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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.

PubMed | Service de chirurgie cardiovasculaire and Service de chirurgie thoracique
Type: Case Reports | Journal: Revue de pneumologie clinique | Year: 2014

Surgical resection is a validated therapeutic option for selected cases of pulmonary tumors invading the important mediastinal structures (caval vein, atrium, aorta or supra-aortic trunks). Here, we present a patient with a necrosed pulmonary tumor invading the left atrium, causing cardiac insufficiency. A complete surgical resection under extracorporeal circulation was performed by the thoracic and cardiac teams. Admitted in a bed-ridden state, the patient was discharged completely rehabilitated on postoperative day 13. He survived 1 year at home with a good quality of life.

PubMed | Service de Chirurgie Cardiovasculaire and Reanimation de Chirurgie Cardiovasculaire
Type: | Journal: The Pan African medical journal | Year: 2016

Subaortic diaphragm is characterized by a certain clinical latency and low morbi-mortality. Surgery remains the treatment of choice despite the real risk of long-term recurrence. Our study involved 18 patients with subaortic diaphragm operated between April 1994 and March 2011. The average age was 18.1 9.7 years, 11 patients were male. The diaphragm was fibrous in 13 patients and fibromuscular in 5 patients. All patients underwent diaphragm resection associated with myectomy, aortic plasty, closure of ventricular septal defect and permeable ductus arteriosus ligation in 3, 3, 2 and 2 patients respectively. Operative mortality was zero and there were no cases of postoperative conduction disorder. With a median follow-up of 44.336.8 months, there was no late death. Two patients had a diaphragm recurrence which required reoperation with good evolution. The current trend in diaphragm surgery is towards early interventions and more extensive resections. However, the risk of recurrence requires a systematic and close ultrasound monitoring.

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.

PubMed | Service de chirurgie cardiovasculaire, Service de cardiologie and Service danatomie pathologique
Type: Case Reports | Journal: Annales de cardiologie et d'angeiologie | Year: 2014

Hydatid disease is a parasitic infection caused by the development of the larval form of the Teania of Echinococcus granulosus. It is endemic in many regions of the world such as the Mediterranean basin. Location without pericardial cardiac involvement is extremely rare. In this case study, we will elaborate the case of an intra-pericardial hydatidosis disease without cardiac location revealed by a tamponade.AA is a 60-year-old man with no pathological history and who was admitted for a tamponade assessment. Indeed, the cardiovascular examination showed a muffling of the heart sound and signs of a right heart failure. Besides, the ECG shows a microvoltage, and the chest radiography shows cardiomegaly. Moreover, the transthoracic echocardiogram confirmed the presence of an abundant pericardial effusion along with signs of a tamponade. It also reifies the presence of, at the intra-pericardial level, a multiple vesicular formation giving a cluster of grapes highly suggestive of an intra-pericardial hydatid disease. An emergency surgical drainage allowed removing about two liters of suspicious fluid along with cysts and white membranous. The pathological examination of the membranous confirmed the diagnosis of a pericardial hydatid cyst. The performance of a chest CT and an abdominal ultrasounds scan to identify other locations shows no further anomalies. The patient was put under medical treatment (Albendazole()) and is showing a good clinical improvement.The intra-pericardial hydatid disease is another cause of tamponade not to fail despite its rareness, as it is endemic to North African countries.

PubMed | Service de chirurgie cardiovasculaire and Service danesthesie reanimation chirurgie cardiaque
Type: Case Reports | Journal: Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | Year: 2014

Infective endocarditis (IE) is a rare, polymorphic disease in children. Mycotic aneurysm is a rare condition that complicates about 2.5 to 10% of cases of endocarditis. It is responsible for significant morbidity and mortality [1,2]. Mycotic aneurysms are often asymptomatic, physical examination is poor, but the diagnosis should be considered with the triad including fever, abdominal pain, and abdominal mass beating. Abdominal ultrasound and computed tomography are the most useful for the identification of the aneurysmal mass. However, angiography is an interesting addition to confirm the diagnosis and implement a treatment procedure [3]. The treatment of SMA aneurysms is largely surgical. IE treatment is based on antibiotic therapy combined with surgical repair. We report the case of a 15-year-old patient, first operated for an SMA aneurysm complicating the course of IE, who secondarily underwent mitral valve repair. We review the epidemiology, diagnosis, and care principles of mycotic aneurysms of the SMA.

PubMed | Service de Chirurgie Cardiovasculaire and Institut Universitaire de France
Type: | Journal: Frontiers in physiology | Year: 2016

Left ventricle (LV) transmural gradient in mitochondrial respiration has been recently reported. However, to date, the physiological mechanisms involved in the lower endocardium mitochondrial respiration chain capacity still remain to be determined. Since, nitric oxide (NO) synthase expression in the heart has spatial heterogeneity and might impair mitochondrial function, we investigated a potential association between LV transmural NO and mitochondrial function gradient.Maximal oxidative capacity (VMax) and relative contributions of the respiratory chain complexes II, III, IV (VSucc) and IV (VTMPD), mitochondrial content (citrate synthase activity), coupling, NO (electron paramagnetic resonance), and reactive oxygen species (ROS) production (H2O2 and dihydroethidium (DHE) staining) were determined in rat sub-endocardium (Endo) and sub-epicardium (Epi). Further, the effect of a direct NO donor (MAHMA NONOate) on maximal mitochondrial respiratory rates (Vmax) was determined.Mitochondrial respiratory chain activities were reduced in the Endo compared with the Epi (-16.92%; P = 0.04 for Vmax and -18.73%; P = 0.02, for Vsucc, respectively). NO production was two-fold higher in the Endo compared with the Epi (P = 0.002) and interestingly, increasing NO concentration reduced Vmax. Mitochondrial H2O2 and LV ROS productions were significantly increased in Endo compared to Epi, citrate synthase activity and mitochondrial coupling being similar in the two layers.LV mitochondrial respiration transmural gradient is likely related to NO and possibly ROS increased production in the sub-endocardium.

PubMed | Service de Chirurgie Cardiovasculaire, Service de Cardiologie and Institute Of Cardiologie
Type: Case Reports | Journal: Annals of vascular surgery | Year: 2015

Floating thrombus of the ascending aorta is a rare and often ignored cause of peripheral embolic events. We report the observation of a patient presenting recurrent peripheral embolic demonstrations: acute ischemia of the right lower limb complicated of a thigh amputation and transient cerebrovascular accident. The assessment by angioscanner highlighted a 40-mm thrombus of the ascending aorta. The thrombus was removed surgically. This diagnosis should not be ignored in the assessment of an embolic pathology with the risk of severe functional after-effects caused by an important diagnostic delay.

Vola M.,Service de Chirurgie Cardiovasculaire | Albertini A.,Salus Hospital GVM Care and Research | Campisi S.,Service de Chirurgie Cardiovasculaire | Caprili L.,Salus Hospital GVM Care and Research | And 4 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2015

Background A sutureless aortic valve can be inserted through a right anterior minithoracotomy (RAMT) with consistent decreased cross-clamping time and ease of insertion. We report the experience of RAMT implantation of the 3f Enable (Medtronic, Inc, Minneapolis, Minn) self-expanding sutureless bioprosthesis, performed in 2 European cardiac surgery centers. Method From September 2012 to April 2014, a total of 71 patients with severe aortic stenosis were selected to receive an aortic valve replacement via RAMT using the sutureless valve. Hemodynamic parameters and clinical outcome were assessed at discharge and up to 16 months postoperatively. Results All the patients received the prosthesis with success. One conversion to median sternotomy was necessary, owing to severe pleural adhesions. Overall in-hospital mortality was 2.8%. Mean cardiopulmonary bypass and cross-clamping time were, respectively, 91 ± 29 minutes and 66 ± 19 minutes. Reclamping was necessary in 4 cases (5.6%). Early incidences of grade I or lower paravalvular leakages and pacemaker implantation were, respectively, 4.2% and 5.6%. No paravalvular leakage greater than grade I was registered. The mean follow-up time was 8.1 months; the mean transvalvular gradient was, at discharge and at 6-12 months, respectively, 10.7 ± 4.3 mm Hg and 9.6 ± 3.1 mm Hg. The degree of regurgitation remained stable in all cases. Freedom from all-cause and valve-related mortality was 97% and 99%, respectively, at 1 year. Conclusions Aortic valve replacement via RAMT with the 3f Enable valve is a reproducible procedure, as it provides satisfactory hemodynamics, and a low valve-related complication rate. Greater experience is needed to compare the performance of the 3f Enable valve with that of other sutureless valves implanted via the same RAMT procedure. © 2015 The American Association for Thoracic Surgery.

PubMed | Service de chirurgie cardiovasculaire
Type: Journal Article | Journal: Annales de cardiologie et d'angeiologie | Year: 2015

With advances in recent decades in the field of congenital heart disease both for imaging in medical therapy, a large number of heart disease is diagnosed before birth. Many of them benefit from surgery and reach adulthood, they do not require further action. Some of them develop later in their lives other problems requiring reoperation in adulthood. This sparked the birth of a subspecialty within the department of congenital heart disease: GUCH Unit grown up congenital heart disease. In developing countries, little heart are detected in childhood, a minority of them are operated and very few reach adulthood or with minor heart disease or become advanced enough then inoperable. Only part may still take advantage of surgery at this age. The aim of our study is to describe the spectrum and characteristics of congenital heart disease in adulthood in Algiers a center of cardiovascular surgery.A retrospective descriptive study of patients aged 15and above operated for congenital heart defects between 1995and 2011.Five hundred and forty patients aged 15to 76years (2910years), including 314women and 226men are operated congenital heart defects between 1995and 2011. The left-right shunts represent two thirds of heart disease, represented mainly (50%) by the atrial septal defect. Barriers to the ejection of the left heart represent one forth of cases with a predominance of subvalvular aortic stenosis. We find the native heart whose survival is considered exceptional in adulthood in the absence of surgery, such as tetralogy of Fallot, aortopulmonary windows wide, double outlet right ventricle and atrioventricular canal that take advantage of always surgery. The results are encouraging with low perioperative mortality (2%).The approach of congenital heart disease in developing countries is different from that of developed countries. Efforts need to be made in early detection and monitoring of congenital heart disease and improve access to surgery centers in close collaboration with pediatricians, cardiologists and obstetricians.

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