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Introduction: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness., Sources of Data: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'., Areas of Agreement: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND., Areas of Controversy: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe., Growing Points: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies., Areas Timely for Developing Research: Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Purpose: The purpose was to describe the use patterns of pharmacological and non-pharmacological therapies and investigate potential determinants of riluzole use in patients newly diagnosed with amyotrophic lateral sclerosis (ALS) in three Italian regions., Methods: Amyotrophic lateral sclerosis patients were selected from administrative healthcare databases of Latium, Tuscany and Umbria from 1 January 2014 to 31 December 2019 based on hospital- and disease-specific co-payment exemption data. The first trace of ALS was considered the index date. Incident ALS cases were those without a trace of ALS during the 3-year look back. Patients were described in terms of demographics, clinical characteristics and drug use at baseline, and were classified into four categories based on riluzole use in the 2 years before and 1 year after the index date: prevalent, incident, former users and non-users. Use of symptomatic pharmacological and non-pharmacological therapies was described across these categories during 12 months after the index date. Determinants of riluzole use were also investigated., Results and Conclusions: A total of 1636 ALS incident subjects were detected in the three regions, mainly aged 65-74 years. Patients were generally fragile with a high prevalence of comorbidities at baseline. Riluzole was used by 27.4% of the overall study cohort at baseline and steeply increased in the first year after the index date differently between regions (Latium 61.2%, Tuscany 85.0%, Umbria 76.5%), with about half of the subjects being incident users. In the 12 months after the index date, also symptomatic therapies increased, in riluzole users and non-users. Determinants analysis showed that higher patient severity and complexity were associated with a lower likelihood of being treated with riluzole., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Currently no curative treatment exists for spinocerebellar ataxias (SCAs). Riluzole repurposing was proposed as a symptomatic treatment in different types of cerebellar ataxia. We report a long-term-follow up under riluzole treatment in SCA type 7., Methods: Six patients received Riluzole 50 mg twice daily on a compassionate use program for a mean of 4.8 years (range 3.5-9). We measured ataxia onset and progression through the Scale for the Assessment and Rating of Ataxia (SARA), and collected extensive ophthalmological data before and after Riluzole treatment. Electrocardiogram and laboratory profile for drug safety were performed every six months., Results: Riluzole treatment showed no effect on visual function in two patients with an advanced retinal damage. Improvements of visual function occurred in four patients followed by ophthalmologic stability up to 5 years after starting treatment. Two patients had a less steep deterioration of ataxia after treatment compared to pre-treatment, during the first 2,5 years of therapy. One showed soon after therapy an improvement of the SARA score, and then overall stability lasting 3,5 years, followed by ataxia worsening. One visually impaired patient without neurological impairment did not worse until the last visit after 3,5 years of follow-up. The remaining 2 patients showed an improvement of SARA scores soon after therapy, and an overall stability lasting respectively 5 and 3 years. No adverse event was registered during the observation period., Discussion: This study suggests a possible beneficial action of Riluzole in SCA7 and provides a detailed description of the ophthalmologic profile of these patients., Competing Interests: Declarations. Ethics Approval and Consent to Participate: The Institutional Review Board of the Robert Hollman Foundation (protocol number 8/2017) approved the study. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and data obtained for clinical purposes to monitor riluzole treatment on a compassionate use program were retrieved from institutional records of the participating centers and collected in an anonymized dataset. The written informed consent to compassionate use of riluzole was obtained from all participants included in the study or the legally authorized representative. Additional written informed consent regarding publishing their data was obtained from all individual participants. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT., Competing Interests: Declaration of interests B.J.T. holds patents on clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72., (Published by Elsevier Inc.)

Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder that is characterized by gradual muscle weakness and atrophy due to the degeneration of alpha motor neurons that are present on the anterior horn of the spinal cord. Despite the comprehensive investigations conducted by global scientists, effective treatments or interventions remain elusive. The time- and resource-intensive nature of the initial stages of drug research underscores the need for alternate strategies like drug repurposing. This review explores the repurposed drugs that have shown some improvement in treating SMA, including branaplam, riluzole, olesoxime, harmine, and prednisolone. The current strategy for medication repurposing, however, lacks systematicity and frequently depends more on serendipitous discoveries than on organized approaches. To speed up the development of successful therapeutic interventions, it is apparent that a methodical approach targeting the molecular origins of SMA is strictly required., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease of motor neuron. Although riluzole and edaravone have been approved for the treatment of ALS, it remains a lethal disease that causes rapid motor impairment, and there is an urgent need to develop more effective treatments. Advances in understanding the pathomechanisms of ALS, efficient clinical trial design, and research support programs have led to many clinical trials for ALS both domestically and internationally.

Introduction: Spinal cord injury (SCI) may bring lifelong consequences for affected patients and a high financial burden to the health care system., Source of Data: Published peer-reviewed scientific articles identified from EMBASE, Google Scholar, PubMed and Scopus., Areas of Agreement: Surgery and blood pressure management are the main targets in acute SCI to avoid secondary damage., Areas of Controversy: The management of secondary chronic SCI is challenging, with unpredictable outcomes., Growing Points: Given the lack of consensus on pharmacological therapy for acute and secondary chronic SCI, the present study analyses the currently available drugs and treatment options to manage secondary chronic SCI., Areas Timely for Developing Research: Different approaches exist for the pharmacological management of secondary chronic SCI. One of the most investigated drugs, 4-aminopyridine, improves central motor conduction and shows improvement in neurological signs. Positive results in different areas have been observed in patients receiving the anti-spastic drugs tizanidine and baclofen or Granulocyte colony-stimulating factor. Growth hormone showed only minimal or no significant effects, and the therapy of secondary chronic SCI with riluzole has been poorly researched to date., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: The modified Japanese Orthopaedic Association (mJOA) scale is the most common scale used to represent outcomes of degenerative cervical myelopathy (DCM); however, it lacks consideration for neck pain scores and neglects the multidimensional aspect of recovery after surgery., Objective: To use a global statistical approach that incorporates assessments of multiple outcomes to reassess the efficacy of riluzole in patients undergoing spinal surgery for DCM., Design, Setting, and Participants: This was a secondary analysis of prespecified secondary end points within the Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-PROTECT) trial, a multicenter, double-blind, phase 3 randomized clinical trial conducted from January 2012 to May 2017. Adult surgical patients with DCM with moderate to severe myelopathy (mJOA scale score of 8-14) were randomized to receive either riluzole or placebo. The present study was conducted from July to December 2023., Intervention: Riluzole (50 mg twice daily) or placebo for a total of 6 weeks, including 2 weeks prior to surgery and 4 weeks following surgery., Main Outcomes and Measures: The primary outcome measure was a difference in clinical improvement from baseline to 1-year follow-up, assessed using a global statistical test (GST). The 36-Item Short Form Health Survey Physical Component Score (SF-36 PCS), arm and neck pain numeric rating scale (NRS) scores, American Spinal Injury Association (ASIA) motor score, and Nurick grade were combined into a single summary statistic known as the global treatment effect (GTE)., Results: Overall, 290 patients (riluzole group, 141; placebo group, 149; mean [SD] age, 59 [10.1] years; 161 [56%] male) were included. Riluzole showed a significantly higher probability of global improvement compared with placebo at 1-year follow-up (GTE, 0.08; 95% CI, 0.00-0.16; P = .02). A similar favorable global response was seen at 35 days and 6 months (GTE for both, 0.07; 95% CI, -0.01 to 0.15; P = .04), although the results were not statistically significant. Riluzole-treated patients had at least a 54% likelihood of achieving better outcomes at 1 year compared with the placebo group. The ASIA motor score and neck and arm pain NRS combination at 1 year provided the best-fit parsimonious model for detecting a benefit of riluzole (GTE, 0.11; 95% CI, 0.02-0.16; P = .007)., Conclusions and Relevance: In this secondary analysis of the CSM-PROTECT trial using a global outcome technique, riluzole was associated with improved clinical outcomes in patients with DCM. The GST offered probability-based results capable of representing diverse outcome scales and should be considered in future studies assessing spine surgery outcomes.

Background: There is an increasing need to better understand the burden of amyotrophic lateral sclerosis (ALS) using real-world data (RWD). However, identifying ALS cases using RWD presents several challenges due to the rarity of ALS and the differences in database coding systems., Methods: MarketScan claims, and the UK Clinical Practice Research Datalink (CPRD) databases were searched for diagnosis codes of ALS or MND, the only drugs approved for treating ALS (riluzole and edaravone) and clinical visits with 12-month enrolment prior to 1 January 2011. The main algorithm required ≥ 1 ALS diagnosis code together with prescriptions or clinical visits. We expanded the existing algorithm to identify unspecific (possible) ALS group that had codes for motor neuron disease (MND) and the ALS drugs. The study period was from 1 January 2011 until 31 December 2020., Results: We identified 16,246 patients with ≥ 1 ALS code in Marketscan (denominator n = 85,279,619), yet only 184 were found in the UK CPRD (denominator n = 21,318,589). Using the main algorithm 9,433 ALS patients were included in MarketScan, with a prevalence ranged between 4.5 per 100,000 in 2019 and 6.2 in 2015. In MarketScan, 3,658 (4.3 per 100,000) had ≥ 1 MND code and the ALS drug codes (possible cases). In CPRD, 47.9% of 2,785 patients with ≥ 1 MND code had a prescription for riluzole (6.3 per 100,000), regarded as possible ALS cases., Conclusions: The expanded algorithm enabled the identification of a large population with ALS, or possible ALS, and the estimation of ALS prevalence in MarketScan and CPRD., (© 2024. Fondazione Società Italiana di Neurologia.)

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

Background: Despite several hundred clinical trials of drugs that initially showed promise, there has been limited clinical improvement in Alzheimer's disease (AD). This may be attributed to the existence of at least 25 abnormal cellular pathways that underlie the disease. It is improbable for a single drug to address all or most of these pathways, thus even drugs that show promise when administered alone are unlikely to produce significant results. According to previous studies, eight drugs, namely, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, have been found to target multiple pathways that are involved in the development of AD. Among these drugs, riluzole is currently indicated for the treatment of medical conditions in both adult patients and children and has gained increased attention from scientists due to its potential in the excitotoxic hypothesis of neurodegenerative diseases., Objective: The aim of this study was to investigate the effects of drugs on AD based on cellular and molecular mechanisms., Methods: The literature search for this study utilized the Scopus, ScienceDirect, PubMed, and Google Scholar databases to identify relevant articles., Results: Riluzole exerts its effects in AD through diverse pathways including the inhibition of voltage-dependent sodium and calcium channels, blocking AMPA and NMDA receptors and inhibiting the release of glutamic acid release and stimulation of EAAT1-EAAT2., Conclusion: In this review article, we aimed to review the neuroprotective properties of riluzole, a glutamate modulator, in AD, which could benefit patients with the disease., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

This systematic review aims to summarize the findings from all clinical randomized trials assessing the efficacy of potential neuroprotective agents in influencing the outcomes of acute spinal cord injuries (SCI). Following the PRISMA guidelines, we conducted comprehensive searches in four electronic databases (PubMed, Scopus, Cochrane Library, and Web of Science) up to September 5th, 2023. Our analysis included a total of 30 studies. We examined the effects of 15 substances/drugs: methylprednisolone, tirilazad mesylate, erythropoietin, nimodipine, naloxone, Sygen, Rho protein antagonist, granulocyte colony-stimulating factor, autologous macrophages, autologous bone marrow cells, vitamin D, progesterone, riluzole, minocycline, and blood alcohol concentration. Notable improvements in neurological outcomes were observed with progesterone plus vitamin D and granulocyte colony-stimulating factor. In contrast, results for methylprednisolone, erythropoietin, Sygen, Rho Protein, and Riluzole were inconclusive, primarily due to insufficient sample size or outdated evidence. No significant differences were found in the remaining evaluated drugs. Progesterone plus vitamin D, granulocyte colony-stimulating factor, methylprednisolone, Sygen, Rho Protein, and Riluzole may enhance neurological outcomes in acute SCI cases. It is worth noting that different endpoints or additional subgroup analyses may potentially alter the conclusions of individual trials. Therefore, certain SCI grades may benefit more from these treatments than others, while the overall results may remain inconclusive., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Amyotrophic lateral sclerosis (ALS) poses a significant clinical challenge due to its rapid progression and limited treatment options, often leading to deadly outcomes. Looking for effective therapeutic interventions is critical to improve patient outcomes in ALS., Patient Concerns: The patient, a 75-year-old East Asian male, manifested an insidious onset of right-hand weakness advancing with dysarthria. Comprehensive Next-generation sequencing analysis identified variants in specific genes consistent with ALS diagnosis., Diagnoses: ALS diagnosis is based on El Escorial diagnostic criteria., Interventions: This study introduces a novel therapeutic approach using artificial intelligence phenotypic response surface (AI-PRS) technology to customize personalized drug-dose combinations for ALS. The patient underwent a series of phases of AI-PRS-assisted trials, initially incorporating a 4-drug combination of Ibudilast, Riluzole, Tamoxifen, and Ropinirole. Biomarkers and regular clinical assessments, including nerve conduction velocity, F-wave, H-reflex, electromyography, and motor unit action potential, were monitored to comprehensively evaluate treatment efficacy., Outcomes: Neurophysiological assessments supported the ALS diagnosis and revealed the co-presence of diabetic polyneuropathy. Hypotension during the trial necessitated an adaptation to a 2-drug combinational trial (ibudilast and riluzole). Disease progression assessment shifted exclusively to clinical tests of muscle strength, aligning with the patient's well-being., Lessons: The study raises the significance of personalized therapeutic strategies in ALS by AI-PRS. It also emphasizes the adaptability of interventions based on patient-specific responses. The encountered hypotension incident highlights the importance of attentive monitoring and personalized adjustments in treatment plans. The described therapy using AI-PRS, offering personalized drug-dose combinations technology is a potential approach in treating ALS. The promising outcomes warrant further evaluation in clinical trials for searching a personalized, more effective combinational treatment for ALS patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The Patient Preference Survey aims to understand unmet needs related to riluzole management in people with Amyotrophic Lateral Sclerosis (ALS) and to identify which characteristics of a new formulation could better match their preferences. The survey involved 117 people with ALS (PALS) treated with riluzole in four European countries. The dysphagic PALS were least satisfied with the riluzole tablet and oral suspension and with ease in self-administration; up to 68% of respondents postponed or missed the treatment due to swallowing difficulties and need of caregiver assistance. Overall, 51% of tablet and 53% of oral suspension users regularly crushed or mixed riluzole with beverages, respectively; PALS who always manipulated riluzole showed low satisfaction with the formulation and considered the risk of choking and pneumonia the most worrisome event. The survey evaluated the driving factors in choosing/switching the therapy: 67% of PALS declared a low risk of choking. The research finally evaluated which attributes of a new formulation would be preferred: the most relevant were ease of use (4.3/5), convenient/portable packaging (4.0/5) and oral-dissolving properties without tongue motility (3.9/5). The Patient Preference Survey suggests that patients have several unmet needs and preferences that could be addressed by a different formulation, e.g. using oral film technologies., (© 2023. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a devastating and progressive neurodegenerative disease with limited treatment options available. Cerebrolysin is a drug candidate for the treatment of ALS because of its neuroprotective and neuroregenerative effects. We initiated a pilot clinical study of a combination of Cerebrolysin and riluzole to assess the therapeutic benefit of Cerebrolysin as an add-on treatment on clinical signs and symptoms in outpatients with ALS. Twenty patients with a clinically definitive diagnosis of ALS were enrolled and randomly assigned in a 1:1 ratio to receive Cerebrolysin or placebo. All patients received 50 mg of riluzole PO twice daily as a standard treatment. Patients in the Cerebrolysin group received intravenous injections of 10 mL of Cerebrolysin once daily, five days a week for the first month and three days a week for the next two months. Analysis of the ALS Functional Rating Scale - revised at Month 1 (primary outcome measure), showed a significant treatment effect in favor of Cerebrolysin with a 2.3-point improvement from baseline to Month 1 compared to a 0.9-point decrease in patients on placebo (P=0.005). The effect was maintained over the three-month study period, and the beneficial effect of Cerebrolysin over placebo was also evident in the secondary outcome measures. The safety analysis showed that the combination of riluzole and Cerebrolyisn was well tolerated. Our results demonstrate for the first time a significant clinical effect of Cerebrolysin in improving functional outcomes in patients with ALS and suggest that Cerebrolysin has potential as a novel therapeutic option for ALS., Competing Interests: One of the authors, Alfredo José Firstenfeld, has received a grant from EVER Neuro Pharma GmbH. The authors have no other conflict of interests to declare., (© 2023 The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a rare disease characterized by a progressive and irreversible degeneration of upper and lower motor neurons leading to death. In France, limited data exist describing the criteria used in clinical practice for diagnosis and follow-up, and how novel therapies may fit in. The objective of this Delphi panel was to obtain an overview of current French practices in ALS diagnosis, management, and follow-up by determining the scales and criteria used in clinical practice outside of clinical trials, as well as the place of a future treatment like AMX0035, acting on endoplasmic reticulum (ER) stress and mitochondrial dysfunction, in the current therapeutic strategies. A questionnaire was administered to 24 ALS healthcare providers practicing in ALS centers in France. Two rounds of remote voting were organized, before proposition of final consensus statements. Consensus was considered reached when at least 66% of the voters agreed. Consensus were obtained to define the new Gold Coast criteria as the ones used in clinical practice to establish the diagnosis of ALS, thus replacing the revised El Escorial criteria, considered too complex and now mainly used to characterize the patient populations to be included in clinical trials. The clinical factors considered to establish ALS diagnosis are mainly the demonstration of progression of the motor deficit and elimination of differential diagnoses. The ALSFRS-R scale is used in daily clinical practice to assess patient's functional impairment in terms of number of points lost, with the bulbar, respiratory, and fine motor subscores being the most important to evaluate independently. A critical medical need was identified regarding the provision of new therapeutic alternatives in ALS. The panel members would support the earliest management of patients. In this landscape, based on data from a very encouraging phase II (Centaur trial), AMX0035 represents a new tool of choice in current treatment strategies for all patients for whom experts are confident in the diagnosis of ALS, in combination with riluzole. These results will need to be confirmed by the ongoing phase III trial (Phoenix trial)., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics.", Competing Interests: Nicholas M Boulis is a consultant for Abbott, UCB, Novo Nordisk, Treefrog, UniQure, and Coave. He serves on the scientific advisory board for Above and Beyond NB LLC. Raymond T. Bartus was a consultant and advisor for Above and Beyond NB LLC. Malú G Tansey is a consultant for INmune Bio, Longevity, and Prevail Therapeutics. She serves on the scientific advisory board for the Garfield Weston Foundation, the Michael J Fox Foundation, the Quebec Parkinson’s Network, and the Alzheimer’s Association. She receives research support from the NIH, the MJ Fox Foundation, and the Parkinson’s Foundation. Above and Beyond NB LLC’s riluzole formulation is protected by a use patent issued June 18th 2019 (N°10,322,114)., (Copyright: © 2023 Keifer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To describe the clinical and demographic characteristics of patients with MND treated with riluzole by comparing two dosage forms (oral suspension and tablets), as well as the impact on survival in patients with and without dysphagia according to the form of dosage. Methods: Retrospective and prospective cohort of patients diagnosed with MND at the multidisciplinary functional unit of Motor Neuron Disease in our center in the period between 1 of January 2011 and 31 of December 2020 ( n  = 742). A descriptive analysis (univariate and bivariate) was carried out and survival curves were estimated. Results: During the follow-up period, 402 males (54.18%) and 340 females (45.82%) were diagnosed with MND. Of these patients, 632 (97.23%) were being treated with 100mg riluzole: 282 (54.55%) patients took this in tablet form and 235 (45.45%) oral suspension. Riluzole in tablet form is taken more frequently by men than women, in younger age ranges, and mostly without dysphagia (78.31%). Also, it is the predominant dosage form for classic spinal ALS and respiratory phenotypes. Dosages via oral suspension are taken by patients in the older age ranges (over 64.8 years), mostly with dysphagia (53.67%) and more frequently with bulbar phenotypes such as classic bulbar ALS and PBP. Because of this, patients using oral suspension (most of them with dysphagia) had a poorer survival rate (at 90% CI) than patients using tablets (most of them without dysphagia). Conclusions: The most appropriate dosage form should be given according to the patient's needs at each stage of the disease and, furthermore, oral suspension could improve adherence to treatment because it avoids having to change from one form (tablet) to the other (suspension) when swallowing disorders appear.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.

Riluzole and edaravone for the treatment of amyotrophic lateral sclerosis (ALS) are currently covered by insurance in Japan. Both have been shown to prolong survival and/or inhibit progression, but neither is a cure-all treatment, and the effects are difficult to realize. The data presented in clinical trials are not applicable to all patients with ALS; the risks and benefits should be explained carefully before use. So far, edaravone has been administered intravenously, but an oral form became available in Japan on April 17, 2023. For symptomatic treatment, morphine hydrochloride and morphine sulfate are insurance-covered alternatives.

Cancer-related cognitive impairment (CRCI) considerably affects the quality of life of millions of cancer survivors. Brain-derived neurotrophic factor (BDNF) has been shown to promote survival, differentiation, and maintenance of in vivo dentate neurogenesis, and chemotherapy induces a plethora of physiological and cellular alterations, including a decline in neurogenesis and increased neuroinflammation linked with cognitive impairments. In our clinical studies, breast cancer patients treated with doxorubicin (Adriamycin ® , ADR) experienced a significant reduction in the blood levels of BDNF that was associated with a higher risk of CRCI. Our past rodent studies in CRCI have also shown a significant reduction in dentate neurogenesis accompanied by cognitive impairment. In this study, using a female mouse model of ADR-induced cognitive decline, we tested the impact of riluzole (RZ), an orally active BDNF-enhancing medication that is FDA-approved for amyotrophic lateral sclerosis. ADR-treated mice receiving RZ in the drinking water for 1 month showed significant improvements in hippocampal-dependent learning and memory function (spatial recognition), fear extinction memory consolidation, and reduced anxiety-like behavior. RZ prevented chemotherapy-induced reductions of BDNF levels in the hippocampus. Importantly, RZ mitigated chemotherapy-induced loss of newly born, immature neurons, dentate neurogenesis, and neuroinflammation. In conclusion, this data provides pre-clinical evidence for a translationally feasible approach to enhance the neuroprotective effects of RZ treatment to prevent CRCI., (© 2023. The Author(s).)

Current medications for Alzheimer's disease help manage symptoms and behavioral problems. Nevertheless, they do not slow the progression of cognitive decline or dementia. A potential approach for treating Alzheimer's disease is to target neurons that are sensitive to disease pathobiology such as glutamatergic neurons. Several patents disclosed methods for treating Alzheimer's disease by administering riluzole or its prodrugs. Clinical trials revealed that 6 months treatment using riluzole or troriluzole is associated with a slower decline in the tomographic measures of the positron emissions of cerebral glucose metabolism in Alzheimer's patients. The proposed strategy claims to prevent and/or slow the cognitive decline of Alzheimer's patients and to enhance global functioning. These claims may also pave the way for other glutamate modulators to be used for Alzheimer's disease.

Background: Satisfactory treatment is often lacking for spasticity, a highly prevalent motor disorder in patients with spinal cord injury (SCI). Low concentrations of riluzole potently reduce the persistent sodium current, the post-SCI increase in which contributes to spasticity. The repurposing of this drug may therefore constitute a useful potential therapeutic option for relieving SCI patients suffering from chronic traumatic spasticity., Objective: RILUSCI is a phase 1b-2b trial designed to assess whether riluzole is a safe and biologically effective means of managing spasticity in adult patients with traumatic chronic SCI., Methods: In this multicenter double-blind trial, adults (aged 18-65 years) suffering from spasticity after SCI (target enrollment: 90 participants) will be randomly assigned to be given either a placebo or a recommended daily oral dose of riluzole for two weeks. The latter dose will be previously determined in phase 1b of the study by performing double-blind dose-finding tests using a Bayesian continuous reassessment method. The primary endpoint of the trial will be an improvement in the Modified Ashworth Score (MAS) or the Numerical Rating Score (NRS) quantifying spasticity. The secondary outcomes will be based on the safety and pharmacokinetics of riluzole as well as its impact on muscle spasms, pain, bladder dysfunction and quality of life. Analyses will be performed before, during and after the treatment and the placebo-controlled period., Conclusion: To the best of our knowledge, this clinical trial will be the first to document the safety and efficacy of riluzole as a means of reducing spasticity in patients with chronic SCI., Trial Registration: The clinical trial, which is already in progress, was registered on the ClinicalTrials.gov website on August 9, 2016 under the registration number NCT02859792., Trial Sponsor: Assistance Publique-Hôpitaux de Marseille., Competing Interests: The authors declare no competing interests, (Copyright: © 2023 Cotinat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). The profile of riluzole is favorable for normalizing glutamatergic dysregulation that perpetuates methamphetamine (METH) dependence, but pharmacokinetic and metabolic liabilities hinder repurposing. To mitigate these limitations, we synthesized troriluzole (TRLZ), a third-generation prodrug of riluzole, and tested the hypothesis that TRLZ inhibits METH hyperlocomotion and conditioned place preference (CPP) and normalizes METH-induced changes in mesolimbic glutamate biomarkers. TRLZ (8, 16 mg/kg) reduced hyperlocomotion caused by METH (1 mg/kg) without affecting spontaneous activity. TRLZ (1, 4, 8, 16 mg/kg) administered during METH conditioning (0.5 mg/kg x 4 d) inhibited development of METH place preference, and TRLZ (16 mg/kg) administered after METH conditioning reduced expression of CPP. In rats with established METH place preference, TRLZ (16 mg/kg) accelerated extinction of CPP. In cellular studies, chronic METH enhanced mRNA levels of glutamate carboxypeptidase II (GCPII) in the ventral tegmental area (VTA) and prefrontal cortex (PFC). Repeated METH also caused enhancement of GCPII protein levels in the VTA that was prevented by TRLZ (16 mg/kg). TRLZ (16 mg/kg) administered during chronic METH did not affect brain or plasma levels of METH. These results indicate that TRLZ, already in clinical trials for cerebellar ataxia, reduces development, expression and maintenance of METH CPP. Moreover, normalization of METH-induced GCPII levels in mesolimbic substrates by TRLZ points toward studying GCPII as a therapeutic target of TRLZ., Competing Interests: Conflict of Interest Authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The present study was initiated with PDB selection and validation where 11 acetylcholinesterase (AChE) and 4 N-methyl-D-aspartate receptor (NMDAR) proteins were considered for docking with Rivastigmine and Riluzole respectively. Out of the 15 proteins, selected significant binding was observed for AChE, with 5FPQ, and NMDA receptors with 5I2K. Molecular docking studies of 5FPQ/Rivastigmine complex displayed a binding score of -8.6 kcal/mol, and the predicted inhibitory concentration (Ki) was found to be 31 nM, whereas the 5I2K/Riluzole complex showed a binding score of -9.6 kcal/mol, with an inhibitory concentration (Ki) of 21 nM. Riluzole in complex with 5I2K formed predominant π-π stacking interactions with Tyr144, pi-alkyl interaction with Pro129, and conventional hydrogen bond with Phe130. In contrast, Rivastigmine in a complex with 5FPQ formed a hydrogen bond with Gln413 and pi-alkyl with Pro537. Molecular dynamics simulation study of both complexes 5FPQ/Rivastigmine and 5I2K/Riluzole exhibited stable RMSD, RMSF, Rg, and significant numbers of hydrogen bonds. From free energy landscape (FEL) analysis both complexes were observed to achieve global minima. Overall, molecular docking and MD simulation with subsequent binding free energies studies (MM-PBSA) elucidate the binding conformations and stability of these reprogrammed drugs in the AChE and NMDAR targets. From these in-silico predictions, it can be suggested that both Rivastigmine and Riluzole combination may provide better insights as a starting point combination therapy for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

Background: Prior research supports a strong link between Alzheimer's disease (AD) and metabolic dysfunction that involves a multi-directional interaction between glucose, glutamatergic homeostasis, and amyloid pathology. Elevated soluble amyloid-β (Aβ) is an early biomarker for AD-associated cognitive decline that contributes to concurrent glutamatergic and metabolic dyshomeostasis in humans and male transgenic AD mice. Yet, it remains unclear how primary time-sensitive targeting of hippocampal glutamatergic activity may impact glucose regulation in an amyloidogenic mouse model. Previous studies have illustrated increased glucose uptake and metabolism using a neuroprotective glutamate modulator (riluzole), supporting the link between glucose and glutamatergic homeostasis., Objective: We hypothesized that targeting early glutamatergic hyperexcitation through riluzole treatment could aid in attenuating co-occurring metabolic and amyloidogenic pathologies with the intent of ameliorating cognitive decline., Methods: We conducted an early intervention study in male and female transgenic (AβPP/PS1) and knock-in (APPNL - F/NL - F) AD mice to assess the on- and off-treatment effects of prodromal glutamatergic modulation (2-6 months of age) on glucose homeostasis and spatial cognition through riluzole treatment., Results: Results indicated a sex- and genotype-specific effect on glucose homeostasis and spatial cognition with riluzole intervention that evolved with disease progression and time since treatment., Conclusion: These findings support the interconnected nature of glucose and glutamatergic homeostasis with amyloid pathology and petition for further investigation into the targeting of this relationship to improve cognitive performance.

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by respiratory failure 3-5 years after diagnosis. Edaravone and Riluzole, the only drugs currently approved for ALS treatment, only provide mild symptomatic relief to patients. Extraordinary progress in understanding the biology of ALS provided new grounds for drug discovery. Over the last two decades, mitochondria and oxidative stress (OS), iron metabolism and ferroptosis, and the major regulators of hypoxia and inflammation - HIF and NF-κB - emerged as promising targets for ALS therapeutic intervention. In this review, we focused our attention on these targets to outline and discuss current advances in ALS drug development. Based on the challenges and the roadblocks, we believe that the rational design of multi-target ligands able to modulate the complex network of events behind the disease can provide effective therapies in a foreseeable future., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a rare, cumulative neurological deteriorating disease that disturbs the neurons (nerve cells) that control voluntary muscle movement (those muscles we choose to move). Currently, the Food and Drug Administration (FDA) approved drugs such as Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta to treat ALS. Given the wide range of pharmaceutical applications of heterocyclic compounds, especially those containing the nitrogen ring systems such as pyridine, pyrimidine, and indole. These molecular frameworks have piqued the interest of medicinal chemists for further investigation in a variety of diseases. We have found several review works done on this research topic. Until now, no reviews published on the nitrogen heterocycles for treating ALS. This review examines the major causes of ALS, a brief history of medications that have been used to treat it so far, and the most recent breakthroughs in nitrogen ring systems for treating ALS. The novelty of this study provides insights on several effective synthetic techniques for nitrogen-based heterocyclic medications that operate as potent anti-inflammatory treatments and guard against ALS. KEY POINTS: • Pharmacological activity of heterocyclic compounds. • Neurodegenerative diseases and their drawbacks are discussed in detail. • Recent survey of nitrogen heterocycles in treating ALS disease are highlighted., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction/aims: Riluzole improves survival in amyotrophic lateral sclerosis (ALS), but optimal time and duration of treatment are unknown. The aim of this study was to examine if timing of riluzole initiation and duration of treatment modified its effect on survival., Methods: Patients from the PRO-ACT dataset with information on ALS Functional Rating Scale, time from onset to enrollment (TFOE), and riluzole use were selected for analysis. Survival from enrollment was the outcome. Multivariable Cox proportional hazard models were examined for interactions between riluzole and TFOE. Inverse probability of treatment weighting (IPTW) was used to assess average treatment effect., Results: Of 4778 patients, 3446 (72.1%) had received riluzole. In unadjusted analyses, riluzole improved median survival significantly (22.6 vs. 20.2 months, log-rank p < 0.001). In multivariable analyses, no significant interaction between TFOE and riluzole was found. Riluzole effect was uniform during follow-up. By IPTW, estimated riluzole hazard ratio was 0.798 (95% confidence interval 0.686-0.927). Delaying riluzole initiation by 1 y (6 to 18 months from onset) may translate to reducing median survival from onset by 1.9 months (40.1 to 38.2 months)., Discussion: Riluzole appears to reduce risk of death uniformly, regardless of time from onset to treatment, and duration of treatment. Earlier treatment with riluzole may be associated with greater absolute survival gain from onset. Early diagnosis of ALS will facilitate early treatment and is expected to improve survival., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Riluzole (RLZ) is a neuroprotective drug indicated for amyotrophic lateral sclerosis. To examine the feasibility of RLZ for repositioning as an anti-inflammatory bowel disease (IBD) drug, RLZ (2, 5, and 10 mg/kg) was administered orally to rats with colitis induced by 2,4-dinitrobenzenesulfonic acid. Oral RLZ was effective against rat colitis in a dose-dependent manner, which was statistically significant at doses over 5 mg/kg. To address safety issues upon repositioning and further improve anti-colitic effectiveness, RLZ was coupled with salicylic acid (SA) via an azo-bond to yield RLZ-azo-SA (RAS) for the targeted colonic delivery of RLZ. Upon oral gavage, RAS (oral RAS) was efficiently delivered to and activated to RLZ in the large intestine, and systemic absorption of RLZ was substantially reduced. Oral RAS ameliorated colonic damage and inflammation in rat colitis and was more effective than oral RLZ and sulfasalazine, a current anti-IBD drug. Moreover, oral RAS potently inhibited glycogen synthase kinase 3β (GSK3β) in the inflamed distal colon, leading to the suppression of NFκB activity and an increase in the level of the anti-inflammatory cytokine interleukin-10. Taken together, RAS, which enables RLZ to be delivered to and inhibit GSK3β in the inflamed colon, may facilitate repositioning of RLZ as an anti-IBD drug.

Background and Purpose: Clarification of propagation patterns in amyotrophic lateral sclerosis (ALS) is challenging, but understanding these has implications for individual prognostication and clinical trial design. However, systematic knowledge in this area is lacking. The aim of this study was to characterize the spatial and temporal features of propagation patterns in ALS, and to evaluate the association between propagation patterns and survival., Methods: A cohort of 833 patients with ALS, diagnosed between January 2018 and December 2019 and followed to August 2021, was analysed. Spatial and temporal features of propagation patterns were determined based on the involved functional regions (bulbar, cervical, thoracic/respiratory and lumbar) in time order. The final propagation pattern was identified in patients with at least three functional regions involved. Kaplan-Meier analysis and Cox regression analysis were performed., Results: During a median follow-up of 21.2 months, 19 final propagation patterns were identified in 657 patients (78.9%). In survival analysis, we found that the earlier the respiratory functional region becomes involved, the higher the risk of death (time order: 1st: hazard ratio [HR], 3.35, 95% confidence interval [CI] 1.23-9.15; 2nd: HR 2.45, 95% CI 1.55-3.87; 3rd: HR 1.94, 95% CI 1.52-2.49), adjusting for age, sex, diagnostic delay, revised ALS Functional Rating Scale score, cognitive impairment and riluzole. Shorter interval time between involved regions was an independent adverse prognostic factor., Conclusions: The propagation patterns of ALS are varied. The order in which the respiratory region becomes involved and the interval time between involvement of functional regions are predictors for prognosis., (© 2022 European Academy of Neurology.)

Background: Little is known about the influence of Riluzole on serum neurofilament light chain (sNfL) levels, a biomarker of prognosis in amyotrophic lateral sclerosis (ALS), and variations with time of sNfL concentrations are controversial., Methods: Sera from ALS patients (n = 141) and controls (n = 33) were collected at inclusion (sNfL1) and second visit (sNfL2, mean delay 10.4 ± 8.7 months). sNfL levels, determined by single-molecule array, were compared between ALS and controls at both time points. sNfL concentration changes were compared between patients with Riluzole (w/Ril) at inclusion in the study and those who were treated by Riluzole following inclusion (w/o Ril). The factors influencing sNfL concentrations and changes were studied using linear regression and multivariate analysis., Results: sNfL levels were higher in ALS patients than in controls at the two time points (p < 0.00001). In ALS patients, sNfL concentrations were higher in females for both sNfL1 (p = 0.014) and sNfL2 (p < 0.001). In the whole ALS group, sNfL levels were higher at sNfL2 than at sNfL1 (p < 0.001). sNfL1 and sNfL2 concentrations were similar between the two ALS subgroups (w/ and w/o Ril). ALS functional rating scale-revised rate of decline and gender were the two main factors significantly influencing both sNfL1 and sNfL2 levels (p < 0.01). However, only gender was shown to significantly influence sNfL changes with time (p = 0.003)., Conclusions: In this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder involving loss of upper and lower motor neurons, with most cases ending in death within 3-5 years of onset. Several molecular and cellular pathways have been identified to cause ALS; however, treatments to stop or reverse disease progression are yet to be found. Riluzole, a neuroprotective agent offering only a modest survival benefit, has long been the sole disease-modifying therapy for ALS. Edaravone, which demonstrated statistically significant slowing of ALS disease progression, is gaining approval in an increasing number of countries since its first approval in 2015. Sodium phenylbutyrate and taurursodiol (PB-TURSO) was conditionally approved in Canada in 2022, having shown significant slowing of disease progression and prolonged survival. Most clinical trials have focused on testing small molecules affecting common cellular pathways in ALS: targeting glutamatergic, apoptotic, inflammatory, and oxidative stress mechanisms among others. More recently, clinical trials utilizing stem cell transplantation and other biologics have emerged. This rich and ever-growing pipeline of investigational products, along with innovative clinical trial designs, collaborative trial networks, and an engaged ALS community', provide renewed hope to finding a cure for ALS. This article reviews existing ALS therapies and the current clinical drug development pipeline., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole ( 1 )-rasagiline ( 2 ) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3 - 8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6 . It showed monoamine oxidase A (MAO-A) inhibitory activity (IC 50 = 6.9 μM) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC 50 = 8.7 μM) might add a piece to the puzzle of its anti-ALS molecular profile.

Introduction: Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2-3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine., Methods and Analysis: Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments., Ethics and Dissemination: MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants., Trial Registration Numbers: European Clinical Trials Registry (2019-000099-41); NCT04302870., Competing Interests: Competing interests: CJW is a member of the independent data monitoring committee for a trial of masitinib in ALS, for which his institution receives funding from AB Science. In the last 3 years, JC has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by: Actelion, Novartis and Roche; and has taken part in advisory boards/consultancy for Azadyne, Janssen, Merck, NervGen, Novartis and Roche., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Evidence-based treatment of pain in people with MS presents a major unmet need., Objective: We aimed to establish if use of Fluoxetine, Riluzole or Amiloride improved neuropathic pain outcomes in comparison to placebo, in adults with secondary progressive MS participating in a trial of these putative neuroprotectants., Methods: In pre-specified secondary analyses of the MS SMART phase-2b double-blind randomised controlled trial (NCT01910259), we analyzed reports of neuropathic pain, overall pain, and pain interference. Multivariate analyses included adjustment for baseline pain severity. Additionally, we explored associations of pain severity with clinical and MRI brain imaging variables., Results: 445 Participants were recruited from 13 UK neuroscience centres. We found no statistically significant benefit of active intervention on any rating of neuropathic pain, or pain overall. Compared to placebo, adjusted mean difference in pain intensity was 0.38 (positive values favouring placebo, 95%CI -0.30 to 1.07, p = 0.27) for Amiloride; 0.52 (-0.17 to 1.22, p = 0.14) for Fluoxetine; and 0.40 (-0.30 to 1.10, p = 0.26) for Riluzole. Pain severity was positively correlated with depressive symptoms (Spearman correlation 0.19, 95%CI 0.10-0.28) and fatigue (Rho 0.30, 95%CI 0.20-0.39)., Conclusion: Use of Fluoxetine, Riluzole or Amiloride was not associated with improvement in neuropathic pain symptoms, in comparison to placebo., (Copyright © 2022. Published by Elsevier B.V.)

Alzheimer's disease (AD) is a neurodegenerative disorder leading to memory loss and impaired cognition. Despite several decades of research, AD therapeutic is not available. In this study, we have investigated the impact of a chronic intervention of riluzole on memory and neurometabolism in the AβPP-PS1 mouse model of AD. The 10-month-old AβPP-PS1 mice were administered 30 doses of riluzole (6 mg/kg, intragastrically) on an alternate day for two months. The memory was assessed using Morris Water Maze, while neurometabolism was evaluated by 1 H-[ 13 C]-NMR spectroscopy together with an intravenous infusion of [1,6- 13 C 2 ]glucose. The normal saline-treated AβPP-PS1 mice exhibited a decrease in learning and memory that were restored to the control level following riluzole treatment. Most interestingly, the reduced 13 C labeling of Glu C4 and Asp C3 from [1,6- 13 C]glucose in the AβPP-PS1 mice was restored to the control level following riluzole intervention. As a consequence, chronic riluzole treatment improved metabolic activity of glutamatergic neurons in AβPP-PS1 mice. Together these data suggest that riluzole may be useful for improving cognition in AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction/aims: Riluzole is a glutamate inhibitor approved for the treatment of amyotrophic lateral sclerosis (ALS). There are scant data on factors associated with riluzole initiation and adherence. The goal of this study was to describe the use of riluzole at the Penn State Hershey Medical Center (PSHMC) ALS clinic., Methods: A retrospective medical record review of ALS patients seen at the PSHMC from January 2007 to December 2016. A timeline of riluzole use was established for each patient. Factors contributing to dose changes or discontinuations were recorded. Riluzole adherence was assessed using the proportion of days covered (PDC) calculated by the patient-reported length of riluzole use divided by total time from prescription to death/censor. Multivariable analysis was performed to evaluate the association of demography and clinical course with adherence., Results: Seven hundred twenty-three records were screened, with 508 (307 men, 201 women) meeting the criteria for inclusion. The median duration of riluzole use was 435 (range, 0-3773) days. The median PDC for the group was 64%. Those with higher initial overall function and slower rate of decline were more likely to have a larger PDC. No trends in patients' demographics, riluzole use, and tracheostomy-free survival were found over time., Discussion: A high rate of riluzole initiation and adherence was found in this sample. The most common reasons for dose modification were related to adverse effects, yet social-, economic-, and patient-related factors were also common. The characteristics of riluzole prescription and use have remained relatively unchanged in a single tertiary ALS center over the past 10 years., (© 2022 Wiley Periodicals LLC.)

Objective: To assess the availability of health workers and medications for clinical management of amyotrophic lateral sclerosis (ALS) in African hospital centers. Availability and affordability analyses of disease-modifying treatments were performed. Methods : A multicenter observational study involving African hospitals was conducted. A standard questionnaire was developed based on the European Federation of the Neurological Societies (EFNS) guidelines. We collected data on multidisciplinary care and availability of medicines. The availability and affordability were evaluated according to the WHO guidelines. Results : Nine hospital centers from eight African countries participated. We observed a low degree of implementation of multidisciplinary care in ALS management. Riluzole was only available in centers from South Africa, Senegal, Tunisia, and Togo. This treatment was unaffordable and the adjusted price was highly variable among countries. The cost of riluzole was partly or fully covered by patients, which implies a substantial economic burden. Conclusion : Our findings strengthen the need to promote multidisciplinary care in the clinical management of ALS in Africa. Disease-modifying medication should be both available and affordable. Local and international collaboration is needed to improve ALS health care access in Africa.

Objective: To determine if inflammation in proximity of the motor unit may contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS). Methods: We identified all patients diagnosed in Sweden with concurrent ALS and multiple sclerosis (MS), myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM) during 1991-2014 according to the Swedish Patient Register ( N  = 263). We validated medical records for 92% of these patients (18 records were not retrieved and three did not contain enough information) and compared patients with a confirmed overlap ( N  = 28) with an independent sample of patients with solely ALS ( N  = 271). Results: Ninety-one patients were deemed as not having ALS (34.6%). Among the remaining 151 with validated ALS, 12 had also a confirmed MS diagnosis, nine a confirmed MG diagnosis, four a confirmed IP diagnosis, and three a confirmed DMPM diagnosis. Seventeen of the patients were women and 11 were men. Seventy-nine percent of the patients with a confirmed overlap had MS, MG, IP, or DMPM diagnosed prior to ALS. Compared to patients with only ALS, the concurrent patients were significantly older at symptoms onset, had higher prevalence of bulbar onset, but used Riluzole and noninvasive ventilation less frequently. Conclusions: We found that a high concurrence of ALS and MS/MG/IP/DMPM diagnoses is largely due to diagnostic uncertainty. A minority of patients had a true concurrence, where MS, MG, IP, and DMPM preceded the ALS diagnosis, which might be due to chance alone. Four patients were diagnosed with MG shortly after onset of ALS, suggesting that neurodegeneration might trigger autoimmunity.

Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein-coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease.

Neuropathic pain since early diabetes swamps patients' lives, and diabetes mellitus has become an increasingly worldwide epidemic. No agent, so far, can terminate the ongoing diabetes. Therefore, strategies that delay the process and the further complications are preferred, such as diabetic neuropathic pain (DNP). Dysfunction of ion channels is generally accepted as the central mechanism of diabetic associated neuropathy, of which hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channel has been verified the involvement of neuropathic pain in dorsal root ganglion (DRG) neurons. Riluzole is a benzothiazole compound with neuroprotective properties on intervention to various ion channels, including hyperpolarization-activated voltage-dependent channels. To investigate the effect of riluzole within lumbar (L3-5) DRG neurons from DNP models, streptozocin (STZ, 70 mg/kg) injection was recruited subcutaneously followed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), which both show significant reduction, whilst relieved by riluzole (4 mg/kg/d) administration, which was performed once daily for 7 consecutive days for 14 days. HCN2 expression was also decreased in line with alleviated behavioral tests. Our results indicate riluzole as the alleviator to STZ-induced DNP with involvement of downregulated HCN2 in lumbar DRG by continual systemic administration in rats., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Dong-mei Zhou et al.)

After spinal cord injury (SCI), emergency treatment intervention can minimize tissue damage, which is closely related to the recovery of long-term function. Here, we examined whether the administration of a single dose of riluzole (6 mg/kg) immediately after SCI was a critical window for the drug to exert its regulatory effect and limit long-term neurological deficits. The animals were sacrificed 1 day after administration for investigation of neuronal survival and a potential neuroinflammatory response, and sacrificed in the 6th week for assessment of neurological function. Riluzole applied in a single dose immediately post-SCI decreased the mRNA level of interleukin-1β at 6 h, reduced the destruction of neurons, and reduced the activation of microglia/macrophage M1 expression at day 1 post-SCI. Additionally, riluzole-treated rats showed higher expressions of interleukin-33 and its receptor ST2 in microglia/macrophages of the spinal cord than vehicle-treated rats, suggesting that this signaling pathway might be involved in microglia/macrophage-mediated inflammation. At 6 weeks, riluzole-treated rats exhibited higher motor function scores than vehicle-treated controls. In addition, riluzole-treated rats exhibited higher expression of GAP43 protein and shorter N1 peak latency and larger N1-P1 amplitude in motor-evoked potentials, compared to vehicle-treated rats. Together, these data suggested that early application of riluzole after SCI could be crucial for long-term functional recovery, so it may represent a promising therapeutic candidate within the critical therapeutic window for acute SCI., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro., (© 2022. The Author(s).)

Introduction: Renal ischemia-reperfusion injury (IRI) can lead to significant morbidity and mortality. It remains a leading cause of acute kidney injury and is therefore an important issue in trauma and renal transplant surgery. Various pharmaceutical agents have been used in an attempt to dampen the harmful effects of IRI but few have been shown to be useful clinically. Riluzole, Lidocaine and Lamotrigine have been demonstrated to show anti-ischaemic properties in other organs; however, their use has not been tested in the kidneys. We investigated Riluzole, Lidocaine and Lamotrigine for their preventive effects of renal IRI using a rat model., Methods: Winstar rats (n = 48) were divided into four groups (n = 12 per group)-three treatment groups and one control group. Riluzole, Lidocaine and Lamotrigine were given prior to renal ischemia only (IO) or IRI. The degree of ischemia was measured by glutathione levels and a TUNEL assay was used to measure DNA fragmentation., Results: Riluzole, Lidocaine and Lamotrigine pre-treatment each resulted in statistically higher glutathione levels compared to controls (P = 0.002; P = 0.007 and P = 0.005, respectively). Riluzole and Lidocaine were also effective at preventing depletion of glutathione following IO (P = 0.007 and P = 0.014 respectively), while Lamotrigine was ineffective in IO (P = 0.71). The degree of DNA fragmentation seen on the TUNEL assay was markedly reduced in all three-drug groups in both IO and IRI., Discussion: Riluzole, Lidocaine and Lamotrigine all have anti-ischaemic effects in the rat kidney and can have potential therapeutic implications., (© 2021 Royal Australasian College of Surgeons.)