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Summary Aim To assess the effects of water immersion on cardiovascular requirements, 30 min immersed versus air steady exercises at neutral temperature were compared in two settings:similar energy expenditure (60% maximal oxygen consumption; series 1) and similar ergometric workload (120 W; series 2). For 15 healthy male subjects, the arterial blood pressure, heart rate, thoracic fluid conductivity (TFC), cardiac index (CI) and stroke index (SI) were monitored at rest, during the exercise period and during 30 min of post-exercise recovery in two conditions. Plasma atrial natriuretic peptide (ANP) was also measured. Results Resting water immersion increased TFC, CI, SI, and systolic arterial pressure (SAP). During exercise the average CI, SI and SAP were not different in water and air in series 1, but in series 2 CI, SI, heart rate, systolic and diastolic arterial pressures were higher in water. Plasma ANP was higher after immersed exercises. During recovery, CI was similar after either exercise, while SI was lower and heart rate higher following immersion, consistent with a lower effective circulatory volume than after exercise in air. TFC was high, as reflecting an increased interstitial fluid content in the lung. Conclusions Cardiovascular requirements for exercising in water were markedly higher than in air and straining of lung parenchyma.

Aims: The aim of this study was to evaluate whether endurance exercise in middle-aged men induces changes in plasma total homocysteine (tHcy) and total cysteine (tCys), and whether these changes depend on the diet especially on vitamin B6, folic acid and vitamin B12 intakes. Methods: Twelve trained subjects (52.33 ± 2.4 years) and twelve untrained subjects (56.23 ± 0.9 years) volunteered for the present study. tHcy and tCys were measured with high-pressure liquid chromatography at rest in both groups and during an incremental exercise performed on a cycle ergometer until exhaustion in the trained subjects. Results: At baseline homocysteinemia and cysteinemia were lower in trained subjects (7.48 ± 0.4 and 183.45 ± 13.6 µmol/l) compared with untrained subjects (9.79 ± 0.4 µmol/l, p < 0.001; 229.01 ±14.7 µmol/l, p < 0.05, respectively). Incremental exercise also induced a decrease in tHcy and tCys concentrations. Moreover, tHcy concentration was negatively related to the folic acid and B12 intakes in untrained (r = –0.589, p < 0.05; r = –0.580, p < 0.05, respectively) as well as in trained groups (r = –0.709, p < 0.01; r = –0.731, p < 0.01, respectively) whereas no correlation between tCys and vitamin in the diet was observed. Conclusion: This study demonstrates that the combined effects of a chronic physical exercise and a high folate and vitamin B12 intake could be responsible for the reduction of plasma tHcy and tCys concentrations that might be a key for the prevention of many diseases.

Resume Objectifs. – Les etudes destinees a determiner les valeurs diagnostiques des tests de l'allergie aux venins d’hymenopteres ont ete souvent realisees dans un objectif de validation methodologique, mais on dispose de tres peu d’etudes d’evaluation dans des situations de routine diagnostique. De fait, la valeur diagnostique des tests de liberation d'histamine, par exemple, a rarement ete etudiee systematiquement chez des patients adresses par leur medecin pour une confirmation diagnostique et/ou l’indication d’une desensibilisation. Le but de cette etude etait d'evaluer les valeurs diagnostiques des prick-tests, des IgE specifiques et des tests de liberation d'histamine en pratique de routine dans une unite d'allergologie. Patients et methode. – Les tests diagnostiques ont ete realises prospectivement chez 25 patients consecutifs atteints d’allergie aux venins d'hymenopteres attestee par l'histoire clinique et la positivite des intradermo-reactions, incluant des patients avec reaction locoregionale accompagnee de malaise et/ou de dyspnee, de meme que chez 21 sujets temoins. Les hymenopteres etudies ont ete la guepe Vespula (V) et l’abeille (A). Ont ete etudiees : la sensibilite, la specificite, la concordance et les valeurs predictives. Resultats. – Les valeurs de sensibilite, specificite, valeur predictives positives et negatives ont ete respectivement de (en pourcentage) : pour les prick-tests (100 μg/mL) : 33,3 ; 100 ; 100 ; 85,7 (A) ; 30 ; 100 ; 100 ; 85,1 (V) ; pour les prick-tests (300 μg/mL) : 75 ; 100 ; 100 ; 94,1 (A) ; 57,1 ; 100 ; 100 ; 90,3 (V) ; pour les IgE specifiques : 100 ; 95,2 ; 84 ; 100 (A) ; 100 ; 76,2 ; 51,2 ; 100 (V) ; et pour le test de liberation d’histamine : 88,9 ; 100 ; 100 ; 97,3 (A) ; 94,1 ; 88,9 ; 67,9 ; 98,4 (V). Conclusions. – Pour le diagnostic de l’allergie aux hymenopteres par les prick-tests, des concentrations de venins inferieures a 300 μg/mL sont trop peu sensibles. Le test de liberation d'histamine represente un bon test complementaire dont la standardisation devrait etre amelioree.

Background: Reactive oxygen species generated by ultraviolet light result in photocarcinogenic and photoaging changes in the skin. Antioxidants protect the skin from these insults. Objective: The aim of this study was to determine the ex vivo ascorbic acid penetration and its degradation in the skin after its topical application from an 8% new formulation. Method: Ascorbic acid was applied to human skin fragments. Ascorbic acid and its metabolites were collected by microdialysis and assessed by gas chromatography mass spectrometry. Results: After topical application of the new formulation, the ascorbic acid level achieved was 8.5% higher than the normal tissue value. This high ascorbic acid dermal concentration remained constant if a topical application was made every 8 h. No degradation of ascorbic acid was detected. Conclusion: Ascorbic acid penetrates rapidly after its topical application. The persistent reservoir of ascorbic acid provides an important and attractive photoprotection strategy.

Resume Objectifs.- etudier les effets d'un programme d'entrainement en endurance chez de jeunes asthmatiques legers (une crise ou moins par semaine). Methodes.- Six jeunes (trois garcons et trois filles, 14 ± 2 ans, 49 ± 12 kg, 157 ± 6 cm) ont suivi ce programme, qui consistait en la repetition trois fois par semaine d'un exercice en creneaux de 45 minutes comportant la succession de neuf creneaux de cinq minutes. Chaque creneau est constitue par une base de 4 minutes et un pic d'une minute. Les intensites sont respectivement celle du seuil d'adaptation, puis de desadaptation ventilatoire, identifies lors d'un test triangulaire prealable. Lintensite des bases et des pics etait reajustee de 10 W chaque fois que la frequence cardiaque mesuree aux 44e et 45e minutes avait baisse de huit a dix battements par minute par rapport a l'epreuve initiale. A l'issue d'un programme total de 20 seances, les effets de l'entrainement furent juges a l'aide d'un second test triangulaire compare au test initial. Resultats.- La puissance maximale supportee (195 contre 152 W, p Conclusion.- L'exercice en creneaux individualise est bien supporte cliniquement. Le rapport bien ajuste de phases de travail intense (pics) et de phases de recuperation active (bases) semble particulerement efficace, en developpant le potentiel aerobie et en augmentant la tolerance de ces jeunes asthmatique a l'hyperventilation d'exercice.

The microdialysis method is extensively developed in neuropharmacological experiments. It is a non-invasive technique with promising applications in biological research. The aim of this work was to establish and to optimize a process to microdialyse chemicals. Three lipophilic molecules used in dermatology were tested: 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP) and trimethylpsoralen (TMP). These psoralens have the same basic chemical structure (furocoumarin). The different radical substitutions are responsible for their different lipophilicities. In this work, different microdialysis parameters were studied: the relative recovery and the equilibrium time in relation to the perfusion rate and to the drug lipophilicity. The equipment was composed of a CMA/100® microinjection pump, CMA/20® microdialysis probes (membrane length of 10 mm, cut off 20 and 100 kDa) and a CMA/140® microcollector. The perfusate was a phosphate buffer 0.06 M (pH 7.4). The psoralen dialysates were assessed by high performance liquid chromatography. The relative recovery of psoralens increased with the decreasing perfusion rates and with the drug lipophilicity. The equilibrium time decreased with the increasing perfusion rates. TMP was not detected under these experimental conditions. This work defines the optimal parameters for in vivo studies and shows the limit of this technique for the investigation of lipophilic drugs.

The aim of the present study was to investigate the effects of a delayed bedtime (3 a.m.), an advanced rising (3 a.m.), a sleep under placebo and under a hypnotic compound, i.e. 10 mg of Zolpidem (Stilnox®) on sleep structure and on the adaptations to a subsequent exercise in 8 male athletes. The chronology of these nights was randomized and each treatment administered in a double blind fashion. During each experimental night, subjects were monitored with conventional EEG/EOG/EMG polygraphic recordings. The next day, athletic performance was tested using a bicycle ergometer. A codified exercise was performed and consisted to a 10 min warm up followed by a 30 min steady state cycling corresponding to 75% of predetermined VO2 max. Then the work load increased progressively by steps of 10 W every minute until exhaustion. The recovery lasted 30 min. Heart rate, ventilation, VO2, ERO2 were monitored during all exercise and recovery. Plasma lactates and catecholamines were also measured at the same ti...

The present study compared the effects of partial sleep deprivation and the effects of an intake of a hypnotic compound (zolpidem) prior to bedtime, on sleep and on hormonal and metabolic adaptations to subsequent exercise. Sleep deprivation consisted of a delayed bedtime and an early getting-up time. Eight young subjects, who slept well and were highly trained athletes, were enrolled in this study. Sleep was recorded polygraphically and the following afternoon exercise was performed on a cycle ergometer for 30 min at 75% of maximal oxygen consumption (VO2max) after a 10-min warm up. Met-enkephalin, β-endorphin, cortisol, and lactate concentrations were measured at rest and during exercise. The data obtained after experimental sleep, with and without medication were compared with those obtained in the reference condition with normal sleep. Both types of sleep reduction decreased the total sleep time, stage 2 sleep, and rapid eye movement sleep, whereas zolpidem administration did not modify either the duration of sleep or the sleep stages. After the reference night, plasma met-enkephalin did not show any significant change at the end of the submaximal exercise, whereas β-endorphin, cortisol, and lactic acid concentrations increased significantly in all subjects. The changes in concentration in β-endorphin were significantly related to the changes in cortisol (r=0.78;P

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The sublingual absorption of vincamine used as tracer occurs in two successive absorption steps: true sublingual absorption and absorption in the gastrointestinal tract of the drug dissolved in the saliva and not absorbed through the buccal mucosa. This is confirmed by a pharmacokinetic study and simulation. These two successive absorptions can explain the increase in the amounts of drug absorbed.

Cytochrome P450-2D6 may be involved in the metabolism of many drugs such as psychotropic drugs and its genetic polymorphism is responsible for inter-individual differences in the therapeutic effect and toxicity of these drugs. Moreover with the same genetic basis, CYP2D6 metabolic capacity variations are observed. Different factors of variation may be involved, among them the prescribed drugs. The aim of this study was to compare the influence of two types of antidepressants, tricyclic (clomipramine) and serotonergic specific recapture inhibitor (SSRI) (fluoxetine), on the CYP2D6 metabolic capacity of depressed inpatients. The CYP2D6 phenotype (dextromethorphan test) was determined in 56 genotyped (PCR-SSCP) depressed caucasian inpatients with a heterozygous genotype. Forty-five subjects were treated with clomipramine and eleven received fluoxetine. The dextromethorphan metabolic ratio (MR) median was significantly higher in the fluoxetine group (0.255) than in the clomipramine group (0.083, p < 0.014). In this study, fluoxetine involved a greater decrease of CYP2D6 metabolic capacity than clomipramine. Clinical implications and the possible connection between a decreased CYP2D6 activity and adverse drug effects were discussed. Caution should be taken when drugs with a low therapeutic index must be coprescribed in such patients.

The evolutions in treatments and clinical practices in organ transplantations led to modifications in the therapeutic drug monitoring (TDM) of immunosuppressive drugs. A focus is made regarding the C2 sampling of cyclosporin, as well as the TDM of mycophenolate mofetil and sirolimus. A review of literature about the evolution of drug monitoring, technical methods and sampling strategies is described. Arguments in favour of TDM are thus a decrease in the frequency of both graft rejection and adverse drug reactions, however, new strategies or new targets are needed in new associations or indications.

Our purpose was to determine the effects of amifostine, a cytoprotective agent, on doxorubicin tolerance and cardiotoxicity in rats.Male Wistar rats were treated every other day with an intraperitoneal injection of amifostine or saline 30 minutes before intraperitoneal injection of doxorubicin or saline. Weight change was recorded, and contractile function was evaluated after 11 injections by means of the isolated heart.Weight evolution and cardiac function were significantly improved by 7 and 20 mg/kg amifostine (p0.001) but not by 50 mg/kg. The final weight were: controls 349 +/- 16 g; doxorubicin alone 258 +/- 54 g; with amifostine: 7 mg/kg 314 + 28 g; 20 mg/kg 312 +/- 32 g; 50 mg/kg 250 +/- 34 g. Left ventricular developed pressure were: controls 137 +/- 15 mmHg; doxorubicin alone 119 +/- 20 mmHg; with amifostine: 7 mg/kg 140 +/- 20 mmHg; 20 mg/kg 137 +/- 25 mmHg; 50 mg/kg 124 +/- 20 mmHg.Seven and 20 mg/kg amifostine protected rats from the toxicity of doxorubicin at the cumulative dose of 18 mg/kg during a 12-day treatment, with regard to weight loss and heart contraction.

The microdialysis expanded mainly in the field of the neuro- and the dermopharmacology with the study of the transmitters released in the central nervous system and derm. Since ten years, this tool gained other disciplines such as cardiology and cardiovascular surgery. Indeed, the collection and the study of the molecules released in the myocardic interstitial fluid without deteriorating it functioning made microdialysis a powerful tool in the study of the extracellular environment of the cardiomyocyte. The purpose of this study is to point out the principle of the microdialysis and to show its various uses in the field of cardiovascular pharmacology.

The therapeutic drug monitoring aims at optimising the prescribed dosages to improve efficacy and prevent toxicity. The aim of this study were to review the main pharmacodynamic and pharmacokinetic properties of aminoglycosides, glycopeptides and ceftazidime. Then, the therapeutic drug monitoring of these antibiotics and their methods of analysis is reviewed.

This study aimed at evaluating the role of nitric oxide (NO) when generated 24 h prior to ischemia-reperfusion. Three groups were studied in an isolated buffer-perfused heart model: Control (saline = 3.3 mL/kg, n = 10), the precursor of NO, L-arginine, (500 mg/kg, n = 10) and an inhibitor of NO synthase, L-NAME, (10 mg/kg, n = 9). All groups were injected intraperitoneally 24 h before heart extraction. Nitrites, nitrates (an index of nitric oxide release) and cardiac troponine I were assayed. During the reperfusion period, there was a low release of nitric oxide and cardiac troponine I associated with improved recovery of post-ischemic myocardial function. These results indicate that in this model, the pre-treatment improved myocardial function and thus, NO could play a role as a trigger and not as a mediator of cardioprotection.

The genetic polymorphism of human N-acetyltransferase 2 (NAT2) divides the human population into groups with rapid, intermediate and slow acetylator status. Slow acetylator status has been considered a predisposing factor for allergic diseases, lupus erythematosus, toxic epidermal necrolysis or Stevens-Johnson syndrome. The aim of this study was to investigate whether Caucasian patients suffering from atopic dermatitis differed from healthy individuals with regard to the genotype and phenotype of NAT2. Twenty unrelated healthy Caucasian volunteers (9 females and 11 males, aged from 22 to 59 years) and twenty unrelated Caucasian patients suffering from atopic dermatitis (9 females and 11 males, aged between 20 and 54 years) participated in this study. For each one, the NAT2 genotype was determined by polymerase chain reaction with DNA extracted from peripheral blood, using specific primers for the wild-type allele (wt) and the 3 most frequent mutated alleles of NAT2 (C481→T, G590→A and G857→A). The NAT2 phenotype was evaluated with dapsone as a test substrate using high-pressure liquid chromatography. Statistical analysis was performed using the χ2 test. Phenotype and genotype were distributed as follows: (1) of the healthy subjects, 60% were rapid acetylators (RA) and 40% were slow acetylators (SA); 10% of the RA and 15% of the SA were homozygous, 50% of the RA and 25% of the SA were heterozygous; (2) of the patients, 55% were RA, 40% were SA and 5% were intermediate acetylators (IA); 10% of the RA and 10% of the SA were homozygous, 45% of the RA and 35% of the SA were heterozygous. No significant statistical difference was found between the two groups for genotypes (p = 0.75) or phenotypes (p = 0.60). The phenotyping and genotyping results of healthy subjects were comparable to those found in previous studies. The absence of a significant statistical difference between healthy subjects and atopic dermatitis patients is in contrast to the results of previous studies. Some authors considered that allergic patients are mostly SAs. This could be explained by the fact that we only considered patients suffering from atopic dermatitis whereas, in other studies, patients suffered from different (one or several associated) allergic diseases. NAT2 polymorphism does not differ between patients suffering from atopic dermatitis and healthy subjects. The importance attributed to the SA status, which was previously considered a predisposing factor for allergic diseases such as atopic dermatitis, should be reviewed.

IL-10 exhibits anti-inflammatory effects on activated rodent mast cells (MC) in vitro and inhibits allergen-induced airway inflammation in vivo in murine models. The effects of IL-10 on the allergic activation of human MC are presently unknown.In light of the well-known heterogeneity of mast cell reactivity between animal species, one cannot readily predict the response of human MC to IL-10. Moreover, the impact of IL-10 on MC-derived proinflammatory mediators is still unknown. Thus, the objective of this study was to investigate the effects of IL-10 on the release of inflammatory mediators by IgE/anti-IgE-challenged human cord blood-derived mast cells (CBMC), used as an in vitro model of MC phenotypically similar to human lung MC.Highly purified human MC were obtained by a first step of long-term culture of cord blood mononuclear cells in the presence of human recombinant stem cell factor (rhSCF) and of human recombinant IL-6 (rhIL-6), followed by a second step of purification by depletion of contaminating cells with an immunomagneticThe cells were treated with human IgE, then challenged with anti-human IgE, in the presence or the absence of recombinant rhIL-10 used at various concentrations. Histamine, tumour necrosis factor-alpha (TNF-alpha), IL-5 and IL-8 were measured in the various supernatants collected at different times after the beginning of the challenge.IL-10 inhibited the release of TNF-alpha and of IL-8, but not of IL-5, by activated CBMC. Interestingly, IL-10 also inhibited the release of histamine by activated CBMC, contrasting with data reported for rodent MC.These findings suggest that IL-10 might have anti-inflammatory effects on IgE/anti-IgE-challenged human MC by inhibiting their release of TNF-alpha, IL-8 and histamine. These data provide new insights into the control of human mast cell activation and might lead to a better knowledge of the cellular mechanisms controlling allergic reactions.

The aim of this study was to determine the hormonal responses, which are dependent on the sleep wake cycle, to strenuous physical exercise. Exercise was performed after different nocturnal regimens: (i) a baseline night preceded by a habituation night; (ii) two nights of partial sleep deprivation caused by a delayed bedtime or by an early awakening; and (iii) two nights of sleep after administration of either a hypnotic compound (10 mg zolpidem) or a placebo. Eight well-trained male endurance athletes with a maximal oxygen uptake of 63.5 +/- 3.8 ml x kg(-1) x min(-1) (mean value +/- s(x)) were selected on the basis of their sleeping habits and their physical training. Polygraphic recordings of EEG showed that both nights with partial sleep loss led to a decrease (P< 0.01) in stage 2 and rapid eye movement sleep. A delayed bedtime also led to a decrease (P < 0.05) in stage 1 sleep. Zolpidem had no effect on the different stages of sleep. During the afternoon after an experimental night, exercise was performed on a cycle ergometer. After a 10-min warm-up, the participants performed 30 min steady-state cycling at 75% VO(2-max) followed by a progressively increased workload until exhaustion. The recovery period lasted 30 min. Plasma growth hormone, prolactin, cortisol, catecholamine and lactate concentrations were measured at rest, during exercise and after recovery. The concentration of plasma growth hormone and catecholamine were not affected by partial sleep deprivation, whereas that of plasma prolactin was higher (P < 0.05) during the trial after an early awakening. Plasma cortisol was lower (P < 0.05) during recovery after both sleep deprivation conditions. Blood lactate was higher (P < 0.05) during submaximal exercise performed after both a delayed bedtime and an early awakening. Zolpidem-induced sleep did not affect the hormonal and metabolic responses to subsequent exercise. Our results demonstrate only minor alterations in the hormonal responses to exercise after partial sleep deprivation.

beta 2-Adrenoceptor agonists used in the relief of bronchospasm have long been known to produce circulatory side-effects. Salmeterol (CAS 89365-50-4) is a novel long acting highly selective beta 2-agonist. We used the Langendorff-heart rat model (constant perfusion pressure) to compare the direct effects of salbutamol (CAS 18559-94-9, SAL) and salmeterol (SMT) on the cardiac performances and their toxic cardiac effects (induced by 3 mmol/l perfusate calcium). At the first step the concentration-effect curve was established for the maximal concentration (Cmax) of salbutamol leading to the maximal chronotropic effect on the heart for 20 min after a 20 min stabilization period (basal values). All hearts were consequently submitted to a 20 min Krebs-Henseleit perfusion in order to study the reversibility of the myocardial performances. The types of the myocardial and coronary beta-adrenoceptors involved in SAL (Cmax) effects were identified using a selective beta 1 (atenolol) and a beta 2 (butoxamine) antagonist. SAL induced an increase in the heart rate via a selective stimulation of the beta 1-adrenoceptors (beta 1-AR). SMT appeared to be more potent than SAL on the heart rate. Direct toxic drug effects on the heart appeared gradually with SAL whereas they appeared sharply at the highest concentration of SMT. The enzyme leakage observed during the recovery period was more pronounced with SMT than SAL. Perhaps, this phenomenon might be due to the lipophilicity of SMT. However, these direct cardiac effects of SMT have to be considered in association with its airway smooth muscle relaxant effect (therapeutic effect) which has been proven much more potent than those of SAL. Therefore SMT was less cardiotoxic than SAL at similar therapeutic concentrations.

The aim of the study was to investigate the effects of a partial sleep deprivation on a subsequent supramaximal exercise evaluated from the 30 second Wingate test, and on the following recovery. To take into account the active muscle mass, the Wingate test was performed against a constant braking force related to the data of a force-velocity test conducted on a Monark cycle ergometer (Model 814 E with weights) one week before the experimental test. Eight highly trained athletes were enrolled for this study. The changes in ventilatory and metabolic responses were analyzed during and upon completion of physical 30 second exercise, taking place after two nights, in other words, after a reference night and after a night with reduced sleep. Partial sleep deprivation was obtained by delaying bedtime until 3 a.m. The 30 second Wingate test was performed between 9 a.m. and noon the following days, using a Monark ergometer (Model 814 F). The analyses of change scores disclosed that there were no main significant effects for measures of ventilation, lactates and pH(v) levels under the two experimental conditions. The peak power, the mean power output and the peak velocity recorded after partial sleep deprivation were not modified in comparison with the values obtained after the reference night. These findings suggest that acute sleep loss did not contribute to alterations in supramaximal exercise.

The electrophysiological effects of gallium chloride (Ga ) and its activity on arrhythmias induced by digitalis were investigated in guinea pig papillary muscle. KCl microelectrodes were used to record transmembrane electrical activity from Purkinje cells from the papillary muscle of guinea pig hearts during superfusion and electrical stimulation in vitro at 37 degrees C. Myocardial contractility was continuously monitored. Ga was superfused alone in cumulative concentrations(4.5 . 10(-5) to 3.6 . 10(-4) M). Arrhythmias were induced by a superfusion of Digitoxin (7.5 . 10 (-7) M). A superfusion of Ga (4.5 . 10(-5), 9 . 10(-5), 1.8 . 10(-4) M and 3.6 . 10(-4) M) was started 20 min later and maintained for 70 min. Ga alone produced a dose dependent reduction of action potential duration and contractility. Ga potentiated the decrease in the amplitude and duration of the action potential induced by Digitoxin. The incidence of arrhythmias was immediately reduced by two concentrations of Ga (4.5 . 10(-5) and 9 . 10(-5) M) in the digitalized papillary muscles. It is concluded that Ga inhibits calcium movements and has negative inotropic and antidysrhythmic effects.

The purpose of this study was to determine the effect of dietary magnesium supplementation on blood pressure and cardiovascular function of Sprague-Dawley normotensive and mineralocorticoid-salt (DOCA-salt) hypertensive rats. The rats were pair-fed for 5 wk a purified diet containing either a normal or magnesium-supplemented diet (1.5 or 10 g/kg diet). Magnesium supplementation significantly lowered blood pressure levels in hypertensive rats, but not in normotensive rats. Heart rate was not affected in either group. The blood pressure-lowering effect of magnesium supplementation in DOCA-salt hypertensive rats was associated with a lower in vivo cardiovascular reactivity to norepinephrine and angiotensin II. Norepinephrine reactivity in isolated aortae from DOCA-salt hypertensive rats was not modified by magnesium supplementation. However, endothelium-dependent relaxation to acetylcholine was improved and could be related to the release of endothelial relaxant factors. Magnesium supplementation did not affect cardiac hemodynamics in isolated heart from either normotensive or DOCA-salt hypertensive rats. Furthermore, no protective effects upon myocardial ischemia and ventricular arrhythmias were demonstrated. These findings suggest that the lowering effect of magnesium supplementation on blood pressure in hypertensive rats may be related to a vascular effect of magnesium that reduces vascular tone. Mechanisms related to the pathophysiological development of mineralocorticoid-salt hypertension may be involved.

The consequences of sleep deprivation on vigilance and mood were evaluated in six healthy medical students the day after being on night duty and the following day, after recovering from a full night's sleep. Diurnal vigilance was studied using the Multiple Sleep Latency Test (MSLT) and mood was assessed on an anxiety self-evaluation scale. The study was conducted by means of a double-blind randomized trial to measure the effects of benzodiazepine (lormetazepam, 2 mg) compared to a placebo administered before the night recovery/full night's sleep. Sleep deprivation induced a significant decrease in vigilance the day following the night duty. Sleep latencies were shortened during the morning following the night of recovery/full night's sleep. The values obtained after administering the lormetazepam did not differ significantly from those obtained after administering the placebo. There were no considerable differences in the anxiety evaluation scores before and after the night of recovery/full night's sleep between the two sequences of the trial. This study suggests that a significant lack of sleep (a 36-hour sleep deficit) modifies diurnal vigilance over two nyctohemeral periods. Administration of benzodiazepine with a short half-life after occasional sleep deprivation does not change the reorganization of the sleep-waking cycle.

There is no univocal clinical cardiovascular pattern associated with magnesium deficiency. Only an acute hypomagnesaemia gives the evidence of a real magnesium deficiency. Arrhythmias corrected by magnesium are associated with potassium deficiency. Magnesium deficiency appears to be one risk factor of arrhythmias and coronary spasms. The influence of intravenous magnesium salts was clearly evaluated on cardiovascular electrophysiology allowing protocols infusion. The major beneficial effect of magnesium on total incidence of arrhythmias appears to have been due to a reduction in supraventricular tachyarrhythmias and especially in "torsade de pointes". Antiarrhythmic mechanisms still remain to be clarified. It is likely that magnesium influences cardiac conduction and refractoriness by affecting calcium dependent processes as if acting as an indirect inactivator of slow inward calcium current, probably secondary to an inward shift of the background potassium mediated current. Recent studies demonstrated beneficial effect of intravenous magnesium treatment in acute myocardial infraction, both as to mortality and to early cardiac insufficiency. Beside antiarrhythmic and vasodilatator effects, magnesium seems to show cardiac cells protective action against ischaemia.

The effects of two concentrations of GaCl3 (1.79 microM and 7.17 microM) were studied on isolated perfused paced rat hearts. All hearts were submitted to an equilibration period of 20 minutes under normal conditions of oxygenation (95% O2, 5% CO2) and with 11 mM glucose in Krebs-Henseleit buffer. At the end of the perfusion (80 min) tissue Ga contents were 98.0 +/- 13.8 and 200.2 +/- 28.5 nM/g of wet weight for the lower and the higher Ga concentrations respectively. Left ventricular developed pressure (LVdp) as well as +LVdp/dt and -LVdp/dt were similar in control and Ga-treated groups during the 60 minutes following the equilibration period. At the same time mean coronary flow and oxygen consumption were lower (p0.05) in hearts perfused with 7.17 microM Ga than in the control group. Lactate production did not differ in the control and Ga-treated groups. Mean creatine kinase release was lower (p0.05) in the 7.17 microM Ga-treated group than in the 1.79 microM Ga-treated and control groups. Intratissular malondialdehyde as well as glycogen and ATP concentrations did not differ in all groups at the end of the experiment. Gallium chloride partially prevented the unavoidable oedema resulting from using saline Krebs-Henseleit solution. In conclusion, acute GaCl3 administration improves the functionality of the Langendorff-heart model.

Bupivacaine, but not lidocaine, may cause severe cardiac dysrrhythmias in case of accidental intravascular injection. In an attempt to discriminate between a pharmacokinetic and a pharmacodynamic (or both) origin to these differences, we used an isolated rabbit heart model with constant coronary inflow to compare the myocardial uptake and disposition kinetics of lidocaine and bupivacaine. Drug concentration in the outflow perfusate was assayed and surface electrocardiogram was recorded. Drug uptake and disposition kinetics were modeled with a two-compartment open model. An Emax model was used to describe the increase in QRS duration in relation with drug concentration in the central compartment. Lidocaine and bupivacaine exhibited similar myocardial pharmacokinetics (i.e., a rapid decrease in the outflow concentration upon drug administration discontinuation). Bupivacaine-induced maximum increase in QRS duration (Emax) was 15 times superior to lidocaine Emax. The steady-state perfusate concentration producing half Emax was the same for both drugs. We conclude that bupivacaine-induced QRS widening decreases almost at the same rate as does lidocaine-induced QRS widening when drug administration is terminated. Therefore, the different cardiac effects of lidocaine and bupivacaine are not due to differences in myocardial uptake and disposition kinetics.

The isovolumic perfused rat heart model according to Langendorff has been used in order to characterize the changes occurring in the heart following 5-Fluorouracil (5-FU) administration. Preliminary published data pointed out that perfusion of isolated heart with 1 mg/l 5-FU failed to show any differences in contractility and oxygen consumption in comparison with the control group. However, when Wistar rats received 5-FU once a day (50 mg/kg, I.P.) for five consecutive days a consistent increase in oxygen consumption throughout the 80 min of perfusion associated with a decrease in the fractional extraction of oxygen and a lowered + dP/dt max were observed, without any drug added during the in vitro perfusion. Further investigation has been performed for a better understanding of the results observed after 5-FU pretreatment. Magnesium, potassium, calcium, copper and iron contents in the myocardium (at 0 min of perfusion) were measured by flame atomic absorption spectrophotometry. Iron levels were 20% higher in the 5-FU pretreated group than in the control group, whereas as no differences were observed for the other elemental concentrations. Both initial glycogen and ATP contents were respectively 42% and 29% higher in the pretreated than in the control group and alpha-hydroxybutyrate dehydrogenase release was lower after 40 min of perfusion in the pretreated group. However, 5-FU pretreatment increased net tissue water gain after 80 min of perfusion. Increases in mean oxygen partial pressure in the myocardium and in oxygen consumption associated with increased iron level might be candidates responsible for 5-FU induced cardiotoxicity through an increased in oxygen derived free radicals. Sympathetic over-stimulation or calcium overload do not appear to be involved in 5-FU induced cardiotoxicity.

In order to estimate the preoperative evaluation of the respiratory risk, a well adapted clinical examination associated with a routine pulmonary function test (VC, FEV1) can be sufficient. Although some patients with cardiopulmonary disorders or candidates to lung resection need more complex assessments: the flow-volume loop to detect small airways obstruction (MEF 50%, MEF 25%), measure of bronchial hyperreactivity to predict bronchospasm during anaesthesia, residual volume for the diagnosis of emphysema, diffusing capacity (DCO) to discover lung fibrosis: these parameters disruption always make the pronostic worse. It is also useful to couple together preoperative function test and pulmonary scintigraphy to predict post-operative values after lung resection. But, these criteria for operability are not always a good indicator of post-operative complications. So it is possible to use in addition the results of exercise testing to determine cardio-respiratory performances and maximal oxygen consumption (VO2MAX) which seem better correlated with mortality and post-operative lung surgical complications. Preliminary results of our study concerning thirty patients hospitalized in Besancon-St-Jacques Hospital, agree with the hypothesis that exercise testing is an important criterion in the pre-operative evaluation and to predict post-operative mortality and morbidity of patients candidates to thoracic surgery.

This study was designed to assess in vitro the effects of Thiopental alone and Thiopental--Dobutamine association on control and on Diltiazem pretreated papillary muscle. The Diltiazem treatment do not increase the negative inotropic effect of Thiopental but the effect of Dobutamine is less important in pretreated group. The Diltiazem treatment protect to arrhythmogenic action of Thiopental and Thiopental-Dobutamine association.

The purpose of the study was to compare the cardiovascular, respiratory and metabolic responses to exercise of highly endurance trained subjects after 3 different nights i.e. a baseline night, a partial sleep deprivation of 3 h in the middle of the night and a 0.25-mg triazolam-induced sleep. Sleep-waking chronobiology and endurance performance capacity were taken into account in the choice of the subjects. Seven subjects exercised on a cycle ergometer for a 10-min warmup, then for 20 min at a steady exercise intensity (equal to the intensity corresponding to 75% of the predetermined maximal oxygen consumption) followed by an increased intensity until exhaustion. The night with 3 h sleep loss was accompanied by a greater number of periods of wakefulness (P

The influence of 5 days' triiodothyronine (T3) administration (0,1 mg/kg/day) on myocardial uptake kinetics and electrocardiographic effects of amiodarone (4,7 10(-6)M) were examined in isolated perfused rabbit hearts. Pharmacokinetic parameters were determined by plotting the coronary sinus effluent amiodarone concentration time-data. Electrocardiographic effects were measured as percentage changes in PR, QRS and QT electrocardiogram intervals measured in hearts removed from T3 pretreated rabbits. The perfusion of normal rabbit hearts with a modified Krebs Henseleit buffer containing amiodarone prolonged PR, QRS and QT intervals by 74%, 76% and 14% respectively, while in T3 pretreated rabbit hearts, amiodarone induced a prolongation of 84% PR, 27% QRS and 9% QT. Myocardial amiodarone accumulation normalized for heart weight represented myocardial concentrations of 260.6 +/- 20.9 micrograms/g and 235.6 +/- 11.9 micrograms/g of tissue respectively in the normal and T3 pretreated groups after a 60 min perfusion. The relationship between myocardial amiodarone concentration and electrocardiographic effects on PR and QRS were linear in both groups. The data demonstrate that the thyroïd hormone T3 did not change the kinetics of the myocardial uptake of amiodarone, but that it did change the electrocardiographic effects. Although T3 potentialized the amiodarone effect on PR, it reduced its effect on intraventricular conduction and ventricular repolarisation.

The pharmacokinetic properties of propofol given at a constant rate, were studied in 10 children. Propofol was administered at a dose according to I.C.I. Pharma advices. For minor surgery, a low quality of general anesthesia was observed in correlation with low plasma levels of propofol. An increase in dosage would be necessary in children above 8 years old.

Pharmacokinetic study of 458 L. via oral route, was performed in twelve normal volunteers, in a randomized crossover design of three galenic forms. Plasma concentrations were determined, after extraction, by HPLC, with spectrofluorimetric detection. Plasmatic kinetics were fitted to a bi-exponential function with a distribution half-life of 1h and an elimination half-life of 11.5 to 14.7 h according to the form. Pharmacokinetic parameters evaluated as area under the curve (AUC), maximum plasma concentrations (Cmax), relative bioavailability (F'), have shown strong interindividual differences, specially in women group, and this with tobacco smoking.

Immersion is considered to facilitate exercise-based rehabilitation. However, the drag effect of moving limbs in water, likely to increase the respiratory requirements at exercise, is not mentioned in many reports. The energetic and ventilatory requirements of 30 min steady state cycling exercise performed by healthy male subjects in air and during immersion up to the xiphoid in 33 degrees C water were compared. In the first experimental series nine subjects exercised at the same 60% maximal oxygen consumption (V'O2,max) in air and water. In the two ambient conditions, ventilatory variables had similar values, but the ergometric setting had to be reduced during water immersion so that the workload rated only 69+/-20 W (mean+/-SD) in water versus 121+/-32 W (p

The ‘in vitro’ dissolution kinetics of two suppository formulations containing indomethacin were compared and a correlation with the ‘in vitro’ kinetics was established. The device used ‘in vitro’ was a special through flow cell. A mean dissolution curve was obtained for each dosage form, one containing a hydrophilic excipient (PEG), the other, a fatty base. A relative bioavailability study was then carried out on 12 healthy volunteers. Thus, from the pharmacokinetic parameters obtained, the simulation of plasma concentration values was made possible from the amounts of drug released and dissolved during the dissolution test. With the simulation programme used it was possible to predict the plasma level values and the results showed a good superimposition of the experimental plasma concentration curve validating the ‘in vitro’ study method of drug release from suppositories.