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.

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.

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.

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.

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.

Substance use and misuse in a mountain ultramarathon: new insight into ultrarunners population?

Endurance and ultra-endurance events have become increasingly popular. The aim of our study was to explore the use of medication among endurance runners participating in the 2014 Infernal Trail des Vosges. Among the 389 runners engaged, 297 (76.3%) completed a specific questionnaire dealing with substance use/misuse. Our results show a 27% (before the race) and 18% (during the race) prevalence of substance use. The two major classes of substances used were non-steroidal anti-inflammatory drugs (NSAIDs; 9.8%) and painkillers (6.7%), principally because of osteo-articular pain (29.6%) or to prevent pain (28.2%). A positive correlation was found between substance consumption before (past month) and during the race (overall medication: p < 0.0001; NSAIDs: p = 0.008). Our results could be explained by the specific characteristics of ultrarunners predominantly motivated by personal achievement and general health (recreational approach). However, education interventions should further be delivered regarding the risks of substance use in ultra-endurance events.

[Counterfeit and Falsified Drugs: an Overview]. / Trafic de faux médicaments : panorama 2014.

If the traffic of fake medicines may represent an economic threat for the pharmaceutical industry, it can also be responsible of safety concerns for patients. Despite fake drugs represent a real threat for public health, the intended punishments are until now only based on intellectual property rights. Estimated to generate more than 55 billion euros per year, the traffic of falsified drugs varies from a country to another one. Indeed, the proportion of falsified drugs ranges from 1% in industrialized countries with a regulated and controlled distribution system to 60% of medicines in some developing countries. Currently, the measures developed to limit this traffic concern five main areas: legislation / regulation, cooperation, enforcement, technology and communication. Communication actions should be performed to inform health professionals as the populations about the risks of using drugs purchased outside the legal drug market.

Death of an alcohol-dependent patient following intentional drug intoxication: implication of baclofen?

Used in the treatment of spasticity at low doses, baclofen is also prescribed off-label at high doses for the treatment of alcohol dependence. Several cases of baclofen intoxication have been reported, but only 1 case deals with the treatment of alcohol dependence. Thus, we report the first death in the context of baclofen off-label use of an alcohol-dependent patient with a high blood baclofen concentration after intentional drug intoxication. The safety profile of baclofen in the treatment of alcohol dependence is reviewed and discussed, underlining the obligatory caution that may support any prescription of high doses of baclofen in this off-label indication and especially in patients with concomitant psychiatric disorders.

[Methandienone misuse: interest of medical anti-doping units]. / Dopage sportif à la méthandiénone : intérêt des antennes médicales de prévention du dopage.

We report a case of methandienone misuse leading to a preventive action of the Lorraine medicale anti-doping unit.

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.

A biological pharmacology network to secure the risk of drug-drug interaction with nirmatrelvir/ritonavir.

Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent risk of adverse drug reaction and lack of efficacy. In this study, we aimed at describing the expert advices provided by the biological pharmacology network of the SFPT (i.e., the therapeutic drug monitoring specialists working in the laboratories of the pharmacology departments in France/Belgium). From February to August 2022, we collected all specialized advices provided by the biological pharmacology network of the SFPT. Seven pharmacology departments actively participated in the study (Brussels Saint-Luc Hospital in Belgium, Caen, Dijon, Nantes, Nancy, Rennes and Toulouse in France). We collected the following data: patient's age, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments, and advice provided. One hundred and six expert advice on 753 drugs were provided during the seven months of data collection. Two centers provided 83% of all the expert advice (around 8/month). Patients originated form a transplantation department in 65% of the cases. The most common request were for cardiac drugs (28%), immunosuppressive drugs (24%) and endocrine drugs (18%). The advice were distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment, and treatment switch in 59%, 28%, 11%, and 1.6% of the cases, respectively. Only 2 pieces of advice (0.3%) constituted treatment contra-indications. Drug monitoring was proposed in 10% of prescription lines. Expert advice provided by the biological pharmacology network of the SFPT allows securing the combination of nirmatrelvir/ritonavir with other concomitant drugs. Most of eligible patients to the antiviral drug can benefit from it despite the risk of drug-drug interaction.

[Adherence to medication and epilepsy: a current issue]. / Adhésion au traitement médicamenteux et épilepsie : un enjeu d'actualité

As in other chronic diseases, adherence to medication in epilepsy is critical for seizure control. Its assessment remains challenging in research as in clinical practice. Recent evidences showed another face of nonadherence: the overconsumption of antiepileptic drugs. Some educational interventions with easy implementation were found to be effective in improving adherence and should be therefore more used in everyday practice.

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.

Efficacy of early clinical evaluation in predicting direct home discharge of elderly patients after hospitalization in internal medicine.

OBJECTIVES: Early evaluation of direct home discharge (DHD) after hospitalization of elderly patients is important to organize discharge planning quickly. Many scores, scales, and indices have been developed to improve discharge planning. Is clinical judgment better than functional status, comorbidity, or cognitive function scales in predicting DHD of elderly patients after hospitalization? METHODS: Ninety-seven patients, aged 75 years or older, admitted from the emergency department to an internal medicine department in a French teaching hospital between December 1, 2006 and May 1, 2007, were enrolled prospectively in the study. Demographic, clinical, and laboratory characteristics and functional status, comorbidity, and cognitive function scales were determined. The primary outcome was the percentage of correct discharge prediction made by junior and senior doctors within the first 48 hours upon admission. Univariate analysis and logistic regression were assessed to determine predictive variables of patients' discharge. RESULTS: Junior and senior doctors obtained correct prediction in 74.2% and 73.2% of cases, respectively (P > 0.99). Activities of daily living, instrumental activities of daily living, and duration of hospitalization were predictive of DHD (95% confidence interval [CI] -6.1 to 0.2, P = 0.037; 95% CI -2.1 to 9.9, P = 0.003; 95% CI -3 to 9.1, P = 0.0001, respectively) in the univariate analysis. Instrumental activities of daily living was an independent predictive variable of patients' discharge in a logistic regression. No difference between clinical evaluation and the use of an independent predictive variable regarding the prediction of DHD was found. CONCLUSIONS: Early clinical evaluation is as effective as the use of functional status scales to predict DHD of hospitalized elderly patients.

Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years.

BACKGROUND: Liver stiffness measurement (LSM) has been used to measure fibrosis in patients with various types of chronic liver diseases. However, its usefulness as a screening procedure in apparently healthy people had not been evaluated to date. METHODS: 1358 subjects >45 years old from a general population attending for a medical check-up were consecutively enrolled in the study. All subjects were submitted to medical examination and laboratory tests in addition to LSM, performed on the same day by a single operator. Subjects with LSM values >8 kPa were referred to a liver unit for further investigations. RESULTS: 168 subjects were not considered for analysis due to missing data (n=23), LSM failure (n=51) or unreliable LSM values (n=94). Among the 1190 remaining subjects, 89 (7.5%) had LSM >8 kPa including nine patients with LSM >13 kPa. Despite the fact that normal liver tests were observed in 43% of them (38 out of 89), a specific cause of chronic liver disease was found in all cases. Non-alcoholic fatty liver disease (NAFLD) was the likely cause of chronic liver disease in 52 patients, alcoholic liver disease (ALD) in 20, and both causes were associated in seven additional patients. Hepatitis C virus and hepatitis B virus chronic hepatitis was documented in five and four cases, respectively, and primary biliary cirrhosis in one. Liver biopsy was obtained for 27 patients, including the nine patients with LSM >13 kPa, who were diagnosed with liver cirrhosis due to ALD (n=5), chronic hepatitis C (n=3) or chronic hepatitis B (n=1). The 18 remaining biopsies showed liver fibrosis in all cases except one (isolated steatosis), with ALD and NAFLD being present in six and eight cases, respectively. CONCLUSION: LSM proved to be a useful and specific procedure to screen for cirrhosis in the general population and to detect undiagnosed chronic liver disease in apparently healthy subjects.

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.

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.