Minors and young adult's hospitalizations after "chimique" consumption in Mayotte Island: Which substances are involved?

OBJECTIVES: Over the last 10 years, the use of an unknown drug called "chimique" has emerged, among adolescents and young adults in precarious situations in Mayotte Island. To date, the exact composition of "chimique" is still poorly documented, but seizures made on the Island at the same time indicated that it would be mainly composed of synthetic cannabinoids receptor agonists (SCRAs). The objective of this study was to identify which substances, among those consumed under the name of "chimique", leading to hospital admissions. METHODS: Between 1st march and 30th June 2019, all patients, over 14 years old, hospitalized in the emergency department of Mayotte hospital after use of "chimique" for which the physician required toxicological analysis were included. Blood samples and clinical data were recorded for each patient. Toxicological analyses were performed using high resolution mass spectrometry (UPLC-MS/QTOF). RESULTS: Twelve patients were included: 11 males and 1 female. The mean age was 26 years (median age: 22). There were 2 minors. Clinical presentations varied, mainly psychiatric and neurologic disorders were observed. No death was reported. Toxicological analysis identified psychoactive substances such as THC and/or its metabolites (n=3) and MDMB-4en-PINCA (n=2). The other substances identified were mainly part of the patients' treatment. CONCLUSION: This is the first study conducted in the Indian Ocean confirming the presence of SCRAs in the "chimique". For a while, the consumption of SCRAs in France seemed to be of limited importance. However, their use has become important in the Indian Ocean since the spread of "chimique" in Mayotte. It continues to spread especially in Reunion Island since 2017 under the name of "chamane".

Hair Analysis of Methoxphenidine in a Forensic Chemsex Case.

Methoxphenidine (MXP, 2-MeO-diphenidine) is a dissociative anesthetic drug of the diarylethylamine type, recently introduced for recreational purposes through the online-based sale of new psychoactive substances (NPSs). The concentration of MXP in hair has never been reported, either in cases of chemsex use or in fatal cases. A 55-year-old man was found dead at his home the morning after a chemsex party. Toxicological analyses indicated high concentrations of MXP in femoral blood (606 µg/L), cardiac blood (254 µg/L) and hair (13 ng/mg). We also identified 3-methylmethcathinone (3-MMC) in femoral blood (traces) and urine (238 µg/L). The concentrations of all other drugs were consistent with living subjects. This case highlights the risk of MXP poisoning in the context of chemsex and emphasizes the importance of including NPS in postmortem toxicology examinations.

Biomonitoring of occupational exposure to 5-FU by assaying α-fluoro-ß-alanine in urine with a highly sensitive UHPLC-MS/MS method.

5-Fluorouracil (5-FU) is one of the most widely used antineoplastic drugs handled by healthcare professionals (HCP). To monitor occupational exposure to 5-FU, a highly sensitive ESI-UHPLC-MS/MS method was developed for the assay of its main human metabolite, α-fluoro-ß-alanine (FBAL), in urine. After a derivatization step, solid phase extraction was used for the urine. Good linearity (r > 0.996), precision (CV < 14.76%), and accuracy (bias < 12.16%) were achieved. The lower limit of quantification (LOQ), 20 pg ml-1, is the lowest one published to date. Seven urine samples from 73 HCP exposed to 5FU were positive for FBAL, indicating 5FU contamination (9.6%). FBAL urine concentrations ranged from 25 to 301 pg ml-1. Such an efficient analytical tool combining high specificity with high sensitivity is essential for the reliable detection and routine biological monitoring of healthcare professionals occupationally exposed to this widely used antineoplastic drug. This method allows biomonitoring of occupational exposure to 5-fluorouracil in a routine manner, with the aim of assessing the effectiveness of collective and individual protective measures.

High throughput routine determination of 17 tyrosine kinase inhibitors by LC-MS/MS.

Several studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKI) can improve their benefit in cancer. An analytical tool has been developed in order to quantify 17 tyrosine kinase inhibitors and 2 metabolites in human plasma (afatinib, axitinib, bosutinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, ponatinib, regorafenib, regorafenib M2, regorafenib M5, ruxolitinib, sorafenib, sunitinib, vandetanib). Drugs were arranged in four groups, according to their plasma concentration range: 0.1-200ng/ml, 1-200ng/ml, 4-800ng/ml and 25-5000ng/ml. Solid phase extraction was used and separation was performed with HPLC using a gradient system on a solid core particle C18 column (5×2.1mm, 1.6µm). Ions were detected with a triple quadrupole mass spectrometry system. This assay allows rapid determination of 19 TKI in less than 5min per run. This high throughput routine method will be useful to adjust doses of oral anticancer drugs in order to improve treatments efficacy.

Recurrent herpetic keratitis despite antiviral prophylaxis: A virological and pharmacological study.

Recurrent herpes simplex keratitis (HSK) is a leading infectious cause of blindness in industrialized countries. Antiviral prophylaxis (AVP) may fail to prevent recurrence of HSK due to viral resistance, inadequate dosing, or poor patient compliance. In this prospective multicenter study, we enrolled immunocompetent patients with recurrent HSK despite AVP. Ocular samples were tested by PCR for herpes simplex virus 1 (HSV-1). HSV-1 drug resistance was assessed with a genotypic assay based on UL23 and UL30 gene sequencing. After curative full dose valacyclovir (VACV) treatment was started, peak and trough acyclovir (ACV) plasma concentrations were measured, and patient compliance to AVP was assessed with a questionnaire. The study sample was comprised of 43 patients. Six (14%) patients were positive for HSV-1 using PCR, of whom 5 (83%) harbored genotypically ACV-resistant (ACVR) virus, due to mutations in UL23 (n = 4) or UL30 (n = 1). Disease duration was statistically significantly longer in patients with viral resistance compared to other HSK patients [35.5 ± 23.4 years (range, 6.8-68.4 years) versus 11.1 ± 12.3 years (range, 0.8-56.3 year) respectively; Mann-Whitney p = 0.01)]. While patients were treated with full dose VACV, trough ACV plasma concentrations were below the threshold for ACV sensitivity in 9.5% of cases, and compliance was poor in 5.3% of cases. To summarize, HSV-1 resistance to ACV seems to be a significant cause of failure of prophylaxis in patients with HSK and is associated with longer disease duration. Most PCR-positive samples contained genotypically ACVR virus and identification may aid in adapting treatment. Incomplete 24-h drug coverage may also explain some cases of failure of prophylaxis.

Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma.

INTRODUCTION: Dabrafenib and trametinib bitherapy provides significant benefits in BRAFV600mut metastatic melanoma patients; however, adverse events (AE) occur, leading to dose reduction in 33% of patients. We aimed to investigate a relation between plasma dabrafenib and trametinib concentrations and occurrence of AE. METHODS: Plasma samples from metastatic BRAFV600mut melanoma patients treated with dabrafenib±trametinib were prospectively collected at trough concentration before any dose reduction. Dabrafenib and trametinib were measured by UPLC-MS/MS. Plasma threshold of concentration associated with dose reduction for AE was studied by ROC-curve analysis. RESULTS: Twenty-seven patients (13M/14F) were included. Dabrafenib trough plasma concentrations displayed high interindividual variability, ranging from 15.4 to 279.6ng/ml, mean±SD 58.7±61.1ng/ml. Trough trametinib plasma concentrations ranged from 4.1 to 23.8ng/ml, mean±SD 11.9±4.1ng/ml. Mean trough dabrafenib plasma concentration was higher in patients with AE requiring dose reduction (30%) than in other patients: 118.6ng/ml and 33.5ng/ml respectively (P<0.0001). Adverse events leading to dabrafenib dose reduction were all grade≥2. No differences in mean trametinib trough plasma concentrations were observed in patients requiring or not dose reduction. A dabrafenib trough plasma threshold of 48ng/ml can predict the occurrence of adverse events requiring dose reduction.

An UPLC-MS/MS method for the quantification of BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (cobimetinib, trametinib, binimetinib) in human plasma. Application to treated melanoma patients.

Targeted therapies for cancers are fast-growing therapies. For instance kinase inhibitors such as BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are increasingly used to treat malignant melanoma. The metabolic profile of these drugs can result in great interindividual variability, justifying therapeutic drug monitoring (TDM). We describe a rapid and specific method for quantification of 2 BRAFi (vemurafenib, dabrafenib) and 3 MEKi (cobimetinib, trametinib and binimetinib). Chromatography was performed on a Waters Acquity-UPLC system with CORTECS C18+ column, under a gradient of 10% acetic acid in water/acetonitrile. An Acquity-TQD® with electrospray ionization was used for detection. Samples were prepared by solid phase extraction (Oasis® MCX microElution) before injection in the system. Calibration curves ranges from 0.4 to 100µg/ml for vemurafenib, from 1 to 1000ng/ml for dabrafenib, from 0.5 to 500ng/ml for cobimetinib and binimetinib, and from 0.75 to 250ng/ml for trametinib. At all concentrations the bias was within ±15% of the nominal concentrations and precision was ≤15%. All results were within the acceptance criteria of the EMA guidelines on method validation. This rapid, sensitive and specific UPLC-MS/MS method can perform simultaneous quantification of targeted therapies used in malignant melanoma and is usable for routine TDM.

Highly sensitive LC-MS/MS methods for urinary biological monitoring of occupational exposure to cyclophosphamide, ifosfamide, and methotrexate antineoplastic drugs and routine application.

Highly sensitive ESI-LC-MS/MS methods were developed for urinary biological monitoring of occupational exposure to cyclophosphamide (CP), ifosfamide (IF), and methotrexate (MTX), which are hazardous antineoplastic drugs frequently handled by healthcare professionals. Extraction methods consisted of liquid/liquid extraction for simultaneous urinary CP and IF assays, and of solid phase extraction for the urinary MTX assay. A good linearity (r2>0.997), precision (CV<14.6%), and accuracy (bias<9.9%) were achieved for all compounds. The limit of detection (LOD) was 10pg/ml and the lower limit of quantification (LOQ) was 20pg/ml for all three drugs. Applying these methods in routine, more than 116 healthcare professionals occupationally exposed to antineoplastic drugs were monitored and 635 urines were analysed. Eleven healthcare professionals (9.5%) were found to be contaminated to at least one of the three antineoplastic drugs. Among analysed urines, 22 samples were found positives. The measured concentrations ranged from 20.1 to 1850pg/ml and, for six samples, concentrations were at CP trace level, between the LOD and LOQ values (10-20pg/ml). Such efficient analytical tools combining high specificity with high sensitivity are essential for reliable detection and routine biological monitoring of healthcare professionals occupationally exposed to these widely used antineoplastic drugs. These methods allow to monitor the healthcare professionals exposure to antineoplastic drugs in the aim to assess the effectiveness of collective and individual protective measures.

Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting.

BACKGROUND: Imatinib has dramatically improved the prognosis of advanced gastrointestinal stromal tumours (GISTs). Clinical trial data showed that patients with trough imatinib plasma concentrations (Cmin) below 1100 ng/ml (quartile 1) had shorter time to progression, but no threshold has been defined. The main objective of this study was to investigate in advanced GIST whether a Cmin threshold value associated with a longer progression-free survival (PFS) could be specified. This would be the first step leading to therapeutic drug monitoring of imatinib in GIST. PATIENTS AND METHODS: Advanced GIST patients (n=96) treated with imatinib 400 mg/d (41 stomach, 34 small bowel, and 21 other primary site localisations) were prospectively included in this real-life setting study. Routine plasma level testing imatinib (Cmin) and clinical data of were recorded prospectively. RESULTS: Small bowel localisation was associated with an increased relative risk of progression of 3.09 versus stomach localisation (p=0.0255). Mean Cmin (±standard deviation) was 868 (±536) ng/ml with 75% inter-individual and 26% intra-patient variability. A Cmin threshold of 760 ng/ml defined by log-rank test was associated with longer PFS for the whole population (p=0.0256) and for both stomach (p=0.043) and small bowel (p=0.049) localisations when analysed separately. Multivariate Cox regression analysis found that Cmin above 760 ng/ml was associated with 65% reduction risk of progression (p=0.0271) in the whole population independently of the anatomical localisation. CONCLUSION: Concentration of imatinib significantly influences duration of tumour control treatment in GIST patients with a Cmin threshold of 760 ng/ml associated with prolonged PFS in real-life setting.

Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory.

This study set out to examine in a large real-life cohort of patients with chronic myeloid leukemia (CML) the impact of imatinib threshold of 1000 ng/mL on molecular response, as suggested in a small subset of patients. Patient plasma samples were submitted from around France to a central facility, free of charge under the auspices of the European Treatment and Outcome Study (EUTOS) for CML. Submitting physicians were required to complete an 'imatinib monitoring request form', including details of why therapeutic drug monitoring (TDM) was requested, dose and duration of imatinib treatment, cytogenetic and molecular response, adverse events, and concurrent medications. Imatinib trough plasma concentration (C(min)) was measured at the central facility. Among 1985 eligible plasma samples analyzed, from 1216 CML patients, imatinib C(min) correlated positively with reported imatinib dose, but interpatient variability in C(min) was high (60%). A logistic regression analysis revealed that treatment duration and imatinib C(min) > 1000 ng/mL were significantly associated with major and complete molecular responses with odds ratios of 1.69 and 2.08, respectively. These data support in real-life setting that imatinib C(min) threshold of 1000 ng/mL is associated with major and complete molecular response and that TDM could play an important role in dose optimization.

Suicide with cisatracurium and thiopental: forensic and analytical aspects.

The suicide of a 43-year-old male by intravenous injection of cisatracurium, a non-depolarizing neuromuscular blocking agent, and thiopental, an ultra-short-acting barbiturate, is presented. Systematic toxicological screening by gas chromatography-mass spectrometry (GC-MS), liquid chromatography (LC)-diode-array detection, and LC-MS-MS confirmed the presence of thiopental. A large peak in the GC-MS chromatogram was matched by the Pfleger-Maurer library as corlumine, but neither atracurium neither its metabolite, laudanosine, were detected. To confirm the absence or the presence of laudanosine in the blood sample, an ultra-performance liquid chromatography-MS-MS method for cisatracurium and laudanosine quantification was developed. The calibration range was 2.5-500 ng/mL for laudanosine and 10-500 ng/mL for cisatracurium. The biases were lower than 12.3%. Intraday and interday precisions, expressed as coefficient of variation, were lower than 13.3%. This method allowed to confirm the presence of laudanosine and measurement of laudanosine in all samples. The femoral blood concentration was therapeutic (0.46 µg/mL). This case report documents a possible analytical pitfall and describes a simple and fast method for cisatracurium determination. Moreover, the purpose of this case report was to document the postmortem redistribution of cisatracurium and laudanosine, which could help make it possible to interpret tissue or cardiac blood concentrations in forensic cases where femoral blood is not available.

Simultaneous determination of nine tyrosine kinase inhibitors by 96-well solid-phase extraction and ultra performance LC/MS-MS.

BACKGROUND: Tyrosine Kinase Inhibitors (TKIs) are a class of targeted drugs for the treatment of malignant pathologies. The metabolic profile of these drugs can result in great interindividual variability, thus therapeutic drug monitoring (TDM) is of importance. Here, a rapid and specific method for quantification of nine TKIs in plasma samples is described. METHODS: Chromatography was performed on a Waters Acquity-UPLC® system with BEH C18-50*2.1 mm column, under a gradient of ammonium formate-acetonitrile. An Acquity-TQD® with electrospray ionization was used for detection. Samples were prepared by solid phase extraction (Oasis® MCX µElution) and eluate was injected in the system. RESULTS: Calibration curves ranged from 10 to 5000 ng/mL for imatinib, its metabolite, nilotinib, lapatinib, erlotinib and sorafenib and from 0.1 to 200 ng/mL for dasatinib, axitinib, gefitinib and sunitinib. Peaks of each compound (retention time from 0.76 to 2.51 min) were adequately separated. The mean relative extraction recovery was in the range of 90.3-106.5% thanks to the use of stable isotopes as internal standard. There was no significant ion suppression observed at the respective TKI retention times. CONCLUSION: This rapid, sensitive and specific UPLC/MS-MS method is able to perform simultaneous quantification of nine TKIs in human plasma and usable for routine TDM.

Establishment of the medico-legal cause of death in two atypical cases of gas embolism in hospital: Importance of the scene.

Two cases of lethal gas embolism occurring in a hospital setting are presented. These did not differ with regards to the medical cause of death (MCOD), but did so with regard to the medico-legal cause of death (MLCOD). In the first case, the immediate recognition of a suspicious death and subsequent conservation of the scene led to a certain MLCOD (autolysis). In the second case, the death was initially treated as of natural cause. The subsequent disruption of the scene of death led to loss of evidence essential to establish the MLCOD, that was concluded to be undetermined. These cases illustrate the importance of medico-legal treatment of scenes of death to arrive at the MLCOD, and that the hospital setting is no exception especially as in view of potential medical liability.

[Therapeutic drug monitoring of tyrosine-kinase inhibitors in the treatment of chronic myelogenous leukaemia: interests and limits]. / Niveau de preuve du suivi thérapeutique pharmacologique des inhibiteurs de tyrosine-kinase dans le traitement des leucémies myéloïdes chroniques.

During the last decade, imatinib was current gold standard treatment of chronic myelogenous leukemia (CML), showing a great effectiveness. Thus, the Therapeutic Drug Monitoring (TDM), rarely applied in clinical oncology practice, did not appear necessary at the moment. However, the absence of response among patients and the metabolic profile of imatinib (involving the CYP3A4) suggested the existence of a great interindividual variability. During the last 4 years, studies about the pharmacokinetic/pharmacodynamic relationship have confirmed this variability and highlighted a relation between the trough concentrations of imatinib and the clinical response. An effectiveness threshold, close to 1000 ng/mL, seems to be correlated with better cytogenetic and molecular responses. Consequently, TDM could assist in investigation of the observance, the absence of response, the drug-drug interactions, but the proof of its utility requires complementary studies. In conclusion, the level of proof of imatinib TDM in LMC varies between levels "recommended" and "potentially useful".

A method to measure deferasirox in plasma using HPLC coupled with MS/MS detection and its potential application.

Iron overload resulting from transfusion dependency in some patients with chronic anaemia can be prevented by chelation. Deferasirox is an oral alternative to the well studied but inconvenient deferroxamine therapy. The pharmacokinetic parameters of this new drug suggest potential interindividual variability and patients might benefit from pharmacologic drug monitoring. We developed an liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) method to quantify deferasirox in plasma. After protein precipitation, samples were injected onto an XTerra RP18 column with a gradient of acetonitrile and formiate buffer (4 mM, pH 3.0) with 5% methanol. Detection by electrospray ionization mass-spectrometry was performed using the multiple reaction monitoring mode. Sixty-three samples from patients treated with deferasirox were then analyzed to evaluate pharmacokinetic/pharmacodynamic relationships. Calibration curves were linear from 0.5 to 40 microg/mL. Interday and intraday precision were lower than 8.9% and 7.3%, respectively. Bias did not exceed 12.7%. Plasma iron overload did not interfere with analysis. Plasma drug concentrations of patients treated by deferasirox were compared with plasma ferritin, considered as a marker of treatment efficacy. No statistically significant correlation was observed, though higher ferritin concentrations (>1000 microg/L, n = 30) were observed in patients with lower mean deferasirox concentration (9.5 +/- 9.1 microg/mL). This simple method is suitable for routine monitoring of deferasirox concentrations in plasma as it requires very few steps and has a short runtime. It allows evaluation of patient compliance, drug-drug interactions, and further investigations of pharmacokinetic/pharmacodynamic relationships.

[Not Available]. / Niveau de preuve du suivi thérapeutique pharmacologique des inhibiteurs de tyrosine-kinase dans le traitement des leucémies myéloïdes chroniques.

During the last decade, imatinib was current gold standard treatment of chronic myelogenous leukemia (CML), showing a great effectiveness. Thus, the Therapeutic Drug Monitoring (TDM), rarely applied in clinical oncology practice, did not appear necessary at the moment. However, the absence of response among patients and the metabolic profile of imatinib (involving the CYP3A4) suggested the existence of a great interindividual variability. During the last 4 years, studies about the pharmacokinetic/pharmacodynamic relationship have confirmed this variability and highlighted a relation between the trough concentrations of imatinib and the clinical response. An effectiveness threshold, close to 1000 ng/mL, seems to be correlated with better cytogenetic and molecular responses. Consequently, TDM could assist in investigation of the observance, the absence of response, the drug-drug interactions, but the proof of its utility requires complementary studies. In conclusion, the level of proof of imatinib TDM in LMC varies between levels "recommended" and "potentially useful".

Efficiency and safety of oxcarbazepine in mood disorders: a naturalistic study exploring the interest of plasma dosages.

OBJECTIVE: To investigate whether measurement of plasma levels can predict tolerance to oxcarbazepine (OXC). METHODS: We reviewed medical records to identify all inpatients consecutively treated by OXC at the University Department of Psychiatry in Bordeaux. Adverse effects were rated before treatment onset, at day 3, then every week and at discharge or at discontinuation. Residual hydroxy-OXC concentrations were measured on blood samples at the same periods. RESULTS: OXC was prescribed to 20 patients with bipolar (n=18) or schizoaffective bipolar-type disorder (n=2). Reported side effects were transient and occurred mostly at the beginning of the treatment. Three patients stopped OXC because of severe cutaneous side effects. Residual hydroxy-OXC plasma levels were similar in patients with or without occurrence of side effects at all times of assessment. CONCLUSION: Our data suggest that the occurrence of severe side-effects is relatively high with OXC. Measurement of plasma OXC levels does not appear to be of interest in clinical practice since plasma concentrations are not predictive of the occurrence of side effects.

Quantification methods of folpet degradation products in plasma with HPLC-UV/DAD: application to an in vivo toxicokinetic study in rats.

Solid-phase extractions followed by HPLC-UV/DAD methods were developed for occupational biological monitoring or forensic investigations of the fungicide folpet using its degradation products, phthalimide and phthalamic acid as plasma biomarkers. These methods show good linearity (r>0.9955), precision (CV<15%) and accuracy (bias<14.8%). The lower limits of quantification for phthalimide and phthalamic acid were 10 and 20 ng/ml and the absolute recoveries were higher than 86% and 68%, respectively. Applying these methods, a plasma toxicokinetic study of folpet in rats after intratracheal administration of Folpan 80WG showed that inhalation of folpet could be a route of exposure with an important systemic absorption.