Pharmacocinétique du mycophenolate mofetil en transplantation (revue de la littérature et analyse non compartimentale des données obtenues chez 27 patients, à 3 semaines et / ou 3 mois après transplantation hépatique)

RENNES1-BU Santé (352382103) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Certification ISO 9001 d’un système de management qualité dans un centre d’investigation clinique [ISO 9001certification of a quality management system in a clinical investigation center]

International audienceBeyond the application of legal requirements, clinical trials must have a permanent approach of quality control. The clinical investigation centers (CICs) are academic structures of clinical research certified by the French National institute of health and medical research (Inserm) and whose functioning relies on recommendations of good practice. It is important to accompany this standardization of practices by the implementation of a quality management system. This article presents the process that enabled the CIC of Rennes to become certified ISO 9001 by French standards association (Afnor) certification in May, 2016. The application of the fundamental principles of the standard ISO 9001 in the domain of clinical research is approached. The problem of the perimeter for the certification and the related process mapping are exposed. The activities of methodology, management and analysis of clinical studies were chosen for the initial certification of the CIC of Rennes. The perspectives for the extension of the perimeter of certification are also approached at the end of article

Melatonin: Pharmacology, Functions and Therapeutic Benefits

International audienceBackground: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. Methods: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. Results: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. Conclusion: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects

Cardiac MRI studies of transient left ventricular apical ballooning syndrome (takotsubo cardiomyopathy): a systematic review.

International audienceBACKGROUND: Since its first description in 1991, many cases of transient left ventricular apical ballooning syndrome (TLVABS) have been described, but the use of cardiac MRI in this condition is much more recent. METHODS AND RESULTS: We performed a systematic review of the present literature in the MEDLINE and EMBASE databases for relevant case series of TLVABS (>or=5 reported original cases, MRI analysis in the acute phase) and summarized the main results in a narrative synthesis. Only 8 studies met the eligible criteria, counting 176 patients (women: 95%; age: 68, stress trigger: 80%). MRI assessed an improvement of mean left ventricular ejection fraction from 39 (in the acute phase) to 64% (in the recovery phase). A right ventricular dysfunction was reported in 38%, a myocardial oedema in 81% and an apical thrombus in 5%. CONCLUSIONS: Although cardiac MRI is a very useful and inescapable tool in the management of TLVABS, there is no large published study concerning this topic. A systematic and multicentric register of TLVABS studied by cardiac MRI is necessary

Diagnostic contributions of cardiac magnetic resonance imaging in patients presenting with elevated troponin, acute chest pain syndrome and unobstructed coronary arteries.

International audienceAIMS: Myocardial infarction with unobstructed coronary artery disease represents a serious diagnostic challenge. The role of cardiac magnetic resonance in the management of cardiomyopathies is increasing. We examined the diagnostic contributions of cardiac magnetic resonance in patients presenting with acute chest pain syndrome, elevated serum cardiac troponin concentrations and no significant coronary artery stenoses. METHODS: Over a 3-year period, 107 consecutive patients (mean age 43.5 years; 62% men) presented to our institution with acute onset of chest pain, elevated serum troponin concentration and unobstructed coronary arteries, and underwent 3-tesla cardiac magnetic resonance at a mean delay of 6.9 days. A diagnosis was made based on: wall motion abnormalities and pericardial effusion on cine mode; myocardial oedema on T2-weighted imaging; abnormalities on first-pass perfusion imaging; and late gadolinium enhancement on T1-weighted imaging. RESULTS: Cardiac magnetic resonance was normal in 10.3% of patients and contributed a diagnosis in 89.7%, including myocarditis in 59.9%, stress cardiomyopathy (takotsubo syndrome) in 14% and myocardial infarction in 15.8%. Patients with normal cardiac magnetic resonance had a significantly lower mean peak troponin concentration (2.6ng/mL) than patients with diagnostic cardiac magnetic resonance (9.7ng/mL; P=0.01). CONCLUSION: Cardiac magnetic resonance contributed a diagnosis in nearly 90% of patients presenting with acute chest pain, elevated serum troponin and unobstructed coronary arteries

Impact of a targeted monitoring on data-quality and data-management workload of randomized controlled trials a prospective comparative study

International audienceAims: Monitoring risk‐based approaches in clinical trials are encouraged by regulatory guidance. However, the impact of a targeted source data verification (SDV) on data‐management (DM) workload and on final data quality needs to be addressed.Methods: MONITORING was a prospective study aiming at comparing full SDV (100% of data verified for all patients) and targeted SDV (only key data verified for all patients) followed by the same DM program (detecting missing data and checking consistency) on final data quality, global workload and staffing costs.Results: In all, 137,008 data including 18,124 key data were collected for 126 patients from six clinical trials. Compared to the final database obtained using the full SDV monitoring process, the final database obtained using the targeted SDV monitoring process had a residual error rate of 1.47% [95% confidence interval, 1.41% to 1.53%] on overall data and 0.78% [95% confidence interval, 0.65% to 0.91%] on key data. There were nearly four times more queries per study with targeted SDV than with full SDV (mean±SD: 132±101 vs 34±26; p=0.03). For a handling time of 15 min per query, the global workload of the targeted SDV monitoring strategy remained below that of the full SDV monitoring strategy. From 25 minutes per query, it was above increasing progressively to represent a 50% increase for 45 minutes per query.Conclusion: Targeted SDV monitoring is accompanied by increased workload for DM, which allows to obtain a small proportion of remaining errors on key data (<1%), but may substantially increase trial costs

Argument for a Doppler echocardiography during exercise in assessing asymptomatic patients with severe aortic stenosis.

International audienceAims : Exercise stress testing (EST) is recommended by guidelines to risk-stratify patients with asymptomatic valvular aortic stenosis (AS), though the role of quantitative exercise-Doppler echocardiography has rarely been studied. This prospective study sought to correlate standard EST results with the haemodynamic measurements made during exercise by Doppler echocardiography. Methods and results : We performed rest and semi-supine exercise Doppler echocardiography in 44 consecutive patients (mean age = 68 ± 12 years) with aortic valve areas ≤0.6 cm2/m2. The effective aortic valve area (EOA), cardiac output (CO), maximal transvalvular velocity, and pulmonary pressure were monitored over the test. No serious adverse event was observed. EST was positive in 26 (Group 1) and negative in 18 (Group 2) patients. Baseline echocardiographic measurements were similar (EOA 0.77 ± 0.15 vs. 0.78 ± 0.14 cm2; CO 5.5 ± 1.6 vs. 5.9 ± 2 L/min) in both groups. Exercise-induced changes in CO (+2.9 ± 2 vs. +4.3 ± 1.8 L/min, P = 0.04) and EOA (−0.04 ± 0.18 vs. +0.15 ± 0.24 cm2, P = 0.015) were significantly greater in Group 2. A correlation between changes in EOA and changes in CO during exercise was observed, but significantly higher in Group 2 (P = 0.04). Conclusion : In the presence of severe asymptomatic AS, exercise Doppler echocardiography, assessing the mechanisms behind a positive EST, appears very promising but further studies with prognosis assessment remain necessary

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder

International audienceThe role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin’s effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments

Advances in the research of melatonin in autism spectrum disorders: literature review and new perspectives.

International audienceAbnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests