Le Kremlin-Bicêtre, France
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Chauvin B.,Hopitaux Universitaires Paris Sud | Drouot S.,Hopitaux Universitaires Paris Sud | Barrail-Tran A.,Hopitaux Universitaires Paris Sud | Barrail-Tran A.,University Paris - Sud | Taburet A.-M.,Hopitaux Universitaires Paris Sud
Clinical Pharmacokinetics | Year: 2013

The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a CYP3A substrate, but less potent drug-drug interactions have been reported with CYP3A inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. © 2013 Springer International Publishing Switzerland.


Young J.,University Paris - Sud | Young J.,Hopitaux Universitaires Paris Sud | Young J.,Institute National Of La Sante
Journal of Clinical Endocrinology and Metabolism | Year: 2012

The term "congenital hypogonadotropic hypogonadism" (CHH) refers to a group of disorders featuring complete or partial pubertal failure due to insufficient secretion of the pituitary gonadotropins LH and FSH. Many boys (or their parents) will seek medical consultation because of partial or absent virilization after 14 yr of age. Small testes are very frequent, but height is generally normal. Laboratory diagnosis of hypogonadotropic hypogonadismis relatively simple, with very low circulating total testosterone and low to low-normal gonadotropin and inhibin B levels. This hormone profile rules out a primary testicular disorder. Before diagnosing CHH, however, it is necessary to rule out a pituitary tumor or pituitary infiltration by imaging studies, juvenile hemochromatosis, and a systemic disorder that, by undermining nutritional status, could affect gonadotropin secretion and pubertal development. Anterior pituitary function must be thoroughly investigated to rule out a more complex endocrine disorder with multiple hormone deficiencies and thus to conclude that the hypogonadotropic hypogonadism is isolated. The most likely differential diagnosis before age 18 yr is constitutional delay of puberty. A part from non-Kallmann syndromic forms, which are often diagnosed during childhood, the two main forms of CHH seen by endocrinologists are Kallmann syndrome, in which CHH is associated with impaired sense of smell, and isolated CHH with normal olfaction. Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry is necessary to determine reliably whether olfaction is normal or partially defective. This step is important be fore embarking on a search for genetic mutations, which will also be useful for genetic counseling. The choice of a particular hormone replacement therapy protocolaimed at virilizing the patient will depend on age at diagnosis and local practices. Copyright © 2012 by The Endocrine Society.


Teboul J.-L.,Hopitaux Universitaires Paris Sud | Teboul J.-L.,University Paris - Sud
Intensive Care Medicine | Year: 2014

Introduction: The concept of weaning-induced cardiac dysfunction emerged 26 years ago with the publication of a clinical study conducted by François Lemaire and collaborators. Objectives: One objective of this article is to remember the results and the historical context under which our pivotal study was conducted. Another objective is to review some of the subsequent studies that aimed to analyze the underlying mechanisms, to noninvasively detect the cardiac origin of weaning failure, and to propose specific therapies enabling weaning success. Conclusion: Weaning-induced cardiac dysfunction has become an established cause of weaning failure. Underlying mechanisms may differ from one patient to another. Important progress has already been made in its diagnosis thanks to relevant clinical research studies. Ongoing and future technological advances in ultrasonography and in biomarker research should certainly help in diagnosing weaning induced-pulmonary edema and in identifying the main mechanisms responsible for its development. Progress on appropriate therapeutic options on an individual basis is still expected. © 2014 Springer-Verlag and ESICM.


Mazoit J.-X.,Hopitaux Universitaires Paris Sud | Mazoit J.-X.,University Paris - Sud
Paediatric Anaesthesia | Year: 2012

Summary Local anesthetics (LA) block propagation of impulses along nerve fibers by inactivation of voltage-gated sodium channels, which initiate action potentials (1). They act on the cytosolic side of phospholipid membranes. Two main chemical compounds are used, amino esters and amino amides. Amino esters are degraded by pseudocholinesterases in plasma. Amino amides are metabolized exclusively by the liver. Only amide LAs will be considered in this article. © 2011 Blackwell Publishing Ltd.


Hamzaoui O.,Hopitaux Universitaires Paris Sud | Monnet X.,Center Hospitalier University Of Bicetre | Monnet X.,University Paris - Sud | Teboul J.-L.,Center Hospitalier University Of Bicetre | Teboul J.-L.,University Paris - Sud
European Respiratory Journal | Year: 2013

Systolic blood pressure normally falls during quiet inspiration in normal individuals. Pulsus paradoxus is defined as a fall of systolic blood pressure of >10 mmHg during the inspiratory phase. Pulsus paradoxus can be observed in cardiac tamponade and in conditions where intrathoracic pressure swings are exaggerated or the right ventricle is distended, such as severe acute asthma or exacerbations of chronic obstructive pulmonary disease. Both the inspiratory decrease in left ventricular stroke volume and the passive transmission to the arterial tree of the inspiratory decrease in intrathoracic pressure contribute to the occurrence of pulsus paradoxus. During cardiac tamponade and acute asthma, biventricular interdependence (series and parallel) plays an important role in the inspiratory decrease in left ventricular stroke volume. Early recognition of pulsus paradoxus in the emergency room can help to diagnose rapidly cardiac tamponade. Measurement of pulsus paradoxus is also useful to assess the severity of acute asthma as well as its response to therapy. Recent development of noninvasive devices capable of automatic calculation and display of arterial pressure variation or derived indices should help improve the assessment of pulsus paradoxus at the bedside. Copyright © ERS 2013.


Benyamina A.,Hopitaux Universitaires Paris Sud | Stover H.,Frankfurt University of Applied Sciences
Heroin Addiction and Related Clinical Problems | Year: 2012

According to the European Quality Audit of Opioid Treatment (EQUATOR) analysis, there is large variation across Europe in the conditions attached to treatment of opioid dependence. Treatment conditions, such as supervised dosing and the need to attend regular appointments, may constitute important barriers to treatment that may impact on successful outcomes for opioid-dependent individuals. Greater flexibility in the provision of treatment and improved education for patients, users and physicians with regards to therapy options may help to improve recruitment and retention of opioid users in treatment, and consequently improve patient outcomes.


Bendimerad P.,Groupe Hospitalier La Rochelle Re Aunis | Blecha L.,Hopitaux Universitaires Paris Sud
Encephale | Year: 2014

Alcohol consumption represents a significant factor for mortality in the world: 6.3% in men and 1.1% in women. Alcohol use disorder is also very common: 5.4% in men, 1.5% in women. Despite its high frequency and the seriousness of this disorder, only 8% of all alcoholdependants are ever treated. Recent meta-analyses have shown that if we can increase current figures by 40%, we could decrease alcohol-related morality rates by 13% in men and 9% in women. Thus, it is important to motivate both physicians and patients to participate in treatment in alcohol use disorder. Recent epidemiological data from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) are currently challenging the notion of alcohol use disorder as a fixed entity. Among a cohort of 4422 subjects initially diagnosed as having alcohol dependency, only 25% of these could still be diagnosed as alcohol-dependant one year later. Among the others, 27% were in partial remission, 12% had risk use, 18% low risk use and 18% were abstinent. Stable remission rates were observed in 30% of these subjects at 5 years. This study also argues in favour of the newer dimensional approach elaborated in the DSM 5. One potentially interesting treatment option is oriented toward reducing alcohol intake. In a study by Rehm and Roerecke (2013), they modelled the impact of reduced consumption in a typical alcoholic patient who drinks 8 glasses of alcohol per day (92 g of pure alcohol). If he decreases his alcohol intake by just one glass per day (12 g of alcohol per day), his one-year mortality risk falls from 180/100,000 to 120/100,000; if he decreases his intake by two glasses per day (24g), this risk falls to 95/100,000, roughly half his baseline risk. These observations have resulted in integrating reduced consumption as an option into the treatment guidelines of several national institutions such as the National Institute for Clinical Excellence (NICE, UK), European Medicines Agency, as well as the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Decreasing stigmatisation of alcohol use disorder through public service announcements, in addition to more flexible physician attitudes concerning personal alcohol intake objectives may be key in getting increased numbers of patients into treatment programmes. In one study in Great Britain, 50% of patients in treatment for alcohol use disorder would prefer an initial objective of reduced consumption. A recent addition to the pharmacotherapy arsenal is nalmefene, which has been recently released as a medication to aid in reducing alcohol consumption. It is a strong μ and δ opioid receptor antagonist and a partial κ opioid receptor agonist. Opioid receptor antagonism is associated with reduced reward in relation to alcohol use, thus helping patients in reducing their consumption. Patients are instructed to take one nalmefene tablet two hours prior to each drinking occasion. Nalmefene therapy is to be accompanied by a specific psychosocial programme called BRENDA. BRENDA consists of a biopsychosocial evaluation, restitution of the evaluation to the patient, an empathetic approach that responds to patient needs, offering direct advice and adjusting goals and treatment programmes as the patient makes progress. Nalmefene has been associated with decreased heavy drinking days in two clinical trials. Overall, the treatment is well tolerated; adverse effects are fairly mild and short-lived. In conclusion, an approach that integrates reduced alcohol consumption makes sense from both a public and personal standpoint. Medications such as nalmefene have shown efficacy in association with a biopsychosocial approach to help patients attain their personal objectives with respect to alcohol use. © L'Encéphale, Paris, 2014.


Martinovic J.,Hopitaux Universitaires Paris Sud
European Journal of Human Genetics | Year: 2015

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.European Journal of Human Genetics advance online publication, 23 September 2015; doi:10.1038/ejhg.2015.192. © 2015 Macmillan Publishers Limited


Burlaud A.,Hopitaux universitaires Paris Sud
NPG Neurologie - Psychiatrie - Geriatrie | Year: 2013

The contribution of functional imaging has made it possible to increase the legitimacy of the practice of hypnosis in many specialties. Since geriatrics require global management of the patient, it would profit from the contributions of this new therapeutic tool. Although studies are more numerous in analgesia therapy, the field of symptoms accessible to hypnosis is vast. Within the framework of neurodegenerative disorders, the practice will have to be adapted according to each patient and would allow an additional accompaniment for caregivers. © 2013 Elsevier Masson SAS.


De Montblanc J.,Hopitaux Universitaires Paris Sud | Ruscio L.,Hopitaux Universitaires Paris Sud | Mazoit J.X.,Hopitaux Universitaires Paris Sud | Benhamou D.,Hopitaux Universitaires Paris Sud
Anaesthesia | Year: 2014

We systematically reviewed 31 adult randomised clinical trials of the i-gel® vs laryngeal mask airway. The mean (95% CI) leak pressure difference and relative risk (95% CI) of insertion on the first attempt were similar: 0.40 (-1.23 to 2.02) cmH2O and 0.98 (0.95-1.01), respectively. The mean (95% CI) insertion time and the relative risk (95% CI) of sore throat were less with the i-gel: by 1.46 (0.33-2.60) s, p = 0.01, and 0.59 (0.38-0.90), p = 0.02, respectively. The relative risk of poor fibreoptic view through the i-gel was 0.29 (0.16-0.54), p < 0.0001. All outcomes displayed substantial heterogeneity, I2 ≥ 75%. Subgroup analyses did not decrease heterogeneity, but suggested that insertion of the i-gel was faster than for first-generation laryngeal mask airways and that the i-gel leak pressure was higher than first generation, but lower than second-generation, laryngeal mask airways. A less frequent sore throat was the main clinical advantage of the i-gel. © 2014 The Association of Anaesthetists of Great Britain and Ireland.

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