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Saint-Sauveur-en-Rue, France

De Winter B.C.M.,Limoges University Hospital Center | Monchaud C.,Limoges University Hospital Center | Premaud A.,Limoges University Hospital Center | Pison C.,Joseph Fourier University | And 9 more authors.
Clinical Pharmacokinetics | Year: 2012

Background and Objectives: The immunosuppressive drug mycophenolate mofetil is used to prevent rejection after organ transplantation. In kidney transplant recipients, it has been demonstrated that adjustment of the mycophenolate mofetil dose on the basis of the area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil, improves the clinical outcome. Because of the high risks of rejections and infections in lung transplant recipients, therapeutic drugmonitoring of theMPA AUC might be even more useful in these patients. The aims of this study were to characterize the pharmacokinetics of MPA in lung and kidney transplant recipients, describe the differences between the two populations and develop a Bayesian estimator of the MPA AUC in lung transplant recipients. Methods: In total, 460 MPA concentration-time profiles from 41 lung transplant recipients and 116 kidney transplant recipients were included. Nonlinear mixed-effects modelling was used to develop a population pharmacokinetic model. Patients were divided into an index dataset and a validation dataset. The pharmacokinetic model derived from the index dataset was used to develop a Bayesian estimator, which was validated using the 35 lung transplant recipients' profiles from the validation dataset. Results: MPA pharmacokinetics were described using a two-compartment model with lag time, first-order absorption and first-order elimination. The influence of ciclosporin co-treatment and the changes over time post-transplantation were included in the model. Lung transplant recipients had, on average, a 53% slower absorption rate and 50% faster MPA apparent oral clearance than kidney transplant recipients (p < 0.001). In lung transplant recipients, the bioavailability was, on average, 31% lower in patients with cystic fibrosis than in patients without cystic fibrosis (p < 0.001). The Bayesian estimator developed using the population pharmacokinetic model-and taking into account ciclosporin co-treatment, cystic fibrosis and time posttransplantation, with concentrations measured at 0, 1 and 4 hours after mycophenolate mofetil dose administration-resulted in a non-significant bias and mean imprecision of 5.8 mg•h/L. This higher imprecision compared with those of similar estimators that have previously been developed in kidney transplantation might have been caused by the high MPA pharmacokinetic variability seen in the lung transplant recipients and by the fact that a large proportion of the patients did not receive ciclosporin, which reduces variability in the elimination phase of MPA by blocking its enterohepatic cycling. Conclusion: Lung transplant recipients have a slower MPA absorption rate and faster apparent oral clearance than kidney transplant recipients, while cystic fibrosis results in lower MPA bioavailability. A Bayesian estimator using MPA concentration-time samples at 0, 1 and 4 hours post-dose had the best predictive performance.

Abid M.,Service de chirurgie generale | Ben Amar M.,Service de chirurgie generale | Abdenadher M.,Service de Chirurgie Cardiovasculaire | Haj Kacem A.,Service de chirurgie generale | And 2 more authors.
Revue des Maladies Respiratoires | Year: 2010

Isolated thoracic parietal involvement is a very rare form of tuberculosis and multifocal localization is exceptional. It often poses a diagnostic problem with parietal tumours requiring recourse to surgical biopsy. We report a case of tuberculous abscess localized to the anterior and superior part of the chest wall with a second abdominal localization but without any pulmonary involvement. The patient was a woman of 56 years presenting with a one-year history of a swelling to the right of the sternum accompanied after several months by a second swelling to the right side of the abdomen. The radiological and biological investigations revealed a parietal tumour in two separate areas. The diagnosis was confirmed by histological examination of a surgical biopsy and bacteriological examination of a percutaneous aspirate of the collection. Standard anti-tuberculosis treatment was given for nine months with good clinical and radiological resolution. In this case report, we study the anatomical and clinical features of this condition and discuss the diagnostic difficulties. © 2009 Published by Elsevier Masson SAS on behalf of SPLF.

Khattabi W.E.,Service de pneumologie | Afif H.,Service de pneumologie | Berrada Z.,Service de pneumologie | Rhissassi J.,Service de Chirurgie Cardiovasculaire | And 2 more authors.
Revue des Maladies Respiratoires | Year: 2011

Multiple thoracic hydatid disease is rare. Cardiovascular localisation is exceptional. Clinical, radiological and even electrocardiographic signs are not specific. The diagnosis is often difficult. We report a case of multiple pulmonary hydatid disease associated to a hydatid cyst of the infundibulum of the pulmonary artery. This is presented in a young man, aged 21years, in good physical health, with recurrent minimal haemoptysis dating back two years ago. The authors emphasise, throughout this case history, the difficulties of diagnosis and treatment of multiple hydatid cysts especially with cardiovascular localisation. © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Riachy M.,Service de Pneumologie et de Reanimation Medicale | Juvelikian G.,Service de pneumologie | Sleilaty G.,Service de Chirurgie Cardiovasculaire | Bazarbachi T.,Service de Pneumologie et de Reanimation Medicale | And 2 more authors.
Revue des Maladies Respiratoires | Year: 2012

Objectives. - The Epworth Sleepiness Scale (ESS) is a self-completion questionnaire developed in the English language and used for the evaluation of sleepiness. The objective of this study was to develop an Arabic version of ESS (AESS) and to investigate its reliability and the validity. Methods. - The AESS was created according to the recommendations of the ISPOR Task Force for Translation and Cultural Adaptation with bilingual individuals. It was applied to 91 patients referred to three sleep Lebanese centers for suspicion of sleep-related breathing diseases, and to 166 controls in good health. AESS scores of 60 patients were compared to 60 matched controls according to their age, sex and body mass index. Reproducibility was tested in 30 controls. The treatment response was tested among 15 patients after one month of CPAP treatment. Results. - Principal component analysis showed convergence towards only one latent factor. The AESS had a good internal consistency (Cronbach's alpha 0.76, intraclass correlation coefficient of 0.85 (IC95%: 0.76-0.92), Spearman 0.97, P < 0.001). An increase in the severity of sleep apnea was accompanied by an increase in the score on the AESS (P < 0.001). AESS scores improved significantly after CPAP. Conclusion. - The AESS, a reliable and valid instrument for the evaluation of daytime sleepiness, is a valuable tool for clinical practice and multicenter research. © 2012 SPLF.

Monchaud C.,Limoges University Hospital Center | De Winter B.C.,Limoges University Hospital Center | Knoop C.,Free University of Colombia | Estenne M.,Free University of Colombia | And 7 more authors.
Clinical Pharmacokinetics | Year: 2012

Background: Therapeutic drug monitoring of tacrolimus is a major support to patient management and could help improve the outcome of lung transplant recipients, by minimizing the risk of rejections and infections. However, despite the wide use of tacrolimus as part of maintenance immunosuppressive regimens after lung transplantation, little is known about its pharmacokinetics in this population. Better knowledge of the pharmacokinetics of tacrolimus in lung transplant recipients, and the development of tools dedicated to its therapeutic drug monitoring, could thus help improve their outcome. Objectives: The aims of this study were (i) to characterize the population pharmacokinetics of tacrolimus in lung transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator of the tacrolimus area under the blood concentration-time curve from time zero to 12 hours (AUC12) for its therapeutic drug monitoring in lung transplant recipients. Methods: A population pharmacokinetic model was developed by nonlinear mixed-effects modelling using NONMEM® version VI, from 182 tacrolimus full concentration-time profiles collected in 78 lung transplant recipients within the first year post-transplantation. Patient genotypes for the cytochrome P450 3A5 (CYP3A5) A6986G single nucleotide polymorphism (SNP) were characterized by TaqMan allelic discrimination. Patients were divided into an index dataset (n = 125 profiles) and a validation dataset (n = 57 profiles). A Bayesian estimator was derived from the final model using the index dataset, in order to determine the tacrolimus AUC 12 on the basis of a limited number of samples. The predictive performance of the Bayesian estimator was evaluated in the validation dataset by comparing the estimated AUC 12 with the trapezoidal AUC 12. Results: Tacrolimus pharmacokinetics were described using a two-compartment model with Erlang absorption and first-order elimination. The model included cystic fibrosis (CF) and CYP3A5 polymorphism as covariates. The relative bioavailability in patients with CF was approximately 60% of the relative bioavailability observed in patients without CF, and the transfer rate constant between the transit compartments was 2-fold smaller in patients with CF than in those without CF (3.32 vs 7.06 h -1). The apparent clearance was 40% faster in CYP3A5 expressers than in non-expressers (24.5 vs 17.5L/h). Good predictive performance was obtained with the Bayesian estimator developed using the final model and concentrations measured at 40 minutes and at 2 and 4 hours post-dose, as shown by the mean bias (1.1%, 95% CI-1.4, 3.7) and imprecision (9.8%) between the estimated and the trapezoidal AUC 12. The bias was >20% in 1.8% of patients. Conclusion: Population pharmacokinetic analysis showed that lung transplant patients with CF displayed lower bioavailability and a smaller transfer rate constant between transit compartments than those without CF, while the apparent clearance was faster in CYP3A5 expressers than in non-expressers. The Bayesian estimator developed in this study provides an accurate prediction of tacrolimus exposure in lung transplant patients, with and without CF, throughout the first year post-transplantation. This tool may allow routine tacrolimus dose individualization and may be used to conduct clinical trials on therapeutic drug monitoring of tacrolimus after lung transplantation. © 2012 Adis Data Information BV. All rights reserved.

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