Cardiac electrophysiological effects of propafenone and its 5-hydroxylated metabolite in the conscious dog.

We studied the cardiac electrophysiological effects of propafenone and its 5-hydroxylated metabolite in conscious dogs. Sinus rate, corrected sinus recovery time and Wenckebach point were measured in 6 intact dogs. Atrial rate, ventricular rate and atrial effective refractory period were measured in 6 atrioventricular-blocked dogs. In both groups, we also determined blood pressure and plasma drug concentrations. Each dog received, with at least an 8-day interval, propafenone (hydrochloride) and 5-hydroxypropafenone (hydrochloride) in 4 successive intravenous injections, 30 min apart, at 0.5, 0.5, 1 and 2 mg kg(-1). Propafenone increased sinus rate and atrial rate more markedly than 5-hydroxypropafenone, and also transiently ventricular rate, whereas 5-hydroxypropafenone decreased it weakly. Propafenone shortened corrected sinus recovery time and increased Wenckebach point at the highest dose only, whereas 5-hydroxypropafenone did not modify corrected sinus recovery time and increased Wenckebach point less markedly than propafenone. Both drugs produced an identical atrial effective refractory period lengthening. Propafenone either increased mean blood pressure (in intact dogs) or decreased it (in atrioventricular-blocked dogs) at the highest dose only, whereas 5-hydroxypropafenone did not produce any effect on this parameter. Overall, these results show that propafenone and 5-hydroxypropafenone exhibit cardiac electrophysiological effects, reflecting (a) direct vagolytic action for both drugs associated with cardiodepressant effects for 5-hydroxypropafenone, and (b) marked atrial antiarrhythmic properties for 5-hydroxypropafenone probably involved in the therapeutic effect of propafenone.

[Good practices of publication of clinical cases of pharmacovigilance: comments, Groupe de Travail sur les Bonnes Pratiques de Publication de Cliniques en Pharmacovigilance: commentary]. / Les bonnes pratiques de publication de cas cliniques de pharmacovigilance: commentaires. Groupe de Travail sur les Bonnes Pratiques de Publication de Cliniques en Pharmacovigilance: commentaires.

This paper introduces some comments on the complete text of Good Pharmacovigilance Publishing Practices, which forms appendix number 2 of the Good Pharmacovigilance Practices now published by the French Drug Agency, as was Good Clinical Practices. Each good practice is printed in italic and presented in a frame; the following comments are designed to facilitate its application. The technical terms that are used in this text are presented according to the glossary in Good Pharmacovigilance Practices.

French pharmacovigilance survey evaluating the hepatic toxicity of coumarin.

Synthetic coumarin (benzopyrone) was launched in France in 1988 for the adjuvant therapy of lymphoedema of the upper limb following radiosurgical treatment of breast cancer. Further to the reporting of hepatic reactions, a national survey has been carried out. The survey dealt with 22 cases reported to the pharmacovigilance regional centres and 20 to Knoll France company (five duplicate cases) up to June 1996. Thirty-four cases corresponding to an elevation of ALT over 2N and/or alkaline phosphatase over 1.5N (criteria chosen for selection in this survey) had been taken into account. Among these cases, a causal relationship was considered likely or probable for 15 of them. Two positive rechallenges were reported. The hepatic reactions observed between 2 to 6 months of treatment in two-thirds of the cases (average dose: 90 mg/day; i.e. recommended dose) was essentially cytolytic in 85% of the cases, with jaundice in 14 cases and hyperbilirubinaemia reported in five other cases. In 23 cases (68%), the increase of ALT exceeded 10N. Of the patients 41% were hospitalized. Severe liver failure with encephalopathy justified liver transplantation once and likely led to encephalopathy and fatal evolution in two other cases. The evolution was favourable in the other cases. The drug was prescribed for other uses than the registered indication in more than 50% of these cases. No risk factors could be identified in the survey. This survey provides a strong signal for potential hepatotoxicity of coumarin (likely due to the production of a reactive metabolite in some patients exhibiting a coumarin 7-hydroxylation deficiency).

Effect of synchronous and asynchronous pulsatile flow during left, right, and biventricular bypass.

Ventricular assist devices augment flow from the left atrium to the aorta and/or from the right atrium to the pulmonary artery. Most devices are used in the asynchronous full-to-empty mode (asynchronous) but may also be used in a synchronous counterpulsation mode (synchronous). This study determines the optimal assist modes to reduce myocardial oxygen consumption (MVO2) and metabolism. Twelve pigs were instrumented with carotid artery and Baim coronary sinus catheters for determination of MVO2 and myocardial lactate production (LACT). Six were implanted with a Pierce-Donachy left ventricular assist device (LVAD) and 6 with both right and left ventricular assist devices (BIVAD). Two periods each of control, synchronous, and asynchronous bypass were instituted, the midanterior descending coronary artery (LAD) was ligated, and the sequence was repeated. After each period, MVO2 and LACT were determined and myocardial biopsy specimens were obtained for tissue, lactate, and ATP assay. Following LAD ligation, biopsy specimens were obtained from both the infarct and noninfarct zones of the heart. MVO2 decreased (p < 0.05) in the asynchronous BIVAD mode compared with control. MVO2 was unchanged in synchronous BIVAD or either LVAD mode. Tissue ATP and tissue lactate were unaffected by any mode of bypass. Only BIVAD in the asynchronous mode reduced MVO2. When ventricular assist devices are utilized to aid recovery of the natural heart, two devices should always be inserted to allow biventricular assist. Synchronous counterpulsation offers no advantage.

Effect of synchronous and asynchronous pulsatile flow during left, right, and biventricular bypass.

Ventricular assist devices augment aortic or pulmonary flow while the patient's heart recovers from surgery or infarction. Most are used in the asynchronous full-to-empty mode, but they also may be used in a synchronous counter-pulsation mode. This study examines which assist mode optimally reduces myocardial oxygen consumption (MVO2). Eighteen pigs were instrumented with pulmonary artery, carotid artery, and coronary sinus catheters for determination of MVO2. Pierce-Donachy Ventricular Assist Devices (VAD) were used in left, right, or biventricular assist mode. Fifteen minute periods each of control, synchronous, and asynchronous bypass were randomly instituted. The mid-left anterior descending coronary artery was then ligated, and the sequence repeated. At the end of each period, MVO2 was determined. In comparison with controls, MVO2 was statistically significant in the BIVAD asynchronous mode only. Synchronized counterpulsation did not decrease MVO2. When ventricular assist devices are used to aid in cardiac recovery postoperatively or postmyocardial infarction, biventricular assist should be used.