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Bertrand Diquet - One of the best experts on this subject based on the ideXlab platform.
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Riluzole pharmacokinetics in young patients with spinal muscular atrophy
British journal of clinical pharmacology, 2011Co-Authors: Chadi Abbara, Brigitte Estournet, Lucette Lacomblez, Bénédicte Lelièvre, Amal Ouslimani, Blandine Lehmann, Louis Viollet, A. Barois, Bertrand DiquetAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Spinal muscular atrophy (SMA) is a neuromuscular disorder of childhood. • Riluzole is an anti-excitatory agent recommended for the treatment of amyotrophic lateral sclerosis (ALS). • Riluzole pharmacokinetics are well documented in patients with ALS. WHAT THIS STUDY ADDS • Riluzole pharmacokinetics have never documented in patients with SMA. • This study showed that the administration of 50 mg Riluzole once a day to patients with SMA leads to total Riluzole daily exposure comparable with that obtained after the administration of 50 mg twice a day in healthy volunteers or ALS patients. AIMS The objective of the present study was to assess the pharmacokinetics of Riluzole in patients with spinal muscular atrophy (SMA). METHODS Fourteen patients were enrolled in an open-label, nonrandomized and repeat-dose pharmacokinetic study. All participants were assigned to receive 50 mg Riluzole orally for 5 days. Riluzole plasma concentrations were determined from samples obtained at day 5. RESULTS The pharmacokinetic analysis demonstrated that a dose of 50 mg once a day was sufficient to obtain a daily total exposure [AUC(0,24 h) = 2257 ng ml−1 h] which was comparable with results obtained in adult healthy volunteers or ALS patients in whom a dose of 50 mg twice a day is recommended. The pharmacokinetic simulation demonstrated that the administration of 50 mg twice a day could result in higher concentrations, hence reduced safety margin. CONCLUSION The dose of 50 mg once a day was chosen for the clinical trial evaluating the efficacy of Riluzole in SMA patients.
Michael G. Fehlings - One of the best experts on this subject based on the ideXlab platform.
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Riluzole as a Neuroprotective Drug for Spinal Cord Injury: From Bench to Bedside
Molecules (Basel Switzerland), 2015Co-Authors: Narihito Nagoshi, Hiroaki Nakashima, Michael G. FehlingsAbstract:Spinal cord injury (SCI) is a devastating event resulting in permanent loss of neurological function. To date, effective therapies for SCI have not been established. With recent progress in neurobiology, however, there is hope that drug administration could improve outcomes after SCI. Riluzole is a benzothiazole anticonvulsant with neuroprotective effects. It has been approved by the U.S. Food and Drug Administration as a safe and well-tolerated treatment for patients with amyotrophic lateral sclerosis. The mechanism of action of Riluzole involves the inhibition of pathologic glutamatergic transmission in synapses of neurons via sodium channel blockade. There is convincing evidence that Riluzole diminishes neurological tissue destruction and promotes functional recovery in animal SCI models. Based on these results, a phase I/IIa clinical trial with Riluzole was conducted for patients with SCI between 2010 and 2011. This trial demonstrated significant improvement in neurological outcomes and showed it to be a safe drug with no serious adverse effects. Currently, an international, multi-center clinical trial (Riluzole in Acute Spinal Cord Injury Study: RISCIS) in phase II/III is in progress with Riluzole for patients with SCI (clinicaltrials.gov, registration number NCT01597518). This article reviews the pharmacology and neuroprotective mechanisms of Riluzole, and focuses on existing preclinical evidence, and emerging clinical data in the treatment of SCI.
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Riluzole improves outcome following ischemia reperfusion injury to the spinal cord by preventing delayed paraplegia
Neuroscience, 2014Co-Authors: Kajana Satkunendrarajah, Michael G. FehlingsAbstract:The spinal cord is vulnerable to ischemic injury due to trauma, vascular malformations and correction of thoracic aortic lesions. Riluzole, a sodium channel blocker and anti-glutamate drug has been shown to be neuroprotective in a model of ischemic spinal cord injury, although the effects in clinically relevant ischemia/reperfusion models are unknown. Here, we examine the effect of Riluzole following ischemia-reperfusion injury to the spinal cord. Female rats underwent high thoracic aortic balloon occlusion to produce an ischemia/reperfusion injury. Tolerance to ischemia was evaluated by varying the duration of occlusion. Riluzole (8mg/kg) was injected intraperitoneally 4h after injury. Locomotor function (Basso, Beattie and Bresnahan (BBB) scale) was assessed at 4h, 1day, and 5days post-ischemia. Spinal cords were extracted and evaluated for neuronal loss using immunohistology (choline acetyltransferase (ChAT) and neuronal nuclei (NeuN)), inflammation (CD11b), astrogliosis (glial fibrillary acidic protein - GFAP) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Ischemic injury lasting between 5.5 and 6.75min resulted in delayed paraplegia, whereas longer ischemia induced immediate paraplegia. When Riluzole was administered to rats that underwent 6min of occlusion, delayed paraplegia was prevented. The BBB score of Riluzole-treated rats was 11.14±4.85 compared with 1.86±1.07 in control animals. Riluzole also reduced neuronal loss, infiltration of microglia/macrophages and astrogliosis in the ventral horn and intermediate zone of the gray matter. In addition, Riluzole reduced apoptosis of neurons in the dorsal horn of the gray matter. Riluzole has a neuroprotective effect in a rat model of spinal cord injury/reperfusion when administered up to 4h post-injury, a clinically relevant therapeutic time window.
Sanjay J Mathew - One of the best experts on this subject based on the ideXlab platform.
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serum and plasma brain derived neurotrophic factor and response in a randomized controlled trial of Riluzole for treatment resistant depression
Journal of Affective Disorders, 2018Co-Authors: Samuel T Wilkinson, Mounira Banasr, Sanjay J Mathew, Carly Kiselycznyk, Ryan Webler, Colin N HaileAbstract:Abstract Background Serum brain-derived neurotrophic factor (BDNF) is decreased in individuals with major depressive disorder (MDD). Pre-clinical and clinical reports suggest that the glutamate release inhibitor Riluzole increases BDNF and may have antidepressant properties. Here we report serum (sBDNF) and plasma (pBDNF) levels from a randomized controlled, adjunctive, sequential parallel comparison design trial of Riluzole in MDD. Methods Serum and plasma BDNF samples were drawn at baseline and weeks 6 and 8 from 55 subjects randomized to adjunctive treatment with Riluzole or placebo for 8 weeks. Results Riluzole responders had lower baseline serum (19.08 ng/ml [SD 9.22] v. 28.80 ng/ml [9.63], p = 0.08) and plasma (2.72 ng/ml [1.07] v. 4.60 ng/ml [1.69], p = 0.06) BDNF compared to non-responders at a trend level. This pattern was nominally seen in placebo responders for baseline pBDNF to some degree (1.21 ng/ml [SD 1.29] v. 3.58 ng/ml [SD 1.67], p = 0.12) but not in baseline sBDNF. Limitations A number of limitations warrant comment, including the small sample size of viable BDNF samples and the small number of Riluzole responders. Conclusions Preliminary evidence reported here suggests that lower baseline BDNF may be associated with better clinical response to Riluzole.
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a randomized double blind placebo controlled sequential parallel comparison design trial of adjunctive Riluzole for treatment resistant major depressive disorder
Neuropsychopharmacology, 2017Co-Authors: Sanjay J Mathew, Maurizio Fava, Ralitza Gueorguieva, Cynthia Brandt, Gerard SanacoraAbstract:Riluzole is a glutamate-modulating agent with neuroprotective properties approved for use in amyotrophic lateral sclerosis. The efficacy and safety of Riluzole vs placebo as an adjunct to antidepressant medication in outpatients with major depressive disorder (MDD) was examined in a 3-site, 8-week, randomized, double-blind, placebo-controlled, fixed-dose trial using a sequential parallel comparison design comprised of two phases of 4 weeks. Patients with MDD in a current major depressive episode (N=104) with an inadequate response to either a prospective or a historical trial of an antidepressant medication were randomized in a 2 : 3 : 3 ratio to the treatment sequences of Riluzole/Riluzole, placebo/placebo, and placebo/Riluzole, respectively. The primary outcome was change in depression severity, as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary efficacy outcomes included the response rate, defined as at least a 50% improvement in MADRS, Clinical Global Impressions severity and improvement subscales, and patient-reported measures of depression and cognitive function. Eighty-five patients completed the randomized treatment phases. Treatment groups did not differ in mean change in MADRS scores, response rate, or in any secondary efficacy outcomes. Riluzole was generally well tolerated, with a side effect profile consistent with its clinical use. In conclusion, a fixed dose of Riluzole (100 mg/day) did not show adjunctive antidepressant efficacy compared to placebo. The trial was adequately powered to detect a moderate Riluzole effect, and the risk for exaggerated placebo responses was mitigated. The lack of efficacy suggests that mechanisms underlying Riluzole’s neuroprotective effects are insufficient for clinical response in treatment-resistant depression.
Gregor K Wenning - One of the best experts on this subject based on the ideXlab platform.
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Placebo-controlled trial of Riluzole in multiple system atrophy.
European journal of neurology, 2006Co-Authors: Klaus Seppi, Carmen A. Peralta, Anja Diem-zangerl, Zoe Puschban, Joerg Mueller, Werner Poewe, Gregor K WenningAbstract:We performed a placebo-controlled cross-over trial of Riluzole (100 mg b.i.d.) in 10 patients with probable multiple system atrophy (MSA) administering Riluzole and placebo for 4 weeks each with a 4-week washout period. Outcome measures evaluated short-term anti-Parkinsonian effects using the Unified Parkinson's Disease Rating Scale (UPDRS) subscales (UPDRS-II, activities of daily living; UPDRS-III, motor examination; sum of UPDRS-II and -III) before and at the end of each treatment phase. Delta values were calculated by subtracting the UPDRS scores measured at the end of each treatment arm from those before onset of each medication phase. Riluzole was generally well tolerated. There were no significant anti-Parkinsonian effects of Riluzole comparing the UPDRS delta values for both treatment arms using the Wilcoxon signed-rank test. It is unlikely that Riluzole treatment could have clinically meaningful anti-Parkinsonian effects in MSA. A trial assessing the disease-modifying potential of Riluzole in MSA is underway.
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effects of Riluzole on combined mptp 3 nitropropionic acid induced mild to moderate striatonigral degeneration in mice
Journal of Neural Transmission, 2005Co-Authors: Elsa Diguet, Pierre-olivier Fernagut, Gregor K Wenning, Christoph Scherfler, François TisonAbstract:We investigated the potency of Riluzole, an anti-glutamatergic drug, to affect ongoing neuronal death process following combined MPTP + 3-nitropropionic acid (3-NP) intoxication producing combined striatal and nigral degeneration (SND) in mice. We used a “neuronal rescue” strategy by administering Riluzole after the end of intoxication. The motor disorder, its recovery, behavioral performances at motor and sensorimotor integration tasks and histopathological outcome were compared in the saline and Riluzole groups (10 mg/kg and 20 mg/kg), matched by triplets for motor severity. While Riluzole did not produce any effect on the gross motor disorder nor on rotarod task, open-field kinetic variables or on the traversing beam task, it had a subtle effect on the performances at the pole test. The histopathological outcome was significantly better in the Riluzole-treated mice regarding both nigral and dorsolateral striatal cell loss and astroglial activation, with a dose-effect relationship. Thus, Riluzole has limited “neuronal rescue” properties from an histopathological point of view with a subtle motor behavior improvement in a MPTP + 3-NP-induced SND in mice.
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Effects of Riluzole on combined MPTP + 3-nitropropionic acid-induced mild to moderate striatonigral degeneration in mice
Journal of Neural Transmission, 2005Co-Authors: Elsa Diguet, Pierre-olivier Fernagut, Gregor K Wenning, Christoph Scherfler, François TisonAbstract:We investigated the potency of Riluzole, an anti-glutamatergic drug, to affect ongoing neuronal death process following combined MPTP + 3-nitropropionic acid (3-NP) intoxication producing combined striatal and nigral degeneration (SND) in mice. We used a “neuronal rescue” strategy by administering Riluzole after the end of intoxication. The motor disorder, its recovery, behavioral performances at motor and sensorimotor integration tasks and histopathological outcome were compared in the saline and Riluzole groups (10 mg/kg and 20 mg/kg), matched by triplets for motor severity. While Riluzole did not produce any effect on the gross motor disorder nor on rotarod task, open-field kinetic variables or on the traversing beam task, it had a subtle effect on the performances at the pole test. The histopathological outcome was significantly better in the Riluzole-treated mice regarding both nigral and dorsolateral striatal cell loss and astroglial activation, with a dose-effect relationship. Thus, Riluzole has limited “neuronal rescue” properties from an histopathological point of view with a subtle motor behavior improvement in a MPTP + 3-NP-induced SND in mice.
Gilbert Bensimon - One of the best experts on this subject based on the ideXlab platform.
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Brain and plasma Riluzole pharmacokinetics: effect of minocycline combination.
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences Societe canadienne des sciences phar, 2009Co-Authors: Aline Milane, Vincent Meininger, Gilbert Bensimon, Christine Fernandez, Lionel Tortolano, Robert FarinottiAbstract:PURPOSE: amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the loss of motorneurons. The only drug approved is Riluzole. Minocycline is an antibiotic with numerous neuroprotective properties. Riluzole and minocycline were given to an animal model of ALS and had beneficial effect on the disease. The combination was then tested in humans in phase II and phase III studies with less beneficial effects and a faster decline of the disease in the group treated with minocycline. In a previous study, we showed that Riluzole is transported out of the brain by the P-glycoprotein at the blood-brain barrier level. METHODS: in this work, we studied in CF1 mice, the plasmatic and cerebral pharmacokinetics of Riluzole combined or not with minocycline. RESULTS: our results showed that the kinetics of Riluzole are not linear with dose, but that cerebral AUC0-∞ increase proportionally with plasmatic AUC0-∞. At the dose of 10 mg/kg, the cerebral AUC0-∞ /plasmatic AUC0-∞ ratio was 4.6 in mdr1a (-/-) mice and 2.4 in mdr1a (+/+) mice. The combination of minocycline (170 mg/kg) and Riluzole (10 mg/kg) induced a 2 fold increase in the cerebral AUC0-∞ of Riluzole and induced a neuromuscular toxicity in mice. This effect of minocycline was not found at low concentration (10 mg/kg of minocycline). CONCLUSIONS: if our results are confirmed in humans, Riluzole cerebral concentrations could be predicted by plasmatic concentrations. Furthermore, the combination of high doses of minocycline with Riluzole could induce neurological toxicity that lead to deceiving results in ALS clinical studies.
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Interactions between Riluzole and ABCG2/BCRP transporter.
Neuroscience letters, 2009Co-Authors: Aline Milane, Sarah Vautier, Hélène Chacun, Vincent Meininger, Gilbert Bensimon, Robert Farinotti, Christine FernandezAbstract:Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disease. Drugs used in this disease need to cross the blood–brain barrier (BBB). Only Riluzole is approved for ALS treatment. We have investigated Riluzole as a breast cancer resistance protein (BCRP) substrate by studying its brain transport in CF1 mdr1a (−/−) mice and its intracellular uptake on BeWo cells (human placental choriocarcinoma cell line). We have also investigated the effect of Riluzole on BCRP expression level and on its activity using the prazocin as a test probe for brain transport and intracellular uptake. Assays on mdr1a (−/−) mice and BeWo cells showed a higher uptake of Riluzole when pretreated with a BCRP inhibitor. After repeated doses of Riluzole, BCRP activity was increased in CF1 mdr1a (−/−) mice, Riluzole uptake was decrease and both BCRP expression and activity were increased in BeWo cells. In conclusion, we report in this study that Riluzole is transported by BCRP at the BBB level and can enhance its function. These results taken with our previous studies on Riluzole and P-glycoprotein show that drug–drug interactions between Riluzole and efflux transporters substrates may occur at the BBB level and should be taken into account in future clinical trial design in ALS.
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The tolerability of Riluzole in the treatment of patients with amyotrophic lateral sclerosis.
Expert opinion on drug safety, 2004Co-Authors: Gilbert Bensimon, Adam DobleAbstract:Riluzole is the only disease-modifying drug approved for the treatment of amyotrophic lateral sclerosis (ALS), in which it has been demonstrated to extend survival. The overall tolerability of Riluzole is good and the drug can be used in all patients with ALS except those with elevated transaminase levels or active liver disease. The most frequently encountered adverse events (AEs) that appear to be attributed to Riluzole are asthenia and nausea, observed in 18 and 15% of patients taking Riluzole in the randomised clinical trial programme, respectively. These same AEs, albeit at a lower frequency, are also reported in Phase IV observational studies and in pharmacovigilance surveys. No unexpected AE clearly related to Riluzole has emerged in the seven years that Riluzole has been in extensive use in ALS patients. The most important potential safety issue with Riluzole is hepatic impact with elevations of transaminases. Serum alanine aminotransferase levels more than three times the upper limit of normal ar...
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a study of Riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis
Journal of Neurology, 2002Co-Authors: Gilbert Bensimon, Lucette Lacomblez, R. Bejuit, P. Truffinet, J C Delumeau, Vincent MeiningerAbstract:Treatment with the neuroprotective drug Riluzole has previously been shown to increase the probability of survival in patients with amyotrophic lateral sclerosis. This report describes a placebo-controlled, double-blind randomised clinical trial of Riluzole carried out in ALS patients with advanced stage disease or aged over 75 years. The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel. Another goal was to assess the safety of Riluzole in patients with advanced-stage disease. One hundred and sixty-eight patients were included, randomised to either Riluzole 50 mg b. i. d. or to placebo, and treated for eighteen months. Riluzole was well-tolerated in this patient population, and the adverse events observed were similar in nature and frequency to those observed in previously published clinical trials in patients included in pivotal trials. The study could not include enough patients to reach adequate power to detect differences in survival between the two treatment groups, and no such difference was in fact observed. In conclusion, Riluzole is well-tolerated in ALS patients with advanced stage disease.
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Long-term safety of Riluzole in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology Research Group on Motor Neu, 2002Co-Authors: Lucette Lacomblez, Gilbert Bensimon, Peter Nigel Leigh, C Debove, R. Bejuit, P. Truffinet, Vincent MeiningerAbstract:OBJECTIVES : This international, open-label, multicentre extension of Riluzole pivotal studies was designed to assess the long-term safety of Riluzole in the treatment of amyotrophic lateral sclerosis (ALS). METHOD : The studies were carried out at 31 different centres, 23 in Europe and eight in North America. 516 patients with diagnosed probable or definite ALS and who had participated previously in one of two international multicentre randomized double-blind placebo-controlled, parallel-group trials, were enrolled in the extensions. 58 of these patients had taken part in a randomized phase II trial (placebo or Riluzole 100 mg/day) and 458 in a randomized, dose-ranging phase III trial (placebo or Riluzole, 50, 100 or 200 mg/day). All participants in the open-label continuation received 100 mg/day of Riluzole (50 mg b.i.d. ) RESULTS : At the end of the open-label study, the average exposure time of the patients to Riluzole was 28.7 - 14.4 months, with a maximum exposure time of 81 months. Most of the a...
