[Characteristics of a cohort of 4,000 French patients with angina. The ELAN study]. / Caractéristiques d'une cohorte française de 4,000 patients angineux. L'étude ELAN.

The ELAN (Etude Longitudinale dans l'ANgor) study was carried out to evaluate factors influencing the occurrence of death, myocardial infarction and revascularization procedures in patients with known angina pectoris. Analysis of baseline data collected in January 1997 involves 4,035 patients throughout France, which were recruited by 613 cardiologists practising on a private, hospital or mixed basis. The study population comprised 75% of men with a mean age of 65 years and 25% of women with a mean age of 70 years. Eighty eight percent of the patients had at least one cardiovascular risk factor, and nearly half of them had two or more factors; hypercholesterolemia and hypertension were the two most frequent ones. Reported cardiovascular past events included myocardial infarction in 47% of patients, PTCA in 33% and aorto-coronary bypass in 24%. Angina pectoris had been diagnosed within the previous year in 39% of patients. Exertional angina was the most common type (66%), with grade I/II angina being most frequently found (more than 70% of all cases). Management strategies are especially described for angina patients diagnosed within the previous year. More than half of the patients had undergone exercise testing within the previous 12 months, while scanning and coronary arteriography had been performed in 15% and 72%, respectively. Ninety five percent of patients were under antianginal drug therapy, with combined therapies being used in 58% of them. The most frequently prescribed drugs were betablockers (63%) and nitrates (53%). In 74% of patients, aspirin was given in addition to conventional antianginal agents. These data will be reviewed in a one-year cohort analysis as potential predictive factors for the occurrence of cardiovascular events.

[One-year follow-up of a population of patients with angina. Factors influencing mortality and occurrence of cardiovascular events. Results of the ELAN study]. / Le devenir à un an d'une population de patients angineux. Facteurs influençant la mortalité et la survenue des événements cardiovasculaires. Les résultats de l'étude ELAN.

The ELAN (Etude longitudinale dans l'angor) study was carried out both to acquire better knowledge of the occurrence of major cardiovascular events (myocardial infarction, revascularization surgery, death) in patients followed up for angina pectoris, and to determine the factors influencing such events. A cohort of angina patients was formed in January 1997, and 3,284 patients were followed up by 488 French cardiologists during a one-year period. Of these 3,284 patients, 96 (29/1000) died; causes of death included underlying coronary heart disease in 31, sudden death in 8, other cardiac aetiologies in 35, and noncardiac causes in 22. Sixty-nine (21/1000) patients developed myocardial infarction, 240 (73/1000) underwent PTCA, and 119 (36/1000) underwent coronary bypass surgery. Factors associated with an increased risk of death were age, diabetes mellitus, heart failure and angina type, mixed and rest angina being associated with poorer prognosis compared to exertional angina. Infarction risk increased with age and a history of previous infarction. Analysis of therapeutic factors after adjustment for the above risk factors showed a beneficial effect of betablockers on both cardiovascular and all-cause mortality and of aspirin on all-cause mortality.

Gastroduodenal tolerability of medium dose enteric-coated aspirin: a placebo controlled endoscopic study of a new enteric-coated formulation versus regular formulation in healthy volunteers.

We compared, in a cross-over study, the toxicity of 300 mg enteric-coated aspirin with regular aspirin used for the prevention of cardiovascular events. In terms of endoscopic haemorrhagic lesions, enteric-coated aspirin is less gastrotoxic than regular aspirin.

Can anaerobic threshold be used as an end-point for therapeutic trials in heart failure? Lessons from a multicentre randomized placebo-controlled trial. The VO2 French Study Group.

Anaerobic threshold (AT), proposed as a non-invasive index of exercise tolerance, independent of patient motivation, is considered more reliable than exercise duration in assessing the effect of drug therapy in chronic heart failure (CHF). However, inter-observer variation in patients may be more difficult than in normal subjects. In a multicentre study, 85 patients from 10 centres performed a total of 331 bicycle maximal tests (ramp protocols, 10 watts.min-1) with respiratory gas analysis by different systems. A central committee reviewed all the tests. Percentages of AT determination ranged from 34% to 71% depending on the method used. Apart from the respiratory exchange ratio (RER) method, which yielded the lowest rate of determination: 34%, and the crossing point (when RER = 1), which yielded the highest rate, 71%, other methods of determination, such as carbon dioxide (42%), minute ventilation (52%) or ventilatory equivalents plotted vs time (57%), did not differ in the rate of AT determination. Thus, even among trained physicians, AT determination was not reliable. The crossing point may nevertheless be a valuable index from a pragmatic standpoint, although it occurs after the actual AT. Peak oxygen uptake should remain the main end-point in assessment of exercise capacity.

Hemodynamics, tolerability, and pharmacokinetics of linsidomine (SIN-1) infusion during the acute phase of uncomplicated myocardial infarction.

To determine a dose regimen and evaluate the hemodynamic effects of linsidomine administered by continuous intravenous (i.v.) infusion, 10 patients were studied during the acute phase of uncomplicated myocardial infarction (MI). Systolic, diastolic, and mean (SBP, DBP, MBP) systemic blood pressure and heart rate (HR) were measured noninvasively. Pulmonary artery pressures were monitored after insertion of a Swan-Ganz catheter, which also enabled measurement of cardiac output (CO) and cardiac index (CI) by thermodilution. After baseline hemodynamic values (period A) were determined, linsidomine (SIN-1) was infused at a rate of 0.8 mg/h and subsequently adjusted to obtain a 10% decrease in MBP from its baseline value (period B). The infusion was then continued for 3 h at a constant rate (period C), and pressures were monitored for 1 h after the infusion was discontinued (period D). There were no significant changes in systemic or pulmonary arterial pressures or in HR between period B and period C. In contrast, CI decreased moderately (p < 0.05), with no clinical consequences. Return to baseline hemodynamics was obtained at the end of period D. Our findings indicate that continuous i.v. administration of SIN-1 (at a mean flow rate of 1 mg/h) is well tolerated and appears to be suitable for use in acute coronary syndromes.

Multicentre study of the determination of peak oxygen uptake and ventilatory threshold during bicycle exercise in chronic heart failure. Comparison of graphical methods, interobserver variability and influence of the exercise protocol. The VO2 French Study Group.

Assessment of the ventilatory threshold (VT) has been proposed to assess exercise tolerance more objectively, particularly in clinical trials, but reproducibility, interobserver variability and feasibility of the graphical methods for determination of VT have not been properly studied in patients with chronic heart failure (CHF). Fifty-one patients with mild to moderate CHF (mean peak oxygen uptake (VO2): 20.5 ml.min-1.kg-1) were assessed during two consecutive bicycle exercise tests within 8 days. Two graded exercise protocols were compared with stages of 30 W every 3 min (22 patients) or 10 W/min (29 patients). VT was determined separately by five trained physicians using five different graphical methods. The 'crossing method' (first crossing of the VCO2 and VO2 curves) yielded the highest rate of determination (88%) but tended to overestimate the mean VT. The VE method (disproportionate increase of ventilation relative to VO2) produced the best interobserver agreement (coefficient of variation = 78%). Peak VO2 was very highly reproducible in both exercise protocols (relative difference 2-test 1/test 1 = -0.32% for the 30 W 3 min protocol; +2.18% for the 10 W.min-1 protocol). The reproducibility of VT was slightly lower regardless of the graphical method used to determine it (relative differences varied from -3.3% to +7.3%). Therefore, peak VO2 appears more suitable than VT for assessment of exercise tolerance in CHF.

[Plasma pharmacokinetics of roxatidine in the healthy man: correlation with gastric antisecretory effect]. / Pharmacocinétique plasmatique de la roxatidine chez l'homme sain: corrélation avec l'effet antisécrétoire gastrique.

Inhibitory effects of roxatidine acetate upon human gastric secretion have been shown to be dose-related after oral administration. In order to correlate this effect with drug pharmacokinetics, blood concentration of the active metabolite, roxatidine, was assessed in 10 healthy volunteers, each receiving in random order 75, 150, 300, 600 mg of roxatidine acetate and placebo. Blood was drawn for roxatidine measurement at T 0 (time of drug intake) T 75, 90, 120, 150, 210, 240 and 300 min. Meal-induced gastric secretion was studied by intragastric titration (IGT) at 15 min intervals, from T 150 to T 240. Mean peak of blood concentration occurred at T 150 with significant correlation with the administered dosage. Gastric secretion inhibition over the 90 min of IGT correlated with peak concentration exclusively for the subpopulation with peak occurrence at T 150. Beyond the peak, decrease in roxatidine concentrations was slow, as expected from a known 6-h half-life. However, overall results showed that mean blood concentration was correlated with gastric secretion inhibition from T 180 on. The last IGT sample also correlated with the peak. Interpretation of these results would be different whether roxatidine concentration variations are appreciated as exhibiting a significant decrease or not. Infusion studies of roxatidine would be a valuable technique for further analysis and comparison of blood-concentration/efficacy relationships as compared with other H2-antagonists.

The influence of molsidomine on infarct size: an acute post-infarction pilot study with 303 patients.

In a multicenter, randomized and double-blind study, the efficiency of molsidomine on infarct size has been examined in 303 patients suffering from a first myocardial infarction and compared with a placebo. According to previous enzyme studies, and in order to detect a 20% reduction infarct size with conventional levels of risk, alpha = 0.05 and beta = 0.20, the recommended sample size was 264 patients. Thirty-three patients initially selected were excluded for protocol violation and, among the 270 patients definitively included, 133 were allocated to molsidomine and 137 to placebo, without any difference concerning age, delay of treatment, infarct location, and initial blood pressure. Test drugs were both initiated within the 6 first hours and administered orally at decreasing doses for 10 days: 16 mg on the first day, 12 mg on the second day, and 6 mg daily from the third to the tenth days. There was not a significant difference between the molsidomine and placebo groups regarding the enzyme evaluation of infarct size, neither for CK dosage (101.72 +/- 74.76 gram equivalents vs. 92.71 +/- 65.91 gram equivalents, NS) nor for its MB fraction (67.34 +/- 50.07 gram equivalents vs. 63.50 +/- 43.01 gram equivalents, NS). Moreover, changes in the Q- or R-wave sum during the 10 days of follow-up were strictly identical. However, in-hospital mortality was lower in the molsidomine group than in the placebo group (4.5% vs. 8.0%), but this reduction was not statistically significant. During the study, there were few side effects, mainly headaches, without withdrawal of the treatment.

[Treatment of unstable angina. A randomized double-blind study of propranolol, diltiazem and molsidomine]. / Traitement de l'angor instable. Etude randomisée en double aveugle du propranolol, du diltiazem et de la molsidomine.

A randomized, multicentric, double blind study attempted to compare in 41 patients hospitalized for unstable angina, the efficacy of diltiazem (D) 240 mg/day, propranolol (P) 160 mg/day and molsidomine (M) 8 mg/day. The patients included in the study presented one or several spontaneous angina episodes accompanied by a transient and significant lowering of ST and/or an inverted T wave without necrosis. The evaluation criteria were the occurrence of new angina pain and electrical alterations on a continuous Holter for 5 days. 11 patients received diltiazem, 13 patients received propranolol and 15 patients received molsidomine (including an early death). Clinically, the number of painful episodes per day and per patient goes, in an average, from 1.2 to 0.23 diltiazem, from 2.2 to 0.44 for propranolol and from 2.2 to 0.45 for molsidomine. Pain disappeared on the 5th day in 54.5 per cent of patients under diltiazem, 58.8 per cent of patients under propranolol and 53.5 per cent of patients under molsidomine. Electrically, the number of ischemic accidents per day and per patient was 0.45 under diltiazem, 2.12 under propranolol (0.53 in excluding one patient with latent angina) and 0.81 under molsidomine. The number of patients without any ischemic accident was 63.6 per cent under diltiazem, 53.8 per cent under propranolol and 40 per cent under molsidomine. In conclusion, diltiazem, propranolol, and molsidomine have a comparable efficacy in unstable angina. The association of these medications could have a synergistic effect.

A comparative trial of ordinary metoprolol tablets and metoprolol sustained-release tablets in hypertensive patients at rest and on exercise.

An open, randomized crossover trial was carried out in 10 patients with hypertension to compare the degree and duration of antihypertensive effect of metoprolol given as 100 mg ordinary tablets twice daily and as single daily doses of a 200 mg sustained-release tablet. Blood pressures and heart rate were measured, at rest and during maximum exercise effort, before treatment, at the second hour after the start of each treatment sequence, and at the end of both 14-day treatment periods: after 12 hours in the case of ordinary metoprolol and after 24 hours with sustained-release metoprolol. The results showed that heart rate was greatly reduced (less than 0.001) both at rest and on exercise at all times studied with both treatments. At rest, blood pressure was significantly reduced except by sustained-release metoprolol at 2 hours. On exercise, blood pressure was also significantly reduced except for the 12-hour value for diastolic pressure with ordinary metoprolol. It is concluded that, for similar reductions in heart rate reflecting satisfactory beta-receptor blockade, the antihypertensive effect of metoprolol given at a dosage of 200 mg per day was more rapid in onset after the ordinary tablet formulation but less marked at 12 hours than at 24 hours after the sustained-release formulation.

[Molsidomine in exertion angina]. / La molsidomine dans l'angor d'effort.

Molsidomine (M), a new anti-angina drug, was studied by stress tests in 50 cases of stable angina and clinically in 33 patients not controlled by beta-blockers. One hour after sublingual administration of 2 mg of M. to 10 patients, the work required to cause ST depression of 1 mm (WST1) was increased by 94 per cent (p less than 0.005), the total work was increased by 52 per cent (p less than 0.005) and the maximal ST depression (ST max) was reduced by 45 per cent (p less than 0.01). The resting heart rate was unchanged and the blood pressure dropped mildly. In 4 of the 10 patients with exertional angina even while taking beta-blockers, the synergistic effect of M was remarkable. With a sublingual dose of 1 mg, the WST1 and the ST max are very significantly improved. The effect is even more marked at a dose of 2 mg. With a sublingual or oral of 2 mg, WST1 and ST max are very significantly improved at 1 hour and at 3 hours (p less than 0.005). Data from the literature show a significant anti-ischaemic effect until the 6th hour. In two series of 10 patients, 2 mg of M administered orally were compared to 20 mg of isosorbide dinitrate and to 10 mg of nifedipine at the 2nd hour. The WST1 and ST max were very significantly improved by all three drugs to a similar degree.(ABSTRACT TRUNCATED AT 250 WORDS)

The elastic behavior of the urinary bladder for large deformations.

The purpose of this paper is to investigate the theoretical basis for the pressure-distension behavior of the urinary bladder. A finite strain theory is developed for hollow spherical structures and it is shown that the Treloar model is a good prototype only for rubber balloons. The pressure-extension ratio relationship is inverted to lead a general form of strain energy function, and fitted by an empirical relation involving one exponential. The following form of strain energy function is derived: W(lambda, lambda, lambda -2) = C1 (P(1), a) + P(1)C2 (a, lambda)ea(lambda -1). Where C1(P(1), a) is a constant (N m-2), P(1) is the initial pressure, a is the rate of pressure increase and C2 (a, lambda) a third degree polynomial relation. P(1) and a are experimentally determined through volumetric pressure-distension data. It is verified that this type of energy function is also valid for uniaxial loading experiments by testing strips coming from the same bladder for which P(1) and a were computed. There is a good agreement between the experimental points and the theoretical stress-strain relation. Finally, the strain energy function is plotted as a function of the first strain invariant and appears to be of an exponential nature.

[Ergometric study of a new vasodilator agent in angina: molsidomine. Value of combination with beta-blockaders]. / Etude ergométrique dans l'angor d'un nouveau vasodilatateir : la molsidomine. Intérêt de l'association aux bêta-bloqueurs.

Molsidomine, a new venous vasodilator, was studied in 40 cases of stable angina by ergometric stress testing. 1. In 10 patients, one hour after 2 mg molsidomine sublingually, the work inducing a 1 mm ST depression (WST 1) increased by 94% (p less than 0,05), the total work by 52% (p less than 0,005) and the maximum ST depression (ST max) fell by 45% (p less than 0,01). Resting heart rate was unchanged. There was a mild fall in systemic blood pressure. 2. Molsidomine had a significant synergic effect in 3 groups of 10 patients on betablocker therapy but with ischaemic changes on exercise: a) Molsidomine 1 mg sublingually increased WST 1 by 36% (p less than 0,05); at a 2 mg dosage, by 55% (p less than 0,001). ST max decreased from 2,4 +/- 0,4 mm to 1,3 +/- 0,3 (p less than 0,005) and 1,2 +/- 0,33 (p less than 0,001) respectively. The maximal effect was obtained with 1 mg in 5 out of 10 patients. b) One and three hours after 2 mg Molsidomine sublingually or orally: WST 1 increased from 97% to 110% (p less than 0,005): ST max decreased in similar proportions (p less than 0,005). c) 2 mg Molsidomine and 230 mg isosorbide dinitrate orally were compared after two hours: WST 1 increased by 130% after Molsidomine (p less than 0,005) and by 112% after isosorbide (p less than 0,005). ST max decreased in similar proportions (p less than 0,005). The blood pressure fell less with molsidomine. Molsidomine appeared to be better tolerated than isosorbide. (5 cases of mild headache in 40 patients compared to 4 cases out of 10 patients). The results of a preliminary clinical trial are reported. The association of molsidomine (2 mg per os three times daily) reduced the number of anginal attacks by over 50% in 16 out of 17 patients inadequately controlled by betablockade alone. 3 patients complained of headache at the onset of therapy. The efficacity was comparable and the tolerance better than in 28 patients with isosorbide dinitrate and betablockade, and in 10 patients with nifedipine and betablockade. In conclusion, molsidomine is a venous vasodilator with useful pharmacokinetic properties. It seems to be effective and well tolerated in the treatment of angina whether used alone or in association with betablockers.

[Biological determination of the beta blocking activity of human serum]. / Détermination biologique du pouvoir bêta-bloquant du sérum humain.

A method of biological assessment of the Beta blocking activity of human serum is reported. It is based on the catecholamine response of rat myocardial cells in culture, incubated in the serum to be tested. Its advantage is that it takes into account all block-blocking substances present in the serum, not only the drug itself but also its possible active metabolites. The results obtained by this method in 10 healthy subjects after 60 mg penbutolol were compared with those given by chemical dosage and ergometry. The ergometric and biological changes were parallel from the 2nd and the 8th hour while the serum levels of the drug rapidly. This discordance could be due to the presence of an active metabolite, 4-hydroxy-penbutolol.

[Anti-arrhythmic effects of injectable amiodarone. Apropos of 100 cases]. / Les effets antiarythmiques de l'amiodarone injectable. A propos de 100 cas

The effects of amiodarone by injection have been studied in 100 patients. 50% of these patients were in cardiac failure. Amiodarone was given intravenously over 30 seconds in a dose of 300 mg; in 15 of the patients a further dose of 150 mg was given after ten minutes. Amiodarone was found to be particularly effective in the tachy-arrhythmias (90% successful) in which it brought about slowing (18 cases out of 30) or conversion (17 cases out of 30). Just as good results were obtained for the atrial tachycardias (90% success rate) and in the junctional tachycardias. This treatment is less effective for atrial flutter (50% successful) and for ventricular arrhyrthmia, in which the success rate was only 60%. It is possible to use the defibrillator after amiodarone has been administered. This drug is well tolerated, and no increase in cardiac failure has been noted in these patients. There does remain, however, the possibility of hypotension and perhaps of circulatory collapse, which is rapidly reversable; this is probably due to vasodilator activity. Intracavitary studies in 8 patients have shown that amiodarone causes slowing of sino-atrial and of atrio-ventricular conduction. Amiodarone may equally worsen a distal conduction defect. The uses for this anti-arrhythmic drug, which is particularly effective at the atrial level, are discussed in this paper.