Alpha1-glycoproteine acide et lipoproteines plasmatiques : leur role dans le transport et la distribution des medicaments dans l'organisme

SIGLECNRS T 67289 MIC / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria

International audienc

Fine Particulate Pollution and Asthma Exacerbations

International audienceObjective : as the results from epidemiological studies about the impact of outdoor air pollution on asthma in children are heterogeneous, our objective was to investigate the association between asthma exacerbation in children and exposure to air pollutants.Methods : a database of 1 264 585 paediatric visits during the 2010–2015 period to the emergency rooms from 20 emergency departments (EDs) of ‘Assistance Publique Hôpitaux de Paris (APHP)’, the largest hospital group in Europe, was used. A total of 47 107 visits were classified as asthma exacerbations. Concentration of air pollutants (nitrogen dioxide, ozone, fine particulate matter (PM) with an aerodynamic diameter smaller than 10  µm (PM10) and 2.5 µm (PM2.5)), as well as meteorological data, evolution of respiratory syncytial virus infection and pollen exposition, were collected on an hourly or daily basis for the same period using institutional databases. To assess the association between air pollution and asthma, mixed-effects quasi-Poisson regression modelling was performed.Results : the only compound independently associated with ED visits for asthma was PM2.5 (P<10−4). The association between asthma exacerbation and PM2.5 was not linear and a sigmoid function described the relationshipsatisfactorily. PM2.5 concentration which gives half the maximum effect was estimated at 13.5 µg/m3.Conclusions : we found an association between daily asthma exacerbation in paediatric visits to the ED and fine particulate air pollutants

Population pharmacokinetics and pharmacodynamics of cysteamine in nephropathic cystinosis patients

<p>Abstract</p> <p>Background</p> <p>Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of cystine trough the lysosomal membrane causing an accumulation of free cystine in lysosomes. The only specific treatment for nephropathic cystinosis is cysteamine bitartrate. This study was aimed to describe the relationship between cysteamine plasma concentrations and white blood cell cystine levels, and to simulate an optimized administration scheme to improve the management of patients with cystinosis.</p> <p>Methods</p> <p>Cysteamine and cystine concentrations were measured in 69 nephropathic cystinosis patients. A total of 250 cysteamine plasma concentrations and 243 intracellular cystine concentrations were used to perform a population pharmacokinetic and pharmacodynamic analysis. An optimized administration scheme was simulated in order to maintain cystine levels below 1 nmol half-cystine/mg of protein and to investigate the possibility of administrating the treatment less than 4 times a day (QID, recommended). The current dosing recommendations are 1.3 g/m²/day for less than 50 kg BW and 2 g/day thereafter; the maximum dose should not exceed 1.95 g/m²/day.</p> <p>Results</p> <p>Cysteamine concentrations were satisfactorily described by a one-compartment model. Parameter estimates were standardized for a mean standard bodyweight using an allometric model. WBC cystine levels were adequately described by an indirect response model where the first-order removal rate constant is stimulated by the cysteamine concentrations.</p> <p>Conclusions</p> <p>According to simulations, in order to increase the percentage of patient with cystine levels below 1 nmol half-cystine/mg of protein, the current dosages could be changed as follows: 80 mg/kg/day (QID) from 10 to 17 kg, 70 mg/kg/day (QID) from 17 to 25 kg, 60 mg/kg/day (QID) from 25 to 40 kg and 50 mg/kg/day (QID) from 40 to 70 kg (these dosages remain under the maximum recommended dose). However an 8-hourly daily treatment (TID) did not provide acceptable cystine levels and should not be proposed.</p

Effectiveness of heart rate control on hemodynamics in critically ill patients with atrial tachyarrhythmias managed by amiodarone

International audienceAtrial tachyarrhythmias (AT) are common in intensive care unit (ICU) patients and might contribute to hemodynamic instability if heart rate (HR) is persistently too rapid. We aimed to assess if HR control below 115 or 130 bpm with amiodarone improves hemodynamics in ICU patients with AT.This observational study included 73 ICU patients with disabling AT receiving amiodarone for HR control. A total of 525 changes (mainly within 4–8 h) in mean arterial pressure (MAP) and 167 changes in plasma lactate in response to HR variations above 115 or 130 bpm were analyzed. Epinephrine, sedative drugs, fluid loading, use of diuretics, continuous renal replacement therapy and amiodarone dosing were among covariables assessed.Univariable analysis showed that HR variations above 115 bpm were poorly correlated to change in MAP (r = 0.11, p < 0.01). Multivariable analysis showed that changes in MAP were still positively associated to HR variation (p < 0.05) and to initiation or termination of epinephrine (p < 0.05) or sedatives infusions (p < 0.05). Changes in plasma lactate did not correlate to HR variations above 115 bpm. When considering 130 bpm as a threshold, HR variations were not associated to changes in MAP or to changes in plasma lactate. Amiodarone dose was associated to HR decrease but not to MAP or plasma lactate increase

Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in renal transplant recipients on a new once-daily formulation.

International audienceBACKGROUND AND OBJECTIVES: Advagraf is a new extended-release once-daily formulation of tacrolimus, a potent immunosuppressant widely used in renal transplantation. The aims of his study were (i) to develop a population pharmacokinetic model for once-daily tacrolimus in adult renal transplant patients; and (ii) to develop a Bayesian estimator able to reliably estimate individual pharmacokinetic parameters and exposure indices. METHODS: Full pharmacokinetic profiles obtained from 41 adult renal transplant patients who had been switched from ciclosporin to a single daily dose of the new once-daily tacrolimus formulation for more than 6 months were analysed. Tacrolimus concentrations were measured using validated turbulent flow chromatography-tandem mass spectrometry methods. Population parameters were computed using nonlinear mixed-effect modelling software (NONMEM Version VI). The patients were randomly divided into (i) a model-building test group (n = 29); and (ii) a validation group (n = 12). Population pharmacokinetic analysis was performed to estimate the effects on tacrolimus pharmacokinetics of demographic characteristics (sex, bodyweight, age), drug interaction with prednisolone, laboratory test results (the haematocrit, haemaglobin level and serum creatinine level) and cytochrome P450 (CYP) 3A5 (CYP3A5) genetic polymorphism. The population pharmacokinetic model was further refined by taking into account all of the data from the 41 patients, and the final model was validated using a bootstrap and a visual predictive check. For Bayesian estimation, the best limited-sampling strategy was determined on the basis of the D-optimality criterion and validation performed in the validation group. RESULTS: The trapezoidal area under the whole-blood concentration time curve from 0 to 24 hours (AUC(24)) of tacrolimus varied by up to 50% for the same trough concentration value. The pharmacokinetics of once-daily tacrolimus were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase. The CYP3A5 genotype was the only covariate retained in the final model. The apparent clearance of tacrolimus was 2-fold higher in expressers (with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes) than in non-expressers (with the CYP3A5*3/*3 genotype). This factor explained around 25% of the interindividual variability in the apparent clearance. A posteriori Bayesian estimation allowed accurate prediction of the AUC(24) of once-daily tacrolimus, using just three sampling times (0, 1 and 3 hours post-dose) with a nonsignificant mean bias of 0.7% (range 16-20%) and good precision (root mean square error 9%). CONCLUSIONS: Population pharmacokinetic analysis of once-daily tacrolimus in renal transplant recipients resulted in identification of the CYP3A5*1/*3 genotype as a significant covariate on the apparent clearance of tacrolimus, and the design of an accurate maximum a posteriori Bayesian estimator based on three blood concentration measurements and this covariate. Such a tool could be helpful for comparing different exposure indices or different target levels. It could contribute to improvement of the efficacy and tolerability of once-daily tacrolimus in some patients