Methoxpropamine (MXPr) in powder, urine and hair samples: Analytical characterization and metabolite identification of a new threat.

Methoxpropamine (MXPr) is an arylcyclohexylamine dissociative drug with structural similarities with 3-MeO-PCE, ketamine and deschloroketamine. MXPr was identified for the first time in Europe in October 2019 in Denmark and is considered a new psychoactive substance. We undertook the molecular identification and characterization of MXPr in urine, hair and powder samples. We used a combination of several analytical methods: liquid-state nuclear magnetic resonance (NMR), infra-red spectroscopy (IR) and liquid chromatography high-resolution mass spectrometry (LC-HRMS). The second objective was to explore the metabolism of MXPr in silico and in vitro. To detect characteristic metabolites that prove MXPr consumption by urine analysis, pooled human liver microsome (pHLM) assays were performed and evaluated using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS). A software algorithm (Unifi®) was used to predict in silico biotransformations of MXPr. Three metabolites were identified in the in vitro studies including N-despropyl(nor)MXPr, O-desmethyl MXPr and dihydroMXPr. Most of these phase II metabolites were confirmed to be present in urine and hair samples collected from an MXPr consumer. This is the first report of the identification of MXPr in France with analytical findings. This study highlights the challenge of identifying new psychoactive substances (NPS) when they are missing from compound libraries and if a standard is not available. The use of various complementary analytical methods combined with HRMS offers a promising approach for the molecular characterization of NPS.

Suitability of infrared spectroscopy for drug checking in harm reduction centres.

Drug checking is a service for people who use drugs that includes product analysis and an individual interview including results feedback and harm reduction counselling. It uses different analytical methods but few studies demonstrate their value in current practice. The main objective of this work is to compare the analytical performance of IR spectroscopy to laboratory reference method in the context of drug checking in a harm reduction centre. The secondary objectives are to carry out a description of the people who use drugs requesting a product analysis, and to compare the assumed compositions of products purchased with their real compositions. During 2018, all requests for drug testing analysis were included for on-site analysis by IR spectrometry in a harm reduction center and verified by the reference method (UPLC-HRMS) at Bordeaux University Hospital Center. Socioeconomic and product data were also collected. One hundred and thirty-six samples were collected. The results obtained with IR and UPLC-HRMS were compared. IR spectrometry results did not match with reference method in 8 % (n=11) of cases, corresponding to blotters, cannabis and some psychoactive substances present in mixture or in small quantities. Among the products collected, only 5.1 % (n=7) did not correspond to the declared product, either alone or with adulterants. The IR spectrometer allows a simple and rapid detection of at least one molecule, most often the one of interest. However, it is limited to powder and tablet type matrices and is not suitable for blotters, cannabis, mixed or low content substances for which high resolution mass spectrometry remains the reference method.

Death related to nicotine replacement therapy: A case report.

Transdermal nicotine patches and nicotine tablets are widely used for substitution therapies after cessation of smoking. Toxic concentrations of nicotine and cotinine, its main metabolite, are rarely reported, either in cases of misuse or in a fatal context. We report here a rare fatal case due to massive exposure to nicotine replacement therapy. A 41-year-old man was found dead by his cellmate with 7 nicotine patches on the body. There were 14 nicotine patches (21 mg) and 5 empty blisters of nicotine tablets (Nicopass® 1.5 mg) in the bin. External, internal, and histological examinations revealed asphyxia syndrome. Toxicological analyses indicated lethal concentrations of nicotine and cotinine in femoral (2239 and 1230 ng/mL) and cardiac blood (1344 and 1090 ng/mL). Screening for ethanol, drugs, and illicit drugs revealed therapeutic concentrations of cyamemazine, lormetazepam, nordiazepam, oxazepam, and buprenorphine and its metabolite. THC and its metabolites were also detected, reflecting use of cannabis. The findings highlight the risk of nicotine poisoning in persons using nicotine patches. This case emphasises the importance of carrying out complete toxicological analyses to prevent other instances of nicotine poisoning from being overlooked.

Acute Methiopropamine Intoxication After "Synthacaine" Consumption.

Use of methiopropamine (MPA), a synthetic metamfetamine analog, has been detected since 2011 in Europe, but there is limited information on its acute toxicity. A 30-year-old man was admitted to the emergency department in a confused state, with paranoid delusion, auditory and visual hallucinatory experiences, and incoherent speech following the use of "synthacaine" (a slang term derived from "synthetic" and "cocaine"). Toxicological screening for pharmaceuticals and drugs of abuse by liquid chromatography-diode-array detector, gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS-MS) detected MPA, which was subsequently quantified by a specific LC-MS-MS method. Of note, 13 h after presentation to the emergency department, the plasma concentration of MPA was 14 ng/mL. This case report confirms the toxicity of MPA and the need for toxicological analysis to confirm the substance actually ingested by users of new psychoactive substances.

Tigecycline versus levofloxacin for the treatment of community-acquired pneumonia: European experience.

Tigecycline (TGC), a first-in-class glycylcycline that has been approved for treating complicated skin and skin structure infections and complicated intra-abdominal infections, has an expanded spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, including resistant strains. The purpose of this study was to compare the efficacy and safety of TGC with levofloxacin (LEV) in adult hospitalised patients with community-acquired pneumonia (CAP) in a randomised, doubleblind, phase 3 multinational trial. This analysis evaluated TGC efficacy and safety in the European region. Hospitalised patients from 53 centres in 18 countries received 7-14 days of i.v. TGC (100-mg loading dose followed by 50 mg every 12 hours) or i.v. LEV (500 mg once or twice daily). Co-primary efficacy endpoints were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC). Results indicated that 358 patients received at least 1 dose of study medication (mITT: TGC 177, LEV 181), 245 were CE (TGC 125, LEV 120). Demographics were similar in both groups and the majority of patients had a Fine Pneumonia Severity Index of II to IV (84.4% TGC, 78.2% LEV, mITT). At TOC (CE), TGC cured 112/125 patients (89.6%; 95% CI 82.9, 94.3) and LEV cured 103/120 patients (85.8%; 95% CI 78.3, 91.5), absolute difference of TGC-LEV 3.8% (95% CI -5.3, 12.8; test for noninferiority p<0.001). For those CE patients with a Fine score of

The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections - the European experience.

The polymicrobial nature of complicated intra-abdominal infections makes these infections particularly challenging to treat. The initial selection of antimicrobial therapy is therefore extremely important. Inappropriate empiric antimicrobial therapy has been shown to delay clinical resolution, increase length of hospital stay, and increase the risk of mortality. In addition, the increasing frequency with which resistant isolates (e.g., extended spectrum beta-lactamases [ESBLs]) are recovered from patients mandates that empiric antimicrobial therapy covers these difficult-to-treat organisms. Here, we assessed the efficacy of a new antimicrobial agent, tigecycline. This is a combined analysis of data from the European sites that participated in two Phase III, double-blind trials to evaluate the efficacy and safety of tigecycline, versus that of imipenem/cilastatin, in adults with complicated intra-abdominal infections. Patients received either tigecycline (initial dose of 100 mg, followed by 50 mg intravenously every 12 hours) or imipenem/cilastatin (500/500 mg intravenously every 6 hours) for 5-14 days. The primary end point was the clinical response at the test-of-cure visit (12-44 days after therapy) in the co-primary microbiologically evaluable (ME) and microbiological modified intent-to-treat (m-mITT) populations. For the ME group, clinical cure rates at the test-of-cure visit were 92.4% (219/237) for tigecycline versus 88.8% (198/223) for imipenem/cilastatin (95% CI = -2.2, 9.4). Clinical cure rates for the mmITT populations were 87.3% (247/283) for tigecycline versus 83.5% (228/273) for imipenem/cilastatin (95% CI = -2.5, 10.0) at the test-of-cure visit. Pretherapy in vitro activity against baseline isolates for tigecycline and imipenem/cilastatin were also determined. The mean MIC(90) for tigecycline against the most commonly isolated aerobes and anaerobes was < or =2.0 microg/mL. No pretherapy isolates displayed resistance to tigecycline based on the breakpoints used. Bacterial susceptibilities to tigecycline appeared to be consistent with clinical responses. Most commonly reported treatment emergent adverse events for tigecycline and imipenem/cilastatin were nausea (14.7% and 11.8%, respectively, p = 0.267) and vomiting (10.7% and 7.3%, respectively p = 0.146). This combined analysis demonstrates that tigecycline is safe and effective for the treatment of complicated intra-abdominal infections, and reflects the findings of the global population.

[Is tubal and uterine surgery deleterious to ovarian reserve?]. / La chirurgie tubaire et utérine a-t-elle un effet délétère sur la fonction ovarienne?

Changes in menstrual pattern after tubal sterilisation have been reported for more than 50 years. Hence all tubal surgeries have been suspected of altering the ovarian reserve, by damage to the ovarian blood vessels. Recent studies showed that tubal surgery has no significant adverse effect on doppler flow indice and hormonal markers. Hysterectomy and uterine artery embolization seem to decrease ovarian reserve in perimenopausal women. Uterine artery embolization does not seem to have adverse effects on normally functioning ovaries.

Sirolimus-based therapy with or without cyclosporine: long-term follow-up in renal transplant patients.

This open-label, phase 3b, extension trial in renal transplant recipients (Sirolimus Study 311) assessed the long-term safety of sirolimus (SRL) administered with cyclosporine (CsA) (SRL + CsA group, n = 98) or without CsA (SRL group, n = 69). Renal transplant recipients who had either completed one of seven previous SRL studies sponsored by Wyeth Research or had participated for > or =3 months and reached a protocol-designated endpoint were eligible for enrollment. Data were available for 167 patients, all of whom initially received steroids. Mean total SRL exposure was 1526 days, including previous study participation. After enrollment in the extension study, there were significantly more acute rejections in the SRL + CsA group (6.1% vs 0%, P < .05). Differences in rates of graft loss (3.1% vs 1.4%) and death (6.1% vs 1.4%) were not significantly different between SRL + CsA and SRL groups, respectively. At 48 months after transplantation, calculated GFR (53.4 vs 70.9 mL/min) and hemoglobin (124.9 vs 136.6 g/L) were significantly better in the SRL group. Lipid values were not significantly different between groups at 48 months. The incidence of treatment-emergent increased creatinine, anemia, hypertension, headache, epistaxis, abnormal kidney function, and upper respiratory infection were significantly higher in the SRL + CsA group, whereas no adverse events were significantly higher in the SRL group. Malignancies were reported more frequently (11.2% vs 0%) with SRL + CsA. Results from this extension study indicate that SRL-based therapy without CsA is a safe alternative to combination therapy with CsA, offering long-term improvement in renal function with no increased risk of late acute rejection.

[Mechanical and metabolic complications of hysteroscopic surgery: report of a retrospective study of 352 procedures]. / Complications mécaniques et métaboliques de l'hystéroscopie opératoire: à propos d'une étude rétrospective de 352 interventions.

Our objective was to determine, in a retrospective study of 352 operative hysteroscopies: (a) the rates and the types of complications and (b) the risk factors of peroperative perforations. The most important complications represented 1.7% including two haemorrhage, one symptomatic metabolic abnormalities and three uterine perforations with bowel injuries (0.8%). Furthermore, minor complications were observed in 9.3% including non symptomatic metabolic abnormalities (5.5%) and uterine perforations without visceral injury. Among mechanical complications, the majority were uterine perforations (4%). No relation was found between menopausal status of the patients and the occurrence of uterine perforation. In contrast, the perforation rate was statistically greater in patients treated for synechia than those found for myoma (p < 0.0001). Furthermore, the perforation rate was statistically higher for resection of myomas as compared with endometrial resection (p < 0.0001) or polyp resection (p < 0.0008). Moreover, in our experience, the perforation rate depended on hysteroscopic experience of surgical operators.

[Methods of in vitro evaluation for nephrotoxicity]. / Les méthodes d'évaluation in vitro de la néphrotoxicité.

Mechanisms and precise targets of nephrotoxicants have been evidenced in experimental animals, a very important contribution for decades. But, structural and functional heterogeneity in renal tissue makes often difficult the exact determination of the molecular targets at renal cell level. Indeed, some new in vitro models have been gradually reported. This non exhaustive review purposes to present the different recent models, ever more reductionist, as isolated kidneys, kidney slices, isolated renal cells or renal cultured cells to assess the nephrotoxicity of new molecules. For every model are presented a brief history, the principle of the technique, viability criteria and its relative interest for renal toxicology. In conclusion, a general discussion points out the main advantages and limits of each one.

[Non-arthrosic geodes in the femur head. Isolated or predominant geodes]. / Les géodes non arthrosiques de la tête fémorale. Géodes isolées ou prédominantes.

The isolated or predominant geodes of the femoral head without signs of coxarthritis or coxitis, seem to form in response to: osteochondritis dissecans in 9 cases where the sequester was only visible in profile films or oblique images for 5 cases, and only at time of operation in 2 cases; incipient necrosis in 3 adult cases, not evidenced in frontal films and only seen in profile films with the patient under axial traction; femoral head dysmorphia in 6 cases among which were 4 polyepiphyseal dysplasias and 2 coxa plana without radiographically apparent sequesters; induced increased pressure caused by congenital subluxation or a major disorder of posture and locomotion of lower limbs in 3 cases. In 2 cases no classification could be assigned to isolated or predominant geodes of the femoral head in spite of anatomic examination. The diagnosis of these isolated or predominant geodes of the head of the femur necessitates excellent films made from different angles of view (profile, "false" profile, usual profile, sometimes oblique shots, tomograms) and often enough a biopsy which must be obtained directly through the joint, not transcervically through the neck if a reliable specimen is desired. The surgical treatment indicated is voiding and packing to a maximum the geodes possibly correcting the former increased pressure discordance. But, in lots of cases the intensity of pain and discomfort remains moderate for years, so indication for surgery arises late after onset.

[Ischaemic stenosis of the ureter during Henoch-Shoenlein purpura (author's transl)]. / Sténose ischémique de l'uretère au cours d'un purpura rhumatoïde.

Involvement of the ureters (rigid and segmented) and bladder was seen in a 6-year-old child whose clinical lesions were typical of Henoch-Schoenlein purpura. Infrapelvic left uretic stenosis developed secondarily whilst the other lesions disappeared. Histological study and in particular cutaneous and renal immunofluorescence made it possible to eliminate the possible diagnosis of polyarteritis nodosa, and to confirm that of Henoch-Schoenlein purpura. An ischaemic vasculitis was the cause of the ureteric and bladder lesions, and of the progression to stenosis. The existence of this possibility should lead to routine examination to detect such lesions. Sequential radiological studies are necessary whenever such lesions are recognised.