Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation: impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels.

Voriconazole (VRC) plasma trough concentrations (Cmin) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra- and interindividual variation of VRC Cmin throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC Cmin (n = 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRC Cmin inter- and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC Cmin (r = 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC Cmin. Considering oral therapy, patients with a genetic score of <2 had higher initial VRC Cmin/D than patients with a genetic score of >2 (P = 0.009). Subsequent VRC Cmin remained influenced by the genetic score (P = 0.004) but were also affected by pump proton inhibitor comedication (P < 0.0001). The high variability of VRC Cmin in AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualize a priori the VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRC Cmin within the therapeutic range.

[Accreditation of the toxicological screening: recommendations of the SFBC-SFTA group]. / Accréditation du criblage toxicologique : recommandations du groupe SFBC-SFTA.

Toxicological screening is a specific approach to analytical toxicology that uses analytical tools such as GC-MS, LC-UV (diode array) or LC-MS. Toxicological screening allows the detection and simultaneous identification of a large number of compounds. The results may be based on the use of one or more techniques. As part of the accreditation process for medical biology examinations according to standard NF EN ISO 15189, the group from SFTA and SFBC recommends an approach to accredit toxicological screening. Indeed, the complexity of the accreditation of this analysis comes in particular from the high number of compounds that can be detected. Validation parameters are discussed in the specific context of toxicological screening by considering two distinct approaches: the simple identification of compounds, or the identification and estimation of a range of concentration related to clinical outcomes.

Amitriptyline poisoning of a baby: how informative can hair analysis be?

We reported a case of a 6-month-old baby girl who was hospitalized in the pediatric emergency for central nervous system disorders then coma. Toxicology analysis showed the presence of amitriptyline (AMI) and its metabolite nortriptyline (NOR) in blood and urine of the baby. Additional investigations suggested a shaken baby syndrome. Given the family context, a judge ordered hair tests for both the child and his parents to document drug exposure. A liquid chromatography tandem mass spectrometric (LC-MS/MS) method was then developed to quantify AMI and NOR in hair. After decontamination and segmentation, 20 mg of hair was incubated overnight at 55 °C in methanol (MeOH). The LC-MS/MS method used an online solid phase extraction and the analysis was performed using two transitions per compound. The LOQ and LOD for the two compounds were estimated at 0.0075 ng/mg and 0.005 ng/mg respectively. All hair segments tested for both parents were negative. For the baby two strands of hair were collected one day after the acute intoxication for the first and 5 weeks later for the second. The first strand was not decontaminated before analysis to avoid losing specimen. The high and relatively homogenous concentrations of AMI (with a range of value from 6.65 to 9.69 ng/mg) and NOR (with a range of value from 7.12 to 8.96 ng/mg) measured suggested that contamination could have occurred. The analysis of the second strand after decontamination allowed to detect AMI and NOR in all hair segments. The obtained values varied between 0.54 and 1.41 ng/mg for AMI and between 1.26 and 4.00 ng/mg for NOR. These results supported the hypothesis of a chronic exposure during several months before hair collection with regular increase. However a single overdose could not be totally excluded. The interpretation of results must take into account the pharmacological and physiological parameters of hair of the children.

Severity of deliberate acute baclofen poisoning: a nonconcurrent cohort study.

Interest in high-dose baclofen treatment for alcohol dependence has increased over the past few years. In the meantime, the rate of acute baclofen poisoning has increased and life-threatening cases have been reported. Thus, severity of acute poisoning could lessen the benefit of baclofen treatment. Our aim was to evaluate the severity of acute baclofen poisoning independently of confounders and to assess whether severity is correlated with the reported ingested dose. We prospectively included consecutive patients with acute and deliberate baclofen overdose and compared them with gender and age-matched patients from a retrospective cohort of common acute medicine self-poisoning. The primary end-point was the adjusted risk ratio of mechanical ventilation. We also analysed the lengths of mechanical ventilation and risks of aspiration pneumonitis and convulsions. We finally examined the correlation between the supposed reported ingested dose and the severity of poisoning. Fourteen baclofen-poisoned patients were included and matched to 56 poisoned patients. Median age was 45 y/o (40-58), and men comprised 43% of patients. In logistic regression, the adjusted risk ratio of mechanical ventilation was 7.9 (1.4-43.5; p=0.02) for baclofen-treated patients. Aspiration pneumonitis was more frequent in baclofen-treated patients (29% versus 2%; p=0.005), and the length of mechanical ventilation was significantly correlated with the reported ingested dose of baclofen (Spearman coefficients: 0.48; p<0.001). Our results show that acute baclofen poisoning is more severe than other acute medicine overdoses, and severity seems to be correlated with the ingested dose of baclofen. These results raise some questions about the safety of high-dose baclofen treatment for alcohol dependence.

[Recommendations for the prescription, implementation and interpretation of medical examinations in biology in the context of severe poisoning]. / Recommandations pour la prescription, la réalisation et l'interprétation des examens de biologie médicale dans le cadre des intoxications graves.

A multidisciplinary working group named "Toxicology and clinical biology" and whose members belong to the French Society of Clinical Biology (SFBC), Critical Care Medicine Society of French Language (SRLF), the French Society of Medical Emergency (SFMU), the French Society of Analytical Toxicology (SFTA), the Society of Clinical Toxicology (STC), and the National College of Biochemistry (CNBH) updated the professional practice recommendations published in 2003. These recommendations aimed the biologists who are not specialized in toxicology and more largely all the health professionals involved the management of severely poisoned patients. Among the data published in the initial edition, only the major table dealing with severe poisonings was updated, as all other supplements remained valid. The current revised table details poisonings due to fifty-five different xenobiotics and presents their main clinical features, useful biomarkers of toxicity, methods of identification or assays available in the emergent setting with their respective relevance and recommended delays to obtain their result. Assessments with a good agreement among the working group members regarding all laboratory issues for poisoning management are presented. A table updates the list of the main currently useful antidotes. A section on the value and place of toxicology screening was added.

Lack of specificity for the analysis of raltegravir using online sample clean-up liquid chromatography-electrospray tandem mass spectrometry.

BACKGROUND: Raltegravir is the first antiretroviral agent to target the human immunodeficiency virus-1 (HIV-1) integrase. It is indicated, in association with other antiretrovirals, in the treatment of acquired immunodeficiency syndrome (AIDS) in antiretroviral treatment-experienced adult patients with viral resistance. To evaluate the feasibility of raltegravir therapeutic drug monitoring, we developed a rapid and specific analytical method for the quantification of raltegravir in human plasma by online sample clean-up liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: After protein precipitation (with 100 microL of acetonitrile/methanol (50/50)) of 25 microL of plasma, fast online matrix-clean-up was performed using a column switching program. The chromatographic step was optimized to separate raltegravir and its glucuronide metabolite (G-raltegravir). Multiple reaction monitoring (MRM) was used for detection of raltegravir and G-raltegravir. In the absence of G-raltegravir standard, G-raltegravir identification was confirmed by beta-glucuronidase pre-treatment. RESULTS: A total analysis of 3.8 min was needed to separate raltegravir to G-raltegravir. The method was linear between 10 and 3000 ng/mL for raltegravir. Analytical recovery was 94+/-1%. Variation coefficients ranged between 5% and 8.4%. Pre-treatment of plasma from a patient under raltegravir treatment with beta-glucuronidase suppressed G-raltegravir peak. CONCLUSION: We describe a fast online LC-MS/MS assay that is valid and reliable for the quantification of raltegravir, despite the lack of specificity that could occur in MRM scanning mode experiments.