Prevention of postischaemic ventricular fibrillation by long term beta adrenoceptor blockade with acebutolol in the anaesthetised dog.

Acute occlusions of the proximal left circumflex coronary arteriovenous pedicle were performed in open chest anaesthetised dogs. Twenty eight dogs were randomly allocated to receive acebutolol (3 mg X kg-1 twice daily) or placebo given blindly by mouth for five days; a control group of 14 dogs without any pretreatment underwent the same procedure. Coronary ligations in the randomised study were performed during seven consecutive days, and four dogs were operated on each day. This schedule was chosen in order to measure acebutolol plasma concentrations just before ligation from 60 to 540 min after the last dose of the drug. Long term oral treatment with acebutolol protected against postischaemic ventricular fibrillation and significantly reduced the incidence of both early phase (0-10 min postocclusion) ventricular arrhythmias and ventricular fibrillation. As a result the outcome was significantly improved after 60 min of ischaemia in acebutolol compared with placebo treated animals. The results in the control animals were similar to those in the placebo treated dogs. The protective effect of long term oral treatment with acebutolol lasted for nine hours and was apparently independent of the plasma concentrations of the drug. These data show that improved outcome in this canine model is due to the prevention of ischaemia induced ventricular fibrillation by long term beta adrenoceptor blockade, which is able to overcome the effect, if any, of partial agonist activity of acebutolol. A direct myocardial anti-ischaemic effect might explain the effectiveness of long term oral treatment, which is independent of plasma concentrations of the drug.

Molsidomine prevents post-ischaemic ventricular fibrillation in dogs.

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.

Effects of cicletanine in the left circumflex coronary artery occlusion-reperfusion canine model of sudden death: analysis of 107 experiments using Cox's proportional hazards model.

Multivariate analysis of survival using Cox's proportional hazards model demonstrates that several clinically measurable covariates are determinants of life-threatening arrhythmias following left circumflex coronary artery occlusion-reperfusion in 107 dogs. These are heart rate, ST segment elevation and mean aortic pressure immediately (3 min) following occlusion, and the presence of early (0-10 min) post-occlusion sustained ventricular tachycardia. The risk of occlusion-reperfusion ventricular fibrillation was determined according to Cox's solution based on ST segment elevation, thus enabling quantification of the role of cicletanine. Since cicletanine-treated dogs had reduced mean ST segment elevation at 3 min post-occlusion, lower incidence of early post-occlusion (0-10 min) sustained ventricular tachycardia, and increased endogenous production of prostacyclin, and the latter was inversely correlated with the level of ST segment elevation, it is concluded that such favourable effects on the ischaemic myocardium were contributory to the improved outcome in these experiments. These effects on the ischaemic myocardium obtained in spite of a hypotensive action in the experimental setting might be regarded as desirable and it is therefore suggested that they should be further investigated by pharmacodynamic studies in human subjects.

Bretylium tosylate--induced stabilization of electrical systole duration in patients with acute myocardial infarction.

The electrical systole duration (QTc), heart rate, and the QTc/QTt ratio were studied during the hospital course of an uncomplicated AMI in 13 patients treated with bretylium tosylate (10 mg/mg/24 hr over 5 days since confirmation of AMI) and in 19 controls. The QTc/QTt ratio showed prolongation of electrical systole duration in control subjects with a maximal value at the second day after AMI. QTc increased in these patients from day 1 to day 2 after AMI (402 +/- 4 msec vs. 430 +/- 3 msec, p less than 0.05) and decreased in the following days (p less than 0.05). During hospitalization cardiac rate was constant in both groups. In contrast, patients treated with bretylium tosylate showed a stable duration of QTc and the QTc/QTt ratio did not indicate prolongation of electrical systole duration. After drug discontinuation a slight increase in QTc duration was noticed (391 +/- 6 msec vs. 413 +/- 5 msec, p less than 0.05). These observations may contribute to the understanding of the antiarrhythmic action of bretylium and would indicate its usefullness in AMI patients with prolonged QTc and high risk of life-threatening arrhythmias.

[Eicosanoids, vascular function and atherosclerosis]. / Icosanoïdes, fonction vasculaire et athérosclérose.

Icosanoides (prostaglandins, leukotrienes) seem to play an essential part in cardiovascular pathology. A range of experimental data obtained both in vitro and in vivo has resulted in a rapid progression of our understanding of their biochemical and functional properties and has opened up new fields of pharmacological research. However, a clear cut demonstration of their clinical relevance remains difficult. Improved methodology will no doubt provide more information about the importance of these compounds. For the present, we recommend reexamination of previously reported results.

[Eicosanoids, myocardial ischemia and sudden death]. / Icosanoïdes, ischémie myocardique et mort subite.

An activation of the arachidonic acid cascade has long been reported in coronary artery diseases. However, no clear-cut connection has been demonstrated between this activation and the clinical manifestations of myocardial ischemia. Controlled trials with the available cyclooxygenase inhibitory drugs support the view that these agents might be useful in subgroups of patients. However, these are not known. The peculiar pharmacologic properties of prostacyclin and PGE1 have been documented to improve experimental and clinical acute myocardial ischemia. Further efforts are needed to elucidate the usefulness of some PGs in the management of patients with ischemic heart disease and their contributory role to the disease.

[Acute phase of ventricular fibrillation in myocardial infarct. Importance of studying electrical systole by determining the QTc]. / Fibrillation ventriculaire à la phase aiguë de l'infarctus du myocarde. Intérêt de l'étude de la systole électrique par la détermination du QTc.

Recent reports have drawn attention to the association between long QT intervals and sudden death in myocardial infarction and certain congenital syndromes. This study was undertaken to determine the relationship between lengthening of the QT interval and primary ventricular fibrillation in acute myocardial infarction. Thirteen cases were chosen out of a total of 21 cases of primary ventricular fibrillation (5.09% of 412 cases of myocardial infarction hospitalised during this period). Ten other cases of myocardial infarction with the same features apart from the arrhythmia were used as controls. Three series of electrocardiogrammes recorded under the same technical and chronological conditions (2 before and 1 after ventricular fibrillation) were analysed. The average QT interval was corrected for heart rate (RR) with Bazett's formula. The average QTc in acute myocardial infarction was longer than the theoretical QTc (p less than 0.05). The graph showing this increase reached a peak at the 48th hour. The average QTc in patients with primary ventricular fibrillation was longer than in the control patients (p less than 0.05) and significantly longer than the theoretical value (p less than 0.001). The average QTc in survivors of ventricular fibrillation was not significantly longer than that of the control group but was longer than the theoretical value (p less than 0.01). These results justify the strict surveillance of the length of electrical systole in the first hours of the acute phase of myocardial infarction. In this series, values greater than 440 ms were associated with a high risk of ventricular fibrillation in the first week after myocardial infarction.

[Prevalence of arterial hypertension and its treatment in 2,595 adults]. / Prévalence de l'hypertension artérielle et de son traitement chez 2,595 adultes.

The prevalence of arterial hypertension, as defined by the W.H.O. (systolic BP greater than 160 mmHg and/or diastolic BP greater than 95 mmHg), and the prevalence of its treatment were studied in 2595 local government employees of Marseilles, aged from 20 to 65 years. The prevalence of hypertension was 17.96 p. 100 (466/2595, including 222 men and 244 women). The prevalence of normal tension was 57.50 p. 100 (1492/2595, including 802 men and 690 women). The prevalence of treated hypertension was 37.98 p. 100 (177/466) divided into 29.27 p. 100 (65/222) in men and 45.90 p. 100 (112/244) in women (p less than 0.0001). Blood pressure was controlled by treatment in 32.30 p. 100 (21/65) of treated men and in 36.61 p. 100 (41/112) of treated women (NS). 81.14 p. 100 (198/244) of hypertensive women and 57/82 p. 100 (399/690) of normotensive women were active (managers, executives). In treated men, the plasma level of apoprotein A1 was decreased and that of apoprotein B was increased. Among men, the global score at Bortner questionnaire was significantly lower in the group of 175 untreated hypertensive patients (176 +/- 46) than in the group of treated hypertensive patients (192 +/- 48, p less than 0.05) and in the group of normotensive subjects (186 +/- 41, p less than 0.05). This indicated that untreated hypertensive men have a tendency to type B pattern and suggested a line of research aimed at a better understanding of the relative failure of anti-hypertensive treatments in the prevention of coronary disease.

[Evaluation of the effectiveness of medical treatment of intermittent claudication]. / Evaluation de l'efficacité des traitements médicaux de la claudication intermittente.

The effectiveness of drugs to improve the walking distance in intermittent claudication patients is looked into five points: pathophysiology, drugs, methodology of clinical trials, sample survey among the members of the hemodynamic section of the French College of Vascular Diseases and biometric aspects. Finally, some important points of a clinical trial in this field are presented.

[Plasma thromboxane B2 and capacity of the aorta to produce prostacyclin in arteriopathies of the lower extremities]. / Thromboxane B2 plasmatique et capacité de production de prostacycline par l'aorte dans les artériopathies des membres inférieurs.

Plasma levels of thromboxane B2, and 6-Keto-PGF1 alpha, stable metabolites of thromboxane and of prostacyclin were determined by radioimmunoassay in 17 patients with arterial disease and 10 control subjects. The production of prostacyclin from incubates of aortic microsomal fractions of patients was also studied. There was a significant elevation of thromboxane B2 in the peripheral venous blood of patients with arterial lesions (142 +/- 152 pg/ml vs 22 +/- 2 pg/ml, p less than 0.005); levels of 6-KetoPGF1 alpha were equally low in controls and patients. Rate of production of prostacyclin, which was 450 +/- 24 pmol/50 mg of proteins in 10 minutes in controls, was reduced to 97 +/- 86 pmol/50 mg prot. 10 min (p less than 0.01) in patients. Co-existence of raised plasma thromboxane levels and a reduced capacity for prostacyclin synthesis in the same patients is supportive evidence of the thrombogenic theory of arterial disease.

[Calcium channel blockers in ischemic cardiopathies]. / Les inhibiteurs du canal calcique lent dans les cardiopathies ischémiques.

Calcium-entry blockers are the drugs of choice in coronary spasm, unstable angina, and when patients do not have any effort limitation. However, beta-blockers, without sympathomimetic activity, remain the treatment of angina pectoris. When clinical situation is difficult to control, association calcium blockers and bêta-blockers are more efficient than monotherapy. In myocardial infarction, results are controversial: calcium channel blockers should be administered only with beta-blockers.

[Duration of electric systole in the acute phase of myocardial infarct. Methodology, natural history, semiological value, therapeutic consequences]. / Durée de la systole électrique à la phase aiguë de l'infarctus du myocarde. Méthodologie, histoire naturelle, valeur séméiologique et conséquences thérapeutiques.

Extension of the duration of electric systol in the acute phase of coronary thrombosis can be analysed in satisfying conditions whatever the physiological frequencies by the measurement (formula; see text) represents the average QT measurement of three non-consecutive complexes in five derivations (DI, DIII, aVF, VI and V6). This extension is of prognostic value when the QTc is greater than 44 c/s. Out of 1 255 acute phase thrombosis patients, 18 Out of 20 cases of ventricular fibrillation revealed a QTc greater than 44 c/s in the 24 hours preceding sudden death. Therapeutic intervention with anti-andrenergic drugs such as bretylium tosylate or beta-blocking agents appears to reduce the QTc of these patients and thus prevent sudden death.

[Apparent internal male pseudo-hermaphroditism. Gynecomastia. Negative gonad surgical research. Caryotype 46, XX. Presence of H-Y antigen (author's transl)]. / Pseudo-hermaphrodisme mâle interne apparent. Gynécomastie. Recherche chirurgicale des gonades négatives. Caryotype 46, XX. Présence d'antigène H-Y.

Boy 15. Aspect of delayed puberty with empty scrotum and gynecomastia. Caryotype 46, XX. Presence of H.Y. Antigen. Plasmatic testosterone 1 020 pg/ml. Normal plasmatic FSH and LH. Hypotrophic uterus and tubes. No gonad found. Small right epididymis. Complete virilization by testosterone.

[Platelet antiaggregants in other pathologies]. / Antiagrégants plaquettaires dans les autres pathologies.

Platelet aggregation inhibitors are used in numerous clinical situations on the basis of claims that platelets are involved. As a result of controlled clinical trials, some of these situations have become formal indications for some of these drugs. The situations in which platelet aggregation inhibitors are used include: arteritis of the lower limb at the intermittent claudication stage, leg ulcers of arterial origin, emboligenic arteritis with focus of platelet hyperfixation, progression of atherosclerosis as assessed by angiography, implantation of vascular surfaces, diabetic retinopathy, retinal venous thrombosis, cycle cell anaemia and perhaps thrombocythaemia. Other, more discussed indications of antiplatelet drugs are mentioned.

Experimental and clinical pharmacology of bretylium tosylate in acute myocardial infarction: a 15-year journey.

Experimental and clinical studies demonstrate the antifibrillatory effectiveness of bretylium tosylate: Experimental ventricular fibrillation induced either by electrical stimulation or by ischemia is prevented by bretylium. In 2,000 acute myocardial infarction patients who received bretylium prophylactically primary ventricular fibrillation occurred in less than 1% of cases. In a randomized hemodynamic study in acute myocardial infarction patients bretylium induced a significant decrease in heart rate, systolic and mean left ventricular pressures, and in systolic and mean aortic pressures. In addition, a parallel and significant decrease in total pulmonary and systemic resistances was seen, accompanied by decreases in tension time and left ventricular (delta P/delta V) indexes. Bretylium tosylate induces stabilization of electrical systole duration (QTc) in acute myocardial infarction patients. The conclusions of the present review strongly support those of the United States Food and Drug Administration, approving bretylium for prophylaxis and treatment of ventricular fibrillation.