Evaluation of amphetamines diffusion in hair after contact with amphetamines-containing blood.

Amphetamine-type stimulants are the third most widely consumed category of illicit drugs worldwide. Faced with the growing problem of amphetamine-type stimulants, numerous qualitative and quantitative techniques have been developed to detect amphetamine (AMP), methamphetamine (MET), MDMA, MDEA or MDA in biological matrices, including hair. Hair analysis is widely used in forensic medicine, but one of its main drawbacks remains external contamination. In this study, we investigated the possibility of hair contamination through external exposure to blood containing AMP, MET MDMA, MDEA or MDA at 2 ng/mL; 20 ng/mL; 200 ng/mL or 2000 ng/mL after 6 h, 1, 3, 7 or 14 days of contact protected from light at room temperature (RT or 20 °C) or at 4 °C. Dried extracts of hair samples were analyzed by UPLC-MS/MS after extensive washings in several baths of water, methanol and acetone before grounding. At the end of our study, contamination of hair was observed from 6 h of contact with all tested amphetamine-type stimulants. The concentrations found in hair ranged from 3 ± 1 to 1464 ± 10 pg/mg, 5 ± 1 to 5070 ± 160 pg/mg, 3 ± 1 to 1269 ± 60 pg/mg, 4 ± 1 to 1860 ± 113 pg/mg and from 8 ± 1 to 1041 ± 44 pg/mg for AMP, MET, MDMA, MDEA and MDA, respectively. Possibly due to its low polar surface area, MET was the most prone to contaminate. As anticipated, hair contamination was mainly dependent on the concentration of all molecules in the contaminating blood, reaching the SOHT cut-off of 200 pg/mg when amphetamine-type stimulants are at toxic or lethal concentrations in the blood. These observations call for caution in interpreting exposure to these substances in such forensic situations.

In vitro stability study of 10 beta-lactam antibiotics in human plasma samples.

BACKGROUND AND OBJECTIVES: Beta-lactam antibiotics are reported for some of them to be subject to a rapid degradation in infusion solutions and in human blood samples. However, the current data of stability available in blood samples are limited to a few number of beta-lactam antibiotics, and the methodology of the corresponding studies may be discussed. The objective of the present study is to evaluate the stability of 10 beta-lactam antibiotics in human plasma samples. METHODS: Stability of amoxicillin, cefazolin, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, imipenem, meropenem, and piperacillin was evaluated at low and high concentrations at 20°C, 4°C, -20°C, and -80°C for 1, 7, 60, and 90 days, respectively. RESULTS: Amoxicillin, cefepime, meropenem, and piperacillin were the least stable antibiotics. The maximum durations allowing the stability for all the evaluated beta-lactams at both tested concentrations were estimated at 3 h, 23 h, 10 days, and 35 days at 20°C, 4°C, -20°C, and -80°C, respectively. CONCLUSION: We recommend to transport antibiotic plasma samples in ice at 4°C and even at -20°C if these samples come from external hospitals. Ideally, plasma samples should be stored at -80°C if possible; if not, the analysis of the samples should be performed as soon as possible in the limit of 10 days after a storage at -20°C.

Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study.

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Rat synovial tissue and blood rapamycin pharmacokinetics after intra-articular injection of free solution or nanoparticles vs free rapamycin intravenous shot.

Intra-articular (IA) injection of a chondroprotective candidate may delay the osteoarthritis (OA) course, but its rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics (PK) of IA rapamycin injected as sustained release in nanoparticles (NPs) versus a free rapamycin suspension in the rat knee compared to an intravenous (IV) free rapamycin shot taken as a reference. Rats received either a single IV injection of free rapamycin (10 µM) or an IA of free or NPs-loaded rapamycin. After sequential exsanguination (15, 30, 60, 180, 360 min, D1, and D7), knee synovial tissue (ST) and cartilage histology were performed. Blood and ST concentrations (LC-MS/MS), PK parameters (area under the curve: AUC; mean residence time: MRT; elimination half-life: T1/2), and IA biocompatibility were assessed. AUCIV was significantly higher for IV than for both IA injections (AUCIA free and AUCIA NPs), with 4248 vs 28 and 74 µg.min.L-1. For ST parameters, we observed a significant difference between AUCIA free and AUCIA NPs with 3735 and 10513 µg.min.L-1 correspondingly. Articular T1/2 and MRT were higher after NPs than after free rapamycin injection: 57.8 and 5.0 h for T1/2 and 80.6 and 5.5 h for MRT, respectively. Histological analysis revealed no chondral injuries and slight transient synovitis only 3 h after the administration of NPs. In the rat knee, rapamycin-loaded NPs delivery via a single IA injection is biocompatible and prolongs synovium joint residency, diminishes blood levels, and reduces detrimental systemic exposure.

Impaired Pharmacokinetics of Amiodarone under Veno-Venous Extracorporeal Membrane Oxygenation: From Bench to Bedside.

BACKGROUND: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. METHODS: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters Cmax, Tmax AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. RESULTS: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of Cmax in the VV ECMO group as compared to controls. No difference in Tmax was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. CONCLUSIONS: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO.

Online SPE UPLC-MS/MS method for the simultaneous determination of 33 psychoactive drugs from swab-collected human oral fluid samples.

Oral fluid is easy and safe to collect and allows the detection of drugs of abuse after local exposure by oral, smoked, and/or inhaled intake, or systemic exposure. A routine online solid-phase extraction UPLC-MS/MS method was developed for the simultaneous determination of 33 psychoactive drugs in oral fluid. The selected drugs were fourteen fentanyl analogs and nineteen other abused psychoactive compounds, including classical narcotics, which were analyzed in a run of 10 min. Limits of detection and of quantification ranged from 0.02 to 1 ng/mL and from 0.02 to 5 ng/mL depending on the analyte, respectively. Matrix effect was in the range - 17 to + 15.7% for all analytes having a deuterated analog. Accuracy ranged from 82.7 to 113.4% and precision CV was at worst of 18.6%. Carryover was below 0.8% for all analytes. Recovery from FLOQSwabs™ showed high variability between analytes with THC, D2FF, 4-ANPP, ocfentanil, and valerylfentanyl being recovered below 40%. A stability study performed over 2 weeks on collecting devices loaded with artificial oral fluid showed huge variation between analytes with morphine, BZE, and norfentanyl being the more stable. Storage at 4 °C allowed drug detection for 1 week except for THC and remifentanil. The method was successfully applied to the detection of abused psychoactive compounds in oral fluid samples from 6 patients admitted to an addiction department.

Tocilizumab plus dexamethasone versus dexamethasone in patients with moderate-to-severe COVID-19 pneumonia: A randomised clinical trial from the CORIMUNO-19 study group.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche.

Rapamycin-loaded Poly(lactic-co-glycolic) acid nanoparticles: Preparation, characterization, and in vitro toxicity study for potential intra-articular injection.

Osteoarthritis (OA) is the most common degenerative joint disease. Rapamycin is a potential candidate for OA treatment by increasing the autophagy process implicated in its physiopathology. To optimize Rapamycin profit and avoid systemic side effects, intra-articular (i.a.) administration appeared helpful. However, Rapamycin's highly hydrophobic nature and low bioavailability made it challenging to develop purpose-made drug delivery systems to overcome these limitations. We developed Rapamycin-loaded nanoparticles (NPs) using poly (lactic-co-glycolic acid) by emulsion/evaporation method. We evaluated these NPs' cytocompatibility towards cartilage (chondrocytes) and synovial membrane cells (synoviocytes) for a potential i.a. administration. The in vitro characterization of Rapamycin-loaded NPs had shown a suitable profile for an i.a. administration. In vitro biocompatibility of NPs was highlighted to 10 µM of Rapamycin for both synoviocytes and chondrocytes, but significant toxicity was observed with higher concentrations. Besides, synoviocytes are more sensitive to Rapamycin-loaded NPs than chondrocytes. Finally, we observed in vitro that an adapted formulated Rapamycin-loaded NPs could be safe at suitable i.a. injection concentrations. The toxic effect of Rapamycin encapsulated in these NPs on both articular cells was dose-dependent. After Rapamycin-loaded NPs i.a. administration, local retention, in situ safety, and systemic release should be evaluated with experimental in vivo models.

SporTRIA study-a multicentre trial protocol for excretion kinetics of triamcinolone acetonide following sport-related intra-articular injections in knees: definitions of the washout periods.

INTRODUCTION: Intra-articular (IA) and peri-articular glucocorticoid (GC) injections are common in sports medicine. However, from 1 January 2022, all injectable GC routes (including IA administration) will be prohibited in-competition by World Anti-Doping Agency (WADA). Owing to these rules, an IA GC treatment out-of-competition could result in an adverse analytical finding in-competition if the washout period is not clearly defined. The aim of this study is to determine the urinary excretion profile of triamcinolone acetonide following IA injection to strengthen the definition of the washout periods. METHODS AND ANALYSIS: This is a prospective multicentre trial to include 20 subjects who practice sports for at least 4 hours/week and present a knee disorder requiring IA injection of triamcinolone acetonide for therapeutic purposes. To determine the excretion profile of triamcinolone acetonide in both urine and blood following IA injection of the drug, We will perform 20 urinary tests and 20 dried blood spot tests, two prior to GC injection (baseline) and the last one at 35 days. Analyses will be performed by the French antidoping agency laboratory in accordance with WADA standards and regulations. ETHICS AND DISSEMINATION: The study protocol was approved by the French ethics committee (CPP Sud Est III-Lyon-2020-070B on 06 October 2020). All subjects will provide written informed consent. The results of this study will be accessible in peer-reviewed publication and be presented at academic conference. TRIAL REGISTRATION NUMBER: NCT04574232.

Multiplex detection of 14 fentanyl analogues and U-47700 in biological samples: Application to a panel of French hospitalized patients.

Synthetic opioids (SO) associated with the recent alarming increase of deaths and intoxications in United States of America and Europe are not detected by the usual first-line opiates drug screening assays. We developed a liquid chromatography tandem mass spectrometry analytical method for the multiplex detection of 14 fentanyl analogues (2-furanylfentanyl, 4-ANPP, 4-methoxybutyrylfentanyl, acrylfentanyl, alfentanil, carfentanil, despropionyl-2-fluorofentanyl, fentanyl, methoxyacetylfentanyl, norfentanyl, ocfentanil, remifentanil, sufentanil and valerylfentanyl) and U-47700 in whole blood and urine samples. The method was validated according to the requirements of ISO 15189. A simple and fast liquid-liquid extraction (LLE) with De-Tox Tube-A was performed leading to better recovery of molecules in urine than in blood samples. Depending on the compound, the limits of detection (LODs) ranged from 0.01 to 0.10 ng/mL and from 0.02 to 0.05 ng/mL in whole blood and urine, respectively. Calibration curves were linear in the range 0.5-50.0 ng/mL and the limit of quantification (LOQ) ranged from 0.10 to 0.40 ng/mL in blood. Internal quality controls at 1 and 40 ng/mL showed intra-day and between-day precision and accuracy bias below 10% in urine and 15% in blood. The method was applied to the screening of 211 urine samples from patients admitted in emergency or addiction departments. The presence of legal fentanyl analogues in 5 urine samples was justified by their therapeutic use as analgesics. Only one patient was concerned by fentanyl misuse and addiction whereas no illegal SO was detected. This study is not in favor of a huge misuse of SO in the Lorraine region.

Temocillin dosage adjustment in a preterm infant with severe renal disease: a case report.

BACKGROUND: Temocillin is a carboxypenicillin antibiotic indicated in complicated urinary tract infections due to susceptible ESBL-producing Enterobacteriaceae. While temocillin therapeutic schemes for adult patients with normal or impaired renal function are evidence based, little is known in paediatric populations. OBJECTIVES: We report herein the management of temocillin treatment in a preterm infant with end-stage renal disease. PATIENTS AND METHODS: The patient was a 7-month-old preterm infant born at 35 weeks gestation and treated by temocillin for 10 days for a bacteraemic urinary tract infection due to a susceptible ESBL-producing Enterobacter cloacae complex strain. Temocillin was administered by continuous infusion using a loading dose of 25 mg followed by a maintenance dose of 70 mg daily. Determination of MIC and temocillin plasma and urinary concentration was performed. RESULTS: Clinical improvement was observed 24 h after the initiation of temocillin treatment. Temocillin concentrations ranged between 21.6 and 35.5 mg/L in urine between the first and the sixth day of treatment and between 47.0 and 61.8 mg/L in plasma after 6 and 10 days of treatment, respectively. Temocillin concentrations were found to be above the determined MIC of 6 mg/L. From the measured concentrations, we can postulate that 100%fT>MIC was achieved in urine and at least equal to 40% in plasma. CONCLUSIONS: Temocillin dosing adjustment performed in the present reported case allowed safe and effective treatment. The strategy described herein could be used as a basis for further clinical studies relative to temocillin use in a paediatric population with renal impairment.

Evaluation of KRAS, NRAS and BRAF mutations detection in plasma using an automated system for patients with metastatic colorectal cancer.

BACKGROUND: Cell-free DNA detection is becoming a surrogate assay for tumor genotyping. Biological fluids often content a very low amount of cell-free tumor DNA and assays able to detect very low allele frequency mutant with a few quantities of DNA are required. We evaluated the ability of the fully-automated molecular diagnostics platform Idylla for the detection of KRAS, NRAS and BRAF hotspot mutations in plasma from patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: First, we evaluated the limit of detection of the system using two set of laboratory made samples that mimic mCRC patient plasma, then plasma samples from patients with mCRC were assessed using Idylla system and BEAMing digital PCR technology. RESULTS: Limits of detection of 0.1%, 0.4% and 0.01% for KRAS, NRAS and BRAF respectively have been reached. With our laboratory made samples, sensitivity up to 0.008% has been reached. Among 15 patients' samples tested for KRAS mutation, 2 discrepant results were found between Idylla and BEAMing dPCR. A 100% concordance between the two assays has been found for the detection of NRAS and BRAF mutations in plasma samples. CONCLUSIONS: The Idylla system does not reach as high sensitivity as assays like ddPCR but has an equivalent sensitivity to modified NGS technics with a lower cost and a lower time to results. These data allowed to consider the Idylla system in a routine laboratory workflow for KRAS, NRAS and BRAF mutations detection in plasma.

Antibiotic prophylaxis with high-dose cefoxitin in bariatric surgery: an observational prospective single center study.

BACKGROUND: The optimal dose of cefoxitin for antibiotic prophylaxis in obese patients remains uncertain. We evaluated the adequacy of a 4-gram dosing regimen of cefoxitin against the most frequent pathogens that infect patients undergoing bariatric surgery. METHODS: This observational prospective study included obese patients who required bariatric surgery and a 4-gram dose of cefoxitin as an antibiotic prophylaxis. Serum concentrations were measured during surgery (incision, wound closure and in case of reinjection). The pharmacokinetic/pharmacodynamic (PK/PD) target was to obtain free cefoxitin concentrations above 4× MIC, from incision to wound closure (100% ƒT>4xMIC). The targeted MIC was based on the worst-case scenario (the highest ECOFF value of Staphylococcus aureus, Enterobacteriaceae and anaerobic bacteria). The secondary outcomes were the factors related to underdosage. RESULTS: Two hundred patients were included. The mean age of the patients was 46 (±12) years-old, and the mean BMI was 45.8 (±6.9) kg/m2 Bypass surgery was the preferred technique (84%). The percentages of patients who met the PK/PD target (100% fT>4xMIC) of cefoxitin were 37.3%, 1.1% and 0% for S. aureus, Enterobacteriaceae and anaerobic bacteria, respectively. BMIs below 50 kg/m2 (OR 0.29, 95% CI [0.11-0.75], P = 0.0107) and a shorter duration of surgery (OR 0.97, 95% CI [0.95-0.99], P = 0.004) were associated with reaching the target concentrations. CONCLUSIONS: In obese patients undergoing bariatric surgery, a regimen of 4 grams of cefoxitin led to an inadequate coverage for most common pathogens. A longer surgery duration and BMI over 50 kg/m2 increase the risk of underdosage.

AEME production in cocaine positive hair after thermal hair treatment.

INTRODUCTION: Currently, hair straightening has become a regular hair treatment for women but likewise for men. Several studies have shown that thermal straightening has an influence on the concentration of ethyl glucuronide and of drugs of abuse content in hair. Heat treatment of hair may decrease concentrations of cocaine (COC) and of cocaethylene (CE) in hair and increase concentrations of benzoylecgonine (BZE). The goal of this study was to evaluate the influence of thermal straightening on anhydroecgonine methyl ester (AEME), a known cocaine smoking marker, in hair. METHOD: 42 positive COC hair samples were treated in vitro with iron plates heated to 200°C. During this treatment one lock of hair was put sequentially 30 times in contact with a hair straightener during 2s, the other lock was not treated. The hair samples were analyzed by a validated GC/MS method for AEME, COC and its metabolites BZE, norcocaine (NC), ecgonine methyl ester (EME) and CE. RESULTS: After treatment, a median increase of concentrations was observed for AEME (110.3%) and BZE (27.6%) whereas a median decrease was found for COC (56.9%), NC (46.7%), EME (33.3%) and CE (41.7%). The median BZE/COC ratio of 0.6 in not treated hair increased to 1.5 in treated hair. CONCLUSION: Regarding our in vitro results, AEME may be produced by thermal hair straightening. Therefore, the presence of AEME in hair should not be used as an irrefutable prove of cocaine smoking. Our study shows that for the interpretation of AEME results in hair, potential heat treatment of hair should be considered. A ratio BZE/COC higher 1 appears to be a good marker to identify thermal treatment of hair before collection. Finally, thermal straightening should be documented during hair collection and should also be considered for the interpretation of COC results in hair.

Paracetamol Misuse and Dental Pain: Results from the French Observational DAntaLor Study.

AIMS: To evaluate the risk of hepatotoxicity due to unintentional paracetamol misuse in patients with acute dental pain. METHODS: A prospective multicenter observational survey was performed in patients consulting, without appointment, the odontology departments of three main French hospitals in the Lorraine region over a 3-month period. Patients were asked to fill out a medical questionnaire while seated in the waiting room. Those who completed the questionnaire, had dental pain, and took paracetamol were included in the DAntaLor study. Misuse was defined as a daily dose of more than 4 g of paracetamol per day. The risk of hepatotoxicity was considered high if the supposed ingested dose was above the threshold of 150 mg.kg-1.24h-1, 125 mg.kg-1.24h-1, or 100 mg.kg1.24h-1 over periods of 24, 48, and 72 hours, respectively. Hepatotoxicity was suspected in the presence of clinical symptoms. RESULTS: Of the 1,810 patients consulting the odontology departments, 741 were included in the study. Painkillers were used in 74.4% of the cases, and paracetamol was taken by 81.7%. Paracetamol was self-medicated in 85.5% of the patients and misused by 6.0%. Clinical symptoms were observed in 1.6% of the patients with no paracetamol misuse. For patients consuming more than 4 g per day and experiencing mild unspecific clinical symptoms of hepatotoxicity, the suspected ingested dose category was below one of the three previously defined thresholds for 11.8% and was above for 40.0%. CONCLUSION: Patients with dental pain are at risk of paracetamol overdose and hepatotoxicity.

Intravenous single administration of amiodarone and breastfeeding.

Amiodarone treatment is contraindicated during breastfeeding. As the regional pharmacovigilance centre, we were contacted for information relative to the possibility of breastfeeding after single intravenous administration of 450 mg amiodarone to a breastfeeding woman. A monitoring of amiodarone concentration in plasma and milk was performed in the mother. At day 4, milk concentration of amiodarone reached a peak (233 µg/L) and milk to plasma ratio was determined to 3.5. Milk concentration was still detectable at day 10 (132 µg/L). The maximal relative infant dose was estimated to be 0.6% of the maternal weight-adjusted dosage, corresponding to 0.18% of the usual posology used in children by parenteral route. The review of the literature retrieved one publication suggesting that a single intravenous administration of 150 mg of amiodarone to a mother represents a negligible infant risk based on low breast milk concentration. The French National Pharmacovigilance database query did not disclose any case of side effects during breastfeeding after a single dose of amiodarone. A very limited exposition of breastfed newborns to amiodarone, as well as a low risk of side effects, is expected after a single administration of amiodarone to their mothers.

Postmortem Hyperthermia: Two Case Reports and a Review of the Literature.

In this daily practice, the forensic pathologist is rarely confronted with postmortem hyperthermia associated with the rapid onset of rigor mortis. We report 2 similar cases where the rectal temperature value taken during the on-scene investigations by the forensic pathologist was greater than 40°C (104°F) in both cases, and rigor mortis was complete within less than 6 hours postmortem. The first case was due to a deadly intoxication by ecstasy and the second one to the deadly association of methadone and a possible neuroleptic malignant syndrome. Infection-related deaths were eliminated. Thus, the association of postmortem hyperthermia and rapid-onset rigor mortis would suggest in the first hypothesis a toxic death, particularly 3,4-methylenedioxymethamphetamine. However, an autopsy and toxicological analysis are necessary to confirm the cause of death.