Plasma concentrations of antiretroviral drugs in a successful 4-days-a-week maintenance treatment strategy in HIV-1 patients (ANRS 170-Quatuor trial).

OBJECTIVES: Charaterization of the plasma concentrations of antiretrovirals in a 4-days-a-week maintenance treatment strategy in the ANRS-170-QUATUOR study. METHODS: Patients were randomized in two groups receiving triple therapy taken 4-days-ON and 3-days-OFF (4/7) or continuous therapy (7/7). Plasma antiretroviral concentrations were monitored during the 'ON-treatment period' (Day 3 or 4 of the 4-day treatment block) and the 'OFF-treatment period' (Day 3 of the 3-day drug cessation) for the 4/7 group, or before the daily drug intake for the 7/7 group, until week-48 (W48). After W48, all patients switched to the 4/7 strategy and were followed until W96. RESULTS: W0 measured concentrations were comparable in both groups, except for raltegravir, concentrations of which were higher in the 4/7 group, and were all above the values usually recommended to be effective in therapeutic drug monitoring. Comparison of ON-period median concentrations between the two groups showed a statistical difference for rilpivirine [88 ng/mL (interquartile range (IQR) = 64-112) for 4/7 arm versus 130 ng/mL (82-160) for 7/7 arm, P < 0.001] and tenofovir [tenofovir disoproxil fumarate: 93 ng/mL (73-135) for 4/7 arm versus 117 ng/mL (83-160) for 7/7 arm, P < 0.001; tenofovir alafenamide: 11 ng/mL (7-15) for 4/7 arm versus 14 ng/mL (11-18) for 7/7 arm, P = 0.001]. Median OFF concentrations were significantly lower (P < 0.001) at the 48 week analysis for all medications except for raltegravir (P = 0.493) and atazanavir (P = 0.105), for which the numbers of patients were very small. CONCLUSIONS: The 4/7-day treatment option led to antiretroviral blood levels close to continuous treatment after the four consecutive days of medication, and to low levels at the end of the non-treatment period.

Four days/week antiretroviral maintenance strategy (ANRS 170 QUATUOR): substudies of reservoirs and ultrasensitive drug resistance.

BACKGROUND: In a 4 days/week (4/7 days) maintenance strategy (ANRS-170 QUATUOR trial), the virological impact of an intermittent strategy was assessed by ultrasensitive virological analyses of reservoirs and resistance. METHODS: HIV-1 total DNA, ultra-sensitive plasma viral load (USpVL) and semen VL were measured in the first 121 participants. Sanger and ultra-deep sequencing (UDS) were performed on the HIV-1 genome (Illumina technology) according to the ANRS consensus. A generalized estimation equation with a Poisson distribution was used to compare changes in the proportion of residual viraemia, detectable semen HIV RNA and HIV DNA within and between the two groups over time. RESULTS: The proportion of participants with residual viraemia at Day 0 (D0) and Week 48 (W48) was 16.7% and 25.0% in the 4/7 days group and 22.4% and 29.7% in the 7/7 days group, respectively (+8.3% versus +7.3%, P = 0.971). The proportion of detectable DNA (>40 copies/106 cells) at D0 and W48 was 53.7% and 57.4% in the 4/7 days group and 56.1% and 51.8% in the 7/7 days group, respectively (+3.7% versus -4.3%, P = 0.358). Semen HIV RNA was detectable (≥100 copies/mL) in 2.2% of participants at D0 and 4.5% at W48 in the 4/7 days group versus 6.1% and 9.1% in the 7/7 days group, respectively (+2.3% versus +3.0%, P = 0.743). Emerging resistance at failure was more frequent in the 4/7 days group detected by Sanger sequencing: 3/6 participants versus 1/4 in the 7/7 days group, and similar with the UDS assay: 5/6 versus 4/4, respectively. CONCLUSIONS: These findings support the potency of a 4/7 days maintenance strategy on virological suppression at the reservoirs and emergent resistance level, including minority variants.

Valproic acid as adjuvant treatment for convulsive status epilepticus: a randomised clinical trial.

BACKGROUND: Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20-40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE. METHODS: This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90. RESULTS: A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) versus placebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89-1.19); p = 0.58]. There were no between-group differences for secondary outcomes. CONCLUSIONS: VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15. TRIAL REGISTRATION NO: NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.

The Role of Uremic Retention Solutes in the MIA Syndrome in Hemodialysis Subjects.

INTRODUCTION: In chronic kidney disease (CKD), the high morbidity and mortality risk for cardiovascular disease (CVD) are not easily explained only on the basis of traditional factors. Among nontraditional ones involved in CKD, malnutrition, inflammation, and atherosclerosis/calcification have been described as the "MIA syndrome." METHODS: In this pilot study, we evaluated the association between the variation in serum levels of 27 uremic retention solutes plus 6 indexes related to the MIA syndrome processes in a population of dialysis patients. RESULTS: As expected, we found a direct correlation between serum albumin and both phosphate and total cholesterol (r = 0.54 and 0.37, respectively; p < 0.05). Moreover, total cholesterol and phosphate directly correlate (r = 0.40, p < 0.05). The relationship between malnutrition and inflammation is highlighted by the correlation of serum cholesterol levels with serum alpha-1 acid glycoprotein and IL-6 levels (r = -0.56, r = -0.39, respectively; p < 0.05). Moreover, the relation between inflammation and atherosclerosis/calcification is supported by the correlation of IL-6 with VEGF levels and vascular smooth muscle cell high-Pi in vitro calcification (r = 0.81, r = 0.66, respectively; p < 0.01). CONCLUSION: We found significant correlations between several uremic retention solutes and malnutrition, inflammation, and atherosclerosis/calcification. Our findings support the hypothesis of a central role of the uremic milieu in the MIA syndrome and ultimately in the pathogenesis of CKD-specific CVD risk factors.

Toxicity and Metabolomic Impact of Cobalt, Chromium, and Nickel Exposure on HepaRG Hepatocytes.

Cobalt, chromium, and nickel are used in orthopedic prostheses. They can be released, accumulate in many organs, and be toxic. The aim of this study is to evaluate the cytotoxicity of these metals on human hepatocytes and to improve our knowledge of their cellular toxicity mechanisms by metabolomic analysis. HepaRG cells were incubated for 48 h with increasing concentrations of metals to determine their IC50. Then, a nontargeted metabolomic study using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was done at IC50 and at a lower concentration (100 nM), near to those found in the blood and liver of patients with prostheses. IC50 were defined at 940, 2, and 1380 µM for Co, Cr, and Ni, respectively. In vitro, Cr appears to be much more toxic than Co and Ni. Metabolomic analysis revealed the disruption of metabolic pathways from the low concentration of 100 nM, in particular tryptophan metabolism and lipid metabolism illustrated by an increase in phenylacetylglycine, a marker of phospholipidosis, for all three metals. They also appear to be responsible for oxidative stress. Dysregulation of these pathways impacts hepatocyte metabolism and may result in hepatotoxicity. Further investigations on accessible biological matrices should be conducted to correlate our in vitro results with the clinical data of prostheses-bearing patients.

Glyphosate and aminomethylphosphonic acid in human hair quantified by an LC-MS/MS method.

An LC-MS/MS method for hair testing of glyphosate and aminomethylphosphonic acid (AMPA), its main biodegradation product, has been developed. After decontamination, 50 mg of hair was ground and sonicated in water for 2 h. The method was fully validated in the 5-500 pg/mg range for glyphosate and 10-500 pg/mg for AMPA, and the limits of detection were 2 and 5 pg/mg, respectively. Matrix effect for glyphosate and AMPA was compensated by an isotope-labeled internal standard. Hair samples from four farmers who regularly used glyphosate and one farmer who used glyphosate but not his wife and 14 hair samples from nonoccupationally exposed subjects were tested. Glyphosate was found in head hair of three farmers, with concentration in the range 14-188 pg/mg. The fourth was found negative but with hair colored in red. Glyphosate was detected in 10 of 14 hair samples from nonoccupationally exposed subjects at concentrations of 11.5 pg/mg or lower and only in one segment (0-3 cm) of the farmer's spouse (6 pg/mg). AMPA was detected in five subjects, above the limit of quantification only in two of three occupationally exposed subjects with positive glyphosate. Further studies should be conducted to validate this potential new biomarker that could be useful for assessing long-term exposure to glyphosate.

Toxicological analysis of a "poison vial" found in the remains of an SS soldier (Maltot, Normandy, France).

In Maltot (Normandy, France), one grave containing the remains of a German soldier, who died in 1944, was excavated amongst other graves and isolated elements. A dozen whole vials were unearthed, resulting in questions about their content. Various screenings were carried out on the contents of one single vial: HPLC-DAD and HR-LC-MS screening after 1/10 dilution in mobile phase, GC-MS and HS-GC-MS after 1/10 dilution in methanol, multi-element research by HR-ICP-MS after total mineralization, and cyanide analysis. Analyzed vial contained approximately 300 µL of a colorless, water-immiscible liquid with a characteristic solvent odor. HPLC-DAD, GC-MS, HR-LC-MS/MS, ICP-MS, and cyanide screenings were negative excluding the presence of cyanide, arsenic, barbiturates, amphetamines, or narcotics. HS-GC-MS analysis highlighted the presence of ethanol, chloroform, and diethyl ether at significant concentrations. Chloroform and diethyl ether were anesthetic products mainly reserved for urgent situations. We hypothesized that the soldier may have been a combat medic working on battlefields. as he was wounded, another possibility could be that he may have used the vials to relieve his pain; however, the immediate severity of the wounds drove us to assess the second hypothesis of delayed death as being less plausible. The high number of vials containing ethanol, chloroform, and diethyl ether, and the massive blood loss leading to quick death led us to support the combat medic or paramedic hypothesis.

Atropine-induced toxicity after off-label sublingual administration of eyedrop for sialorrhoea treatment in neurological disabled patients.

Sialorrhea is a troublesome and disabling symptom defined by the unintentional loss of saliva from the mouth, usually associated with swallowing disorders. Today there is no consensus about the management of sialorrhoea, but off-label use of ophthalmic atropine eyedrop administered sublingually may offer benefits, despite limited safety data. We report 2 cases of atropine overdose after sublingual administration illustrating that atropine can expose to severe adverse effects when administered sublingually. The noncompartmental pharmacokinetic study of atropine performed in 1 patient highlighted that systemic absorption of sublingual atropine was effective (Cmax [1 h] = 2.2 ng mL-1 ; approximately) after a single dose of 1 mg.

Population pharmacokinetic model of blood THC and its metabolites in chronic and occasional cannabis users and relationship with on-site oral fluid testing.

AIMS: To develop a population pharmacokinetic (PP) model of delta-9-tetrahydrocannabinol (THC) and its metabolites in blood and to determine the relationship between blood THC pharmacokinetics and results of on-site oral fluid (OF) testing in chronic (CC) and occasional (OC) cannabis users. METHODS: Fifteen CC (1-2 joints/day) and 15 OC (1-2 joints/week) aged 18-34 years were included, genotyped for their CYP2C9 polymorphisms. Twelve measurements of blood THC, 11-OH-THC and THC-COOH were carried out during the 24-hour period after controlled cross-over random inhalation of placebo, 10 mg or 30 mg of THC. OF tests (DrugWipe® 5S) were performed up to 6 hours and then stopped after two successive negative results. The blood concentrations and their relationship to OF testing results were analysed using a PP approach with NONMEM® and R. RESULTS: A three-compartment model described the pharmacokinetics of THC, with zero-order absorption, and a two-compartment model the metabolites. The fraction of THC converted to 11-OH-THC was 0.27 and the fraction of 11-OH-THC to THC-COOH was 0.86. Smoking 30 mg of THC decreased the THC bioavailability to 0.68 compared to 10 mg. CC showed a 2.41 greater bioavailability than OC, leading to higher Cmax and AUC for the three compounds for the same dose. The best model describing the probability of a positive OF test included THC blood concentration and the group as covariate: for a similar THC blood concentration, a CC was less likely to be positive than an OC. CONCLUSION: OC are more likely to screen positive than CC for a similar blood concentration.

Pharmacological data of a successful 4-days-a-week regimen in HIV antiretroviral therapy (ANRS 162-4D trial).

INTRODUCTION: Few data are available on plasma concentrations of antiretroviral therapy (ARV) during intermittent treatment. OBJECTIVE: To compare plasma concentrations in OFF vs ON treatment periods at several time points during treatment. METHODS: During a successful 48-week multicenter study (ANRS 162-4D trial) of 4 days with treatment (ON) followed by 3 days without treatment (OFF) in adults treated by two nucleoside analogues and a third agent belonging to a boosted protease-inhibitor (PI, darunavir [DRV], atazanavir [ATV], lopinavir [LPV]) or a non-nucleoside-reverse-transcriptase inhibitor (NNRTI, efavirenz [EFV], etravirine [ETR], rilpivirine [RPV]) conducted in 100 patients (96% success), we determined the plasma concentrations of ARV. Blood samples were collected for analysis at inclusion (W0, 7/7 strategy for all patients), W16 and W40 (ON) and at W4, W8, W12, W24, W32 and W48 (OFF). RESULTS: A total of 866 samples was analysed. Plasma concentrations were not statistically lower after 4 days (ON) vs 7/7 days of treatment except for RPV (-30 ng/mL at 4/7, P = 0.003). Significant lower plasma concentrations were observed for OFF vs ON except for ETR (n = 5, P = 0.062). Overall, 87.1% of ON concentrations (ATV 92.1%, DRV 51.1%, LPV 62.5%, EFV 94.4%, ETR 100% and RPV 94.9%) and 21.8% of OFF concentrations (ATV 1.4%, DRV 0.0%, LPV 0.0%, EFV 16.0%, ETR 92.6% and RPV 39.0%) were above the theoretical limit of efficacy of the molecule. In the OFF period, 85.8% of PI concentrations were under the limit of quantification, while 98.0% of NNRTI concentrations were quantifiable. CONCLUSION: Despite low/undetectable PI/NNRTI plasma concentrations in the OFF period, patients maintained an undetectable viral load. The mechanistic explanation should be investigated.

Population pharmacokinetics of lopinavir/ritonavir in Covid-19 patients.

OBJECTIVE: To develop a population pharmacokinetic model for lopinavir boosted by ritonavir in coronavirus disease 2019 (Covid-19) patients. METHODS: Concentrations of lopinavir/ritonavir were assayed by an accredited LC-MS/MS method. The population pharmacokinetics of lopinavir was described using non-linear mixed-effects modeling (NONMEM version 7.4). After determination of the base model that better described the data set, the influence of covariates (age, body weight, height, body mass index (BMI), gender, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C reactive protein (CRP), and trough ritonavir concentrations) was tested on the model. RESULTS: From 13 hospitalized patients (4 females, 9 males, age = 64 ± 16 years), 70 lopinavir/ritonavir plasma concentrations were available for analysis. The data were best described by a one-compartment model with a first-order input (KA). Among the covariates tested on the PK parameters, only the ritonavir trough concentrations had a significant effect on CL/F and improved the fit. Model-based simulations with the final parameter estimates under a regimen lopinavir/ritonavir 400/100 mg b.i.d. showed a high variability with median concentration between 20 and 30 mg/L (Cmin/Cmax) and the 90% prediction intervals within the range 1-100 mg/L. CONCLUSION: According to the estimated 50% effective concentration of lopinavir against SARS-CoV-2 virus in Vero E6 cells (16.7 mg/L), our model showed that at steady state, a dose of 400 mg b.i.d. led to 40% of patients below the minimum effective concentration while a dose of 1200 mg b.i.d. will reduce this proportion to 22%.

Quantification of plasma remdesivir and its metabolite GS-441524 using liquid chromatography coupled to tandem mass spectrometry. Application to a Covid-19 treated patient.

Objectives: A method based on liquid chromatography coupled to triple quadrupole mass spectrometry detection using 50 µL of plasma was developed and fully validated for quantification of remdesivir and its active metabolites GS-441524. Methods: A simple protein precipitation was carried out using 75 µL of methanol containing the internal standard (IS) remdesivir-13C6 and 5 µL ZnSO4 1 M. After separation on Kinetex® 2.6 µm Polar C18 100A LC column (100 × 2.1 mm i.d.), both compounds were detected by a mass spectrometer with electrospray ionization in positive mode. The ion transitions used were m/z 603.3 â†’ m/z 200.0 and m/z 229.0 for remdesivir, m/z 292.2 â†’ m/z 173.1 and m/z 147.1 for GS-441524 and m/z 609.3 â†’ m/z 206.0 for remdesivir-13C6. Results: Calibration curves were linear in the 1-5000 µg/L range for remdesivir and 5-2500 for GS-441524, with limit of detection set at 0.5 and 2 µg/L and limit of quantification at 1 and 5 µg/L, respectively. Precisions evaluated at 2.5, 400 and 4000 µg/L for remdesivir and 12.5, 125, 2000 µg/L for GS-441524 were lower than 14.7% and accuracy was in the [89.6-110.2%] range. A slight matrix effect was observed, compensated by IS. Higher stability of remdesivir and metabolite was observed on NaF-plasma. After 200 mg IV single administration, remdesivir concentration decrease rapidly with a half-life less than 1 h while GS-441524 appeared rapidly and decreased slowly until H24 with a half-life around 12 h. Conclusions: This method would be useful for therapeutic drug monitoring of these compounds in Covid-19 pandemic.

Correction to: Suspected paracetamol overdose in Monrovia, Liberia: a matched case-control Study.

An amendment to this paper has been published and can be accessed via the original article.

Effect of Smoked Cannabis on Vigilance and Accident Risk Using Simulated Driving in Occasional and Chronic Users and the Pharmacokinetic-Pharmacodynamic Relationship.

BACKGROUND: The pharmacokinetic-pharmacodynamic relationship between whole blood δ-9-tetrahydrocannabinol (THC) and driving risk is poorly understood. METHODS: Fifteen chronic cannabis consumers (1-2 joints/day; CC) and 15 occasional cannabis consumers (1-2 joints/week; OC) of 18 to 34 years of age were included. A pharmacokinetic study was conducted with 12 blood samplings over a 24-h period before and after controlled random inhalation of placebo or 10 mg or 30 mg of THC. THC and metabolites were quantified using LC-MS/MS. Effects on reaction time by psychomotor vigilance tests and driving performance through a York driving simulator were evaluated 7 times. A pharmacokinetic-pharmacodynamic analysis was performed using R software. RESULTS: Whole blood peak THC was 2 times higher in CC than in OC for a same dose and occurred 5 min after the end of consumption. THC remained detectable only in CC after 24 h. Despite standardized consumption, CC consumed more available THC from each cigarette regardless of dose. Maximal effect for reaction time was dose- and group-dependent and only group-dependent for driving performance, both being decreased and more marked in OC than in CC. These effects were maximal around 5 h after administration, and the duration was longer in OC than in CC. A significant pharmacokinetic-pharmacodynamic relationship was observed only between T max for blood THC and the duration effect on mean reciprocal reaction time. CONCLUSIONS: Inhalation from cannabis joints leads to a rapid increase in blood THC with a delayed decrease in vigilance and driving performance, more pronounced and lasting longer in OC than in CC. ClinicalTrials.gov Identifier: NCT02061020.

Poisoning associated with inappropriate use of a eutectic mixture of lidocaine and prilocaine before laser-assisted hair removal: about 3 cases.

BACKGROUND: Eutectic mixtures of lidocaine and prilocaine are used during painful dermatological procedures. Poisoning is rarely reported in adults. MATERIAL AND METHOD: We report three cases of women who experienced lidocaine and prilocaine poisoning after laser-assisted hair removal. Plasma levels of local anesthetics were assayed by a fully validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method. CASE REPORTS: The rules of application of the anesthetic cream were observed apart from the maximum dose and/or maximum surface area. One patient applied a higher dose than the maximum recommended dose (140 instead of 60 g) and all patients failed to comply with the maximum recommended surface area (600 cm2). The patients presented an unusual clinical pattern as compared with other local anesthetics overdose: signs of cardiac toxicity with no ECG changes or arrhythmia, neurological toxicity without seizures or coma, and methemoglobinemia. DISCUSSION: Health authorities should publish explicit recommendations targeting users and prescribers with particular emphasis on the maximal surface area of application.

Four-days-a-week antiretroviral maintenance therapy in virologically controlled HIV-1-infected adults: the ANRS 162-4D trial.

Background: Intermittent treatment could improve the convenience, tolerability and cost of ART, as well as patients' quality of life. We conducted a 48 week multicentre study of a 4-days-a-week antiretroviral regimen in adults with controlled HIV-1-RNA plasma viral load (VL). Methods: Eligible patients were adults with VL < 50 copies/mL for at least 1 year on triple therapy with a ritonavir-boosted PI (PI/r) or an NNRTI. The study protocol consisted of the same regimen taken on four consecutive days per week followed by a 3 day drug interruption. The primary outcome was the proportion of participants remaining in the strategy with VL < 50 copies/mL up to week 48. The study was designed to show an observed success rate of > 90%, with a power of 87% and a 5% type 1 error. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29). Results: One hundred patients (82 men), median age 47 years (IQR 40-53), were included. They had been receiving ART for a median of 5.1 (IQR 2.9-9.3) years and had a median CD4 cell count of 665 (IQR 543-829) cells/mm3. The ongoing regimen included PI/r in 29 cases and NNRTI in 71 cases. At 48 weeks, 96% of participants (95% CI 90%-98%) had no failure while remaining on the 4-days-a-week regimen. Virological failure occurred in three participants, who all resumed daily treatment and became resuppressed. One participant stopped the strategy. No severe treatment-related events occurred. Conclusions: Antiretroviral maintenance therapy 4 days a week was effective for 48 weeks in 96% of patients, leading to potential reduction of long-term toxicities, high adherence to the antiretroviral regimen and drug cost saving.

Hair analysis does not allow to discriminate between acute and chronic administrations of a drug in young children.

There are many differences between the hair from children and that of adult subjects, the hair being thinner, more porous with a different growth rate from the usual 1 cm/month observed in adults. In order to determine whether hair analysis could discriminate between chronic use and acute administration of a drug in children like in adults, we analyzed hair from 18 children aged between 1 day and 15 years in whom the administration of different drugs was known (single therapeutic administration or acute intoxication). A strand of hair was sampled within 1 to 45 days after treatment or intoxication. Analysis was conducted using LC/MS/MS. In the 10 youngest children, aged between 1 day and 29 months, the compounds administered in hospital or responsible for intoxication (lidocaine, ropivacaine, diazepam, midazolam, levetiracetam, morphine, ketamine, methadone, buprenorphine, THC, MDMA) were found in all segments of the hair independently of the time of sampling (1-45 days after ingestion). The concentrations detected were similar along the hair shaft, showing a radial diffusion and incorporation of the analytes in the hair of young children from the sebum. Concentrations could be very high when sampled shortly after administration (72 ng/mg for methadone, 75 ng/mg for MDMA after 3 days) and lower when sampling later (1.2 ng/mg for MDMA after 45 days). In these cases, hair analysis allowed to highlight the compounds responsible for intoxication even when they had disappeared from the blood or urine but should not be used to discriminate long-term exposure to a drug. In the eight remaining children aged from 34 months to 15 years, the drugs used in hospital (lidocaine, diazepam, morphine) or responsible for intoxication (THC, codeine, buprenorphine) were not found in any analyzed segments sampled 1 to 5 days after administration of the drugs, in agreement with the non-incorporation of the drugs from the sebum into the hair. For those children aged over 34 months, hair analysis allows to determine the chronic administration of a drug, like in adults.

Detection and quantification of 12 anabolic steroids and analogs in human whole blood and 20 in hair using LC-HRMS/MS: application to real cases.

We developed and validated a method to detect and quantify 12 anabolic steroids in blood (androstenedione, dihydrotestosterone, boldenone, epitestosterone, mesterolone, methandienone, nandrolone, stanozolol, norandrostenedione, tamoxifene, testosterone, trenbolone) and eight more in hair samples (nandrolone phenylpropionate, nandrolone decanoate, testosterone propionate, testosterone benzoate, testosterone cypionate, testosterone decanoate, testosterone phenylpropionate, testosterone undecanoate) using liquid chromatography coupled to high-resolution mass spectrometry. This method used a benchtop Orbitrap mass spectrometer operating with an APCI probe under positive ionization mode. Analysis was realized in full scan experiment with a nominal resolving power of 140,000. After addition of the internal standard (testosterone-D3) and incubation in phosphate buffer pH = 5 for hair, 200 µL of blood and 30 mg of hair samples were extracted with heptane. LOQ and LOD were determined at 5 and 1 ng mL-1 in whole blood and 10 to 100 pg mg-1 and 2 to 20 pg mg-1 in hair according to the compounds, respectively. The method was linear in the 5-1000 ng mL-1 range in whole blood and between 10 or 100 pg mg-1 and 1000 pg mg-1 in hair with correlation coefficients >0.99, and intra- and inter-day accuracy and precision were <14.8% for all compounds except for some esters in hairs (<19.9%) probably due to an important matrix effect for these compounds. This sensitive and specific method to detect anabolic steroids has been successfully applied to two real cases, for which various anabolic steroids in whole blood, urine, and hair were identified and quantified.

Preoperative Evaluation of the Renal Function before the Treatment of Abdominal Aortic Aneurysms.

BACKGROUND: Chronic impaired renal function constitutes a major risk factor of morbi-mortality during the treatment of an abdominal aortic aneurism (AAA). The inflammatory state due to the AAA could result in a reduction in the muscular mass and an overestimation of the glomerular filtration rate (GFR) with the usual formulas. The objective of this study was to determine if the formulas used to evaluate the estimated GFR were adapted in patients with AAA. MATERIALS AND METHODS: Between August 2013 and November 2014, we conducted an exploratory study to evaluate the renal function before surgery for AAA in 28 patients. The renal function was evaluated by (1) the dosage of plasmatic creatinine, (2) the GFR estimated with the Cockroft-Gault, Modification of Diet in Renal Disease (MDRD), and chronic kidney disease epidemiology collaboration (CKD-EPI) formulas, (3) the creatinine clearance (CC), and (4) the direct measurement of the GFR with a reference method (iohexol clearance). Statistical analysis was carried out to compare and correlate the GFR estimated by the various formulas with the GFR measured by the reference technique. RESULTS: The study included 21 men (75%) and 7 women (25%), with a median age of 76 years (58-89). The measured GFR was correlated with the GFR estimated from the CKD-EPI (rho = 0.78, P < 0.0001), the MDRD (rho = 0.78, P < 0.0001), the Cockroft-Gault (rho = 0.65, P = 0.0002), and CC (rho = 0.86, P < 0.0001). However, there were important individual variations between estimated and measured GFR. As regards the detection of the patients presenting a GFR <60 mL/min/1.73 m2, the sensitivities of the CKD-EPI, MDRD, Cockroft-Gault formulas and CC were 64%, 64%, 71%, and 70%, respectively. Specificities were 71%, 79%, 57%, and 100%, respectively. The estimation of the GFR by the CKD-EPI formula had the lowest bias (-3.0). Bland-Altman plots indicated that the estimation of the GFR by the CKD-EPI formula had the best performance in comparison with the other methods. CONCLUSIONS: This study found a statistical correlation between the measurement of the GFR and the various formulas available to estimation the GFR among AAA patients. The CKD-EPI formula is most appropriate. However, there were important individual variations between the measurement and the estimations of the GFR. A larger scale study is necessary to determine the profile of the patients with a risk of error in the estimation of the GFR. The French recommendations on the evaluation of the renal function before AAA treatment remain based on serum creatinine and should be revalued.