[Treatment of chronic cardiac insufficiency with intravenous bolus enoximone. Study of a pharmacokinetic-hemodynamic relation]. / Traitement de l'insuffisance cardiaque chronique par l'énoximone en bolus intraveineux. Recherche d'une relation pharmacocinétique-hémodynamique.

The aim of this study was to evaluate the efficacy and pharmacokinetics of enoximone administered as an intravenous bolus in 12 patients (mean age 62 years) with severe chronic congestive cardiac failure (Stage IV of the NYHA) due to ischemic (N = 6) or idiopathic (N = 6) cardiomyopathy. The haemodynamic parameters and plasma concentrations of enoximone and its metabolite were measured 15, 30, 60, 90, 120 minutes, 4 and 6 hours, after IV bolus of enoximone 1 mg/kg in 10 minutes. Enoximone increased the cardiac index by an average of 37 p. 100 (1.92 +/- 0.3 to 2.63 +/- 0.35 l/mn/m2; p less than 0.001); pulmonary artery diastolic pressures fell by 33 p. 100 (p less than 0.01). Systemic arterial resistances decreased by 23 p. 100 (p less than 0.05). No significant changes in heart rate or blood pressure were observed. The peak effect was recorded between the 15th and 30th minute. The pharmacokinetic study showed the half life of enoximone to be 2.2 +/- 0.78 hours, the area under the curve to be 2,818 +/- 953, the volume of distribution to be 69.6 +/- 24 l and the total clearance to be 22.8 +/- 8.5 l/hour. The half life of the metabolite was 4.45 +/- 1.05 hours. There was a significant correlation between the percentage increase in cardiac index and peak enoximone concentration (r = 0.91; p less than 0.001). In conclusion, an IV bolus of enoximone is an effective treatment for chronic cardiac failure. The haemodynamic response was related to the peak enoximone plasma concentration.

Effects of short-term administration of dobutamine on left ventricular performance, exercise capacity, norepinephrine levels, and lymphocyte adrenergic receptor density in congestive heart failure.

This study was designed to determine the feasibility of identifying those patients with chronic heart failure who will be improved by dobutamine infusion. Twenty-two patients with stable heart failure were treated by infusion of an average dobutamine dose of 12.5 ng/kg/min for 36 hours, then again during a 4-hour session once a week for 1 month. Patients were evaluated by clinical, ergometric, and biochemical parameters (plasma norepinephrine and lymphocyte beta-receptor density) before and after every infusion. Hemodynamics were assessed before and during the first dobutamine infusion. A test with isoproterenol was performed prior to the start of dobutamine therapy. All patients exhibited hemodynamic improvement, which peaked at the 12th hour (55% increase in the cardiac index [p less than 0.01]; 35% reduction in the filling pressure and systemic arterial resistance). Five patients stopped the study prematurely. Nine patients (group 1) were clinically improved according to their NYHA classification. Eight patients (group 2) remained stable or had progressive disease. The lymphocyte beta-receptor density before dobutamine infusion was significantly higher in group 1 than in group 2 (66 +/- 12 vs. 46.7 +/- 18 fM/mg; p less than 0.01). Finally, a good correlation (p less than 0.05) was observed between the beta-receptor level and the isoproterenol dose required to obtain a heart rate of 130 beats/min.

[Influence of some antibiotics on eicosanoid production by human macrophages in vitro]. / Influence de quelques antibiotiques sur la production d'Eicosanoïdes par des macrophages humains in vitro.

Non antibacterial effects of antibiotics are presently investigated by several authors. They estimate the effects of different molecules on polynuclear chemotaxis, cytokine production or macrophage activity. In this experiment we have studied the effects of two betalactams, two macrolides, a fluoroquinolone and a tetracycline on eicosanoïd production by stimulated human macrophages in vitro. All evaluated antibiotics are able to modify the prostaglandin and/or leukotriene production. Taking into account the immunomodulative and inflammatory properties of the eicosanoids, the variation of their production could be relevant in clinical practice.

[Role of myocardial beta-adrenergic receptors in cardiac insufficiency]. / Rôle des récepteurs bêta-adrénergiques myocardiques dans l'insuffisance cardiaque.

The beta-adrenoceptors are now well individualized. They are divided into three distinct units: the receptor site, a regulating protein and a catalytic unit. The receptor density of the cell membrane varies according to the degree of stimulation of the receptor by agonists or the degree of blockade by antagonists. The myocardial or lymphocytic beta-adrenoceptor density is measured by "radioreceptor" assay using a radioactive beta-blocker. The myocardial beta-receptor density falls during heart failure, mainly to the detriment of beta 1 receptors. The density of beta 2 receptors remains unchanged. This fall in beta 1 receptors is related to the increase in the circulating catecholamines (down regulation) and is proportional to the severity of the disease. These physiological and physiopathological consequences can be directly applied to the treatment of heart failure by positive inotopic drugs or by beta-blockers.

Human lymphocyte and myocardial beta-adrenoceptors: up and down regulation.

Radioreceptor assays have extended the knowledge of beta-adrenoceptor regulation. To evaluate the usefulness of this method in cardiovascular pharmacology, this study was designed to determine: (1) the correlation between beta-adrenoceptor density in human lymphocytes and myocardial cell membranes. This was achieved by using simultaneously harvested left auricles and whole blood samples in 10 patients scheduled to undergo cardiothoracic surgery. The correlation was found to be linear (r = 0.65; P less than 0.05; N = 10); (2) the changes in lymphocyte receptor density and affinity in heart failure. Lymphocytes were harvested from 6 healthy volunteers, 8 patients with moderate heart failure (NYHA class I or II) and 8 patients with severe heart failure (NYHA class III or IV). Mean densities observed were 75.6 +/- 11, 46.3 +/- 18 and 26.4 +/- 5.9 fmol/mg protein, respectively, and dissociation constants were 62.8 +/- 16; 67.8 +/- 14, and 46 +/- 26 pM. The number of receptors fell significantly from one heart failure class to that immediately above it (P less than 0.01; N = 22); (3) the beta-adrenoceptor regulatory properties of a class I antiarrhythmic drug, propafenone, the chemical structure of which is similar to that of the beta-blocking drug propranolol. Five patients needing antiarrhythmic treatment were given 10 d of oral propafenone treatment (450-900 mg/day). Mean adrenoceptor densities (Bmax) were 22.7 +/- 9 and 43.7 +/- 9 fmol/mg protein, and dissociation constants (KD) values were 24.7 +/- 20 and 27 +/- 18 pM respectively, before and after 10 d of chronic treatment. The number of receptors increased significantly after 10 d of treatment (P less than 0.01; N = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in lymphocyte beta-adrenoceptor density after dilevalol oral treatment.

Dilevalol (R,R'-isomer of labetalol) is an antihypertensive agent combining non-specific beta blockade with peripheral vasodilatation due to beta 2-receptor agonism. The aim of this study was to determine the effects of chronic dilevalol administration on lymphocyte beta 2-adrenoceptor density. The investigation was conducted as a double-blind, placebo-controlled comparison. Ten days of chronic dilevalol (400 mg) or placebo treatment was administered to 12 healthy normotensive volunteers. Clinical and biochemical parameters: heart rate (HR) systolic and diastolic blood pressure (SBP, DBP), electrocardiogram, norepinephrine (NE), epinephrine (E), MHPG (3-methoxy-4-hydroxyphenylethylene glycol; one of the major brain metabolites of NE) were analysed on the first day (D1) before (H0) and 3 h after oral treatment (H3) and on the tenth day (D10). Clinical results showed no significant changes in HR, DBP, SBP in the two groups (placebo, n = 6; dilevalol, n = 6). NE increased 3 h after the first oral dilevalol intake (p less than 0.05). This increase is greater than that due to the circadian variation observed in the placebo group. Acute dilevalol treatment seems to increase the plasma circulating NE level, which returns to normal values after 10 days of chronic treatment. Binding assays were performed before and after 10 days of treatment. In the placebo group, no change in beta-adrenoceptor density was observed (36.6 +/- 8.3 versus 38.3 +/- 9.4 femtomol/mg of protein). Lymphocyte beta-adrenoceptor density (Bmax) significantly decreased after 10 days of dilevalol treatment without any changes in affinity (KD). Results were 40.3 +/- 11.6 (D1) and 30 +/- 7.6 (D10) (p less than 0.05). It was concluded that dilevalol down-regulated lymphocyte beta 2-adrenoceptor density, suggesting that beta 2 agonism of dilevalol is predominant.