Biomedical subjects
Publications and source records attributed to L Guedon-Moreau.
The news concerning anticoagulant therapy is very rich. It was also keenly awaited in view of the real imperfection of antivitamin K drugs on which the present strategy of prevention of thromboembolic risk related to atrial fibrillation is based. The new anticoagulants have differing targets identified from the physiological mechanism of coagulation and the physiopathology of thrombosis.
The aim of this study was to evaluate the effect of an angiotensin-converting enzyme (ACE) inhibitor, ramipril, on heart rate variability in patients with heart failure simultaneously treated with digitalis. This study was a multicentric, randomized, double-blind, placebo-controlled study including 50 patients with chronic heart failure (CHF). All patients were in NYHA functional class II and III. The etiology of CHF was mainly idiopathic dilated cardiomyopathy and ischemic heart disease. After a 4-week placebo run-in period with digoxin and diuretics, patients were randomized to receive additional ramipril or placebo. To assess heart rate variability (HRV) and arrhythmias, 24-hour ECGs were recorded at the end of the placebo run-in period, 8 and 24 weeks after randomization. Spectral analysis of HRV was performed during one diurnal and one nocturnal 5-minute time period. No statistically significant differences in HRV within low-, high-, and total-frequency bands were induced by ramipril in either the diurnal or nocturnal periods, both at 8 and 24 weeks after randomization. Ramipril produced a significant decrease in nonsustained ventricular tachycardia at 24 weeks of treatment (p = 0.01). These results run against previous observations showing an increase in parasympathetic tone with ACE inhibitors in heart failure. The present study thus suggests that the effects of ACE inhibitors in CHF are variable and depend on the patient and concomitant treatment that might influence HRV such as digoxin treatment.
Milnacipran is a new antidepressant agent selected from a series of cycloproprane derivatives. The aim of this study was to investigate the acute electrophysiological effects and the tolerance of intravenous administration of this drug in 10 patients without any abnormality as shown in an electrophysiological study done for various complaints. Milnacipran was given over a 30-min period at doses of 0.2 mg/kg (2 patients), 0.4 mg/kg (2 patients) and 0.8 mg/kg (6 patients). The most significant alterations observed in this study were increases in heart rate (average of maximal increase: +19.5% at 50 min, P = 0.06) and systolic blood pressure (average of maximal increase: +21.5% at 10 min, P < 0.005), and decreases in the functional refractory period of the atrium (-3%, P < 0.05), the atrioventricular node (-9%, P < 0.005) and the effective refractory period of the right ventricle (-10.8%, P < 0.05) at 50 min. The sinus node function was improved in nine patients but depressed in one patient with previous slight baseline sinus node alterations. Milnacipran being devoid of both anticholinergic and monoamine oxidase inhibition activities, these alterations could be related to inhibition of noradrenaline uptake leading to an increase of adrenergic activities. No other ECG or electrophysiological parameters were significantly altered. Five of the 10 patients reported transient nausea, four of them for the highest dosage (0.8 mg/kg) and at the moment of peak of milnacipran plasma level. In conclusion, electrophysiological effects of intravenous milnacipran are negligible. These findings differ from those, well described in the literature, for imipramine-like antidepressant agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Arrhythmogenic right ventricular dysplasia is responsible for ventricular tachycardia affecting an apparently healthy heart. It can sometimes lead to sudden death, which may be the presenting symptomatology of the disease. It results from fibro-adipose infiltration of the free wall of the right ventricle, and sometimes of the septum, possibly secondary to myocarditis. The prognosis depends upon the quality of the left ventricle. If it is healthy, the only risk is that of arrhythmia. Treatment using anti-arrhythmic drugs is most often effective and, with proper management, the prognosis is good and the risk of sudden death eliminated. If the left ventricle is abnormal, there is the risk that dysplasia associated with arrhythmia will progress to right then congestive cardiac failure in the context of a dilated idiopathic cardiomyopathy with ventricular tachycardias originating on the right side. Arrhythmogenic right ventricular dysplasia is a notable cause of sudden death in athletes. Routine screening of such individuals is justified, as is that of those with high risk occupations (locomotive and vehicle drivers, etc.).
Angiotensin converting enzyme inhibitors, in comparison with other antihypertensive agents, offer unquestionable advantages in the treatment of hypertension. They do not alter cerebral blood flow. They improve cardiac function by decreasing postload, by preventing left ventricular hypertrophy and by decreasing myocardial excitability which engenders dysrhythmias. They increase compliance of large arteries and correct renal hemodynamic disturbances in hypertensive patients. Finally, they do not cause metabolic disturbances involving serum blood sugar, uric acid or lipids, and they help conserve potassium in patients on diuretics.
Antiarrhythmic drugs are able to save patients from emergency dysrhythmic situations or to avoid symptomatic disorders when used in a prophylactic goal. However they can also induce adverse effects. Cardiovascular adverse effects, and especially proarrhythmic effects, are the most dreaded. Analysis of the underlying mechanisms of the onset and perpetuation of sustained arrhythmias could lead to a better understanding of causes of proarrhythmic effects and thus to a limitation of their occurrence. Antiarrhythmic drugs can modulate the three principal factors which are involved in the onset of arrhythmias: individual predisposing factors, trigger mechanisms and environmental factors. This multiparameter modulation will conduct either to suppress the arrhythmic disorders (antiarrhythmic effect) or to impair it (proarrhythmic effect). According to the numerous factors which take part in the onset and perpetuation of arrhythmia, incidence of proarrhythmic effect of antiarrhythmic drugs is very difficult to evaluate.
The antiarrhythmic drugs are unfortunately not devoid of adverse effects. A good watching of their safety is necessary, according to their cardiovascular adverse effects which are the most dreaded. Among these and beside the proarrhythmic effects, the negative inotropic effects can impair cardiac function. Different mechanisms could explain the negative inotropic effects of antiarrhythmic drugs: reduction of adrenergic sensitivity, decrease of calcium concentration in the cardiac cells. Pharmacokinetic properties of antiarrhythmic drugs can modulate their cardiovascular adverse effects. As a matter of fact the plasmatic concentration of the unbound drug, which could be correlated to the adverse effects, fluctuates according to the protein binding of the drug. In an other way the first pass hepatic effect of a drug can be saturable so that the resulting dose-concentration curve becomes exponential. Drug disposition might also be very different from one patient to another depending on kidney and/or hepatic function and genetically determined metabolic pathways.
Explore the source record for details and available documents.
Dihydropyridines are the most numerous available calcium antagonists. While belonging to the same group these drugs have physical, chemical, pharmacokinetic or pharmacodynamic properties which are sometimes specific and can explain differences in the targets and the vascular selectivity. These properties can be related to lipophilic or hydrophilic characteristics, existence or lack of 'use-dependence', possible liaison to membrane phospholipids, and differences in elimination half lives. Selectivity of dihydropyridines also depends on the nature of the target structure (amount of intra-cellular calcium storage and mechanism of its release, electrophysiological properties of these cells) and of its pathological state (atherosclerosis and/or hypertension). Some of these properties could explain the anti-atherogenic effects, myocardial impact, cerebral and renal vascular flow and action in some pathological situations (Raynaud's syndrome, chronic arteriopathy, migraine...). A better knowledge of these different properties could lead to a more accurate choice of the drugs and to a decrease in the incidence of their side effects.
Antiarrhythmic drugs (AA) are useful in some critical situations but their use remains questionable. Evaluation of their efficacy and possible side effects required accurate knowledge of various methods. ECG gives relevant informations on the conduction intervals alterations caused by AA. Holter monitoring allows evaluation of the efficacy and/or proarrhythmic effects throughout 24-48 hour periods provided that spontaneous variability is taken into account. Ambulatory sequential loop ECG allows a longer monitoring of treatment in patients with symptomatic arrhythmias. Provocative electrophysiological testings give good evaluation of AA efficacy in some supraventricular or ventricular arrhythymias but predictivity of efficacy or proarrhythmic effects is sometimes problematical. Use of effort testing is limited to evaluation of antiarrhythmic effects of drugs in major dysrythmias and in some frequency-dependent dysrythmias, but this technique allows also detection of proarrhythmic incidence in those extremely altered autonomic nervous system tone. Other techniques of evaluation (Signal averaged ECG, automatic implantable cardiovecter defibrillator with holter monitoring, drug plasma concentration monitoring) are still under discussion.
Since transmembrane myocardiac calcium-exchanges play an important role in myocyte electrogenesis as well as in triggering and maintenance of some cardiac arrhythmias, it might be true that calcium antagonists possess antiarrhythmic properties. However, use of calcium antagonists as antiarrhythmic agents is only possible if the drug is devoid of sympathetic reflex stimulation and possesses use-dependence properties. These drugs are of most efficiency in cardiac arrhythmias (especially of supraventricular origin), caused by reentry phenomena in which part of the circuit is governed by calcicosodic cells. The use of calcium antagonists for ventricular arrhythmias is limited to some specific indications (idiopathic ventricular tachycardia with right bundle branch block and left axis, reperfusion arrhythmias...). Choice of the type and the route of administration of calcium antagonists has to take into account their pharmacokinetic specificities which can alter their antiarrhythmic potency.