[Peripheral neuropathy with autonomous nervous system involvement in the course of dermatomyositis]. / Neuropathie périphérique avec atteinte du système nerveux autonome au cours d'une dermatomyosite.

A peripheral neuropathy occurs rarely during the course of an inflammatory myopathy. Once the classical aetiologies of peripheral neuropathies are ruled out, the diagnosis of neuromyositis can be accepted. We report a patient with dermatomyositis who presented a peripheral neuropathy revealed by dysautonomia. The presence of associated vasculitis led us to consider that this constituted the mechanism of the neurological involvement.

[Arrhythmogenic effects of non cardiovascular drugs]. / Effets arythmogènes des médicaments non cardiovasculaires.

Among the unwanted effects of drugs, arrhythmogenic effects are particularly fearsome. Although rare they are serious, and responsible for syncope or sudden death, often linked with torsades de pointe on established long QT. For non cardiovascular drugs, detection is difficult because patients do not undergo systematic cardiological surveillance. Nevertheless understanding the risk, identification of predisposing factors, and consideration of the contra-indications are the rules of prescription, which are even more indispensable when the pathology being treated is benign. In effect, the implicated drugs are mainly anti-histamines, antibiotics, neuroleptics and antidepressants. The pharmaceutical companies, regulatory agencies, and pharmacological surveillance services must recognise the greatest possible risk of a drug, thanks to pre-clinical data, experimental electrophysiology both in vivo (measurement of the QT interval) and in vitro (action potential duration) or even in the elementary channel (essentially analysis of the iKr current). Correlated with clinical data (QT changes, pharmacokinetic interactions), a risk/benefit profile can therefore be established, which is even more demanding when the pathology is benign or when alternative drugs are available.

A longitudinal investigation of the concordance between individuals with traumatic brain injury and family or friend ratings on the Katz adjustment scale.

Changes in the level of agreement (concordance) between self and family or friend reporting on the Katz Adjustment Scale (KAS) from 6 to 12 months postinjury were assessed in 55 individuals with traumatic brain injury (IwTBI). Although the concordance between self and family/friend reports significantly increased over the course of recovery, possibly reflecting improvements in awareness, the concordance showed limited relationship to measures of injury severity and neuropsychological functioning. Concordance did not significantly relate to clinicians' ratings of inaccurate insight and self-appraisal on the awareness item from the Neurobehavioral Rating Scale (NBRS). Clinicians' ratings of awareness demonstrated only limited relationship to measures of injury severity and neuropsychological functioning, as well. Although similar results in the literature have been interpreted as demonstrating that awareness, defined as concordance, is possibly a unique construct separate from injury severity and neuropsychological functioning, an alternative hypothesis is presented concerning other, noninjury factors that may affect the level of agreement in problem reporting between IwTBI and family/friend informants.

Transmural heterogeneity of ventricular repolarization under baseline and long QT conditions in the canine heart in vivo: torsades de pointes develops with halothane but not pentobarbital anesthesia.

INTRODUCTION: In vitro studies have provided evidence for the existence of M cells. The present study examines the contribution of the M cell to transmural dispersion of repolarization (TDR) and to the development of torsades de pointes (TdP) in the canine heart in vivo in animals anesthetized with either pentobarbital or halothane. METHODS AND RESULTS: Monophasic action potentials (MAPs) were recorded from 4 to 7 transmural sites, before and after d-sotalol. Cells displaying the longest MAP duration (MAPD) generally were localized to the deep subendocardium to mid-myocardium (M region) in the anterior wall of the left ventricle. d-Sotalol preferentially prolonged the MAPD of the M region, increasing TDR significantly more (P < 0.05) in animals anesthetized with halothane (31+/-5 to 88+/-17 msec) than in those receiving pentobarbital (24+/-9 to 53+/-7 msec; basic cycle length 1,500 msec). In halothane-anesthetized dogs, a remarkable transient increase in M cell MAPD followed interpolation of one or more extrasystole(s), leading to a transient increase in TDR and TdP. TdP was never observed with pentobarbital anesthesia. CONCLUSION: Our results demonstrate that transmural heterogeneity of repolarization is amplified under acquired long QT conditions and that the increase in TDR underlies the development of TdP in halothane- but not pentobarbital-anesthetized dogs. The data support an important contribution of M cells to TDR and to the development of TdP in the canine heart in vivo. Our data also highlight the importance of acceleration-induced prolongation of MAPD (a phenomena observed principally in M cells) in the development of TdP.

Effects of the T-type Ca(2+) channel blocker mibefradil on repolarization of guinea pig, rabbit, dog, monkey, and human cardiac tissue.

At supratherapeutic doses (2- to 5-fold), the T-type Ca(2+) antagonist mibefradil modifies the T/U wave of the human ECG. In this study, we show that this effect is observed in conscious monkeys and is duplicated by verapamil or diltiazem. We then evaluate the proarrhythmic risk of such alterations of cardiac repolarization by examining the actions of mibefradil on cardiac action potentials (APs). In isolated cardiomyocytes from guinea pigs or humans, mibefradil dose dependently shortens the plateau of the AP; this effect is similar to other Ca(2+) antagonists and opposite to drugs having class III antiarrhythmic properties. The metabolites of mibefradil, singly or in combination, also shorten APs. In isolated rabbit hearts, noncardiodepressant concentrations of mibefradil have no effect on monophasic action potentials (MAPs), whereas cardiodepressant levels produce a slight nonsignificant lengthening. In hearts of open-chest bradycardic dogs, mibefradil has no effect on MAP dispersion or on QT interval and shortens MAPs slightly; although high doses produce atrioventricular block, likely through Ca(2+) antagonism, arrhythmias are never observed. In contrast, d-sotalol lengthens QT interval and MAPs, increases dispersion, and produces arrhythmias. Together, these in vitro and in vivo results suggest that mibefradil carries no proarrhythmic risk despite changes in T/U wave morphology. Although these changes resemble those observed with class III compounds, they also are seen with nonproarrhythmic compounds such as verapamil and diltiazem. In conclusion, the classical models used in the present study could not link the changes in T/U wave morphology produced by mibefradil and verapamil to any experimental marker of proarrhythmic liability.

The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart.

The discovery and characterization of the M cell, a unique cell type residing in the deep layers of the ventricular myocardium, has opened a new door in our understanding of the electrophysiology and pharmacology of the heart in both health and disease. The hallmark of the M cell is the ability of its action potential to prolong much more than that of other ventricular myocardial cells in response to a slowing of rate and/or in response to agents that act to prolong action potential duration. Our goal in this review is to provide a comprehensive characterization of the M cell, its contribution to transmural heterogeneity, and its role in the normal electrical function of the heart, in the inscription of the ECG (particularly the T wave), and in the development of QT dispersion, T wave alternans, long QT intervals, and cardiac arrhythmias, such as torsades de pointes. Our secondary goal is to address the controversy that has arisen relative to the functional importance of the M cell in the normal heart. The controversy derives largely from the failure of some investigators to demonstrate transmural heterogeneity of repolarization in the dog in vivo under control conditions and after administration of quinidine. The inability to demonstrate transmural heterogeneity under these conditions may be due to the use of bipolar recording techniques that, in our experience, seriously underestimate transmural dispersion of repolarization (TDR). The use of sodium pentobarbital and alpha-chloralose as anesthesia also is problematic, because these agents reduce or eliminate TDR by affecting a variety of ion channel currents. Finally, attempts to amplify transmural dispersion of repolarization with an agent such as quinidine must take into account that relatively high concentrations can result in effects opposite to those desired due to drug inhibition of multiple ion channels. These observations may explain the inability of earlier studies to detect the M cell.

Electrophysiological effects of cetirizine, astemizole and D-sotalol in a canine model of long QT syndrome.

Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to D-sotalol and to astemizole in a model of acquired long QT syndrome. Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with beta-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400-1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for D-sotalol). Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by D-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 +/- 8 msec (mean +/- SE) at baseline to 343 +/- 10, 379 +/- 13 and 468 +/- 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 +/- 6 msec to 377 +/- 7, 444 +/- 15 and 485 +/- 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 +/- 8 msec at baseline Vs 330 +/- 8, 324 +/- 9 and 323 +/- 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 +/- 19 msec after astemizole, +59 +/- 21 msec after D-sotalol and only +7 +/- 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and D-sotalol (4/7 dogs) but never during cetirizine. In the present model, astemizole and D-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.

Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol.

OBJECTIVE: The present study was designed to examine the effects of chronic amiodarone on the different ventricular cell subtypes in situ and to evaluate its interactions with sotalol. METHODS: Three groups of dogs were studied. Group I (n = 8) received no treatment. Group II (n = 7) and group III (n = 8) received, respectively, 100 and 200 mg amiodarone orally twice a day for 6 weeks to 8 months. In vivo studies were performed under halothane anesthesia 14 h after the last administration of amiodarone. Three leads ECG, femoral blood pressure and left ventricular intramural monophasic action potentials (MAP) were continuously recorded. Bradycardia was obtained by clamping the sinus node and beta-blockade and the heart was driven by atrial pacing. Three weeks before the in vivo experiments, the cellular electrophysiologic properties of right ventricular tissues obtained by cardiac biopsy in six treated and six control dogs were studied with standard microelectrodes. RESULTS: Amiodarone produced a dose-dependent decrease in plasma levels of triiodothyronine (T3; 5.9 +/- 0.4 pM in control dogs, 3.1 +/- 0.2 pM in group III, P < 0.001) without affecting thyroxine (T4). Under anesthesia, the QT interval was 14% larger in group III compared to group I at a paced cycle length (PCL) of 1500 ms (P < 0.05). This is consistent with the 10% increase in endocardial MAP duration in group III at the same PCL (P < 0.05). There was no significant increase in transmural dispersion of MAP duration. In group I, sotalol induced a significant reverse use-dependent increase in MAP duration. This effect was reduced in group II and completely suppressed in group III. Amiodarone prevented the sotalol-induced increase in transmural dispersion of ventricular repolarization which was 69 +/- 12 ms in untreated dogs, 41 +/- 8 ms in group II (P < 0.05) and 34 +/- 8 ms (P < 0.05) in group III at PCL = 1500 ms. Amiodarone also prevented the sotalol-induced ventricular tachyarrhythmias. In vitro, the action potential duration was longer in amiodarone-treated dogs that in control ones (208 +/- 5 ms versus 188 +/- 9 ms at PCL = 1000 ms, P < 0.05). The sotalol-induced prolongation of repolarization was reduced in amiodarone-treated dogs. CONCLUSION: Chronic treatment of dogs with amiodarone induced a moderate prolongation of the QT interval and MAP duration without affecting transmural dispersion of repolarization and inhibited the effects of acute sotalol, including the prolongation of repolarization, the increase in transmural dispersion of repolarization and the induction of arrhythmias.

[QT interval and drugs. Recommendation for drug prescription for patients with long QT syndrome. Clinical Research Group of INSERM 4940 12: Diagnostic Clinic of Congenital Long QT Syndrome]. / Intervalle QT et médicaments. Recommandations pour la prescription des médicaments chez les patients atteints du syndrome de QT long. Les Membres du Réseau de Recherche Clinique INSERM 4940 12: "Génétique, Physiopathologie et Diagnostic Clinique du Syndrome du QT long Congénital".

The genetics of the long QT syndrome are now better understood. However, there is much heterogeneity as three different genes have already been identified affecting the function of sodium and potassium channels. The aim of these recommendations is to draw up a list of drugs which are contraindicated or not recommended in patients with congenital long QT syndromes. The conraindicated drugs are those with which torsades de pointe have already been described. Drugs not recommended are substances which are not electrohysiologically neutral and for which, in view of their modes of action, their metabolism or belonging to a particular therapeutic class, make them very difficult to use in those patients. It is therefore better not to prescribe them whenever possible in this condition. These substances belong mainly to cardiovascular (especially antiarrhythmic), psychotropic, anti-infectious and antiallergic groups of drugs.

Combination of sotalol and quinidine in a canine model of torsades de pointes: no increase in the QT-related proarrhythmic action of sotalol.

INTRODUCTION: Clinical treatment with a combination of Class IA and III antiarrhythmic drugs is not recommended, as they both favor bradycardia-dependent proarrhythmic events such as torsades de pointes (TdP). However, this theoretical additive effect on ventricular repolarization has never been demonstrated and could be questioned as other Class I drugs, such as mexiletine, a Class IB drug, limit the number of sotalol-induced TdP in dogs with AV block, suggesting the possibility of an antagonistic action of Class I properties against Class III effects. METHODS AND RESULTS: We compared the electrophysiologic and proarrhythmic effects of sotalol (Class III) alone and combined with quinidine (Class IA) in a canine model of acquired long QT syndrome. Seven hypokalemic (K+: 3 +/- 0.1 mEq/L) dogs with chronic AV block had a demand pacemaker implanted and set at a rate of 25 beats/min. They were submitted to two (sotalol-alone and sotalol-plus-quinidine) experiments 48 hours apart using a randomized cross-over protocol. They were pretreated with quinidine (10 mg/kg + 1.8 mg/kg per hour) or saline infused throughout the experiment, and given sotalol (4.5 mg/kg + 1.5 mg/kg per hour) for 2 hours, 30 minutes after the beginning of the pretreatment infusion during both experiments. Ventricular and atrial cycle lengths were similarly increased by sotalol after quinidine or saline. The sotalol-induced prolongation of the QT interval was significantly shorter in quinidine-pretreated dogs (24 +/- 7 msec after quinidine vs 40 +/- 8 msec after saline). Fewer dogs developed TdP: significantly during the first hour of infusion (1/7 sotalol-plus-quinidine vs 6/7 sotalol-alone dogs, P < 0.05) but nonsignificantly during the second hour (3/7 vs 6/7). CONCLUSION: In this model, the sotalol-plus-quinidine combination is at least no more arrhythmogenic than either of the drugs given alone.

Plasma itraconazole concentrations in patients with neutropenia: advantages of a divided daily dosage regimen.

A group of 36 patients in the hematology department of Saint-Antoine Hospital, Paris, France, was on chemotherapy. The patients were also given antiacid drugs to prevent gastrointestinal toxicity and itraconazole as prophylaxis against aspergillosis. The antifungal drug was given as 100-mg capsules three times a day shortly after meals. The plasma itraconazole and hydroxyitraconazole concentrations were measured by high-performance liquid chromatography at steady state. Of 36 patients, 29 (81%) had adequate plasma itraconazole concentrations (> or = 250 ng/ml) after 8 +/- 2 days. The 7 patients with low plasma itraconazole concentrations were given 200 mg three times a day. Of the 36 patients, 34 (94%) had effective plasma concentrations within 2 weeks of the beginning of treatment. The two remaining patients were lost to follow-up. The proposed itraconazole regimen provides effective prophylaxis against aspergillosis and represents a substantial economic advantage over a single daily dose of 400 to 600 mg. The marked intrapatient and interpatient variations in plasma itraconazole indicate the need for regular therapeutic drug monitoring to ensure effective plasma itraconazole concentrations in all neutropenic patients.

Pharmacokinetics of beta-adrenoceptor blockers in obese and normal volunteers.

AIMS: Obesity can modify the pharmacokinetics of lipophilic drugs. As beta-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic beta-adrenoceptor blockers in obese and control subjects. METHODS: Nine obese (157 +/- 24% of ideal body weight (IBW) mean +/- s.d.) and nine non-obese healthy volunteers (98 +/- 10% IBW), aged 32 +/- 9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic beta-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of beta-adrenoceptor blockers were assessed. RESULTS: The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five beta-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well-correlated (r2 = 0.90; P < 0.01) with their distribution coefficient at pH 7.4 (log D7.4), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar. CONCLUSIONS: Lipophilic beta-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects. Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.

Dexamethasone response, thyrotropin-releasing hormone stimulation, rapid eye movement latency, and subtypes of depression.

Most prior studies of mood disorders have used a single laboratory test to assist in differential diagnosis, prediction of treatment response, and prediction of relapse. This study compared three laboratory measures in a combined in- and outpatient sample of depressed patients. Dexamethasone suppression test (DST) nonsuppression occurred in 46% of patients with endogenous major depression, in 15% with nonendogenous major depression, and in 56% with bipolar, depressed phase disorder. A blunted thyrotropin-releasing hormone stimulation test (TRH-ST) occurred in 25% of patients with endogenous, 10% with nonendogenous, and 44% with bipolar, depressed phase disorder. Reduced REM latency was found in 65% of endogenous major depressions, in 34% of nonendogenous major depressions, and in 53% of bipolar, depressed phase disorders. Fifty-one percent of those with reduced REM latency also evidenced DST nonsuppression. When the endogenous major depression and bipolar, depressed phase groups were combined, 28% had no laboratory abnormality, whereas 8% evidenced all three. These findings suggest that 1) endogenous/nonendogenous unipolar groups are distinguished by all three laboratory tests; 2) most patients with a blunted TRH-ST also evidence DST nonsuppression; and 3) one half of patients with reduced REM latency evidence DST nonsuppression. Sensitivity is greatest and specificity is lowest for REM latency, followed by the DST and then the TRH-ST.

The dexamethasone suppression test in patients with mood disorders.

BACKGROUND: This study was undertaken to (1) determine whether the endogenous/nonendogenous mood disorder dichotomy is validated by the dexamethasone suppression test (DST); (2) determine whether other subtyping schemes (unipolar/bipolar, DSM-III melancholic/nonmelancholic, Winokur's family history subtypes) relate to the DST; (3) evaluate the relative contributions of symptom severity, weight loss, and other factors to DST status; and (4) assess the relative sensitivity of various post-dexamethasone cortisol determinations in the detection of dexamethasone nonsuppression. METHOD: 487 consecutive adult inpatients (N = 131) and outpatients (N = 356) with unipolar (N = 422) or bipolar disorder (N = 65) underwent the 1.0-mg DST. Nonsuppression was defined as at least one post-dexamethasone cortisol measurement > 4.0 micrograms/dL. RESULTS: Nonsuppression occurred in 27% of all patients with major depression and 43% of all bipolar depressed phase patients. For outpatients, dexamethasone nonsuppression occurred in 35.2% of subjects with endogenous (unipolar + bipolar; N = 145) and 9.0% of those with nonendogenous (unipolar only; N = 211) depressions (single 4 p.m. post-dexamethasone cortisol). For inpatients, dexamethasone nonsuppression was found in 61.5% of subjects with endogenous (N = 104) and 18.5% of those with nonendogenous (N = 27) depressions (three post-dexamethasone cortisol determinations). For the inpatient and outpatient sample together, the DST had a sensitivity of 46.2% and a specificity of 89.9% in differentiating endogenous from nonendogenous major depressive episodes. Weight loss, gender, and symptom severity added little to the endogenous/nonendogenous dichotomy. The Research Diagnostic Criteria (RDC) primary/secondary and Winokur and colleagues' family history subtypes for unipolar depression were not strongly validated by the DST. The 4 p.m. and 11 p.m. samples together detected 91.0% of those inpatients with abnormal three-sample DST results. The 8 a.m. sample alone detected 30% of those, the 4 p.m. sample alone detected 67%, and the 11 p.m. sample alone detected 62%. CONCLUSION: The RDC endogenous/nonendogenous dichotomy was validated by the DST.

Depression spectrum disease with and without depression in first-degree relatives.

Family history was assessed in 211 outpatients with unipolar major depression and diagnoses were rendered according to Winokur et al. (Winokur et al. (1978) J. Nerv. Ment. Dis. 166, 764-768) family history typology. The subclassification of Depression Spectrum Disease with Alcoholism and Depression (DSDA + D) was applied to those patients reporting at least one first-degree relative suffering from alcoholism and another first-degree relative suffering from depression (n = 103), while Depression Spectrum Disease with Alcoholism (DSDA) was applied to those patients with at least one first-degree relative suffering from alcoholism, but none suffering from depression (n = 108). These two groups were compared on demographic, clinical and biological characteristics. They were also compared with 162 patients who reported the presence of depression and absence of alcoholism in first-degree relatives, designated as Familial Pure Depressive Disease (FPDD) by the Winokur et al. (1978) classification. Results revealed that the DSDA + D group was younger, had an earlier age at onset of depression and experienced more episodes of depression than did the DSDA group. No differences were found between the two groups on biological measures. The FPDD group was more similar to the DSDA + D group than the DSDA group in terms of age at onset and number of depressives episodes. However, the FPDD group had a longer length of illness than either of the DSD groups. These data suggest that the DSD group should be more narrowly defined (excluding those with a positive family history of depression) in future clinical research studies.

Mexiletine antagonizes effects of sotalol on QT interval duration and its proarrhythmic effects in a canine model of torsade de pointes.

OBJECTIVES: The arrhythmogenic and electrophysiologic properties of sotalol, a class III antiarrhythmic drug, administered alone and in combination with mexiletine, a class I antiarrhythmic drug, were compared in conscious dogs predisposed to torsade de pointes arrhythmias. BACKGROUND: The utility of sotalol is limited by proarrhythmia related to excessive delays in repolarization. The addition of mexiletine may limit the risk of torsade de pointes because it reduced in vitro the sotalol-induced increase in action potential duration. METHODS: Two studies were performed in eight hypokalemic dogs (plasma potassium level < or = 3.2 mmol/liter) with chronic atrioventricular block (mean ventricular cycle length, RR 1,100 ms) at 3-day intervals using a crossover protocol. Intravenous sotalol (4.5 + 1.5 mg/kg body weight per h) alone was given for 2 h, or, on another day, an intravenous mexiletine infusion (4.5 + 1.5 mg/kg per h) was begun 30 min before sotalol infusion. Spontaneous ventricular cycle length and QT interval and ventricular effective refractory period at the 1,000-ms pacing cycle length were measured at baseline and 30 min after the onset of each drug infusion. The electrocardiogram (ECG) was continuously monitored for torsade de pointes. RESULTS: Sotalol plus mexiletine and sotalol alone had a significant (p < or = 0.05) and similar effect on ventricular cycle length (+ 800 +/- 93 vs. + 690 +/- 104 ms [mean +/- SEM]) and ventricular effective refractory period (+ 20 +/- 4 vs. + 25 +/- 4 ms), but sotalol plus mexiletine had a lesser effect on QT interval (+ 20 +/- 6 vs. + 50 +/- 8 ms, p < or = 0.05). Torsade de pointes is less frequent (one of eight dogs vs. six of eight dogs, p = 0.02) with sotalol plus mexiletine than with sotalol alone. CONCLUSIONS: The coadministration of a class Ib agent can reduce the proarrhythmic potential of a class III drug in experimental animals predisposed to torsade de pointes arrhythmias and further suggests the clinical utility of such a strategy.

The pharmacokinetics of dexfenfluramine in obese and non-obese subjects.

The pharmacokinetics of dexfenfluramine (d-F) and its metabolite dexnorfenfluramine (d-NF) were compared in 10 obese (145 +/- 13 s.d. % of ideal body weight (IBW)) and 10 non-obese healthy volunteers (93 +/- 8% IBW). Each group included five men and five women, aged 28 +/- 8 years. Subjects were given single doses of d-F i.v. (15.5 mg base infused over 3 h) and orally (25.9 mg base in capsules) on separate occasions. After i.v. infusion in obese subjects, the volume of distribution (Vss) of d-F was significantly higher (969.7 +/- 393.3 l; 95% CI 688.6-1250 l) than in controls (668.7 +/- 139.6 l; 95% CI 568.9-768.5 l; P < 0.01). Clearance was not significantly different (43.9 +/- 21.0 l h-1 vs 37.3 +/- 10.6 l h-1) and the terminal half-life tended to be longer (17.8 +/- 9.4 vs 13.5 +/- 3.9 h NS). Combined data from the two groups indicated a positive correlation between Vss and % IBW (r = 0.544; P < 0.02). The oral bioavailability of d-F was 0.61 +/- 0.15 in obese subjects and 0.69 +/- 0.11 in controls. There was no significant difference between obese subjects and controls in Cmax, tmax and t1/2,z (Cmax: 20.1 +/- 6.7 and 27.3 +/- 6.2 micrograms l-1; tmax: 3.5 vs 3.0; t1/2,z: 16.5 +/- 7.1 vs 14.5 +/- 2.6 h respectively). The AUC ratio expressed in molar units for d-F/d-NF was 2.29 +/- 1.78 (i.v.) vs 1.25 +/- 0.64 (oral) in obese subjects and 2.05 +/- 1.26 (i.v.) vs 1.40 +/- 0.87 (oral) in controls.(ABSTRACT TRUNCATED AT 250 WORDS)