Nguyen T.-V.-A.,Pharmacocinetique et Evaluation DuMedicament |
Vu D.H.,University of Groningen |
Nguyen T.-M.-H.,Pharmacocinetique et Evaluation DuMedicament |
Lachaux A.,Service de Pediatrie |
And 2 more authors.
Inflammatory Bowel Diseases | Year: 2013
Background: Metabolite monitoring and response predictors to azathioprine (AZA) in pediatric inflammatory bowel disease (IBD) are debatable. In an attempt to optimize thiopurine therapy and understand the mechanism of action of thiopurines, we correlated metabolites and other factors with AZA efficacy in children with IBD. Methods: Data from 86 children with IBD with 440 metabolite measurements were retrospectively analyzed using multilevel logistic regression analyses. A therapeutic response was defined as a pediatric Crohn's disease activity index ≤10 for Crohn's disease or a pediatric ulcerative colitis activity index ≤10 for ulcerative colitis without any treatment with steroids, antitumor necrosis factor, other immunomodulators, or exclusive enteral nutrition. Results: The 6-thioguanine nucleotide levels .250 pmol per 8 • 108 red blood cells correlated with a higher response (odds ratio, 4.14; 95% confidence interval, 1.4911.46, P = 0.007), whereas 6-methyl-mercaptopurine and 6-methyl-mercaptopurine:6-thioguanine nucleotide ratio showed no correlation. Other novel response predictors in children with IBD were relative leukopenia (odds ratio, 14.01; 95% confidence interval, 3.7752.10; P , 0.001) and the absence of lymphopenia (odds ratio, 3.71; 95% confidence interval, 1.2610.89; P = 0.017). Lower thiopurine methyltransferase activity (P = 0.015), lower platelet count (P = 0.020), and higher aspartate aminotransferase level (P = 0.009) also predicted therapeutic response. Age, gender, patient adherence, the duration of AZA therapy, IBD type, erythrocyte count, and erythrocyte sedimentation rate did not predict efficacy. The high interindividual variability accounting for 57.7% of variance in therapeutic response was observed. Conclusions: The significant 6-thioguanine nucleotide level response relationship may support metabolite monitoring to improve thiopurine efficacy in pediatric IBD. The reported response predictors may be helpful for treatment optimization in AZA-treated children with IBD, but should be proved in prospective studies. © 2013 Crohn's & Colitis Foundation of America, Inc.
Nguyen T.-V.-A.,Pharmacie Clinique |
Vu D.H.,University of Groningen |
Nguyen T.-M.-H.,Pharmacie Clinique |
Lachaux A.,Service de Pediatrie |
And 2 more authors.
Therapeutic Drug Monitoring | Year: 2013
BACKGROUND:: Previous studies have reported no or only a very poor correlation between 6-methylmercaptopurine/6-thioguanine nucleotide (6-MeMPN/6-TGN) and azathioprine (AZA) dose in the treatment of inflammatory bowel disease (IBD). However, metabolite levels are often repeatedly measured yielding a hierarchical data structure that requires more appropriate data analysis. METHODS:: This study explored the relationship between the weight-based dosage of AZA and metabolites levels in 86 pediatric IBD patients using multilevel analysis. Other covariates related to patient characteristics and treatment were evaluated. RESULTS:: This is the first study to demonstrate positive correlations between AZA dose and 6-TGN and 6-MeMPN levels and 6-MeMPN/6-TGN ratio (P < 0.001) in IBD children. Other novel predictors of metabolites were reported. Younger children exhibited lower 6-TGN and 6-MeMPN levels, probably suggesting age-related differences in metabolism and/or absorption of thiopurines. Coadministration of infliximab resulted in a significant increase in 6-TGN levels (P = 0.023). Moreover, alanine aminotransferase values positively correlated with 6-MeMPN levels (P = 0.032). The duration of AZA therapy, gender, and thiopurine methyltransferase activity were associated with metabolite levels. The wide interindividual variability in metabolite levels that accounted for 67.7%, 48.6%, and 49.4% of variance in the 6-TGN and 6-MeMPN levels and the ratio, respectively, were confirmed. CONCLUSIONS:: The reliable AZA dose-metabolites relationship is useful for clinicians to guide the dosing regimen to maximize clinical response and minimize side effects or to consider alternative therapies when patients have preferential production of the toxic 6-MeMPN. These results may be of potential interest for optimizing thiopurine therapy to achieve safe and efficacious AZA use in pediatric IBD patients. Copyright © 2013 by Lippincott Williams & Wilkins.
Tran T.-A.,University Paris - Sud |
Kone-Paut I.,University Paris - Sud |
Marie I.,University Paris - Sud |
Ninet J.,Groupement Hospitalier Edouard Herriot |
And 2 more authors.
Seminars in Arthritis and Rheumatism | Year: 2012
Objectives: Muckle-Wells syndrome (MWS) is a rare autoinflammatory disorder associated with NLRP3 gene mutations, which cause excessive caspase-1 activation and processing of interleukin (IL)-1β and IL-18. Here we investigated whether MWS disease may be associated with impaired fertility in male patients. Methods: Medical records of all male MWS patients with NLRP3 mutations followed in our tertiary center for inherited autoinflammatory diseases were reviewed retrospectively for data indicating fertility problems. Results: Six of 9 patients were unable to have children despite regular sexual activity during at least 2 years; 3 succeeded in having children through in vitro fertilization. Infertility was the main reason for divorce in 1 patient. Spermiogram analyses were available in 8 of the 9 patients. Oligozoospermia was observed in 5 patients and azoospermia in 3 patients. In 2 patients, treatment with IL-1-targeting drugs for 6 and 12 months, respectively, had a moderate or no effect on spermatozoa counts. In 2 patients testosterone levels were low and testosterone treatment significantly increased spermatozoa counts in 1 of them. Conclusions: MWS may be associated with subfertility and infertility in male patients. Consequently, sexual health and fertility should be assessed systematically in adolescent and adult male patients. Additional studies are required to establish the frequency of subfertility in male MWS patients, to understand when subfertility occurs in the disease natural history, and, finally, to investigate whether early management with IL-1-targeting drugs, or testosterone treatment or early sperm cryo-conservation may help to allow procreation. © 2012 Elsevier Inc.
Szkulmowski Z.,Nicolaus Copernicus University |
Belkhouja K.,University of Lyon |
Le Q.-H.,Groupement Hospitalier Lyon Sud |
Robert D.,University of Lyon |
And 2 more authors.
Intensive Care Medicine | Year: 2010
Purpose: Use of bilevel positive airway pressure (BLPAP) ventilators for noninvasive ventilation (NIV) is an established treatment for both acute and chronic ventilatory failure. Although BLPAP ventilator circuits are simpler than those of conventional ventilators, one drawback to their use is that they allow variable amounts of rebreathing to occur. The aim of this work is to measure the amount of CO2 reinsufflated in relation to the BLPAP ventilator circuit in patients, and to determine predictive factors for rebreathing. Methods: Eighteen adult patients were ventilated on pressure support, either by intubation or with mask ventilation, during a weaning period. The mean inspiratory fraction of CO2 (tidal FiCO2) reinsufflated from the circuit between the intentional leak and the ventilator was measured for each breath. The influence of end-tidal CO2 concentration (ETCO2), respiratory rate (RR), percentage of inspiratory time (T i/T TOT), application of expiratory positive airway pressure (EPAP), and inspiratory tidal volume on magnitude of tidal FiCO 2, as well as the influence of intubation versus NIV, were studied by univariate comparisons and logistic regression analysis. Results: In a total of 11,107 cycles, tidal FiCO2 was 0.072 ± 0.173%. Of fractions measured, 8,976 (81%) were under 0.10% and 2,131 (19%) were over 0.10%, with mean values of 0.026 ± 0.027% and 0.239 ± 0.326%, respectively. ETCO2, EPAP, NIV versus intubation, and RR had significant predictive value for tidal FiCO2 >0.10%. Conclusions: BLPAP ventilators present a specific rebreathing risk to patients. However, that risk remains modest, even in intubated patients, provided that EPAP is applied. © 2010 Copyright jointly hold by Springer and ESICM.
Cuzin B.,Groupement Hospitalier Edouard Herriot
Sexologies | Year: 2014
Lower urinary tract symptoms are frequent in both men and women and group several entities, the most frequent of which is bladder hyperactivity with or without incontinence, benign prostatic hyperplasia, painful urinary disorders, stress incontinence, and recurrent urinary infections. Bladder hyperactivity is said to be present in 17% of women and 15% of men over 40 years of age. In the past 10 years, studies have shown that these problems interfere with the quality of life of most patients and were particularly associated with sexual dysfunctions. In bladder hyperactivity, nearly one woman in two has a sexual disorder (mainly pain or libido disorders); in men, significantly more Bladder hyperactivity erectile or ejaculatory dysfunction is noted. These diseases have benefitted from notable Sexual dysfunction therapeutic progress. Given the frequency of urinary disorders, their repercussions on Couple male and female sexuality, and the existence of effective treatments, it is indispensable Global approach to think of screening for them within a coherent and global approach to couples seeking treatment for sexual dysfunction. © 2014 Elsevier Masson SAS.
Bouvet L.,French Institute of Health and Medical Research |
Bouvet L.,Groupement Hospitalier Edouard Herriot |
Albert M.-L.,University of Lyon |
Augris C.,University of Lyon |
And 5 more authors.
Anesthesiology | Year: 2014
BACKGROUND:: The authors sought to determine the level of inspiratory pressure minimizing the risk of gastric insufflation while providing adequate pulmonary ventilation. The primary endpoint was the increase in incidence of gastric insufflation detected by ultrasonography of the antrum while inspiratory pressure for facemask pressure-controlled ventilation increased from 10 to 25 cm H2O. METHODS:: In this prospective, randomized, double-blind study, patients were allocated to one of the four groups (P10, P15, P20, and P25) defined by the inspiratory pressure applied during controlled-pressure ventilation: 10, 15, 20, and 25 cm H2O. Anesthesia was induced using propofol and remifentanil; no neuromuscular-blocking agent was administered. Once loss of eyelash reflex occurred, facemask ventilation was started for a 2-min period while gastric insufflation was detected by auscultation and by real-time ultrasonography of the antrum. The cross-sectional antral area was measured using ultrasonography before and after facemask ventilation. Respiratory parameters were recorded. RESULTS:: Sixty-seven patients were analyzed. The authors registered statistically significant increases in incidences of gastric insufflation with inspiratory pressure, from 0% (group P10) to 41% (group P25) according to auscultation, and from 19 to 59% according to ultrasonography. In groups P20 and P25, detection of gastric insufflation by ultrasonography was associated with a statistically significant increase in the antral area. Lung ventilation was insufficient for group P10. CONCLUSION:: Inspiratory pressure of 15 cm H2O allowed for reduced occurrence of gastric insufflation with proper lung ventilation during induction of anesthesia with remifentanil and propofol in nonparalyzed and nonobese patients. (Anesthesiology 2014; 120:326-34) Copyright © 2013, the American Society of Anesthesiologists, Inc.
Louis G.,Service de Reanimation Polyvalente |
Megarbane B.,Service de Reanimation Medicale |
Lavoue S.,Rennes University Hospital Center |
Lassalle V.,Service de Reanimation Medico chirurgicale |
And 4 more authors.
Critical Care Medicine | Year: 2012
OBJECTIVE: Very few data are available for critically ill patients with central or extrapontine myelinolysis and according to available evidence, the prognosis seems to be poor. We aimed to describe the baseline characteristics, the management, the long-term prognosis, and the prognostic factors in central or extrapontine myelinolysis. DESIGN: Retrospective observational study considering modified Rankin Scale score >3 or death as an unfavorable outcome. SETTING: Forty-six French intensive care units. PATIENTS: Thirty-six patients with central or extrapontine myelinolysis treated in 2000-2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At baseline, 31 (86%) patients were alcoholics and 33 (92%) presented with hyponatremia. Mechanical ventilation was required in 32 (89%) patients. At 1-yr follow-up, 11 (31%) patients have died, whereas 14 (56%) survivors have returned to a Rankin score ≤1. Life-supporting therapies were withheld in 11 (31%) patients. Severe cerebral motor disability was the most frequently cited reason. However, five of them were still alive at 1 yr with Rankin score ≤1 for four of them. We found no statistical difference between the 18 (50%) patients with a favorable outcome and the 18 (50%) patients with an unfavorable outcome with regard to severity of illness, suggesting that recovery is possible and unpredictable on the basis of clinical presentation. Chronic alcoholism was less frequent in patients with a favorable outcome as compared with patient with an unfavorable outcome (13 [72%] vs. 18 [100%], p = .04). CONCLUSIONS: The prognosis of critically ill patients with central or extrapontine myelinolysis is better than thus far thought despite initial severe clinical manifestations. Regarding the high rate of decisions to withhold life-supporting therapies, the probability of a favorable outcome might be underestimated by intensivists. Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
Salmon D.,Groupement Hospitalier Edouard Herriot
International journal of pharmaceutics | Year: 2013
Hypospadias is a birth defect in which the urinary tract opening is not at the tip of the penis. Hypospadias surgery is frequently complicated by healing deficiencies. Topical treatments with oestrogens were reported to improve healing. In the present study, ex vivo percutaneous absorption of promestriene, a synthetic oestrogen resulting of the double esterification of estradiol was conducted as a pre-requisite for further clinical trial in infants. Penetration of promestriene into infant foreskin treated with commercial oil in water emulsion (10 μg mg(-1)) for 24 h was characterized showing controlled release properties enabling epidermal concentration more than six times higher than dermal concentration (4.13±2.46 mg g(-1) versus 0.62±0.84 mg g(-1), respectively). Furthermore, apparent promestriene fluxes into and through the skin (i.e., 1.5 μg cm(-2) h(-1) and<0.89 μg cm(-2) h(-1), respectively) were calculated from (i) drug amount retained into epidermis and dermis, or (ii) the limit of detection into the receptor fluid. In conclusion, less than 2% of initial dose were absorbed within 24h which compared well with others steroids applied topically in colloidal systems. Copyright © 2013. Published by Elsevier B.V.
Spring P.,University of Lausanne |
Fellmann F.,University Hospitals Geneva Medical Center |
Giraud S.,Groupement Hospitalier Edouard Herriot |
Clayton H.,University of Lausanne |
Hohl D.,University of Lausanne
American Journal of Dermatopathology | Year: 2013
Birt-Hogg-Dubé Syndrome (BHD) is a rare condition, transmitted as an autosomal-dominant trait. The etiology is due to a mutation in the BHD gene, which encodes folliculin (FLCN), located on chromosome 17p. The skin changes observed are benign skin tumors consisting of hamartomas of the hair follicle with dermal changes. Patients with BHD have an increased risk of spontaneous pneumothorax due to rupture of lung cysts and an increased risk of kidney tumors. We report 3 new cases of BHD and discuss their clinical features, histopathological findings, and molecular diagnostics. We highlight the importance of genetic analysis to confirm the diagnosis because of the clinical pitfalls involved in establishing a diagnosis. Finally, we discuss the histopathological features in BHD and tuberous sclerosis complex and focus on their overlapping criterias. A correct diagnosis is essential as it can be life saving for patients. Copyright © 2013 by Lippincott Williams & Wilkins.
Cour M.,French Institute of Health and Medical Research |
Cour M.,Groupement Hospitalier Edouard Herriot |
Cour M.,University of Lyon |
Loufouat J.,French Institute of Health and Medical Research |
And 8 more authors.
European Heart Journal | Year: 2011
AimsResuscitated cardiac arrest (CA), leading to harmful cardiovascular dysfunction and multiple organ failure, includes a whole-body hypoxiareoxygenation phenomenon. Opening of the mitochondrial permeability transition pore (mPTP) appears to be a pivotal event in ischaemiareperfusion injury. We hypothesized that pharmacological inhibition of mPTP opening may prevent the post-CA syndrome.Methods and resultsAnaesthetized New Zealand White rabbits underwent a 15 min primary asphyxial CA and 120 min of reperfusion following resuscitation. At reflow, animals received an intravenous bolus of either cyclosporine A (CsA, 5 mg/kg) or NIM 811 (2.5 mg/kg), two potent inhibitors of mPTP opening, or the CsA vehicle (control). Short-term survival, haemodynamics, regional (sonomicrometry), and global cardiac function (dP/dt and aortic flow) were assessed. We measured markers of cellular injuries and/or organ failure, including troponin Ic release, lacticodehydrogenase, lactate, creatinine, and alanine aminotransferase. Cyclosporine A and NIM 811 significantly improved short-term survival, post-resuscitation cardiac function, as well as liver and kidney failure (P < 0.05). CsA and NIM 811 both attenuated in vitro mPTP opening (calcium retention capacity by spectrofluorimetry) and restored oxidative phosphorylation when compared with controls (P < 0.05).ConclusionThese data suggest that pharmacological inhibition of mPTP opening, added to basic life support, attenuates the post-CA syndrome and improves short-term outcomes in the rabbit model. © 2011 The Author.