Kinetics of medroxalol, a beta- and alpha-adrenoceptor antagonist.

Eight healthy men received single oral doses of 400, 800, and 1200 mg medroxalol and a single intravenous dose of 1 mg per kg body weight on four occasions separated by at least 2 wk. Plasma medroxalol concentrations were assayed up to 24 hr after each dose by a specific high-pressure liquid chromatographic assay. Urinary excretion of parent compound was determined as well. Following oral doses medroxalol reached peak plasma concentrations within 2.5 to 3 hr. The t 1/2 of the terminal decay phase was 11.1 hr. Mean apparent volume of distribution (aVD) was between 11.2 and 16.4 l/kg, and mean total body clearance (ClT) was between 0.73 and 0.99 l hr-1 kg-1. Mean urinary recovery of parent drug within 48 hr was 2.3%, 3.9%, and 3.6% after the oral doses compared to 8.2% after the intravenous dose. Bioavailability estimated from AUC was 27.2% after 400 mg, 31.3% after 800 mg, and 37.4% after 1200 mg by mouth. Since aVD, t 1/2, ClT, and urinary excretion did not differ significantly after the three oral doses, medroxalol kinetics appear to follow a dose-linear model.

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.

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.

Effects of obesity on pharmacokinetics implications for drug therapy.

Obesity is a worldwide problem, with major health, social and economic implications. The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow and the affinity of the drug for plasma proteins and/or tissue components. Obese people have larger absolute lean body masses as well as fat masses than non-obese individuals of the same age, gender and height. However, the percentage of fat per kg of total bodyweight (TBW) is markedly increased, whereas that chrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available. Pharmacokinetic studies provide differing data on renal function in obese patients. This review analyses recent publications on several classes of drugs: antibacterials, anticancer drugs, psychotropic drugs, anticonvulsants, general anaesthetics, opioid analgesics, neuromuscular blockers, beta-blockers and drugs commonly used in the management of obesity. Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity (e.g. lithium and vecuronium) is generally rather predictable, as these drugs are distributed mainly in lean tissues. The dosage of these drugs should be based on the ideal bodyweight (IBW). However, some of these drugs (e.g. antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient's excess bodyweight. There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g. remifentanil and some beta-blockers) and their distribution in obese individuals. The distribution of a drug between fat and lean tissues may influence its pharmacokinetics in obese patients. Thus, the loading dose should be adjusted to the TBW or IBW, according to data from studies carried out in obese individuals. Adjustment of the maintenance dosage depends on the observed modifications in clearance. Our present knowledge of the influence of obesity on drug pharmacokinetics is limited. Drugs with a small therapeutic index should be used prudently and the dosage adjusted with the help of drug plasma concentrations.

Optimisation of itraconazole therapy using target drug concentrations.

Itraconazole is a new triazole compound with a broad spectrum of activity against a number of fungal pathogens, including Aspergillus species. The drug is being used increasingly as prophylaxis in patients with immunodepression. Itraconazole is highly lipophilic and only ionised at low pH. The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to human plasma proteins and its apparent volume of distribution is about 11 L/kg. The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole. Mean total itraconazole blood clearance determined in healthy volunteers following a single intravenous infusion was 39.6 L/h. After a single oral dose, the terminal elimination half-life of itraconazole is about 24 hours. The drug exhibits a dose-dependent pharmacokinetic behaviour. Renal failure does not affect the pharmacokinetic properties of itraconazole; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by gastrointestinal disorders caused by diseases and cytotoxic chemotherapy. The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably change the pharmacokinetics of other drugs. Such changes may have clinically relevant consequences. Itraconazole appears to be well tolerated. Gastrointestinal disturbances and dizziness are the most frequently reported adverse effects. Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography (HPLC)] > or = 250 micrograms/L itraconazole, or 750 to 1000 micrograms/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 micrograms/L. The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy. Thus, in patients with life-threatening fungal infections treated with itraconazole drug, plasma concentrations should be regularly monitored to ensure sufficient drug exposure for antifungal activity.

Suppression of arrhythmias within hours after a single oral dose of amiodarone and relation to plasma and myocardial concentrations.

In 65 patients a single oral dose of amiodarone (30 mg/kg) produced an antiarrhythmic effect on supraventricular or ventricular arrhythmias within 3 to 8 hours and lasted for 17 to 19 hours. On the second day a 15-mg/kg dose reproduced this effect within 3 to 9 hours. Plasma concentration of amiodarone increased to a maximum (2.2 +/- 1.7 mg/liter) mean +/- standard deviation) at 6 +/- 3.5 hours and plasma levels of N-desethylamiodarone (NDA) rose to 0.2 +/- 0.08 mg/liter at 12 +/- 6.4 hours. Sixty-one other patients were given a single 30-mg/kg dose 7 hours to 4 days before open heart surgery. Biopsies of the right atrial and left ventricular walls were taken during surgery. Myocardial concentration of amiodarone was maximal in the atrium after 7 hours (13 +/- 8 mg/kg) and in the ventricle after 24 hours (17 +/- 11 mg/kg). NDA myocardial concentration increased progressively until 24 hours and then remained stable over 4 days (1.5 mg/kg). The amiodarone myocardial to plasma concentration ratio was similar in the atrium and in the ventricle and averaged 22 and 10 for amiodarone and NDA, respectively. A significant relation existed between amiodarone concentration and the effect on ventricular premature complexes (r = 0.74, p less than 0.001) and between amiodarone plasma concentration and the effect on the atrioventricular conduction (r = 0.58, p less than 0.001). The plasma concentration of amiodarone corresponding to a 60% decrease in arrhythmias averaged 1.5 to 2 mg/liter.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Effects of the beta-adrenergic blocking agents propranolol and timolol on canine cardiac refractory periods.

The effects of d,1-propranolol and 1-timolol on cardiac refractory periods (RP) were compared in 14 phentobarbital-anesthetized dogs using endocavitary His bundle electrograms and programmable electrical stimulation. Beta-blocking agents were injected at cumulative doses in each dog at 3 day intervals. A control group (6 dogs) received 4 successive saline injections at the same time intervals. RP measurements at a constant drive rate were done before and 10 minutes after each dose of either drug or saline. Propranolol and timolol produced a dose-dependent increase of atrial and atrioventricular nodal refractory periods; dose-response curves were parallel. Depending on the parameter chosen timolol exerted an 8--36 times more potent effect than propranolol. The effects of propanolol and timolol on ventricular effective (VERP) and functional (VFRP) RP were measured in 6 dogs. Both drugs increased VFRP significantly, but saline had the same effect. Only the higher doses of timolol increased VERP significantly. These data confirm that blockade of myocardial beta-adrenergic receptors exerts predominant effects on supraventricular refractoriness and that in anesthetized dogs timolol has more potent beta-blocking properties than does propranolol.

Cardiovascular and beta-adrenergic blocking effects of timolol.

The haemodynamic effects of timolol and its inhibiting action on the cardiovascular and bronchial effects of isoproterenol have been studied. Splanchnic nerve activity was recorded. The antiarrhythmic action of timolol was studied on guinea pig isolated atria, using arrhythmias induced by epinephrine, ouabain or coronary ligation in the dog. Timolol is a very potent beta-adrenoceptor blocking agent, without specificity on beta1- or beta2-receptors. No intrinsic beta-stimulating or depressant effects were found. Timolol reduced splanchnic discharges. The antiarrhythmic effect of timolol was limited to epinephrine-induced arrhythmias.

Comparative dromotropic activity of timolol and propranolol in anesthetized dogs.

The comparative dromotropic activity of timolol (TML) and propranolol (PPL) was studied by means of His bundle electrograms in two groups of pentobarbital-anesthetized dogs: group I, 7 non-atropinized dogs; group II, 8 atropinized dogs. beta-Blocking agents were injected in 4 cumulative doses in each dog at 3 days' interval. The effects upon heart rate (HR), and A-V nodal (AH), His--Purkinje (HV) and intraventricular (QS) conduction times were measured. The dromotropic effects of PPL and TML during atrial electrical stimulation and their effects upon chronotropic and dromotropic isoprenaline-induced changes were compared. TML exerted a 9--10 times more potent negative chronotropic effect than PPL and a 4--5 times more potent negative dromotropic effect than PPL on AH conduction time. PPL and TML increased the duration of HV only in higher doses. This effect which was not modified by isoprenaline may be related to their membrane depressant effect. Neither TML, nor PPL nor isoprenaline modified QS duration. TML was 25 times more potent than PPL to antagonize the chronotropic action of isoprenaline and 11--8 times more potent than PPL to antagonize the dromotropic action of isoprenaline upon AH. Parasympathic blockade with atropine did not modify the negative dromotropic activity of PPL and TML but modified their chronotropic effects.

Reproducibility of the model of induced ventricular tachycardia in conscious dogs with infarction.

The canine model of ventricular tachycardias (VT) induced by programmed stimulation is used routinely in several laboratories to test antiarrhythmic drugs. The aim of the present study was to determine the rate of success and reproducibility of this model. We analyzed a group of 58 dogs that underwent a 2-hr occlusion and were submitted to programmed electrical stimulation at least 4 days after the surgery. Only 29 dogs (50%) were inducible and included in the study, as 22 dogs died following myocardial infarction, and seven dogs were never inducible. Out of 130 trials, 92 (70%) performed on inducible dogs were positive with 11% of nonsustained ventricular tachycardias, 63% of sustained monomorphic ventricular tachycardias, and 26% of ventricular fibrillation. Inducibility decreased over time in a subgroup of 19 dogs that was submitted to four trials during the first month after the infarction (68% of inducible dogs versus 46% in trials 1 and 4, respectively). Ventricular effective refractory period decreased significantly from 146 +/- 7 msec at trial 1 to 114 +/- 6 msec at trial 4, and the severity of the induced ventricular tachycardias increased. This variability should be considered when planning studies on antiarrhythmic drugs in this model.

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.

Proarrhythmic effects of a quinidine analog in dogs with chronic A-V block.

The proarrhythmic effects of 3-hydroxy-hydroquinidine (3-OH-HQ) and quinidine were compared in a canine model of QT-dependent ventricular arrhythmias. Eight hypokalemic ([K+] < or = 3.2 mmol/l) dogs with AV block (around 45 bpm) were given either drug in a randomized order at 2-day intervals. Each drug was given as two 1 hour doses, with a bolus (low dose: 5 mg/kg or high dose: 10 mg/kg) plus infusion (25 or 50 micrograms/kg/min) protocol. Propranolol infusion was combined with a third hour of the high dose infusion. Electrophysiologic measurements were performed at baseline and 30 minutes after the beginning of each dose and propranolol infusion, and proarrhythmic events were recorded 30 minutes before and during the experiment. Neither drugs altered the ventricular cycle length. Quinidine and 3-OH-HQ prolonged the QT interval similarly and significantly when paced at 60 bpm after the low dose (+39 +/- 18 and +28 +/- 22 msec, respectively) and after the high dose (+51 +/- 29 and +50 +/- 22 msec). Quinidine was more arrhythmogenic than 3-OH-HQ: 7/8 dogs (p < or = 0.05) developed ventricular arrhythmias (isolated, repetitive ventricular beats, or polymorphic ventricular tachycardias) during quinidine infusion (low dose: 4 dogs) compared to 3/8 dogs (NS) during 3-OH-HQ infusion (low dose: 1 dog). Addition of propranolol-induced bradycardia (around 30 bpm) caused torsades de pointes (wave burst arrhythmias) or polymorphic ventricular tachycardias after both drugs (in 3 dogs after quinidine and in 2 dogs after 3-OH-HQ). Thus 3-OH-HQ was slightly less arrhythmogenic than quinidine in this model of torsades de pointes, but the addition of an extra favouring factor (bradycardia) reduced that difference.

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.

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.

[The effect of cardiac insufficiency on pharmacokinetics]. / Influence de l'insuffisance cardiaque sur la pharmacocinétique.

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)

[Electrophysiologic effects of intravenous 3-hydroxy-dihydroquinidine (LNC-834) in man]. / Etude des effets électrophysiologiques de la 3-hydroxy-dihydroquinidine (LNC-834) intraveineuse chez l'homme.

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.

[Sotalol-induced torsades de pointe in the conscious dog with atrioventricular block. Role of hypokalemia]. / Torsades de pointe expérimentales avec le sotalol chez le chien vigile en bloc auriculo-ventriculaire. Rôle de l'hypokaliémie.

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)

[Anti-arrhythmia effect of long-term encainide in chronic ventricular extrasystole]. / Etude de l'effet anti-arythmique de l'encaïnide au long cours dans l'extrasystolie ventriculaire chronique.

The long term efficacy and tolerance of encainide were studied in 48 patients with chronic/ventricular extrasystoles (VES) treated for 6 months. Holter monitoring was performed before treatment and at each dose increment (75 mg/day; 150 mg/day and 225 mg/day) during the first week of titration, and then after 1 month and 6 months of treatment. The dose administered in the long-term study corresponded to the minimum effective dose during the titration phase (the dose which reduced the number of VES/24 hours by at least 75%). The average number of VES/hour decreased significantly from 480.6 before treatment to 2.0 at the end of the study. The frequency of episodes of ventricular tachycardia decreased significantly during treatment. The commonest side effects were vertigo, visual disturbances and headaches. Treatment was interrupted because of side-effects or inefficacy in 6 patients. The surface ECG showed significant lengthening of the PR, QRS and QTc periods and encainide appeared to have aggravated the ventricular arrhythmias of 4 patients receiving 200 mg/day. The plasma concentrations of encainide and its two principal metabolites were measured during the titration phase, at 1 month and after 6 months of treatment. 15.6 per cent of patients were slow and 84.4% of patients were rapid metabolizers. The wide individual variations of plasma concentrations and the absence of correlation between the plasma concentrations of encainide and its metabolites and the antiarrhythmic effect suggest that the compound and its metabolites play a role in the antiarrhythmic effect of the drug.

[Electrophysiological effects of intravenous sotalol. Relation with plasma levels]. / Etude des effets électrophysiologiques du sotalol intraveineux. Relation avec les concentrations plasmatiques.

The object of this study was to confirm the electrophysiological effects of sotalol, a betablocker which increases the duration of the action potentials of myocardial cells, and to investigate the relationship of these effects with the doses used and plasma concentrations (PC) of the drug. 13 patients (23 to 72 years) were divided into 3 groups: Group 1 (n = 5): 0.6 mg/kg; Group 2 (n = 4): 1.2 mg/kg; and Group 3 (n = 5): 1.8 mg/kg. Measurements were performed before and 35 minutes after starting a 15 minute intravenous infusion of sotalol. At all doses, sotalol decreased the heart rate (HR), increased the corrected sinus node recovery time (CSNRT), prolonged the effective refractory periods (ERPA) and functional refractory periods (FRPA) of the right atrium. Atrioventricular conduction was depressed; prolongation of AH at an imposed rate of 100/min, prolongation of the nodal refractory periods (ERPN and FRPN), and an earlier Wenckebach point. The corrected QT interval (QTc) and ventricular refractory period (ERPV) increased. The QRS complexes and HV intervals were unchanged. Increases of CSNRT, AH, ERPN, FRPN, QTc, and ERPV were observed after the first dose (Group 1). At the dose of 1.8 mg/kg (Group 3) all parameters were modified (except the QRS and HV). All patients increased their ERPV by more than 20 p. 100. The parameters which illustrated the dose-effect relationship were the HR, ERPA, FRPN, and CSNRT. The PC of sotalol measured 60 minutes after starting the infusion were 0.58 +/- 0.23 microgram/ml (Group 1), 0.78 +/- 0.32 microgram/ml (Group 2) and 1.73 +/- 0.43 microgram/ml (Group 3).(ABSTRACT TRUNCATED AT 250 WORDS)