Bénédicte Lelièvre

Elucidation of the metabolites of the novel psychoactive substance 4-methyl-N-ethyl-cathinone (4-MEC) in human urine and pooled liver microsomes by GC-MS and LC-HR-MS/MS techniques and of its detectability by GC-MS or LC-MS(n) standard screening approaches.

4-methyl-N-ethcathinone (4-MEC), the N-ethyl homologue of mephedrone, is a novel psychoactive substance of the beta-keto amphetamine (cathinone) group. The aim of the present work was to study the phase I and phase II metabolism of 4-MEC in human urine as well as in pooled human liver microsome (pHLM) incubations. The urine samples were worked up with and without enzymatic cleavage, the pHLM incubations by simple deproteinization. The metabolites were separated and identified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS). Based on the metabolites identified in urine and/or pHLM, the following metabolic pathways could be proposed: reduction of the keto group, N-deethylation, hydroxylation of the 4-methyl group followed by further oxidation to the corresponding 4-carboxy metabolite, and combinations of these steps. Glucuronidation could only be observed for the hydroxy metabolite. These pathways were similar to those described for the N-methyl homologue mephedrone and other related drugs. In pHLM, all phase I metabolites with the exception of the N-deethyl-dihydro isomers and the 4-carboxy-dihydro metabolite could be confirmed. Glucuronides could not be formed under the applied conditions. Although the taken dose was not clear, an intake of 4-MEC should be detectable in urine by the GC-MS and LC-MS(n) standard urine screening approaches at least after overdose.

Pharmacokinetic analysis of pralidoxime after its intramuscular injection alone or in combination with atropine-avizafone in healthy volunteers

BACKGROUND AND PURPOSE Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with avizafone and atropine using an auto‐injector device.

Riluzole pharmacokinetics in young patients with spinal muscular atrophy

AIMS The objective of the present study was to assess the pharmacokinetics of riluzole in patients with spinal muscular atrophy (SMA). METHODS Fourteen patients were enrolled in an open-label, nonrandomized and repeat-dose pharmacokinetic study. All participants were assigned to receive 50mg riluzole orally for 5 days. Riluzole plasma concentrations were determined from samples obtained at day 5. RESULTS The pharmacokinetic analysis demonstrated that a dose of 50mg once a day was sufficient to obtain a daily total exposure [AUC(0,24h)=2257ng ml(-1) h] which was comparable with results obtained in adult healthy volunteers or ALS patients in whom a dose of 50mg twice a day is recommended. The pharmacokinetic simulation demonstrated that the administration of 50mg twice a day could result in higher concentrations, hence reduced safety margin. CONCLUSION The dose of 50mg once a day was chosen for the clinical trial evaluating the efficacy of riluzole in SMA patients.

Recreational phenethylamine poisonings reported to a French poison control center

OBJECTIVES Over the last decade, use of phenethylamines has become increasingly prevalent. This study aimed to describe typical aspects of phenethylamine poisoning in order to better inform patient care. METHODS Phenethylamine poisoning cases reported to the Poison Control Center of Angers, France, from January, 2007 to December, 2013 were examined. Clinical findings were examined in 105 patients, including phenethylamine used, symptoms and final outcome. Patients were predominantly male (80%), with mean age 26±8 years. RESULTS MDMA (38%), amphetamine (18%) and methamphetamine (14%) were the most commonly reported. Synthetic cathinones (10%) and the 2C series (7%) were also found. Substances most commonly associated with phenethylamine poisoning were cannabis (27%), ethanol (20%) and cocaine (9%). The most frequently reported symptoms included anxiety and hallucinations (49%), mydriasis and headache (41%), tachycardia (40%) and hypertension (15%). Complications such as seizures (7%), cardiac arrest (5%), toxic myocarditis (1%) and hemorrhagic stroke (1%) were also observed. Of the cases, the Poison Severity Score was: null or low, 66%, moderate, 21%, severe or fatal, 13%. Of the patients, 77% received hospital care and 12.4% were admitted to an intensive care unit. Analytical confirmations were obtained for all severe cases. While 93% of patients recovered, there were 5 deaths and 2 patients presented with neurological sequelae. CONCLUSIONS Phenethylamine poisonings may be severe in young and healthy individuals. Physicians, toxicologists and analysts should be aware of new phenethylamine consumption trends in order to inform management of patient care and to contribute to a more responsive drug policy.

Experimental Models of Disseminated Scedosporiosis with Cerebral Involvement

Scedosporium apiospermum is a soil fungus which can cause severe and often fatal cerebral infections in both immunocompetent patients in the event of near drowning and immunosuppressed patients such as lung transplant recipients. Because of the low susceptibility of this fungus to antifungal drugs, and the low permeability of the blood-brain barrier (BBB), therapeutic drug monitoring is necessary to reach an effective tissue concentration with limited side effects. Indeed, diffusion of the drug in the brain is dependent on several parameters, such as the integrity of the BBB and the activity of efflux pumps. To evaluate drug diffusion, two experimental models were developed in immunocompetent and immunosuppressed rats. Inocula were administered via the penile vein and a clinical scale (0–9) was established, based on weight and clinical and neurologic signs evaluated by the tail suspension test. Cerebral involvement was confirmed by magnetic resonance imaging and histologic examination of brain sections after hematoxylin-eosin-safran or silver staining. Voriconazole or posaconazole was given to the rats at doses ranging from 10 to 75 mg/kg/day via i.v. or oral routes, respectively. Whatever the immune status, the effective doses (defined by a doubling of the survival time and the absence of neurologic sequelae) were 30 mg/kg/day for voriconazole and 50 mg/kg/day for posaconazole. Overall, the results demonstrated that these models may constitute valuable tools for the performance of pharmacokinetic and pharmacodynamic studies for pharmacokinetic-pharmacodynamic modeling.

Therapeutic management of allergic diseases

Allergic diseases are characterized by the activation of inflammatory cells and by a massive release of mediators. The aim of this chapter was to describe succinctly the modes of action, indications, and side effects of the major antiallergic and antiasthmatic drugs. When considering the ideal pharmacokinetic characteristics of a drug, a poorly metabolized drug may confer a lower variability in plasma concentrations and metabolism-based drug interactions, although poorly metabolized drugs may be prone to transporter-based disposition and interactions. The ideal pharmacological properties of a drug include high binding affinity, high selectivity, and appropriate association and dissociation rates. Finally, from a patient perspective, the frequency and route of administration are important considerations for ease of use.

Ongles et médicaments

Resume Les ongles peuvent etre la cible d’effets indesirables medicamenteux, soit en parallele d’une atteinte cutanee plus diffuse, soit de facon isolee. La semiologie ungueale et les termes qui lui sont rattaches sont tres specifiques. L’agression de la matrice conduit a un ralentissement ou un arret de la croissance de l’ongle a l’origine des lignes de Beau, des lignes de Mees ou d’une onychomadese. Celle du lit de l’ongle se traduit par une onycholyse, parfois induite ou favorisee par l’exposition solaire (photo-onycholyse). Parmi les medicaments impliques dans ces effets, figurent de nombreux anticancereux dont les taxanes. L’atteinte des plis peri-ungueaux est a l’origine d’une paronychie et de botriomycomes, manifestations decrites avec les retinoides, l’indinavir et les anticancereux de la famille des anti-EGFR. Ces atteintes ungueales et peri-ungueales sont souvent douloureuses, retentissent sur la qualite de vie et peuvent se compliquer de surinfection. Enfin, de nombreux medicaments peuvent induire une pigmentation ungueale (anticancereux, cyclines, antimalariques, zidovudine).

IMMUNOCHROMATOGRAPHIC TESTS: FALSE-POSITIVE RESULTS FOR METHADONE AND PHENCYCLIDINE AFTER ACUTE POISONING WITH TRAMADOL AND DEXTROPROPOXYPHENE

Abstract Background: Immunochromatographic drug tests are more and more involved in the initial biological survey of acute poisoning, even with “on site” use at the emergency unit. Specificity of the drug-antibody interaction is both an advantage (rapid, easy-to-perform tests, no apparatus) and a limitation (cross-reactivity, interferences). Patient cases: A 13-year-old girl was admitted at an emergency unit for somnolence and respiratory acidosis. A multi8 rapid drug test was positive for benzodiazepines, methadone (MTD) and phencyclidine (PCP). To avoid false diagnosis, fluorescence polarization immunoassay, liquid- and gas-chromatography were also performed on both plasma and urine. Rapid tests (different batches) from the same and other manufacturers were involved for this patient and other therapeutic, acute or forensic cases. Results: Bromazepam was identified in plasma (0.4 mg/L) and urine but also tramadol (respectively 0.5 and 25 mg/L), its metabolites and, in urine only, norpropoxyphene (NPPX). No methadone was detected. Among 7 other cases with tramadol detected in urine, 5 were positive with PCP test and 5 with MTD. Drug-added urines confirmed false-positive results for PCP with tramadol but for MTD with NPPX. While tramadol cross-reactivity is very low (0.05%), positive tests, even in a therapeutic context, were observed because phencyclidine cut-off is only 25μg/L. Tramadol can also positive MTD test at very high urine level. The NPPX cross-reactivity, initially 100%, was theoretically reduced to less than 0.025% after a modification of antibody by the manufacturer. Structurally-related formulas could explain such positive results but tests from other manufacturers were negative except in one case with tramadol. Conclusion: The analytical performances (sensitivity, specificity) of such rapid tests must be known by clinicians to avoid false-positive diagnosis. The “on site” use at the emergency unit must be considered as a preliminary test that should be confirmed by alternative methods in a laboratory area. Data exchange between biologists, clinicians and manufacturers is needed to improve the quality of results.

CONTRIBUTION OF TOXICOLOGICAL ANALYSIS TO THE CARE OF DIMETHYL FUMARATE DERMATITIS

Abstract Background: Dimethyl fumarate (DMFu) is a fungicide which is used in Chinese manufactures of furniture and shoes to avoid mould spoiling of fabrics. In 2008, DMFu was found the responsible allergen for several cases of contact dermatitis from armchairs and shoes observed in Europe. In France a national toxicovigilance survey was set up and importation of products containing dimethyl fumarate is now forbidden. Case report: a 36 year-old woman, with no history of previous allergy, was hospitalized because of a severe acute eczema of her feet after wearing a new pair of boots inside which she had noticed desiccant sachets. She strongly reacted on patch testing to DMFu and to the content of a sachet which was identified as DMFu, both at 0.01%, 0.1%, 1% in petrolatum, and also to a piece of the fabric of her boots, patch tested as is. Materials and method: boot fabrics and mould-proof sachets found in the boots were analysed by HPLC/UV/DAD and GC/MS after methanol extraction. Further samples of anti mould agent sachets or shoe fabrics from 5 other patients with suspicion of DMFu dermatitis were analysed with the same procedure. Some of them were transferred to the laboratory several months after healing of the dermatitis. Results: DMFu was found in all the samples from 1 to 100% in sachets or from 20 to 2000 μg/g in the fabrics of shoes, even after one year. These findings contributed to ensure the responsibility of DMFu in the dermatitis of the patients and demonstrate that DMFu may remain a long time in the contaminated fabrics after removal of the sachets. This study also points out the usefulness of the collaboration between dermatologists, biologists and poison centre practitioners.

Impact of Infection Status and Cyclosporine on Voriconazole Pharmacokinetics in an Experimental Model of Cerebral Scedosporiosis

Cerebral Scedosporium infections usually occur in lung transplant recipients as well as in immunocompetent patients in the context of near drowning. Voriconazole is the first-line treatment. The diffusion of voriconazole through the blood-brain barrier in the context of cerebral infection and cyclosporine administration is crucial and remains a matter of debate. To address this issue, the pharmacokinetics of voriconazole was assessed in the plasma, cerebrospinal fluid (CSF), and brain in an experimental model of cerebral scedosporiosis in rats receiving or not receiving cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administered to six groups of rats randomized according to the infection status and the cyclosporine dosing regimen (no cyclosporine, a single dose, or three doses; 15 mg/kg each). Voriconazole concentrations in plasma, CSF, and brain samples were quantified using ultra-performance liquid chromatography–tandem mass spectrometry and high-performance liquid chromatography UV methods and were documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a noncompartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and brain in all groups studied. The voriconazole Cmax and area under the curve (AUC) (AUC0 ≥ 48 hours) values were significantly higher in plasma than in CSF [CSF/plasma ratio, median (range) = 0.5 (0.39–0.55) for AUC0 ≥ 48 hours and 0.47 (0.35 and 0.75) for Cmax]. Cyclosporine administration was significantly associated with an increase in voriconazole exposure in the plasma, CSF, and brain. In the plasma, but not in the brain, an interaction between the infection and cyclosporine administration reduced the positive impact of cyclosporine on voriconazole exposure. Together, these results emphasize the impact of cyclosporine on brain voriconazole exposure.