[Psychiatric disorders associated with montelukast: data from the National Pharmacovigilance Database]. / Troubles psychiatriques associés au montélukast : données de la base nationale de pharmacovigilance.

Montelukast (Singulair(®)) has been the subject of post-marketing warnings about psychiatric events occurring that had not been identified during clinical trials. The objective of this study was to take stock of the adverse events (AEs) related to montelukast reported in France. Cases of psychiatric disorders reported to regional pharmacovigilance centers (CRPV) and the literature data were analyzed. The 56psychiatric AEs account for 20% of all AEs reported in the montelukast CRPV: essentially sleep disorders, behavioral disorders and depression. This risk is also found in pharmacovigilance databases in other countries, especially in the North American database, which recorded a significant number of cases of "suicidality", including suicidal ideation, suicide attempts, and suicides. Analysis of clinical efficacy studies have failed to confirm these AEs. The potential severity of these events prompts physicians to seek the existence of psychiatric disorders before prescribing the drug and to carefully monitor the occurrence of AEs during treatment.

[Pharmacovigilance in children]. / Pharmacovigilance en pédiatrie.

Drug safety in children must take into account the frequency of « off label ¼ prescriptions, children's growth dynamics, and possible long-term consequences (growth, neurodevelopment). The pharmacovigilance methodology is based on spontaneous notification and pharmacoepidemiology studies usually included the in risk management plan. Despite an increased drug risk (pharmacokinetic and pharmacodynamic specificities), drug safety is better in children than in adults. The incidence of drug side effects depends on the country, the type of study (in or out of the hospital), and age. Antibiotics, central nervous, respiratory and dermatologic drug systems are most often involved. The target organs are gastrointestinal and neurologic. In neonates, the most frequent side effects are due to pregnancy exposure to psychotropic drugs, beta-blockers, and antiepileptics. Some studies have shown an increased risk of off-label prescriptions in children. During the last 6 years in France, pediatric alerts (desmopressin, metoclopramide, bronchial mucolytic drugs, first-generation anti-H1, Uvesterol D(®), and Uvesterol A.D.E.C(®), rotavirus vaccines, growth hormone, cisapride) have been less frequent than in adults.

[The use of postnatal corticosteroid therapy in premature infants to prevent or treat bronchopulmonary dysplasia: current situation and recommendations]. / Utilisation de la corticothérapie postnatale chez le nouveau-né prématuré dans la prévention et le traitement de la dysplasie bronchopulmonaire : état des lieux et conduite à tenir.

In the last few years, several studies related to the benefit/risk balance of postnatal corticosteroids administered to premature neonates for prevention or treatment of bronchopulmonary dysplasia (BPD) have been published. These data encourage caution, given the risk of long-term adverse neurodevelopmental outcomes. In the meantime, the clinical profile of BPD has been altered based on the progress made in the pre- and postnatal care of premature infants. In 2006, a survey conducted in France in neonatal centers showed that corticosteroids were still frequently used (57% of the centers) following various protocols in very preterm-born infants for respiratory impairment. To promote safer practices and rational use of corticosteroids in the prevention and treatment of BPD in preterm-born neonates, we reviewed the available data in order to establish recommendations. Systemic administration of corticosteroids for prevention or treatment of BPD: (i) should not be used during the first 4 days of life; (ii) is not indicated in the first 3 weeks of life nor (iii) in extubated infants (nasal ventilation or oxygen therapy). The systemic administration of steroids can only be considered after the first 3 weeks of life in very preterm-born ventilator-dependent infants to facilitate extubation (or prevent reintubation related to the severity of BPD). Postnatal dexamethasone administration studied in several randomized clinical trials was shown to have an unfavorable benefit/risk profile, mainly because of the long-term adverse neurocognitive outcomes. Very few studies have been conducted with betamethasone in the postnatal period. According to sparse data, this drug might be as efficacious as dexamethasone, but its long-term risk profile is unknown. It should be noted that following prenatal administration, the benefit/risk profile of betamethasone is better than that of dexamethasone, especially with regard to neurocognitive development. Intravenous hydrocortisone administered at an early stage for the prevention of BPD is being evaluated and should not be administered in this indication, except within clinical trials approved by the ethics committee. No other corticosteroids have been evaluated in the postnatal period in respiratory indications. In conclusion, in the situations described above for which systemic corticosteroids could be justified, the use of betamethasone (or hydrocortisone) appears to be better. As usual, the lowest possible dose of corticosteroids should be administered for the shortest possible duration. The betamethasone-equivalent dose of 0.125 mg/kg/day for 3 days is deemed adequate. If inhaled, corticosteroid therapy may facilitate extubation. Neither its efficacy in respiratory diseases nor its long-term risk profile has been so far established.

[Most innovative drugs labelled during the last years in paediatrics: does the paediatrician have the tools for their identification?]. / Molécules les plus innovantes des dernières années en pédiatrie: le médecin a-t-il des outils pour les identifier?

When a new drug is labelled, before deciding its integration in the therapeutic strategy, the doctor has to know the degree of innovation of the drug, i.e. its actual benefit and the improvement of actual benefit, also called added value over other available drugs. For each new medicine in France, after drug approval by the French Drug Agency, the French National Authority for Health thought its "Commission de transparence" (Transparency Commission) issues an opinion about the degree of innovation of the drug, which is independent of the marketing authorization. The added value over other available drugs is quantified by five levels of improvement: level I, major progress to level V, no progress. The complete opinion of the Transparency Commission and its synthesis (one page) is online http://www.has-sante.fr/. Between 2006 and 2008, no paediatric drug has obtained a level I of improvement (major progress), ten have obtained a level II (significant progress), 11 a level III (moderate progress), 12 a level IV (minor progress) and for 38 drugs, no progress has been retained. The need to know and to follow therapeutic recommendations is the evidence based medicine. The opinions of the Transparency Commission are one of those recommendations.

[Glucocorticoide therapy in premature infants: French practices in 2006]. / Corticothérapie postnatale chez le prématuré : étude des pratiques des centres français de néonatologie en 2006.

BACKGROUND AND AIM: In 1999, 80% of French neonatal centers used corticosteroids, mainly betamethasone (BMT), to prevent or treat bronchopulmonary dysplasia (BPD) [Lee SK, McMillan DD, Ohlson A, et al. Variations in practice and outcomes in the canadian NICU Network 1996-1997. Pediatrics 2000;106:1070-9]. As many data suggested a low risk-benefit ratio, an updated assessment of this use was necessary [Desnoulez L, Empana J, Anceschi M, et al. Prise en charge de l'immaturité pulmonaire en néonatologie : enquête sur les pratiques européennes. Arch Pediatr 2005;12:4-9; Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (less than 96h) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003:CD001146; Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304-13; Lin YJ, LKin CH, Wu JM, et al. The effects of early postnatal dexamethasone therapy on pulmonary outcome in premature infants with respiratory distress syndrome: a 2-year follow-up study. Acta Paediatr 2005;94:310-16]. METHODS: Questionnaires addressing the use of and indications for corticosteroids were sent to all French neonatal centers. RESULTS: The study was conducted over 5 months (July to November 2006). Of 202 questionnaires sent out, 186 (92%) were completed. Of these 186 centers, 147 (79%) had a standard protocol for corticosteroid use, covering systemic and inhaled steroids (76 units), only systemic steroid therapy (30 units) and only inhaled steroids (41 units). Systemic corticosteroids were used in 106 centers for hemodynamic purposes in 42 cases (40%), prevention of BPD in 1 case (1%), early treatment of BPD (day 4 to day 21) in 23 cases (22%) and late treatment of BPD (after day 21) in 74 cases (70%). Hemisuccinate hydrocortisone (HSHC) was the only corticoid used for hemodynamic failure. The steroid used for early treatment of BPD was BMT (21 out of 23). The duration of treatment was less than 4 days in 10 centers (43%). The steroid most often used for late treatment was BMT (67 out of 74). The duration of treatment was less than 4 days in 29 centers, between 4 and 8 days in 22 centers, and longer than 8 days in 26 centers. Among 117 centers administering corticosteroids by inhalation, 74% used budesonide. Use of corticosteroids was higher in teaching hospitals (86%) than in others (49%), likely due to the immaturity of the neonates hospitalized in these centers. CONCLUSION: We showed a still frequent use of corticosteroids in preterm infants in France but only after the fourth day of life to treat BPD and not as a prevention therapy. We also found a marginal use of DXM in accordance with both short-term and long-term adverse side effects, suggesting an unbalanced risk-benefit ratio even though it has a beneficial effect on respiratory status. Our findings indicate the need for national recommendations and trials to assess oral BMT treatment in premature neonates with BPD.

[Alveolo-interstitial pneumonia due to Temozolamide]. / Pneumonie alvéolo-interstitielle au témozolomide.

INTRODUCTION: Temozolomide is an alkylating agent approved for treatment of glioblastoma in association with radiotherapy. CASE REPORT: We report the case of a 56 year old woman presenting with alveolo-interstitial pneumonia after treatment with Temozolomide. Initially she received induction treatment with Temozolomide and concomitant radiotherapy for bifocal high grade glioblastoma. A month later she received, as scheduled, the first course of Temozolomide maintenance chemotherapy. Grade II dyspnoea developed a few days later. High resolution computed tomography showed alveolo-interstitial opacities with basal predominance, associated with alveolar nodules. Broncho-alveolar lavage showed a lymphocytosis. No bacteria were isolated from microbiological samples. A final diagnosis of drug-induced pneumonia was based on the time sequence and absence of other causes. CONCLUSION: There is little literature concerning the pulmonary toxicity of Temozolomide. However, our case report of drug-induced pneumonia and similar observations in the databases of regional pharmacovigilance centres suggest that this side effect should be included in the summary of product characteristics.