Modifications, pharmacocinetiques dans l'obesite. [Pharmacokinetic changes in obesity]

The obesity-induced kinetic changes have been studied only from twenty years, despite the frequency of such a pathological state; thus many work need to be done in this area. The tissular distribution of drugs may depend on the obesity-induced changes in the body composition taking into account the degree of drug liposolubility. Some other factors such as protein binding and regional blood flow may also be involved in tissular diffusion of drugs in obesity. Drug binding to albumin does not seem to be modified in obesity. On the contrary, the protein binding of some basic drugs is increased because of the rise of the plasma alpha 1 glycoprotein acid levels in obesity. Although the cardiac output and the total blood volume are increased in obese patients, the blood flow recalculated according to the adipose tissue weight, is less than in non obese subjects: this point could reduce the diffusion of some lipophilic drugs. More complex are the obesity induced changes in the hepatic clearance of drugs: some reactions such as oxydo-reduction and acetylation do not vary, some others such as sulfoconjugation or glucuronoconjugation are increased. The renal clearance is increased for drugs totally eliminated by glomerular filtration and for drugs which are both filtrated and secreted. According to the liposolubility characteristic of a drug and its clearance, one can calculate the loading dose and the maintenance dose

[Effects of trimetazidine on altered functions of rat kidney induced by cyclosporine].

International audienceA mitochondrial dysfunction has been suggested to explain chronic renal toxicity observed in ciclosporine A therapy. Our study has investigated whether trimetazidine allows inhibition of mitochondrial alteration induced by ciclosporine A. Oxidative phosphorylation was measured by polarography, calcium fluxes by a specific calcium electrode and the mitochondrial swelling by determination of the optical density at 520 nm, using a spectrophotometer. The ciclosporine A effect on the respiratory control was fully inhibited by trimetazidine (EC50 5.10 x 10(-7) M; Emax 11 per cent). Trimetazidine also inhibited the ciclosporine effects on calcium fluxes, i.e. calcium accumulation into the matrix and delay of efflux. Trimetazidine allows a decrease of mitochondrial dysfunction induced by ciclosporine A

Effects of anxiety on emotional reactivity, performance and vigilance, in healthy volunteers.

Healthy volunteers who participate in clinical trials usually present a specific personality profile characterized by high extroversion and low anxiety traits. Herein, we examined whether anxiety traits influence performance and vigilance, as well as reactivity for six emotions (fear, anger, disgust, sadness, happiness and a neutral state), the latter being induced by the presentation of six film excerpts. Sixty-four healthy volunteers were stratified into high and low anxiety groups on the basis of their score on the Cattell and Hamilton Anxiety Scales. They were assessed on the Digit Symbol Substitution Scale (DSST), Choice Reaction Time (CRT) and Visual Analogue Scales (VAS). Their emotional reactivity was evaluated before and after each film excerpt, on responses to the Differential Emotions Scale (Izard DES). Prior to emotional induction, high-anxious subjects presented a pattern of low positive emotions and high negative emotions. After each film excerpt, emotional reactivity was more pronounced for high-anxious subjects compared with low-anxious subjects. However, there were no significant interactions between anxiety level and the values of DSST, CRT or VAS. The present findings raise the question of the relevance of selecting healthy volunteers according to their personality traits. In future studies, anxiety level will be further investigated as a factor of response variability to drugs, by examining differences in response to psychotropic drugs as a function of this factor

Effects of lorazepam on film-induced differentiated emotions in healthy volunteers.

We studied the effects of lorazepam, a benzodiazepine, on differentiated emotions in healthy volunteers. In order to induce differentiated emotions, film excerpts were selected on the basis of the type of emotion they induced (fear, anger and for affective tone neutral film). For 6 days (D1 to D6), ten healthy volunteers received lorazepam (1 mg bid) or placebo in a randomized cross-over double-blind trial. During each treatment period, emotional induction occurred on D4, D5 and D6. One film excerpt (fear, anger or neutral) was presented each morning after relaxation. Evaluation was performed before and after each emotional induction and included questionnaires (Differential Emotions Scale and physical activation visual analog scales), and neurophysiological parameters (systolic and diastolic blood pressure, heart rate and norepinephrine levels). Globally, the film excerpts induced the predicted emotions. An analysis of variance was undertaken and revealed a significant effect of lorazepam versus placebo. On the Differential Emotions Scale and during fear induction, lorazepam induced a significantly higher increase in fear, anxiety and disgust emotions than placebo, whereas no effect was observed after anger induction. Lorazepam also induced a significantly higher increase in diastolic and systolic blood pressure with no change in heart rate, and physical activation items ("tears" and "faster breathing") without no significant change in norepinephrine. In conclusion, our results are consistent with an overall increase in emotional reactivity with lorazepam (1 mg bid) as compared to placebo. The pertinence of film-induced differentiated emotions has to be confirmed for clinical pharmacological use