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Objective: Assess the validity and reproducibility of the updated version of the French causality assessment method in conditions approaching real-life use., Methods: A random sample of 31 drug-event pairs from the French pharmacovigilance database was assessed by the consensual judgement of three experts (gold standard). Separately, a team from a pharmacovigilance centre (PhVC) and another from a pharmaceutical company assessed these pairs using the current method, then with the updated method. To test the inter- and intra-rater reproducibility, two seniors and two juniors from a PhVC and a pharmaceutical company assessed the pairs twice with the updated method. A weighted kappa coefficient was used to measure the agreement of the two causality assessment methods with the consensual expert judgement (validity) as well as the agreement of the updated causality assessment over time (intra-rater reproducibility) and between evaluators (inter-rater reproducibility)., Results: Agreement between the current method and consensual expert judgement was fair for the PhVC team (weighted kappa [Kw] 0.33) and moderate for the pharmaceutical company team (Kw 0.41). For the updated method, agreement was better for both the PhVC (Kw 0.58) and the pharmaceutical company (Kw 0.52) teams. The inter- and intra-rater reproducibility of the updated method based on the intrinsic imputability was satisfactory overall (Kw 0.30-0.91). Discrepancies between evaluations from PhVC and pharmaceutical companies were observed with the updated method., Conclusion: The updated method performed better than the current one for drug causality assessment, suggesting that it should be used in routine pharmacovigilance., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

The Imputability Working Group (CRI) updated the French drug reaction causality assessment method. This tripartite group is made up of staff from the French network of regional pharmacovigilance centres, pharmaceutical companies, and the French National Agency for the Safety of Medicines and Health Products (ANSM). After reviewing the strengths and weaknesses of the previous method, several ideas for improvement were proposed: a better-worded and more discriminating scale for certain chronological and semiological criteria, a larger scale for the intrinsic score (increased from 5 to 7 levels), a new bibliographical scale to differentiate between expected and unexpected adverse drug reactions, and a new informativeness scale., (© 2013 Société Française de Pharmacologie et de Thérapeutique.)

A tripartite group, entitled « CRI » (for Cercle de réflexion sur l'imputabilité), involving French pharmacovigilance staff from the French network of the Regional centers of pharmacovigilance, from pharmaceutical companies, and from French Health Authorities (Agence française de sécurité sanitaire des produits de santé) has worked to update the French drug reaction assessment method. Following assessment of strengths and weaknesses of the previous method, several points for improvement are proposed: a more precise wording and a more discriminating scale for some of the chronological and semiological criteria, a wider distribution of the intrinsic score from 5 to 7 levels, a new bibliographic scale for differentiating expected and unexpected adverse drug reactions, and a new informativness scale. This updated method would lead to a more relevant assessment of relationship between a drug and the occurrence of an adverse reaction. Furthermore, this method is a teaching tool to assess the level of relationship between a drug and the occurrence of an adverse reaction., (© 2011 Société Française de Pharmacologie et de Thérapeutique.)

A tripartite group, entitled « CRI » (for Cercle de réflexion sur l'imputabilité), involving French pharmacovigilance staff from the French network of the Regional centers of pharmacovigilance, from pharmaceutical companies, and from French Health Authorities (Agence française de sécurité sanitaire des produits de santé) has worked to update the French drug reaction assessment method. Following assessment of strengths and weaknesses of the previous method, several points for improvement are proposed : a more precise wording and a more discriminating scale for some of the chronological and semiological criteria, a wider distribution of the intrinsic score from 5 to 7 levels, a new bibliographic scale for differentiating expected and unexpected adverse drug reactions, and a new informativness scale. This updated method would lead to a more relevant assessment of relationship between a drug and the occurrence of an adverse reaction. Furthermore, this method is a teaching tool to assess the level of relationship between a drug and the occurrence of an adverse reaction., (Copyright © 2011 Société Française de Pharmacologie et de Thérapeutique. Publié par Elsevier Masson SAS.)

Anticholinergic adverse-effects in children treated with conventional doses of oxybutynine led us to measure plasma oxybutynine levels in children. 18 children, aged 5 to 13 y, who required treatment with oxybutynine chloride for daytime incontinence were studied. Plasma concentrations were measured on the fifth day of a course of treatment in which the dose was adapted to the child's body weight; the dose was given twice daily at 12-hour intervals. In 10 children aged between 5 and 8 y, the mean dose was 0.1 mg.kg-1. In 8 children aged between 10 and 13 years, the mean dose was 0.15 mg.kg-1. The highest concentration was usually found between 1 and 2 h after administration. The subsequent fall in concentration was rapid and after 6 h oxybutynine was no longer measurable in 14 of the children. The concentrations found were not different from those seen in adults given equivalent doses. The results show that plasma concentrations in children were not very different from those observed in adults if the dose were adapted to the body weight of the children. No special differences in paediatric use were revealed that might explain the particular adverse-effects. The results of the study argue against the dosage regimen proposed before these adverse events were detected. They strongly favour a dose adapted to the body weight of the child, with a 12-hour interval between doses.

Background: We have interviewed the parents of children born at two maternity hospitals to evaluate the knowledge of parents concerning the French Huriet law and their consent to the participation of their child in a randomized therapeutic trial., Methods: The inquiry was conducted between 15 February and 30 April 1991. Each couple of parents of whom the mother had given birth in one of the hospitals was sent an explanatory letter and a questionnaire on the second day after delivery. Parents who were unable to read adequately and those whose baby was ill were excluded from the study. The main questions were: age of parents, country of origin, education, profession, social insurance, frequency of medical consulting, their knowledge of the Huriet law, the source of that knowledge, their attitude to giving parental consent for their child to participate in a trial, the reasons for their consent or refusal., Results: Five hundred and eighty two questionnaires were distributed but only 541 were used. 73% of the parents said they knew that drugs were tested on volunteers. 59% claimed to know of the Huriet law, through the media (75%), their practitionist (12%), their environment (8%). 21% of the parents would consent to one of their children participating in such trial; 74% would refuse. Both parents were in agreement in 79% of cases, 12% of them for consent. The main reasons for refusal were the risk for side-effects of the drug (75%), lack of proof for efficacy (49%), disagreement in principle (19%). The mothers who consented were older than those who refused. The members of the "consent" group were more highly educated., Conclusions: Law Huriet is still inadequately understood in France. Pediatricians should consider how best to provide parents and the media with better information before trying to obtain parental consent.

The pharmacokinetic parameters of paracetamol were studied after 15 min intravenous infusion of 15 mg/kg of propacetamol (Prodafalgan) in 5 neonates aged less than 10 days and 7 infants aged between 1 and 12 months. Blood was sampled at 0, 0.5, 2 and 6 h after the first intravenous infusion of propacetamol. The infants aged less than 10 days had higher plasma concentrations of paracetamol, a longer half-life (3.5 vs. 2.1 h) and a lower plasma clearance (0.149 vs. 0.365 l/h/kg) than the older children. Dose simulations were performed on the basis of individual data of each child in order to obtain steady-state plasma concentrations between 4 and 18 mg/l permitting the best antipyretic effect for each child. In infants aged less than 10 days a 15 mg/kg dose of propacetamol four times a day (i.e. 30 mg/kg/day paracetamol) is sufficient, corresponding to the dosage recommended by the French pharmacopoeia. On the other hand, double the dosage, nearer to the American dosage, is necessary for children aged over 10 days.

Background: The side effects of oxybutynin chloride (Ditropan) often include atropinic and allergic reactions. Their relative frequency in children merits a nationwide investigation., Methods: All the side effects of Ditropan reported to the French Regional ADR monitoring centers and to the pharmaceutical firm Debat between January 1985 and June 1990 were analysed. Only 87 effects of the 286 side effects reported in adults and children occurred with sufficient frequency in 84 children to warrant study., Results: The 84 children (38 males, 43 females, 3 of unknown sex) were 30 months to 15 years old (mean: 6.5 years); 13 of them were less than 5 years. The mean dose of Ditropan prescribed was 0.5 +/- 0.12 mg/kg/day. 52 children developed atropinic symptoms, 20 skin and/or allergic reactions and 15 various other manifestations. These side effects required admission to hospital in 14% of cases. The side effects were 4 times more frequent in children (1/4,000 regulations) than in adults., Conclusions: The higher frequency of atropinic reactions in children may be due to the higher dosage of the drug used and/or to differences in hydroxylation metabolism, that is genetically determined in adults. New recommendations for use of this drug are proposed.

In order to evaluate parental awareness of the law governing clinical trials in France (Loi Huriet), a study was performed by questionnaire between February and April 1991 in a maternity unit during the days following delivery. The response rate was 59%. 59% of the parents (319/541) were informed of the existence of the law by the media (75%) or their general practitioners (12%). Twenty-one percent (116/541) of the parents would accept the participation of their children in a clinical trial and 74% would refuse. The principal reasons for acceptance were: for the benefit of other children, contribution to medical progress and confidence in physicians. The reasons for refusal were: risk of side effects and unproven efficacy. Parents who would accept had more often received higher education (44%) than parents who would refuse (30%), the latter being less influenced by the explanations of physicians and less willing to accept that a physician should decide for them. Physicians should consider transmitting information directly to parents and indirectly via the media.

We analyzed the 200 reported cases of adverse reactions to Ditropan (209 side-effects) collated by the Centres Régionaux de Pharmacovigilance and Laboratoire Debat since the drug was first marketed. The frequency of such side-effects was of the order of 1 per 20,917 treatment months. Children were affected four times more frequently than adults. The manifestations resembled atropine overdose in 103 cases (52 children, 51 adults), and were mainly neurological (59%) and ocular (22%). Two cases of erythema multiform and 33 of miscellaneous allergic skin reactions occurred. The fact that atropine overdose was more frequent in children can be explained by the proportionately higher dosage. Dose adjustment based on pediatric pharmacokinetic studies appears to be essential. In children, the drug is prescribed most frequently (56%) for conditions outside the licensed indications, particularly nocturnal enuresis, a condition for which the efficacy of Ditropan has not been established. We consider that this calls for a specific contraindication in isolated nocturnal enuresis and in children aged less than five years.

We have studied 12 reports of pneumonitis associated with nilutamide (Anandron) and notified to the French regional ADR monitoring centers between November 1987 and June 1990. The mean age of the patients was 71.5 +/- 9.5 years, and 35% (5/12) had a history of lung disease. All 12 patients developed dyspnea, cough and fever, 4.7 +/- 6 months after starting nilutamide. Ten patients (83%) required admission to hospital. The symptoms revolved in 11 cases when the drug was withdrawn. In the other case, they disappeared when another drug was stopped and the dose of nilutamide was reduced. Six patients were treated with glucocorticoids. The severity of nilutamide-associated pneumonitis appears to be related to the time between the onset of dyspnea and consultation.

We report a case of hyponatremia associated with a grand mal seizure in a 28 month-old child after intra-nasal desmopressin administration for high fluid intake with nocturnal enuresis. In view of the temporary symptomatic action and the seriousness of certain side-effects of desmopressin we recommend that desmopressin be used with caution in childhood enuresis.

A case of severe poisoning in a 2 year-old child who ingested 150 mg of oxaflozane, a non-tricyclic antidepressant, is reported. After loss of consciousness, opisthotonos and coma, recovery was obtained with conservative treatment. Atropine-like symptoms were noted. The maximal plasma concentration of oxaflozane was 63 ng/mL. The elimination half-life for N-dealkyloxaflozane was 4.8 h.

We relate the case of a drug addict of 31 years old whose dependence to the amineptine got complicated with severe acne-like lesions, as it sometimes happens. Compared, with teenage acne, severe acne can be distinguished by its late out break, its monstrous nature and its larger surface area. Amineptine has been found (or its metabolites) in the plasma, the urine. The treatment consists in the stopping of the drug addiction, combined with the prescription of isotretinoin.

To evaluate drug utilization during the last 15 days of pregnancy, one hundred six women were interviewed post-delivery in the CHU Bretonneau in Tours. Eighty-three percent received at least one drug during the 15 days preceding delivery and 27% more than 3 different drugs. Treatments for venous disorders (31% of patients), iron (31%), analgesics (25%), antacids (11%), magnesium (11%) and laxatives (11%) were most frequently used. In 92% of cases the drug was prescribed. Five women received a drug with potential risk for the neonate. However only one infant developed and adverse effect, possibly due to benzodiazepine (hypotonia).

Dehydration is frequently encountered in elderly patients and hypodermoclysis is an alternative method of parenteral rehydration. Hyaluronidase is classically added to the solution infused subcutaneously. The local effects of hypodermoclysis with or without hyaluronidase were investigated by using a randomized double-blind study in 12 dehydrated elderly patients. Five hundred millilitres of a 5% glucose saline solution was infused subcutaneously in 2 hours in each thigh, (A) with and (B) without 250 U of hyaluronidase. Circumference and temperature of each thigh were assessed before and after the infusion. Color was evaluated after the infusion. The gain in thigh circumference was less in the presence of hyaluronidase, but the other variables did not differ. The patients were thoroughly questioned about pain: no difference was noted between solutions A and B. We conclude that hyaluronidase adds no comfort that justifies its systematic use in the hypodermoclysis of glucose saline solutions.

Hypodermoclysis consists of infusing solutions in the subcutaneous tissues. It is a convenient means of correcting a moderate dehydration, notably in elderly people, when oral feeding is impossible or insufficient. The only potential problem with this technique is the occurrence of hypovolaemia due to infusion of hypo- or hypertonic solutions in subjects with previous severe salt and water disorders. For this reason, hypodermoclysis should not be used in emergencies.

The authors report a case of a skin defect in the scalp of a child whose mother took carbimazole during her pregnancy. Including our case there are now 15 congenital scalp defects reported: however, these rare cases do not show that carbimazole should not be used during pregnancy.

A retrospective study was undertaken to evaluate the relevance of benzodiazepine detection in 42 children with accidental poisoning. Immunoenzymatic assay for benzodiazepine in serum and colorimetric method in urines were positive respectively in 3 and 4 patients only. Several reasons could explain these results: the high detection threshold, the different drug reactivity according to the molecular structure and the great delay between intoxication and toxicology analysis. An advised physician should not prescribe a toxicological analysis after a small quantity of benzodiazepine ingestion.