature and the critical minimal efficacy plasma molsidomine concentration of 5 µg/L; (iii) to demonstrate a possible bioequivalence between 8mg twice-daily and 16mg once-daily tablets when used at their recommended therapeutic dosage regimen; and (iv) to assess the effect of food and age on the absorption, distribution, and elimination of the new once-daily formulation.MethodsDifferent dosages of various formulations of molsidomine were administered to young and elderly healthy volunteers and plasma concentrations of molsidomine and its active metabolite, linsidomine (SIN-1), were determined. Plasma concentrations were determined using solid-phase extraction and enrichment of the extracts on a short column followed by elution of the analytes by liquid Chromatographic mobile phase and ultraviolet detection.ResultsCompared with previous formulations, molsidomine 16mg once daily showed an increased time to maximum plasma concentration and a tendency to a lower mean maximum plasma concentration. Plasma molsidomine concentrations were always above the efficacy threshold of 5 µg/L during the whole 24-hour cycle and the concentration at trough was still in the therapeutic range. No drug accumulation was observed after repeated administration. Bioequivalence between molsidomine 16mg once daily and molsidomine 8mg twice daily could not be demonstrated after 1 and 5 days of treatment, the relative bioavailability being significantly larger with the latter regimen. Pharmacokinetics of molsidomine 16mg once daily was not significantly affected by either concomitant food ingestion (no major effect of a high-fat meal) or aging (no major difference between young and elderly healthy volunteers).ConclusionsMolsidomine 16mg once daily allowed the maintenance of a therapeutically active plasma concentration over 24 hours after single or repeated oral administration. The bioavailability of molsidomine from the once-daily preparation is apparently not affected by concomitant administration of food or age of the recipient.

Short- and long-term effects of molsidomine retard and molsidomine nonretard on exercise capacity and clinical status in patients with stable angina: A multicenter randomized double-blind crossover placebo-controlled trial

A multicenter, randomized, double-blind, crossover, placebo-controlled study was conducted in 90 isosorbide dinitrate responders showing stable angina to compare the efficacy of molsidomine retard, 8 mg b.i.d., with that of molsidomine, 4 mg t.i.d., for 6 weeks. Total work performance (workload x min) was significantly improved, compared with baseline and placebo until 8 and 12 h after molsidomine and molsidomine retard administration, respectively. ST-segment depression decreased significantly under the two treatments at 60 W as well as at maximal exercise. The rate-pressure product (heart rate x systolic blood pressure) decreased and increased significantly at submaximal and maximal exercise level, respectively. All these effects remained significant after 6-week treatment, with only the ST segment showing a nonsignificant tendency to improvement at maximal work. The frequency of anginal attacks and of sublingual nitroderivative-tablets consumption decreased significantly with molsidomine, 4 mg, and molsidomine retard, 8 mg. However, overall results showed that the latter form reduces myocardial ischemia more efficiently at submaximal exercise level, has a more prolonged effect on exercise tolerance, and maintains it at a somewhat higher level after 6-week treatment.

Tolerability to 1-Year Treatment With Once-Daily Molsidomine in Patients With Stable Angina

Prolonged-release molsidomine 16 mg once daily (QD) has proved effective in the short-term treatment of patients with stable angina. The purpose of this multi-center study was to assess its long-term tolerability and clinical effectiveness. A total of 320 patients with stable angina were treated for 1 year with molsidomine 16 mg QD administered open label as monotherapy or add-on therapy, when beta blockers and/or calcium antagonists were prescribed concomitantly (in 128 patients, ie, 40% of cases), depending on the severity of disease and/or local therapeutic policies. In all, 293 patients (91.6%) completed the study. The proportion of patients who reported drug-related adverse events (AEs) was 9.1%, which is not significantly different (P=.13) from the 5.9% observed during previous short-term (2–4 wk) treatment. Headache accounted for 80.6% of all drug-related AEs and required discontinuation of the drug in one quarter of patients who reported the symptom (ie, 1.9% of the 320 patients involved in the study). No serious drug-related AEs occurred during the study. Tolerability to molsidomine, evaluated with use of a visual analog scale (VAS), improved by 20% from beginning to end of 1-year follow-up. Two-by-two Bonferroni’s comparisons were significant at the .05 level between the 2-month assessment and assessments performed at 8, 10, and 12 months. No age-time interaction was noted (P=.82). Heart rate, blood pressure, electrocardiogram, and blood parameters showed no statistically significant or clinically relevant changes during the study. Compliance with treatment was satisfactory throughout the follow-up period. There was no significant change in the weekly frequency of anginal attacks and consumption of short-acting nitroderivatives during the 1-year study (P=.07 andP=.12, respectively), but their frequency was significantly (ie, ~50%) lower than during a preceding short-term treatment period (P<.0001 andP=.014, respectively). Subjective clinical status, evaluated through an appropriate VAS, improved by 38% from start to end of 1-year follow-up. Bonferroni’s comparisons between baseline and subsequent 2-month evaluations were all significant at the .05 level. No age-time interaction could be seen for frequency of anginal attacks and consumption of short-acting nitroderivatives, nor for clinical status (P=.10,P=.11, andP=.51, respectively). Neither tolerability to molsidomine nor effectiveness of the drug was biased by concomitant antianginal therapies, insofar as none of these parameters showed a significant treatment type (ie, molsidomine administered as monotherapy or add-on therapy)-time interaction (VAS for tolerability:P=.44; angina:P=.39; nitroderivatives:P=.72; VAS for clinical status:P=.62). Molsidomine 16 mg QD administered for 1 y to patients with stable angina was well tolerated and remained effective during the entire treatment period, independent of age and concomitant antianginal therapy.

Normal pulmonary pressure-flow relationship during exercise in the sitting position

SummaryPulmonary arterial pressure flow relationships were determined in middle-aged male healthy subjects selected amidst patients intending to an invalidity pension for anthracosilicosis.At rest in the sitting position the mean pulmonary artery pressure was 10.8 ± 4.3 mm Hg for a cardiac output of 5.0 ± 0.9 l/min. The average relationship between increase of pulmonary artery pressure and increase of cardiac output during bicycle exercise was approximately linear. With a cardiac output of 13.3 ±1.7 l/min the mean pulmonary artery pressure reached 22.5 ± 4.6 mm Hg.The total pulmonary resistance (left atrial pressure assumed to be 0) decreased during exercise; the extent of this decrease showed considerable variation from one subject to another.

Efficacy and safety of once- and twice-daily formulations of molsidomine in patients with stable angina pectoris: Double-blind and open-label studies

Molsidomine, a sydnonimine acting as a heterocyclic direct nitric oxide donor, has been used for many years in several European countries for the treatment of patients with stable angina pectoris. The efficacy and tolerability of a novel oncedaily 16-mg formulation of molsidomine (M16) were compared with those of the currently used twice-daily 8-mg molsidomine tablet (M8) in 666 patients. Study 1, a multicenter, randomized, double-blind, placebo-controlled, twin crossover study, involved 533 patients given acute and 2-week treatment with each drug formulation. Study 2, a multicenter, open-label, sequential, add-on trial, compared M16 and M8 in 133 patients. Drug effects on exercise capacity (study 1 only), frequency of anginal attacks and consumption of short-acting nitroderivatives, and incidence of adverse events (AEs) were evaluated. Compared with placebo, M16 increased exercise capacity by 15% (P < .001) at the start of study 1 and by 13% (P < .001) after 2 weeks’ treatment, and was not inferior to M8. In terms of anginal attack frequency and nitroderivative consumption, M16 was not inferior to M8 in either study. Moreover, compared with M8, M16 produced a statistically and clinically significant reduction in the incidence of anginal attacks in elderly (≥75 y) but not in younger patients (< 75 y) (study 2), nor in patients from study 1. No significant difference from M8 was found in either study in short-acting nitroderivative consumption. No tolerance to M8 or M16 was observed after 2-week treatment. No statistically significant differences in incidences of all AEs and drug-related AEs were observed between M16 and M8 in either study. The same held true for proportions of patients experiencing AEs and drugrelated AEs on M16 vs M8: in study 1–14.3% and 11.8% for all AEs (P=.218), 6.9% and 5.4% for drug-related AEs (P=.280); in study 2–1.3% and 1.3% for all AEs, 0% and 1.3% for drug-related AEs (P > .10) in young patients; and in the elderly, 3.6% and 0% for drugrelated AEs (P > .10). Only the proportion of elderly patients with all AEs was significantly higher with M16 than with M8: 14.5% vs 1.8% (P=.039). M16 once daily was effective and well tolerated in investigated patients with stable angina pectoris, particularly the elderly, affording 24 hours of therapeutic activity. M16 was not inferior to M8 given twice daily in terms of efficacy, safety profile, and tolerability.

Exercise tolerance in coronary patients: Randomized trial of two-week treatment with molsidomine versus placebo

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.

Diastolic function and modifications of left ventricular architecture in ultraendurance athletes.

Although diastolic function is altered in left ventricular hypertrophy due to aortic stenosis or systemic hypertension, it has been shown to be normal in athletes. To analyze the reason for this discrepancy, we have studied left ventricular masses and volumes and diastolic flow velocities in 13 ultraendurance athletes and in 8 sedentary subjects as a control group by M-mode (TM), two-dimensional (2D) and Doppler echocardiography. Significant differences in the measurements of mass and volume have been found depending upon the method used. Considering that two-dimensional echocardiography is more appropriate for estimations of LV mass and LV volume, especially when the shape of the left ventricle is modified, overestimation of LV mass and underestimation of LV volume in ultraendurance athletes by TM could be explained by an elongation of LV cavity in athletes. Doppler velocimetry showed similar results in athletes and control subjects. We suggest that those LV configurational changes partly explain the preservation of diastolic function in athletes by restoring in diastole the energy stored in systole.

Effects of molsidomine on exercise tolerance in patients with coronary heart disease

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.