Comparison of two acquisition modes in mass spectrometry for quantification of 12 antibiotics, including beta-lactams, linezolid, fluoroquinolones and clindamycin: Multiple reactions monitoring (MRM) and fullMS/dd-MS2.

The quantification of antibiotics, using mass spectrometry, for monitoring therapeutic drugs is a key benefit in infection management. After an easy work-up of plasma samples, analysis were performed using both two widely used acquisition modes: MRM for the triple quadrupole spectrometer and fullMS/ddMS2 for the HRMS to quantify twelve antibiotics. Comparison between the two acquisition modes were performed. Validation parameters and sample values were used as comparison criteria. The results indicated a good correlation between the two methods, with an advantage for HRMS concerning the matrix effect. Both methods were applied to routine therapeutic drug monitoring.

High amylase concentration in drainage liquid can early predict proximal and distal intestinal anastomotic leakages: A prospective observational study.

Background: Anastomotic leak (AL) is a serious complication in digestive surgery. Early diagnosis might allow clinicians to anticipate appropriate management. The aim of this study was to assess the predictive value of amylase concentration in drain fluid for the early diagnosis of digestive tract AL. Materials and Methods: Hundred and fourteen consecutive patients "at risk" of AL, in whom a flexible drainage was placed by surgeon's choice after digestive anastomosis were included. Patients with eso-gastric, bilio-digestive, and pancreatic anastomoses were excluded. Drain amylase measurement (DAM) was routinely performed on postoperative day (POD) 1, 3, 5-7. DAM values were compared between patients with postoperative AL versus patients without AL. A receiver-operating curve (ROC) with calculation of the areas under the ROC curves area under curves was performed and a cutoff value of DAM was calculated. Results: AL occurred in 25 patients (AL group) and 89 patients did not present AL (C group). The mean DAM was significantly higher in AL group versus C Group on POD 1, 3, and 5. A cutoff value of 307 IU/L predicted the occurrence of AL with a sensitivity and specificity of 91% and 100%, respectively. Positive and negative predictive values were 100% and 97.5%, respectively. Patients with AL had an elevated DAM prior to the appearance of any clinical signs of AL. Conclusion: High level DAM could accurately predict AL for proximal and distal digestive tract anastomoses. This simple, noninvasive, and low-cost method can accurately predict early AL and help physicians to perform appropriate imaging and treatment.

Preoperative analgesic instruction and prescription reduces early home pain after outpatient surgery: a randomized controlled trial.

BACKGROUND: Home pain remains the most common complication in outpatient surgery. Optimal management requires good information and early availability of analgesics. The main objective of this randomized controlled trial was to compare the effects of pre- vs postoperative analgesic instruction and prescription on postoperative home pain. METHODS: Patients were randomized into an anesthesia consultation group (AC group) and a standard postoperative group (POP group). The AC group and the POP group received analgesic prescription and instruction during the anesthesia consultation and after surgery, respectively. The primary outcome was the incidence of home pain on postopertive day one (D1). Home pain was defined by at least one episode with a numeric rating scale score > 3/10 at rest. Treatment compliance and postoperative nausea and vomiting (PONV) were also assessed on D1 and postoperative day 7 (D7). RESULTS: One hundred and eighty-six patients were included between May 2017 and May 2018 at Rouen University Hospital, France. Ninety-four patients were randomized to the AC group and 92 to the POP group. On D1, the incidence of pain was 23/94 (24%) in the AC group and 44/92 (48%) in the POP group (P < 0.001). On D1, the rate of treatment compliance was significantly higher in the AC group than in the POP group (85% vs 69%; P = 0.02). There was no statistically significant difference in the incidence of pain or treatment compliance between groups on D7 or in PONV on D1 and on D7. CONCLUSIONS: Preoperative analgesic instruction and prescription during anesthesia consultation reduces the incidence of early postoperative home pain in outpatient surgery. TRIAL REGISTRATION: www.clinicaltrialsgov (NCT03205189); registered 2 July 2017.

RéSUMé: CONTEXTE: La douleur à la maison demeure la complication la plus fréquente après une chirurgie ambulatoire. Une prise en charge optimale nécessite de bonnes informations et la disponibilité précoce d'analgésiques. L'objectif principal de cette étude randomisée contrôlée était de comparer les effets d'instructions et d'une prescription pré- vs postopératoires d'analgésiques sur la douleur postopératoire à la maison. MéTHODE: Les patients ont été randomisés dans un groupe de consultation pré-anesthésique (groupe pré) et un groupe postopératoire standard (groupe post). Le groupe pré et le groupe post ont reçu une prescription d'analgésiques ainsi que les instructions s'y rattachant pendant la consultation en anesthésie préopératoire et après la chirurgie, respectivement. Le critère d'évaluation principal était l'incidence de douleur à la maison au premier jour postopératoire (post-op 1). La douleur à domicile était définie par un épisode de douleur ou plus avec un score > 3/10 au repos sur l'échelle d'évaluation numérique. L'observance du traitement et les nausées et vomissements postopératoires (NVPO) ont également été évalués les jours post-op 1 et 7. RéSULTATS: Cent quatre-vingt-six patients ont été inclus entre mai 2017 et mai 2018 au Centre hospitalier universitaire de Rouen. Quatre-vingt-quatorze patients ont été randomisés au groupe pré et 92 au groupe post. Au jour post-op 1, l'incidence de la douleur était de 23/94 (24 %) dans le groupe pré et de 44/92 (48 %) dans le groupe post (P < 0,001). Au jour post-op 1, le taux d'observance du traitement était significativement plus élevé dans le groupe pré que dans le groupe post (85 % vs 69 %; P = 0,02). Il n'y avait aucune différence statistiquement significative dans l'incidence de douleur ou d'observance du traitement entre les groupes au jour post-op 7 ou dans les NVPO aux jours post-op 1 et 7. CONCLUSION: L'instruction et la prescription préopératoires d'analgésiques pendant la consultation anesthésique préopératoire réduisent l'incidence de la douleur postopératoire précoce à domicile en chirurgie ambulatoire. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03205189); enregistrée le 2 juillet 2017.

Priming of Cardiopulmonary Bypass with Human Albumin Decreases Endothelial Dysfunction after Pulmonary Ischemia-Reperfusion in an Animal Model.

The routine use of mechanical circulatory support during lung transplantation (LTx) is still controversial. The use of prophylactic human albumin (HA) or hypertonic sodium lactate (HSL) prime in mechanical circulatory support during LTx could prevent ischemia−reperfusion (IR) injuries and pulmonary endothelial dysfunction and thus prevent the development of pulmonary graft dysfunction. The objective was to investigate the impact of cardiopulmonary bypass (CPB) priming with HA and HSL compared to a CPB prime with Gelofusine (GF) on pulmonary endothelial dysfunction in a lung IR rat model. Rats were assigned to four groups: IR-CPB-GF group, IR-CPB-HA group, IR-CPB-HSL group and a sham group. The study of pulmonary vascular reactivity by wire myograph was the primary outcome. Glycocalyx degradation (syndecan-1 and heparan) was also assessed by ELISA and electron microscopy, systemic and pulmonary inflammation by ELISA (IL-1ß, IL-10, and TNF-α) and immunohistochemistry. Clinical parameters were evaluated. We employed a CPB model with three different primings, permitting femoral−femoral assistance with left pulmonary hilum ischemia for IR. Pulmonary endothelium-dependent relaxation to acetylcholine was significantly decreased in the IR-CPB-GF group (11.9 ± 6.2%) compared to the IR-CPB-HA group (52.8 ± 5.2%, p < 0.0001), the IR-CPB-HSL group (57.7 ± 6.3%, p < 0.0001) and the sham group (80.8 ± 6.5%, p < 0.0001). We did not observe any difference between the groups concerning glycocalyx degradation, and systemic or tissular inflammation. The IR-CPB-HSL group needed more vascular filling and developed significantly more pulmonary edema than the IR-CPB-GF group and the IR-CPB-HA group. Using HA as a prime in CPB during Ltx could decrease pulmonary endothelial dysfunction's IR-mediated effects. No effects of HA were found on inflammation.

COMPARING INTRAVITREAL AIR AND GAS FOR THE TREATMENT OF VITREOMACULAR TRACTION.

PURPOSE: To compare the effect of intravitreal injections of air with gas on vitreomacular traction (VMT) release and attempt to analyze predictive factors for success. METHODS: The medical records of patients with symptomatic VMT undergoing intravitreal injections (0.3 mL) of either octafluoropropane (C3F8) or air were retrospectively reviewed. The VMT release (primary end point) and the best-corrected visual acuity (secondary end point) were noted 1 month after injection. At baseline and 1 month after the injection, a macular optical coherence tomography was performed. RESULTS: Twenty-four eyes of 22 patients were included. Vitreomacular traction was released in 10 cases, 7 among 11 C3F8-injected eyes (63%) and 3 among 13 air-injected eyes (23%) (P = 0.045). In eyes with released VMT, ETDRS improved from 61 ± 35 (0-100) to 65 ± 37 (0-100) 1 month after the injection (P = 0.03). All patients with VMT release had a horizontal vitreomacular adhesion of less than 600 µm. Five eyes (23%) underwent vitrectomy after the injection of gas or air. CONCLUSION: Posterior vitreous detachment in VMT can be observed with both air and gas injection with a low complication rate. The occurrence of VMT release observed with air seemed to be less frequent than that observed with gas.

Glibenclamide oral suspension: Suitable and effective in patients with neonatal diabetes.

BACKGROUND: Results of genetic have led to off-label glibenclamide treatment in patients with neonatal diabetes (NDM) because of potassium channel mutations. No pediatric form of glibenclamide was available. Glibenclamide was designated an orphan drug designation for NDM and a suspension was developed. As a part of the pediatric plan investigation, we assessed its acceptability, efficiency, and safety. METHODS: In this Phase II, prospective, non-randomized, single-center study, patient received glibenclamide tablets for 1 month then the suspension for 3 months. We assessed acceptability using hedonic scales and patient questionnaires, effectiveness using glycated hemoglobin (HbA1C) assays and safety based on hypo and hyperglycemia, and other adverse events. RESULTS: We included 10 patients (0.1-16.2 years, 6 < 5 years) were included. Younger patients preferred the suspension and older the tablets. All parents were satisfied with the ease of suspension administration. The parents of 5 of 6 younger children preferred the suspension over the tablets and kept it. Switching from tablets to suspension did not affect the excellent metabolic control (median HbA1c change, -0.40%, [-1.3% to 0.5%] P = 0.08). Median frequencies of hypoglycemia and hyperglycemia were less than 5% of routine blood glucose assays and were similar with both dosage forms. Two patients each experienced one episode of hypoglycemia below 35 mg/dL highlighting the need for dosage titration when switching from tablets to suspension. Transient and non-severe abdominal pain or diarrhea occurred in three patients. None of the patients discontinued the treatment. CONCLUSION: The glibenclamide oral suspension Amglidia, the first anti-diabetic drug specifically developed for pediatric patients, is acceptable, effective, and safe in patients with NDM (NCT02375828). CLINICAL TRIAL REGISTRATION: Glibentek in Patients with Neonatal Diabetes Secondary to Mutations in K + -ATP Channels, clinicaltrials.gov, NCT02375828, https://clinicaltrials.gov/ct2/show/NCT02375828.

Complementary Role of P2 and Adenosine Receptors in ATP Induced-Anti-Apoptotic Effects Against Hypoxic Injury of HUVECs.

BACKGROUND: Vascular endothelial injury during ischemia generates apoptotic cell death and precedes apoptosis of underlying tissues. We aimed at studying the role of extracellular adenosine triphosphate (ATP) on endothelial cells protection against hypoxia injury. METHODS: In a hypoxic model on endothelial cells, we quantified the extracellular concentration of ATP and adenosine. The expression of mRNA (ectonucleotidases, adenosine, and P2 receptors) was measured. Apoptosis was evaluated by the expression of cleaved caspase 3. The involvement of P2 and adenosine receptors and signaling pathways was investigated using selective inhibitors. RESULTS: Hypoxic stress induced a significant increase in extracellular ATP and adenosine. After a 2-h hypoxic injury, an increase of cleaved caspase 3 was observed. ATP anti-apoptotic effect was prevented by suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and CGS15943, as well as by selective A2A, A2B, and A3 receptor antagonists. P2 receptor-mediated anti-apoptotic effect of ATP involved phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases (ERK1/2), mitoKATP, and nitric oxide synthase (NOS) pathways whereas adenosine receptor-mediated anti-apoptotic effect involved ERK1/2, protein kinase A (PKA), and NOS. CONCLUSIONS: These results suggest a complementary role of P2 and adenosine receptors in ATP-induced protective effects against hypoxia injury of endothelial. This could be considered therapeutic targets to limit the development of ischemic injury of organs such as heart, brain, and kidney.

Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice.

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.

Protein tyrosine phosphatase 1B inactivation limits aging-associated heart failure in mice.

We have previously shown that protein tyrosine phosphatase 1B (PTP1B) inactivation in mice [PTP1B-deficient (PTP1B-/-) mice] improves left ventricular (LV) angiogenesis, perfusion, remodeling, and function and limits endothelial dysfunction after myocardial infarction. However, whether PTP1B inactivation slows aging-associated cardiovascular dysfunction remains unknown. Wild-type (WT) and PTP1B-/- mice were allowed to age until 18 mo. Compared with old WT mice, in which aging increased the LV mRNA expression of PTP1B, old PTP1B-/- mice had 1) reduced cardiac hypertrophy with decreased LV mRNA levels of hypertrophic markers and atrial and brain natriuretic peptides, 2) lower LV fibrosis (collagen: 16 ± 3% in WT mice and 5 ± 3% in PTP1B-/- mice, P < 0.001) with decreased mRNA levels of transforming growth-factor-ß1 and matrix metalloproteinase-2, and 3) higher LV capillary density and lower LV mRNA level of hypoxic inducible factor-1α, which was associated over time with a higher rate of proangiogenic M2 type macrophages and a stable LV mRNA level of VEGF receptor-2. Echocardiography revealed an age-dependent LV increase in end-diastolic volume in WT mice together with alterations of fractional shortening and diastole (transmitral Doppler E-to-A wave ratio). Invasive hemodynamics showed better LV systolic contractility and better diastolic compliance in old PTP1B-/- mice (LV end-systolic pressure-volume relation: 13.9 ± 0.9 in WT mice and 18.4 ± 1.6 in PTP1B-/- mice; LV end-diastolic pressure-volume relation: 5.1 ± 0.8 mmHg/relative volume unit in WT mice and 1.2 ± 0.3 mmHg/relative volume unit in PTP1B-/- mice, P < 0.05). In addition, old PTP1B-/- mice displayed a reduced amount of LV reactive oxygen species. Finally, in isolated resistance mesenteric arteries, PTP1B inactivation reduced aging-associated endothelial dysfunction (flow-mediated dilatation: -0.4 ± 2.1% in WT mice and 8.2 ± 2.8% in PTP1B-/- mice, P < 0.05). We conclude that PTP1B inactivation slows aging-associated LV remodeling and dysfunction and reduces endothelial dysfunction in mesenteric arteries. NEW & NOTEWORTHY The present study shows that protein tyrosine phosphatase 1B inactivation in aged mice improves left ventricular systolic and diastolic function associated with reduced adverse cardiac remodeling (hypertrophy, fibrosis, and capillary rarefaction) and limits vascular endothelial dysfunction. This suggests that protein tyrosine phosphatase 1B inhibition could be an interesting treatment approach in age-related cardiovascular dysfunction.

Current knowledge on the role of P2Y receptors in cardioprotection against ischemia-reperfusion.

During ischemia, numerous effective endogenous extracellular mediators have been identified, particularly, nucleosides such as adenosine as well as purinergic and pyrimidinergic nucleotides. They may play important regulatory roles within the cardiovascular system and notably as cardio-protectants. Indeed, the distribution of the P2Y receptors in mammalian heart includes several cellular constituents relevant for the pathophysiology of myocardial ischemia. Beside the well-known cardioprotective effect of adenosine, the additional protective role of P2Y receptors has emerged. However, interpretation of experimental results may be sometimes perplexing. This is due to the variability of: the experimental models, the endpoints criteria, the chemical structure of agonist and antagonist ligands and their concentrations, the sequences of drug administration with respect to the model used (before and/or during and/or after ischemia). The net effect may be in the opposite direction after a transient or a prolonged stimulation. Nevertheless, the overall reading of published data highlights the beneficial role of the P2Y2/4 receptor stimulation, the useful and synergistic role of P2Y6/11 receptor activation and even of the P2Y11 receptor alone in cardioprotection. More, the P2Y11 receptor could be involved in counter-regulation of profibrotic processes. Paradoxically, transient P2X7 receptor stimulation could contribute to the net cardioprotective effect of ATP. Recently, experimental data have shown that blocking the P2Y12 receptor after ischemia confers cardioprotection independently of platelet antiaggregatory effect. This suggests for P2Y receptors an important role in primary prevention and as a therapeutic target in myocardial protection during ischemia and reperfusion.

A Slight Smell of Lemon.

We present here an example of urine substituted with a yellow cleaning product that leads us to develop the main risks to consider in urine toxicology analysis, ie, adulteration and analytical interferences, and how to deal with them. This grand round highlights the importance of the dialog between the clinician and a TDM consultant for optimal care of the patient.

Therapeutic drug monitoring of mitotane: Analytical assay and patient follow-up.

Adrenocortical carcinoma (ACC) is an aggressive malignancy of the adrenal gland. Mitotane (o,p'-DDD) is the most effective chemotherapy for ACC. According to the literature, mitotane plasma trough concentrations within 14-20 mg L-1 are correlated with a higher response rate with acceptable toxicity. Therapeutic drug monitoring (TDM) of mitotane is therefore recommended. The aim of this study was to propose a robust and simple method for mitotane quantification in plasma. The validation procedures were based on international guidelines. Sample preparation consisted of a single protein precipitation with methanol using 100 µL of plasma. The supernatant was submitted to liquid chromatography coupled with ultra-violet detection at 230 nm. Mitotane retention time was 7.1 min. The limit of detection was 0.1 mg L-1 and the limit of quantification was 0.78 mg L-1 . The assay demonstrated a linear range of 0.78-25 mg L-1 with correlation coefficients (r2 ) at 0.999. Inter- and intra-assay precision was <4.85%. Evaluation of accuracy showed a deviation <13.69% from target concentration at each quality control level. This method proved easy and rapid to perform mitotane TDM and required a small volume of sample. It was successfully applied to routine TDM in our laboratory.

Evaluation of the pharmacokinetics of glibenclamide tablet given, off label, orally to children suffering from neonatal syndromic hyperglycemia.

PURPOSE: Glibenclamide (Gb) is used in type II diabetes mellitus but also in the last 10 years, off label, in patients with neonatal syndromic hyperglycemia carrying a mutation of Kir6.2 or SUR1. No studies have reported Gb pharmacokinetics in children. In this study, oral Gb pharmacokinetics was investigated in children in order to describe the concentration time courses, the influence of covariates, and the relationships between drug concentrations and efficacy. METHODS: Gb concentrations were measured in 18 children after the switch from subcutaneous insulin to oral tablets of Gb (crushed tablets for 33 % of patients). A total of 229 plasma Gb concentrations and 187 blood glucose measurements were available. A population model was developed with NONMEM. RESULTS: Body weight was the most significant parameter on clearance and explained a substantial part of the variability. A variant genotype of CYP2C9 (i.e., *1/*2 and *1/*3) explained also a part of the remaining variability on Gb clearance. Patients carrying these allelic variants had a clearance decreased by 45 %. A link between daily area under the curve (AUC0-24 h) and metabolic control diabetes was found. CONCLUSIONS: This study evaluates for the first time the pharmacokinetics of oral Gb in children and constitutes a first step towards dose individualization of this drug in a particularly vulnerable population.

Critical limb ischemia: thrombogenic evaluation of two autologous cell therapy products and biologic profile in treated patients.

BACKGROUND: Cell therapy has been proposed as a salvage limb procedure in critical limb ischemia (CLI). Autologous cell therapy products (CTP) are obtained from patients with advanced peripheral arterial disease to be injected at the site of ischemia. Thrombogenicity of CTPs has not yet been assessed. The objectives were: 1) to assess thrombotic risk in candidates for cell therapy, 2) to evaluate two different CTPs in terms of thrombogenic potential, and 3) to evaluate clinical thrombotic events. STUDY DESIGN AND METHODS: In this ancillary study of a Phase I and II clinical trial, bone marrow (BM)-CTPs (n = 20) and CTPs obtained by cytapheresis (peripheral blood [PB]-CTPs; n = 20) were compared. Inflammatory and coagulation markers were measured at baseline and 24 hours after CTP implantation. CTP cell content and tissue factor (TF) expression (mRNA and protein) were analyzed. Thrombin generation assessed CTP-related thrombogenicity. RESULTS: All patients presented cardiovascular risk factors. At baseline, the patients' biologic profile was characterized by high levels of fibrinogen, C-reactive protein (CRP), D-dimer, interleukin (IL)-6, and plasmatic TF, whereas IL-10 was low. Although different in terms of cell composition, both BM- and PB-CTPs support low thrombin generation. Twenty-four hours after implantation, biologic markers remained stable in the PB-CTP group, except for IL-6. In the BM-CTP group, a significant increase of IL-6 but also of CRP and D-dimer was observed. Clinically, one single patient developed deep vein thrombosis 24 hours after the implantation of autologous PB-CTP. CONCLUSION: CTPs supported low thrombin generation and were well tolerated after calf implantation.

Methylphenidate and stuttering.

Methylphenidate (MPH) is a piperidine similar to amphetamines, and is indicated for attention deficit hyperactivity disorder. Studies concerning stuttering occurring with MPH are contradictory. We investigated the association between MPH and stuttering. We analysed reports in the World Health Organization global individual case safety reports database, Vigibase, up to 31 December 2018, with the MedDRA preferred term "dysphemia" and the lower level terms "stutter" and "stuttering". The association between exposure to MPH and occurrence of the adverse drug reaction was estimated by disproportionality analysis. Reporting odds ratios (RORs) were calculated with 95% confidence intervals (CIs). In total, 2975 cases of dysphemia were reported, of which 46 reports were associated with MPH. For the Preferred Term "dysphemia", the ROR was 7.3 (95% CI: 5.4-9.8). With the Lower Level Term "stuttering", 584 cases were registered in the database of which 17 involved MPH. The ROR was 13.9 (95% CI: 8.6-22.5). This study found a signal for stuttering with MPH.

Population pharmacokinetics of nefopam in elderly, with or without renal impairment, and its link to treatment response.

AIMS: Nefopam is a nonmorphinic central analgesic, for which no recommendation exists concerning adaptation of regimen in aged patients with or without renal impairment. The objective was to describe the pharmacology of nefopam in aged patients to obtain guidelines for practical use. METHODS: Elderly patients (n = 48), 65-99 years old, with severe or moderate renal impairment or with normal renal function, were recruited. Nefopam (20 mg) was administered as a 30 min infusion postoperatively. Simultaneously, a 1 min intravenous infusion of iohexol was performed, in order to calculate the glomerular filtration rate. Blood samples were drawn to determine nefopam, desmethyl-nefopam and iohexol plasma concentrations. Nefopam and desmethyl-nefopam concentrations were analysed using a nonlinear mixed-effects modelling approach with Monolix version 4.1.3. The association between pharmacokinetic parameters and treatment response was assessed using logistic regression. RESULTS: A two-compartment open model was selected to describe the pharmacokinetics of nefopam. The typical population estimates (between-subject variability) for clearance, volume of distribution, intercompartmental clearance and peripheral volume were, respectively, 17.3 l h(-1) (53.2%), 114 l (121%), 80.7 l h(-1) (79%) and 208 l (63.6%). Morphine requirement was related to exposure of nefopam. Tachycardia and postoperative nausea and vomiting were best associated with maximal concentration and the rate of increase in nefopam plasma concentration. CONCLUSIONS: We identified the nefopam pharmacokinetic predictors for morphine requirement and side-effects, such as tachycardia and postoperative nausea and vomiting. In order to maintain morphine sparing and decrease side-effects following a single dose of nefopam (20 mg), simulations suggest an infusion time of >45 min in elderly patients with or without renal impairment.

Association between olanzapine plasma concentrations and treatment response: A systematic review, meta-analysis and individual participant data meta-analysis.

AIMS: By meta-analysing pooled studies and available individual participant data, we aim to provide new insight on olanzapine therapeutic drug monitoring in schizophrenia. METHOD: We conducted a computerized search of bibliographic databases (Pubmed, Cochrane library, Web of Science and PsycINFO) to identify studies that assessed the relationship between olanzapine plasma concentration and the change in patients' clinical scores. We investigated this relationship with olanzapine plasma level 12h00 post-intake using a random-effects model. RESULTS: 7 studies were included in the pooled data analysis (781 patients). We found no difference in oral dose between responders and non-responders but a significantly higher concentration of 4.50 µg/L in responders (p < 0.01). Olanzapine concentration above the thresholds identified in each study was associated with response (odd ratio = 3.50, p = 0.0007). We identified that non-responder patients showed greater inter-individual variability than responders. In the individual data analysis (159 patients), we found no relationship between dose and clinical response but an association between plasma level and response in the shape of a parabolic curve. The Receiver Operating Characteristic curve found a threshold of 22.07 µg/L to identify responders (96% sensitivity, 86% specificity) and a threshold of 56.47 µg/L to identify a decreased probability of response. CONCLUSION: In contrast to oral dose, our work confirmed that plasma olanzapine levels are associated with clinical response and should therefore be used to optimise treatment. We determined a treatment response threshold of 22.07 µg/L and suggest that a concentration above the therapeutic window may result in a decreased response.

Methylglyoxal induces cardiac dysfunction through mechanisms involving altered intracellular calcium handling in the rat heart.

Methylglyoxal (MGO) is an endogenous, highly reactive dicarbonyl metabolite generated under hyperglycaemic conditions. MGO plays a role in developing pathophysiological conditions, including diabetic cardiomyopathy. However, the mechanisms involved and the molecular targets of MGO in the heart have not been elucidated. In this work, we studied the exposure-related effects of MGO on cardiac function in an isolated perfused rat heart ex vivo model. The effect of MGO on calcium homeostasis in cardiomyocytes was studied in vitro by the fluorescence indicator of intracellular calcium Fluo-4. We demonstrated that MGO induced cardiac dysfunction, both in contractility and diastolic function. In rat heart, the effects of MGO treatment were significantly limited by aminoguanidine, a scavenger of MGO, ruthenium red, a general cation channel blocker, and verapamil, an L-type voltage-dependent calcium channel blocker, demonstrating that this dysfunction involved alteration of calcium regulation. MGO induced a significant concentration-dependent increase of intracellular calcium in neonatal rat cardiomyocytes, which was limited by aminoguanidine and verapamil. These results suggest that the functionality of various calcium channels is altered by MGO, particularly the L-type calcium channel, thus explaining its cardiac toxicity. Therefore, MGO could participate in the development of diabetic cardiomyopathy through its impact on calcium homeostasis in cardiac cells.

Urinary methotrexate dosage in rheumatoid arthritis, in patients treated for at least 6 months: a potential marker of adherence.

OBJECTIVES: Non-adherence to rheumatoid arthritis (RA) treatments must be identified. A methotrexate (MTX) urinary dosage (METU) was recently developed. The aim of our study was to assess adherence to MTX in RA using METU in real-life conditions and to compare it with indirect adherence measurement technics. METHODS: We performed a cross-sectional study at Reims University Hospital. We included over 18-year-old patients with RA treated by MTX for more than 6 months. Patients were invited to complete demographic, clinical and psychological questionnaires and adherence measurement technics (Compliance Questionnaire of Rheumatology (CQR) and Medication Possession Ratio (MPR)). A urinary sample was collected to measure MTX and information about tolerance was evaluated through Methotrexate Intolerance Severity Score. RESULTS: 84 patients were included, 26 using oral MTX, 58 subcutaneous (SC) MTX. Among them, 73% were female, mean age was 61.5 years, MTX mean dose was 15 mg/week and 61.9% were treated by biological DMARDs (Disease Modifying Antirheumatic Drugs). 77 patients (91.7%) were adherent to treatment according to METU, whereas MPR and CQR reported less adherence (69.5% and 61.9%, respectively). MPR and METU were not significantly different in SC MTX users (p=0.059). Non-adherent patients had a higher number of tender joints and C reactive protein value (p<0.05). CONCLUSION: This is the first largest study evaluating MTX adherence in patients with RA using a urinary dosage. We identified that indirect adherence measurements did not reflect real-life adherence. It would be appreciable to realise METU, in a new study, in patients with RA with unexplained response to treatment, to consider it before escalating therapeutic strategy.