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PVC microspheres included with Aliquat-336 as extractant were prepared by phase inversion method. Theirs morphology and structure was determined by scanning electronic microscopy (SEM) and BET analysis. SEM images show an asymmetric structure and different morphologies, obtained by varying the concentration of the polymer. The prepared microspheres were used as adsorbent to the removal of Cr(VI) from an aqueous solution. Various parameters were studied like, the extractant dosage, the microspheres dosage, the agitation speed and the aqueous solution pH. The prepared microspheres were able to remove chromium from aqueous solution and had a maximum adsorption capacity qm more than 35mg/g. [ABSTRACT FROM AUTHOR]

Phase inversion process has been successfully applied for polymeric microspheres preparation, based on the use of a modified polyether ether ketone (PEEK-WC) polymer doped with Aliquat-336. The modified microspheres were characterized by several techniques such as the Rheometer for measuring the viscosity of dope solution, scanning electron microscopy (SEM), for morphology analysis BET analysis and porometer for surface area and pore size determination. Meso-porous microspheres were obtained. They presented an asymmetric structure and a diameter of about 1.5 mm. The produced microspheres loaded in a column system have been successfully and efficiently used for chromium (VI) adsorption from aqueous solution. [ABSTRACT FROM AUTHOR]

Novel cyclodextrin polymers prepared by using citric acid as cross-linked agent were employed for removal of ibuprofen from aqueous solution; five insoluble cyclodextrin polymers with different cyclodextrin types were used. Adsorption tests were carried out, with experimental apparatus consisting of a continuous up flow column. Results of adsorption experiments showed that these polymers exhibited high adsorption capacities toward ibuprofen. Studies concerning the effect of several operating variables (i.e. the effects of contact time, ibuprofen concentration, and mass of adsorbent, pH, and ionic strength) are presented and discussed. Moreover, the extraction of ibuprofen has been studied alone and in a mixture of two pharmaceuticals, and the extraction mechanism was investigated by using numerous methods of characterization. [ABSTRACT FROM PUBLISHER]

Abstract: The extractive behaviour of the di(2-ethylhexyl) phosphoric acid (DEHPA) adsorbed on the large specific area solid support (Amberlite XAD7) is investigated. Firstly, the retention of this extractant on the solid support is examined. It is shown that the extractant impregnation content varies significantly with the hydrophobicity of the impregnated solvent. Secondly, the kinetics measurements on the extraction of cadmium ions from aqueous sulphate solution with this impregnated resin were conducted. Experiments were carried out while varying the initial pH from 2.5 to 4, cadmium concentrations in the aqueous solution from 10 to 150ppm and DEHPA content in the Amberlite XAD7 from 0.84 to 1.55mmol/g SIR. Analysis of the rate data in accordance with two theoretical models used to explain the metal extraction kinetics showed that the process is always controlled by the rate diffusion of the cadmium ions through the liquid/liquid interface (aqueous solution/extractant) inside the pores resin. Particle diffusion coefficients were determined from the graphical representation of the proposed models. The results show that the homogenous diffusion model predicts a cadmium diffusion coefficient in the order of 10−12 m2/s under the range of parameters studied. These values are lower than those calculated by the shrinking core model, which have an order of magnitude of 10−7 m2/s. [Copyright &y& Elsevier]

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Abstract: Hydrophilic hollow fibre membranes based on a modified polyether ether ketone (PEEK-WC) were prepared and used as membrane contactors for chromium (VI) removal from aqueous solutions using Aliquat-336 as carrier. The hollow fibres, having different morphologies and properties, were prepared by dry/wet phase inversion varying different parameters. It should be underlined that gamma-butyrolactone (GBL) was used as solvent for PEEK-WC for the first time. Several techniques were used to characterize the produced hollow fibre membranes in terms of morphology, porosity and mechanical strength. The prepared fibres were used for Cr(VI) extraction by a liquid/liquid membrane contactor working with an aqueous phase, containing K2Cr2O7 dissolved in water at concentration ranging from 15 to 100ppm, and an organic phase, prepared using Aliquat-336 dissolved in kerosene in concentrations ranging from 10% to 50% (v/v). The influence of several parameters on the extraction process, such as the metal concentration, the pH of feed solution, the temperature and operating mode, was investigated. It was demonstrated that the prepared hydrophilic fibres are very effective for Cr(VI) removal, since an extraction value up to 99% was achieved. A comparison study with commercial polypropylene hollow fibres was also carried out. [Copyright &y& Elsevier]

Background: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide., Objective: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension., Methods: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension., Results: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39-0.98; p  = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33-0.98; p  = 0.043) and 49% (RR 0.511; 95% CI 0.34-0.76; p  = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23-0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group., Conclusion: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings.ClinicalTrials.gov: NCT02201108., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Kumaran Deiva: consulting fees and travel grants from Biogen, Merck, Novartis Pharmaceuticals, Roche, and Sanofi. Tanuja Chitnis: consulting fees from Biogen, Novartis Pharmaceuticals, Roche Genentech, and Sanofi; research support from National Institutes of Health, National MS Society, U.S. Department of Defense, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Novartis Pharmaceuticals, Octave Bioscience, Genentech, and Tiziana Life Sciences. Brenda Banwell: consulting fees from Novartis Pharmaceuticals, Roche, Sanofi, and UCB; non-remunerated advisory input for Biogen, EMD Serono, Novartis Pharmaceuticals, and Teva. Ludwig Kappos: Dr Kappos’ institution (University Hospital Basel) has received in the past 3 years and used exclusively research support, steering committees, advisory boards, and consultancy fees from AbbVie, Actelion, AurigaVision AG, Biogen, Celgene, Desitin, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen, Japan Tobacco, Merck, Minoryx, Novartis, Roche, Sanofi, Santhera, Senda, Shionogi, Teva, and Wellmera; speaker fees from Celgene, Janssen, Merck, Novartis, and Roche; support for educational activities from Biogen, Desitin, Novartis, Sanofi, and Teva; license fees for Neurostatus products and grants from European Union, Innosuisse, Novartis, Roche Research Foundation, Swiss MS Society, and Swiss National Research Foundation. Douglas L Arnold: consulting fees from Alexion, Biogen, Celgene, Eli Lilly and Company, EMD Serono, Frequency Therapeutics, Genentech, Merck, Novartis, Roche, Sanofi, and Shionogi; equity interest in NeuroRx. Kivilcim Gücüyener: no competing interests. Stephane Saubadu: employee of Sanofi, with ownership interest. Wenruo Hu: employee of Sanofi, with ownership interest. Myriam Benamor: employee of Sanofi, with ownership interest. Annaig Le-Halpere: employee of Sanofi, with ownership interest. Philippe Truffinet: employee of Sanofi, with ownership interest. Marc Tardieu: research support from Novartis Pharmaceuticals and Sanofi.

Background: The possibility to perform standard X-rays is mandatory for all French Emergency Department (ED). Initial interpretation is under the prescriber emergency physician-who continually works under extreme conditions, but a radiologist needs to describe a report as soon as possible. We decided to assess the rate of discordance between emergency physicians and radiologists among discharged patients., Methods: We performed a monocentric study on an adult ED among discharged patients who had at least one X-ray during their consult. We used an automatic electronic system that classified interpretation as concordant or discordant. We review all discordant interpretation, which were classified as false negative, false positive, or more exam needed., Results: For 1 year, 8988 patients had 12,666 X-rays. We found a total of 742 (5.9%) discordant X-rays, but only 277 (2.2%) discordance had a consequence (new consult or exam not initially scheduled). We found some factors associated with discordance such as male sex, or ankle, foot, knee, finger, wrist, ribs, and elbow locations., Conclusions: On discharged patients, using a systematic second interpretation of X-ray by a radiologist, we found a total of 2.2% discordance that had an impact on the initial care., (© 2024. The Author(s), under exclusive licence to American Society of Emergency Radiology (ASER).)

SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1). This phase I first-in-human healthy participant study (NCT05795907) was comprised of three parts: randomized, double-blind, placebo-controlled single ascending dose (SAD; part 1a); 14-day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open-label, single-dose part 1b (PK-cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well-tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half-lives (geometric mean) ranged between 5.7-8.0 h and 7.2-8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF-to-unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (C trough ) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547)., (© 2023 Sanofi and The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: We aimed to assess the patients' experience of threat during management of an acute coronary syndrome (ACS) in the Emergency Department (ED) and to analyze the impact of this acute stress on day-30 outcomes., Study Design: This is a prospective study., Methods: We included patients with ACS in the ED. After discharge, the perceived stress (Perceived Stress Scale (PSS); Visual Analogic Scale (VAS) in stress evaluation; Patient Health Questionnaire (PHQ); and Posttraumatic Stress Disorder Checklist Scale (PCLS) were used., Results: 35 patients have developed PTSD on day-30 (31.8%). The independent predictors of developing PTSD at day-30 were high PSS score on admission (OR = 1.4; CI = 1.1-1.8; p = 0.004) and/or elevated PHQ-9 score at day-30 (OR = 1.5; CI = 1.2-1.9; p < 0.001). The recurrence of the chest pain was more frequent in the PTSD group of patients. Patients with PTSD symptoms were more likely to report a non-therapeutic adherence to their cardiovascular medication., Conclusion: Stress management in EDs should become a systematic step in the management of patients with ACS. This study emphasizes the importance of multidisciplinary follow-up and early screening of patients at risk of PTSD to improve their outcomes after discharge., Competing Interests: Declaration of Competing Interest None declared. I am enclosing herewith a manuscript entitled “Post-traumatic symptoms in patients with acute coronary syndrome: maybe an outcome predictor after the ED visit!” for publication in THE AMERICAN JOURNAL OF EMERGENCY MEDICINE. The corresponding author is Olfa CHAKROUN-WALHA and contribution of the authors as mentioned below with their responsibility in the research: The authors declare that they have no conflict of interest. The authors thank Mr. Chokri KHALAF for his help in editing the English of the manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Therapeutic options for children with multiple sclerosis are scarce. Teriflunomide is approved in more than 80 countries for the treatment of adults with relapsing multiple sclerosis. The TERIKIDS study examined the safety and efficacy of teriflunomide in children with relapsing multiple sclerosis., Methods: The TERIKIDS trial was a multicentre, phase 3, double-blind, parallel-group, randomised, placebo-controlled study conducted at 57 clinical centres in 22 countries in Asia, Europe, the Middle East, North Africa, and North America. The trial enrolled patients aged 10-17 years, diagnosed with relapsing multiple sclerosis and with at least one relapse in the year preceding screening or at least two relapses in the 2 years preceding screening. Patients were randomly assigned (2:1) to oral teriflunomide (dosage equivalent to 14 mg in adults) or matching placebo, using an interactive web and voice response system, for up to 96 weeks. Personnel in all sites and all patients were masked to study treatment in the double-blind period. Early entry into a subsequent 96-week open-label extension phase was possible before the end of the double-blind period for patients with confirmed clinical relapse or high MRI activity (at least five new or enlarged T2 lesions at week 24, followed by at least nine new or enlarged T2 lesions at week 36, or at least five new or enlarged T2 lesions at weeks 36 and 48, or at weeks 48 and 72). The primary endpoint was time to first confirmed clinical relapse by the end of the double-blind period. Key secondary imaging endpoints were number of new or enlarged T2 lesions and number of gadolinium-enhancing lesions per MRI scan. Efficacy endpoints were analysed in the intention-to-treat population, and safety was assessed in all patients randomly assigned to treatment and exposed to the double-blind study medication. This study is registered with ClinicalTrials.gov (trial number NCT02201108) and is closed to recruitment, but an additional optional open-label extension is ongoing., Findings: Between July 24, 2014, and the date of last patient visit on Oct 25, 2019, 185 patients were screened for eligibility, 166 (90%) were enrolled, and 109 were randomly assigned teriflunomide and 57 were randomly assigned placebo. 102 (94%) of 109 and 53 (93%) of 57 completed the double-blind period. Switch to the ongoing open-label extension because of high MRI activity was more frequent than anticipated in the placebo group (14 [13%] of 109 patients in the teriflunomide group vs 15 [26%] of 57 in the placebo group), decreasing the power of the study. After 96 weeks, there was no difference in time to first confirmed clinical relapse with teriflunomide compared with placebo (hazard ratio 0·66, 95% CI 0·39-1·11; p=0·29). Teriflunomide reduced the number of new or enlarged T2 lesions versus placebo by 55% (relative risk 0·45, 95% CI 0·29-0·71; p=0·00061), and the number of gadolinium-enhancing lesions by 75% (relative risk 0·25, 0·13-0·51; p<0·0001). Adverse events occurred in 96 (88%) patients in the teriflunomide group and 47 (82%) patients in the placebo group; serious adverse events occurred in 12 (11%) patients in the teriflunomide group and 6 (11%) patients in the placebo group. Nasopharyngitis, upper-respiratory-tract infection, alopecia, paraesthesia, abdominal pain, and increased blood creatine phosphokinase were more frequent with teriflunomide than with placebo. During the double-blind phase, four patients in the teriflunomide group had pancreatic adverse events (two with acute pancreatitis and two with pancreatic enzyme elevation), of which three events led to treatment discontinuation., Interpretation: No significant difference in time to first confirmed clinical relapse was found, possibly because more patients than expected switched from the double-blind to the open-label treatment period because of high MRI activity. Key secondary imaging analyses and a prespecified sensitivity analysis of probability of relapse or high MRI activity suggest that teriflunomide might have beneficial effects in children with relapsing multiple sclerosis by reducing the risk of focal inflammatory activity., Funding: Sanofi., Competing Interests: Declaration of interests TC reports consulting fees (Bayer and Novartis), advisory boards (Biogen, Novartis, Roche-Genentech, and Sanofi), research support (Mallinckrodt, Novartis, Serono, and Verily), and speaker fees (Medscape). BB reports consulting fees (Novartis and UCB), non-remunerated advisory input (Biogen Idec, EMD Serono, Novartis, Sanofi, and Teva Neuroscience), and speaker fees (Medscape). LK's institution (University Hospital Basel) has received in the past 3 years and has used exclusively for research support steering committees, advisory boards, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and XenoPort), speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, and Teva), support of educational activities (Bayer HealthCare, Biogen Idec, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva), licence fees (Neurostatus products), and grants (Biogen, Merck, Novartis, Roche, the Swiss Multiple Sclerosis Society, Innoswiss, the Swiss National Research Foundation, the European Union, and Roche Research Foundations). DLA reports consultant fees (Acorda Therapeutics, Biogen, Celgene, Genentech, GeNeuro, F Hoffmann-La Roche, Merck, Novartis, Roche, Sanofi, Teva, and Wave Life Sciences), financial support for research activities (Biogen Idec Canada, Immunotec, Novartis Canada, and Novartis Global Medical Affairs), and personal compensation (NeuroRx Research). KD reports consulting fees and travel grants (Merck, Novartis, and Sanofi). SS, WH, MB, AL-H, and PT are employees of Sanofi, with ownership interest. MT reports research support (Novartis and Sanofi Genzyme). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In the phase 3 TOWER core study (NCT00751881), the efficacy and safety of teriflunomide compared with placebo were demonstrated in patients with relapsing forms of multiple sclerosis (RMS). Here, the long-term safety and efficacy outcomes from the TOWER extension study (NCT00751881) are reported., Methods: All patients who entered the extension (N = 751) were assigned to teriflunomide 14 mg and assessed for long-term safety and efficacy., Results: Of 751 patients in the TOWER extension study, 253, 265, and 233 patients received placebo/teriflunomide 14 mg, teriflunomide 7 mg/14 mg, and teriflunomide 14 mg/14 mg, respectively. Median teriflunomide exposure was 4.25 years (maximum 6.3 years). The overall frequency of adverse events (AEs) was comparable across treatment groups, but a higher proportion of patients in the teriflunomide 7 mg/14 mg (12.4%) and 14 mg/14 mg (12.4%) groups had serious AEs compared with the placebo/teriflunomide 14 mg group (6.4%). Alanine aminotransferase increase and hair thinning occurred at a higher frequency in the placebo/teriflunomide 14 mg group (11.2% and 14.3%, respectively) compared with the teriflunomide 7 mg/14 mg (3.0% and 4.5%, respectively) and 14 mg/14 mg groups (5.2% and 4.3%, respectively). The incidences of AEs of interest (hematologic and hepatic effects, peripheral neuropathy, hypertension, and malignancy) were low and comparable across treatment arms. Disability worsening and adjusted annualized relapse rates were low and stable over time, and mean Expanded Disability Status Scale scores were unchanged over time, for all treatment groups., Conclusion: In the TOWER extension study, the efficacy of teriflunomide 14 mg was maintained in patients with RMS. No new or unexpected AEs were observed with teriflunomide treatment, supporting a safety profile in the extension that was consistent with the core trial. These findings support the positive benefit:risk profile of teriflunomide as a long-term immunomodulatory therapy., (Copyright © 2020. Published by Elsevier B.V.)

Background: In Phase 3 studies, teriflunomide reduced relapse rates and disability progression compared with placebo; however, decreases in lymphocyte counts were also observed., Objective: To describe the effect of long-term teriflunomide treatment on lymphocyte counts and infection rates among patients in pooled analyses of Phase 3 core and extension studies., Methods: Four randomized trials (TEMSO, TOWER, TENERE, and TOPIC) compared teriflunomide 7 mg or 14 mg treatment with either placebo and/or subcutaneous interferon (IFN) β-1a 44 µg in patients with relapsing forms of multiple sclerosis (MS) (or first clinical episode suggestive of MS in TOPIC)., Results: In 1895, patients ever exposed to teriflunomide, mean (standard deviation) absolute lymphocyte counts declined from Week 0 (1.89 (0.59)) to Week 24 (1.67 (0.52)) and then remained stable thereafter. In the core plus extension studies (up to 10.7 years), 7.3% and 2.2% experienced Grade 1 and Grade 2 lymphopenia, respectively. Infections were reported in 56.9% of patients without lymphopenia, 60.9% with Grade 1 lymphopenia, and 54.8% with Grade 2 lymphopenia. Serious infections occurred in 3.7%, 4.3%, and 7.1%, respectively., Conclusion: Long-term risk of lymphopenia and infections in patients who continue to receive teriflunomide is low, demonstrating a limited impact on adaptive and innate immunity.

Background: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception., Objectives: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting., Methods: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017)., Results: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports., Conclusions: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.

Background: In the phase 3 TOPIC study, teriflunomide significantly reduced the risk of relapse determining conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome, versus placebo. We assessed clinical and safety outcomes associated with extended teriflunomide treatment in the TOPIC extension study., Methods: Patients who completed the TOPIC core study (including those still on study at early termination) or converted to CDMS after at least 24 weeks in the core study were eligible to participate in the extension. The primary efficacy endpoint in the extension was time to conversion to CDMS., Results: Risk of relapse determining conversion to CDMS was 47.1% lower in patients treated with teriflunomide 14 mg during the core and extension studies compared with patients treated with placebo during the core study and teriflunomide 14 mg during the extension. The incidence of adverse events was 75.8% and 81.9% for 7 and 14 mg teriflunomide, respectively., Conclusions: Reduced risk of relapse determining conversion to CDMS in patients with early MS receiving teriflunomide 14 mg in the core study remained throughout the extension supporting the benefits of early treatment. No new safety signals were observed for teriflunomide 7 or 14 mg., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The demographics and management of patients with multiple sclerosis (MS) differ across geographical regions, but it is unclear whether/how these differences affect treatment outcomes. The aim of this post-hoc analysis was to assess teriflunomide use and patient-reported outcomes in the United States (US) and the rest of the world (ROW) in the phase 4 Teri-PRO study (NCT01895335)., Methods: In the phase 4, real-world, Teri-PRO study, patients with relapsing forms of MS received teriflunomide for 48 weeks according to local labeling. The primary endpoint was treatment satisfaction measured using the Treatment Satisfaction Questionnaire for Medication Version 1.4 (TSQM 1.4). Secondary endpoints included scores on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Performance Scale (MSPS), and Patient-Determined Disease Steps (PDDS), and occurrence of adverse events. Primary and secondary endpoints were assessed at baseline and Week 48. An exploratory subgroup analysis assessed PROs in the black patient population., Results: The US and ROW groups included 545 and 455 patients, respectively. The mean age of patients in the ROW group was lower, they had a shorter mean time since first symptoms of MS, and had lower mean EDSS scores at baseline, compared with the US group (all p < 0.0001). Black patients made up 9% of US patients vs 0.2% of ROW patients. TSQM global satisfaction scores and effectiveness, side effects, and convenience subscale scores were significantly improved from baseline to Week 48 (all p < 0.0001). Disability measures were stable from baseline to Week 48 for both groups, despite different baseline level scores between the two groups. The overall proportion of patients who experienced an AE was similar across both groups. Fewer patients in the US group vs the ROW group reported hair thinning (16.1% vs 31.2%). Black patients showed comparable baseline demographics and disease characteristics and similar change over time in PROs compared with the overall US group., Conclusion: Patient differences observed at baseline between the US and ROW groups suggest variation in teriflunomide prescribing practices in the real-world Teri-PRO study. Improvement in treatment satisfaction and stability of disability measures were comparable between patients in the US and ROW. This suggests that teriflunomide was effective despite differences in baseline demographics and possible cultural and management differences between these geographical regions., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

In the phase 3 TOWER (NCT00751881) study, teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of 12-week confirmed disability worsening (12-w CDW) vs placebo in patients with relapsing forms of MS (RMS). The TOWER population included an appreciable proportion of Asian patients. Reductions in ARR and 12-w CDW associated with teriflunomide 14 mg were comparable between the Asian and overall populations, as were the rates for adverse events and serious adverse events, with no new or unexpected safety findings. These observations provide further evidence to support the clinical benefits and safety profile of teriflunomide in a broad range of patients with RMS., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patient-reported outcomes (PROs) can assist clinicians in understanding the impact of disease-modifying therapy (DMT) on the daily lives of patients with multiple sclerosis (MS). With an increased number of DMTs becoming available, patients are now switching treatments more frequently in clinical practice. The effects of switching DMTs on a patient's daily life and their disease course may be reflected in PROs. The global, multicenter, open-label, phase 4 Teri-PRO study (NCT01895335), which was conducted in routine clinical practice, previously showed statistically and clinically significant increases in patient-reported treatment satisfaction in patients switching to teriflunomide from other DMTs. The impact of switching to teriflunomide from other DMTs on treatment satisfaction and a range of additional PROs was also evaluated., Methods: Patients with relapsing forms of MS (N = 1000) received teriflunomide for 48 weeks per local labeling. Outcomes assessed in this analysis included treatment satisfaction (as measured by Treatment Satisfaction Questionnaire for Medication [Version 1.4]), disability worsening (as measured using the Expanded Disability Status Scale [EDSS] score, the Patient-Determined Disease Steps scale, and the Multiple Sclerosis Performance Scale), cognition (as measured using the Symbol Digit Modalities Test [SDMT]), treated relapses, quality of life (as measured by the Multiple Sclerosis International Quality of Life [MusiQoL] questionnaire and the Stern Leisure Activity Scale), and safety/tolerability over the course of the study in the subgroup of patients switching to teriflunomide from another DMT (n = 594)., Results: Patients reported significant improvements in treatment satisfaction scores following the switch to teriflunomide regardless of the reason for treating with teriflunomide (Global Satisfaction, disease worsening: baseline, 46.0, Week 48, 65.1; convenience: baseline, 57.4, Week 48, 72.4; intolerance: baseline, 50.9, Week 48, 71.1; side effects: baseline, 49.7, Week 48, 67.2; P < 0.0001 in all comparisons). These patients also showed improvement or stability in PROs evaluating disability worsening, cognition, and quality of life (EDSS: baseline, 3.1, Week 48, 3.0; SDMT: baseline, 0.975, Week 48, 0.978; MusiQoL: baseline, 67.5, Week 48, 69.5). The safety and tolerability profile of teriflunomide was consistent with that observed in other teriflunomide clinical trials., Conclusion: This analysis of the Teri-PRO study demonstrates the value of switching to teriflunomide from other DMTs in a real-world, clinical practice setting. The high levels of treatment satisfaction associated with teriflunomide in Teri-PRO may lead to improved adherence and thus improved outcomes., (Copyright © 2018. Published by Elsevier B.V.)

This work focuses on the study of the mass transfer of arsenic(V) through asymmetric polyvinylidene fluoride hollow-fiber membrane contactors using Aliquat-336 as an extractant. In the first part of this work, the fibers were prepared and characterized by SEM and by determining their thickness and porosity. From SEM pictures, an asymmetric structure was obtained that was characterized by an inner sponge-like structure and outer finger-like structure with a pore radius and porosity about 0.11 µm and 80%, respectively. In the second part, the prepared fibers were used as membrane contactors for the study of mass transfer of arsenic(V), investigating the effect of several parameters such as pH, temperature, and initial concentration of the feed. The overall mass transfer coefficient of As(V) was around 6 × 10 ⁻6 cm/s.

Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting multiple sclerosis (MS). The objective of this post hoc analysis of the phase 3, pooled TEMSO (NCT00134563) and TOWER (NCT00751881) dataset is to evaluate the effect of teriflunomide treatment on annualised relapse rate and disability worsening across patient subgroups defined according to prior disease-modifying therapy exposure. This analysis provides further supportive evidence for a consistent effect of teriflunomide across a broad range of patients with relapsing MS, including patients who have used and discontinued other disease-modifying therapies.

Background: Patient-reported outcomes (PROs) provide clinicians with further understanding of the impact of treatment on patients' daily lives. In addition, real-world studies, which employ broader inclusion criteria than randomized trials, may help to inform prescribing decisions when selecting a disease-modifying therapy (DMT) to treat relapsing forms of MS (RMS). We sought to use PROs to determine patient treatment satisfaction and other treatment outcomes, and report safety and tolerability associated with teriflunomide, in the global, phase 4 Teri-PRO study (NCT01895335)., Methods: Patients with RMS (N = 1000) received teriflunomide for 48 weeks per local labeling. The primary endpoint was Global Satisfaction with teriflunomide treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM, V1.4). Secondary endpoints included TSQM scores at Week (W)48 vs baseline in patients switching to teriflunomide from other DMTs ('switchers'), additional PROs, and safety., Results: Mean TSQM Global Satisfaction score at W48 was high (68.2). Switchers reported significant improvements across all four TSQM domains at W48 vs baseline (all p < 0.0001). Adverse events were consistent with teriflunomide clinical trials., Conclusion: Patients reported high treatment satisfaction with teriflunomide, with switchers also reporting improved treatment satisfaction vs baseline. High treatment satisfaction in patients with RMS may lead to improved adherence, and hence treatment outcomes., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563)., Methods: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg., Results: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score ≤2.5; probability of 12-week disability progression ≤0.48)., Conclusions: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide., Classification of Evidence: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term., (© 2016 American Academy of Neurology.)

Background: Teriflunomide, a once-daily oral immunomodulator for the treatment of relapsing-remitting multiple sclerosis, has demonstrated consistent efficacy on clinical and MRI parameters in clinical trials., Objective: To summarize the safety and tolerability profile of teriflunomide based on data from four placebo-controlled trials., Methods: Safety and tolerability were assessed using two teriflunomide clinical program data pools. Pool 1 contained 3044 patients randomized to teriflunomide (14 mg or 7 mg) or placebo in the core studies of one phase 2 trial and three phase 3 trials, with cumulative treatment exposure >1500 patient-years per group. Pool 2 comprised 2338 patients who received teriflunomide treatment in the above trials, including those continuing in extension studies, with a duration of treatment up to 12 years, representing >6800 patient-years. Safety assessments included adverse events, laboratory parameters, and physical examinations., Results: In Pool 1, the number of patients experiencing adverse events and serious adverse events was similar in the three treatment groups. Common events occurring in ≥ 10% of patients in either teriflunomide group, and with an incidence ≥ 2% compared with placebo, were alanine aminotransferase (ALT) increase, headache, diarrhea, hair thinning, and nausea. Overall, the nature of events observed in Pool 2 was similar to Pool 1. The majority of events in both pools were of mild-to-moderate intensity, were self-limiting, and infrequently resulted in discontinuation of therapy. The most common reason for treatment discontinuation in all treatment groups was ALT elevation, reflecting the protocol requirement to discontinue treatment on confirmation of ALT > 3 × the upper limit of normal., Conclusions: No new or unexpected safety signals beyond those detected in individual trials were identified in this pooled analysis with treatment duration exceeding 12 years and a cumulative exposure to teriflunomide exceeding 6800 patient-years. Overall, both doses of teriflunomide had consistent and manageable safety profiles., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing-remitting MS., Objective: To evaluate the safety and tolerability of teriflunomide as add-on therapy to a stable dose of glatiramer acetate (GA) in patients with relapsing forms of MS (RMS)., Methods: Phase II, randomized, double-blind, add-on, placebo-controlled study. The primary objective was to assess safety and tolerability; secondary objectives were to evaluate effects of treatment on disease activity assessed by MRI and relapse., Results: Patients with RMS on GA ( N  = 123) were randomized 1:1:1 to receive teriflunomide 14 mg ( n  = 40), 7 mg ( n  = 42), or placebo ( n  = 41) for 24 weeks; 96 patients entered the 24-week extension, remaining on original treatment allocation. Teriflunomide was well tolerated over 48 weeks. The frequency of adverse events (AEs) was low across all groups; 5 (12.2%), 3 (7.1%), and 2 (5.0%) patients in the 14 mg, 7 mg, and placebo groups, respectively, discontinued treatment due to AEs. Teriflunomide reduced the number of T1-Gd lesions vs placebo (14 mg: 46.6% relative reduction, p  = 0.1931; 7 mg: 64.0%: relative reduction, p  = 0.0306)., Conclusions: Teriflunomide added to stable-dose GA had acceptable safety and tolerability, and reduced some MRI markers of disease activity compared with GA alone. NCT00475865 (core study); NCT00811395 (extension).

Objective: To evaluate immune responses to neoantigen and recall antigens in healthy subjects treated with teriflunomide., Methods: This was a randomized, double-blind, placebo-controlled study. Subjects received oral teriflunomide (70 mg once daily for 5 days followed by 14 mg once daily for 25 days) or placebo for 30 days. Antibody responses were evaluated following rabies vaccination (neoantigen) applied at days 5, 12, and 31 of the treatment period. Occurrence of delayed-type hypersensitivity (DTH) to Candida albicans, Trichophyton, and tuberculin (recall antigens) was assessed before and at the end of treatment to investigate cellular memory response. Safety and pharmacokinetics were evaluated., Results: Forty-six randomized subjects were treated (teriflunomide, n = 23; placebo, n = 23) and completed the rabies vaccination. Geometric mean titers for rabies antibodies were lower with teriflunomide at days 31 and 38 than with placebo. However, all subjects achieved sufficient seroprotection following rabies vaccination (titers well above the 0.5 IU/mL threshold). Overall, the DTH response to recall antigens in the teriflunomide group did not notably differ from responses in the placebo group., Conclusions: Following vaccination, geometric mean titers for rabies antibodies were lower with teriflunomide than with placebo. However, teriflunomide did not limit the ability to achieve seroprotective titers against this neoantigen. Evaluation of DTH showed that teriflunomide had no adverse impact on the cellular memory response to recall antigens., Classification of Evidence: This study provides Class II evidence that in normal subjects treated with teriflunomide, antibody titer responses to rabies vaccination are lower than with placebo but sufficient for seroprotection.

Introduction: Teriflunomide, indicated for the treatment of relapsing-remitting multiple sclerosis, is contraindicated in pregnancy based on signs of developmental toxicity in the offspring of rats and rabbits; developmental toxicity has also been observed in preclinical studies of other disease-modifying therapies. Despite the requirement to use reliable contraception in clinical trials evaluating the safety and efficacy of teriflunomide, a number of pregnancies have been reported. This work reports pregnancy outcomes in teriflunomide clinical trials., Methods: Pregnancy outcomes were evaluated in a retrospective analysis of the global pharmacovigilance database. The following information was collected from the pharmacovigilance database or individual patient files: treatment allocation, pregnancy outcome, teriflunomide exposure, and use of the accelerated elimination procedure., Results: At data cut-off, 83 pregnancies were reported in female patients and 22 pregnancies were documented in partners of male patients. All newborns were healthy and did not have any structural or functional abnormalities at birth., Conclusion: Available data do not indicate any teratogenic signals in patients treated with teriflunomide.

Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis., Methods: In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18-55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700., Findings: Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379-0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416-0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515-0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540-0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%])., Interpretation: TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect., Funding: Genzyme, a Sanofi company., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: In previous studies, teriflunomide significantly reduced the annualised relapse rate (ARR) and disability progression., Objective: This phase 3, rater-blinded study (NCT00883337) compared teriflunomide with interferon-beta-1a (IFNβ-1a)., Methods: Patients with relapsing multiple sclerosis were randomised (1:1:1) to oral teriflunomide 7-or 14 mg, or subcutaneous IFNβ-1a 44 µg. The primary composite endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included ARR, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised., Results: Some 324 patients were randomised (IFNβ-1a: 104; teriflunomide 7 mg: 109; teriflunomide 14 mg: 111). No difference in time to failure was observed. There was no difference in ARR between teriflunomide 14 mg and IFNβ-1a, but ARR was significantly higher with teriflunomide 7 mg. FIS scores indicated more frequent fatigue with IFNβ-1a, though differences were only significant with teriflunomide 7 mg. TSQM scores were significantly higher with teriflunomide. There were no unexpected safety findings., Conclusion: Effects on time to failure were comparable between teriflunomide and IFNβ-1a. There was no difference between teriflunomide 14 mg and IFNβ-1a on ARR, though ARR was higher with teriflunomide 7 mg. The teriflunomide safety profile was consistent with previous studies.

Objective: To investigate the effect of teriflunomide on the efficacy and safety of seasonal influenza vaccine., Methods: The 2011/2012 seasonal influenza vaccine (containing H1N1, H3N2, and B strains) was administered to patients with relapsing forms of multiple sclerosis (RMS) treated for ≥6 months with teriflunomide 7 mg (n = 41) or 14 mg (n = 41), or interferon-β-1 (IFN-β-1; n = 46). The primary endpoint was the proportion of patients with influenza strain-specific antibody titers ≥40, 28 days postvaccination., Results: More than 90% of patients achieved postvaccination antibody titers ≥40 for H1N1 and B in all groups. For H3N2, titers ≥40 were achieved in ≥90% of patients in the 7 mg and IFN-β-1 groups, and in 77% of the 14-mg group, respectively. A high proportion of patients already had detectable antibodies for each influenza strain at baseline. Geometric mean titer ratios (post/prevaccination) were ≥2.5 for all groups and strains, except for H1N1 in the 14-mg group (2.3). The proportion of patients with a prevaccination titer <40 achieving seroprotection was ≥61% across the 3 treatment groups and 3 influenza strains. However, fewer patients in the 14-mg than the 7-mg or IFN-β-1 groups exhibited seroprotection to H3N2 (61% vs. 78% and 82%, respectively)., Conclusion: Teriflunomide-treated patients generally mounted effective immune responses to seasonal influenza vaccination, consistent with preservation of protective immune responses., Classification of Evidence: This study provides Class II evidence that teriflunomide generally does not adversely impact the ability of patients with RMS to mount immune responses to influenza vaccination.