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Biomedical subjects

G Cheymol

Publications and source records attributed to G Cheymol.

At least 55 records · Page 3Linked to original sources
PubMed1989

Simultaneous study of the pharmacokinetics of intravenous and oral nicardipine using a stable isotope.

The systemic elimination of nicardipine has been studied by an initial oral administration of nicardipine followed 1.25 h later by intravenous injection of the deuterium-labelled molecule (D3 nicardipine). To check that intravenous kinetics was not modified by the oral administration, an i.v. injection of unlabelled nicardipine (D0 nicardipine) was also given. The study was carried out in six healthy male volunteers, aged between 24 and 27 years, according to a Latin square cross-over design. Similar values were found for each kinetic parameter after i.v. administration regardless of whether it was administered alone by that route or with an oral dose. The plasma level-time curves of nicardipine were described by a three open compartment model. The total plasma clearance was about 800 ml/min, the volume of distribution was of the order of 1 l/kg and the half-life of beta-elimination ranged from 4 to 5 h. The elimination rate constant beta was independent of the route of administration.

Administration, Oral↗
PubMed1989

Comparative hemodynamic study of a new aminosteroid: LND-623 with its 20 alpha-isomer: LND-369, and with digoxin and digoxigenin-rhamnoside in the anesthetized dog.

Hemodynamic effects of LND-623, a new aminosteroid lacking the C17 lactone ring and the C14 hydroxyl group common to the natural glycosides, were studied in the pentobarbital-anesthetized dog and compared to those of its 20 alpha-isomer LND-369 and of digoxin and digoxigenin-rhamnoside (DRh). Twenty-four mongrel dogs were divided into 4 groups. Group I received either LND-623 or saline on study day 1 and the other drug or saline 1 wk later. Saline was replaced by digoxin in group II, digoxigenin-rhamnoside in group III, and LND-369 in group IV. All drugs except LND-369 were infused as 3.10(-9) mol.kg-1.min-1 over 20 minutes. LND-369 was infused at twice the dose. LND-623 increased left ventricular dP/dt for at least 3 h with a peak at end-infusion or 15 min later, accompanied by a transient vasopressor effect. LND-369 induced, at twice the dose, an inotropic effect of comparable magnitude but of shorter duration. Inversely, it provoked a more marked and prolonged vasopressor effect than its 20 beta-isomer, LND-623. Maximal digoxin inotropic effect occurred later but was of comparable magnitude to that induced by LND-623. Its vasopressor effects reached a plateau rapidly and remained sustained until min 200. Digoxigenin-rhamnoside inotropic but not vasopressor effects are weaker than those of LND-623. It is concluded that LND-623, although lacking the most common structural features of the natural cardiac glycosides, provoked rapid and sustained inotropic activities with transient vasopressor effects. These time-course effects differ from digoxin, and these differences are unrelated to their sugar-moiety characteristics. LND-623 inotropic effect is twice as potent as its 20 alpha-isomer.

Anesthesia↗
PubMed1989

[The effect of cardiac insufficiency on pharmacokinetics].

Heart failure may have repercussions on the different stages of pharmacokinetics. Following intramuscular or oral administration, drug absorption may be slowed down by the fall in cardiac output and by peripheral vasoconstriction. Tissue distribution is altered by changes in the plasma protein binding of drugs and by redistribution of cardiac output to the brain and heart, resulting in changes in the apparent volume of distribution. Excretion through the liver is influenced by the decrease of hepatic blood flow and metabolic capacities. Lowering of the renal blood flow alters the glomerular and tubular excretion processes. These hepatic and renal dysfunctions result in a reduction of total plasma clearance. The effects of heart failure on the pharmacokinetics of digitalis compounds seem to consist merely of a delay in digestive tract absorption. More studies have been devoted to the fate of antiarrhythmic agents. Blood concentrations of lidocaine are raised in patients with heart failure; this is accounted for by the redistribution of local blood flows, the increase in plasma protein binding observed after myocardial infarction and the reduced hepatic clearance. A fall in the volume of distribution and total clearance of quinidine has been described. Data concerning disopyramide are discordant, but reduction of the free drug fraction and variations in total clearance have been observed after myocardial infarction. Alterations in the total clearance of prazosin, nitroglycerin and theophylline have been reported by several authors.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1989

[Electrophysiologic effects of intravenous 3-hydroxy-dihydroquinidine (LNC-834) in man].

The object of this study was to determine the electrophysiological effects of 3-hydroxy-dihydroquinidine (3-OH-HQ) in man. The electrophysiological parameters were measured in 12 patients before and after intravenous infusion of 5 mg/kg of 3-OH-HQ in 15 minutes. The mean plasma concentrations obtained varied from 2.4 +/- 1.1 mg/l at the 20th minute to 0.9 +/- 0.3 mg/l at the 60th minute. In these concentrations, 3-OH-HQ did not cause hypotension or affect the heart rate and nodal conduction. It did, however, prolong infra-hisian and intraventricular conduction and ventricular repolarisation from the 20th to the 60th minute after starting the infusion. The peak effect was observed at the 20th minute (+19 +/- 3.4 ms; +14.6 +/- 3.5 ms; and +44.5 +/- 6.6 ms, respectively). The 3-OH-HQ increased the effective atrial and ventricular refractory periods at the 30th minute (+21.8 +/- 5.5 ms and +22.3 +/- 7 ms, respectively). However, the ventricular effect only was discernable at the 60th minute. These effects are quantitatively comparable to those of quinidine. Extrapolation of these results to the effects of chronic oral treatment should be reserved as the therapeutic zone of this new molecule has not yet been determined.

Aged↗
PubMed1988

Drug pharmacokinetics in the obese.

In the obese, modifications in body constitution (higher percentage of fat and lower percentage of lean tissue and water) can affect drug distribution in the tissues. For slightly liposoluble molecules (e.g., digoxin, antipyrine), the equilibrium distribution volume (V), total and per kilogram weight, is significantly less than that of control subjects. With lipophilic drugs (e.g., barbiturates, benzodiazepines), this parameter is significantly increased, explaining the prolongation of the plasma elimination half-life. For drugs that are almost equally soluble in water and oil (methyl xanthines, aminoglycosides), the V is slightly increased in the obese. The other main factors involved in drug diffusion in the tissues are binding to plasma and tissue proteins, and regional blood flow. In the obese the binding of drugs to albumin does not seem to be altered. A marked increase in plasma alpha-glycoprotein acid and in propranolol binding has been reported in some studies; this has not been corroborated by other authors. Although the cardiac output and total blood volume are increased in the obese, the blood flow per gram of fat is less than in nonobese subjects. This could limit diffusion in the tissues of some lipophilic drugs. Studies on hepatic clearance of drugs are not available in the obese, but hepatic histological alterations have been described. In most publications concerning drugs with biotransformation as the principal elimination route, the total plasma clearance is not reduced. Up to the present, there are no reports of any impairment involving renal elimination of drugs in the obese. Dose-adjustment of hydrophilic drugs is assessed according to the ideal weight of the individual obese subject; with lipophilic drugs the loading dose can be fixed according to the total weight; calculation of the maintenance dose depends on possible changes in the total clearance.

Female↗
PubMed1988

[Sotalol-induced torsades de pointe in the conscious dog with atrioventricular block. Role of hypokalemia].

Sotalol is a beta-blocking agent endowed with class III electrophysiological properties. It has proved clinically effective in the treatment of arrhythmia, but episodes of torsades de pointe have been observed, particularly (though not exclusively) in the presence of hypokalaemia. The effect of sotalol with or without hypokalaemia was studied on a recently developed model for experimental torsades de pointe. Conscious dogs with complete atrioventricular block (ventricular cycle RR = 1530 +/- 170 ms) and provided with permanent atrial and ventricular epicardial electrodes were given sotalol intravenously either as a 4.5 mg/kg bolus injection or as a 1.5 mg/kg/h infusion. Group I dogs (n = 8) had normal blood potassium levels (4.3 +/- 0.1 mEq/1); following sotalol (plasma concentration 3.7 +/- 0.2 micrograms/ml) the ventricular rhythm was electrically driven to 25/min (RR = 240 ms) and QT was increased by 68 +/- 11 ms; torsades de pointe occurred in 5/8 animals (62 p. 100). Group II dogs (n = 6) had diuretic-induced hypokalaemia (2.6 +/- 0.1 mEq/1); following sotalol (plasma concentrations 3.8 +/- 0.3 micrograms/ml) the ventricular rhythm also depended on an external pacemaker to reach 25/min (in all but 1 dog) and QT increased by 46 +/- 11 ms; torsades de pointes were obtained in 5/6 animals (83 p. 100). These torsades de pointe were prevented in every case by rapid ventricular pacing (100-120/min). Thus, the pro-arrhythmic effects of sotalol were very frequent on this experimental model, but hypokalaemia was not necessary for torsades de pointe to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers.

Plasma pharmacokinetics of a single IV dl-propranolol dose (8 mg) were investigated in 12 obese subjects (mean +/- SD: 110.3 +/- 20.4 kg; 198.7 +/- 32.5% of ideal body weight) and compared with those of 12 healthy subjects (66.7 +/- 6.8 kg; 94.5 +/- 7.8% of ideal body weight). In obese subjects plasma alpha-1 glycoprotein acid concentrations and propranolol protein binding capacity did not differ significantly from control subjects. When compared with controls, obese subjects showed a significant increase (P less than .01) in AUC (161.0 +/- 67.0 vs 109.6 +/- 23.1 hr.micrograms/L), and significant decreases (P less than .01) in Vss (208.9 +/- 71.9 vs 318.6 +/- 91.8 L), V beta (234.3 +/- 70.4 vs 340.7 +/- 89.1 L), and total clearance (57.5 +/- 18.3 vs 75.9 +/- 15.4 L/hr). Elimination half-life was similar for the two populations (3.5 +/- 0.9 hr in obese subjects vs 3.1 +/- 0.9 hr in controls). Therefore, neither lipophilicity of propranolol nor drug plasma protein binding can explain these data. Altered hepatic function and tissue blood flow in obese subjects are proposed as an explanation for the decrease in total clearance and volume of distribution.

Adult↗
PubMed1987

Cardiovascular beta-adrenergic blocking effects of bornaprolol in humans: relation to dose and plasma concentration.

The cardiovascular beta-blocking effects of bornaprolol were studied in healthy male volunteers after four single oral doses. The inhibition of isoproterenol-induced tachycardia was monitored for 72 h in six subjects, and the inhibition of exercise-induced tachycardia and rise of systolic blood pressure were monitored for 167 h in six other subjects. Plasma drug concentrations were determined by gas chromatography. Bornaprolol significantly reduced the resting heart rate, isoproterenol- and exercise-induced tachycardia, and effort hypertension. The peak effect was obtained within 1-2 h of drug administration and was correlated with dose. The effect on the isoproterenol test remained significant for 6 h after administration of 40 mg bornaprolol, and 72 h after 80, 120, and 240 mg. The effect of bornaprolol on the exercise test in comparison with placebo was significant during 23 h (120 and 240 mg) and 47 h (480 and 960 mg). A positive relationship was found for both tests between the maximum effect and the doses administered. A correlation was also found for each group of subjects between the time course of the plasma drug concentration and the effects of each bornaprolol dose on isoproterenol- and exercise-induced tachycardia. The beta-blocking effects in individual subjects, however, often continued long after the disappearance of detectable plasma drug concentrations.

Administration, Oral↗