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G Cheymol

Publications and source records attributed to G Cheymol.

At least 37 records · Page 2Linked to original sources
PubMed1993

Clinical pharmacokinetics of drugs in obesity. An update.

Obesity is common enough to constitute a serious medical and public health problem. Drug prescription for obese patients is difficult since dosages based on pharmacokinetic data obtained in normal-weight individuals could induce errors. In obese patients, physiopathological modifications are likely to affect drug tissue distribution and elimination. Body constitution is characterised by a higher percentage of fat and a lower percentage of lean tissue and water. Although the cardiac output and total blood volume are increased, the blood flow per gram of fat is less than in nonobese individuals. Histological hepatic alterations are commonly reported in morbidly obese individuals. A higher glomerular filtration rate is also observed. Most of the pharmacokinetic information concerning obesity deals with distribution. Published data concerning molecules with moderate and weak lipophilicity are homogeneous. In obese compared with normal weight individuals, the total volume of distribution (Vd) is moderately increased (aminoglycosides, caffeine) or similar (H2-blockers, neuromuscular blockers), but the Vd corrected by kilogram of actual bodyweight is significantly smaller. These drugs distribute to a limited extent in excess bodyweight. For highly lipophilic drugs, despite this common characteristic, discrepancies in distribution in obesity exist between drugs belonging to different pharmacological classes. Some drugs show a clear augmentation of Vd and elimination half-life (benzodiazepines, carbamazepine, trazodone, verapamil, sufentanil), indicating a marked distribution into adipose tissue. For others, Vd and Vd/kg are decreased (cyclosporin, propranolol), suggesting that factors other than lipid solubility intervene in tissue distribution. As a general trend, the total clearance (CL) of drugs metabolised by oxidation, conjugation or reduction, and also of drugs with flow-dependent hepatic clearance, is not diminished in obesity. Usually CL is identical in obese and nonobese individuals, sometimes it is increased in obesity (enflurane, halothane, prednisolone, some benzodiazepines). With some drugs a significant reduction in CL is observed in obese individuals (methylprednisolone, propranolol). Renal clearance of aminoglycosides and cimetidine increases in obese individuals. Practical guidelines for dosage adjustment are proposed. For drugs with distribution restricted to lean tissues, the loading dose should be based on the ideal bodyweight of patients. For drugs markedly distributed into fat tissue the loading dose is based on total bodyweight. Adjustment of the maintenance dose depends on possible changes in CL. In some cases (atracurium, prednisolone) dosage adjustment does not follow these recommendations, owing to pharmacodynamic data.

Humans↗
PubMed1993

Antiarrhythmic effect of a sotalol-mexiletine combination on induced ventricular tachycardia in dogs.

Mexiletine was recently shown to antagonize the effects of sotalol on repolarization of canine Purkinje fibers. The significance of this interaction for the antiarrhythmic properties of these drugs remains unknown. The antiarrhythmic effects of sotalol and mexiletine alone and in combination on induced ventricular tachycardias (VTs) were assessed in 20 conscious dogs with chronic infarction. Electrophysiological measurements and programmed stimulation were performed before and after the infusion of sotalol (4 mg/kg) or mexiletine (4 mg/kg), and after infusion of the combination. The electrophysiological parameters didn't change after mexiletine. Sotalol alone and the combination both similarly prolonged the QT interval and VERP. Induction of VT by programmed stimulation was not prevented by mexiletine, but the cycle length of monomorphic VT was increased in 7 of 10 dogs. The induction of VT was prevented by sotalol (11/16 dogs), but VTs were not slowed significantly. Sotalol plus mexiletine prevented VT as did sotalol alone (11/16 dogs). The combination also increased the cycle length of VT in all eight dogs with monomorphic VT. Thus, the antagonism shown in vitro appears to have no consequences in this model. On the contrary, the sotalol-mexiletine combination showed some additive antiarrhythmic effects on induced VT in dogs.

Animals↗
PubMed1992

Rapid and sensitive liquid chromatographic assay of mefenamic acid in plasma.

Mefenamic acid (MA) is a nonsteroidal antiinflammatory analgesic agent widely used clinically. A simple and sensitive liquid-chromatographic assay has been developed for the quantitative determination of MA in human plasma. A reverse phase, 10-microns cyano column (25 x 0.4 cm), a mobile phase of water-acetonitrile-methanol-17 M acetic acid (69:15:15:1 by volume), and an ultraviolet detection (290 nm) are used for the separation of MA and internal standard (methyl-clonazepam). MA and internal standard are extracted from acidified plasma into diethyl ether and after evaporation of the organic phase, the residue is redissolved in methanol. Calibration curves are linear in the range 0.05-3.20 micrograms/ml, and at the plasma level corresponding to the quantification limit (0.05 microgram/ml) coefficients of variation are 7.5% and 10.2% for repeatability and reproducibility studies, respectively. This assay was successfully used in the study of pharmacokinetics of MA in human plasma after a single oral administration of a low MA dose.

Carbamazepine↗
PubMed1992

[Pharmacokinetics and therapeutic monitoring of cyclosporine in liver transplant recipients].

Cyclosporine (CsA) has played a major role in the development of organ transplantation. However, its use in the prevention of liver graft rejection is somewhat delicate because the liver plays an essential role in the intestinal absorption, metabolism and excretion of CsA. Interindividual differences in CsA pharmacokinetics are large, and clearance can vary by a factor of 40 in liver transplant recipients. During CsA therapy, the intact molecule is assayed in whole blood by means of specific technique. The margin between immunosuppressive and nephrotoxic concentration is poorly defined. The interpretation of blood concentrations must take into account the mode of administration, associated drug therapy, the time since grafting, and pathological episodes. The recommend trough concentrations are 150-200 ng/ml during the first three months.

Cyclosporine↗
PubMed1991

Pharmacokinetics of intravenous bisoprolol in obese and non-obese volunteers.

The pharmacokinetics of a single i.v. dose of dl-bisoprolol 0.16 mg.kg-1 ideal body weight has been studied in 8 obese women (mean weight 91 kg; 161% of ideal body weight) and 8 non-obese women (51 kg; 94% of ideal body weight). Compared to the controls, the obese subjects showed an increase in the total apparent volume of distribution (Vz) (182 vs 1351) and a decrease in Vz per kg body weight (2 vs 2.71.kg-1). There was a negative correlation between Vz l.kg-1 and the percentage of ideal body weight (r = -0.672). Total body clearance was increased, but t1/2 and renal clearance was unchanged. It is concluded that tissue diffusion of bisoprolol in obese subjects is limited, despite its lipophilicity, possibly because of alteration in the blood flow to adipose tissue produced by bisoprolol.

Adrenergic beta-Antagonists↗
PubMed1991

Methods and limitations of an experimental model of long QT syndrome.

An experimental model of the long QT syndrome has been developed in conscious dogs. This report discusses the methods used in its preparation and the strengths and weaknesses of the model. This new model is suitable for screening the bradycardia-dependent proarrhythmic effects of drugs and for studying the electrophysiology of "torsades de pointes." Permanent bradycardia (RR: 1558 +/- 83 ms) was obtained in 37 dogs by chemically-induced complete atrioventricular block. A 10% further increase of ventricular repolarization (QT: 306 +/- 7.0 ms to 331 +/- 5.5 ms) was obtained in 28 of these dogs by diuretic-induced hypokalemia. Diuretics, despite saline replacement, induced some degree of functional renal failure and extracellular volume losses. The QT interval increased although ventricular cycle length decreased slightly. These biological and electrophysiological parameters were reproducible except for a slow increase in plasma creatinine. Cardiac failure and sudden death rarely occurred. The most severe, but reversible, renal failure occurred in some dogs given the highest diuretic doses. Hypokalemia resulted in ventricular arrhythmias in only 6 dogs, 2 of them exhibiting runs of ventricular tachycardia and even "torsade de pointes" as their potassium levels fell below 2 mmol/L. The results of studies with several drugs using the model, with or without hypokalemia, or with bradycardia worsened by propranolol are analysed.

Animals↗
PubMed1991

Arrhythmogenic activities of antiarrhythmic drugs in conscious hypokalemic dogs with atrioventricular block: comparison between quinidine, lidocaine, flecainide, propranolol and sotalol.

In order to create and evaluate a model sensitive to QT-dependent proarrhythmic effects of drugs, a long QT syndrome was produced in chronically instrumented dogs with bradycardia and hypokalemia. Bradycardia (mean cycle length: 1495 +/- 78 msec) was provided by permanent atrioventricular block and hypokalemia (K+ = 2.6 +/- 0.05 mmol/l) by high doses of diuretics. To evaluate that model, six of these conscious dogs were subjected to quinidine, flecainide, lidocaine, propranolol and sotalol infusions. In crossover design, drugs were infused i.v. at rates allowing stable and nontoxic drug plasma levels during the experiment. Four-lead ECGs were recorded for arrhythmias for 30 min before (base line) and 75 min after onset of infusion. Ventricular cycle length was increased dramatically by sotalol, lidocaine and propranolol (+618 +/- 192, +388 +/- 125 and +329 +/- 114 msec, respectively) and QT interval was increased by sotalol, quinidine and flecainide (+56 +/- 8, +31 +/- 7.9 and +20 +/- 5.7 msec, respectively). Quinidine and sotalol, but not flecainide, propranolol or lidocaine, exhibited significant arrhythmogenic activities. During quinidine infusion, most dogs exhibited some ventricular arrhythmias whose most severe forms were runs of ventricular tachycardia. These arrhythmias were suppressed by pacing at high rates. During sotalol infusion, five out of six dogs exhibited typical "torsades de pointes." This incidence was not related to the slowing effects of sotalol on idioventricular pacemakers, because a similar incidence was obtained in five complementary dogs paced at 40 bpm. It could be related to dose, because torsades de pointes occurred only once in another group of five dogs receiving half the dose used in the controlled study. Only quinidine and sotalol, but not propranolol, flecainide or lidocaine, are clinically associated to torsades de pointes. They were also the only drugs associated with proarrhythmic events in the present study, a fact suggesting that QT-dependent arrhythmogenic effects of drugs can be reliably evaluated in conscious hypokalemic dogs with complete atrioventricular block.

Animals↗
PubMed1990

The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers.

The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg.kg-1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg.kg-1 i.v. of dl-sotalol. There was no significant difference in the disposition of the d-enantiomer and the racemate. The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l.h-1.kg-1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).

Administration, Oral↗
PubMed1990

Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients.

The pharmacokinetics of pentoxifylline were investigated in six healthy volunteers and in 10 patients with alcoholic cirrhosis. After a 100 mg intravenous infusion, pentoxifylline elimination half-life was prolonged in cirrhotic patients (2.12 +/- 1.22 hours versus 0.83 +/- 0.29 hours, p less than 0.05) because of a decrease in its plasma clearance (1.44 +/- 0.46 L.hr-1.kg-1 in patients with cirrhosis versus 3.62 +/- 0.75 L.hr-1.kg-1 in volunteers, p less than 0.001). The elimination half-life of the metabolite (5-hydroxypentoxifylline) was similar to that of the parent compound. After oral administration of a 400 mg sustained-released tablet, absolute bioavailability of pentoxifylline increased in cirrhotic patients (0.71 +/- 0.24 versus 0.33 +/- 0.13, p less than 0.01). Although plasma concentrations of pentoxifylline and hydroxypentoxifylline were significantly increased in cirrhotic patients, the AUCpentoxifylline/AUChydroxypentoxifylline ratio remained unchanged in both groups after either intravenous or oral administration. These findings show that liver cirrhosis profoundly alters the pharmacokinetics of pentoxifylline. However the formation of hydroxypentoxifylline is not modified in these patients, suggesting an extrahepatic metabolism.

Administration, Oral↗
PubMed1990

Comparison of the cardiac electrophysiological effects of flecainide and hydroquinidine in anesthetized dog: concentration-response relationship.

The concentration-dependent effects of flecainide and hydroquinidine were studied in closed-chest anesthetized dogs. The electrophysiological effects of three doses (i.v. infusions followed by an appropriate perfusion to plateau the plasma levels) of flecainide (1, 2, and 3.9 mg/kg) and hydroquinidine (2, 4, 7.5 mg/kg) were tested. Sinus cycle length, QRS duration, His-Purkinje and AV nodal conduction times, Wenckebach period, atrial, nodal, and ventricular refractory periods, and corrected QT interval were measured before and 30 min after the beginning of each bolus infusion. Both hydroquinidine and flecainide increased the sinus cycle length, and slowed cardiac conduction to different degrees. Hydroquinidine and flecainide prolonged ventricular conduction; flecainide had a greater effect at the His-Purkinje level. Hydroquinidine exhibited only a weak and nonsignificant effect at the AV node, whereas flecainide dramatically prolonged conduction and refractoriness. The two drugs increased AERP equally. The QT interval and ventricular refractoriness were similarly prolonged to the same extent by both drugs (32 and 35% after the third doses of hydroquinidine and flecainide, respectively). The high plasma flecainide levels reached in our study (1.47 and 2.9 micrograms/ml after the second and third doses, respectively) may explain these effects, which are unexpected for a class Ic agent. These results suggest that flecainide could increase the QT interval, like a class Ia drug when its plasma level exceeds the therapeutic range.

Anesthesia↗
PubMed1990

Comparison of propranolol and sotalol pharmacokinetics in obese subjects.

Six obese subjects (mean +/- s.d. : 145.1 +/- 16.7% of ideal body weight) were randomly assigned to a single i.v. dose either of (+/-)-propranolol base (0.108 mg kg-1 of ideal body weight) or of (+/-)-sotalol base (1.06 mg kg-1 of ideal body weight). Each subject received the other drug 7 days later. Pharmacokinetic parameters were compared with those obtained previously in non-obese control subjects. In obese subjects, the pharmacokinetic data calculated for sotalol were comparable with those measured in controls (total body clearance = 9.4 +/- 2.9 L h-1; volume of distribution during the terminal phase = 79.8 +/- 19.8 L or 0.9 +/- 0.2 L kg-1; terminal half-life = 6.2 +/- 1.6 h). For propranolol, total clearance (44.3 +/- 15.9 L h-1) and volume of distribution (230.5 +/- 48.2 L or 2.7 +/- 0.7 L kg-1) were significantly less than control values. The terminal half-life (3.9 +/- 1.1 h), was not significantly increased. These results could be explained by altered tissue blood flow and a decreased metabolic capacity of the liver in obese subjects.

Adult↗
PubMed1990

Pharmacokinetic characteristics of bornaprolol in healthy volunteers.

1. Six young male volunteers received five single doses of bornaprolol, i.v. (20 mg) and orally (120, 240, 480, 960 mg) administered at 2-week intervals. Plasma concentrations of bornaprolol and its conjugated metabolite were determined by gas chromatography. 2. After i.v. administration, plasma bornaprolol levels were detectable over 8 h, and mean values were 60 l/h for total clearance (C1), 207 l for volume of distribution (V beta), 2.6 h for elimination half-life (t1/2 beta). After oral administration, plasma bornaprolol levels were detectable over 24-48 h, and mean values of pharmacokinetics parameters were 60 l/h for C1, 1500 l for V beta, 20 h for t1/2 beta. Maximum plasma concentrations and area under the plasma concentration-time curve increased in a non-dose-dependent manner. 3. The glucuronide conjugate appeared in the blood within 5-10 min and its plasma level greatly exceeded bornaprolol concentrations. The mean value of the ratio of the metabolite AUC/parent product AUC was 14 after i.v. administration and 13-21 following oral administration, depending on dose. The AUC for the metabolite did not increase proportionally with oral doses. 4. Bornaprolol is principally eliminated after metabolism. This process did not increase with increasing oral doses and bioavailability seemed to decrease inversely with oral dose.

Adrenergic beta-Antagonists↗
PubMed1990

[Comparison of beta-blocking agents pharmacokinetics in obese and non-obese subjects].

We compared in obese patients and normal subjects, the pharmacokinetics of three drugs with different solubility: d,l-sotalol markedly hydrophilic, d,l-propranolol highly lipophilic, d,l-bisoprolol moderately lipophilic. In obese subjects the pharmacokinetic data calculated for sotalol (total clearance (CL), volume of distribution (V beta), half-life of elimination (t1/2), were comparable with those measured in the controls. Data on bisoprolol showed that total V beta increased with excess of body weight, but V beta/kg of body weight was lower in obese subjects than in the controls, CL tended to increase and t1/2 was similar. As concerned propranolol, total V beta and V beta/kg were significantly lower in obese than in control subjects. Cl was decreased in obese patients and t1/2 was similar for both groups. It appears that in the obese the diffusion of liposoluble beta-blockers in the fatty excess weight remains limited. It is possible that a vasoconstrictive effect induced by beta-blockers in adipose tissues could restrict their tissular distribution.

Adrenergic beta-Antagonists↗