Elisabeth Autret-Leca

Vitamin K in Neonates

Vitamin K-dependent factors are lower in neonates than in adults, and these anomalies are more prevalent in preterm neonates and in breast-fed infants. Vitamin K deficiency can account for vitamin K deficiency bleeding (VKDB) which occurs in 3 forms — early, classic and late. Vitamin K should be administered to all neonates at birth or immediately afterwards. However, the protocols for administration (route of administration, dosage, number of doses) remain a subject of discussion.Oral administration of a single dose of vitamin K protects against classical and early VKDB, but is less effective than intramuscular (IM) prophylaxis for the prevention of late VKDB. Although an increased risk of solid tumour, associated vitamin K administration, can be definitively excluded, a low potential risk of lymphoblastic leukaemia in childhood can not be ruled out.For formula-fed neonates without risk of haemorrhage, a 2mg oral dose of vitamin K at birth, followed by a second 2mg oral dose between day 2 and 7, is probably sufficient to prevent VKDB.For infants who are exclusively or nearly exclusively breast-fed, weekly oral administration of 2mg (or 25 μg/day) vitamin K after the initial 2 oral doses is justified at completion of breast-feeding. For neonates at high risk of haemorrhage (premature, neonatal disease, birth asphyxia, difficult delivery, any illness which will delay feeding, known hepatic disease, maternal drugs inhibiting vitamin K activity), the first dose must be administered by the IM or slow intravenous route. Doses should be repeated, particularly in premature infants, by a route of administration decided for each dose according to the clinical state of the infant.For infants of mothers treated with drugs inhibiting vitamin K activity, antenatal maternal prophylaxis (10 to 20 mg/day orally for 15 to 30 days before delivery) prevents early VKDB. After neonatal prophylaxis, as for infants at high risk of haemorrhage, doses need to be repeated at a rate and route of administration decided for each dose, according to the clotting factor profile specific for each infant.

Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach.

Abstract— High‐dose methotrexate (HD‐MTX) with leucovorin rescue is a component of therapy in children with acute lymphoblastic leukaemia. Since MTX toxicity is related to drug exposure, a monitoring of serum MTX concentrations at H24, H48, H72 and until the concentration is less than 0.2 μmol/L is commonly performed. However, a number of patients may reach concentrations of less than 0.2 μmol/L long before the next sampling is scheduled. The aim of our study was to develop a Bayesian method predicting the time at which MTX concentration reaches 0.2 μmol/L in order to decrease the number of samples drawn and to allow for a more rapid patient discharge. Methotrexate population parameters were estimated from a retrospective analysis of 60 infusions in 23 children and MTX concentrations were predicted from an independent set of 20 courses in 14 children with a Bayesian approach using either one (H48) or two (H24 and H48) samples. The following population parameters were obtained using a two‐compartment model: CL = 3.51 L/h (inter‐individual variability: 66%), Vd = 8.67 L (58%), k12 = 0.0044 h−1 (105%), k21 = 0.039 h−1 (25%). Clearance and Vd were found to increase with weight and age respectively. Both sampling schedules tested for the Bayesian estimation enabled accurate prediction of concentrations and provided satisfactory precision despite a small bias. When considering the ability to predict the time at which the threshold was reached, the one‐sample (H48) schedule gave the best results. We conclude that a sampling schedule involving only one sample and Bayesian parameter estimation may be able to predict the delay necessary to reach 0.2 μmol/L in each individual.

A multicentre case-control study of nonsteroidal anti-inflammatory drugs as a risk factor for severe sepsis and septic shock

IntroductionWe aimed to establish whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during evolving bacterial community-acquired infection in adults is associated with severe sepsis or septic shock.MethodsWe conducted a multicentre case-control study in eight intensive care units. Cases were all adult patients admitted for severe sepsis or septic shock due to a bacterial community-acquired infection. Control individuals were patients hospitalized with a mild community-acquired infection. Each case was matched to one control for age, presence of diabetes and site of infection.ResultsThe main outcome measures were the proportions of cases and controls exposed to NSAIDs or aspirin during the period of observation. In all, 152 matched pairs were analyzed. The use of NSAIDs or aspirin during the observation period did not differ between cases and controls (27% versus 28; odds ratio = 0.93, 95% confidence interval [CI] = 0.52 to 1.64). If aspirin was not considered or if a distinction was made between acute and chronic drug treatment, there remained no difference between groups. However, the median time to prescription of effective antibiotic therapy was longer for NSAID users (6 days, 95% CI = 3 to 7 days) than for nonusers (3 days, 95% CI = 2 to 3 days; P = 0.02).ConclusionsIn this study, the use of NSAIDs or aspirin during evolving bacterial infection was frequent and occurred in one-quarter of the patients with such infection. Although the use of NSAIDs by patients with severe sepsis or septic shock did not differ from their use by those with mild infection at the same infected site, we observed a longer median time to prescription of effective antibiotic therapy in NSAID users.

Incidence of Reye's syndrome in France : A hospital-based survey

At the time of the study no information was available in France about the incidence of Reyes Syndrome (RS) and no warnings about RS and aspirin. The objective was to evaluate the incidence of RS in France by a hospital-based study. For a period of 1 year from November 1995 to November 1996, all French paediatric departments were required to report any child under 15 years with unexplained noninflammatory encephalopathy (i.e., CDC consciousness level stage I or deeper with normal CSF) and a threefold (or greater) increase in serum aminotransferase and/or ammonia. All suspected cases were classified by a panel of experts as probable RS or excluded RS. In 10% of randomly selected paediatric departments we checked that every suspected case had been reported. Forty-six suspected cases were reported during the year of the survey, of which 14 were classified as RS. Five of these 14 cases had a metabolic disorder. Nine children were definitively diagnosed as having RS (i.e., an estimated incidence of RS of 0.79/1,000,000 children, i.e., below 15/year). Eight children had been exposed to aspirin, four to aspirin alone and four to aspirin and acetaminophen. On the basis of these results the incidence of RS in France in 1996-1997 was not substantially different from that of countries where warning labels were already in use, but it was higher than in the US after 1994. This was probably due to the reduction in aspirin prescription in France because of warnings in Europe and the US and also because many cases of RS are now identified as metabolic disease. On the basis of these results and because the relationship between aspirin and RS has already been proved, public and professional warnings concerning RS on aspirin-containing products in cases of varicella and viral febrile illness have been adopted by the French Drugs Agency.

Avoidability of Adverse Drug Reactions Spontaneously Reported to a French Regional Drug Monitoring Centre

AbstractBackground: Adverse drug reactions (ADRs) are now recognized as a major category of iatrogenic illness in terms of morbidity and mortality. Objective: To describe the type and frequency of avoidable ADRs spontaneously reported to a regional drug monitoring centre following inappropriate prescribing, as a basis for preventive actions. Methods: A prospective, observational study of ADRs reported to the Regional Drug Monitoring Centre of Tours, France, between 26 November 2002 and 28 November 2003. The outcome measure was ADRs secondary to inappropriate prescribing that were defined as entirely or partly avoidable, i.e. at least one of the recommendations in various sections of the summary of product characteristics (SPC; indication, route of administration, dose, duration of treatment, dose adaptation, precautions for use, monitoring of treatment, absolute contraindications and contraindicated interactions) had not been respected. The link between the lack of conformity of the drug prescription with the SPC and occurrence of the ADR was evaluated by a working group using two criteria: (i) is nonconformity of the prescription of this drug a known and validated risk factor for this ADR?; and (ii) are there other aetiologies or other risk factors for this ADR? Results: Three hundred and sixty ADRs in 294 adults and 66 children were analysed. The prescription was considered inappropriate for 213 of the 659 (32%) drugs implicated in ADRs, corresponding to 161 patients (45%). The ADR was adjudged entirely avoidable for 32 (9%) patients, partly avoidable for 28 (8%) patients and unavoidable for 300 (83%) patients. Not taking into account a history of allergy or altered renal function and not respecting the recommended dose were the most frequent causes of entirely avoidable ADRs. Allopurinol and lamotrigine were the drugs most frequently involved in serious avoidable ADRs. Conclusions: Preventive actions should focus on more systematic allergy checks when prescribing drugs and on dose adaptation in cases of altered renal function.

Isotretinoin exposure during pregnancy: assessment of spontaneous reports in France.

AbstractBackground: In three previous studies, we have shown that pregnant women were still being exposed to isotretinoin and that compliance with recommendations was incomplete. The relaxation of these recommendations (summary of product characteristics 2004), combined with the release of generic brands, encouraged us to carry out a fourth study. Objective: To assess isotretinoin exposure during pregnancy following the application of less stringent recommendations and the marketing of generic isotretinoin brands. Methods: All cases of isotretinoin exposure during pregnancy, between 1 January 2003 and 31 December 2006, spontaneously reported to pharmacovigilance centres, the Teratogenic Agent Information Centre, and pharmaceutical companies in France were assessed. Cases were classified for analysis into the following groups: ‘conception <1 month after isotretinoin discontinuation’, ‘conception during isotretinoin treatment’ and ‘patient already pregnant when isotretinoin was started’. The rate of spontaneously reported isotretinoin exposure during pregnancy was estimated by dividing the number of isotretinoin-exposed pregnancies by the number of women of child-bearing age treated with isotretinoin. Results:Over 4 years, 147 cases of isotretinoin exposure during the teratogenic risk period were spontaneously reported, i.e. ‘conception <1 month after isotretinoin discontinuation’ (23%), ‘conception during isotretinoin treatment’ (61%), and ‘patient already pregnant when isotretinoin was started’ (16%). Nineteen percent of the patients did not use any form of contraception. In 23% of the patients, the method of contraception used did not comply with recommendations, while in 86% of the cases, isotretinoin was prescribed by a dermatologist. Among the 44 pregnancies with available data on fetuses or neonates, there were two (4.5%) malformations compatible with the time of exposure and with isotretinoin embryopathy. The rate of spontaneously reported isotretinoin exposure during pregnancy has increased by approximately 30%, from 0.32 (95% CI 0.26, 0.38) to 0.41 (95% CI 0.34, 0.49) per 1000 women of childbearing age treated since 1999–2002. Conclusions:We suggest that recommendations be tightened, with specific information regarding the most effective contraceptive method combined with compulsory monthly pregnancy testing during treatment. The French Drug Agency has informed the European Medicines Agency of the need for measures aimed at improving compliance.

Therapeutic drug monitoring of HIV protease inhibitors using high-performance liquid chromatography with ultraviolet or photodiode array detection.

Published data suggest that therapeutic drug monitoring of human immunodeficiency virus protease inhibitors would improve the management of antiretroviral therapy. The authors have developed a high-pressure liquid chromatographic assay allowing simultaneous determination of six protease inhibitors (ritonavir, saquinavir, indinavir, nelfinavir, amprenavir, and lopinavir), using carbamazepine as internal standard. Detection was based on a dual wavelength ultraviolet spectrophotometer and can be improved by the use of a photodiode array detector. Monitoring was performed 1 month after initiation of therapy or in instances of therapeutic failure, side effects, suspicion of noncompliance, drug interactions, or malabsorption. Trough concentrations were 0.15 to 13.6 mg/L for ritonavir, 0.06 to 9.7 mg/L for indinavir, 0.03 to 5.5 mg/L for saquinavir, and 0.15 to 4.15 mg/L for nelfinavir. Concentrations below the limit of quantification were observed in 63/438 (14%) of the patients. Target concentrations are not well established, and reported in vitro inhibitory concentrations may be of limited value. The authors therefore chose to compare observed concentrations with mean plasma concentrations reported in clinical trials. Observed saquinavir and indinavir concentrations were often below or close to these target concentrations, particularly when used as a single protease inhibitor. Concentration-controlled studies should now be used to select proper target concentrations for each protease inhibitor, either prescribed alone or in combination.

Beneficial Effect of Zolpidem for Dementia

TO THE EDITOR: Zolpidem is an oral imidazopyridine sedative–hypnotic agent with an adverse event profile that includes anxiety, dizziness, drowsiness, and irritability.1 It is effective for short-term treatment of insomnia. We report improvement in symptoms of dementia in a patient with a 1-year history of unspecified dementia. Case Report. A recovering 60-year-old alcoholic woman presented with reduced cognitive functions including considerable memory loss, praxis disorders, and inability to join in conversation. Examination revealed extrapyramidal syndrome, minimal pyramidal syndrome, and contralateral synkinesis for each complex movement. Computed tomography to investigate the etiology demonstrated nonspecific cerebral atrophy, and technetium scintigraphy was normal. An electroencephalogram revealed α activity at 10 c/s and slow nonspecific, polymorphous, bilateral activity at 2 c/s in the frontotemporal area. Examination of the cerebrospinal fluid was normal, thus eliminating chronic meningitis, and investigation for Creutzfeldt–Jakob 14-3-3–specific protein on Western blot was also negative. Unspecified dementia resulting from corticobasal atrophy was diagnosed and, after 1 year, she lost the ability to lead a normal social life and perform everyday activities. Zolpidem 10 mg was prescribed for insomnia. The woman received no other treatment. For a few months, her husband gave her zolpidem each day at 2200 at the start of treatment and then earlier, at 1900. After beginning the earlier administration, he began to notice that, approximately 1 hour after each dose of zolpidem, his wife talked more easily and could wash the dishes and do the housework, things she had lost the ability to do. This beneficial effect was detectable 45–60 minutes after zolpidem administration, lasted for 3 hours after each administration, and then relapsed. The subjective improvement in cognitive functions immediately after drug administration was confirmed several times by the general practitioner after observation of the patient (but no MMS evaluation was performed) and by the patient’s family. Discussion. In this case, the temporal relationship between zolpidem intake (consistent with its pharmacokinetic properties) and improvement in cognitive function, with repetition at each dose, indicated a causal relationship with zolpidem. Many reports have indicated that zolpidem impairs psychomotor and cognitive functions in humans,2 whereas beneficial effects of zolpidem have been reported for motor symptoms in Parkinson disease,3 progressive nuclear palsy,4 and catatonia.5 However, to our knowledge, this is the first published case of improvement in dementia with zolpidem. Three other cases of similar beneficial effects of zolpidem have been reported to the French Drugs Agency (equivalent to the Food and Drug Administration). The effect lasted for 1 to a few hours in all patients, but persisted in only 1 patient. The mechanism of this beneficial effect of zolpidem on cognitive functions is not understood, but several cases of zolpidem abuse and/or dependence have been described,6 and some patients have reported stimulating effects and euphoria. Gericke and Ludolph7 reported a 33-year-old man with major depression who developed chronic zolpidem abuse because of a psychomotor stimulant action. He experienced regained energy in mental and physical activity 20 minutes after ingesting zolpidem that lasted 5–6 hours. The kinetic profile of zolpidem (time to maximum concentration 1–3 h, half-life 2.4 h) is compatible with the fact that in some cases4,7 and in our patient, the beneficial effect was detectable 20–60 minutes after zolpidem administration and lasted 2–5 hours. This novel effect of zolpidem is of interest and suggests that larger scale, placebo-controlled studies are warranted.

Glimepiride-Induced Thrombocytopenic Purpura

TO THE EDITOR: Oral sulfonylurea antidiabetic drugs such as glyburide1 and chlorpropamide2 , 3 are known to induce thrombocytopenia. George et a l .4 recently reviewed published reports of drug-induced thrombocytopenia and proposed criteria to evaluate the level of evidence for a causal relationship of each drug to thrombocytopenia. We report a patient who developed thrombocytopenia after glimepiride treatment. According to the criteria developed by George et al., our observations support the existence of a causal relationship between glimepiride and thrombocytopenia. Case Report. A 68-year-old white man was referred to our hospital on April 21, 1998, with a petechial rash associated with hematoma on his trunk, legs, and face. Clinical examination showed hemorrhagic bullae in the mouth and gingival bleeding. No lymphadenopathy or hepatosplenomegaly was observed. His previous medical history included chronic psychosis, which had been treated for 12 years by pipotiazine 12.5 mg every six weeks (last injection April 3, 1998) and trihexyphenidyl 4 mg/d. In February 1998, his physician prescribed glimepiride 1 mg/d, an oral sulfonylurea antidiabetic drug, for hyperglycemia. Platelet counts at the outset of treatment and during the following weeks were not available, but the patient reported no symptoms of bleeding and stopped glimepiride after several weeks of treatment. On April 19, the patient restarted glimepiride treatment and, on April 21, was referred for hemorrhagic syndrome. His platelet count confirmed thrombocytopenia (1 × 1 09/L). A bone marrow aspirate was diluted with peripheral blood, but showed no malignant cells, and there was no serologic evidence of recent viral infection (HIV-1, -2; hepatitis B, C, A; cytomegalovirus; Epstein–Barr virus). The platelet count was too low to assess platelet-associated immunoglobulins, but platelet receptor antibodies were found. All medication was withdrawn; prednisone 1 mg/kg/d and human immunoglobulins 0.4 g/kg/d for 2 d were prescribed. The hemorrhagic syndrome decreased on day 7, but the platelet count was 2 × 1 09/L. After two weeks, the platelet count increased to 23 × 1 09/L and was completely normalized after four weeks of prednisone therapy (281 × 109/L). Prednisone was progressively reduced, and platelet count was normal (346 × 1 09/L) six months after glimepiride was discontinued. D i s c u s s i o n . George et al.4 proposed criteria to evaluate the level of evidence for a causal relationship of drugs to thrombocytopenia. These criteria were: (1) the candidate drug preceded thrombocytopenia, and recovery from thrombocytopenia was complete and sustained after the drug was discontinued; (2) the candidate drug was the only drug used prior to the onset of thrombocytopenia, or other drugs were continued or reintroduced after discontinuation of the candidate drug with a sustained normal platelet count; (3) other etiologies for thrombocytopenia were excluded; and (4) reexposure to the candidate drug resulted in recurrent thrombocytopenia. The level of imputability (definite to unlikely) is definite according to the criteria met. In our observation, the occurrence of thrombocytopenia 48 hours after reintroduction of glimepiride and its resolution after discontinuation of therapy supports the diagnosis of glimepiride-induced thrombocytopenia despite the same criteria of imputability as pipotiazine and trihexyphenidyl according to the Naranjo probability scale.5 The patient had been treated with pipotiazine and trihexyphenidyl for 12 years and had no history of thrombocytopenia or symptoms of bleeding. Pipotiazine and trihexyphenidyl were withdrawn and not reintroduced, but the interval between drug ingestion and the initial occurrence of thrombocytopenia has been reported to be usually less than one day to three years4; therefore, the imputability of these two drugs is unlikely. Other causes of thrombocytopenia were excluded in this patient; even if no reexposure to glimepiride had been attempted, the causal relationship between the drug and thrombocytopenia was probable according to the criteria of George et a l .4 The time to recovery of normal platelet count was four weeks and in agreement with the diagnosis of drug-induced thrombocytopenia. Assay for drug-dependent antiplatelet antibodies was not performed, but no data on the sensitivity and specificity of these assays are available.4 N e vertheless, the occurrence of thrombocytopenia after reintroduction of glimepiride, the severity of thrombocytopenia, and the presence of platelet receptor antibodies argue for an immunoallergic mechanism. In conclusion, some oral antidiabetic drugs such as chlorpropamide and glibenclamide are known to induce thrombocytopenia.1 3 We report the first case of glimepiride-induced thombocytopenia and suggest that platelet counts should be performed when hemorrhagic syndrome is clinically observed during glimepiride treatment.

A well-tolerated 5-FU-based treatment subsequent to severe capecitabine-induced toxicity in a DPD-deficient patient

5-Fluorouracil (5-FU) is widely administered as a continuous infusion to treat gastrointestinal tract or head and neck cancers, and as bolus injections in breast cancer chemotherapy regimens. Grade 3–4 toxicity occurs in about 30% of patients receiving 5-FU as a continuous infusion, and proves lethal in 0.5% of these patients [1]. 5-FU-related toxicity has mostly been reported with intravenous administration [1–3]. However, some cases of severe toxicity, including deaths, have been described after oral administration of 5-FU derivatives, such as capecitabine (Xeloda®) [4, 5]. A polymorphism of the dihydropyrimidine dehydrogenase (DPD) gene has been identified as a frequent cause of such toxicity [6, 7]. DPD catalyses the rate-limiting step of fluoropyrimidine catabolism. Partial or total DPD deficiency therefore leads to substantial overexposure in patients treated with the standard dose, exacerbating drug toxicity. This raises questions about possible screening for DPD deficiency before the administration of fluoropyrimidine drugs, including their oral forms. Patients found to have a deficiency on screening before treatment or following signs of toxicity during a previous course are usually given alternative treatments based on nonfluoropyrimidine compounds. However, 5-FU is highly active and its use may be essential in patients who fail to respond to other treatments. We report the case of a patient with DPD deficiency detected due to severe toxicity during capecitabine treatment, who has since received a continuous infusion of 5-FU at almost the standard dose with no significant signs of toxicity.