Lack of Amphetamine-Like Effects After Administration of Mefenorex in Normal Young Subjects

Mefenorex is an indirect sympathomimetic amine which acts as an anorectic drug and is used in combination with low diet to treat excess weight. The central nervous system (CNS) effects of mefenorex were assessed in a randomized, double-blind, three-way cross-over, placebo-controlled study involving nine healthy young male volunteers. They received either a single oral dose of mefenorex 80 mg (twice the recommended dose) or d-amphetamine sulfate 18 mg or a placebo at 1-week intervals. CNS pharmacodynamic measurements consisted of subjective evaluation (visual analogue scales and the Addiction Research Centre inventory (ARCI)), EEG, psychomotor performance and attention (tracking, simple and choice reaction times, tapping, continuous performance task, DSST, body sway) and memory (working memory and recall of a word list). d-Amphetamine produced a typical psychostimulant EEG profile (significant decrease in slow delta waves and increase in fast beta activities), significantly increased amphetamine, benzedrine and morphine–benzedrine scores of ARCI and significantly decreased body sway compared to placebo and mefenorex. A trend in favour of a stimulant effect occurred for all other parameters (particularly speed of reaction) and no changes of memory were noticed. In contrast, mefenorex did not produce an amphetamine-like EEG profile, neither significantly changed ARCI scores nor significantly modified psychomotor and memory performance compared to the placebo, although it induced a decrease in body sway. In conclusion, the present results indicate that a single oral dose of mefenorex, at twice the recommended daily dose, does not possess amphetamine-like subjective and EEG stimulant effects or sensations of well-being, often encountered with drugs of abuse liability potential, in a healthy young population.     

A radioreceptor assay for benzodiazepines

A simple, rapid and sensitive radioreceptor assay for determining benzodiazepines in serum is based on the displacement by the drug of specific [³H]diazepam binding to a membrane fraction from rat brain. The limit of detection of the more active benzodiazepines is about 0.5 ng. Diazepam, nitrazepam, clobazam and HR 458t have been assayed in human serum after a single oral clinical dose. The results can be used for determining pharmacokinetic parameters. The technique measures not only the parent benzodiazepine but also clinically active metabolites.     

Immunological IgE Cross-Reactions of Bovine and Human α-Lactalbumins in Cow's Milk Allergic Patients

Despite great homology with the equivalent human protein, bovine α-lactalbumin (B α-La), a major component of whey, has been identified as a major milk allergen. The aim of this study was to investigate the relationship between structure and IgE binding capacity in α-Las: (1) the importance of three-dimensional structure using native vs disulfide bridgereduced B α-La; and (2) the incidence of amino acid sequence divergence on specific IgE cross-reactivity to human vs bovine α-La. Purified native, reduced and S-carboxymethylated B α-La and human α-La (H alpha-LA) were prepared. Specific IgE of 20 sera from patients with clinically recognized cow's milk protein allergy and positive RAST tests to B α-La were measured in original direct and competitive ELISA inhibition tests. All sera containing specific anti-native B α-La IgE also reacted with denatured protein, but the IgE levels were generally lower, showing that three-dimensional structure is an important feature in B α-La allergenicity but that sequential epitopes are also exposed after protein denaturation. Despite lower IgE levels, all sera also gave significant IgE responses to H α-La. Competitive ELISA inhibition confirmed results obtained by direct ELISA. The demonstrated IgE cross-reactivity between B α-LA and H α-La could be related to the high degree of sequence homology between the two proteins but did not prove to have a clinical significance. However, it is of great interest for a study of the relationship between structure, IgE binding capacity and allergenicity in alpha-Las.     

A Short‐Term,Randomized, Double‐Blind,Parallel‐Group Study to Evaluate the Efficacy and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial Fibrillation: The DIONYSOS Study

Dronedarone versus Amiodarone in Patients with AF. Introduction: We compared the efficacy and safety of amiodarone and dronedarone in patients with persistent atrial fibrillation (AF). Methods: Five hundred and four amiodarone‐naïve patients were randomized to receive dronedarone 400 mg bid (n = 249) or amiodarone 600 mg qd for 28 days then 200 mg qd (n = 255) for at least 6 months. Primary composite endpoint was recurrence of AF (including unsuccessful electrical cardioversion, no spontaneous conversion and no electrical cardioversion) or premature study discontinuation. Main safety endpoint (MSE) was occurrence of thyroid‐, hepatic‐, pulmonary‐, neurologic‐, skin‐, eye‐, or gastrointestinal‐specific events, or premature study drug discontinuation following an adverse event. Results: Median treatment duration was 7 months. The primary composite endpoint was 75.1 and 58.8% with dronedarone and amiodarone, respectively, at 12 months (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.28–1.98; P < 0.0001), mainly driven by AF recurrence with dronedarone compared with amiodarone (63.5 vs 42.0%). AF recurrence after successful cardioversion was 36.5 and 24.3% with dronedarone and amiodarone, respectively. Premature drug discontinuation tended to be less frequent with dronedarone (10.4 vs 13.3%). MSE was 39.3 and 44.5% with dronedarone and amiodarone, respectively, at 12 months (HR = 0.80; 95% CI 0.60–1.07; P = 0.129), and mainly driven by fewer thyroid, neurologic, skin, and ocular events in the dronedarone group. Conclusion: In this short‐term study, dronedarone was less effective than amiodarone in decreasing AF recurrence, but had a better safety profile, specifically with regard to thyroid and neurologic events and a lack of interaction with oral anticoagulants. (J Cardiovasc Electrophysiol, Vol. 21, pp. 597‐605, June 2010)     

Study of Unipolar Electrogram Morphology in a Computer Model of Atrial Fibrillation

Introduction: Electrograms exhibit a wide variety of morphologies during atrial fibrillation (AF). The basis of these time courses, however, is not completely understood. In this study, data from computer models were studied to relate features of the signals to the underlying dynamics and tissue substrate.
Methods and Results: A computer model of entire human atria with a gross fiber architecture based on histology and membrane kinetics based on the Courtemanche et al. atrial model was developed to simulate paced activation and simulated AF. Unipolar electrograms were computed using a current source approximation at 256 sites in right atrium, to simulate a mapping array. The results show the following: (1) In a homogeneous and isotropic tissue, the presence of highly asymmetric electrograms is rare (<2%), although there is a marked variability in amplitude and symmetry. (2) The introduction of anisotropy increases this variability in symmetry and amplitude of the, electrograms especially for propagation across fibers. The percentage of highly asymmetric electrograms increases to 12% to 15% for anisotropy ratios greater than 3:1. (3) Multiphasic and fractionated electrograms are rarely seen in the model with uniform properties but are more common (15%–17%) in a model including regions with abrupt changes in conductivity. Beat-to-beat variations in the occurrence of multiphasic signals are possible with fixed anatomic heterogeneity, due to beat-to-beat variations in the direction of the wavefront relative to the heterogeneity.
Conclusion: Analysis of the amplitude and symmetry of unipolar atrial electrograms can provide information about the electrophysiologic substrate maintaining AF. (J Cardiovasc Electrophysiol, Vol. 14, pp. S172-S179, October 2003, Suppl.)     

Physiopathology of Ventricular Tachyarrhythmias

Les arythmies ventriculaires peuvent relever de trois mécanismes parfois associés: un automatisme anormal, une activité déclenchée compliquant des postdépolarisations précoces ou tardives; un phénomenène de réntreé par mouvement circulaire ou par réflexion. Ces trois mécanismes fondamentaux ont pu être mis en évidence sur le coeur entier notamment sur les modèles expérimentaux les plus utilisés: l'ischémie myocardique et l'intoxication digitalique. Chez l'homme les arguments en faveur de tel ou tel mécanisme ne sont qu'indirects et reposent essentiellement sur les effets des stimulations. Si aucune certitude n'est actuellement possible, il semble cependant légitime de tirer les conclusions suivantes: (1) Les réntrées sont à I'origine des fibrillations ventriculaires, des exceptionnelles tachycardies ventriculaires de branche à branche, et probablement de la plupart des tachycardies ventriculaires récidivantes chroniques soutenues et aisement inductibles de façon reproductible. (2) Le mécanisme des autres arrythmies ventriculaires reste inconnu. (3) Même lorsque les arrythmies sont en rapport avec des phénomènes de réentrée, les extrasystoles déclenchantes peuvent relever d'un mécanisme focal.     

A glucose transfer from membrane glycoconjugates to haemoglobin in isolated young red blood cells: another biosynthetic way for glycosylated haemoglobins

Abstract. Human red blood cells (RBC) are separated by centrifugation into young and old ones, as demonstrated by lower enzymatic activities and lower potassium content of the older ones. The young RBC fraction represents 5% of total RBC. After incubation for 24 h in a neutral buffer, the young RBC HbA_1c content increases significantly from 4·2 to 5·2% of total Hb. No increase is found in the case of old RBC. When young RBC have been extracted for 1 h by a neutral buffer prior to incubation, there is no more increase of HbA_1c.
The extract contains a glycoconjugate that is both soluble in neutral buffers and in chloroform. A glycolipid extractable from the young RBC membrane contributes to HbA_1c formation but disappears from old RBC, in which glycosylation by free glucose occurs. These processes are stereospecific.     

Chronic Left Main Coronary Artery Occlusion: A Complication of Radiofrequency Ablation of Idiopathic Left Ventricular Tachycardia

We describe in this report the development of chronic left main coronary artery (LMCA) occlusion in a young patient 2 years after an uncomplicated, successful ablation of idiophic left ventricular tachycardia. This complication appears to be a late consequence of trauma to the LMCA during the procedure rather than an acute or subacute embolic event.