[Epidemiology of diabetes in children in Languedoc-Roussillon (France)]. / Registre épidémiologique du diabète chez l'enfant en Languedoc-Roussillon.

Since 1st January 2000, the PEDIAB-LR registry has listed new cases of diabetes in children under 16 years of age in the Languedoc-Roussillon region of France, in order to assess the incidence and epidemiological characteristics of children affected by diabetes. At the end of December 2010, 745 children had been registered. The characteristics of these children included an identical proportion of girls and boys, a mean age of 8 years at diagnosis, and a family history of type 1 diabetes in 8.4% of the cases. Inaugural ketoacidosis was observed in 69.5% of the patients and was severe in 23.7% of these cases. To replace intravenous insulin, a two-injection dosing regimen (in the morning and before dinner) was prescribed in 76.5% of cases, multi-injections of basal-bolus in 16%, and subcutaneous insulin infusion (insulin pump therapy) in 7.5% of cases. Between 2000 and 2010, there was no increase in overall incidence. It is noteworthy that age at diagnosis tended to decrease, but this was not statistically significant. In conclusion, the PEDIAB-LR registry is currently the only French registry on diabetes in children, analyzing many factors related to its incidence, such as age at diagnosis and the existence of ketoacidosis.

Reversibility of the anti-FXa activity of idrabiotaparinux (biotinylated idraparinux) by intravenous avidin infusion.

BACKGROUND: Idraparinux is an inhibitor of activated factor X (FXa) with a long half-life allowing once-weekly dosing. Idrabiotaparinux is a biotinylated version of idraparinux; its activity can be reversed with avidin. OBJECTIVE: To investigate the tolerability, safety and pharmacodynamics of avidin in healthy subjects and patients with deep vein thrombosis (DVT) receiving idrabiotaparinux. PATIENTS AND METHODS: In a placebo-controlled, randomized, double-blind Phase I study, 41 healthy males received subcutaneous idrabiotaparinux before being randomized to a 30-min intravenous avidin infusion or placebo. Idrabiotaparinux plus avidin were re-administered 10-14 months later in eight subjects. In addition, in a prospective substudy of the Phase III EQUINOX trial, 55 patients who received weekly idrabiotaparinux for 6 months were randomized to receive either 100 mg avidin (n = 33) or placebo (n = 22). The primary activity outcome was anti-FXa activity calculated immediately before and after avidin infusion. Adverse events were recorded to assess safety and tolerability. RESULTS: Avidin rapidly reversed the anti-FXa activity of idrabiotaparinux, ranging from 66.1 to 90.3% in healthy subjects and from 67 to 97% (mean 78%) in DVT patients. Avidin was well tolerated, with a similar nature and frequency of adverse events to placebo. No venous thromboembolism recurrence occurred in the 3-month post-avidin infusion. CONCLUSION: A 30-min intravenous infusion of avidin 100 mg is well tolerated, safe, and offers immediate and specific reversibility both after single and repeated doses of idrabiotaparinux in healthy subjects, and in DVT patients following a 6-month treatment period.

[Posterior urethral valves: prenatal diagnosis, neonatal data and outcome]. / Les valves de l'urètre postérieur. Etat des lieux en Languedoc-Roussillon de 1998 à 2007 : données anténatales, néonatales et devenir à moyen terme.

AIM OF THE STUDY: To evaluate the impact of prenatal diagnosis on the epidemiology and outcome of children with posterior urethral valves (PUV), considering that today termination of pregnancy may be proposed in the most severe cases. PATIENTS AND METHODS: Forty-three cases of patients with PUV were diagnosed between 1998 and 2007 in the Languedoc-Roussillon region. In this study, we detailed the prenatal data and postnatal outcome of those patients with a mean follow-up period of 7.6 years. RESULTS: Medical interruption of pregnancy was performed in 15 severe cases. One death in utero was also observed. Twenty-seven patients were managed postnatally and one child died during the neonatal period because of lung hypoplasia. For the 26 remaining patients at the end of the follow-up period, 5 had mild renal insufficiency with a creatinine clearance calculated with the Schwartz formula of less than 80 ml/min/1.73 m2. One reached end-stage renal failure at the age of 7 years. Proteinuria and hypertension were rare. DISCUSSION AND CONCLUSION: Today, because of the increase in medical termination of pregnancy in the most severe cases, most of the children born alive with PUV experienced a better renal prognosis when compared with previous data. Prenatal diagnosis and therapeutic progress significantly modified the epidemiology and outcome of this disease. Nevertheless, the best predictor of renal outcome remains renal function at 1 year of age.

The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials.

BACKGROUND: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. OBJECTIVES: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. PATIENTS AND METHODS: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance<30 mL min(-1)). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. RESULTS: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h(-1), 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux--rapid onset of action and long-acting anticoagulant effect--offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux.

New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humans.

Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces. On the other hand, the aglycone derivative obtained after de-glycosylation of TCC (M2) was observed and, in addition, we identified, as the major circulating metabolic entity, 3-O-glucuronidated aglycone (M1) obtained after glucuro-conjugation of M2. One hour after oral administration, M1 plus M2 accounted for more than 75% of the circulating total radioactivity. The pharmacological activity of these metabolites was assessed using a rat model, the muscle relaxant activity of M1 was similar to that of TCC whereas M2 was devoid of any activity. Subsequently, to investigate the PK profile of TCC in human PK studies, we developed and validated a specific bioanalytical method that combines liquid chromatography and ultraviolet detection to assay both active entities. After oral administration, TCC was not quantifiable with an lower limit of quantification set at 1 ng/mL, whereas its active metabolite M1 was detected. M1 appeared rapidly in plasma (tmax=1 h) and was eliminated with an apparent terminal half-life of 7.3 h. In contrast, after intramuscular administration both active entities (TCC and M1) were present; TCC was rapidly absorbed (tmax=0.4 h) and eliminated with an apparent terminal half-life of 1.5 h. M1 concentration peaked at 5 h and this metabolite was eliminated with an apparent terminal half-life of 8.6 h. As TCC and M1 present an equipotent pharmacological activity, the relative oral pharmacological bioavailability of TCC vs. intramuscular administration was calculated and represented 25%. Therefore, to correctly investigate the PK and bioequivalence of TCC, the biological samples obtained must be assayed with a bioanalytical method able to specifically analyse TCC and its active metabolite M1.