Prophylactic exposure to oral riluzole reduces the clinical severity and immune-related biomarkers of experimental autoimmune encephalomyelitis.

Glutamate-mediated excitotoxicity and immune cell infiltration are hallmarks of multiple sclerosis. The glutamate release inhibitor, riluzole (RIL), has been shown to attenuate the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in mice, but an association between glutamate excitotoxicity and the progression of MOG35-55-induced EAE has not been well defined. This study investigated the effects of prophylactic and chronic oral RIL on the clinical severity of EAE. Prophylactic+chronic RIL reduced the presence of inflammatory infiltrates, altered GFAP and Foxp3, and attenuated disease severity. These findings indicate a need to delineate the distinct role of glutamate in EAE symptomatology.

Randomized Controlled Trial of Riluzole Augmentation for Posttraumatic Stress Disorder: Efficacy of a Glutamatergic Modulator for Antidepressant-Resistant Symptoms.

OBJECTIVE: Current pharmacologic treatments for posttraumatic stress disorder (PTSD) have shown limited efficacy, prompting a call to investigate new classes of medications. The current study investigated the efficacy of glutamate modulation with riluzole augmentation for combat-related PTSD symptoms resistant to treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: A randomized, double-blind, placebo-controlled, parallel trial was conducted at Walter Reed National Military Medical Center and Syracuse VA Medical Center between December 2013 and November 2017. Veterans and active duty service members with combat-related PTSD (per the Clinician Administered PTSD Scale [CAPS]) who were not responsive to SSRI or SNRI pharmacotherapy were randomized to 8-week augmentation with a starting dose of 100 mg/d of riluzole (n = 36) or placebo (n = 38) and assessed weekly for PTSD symptoms, anxiety, depression, disability, and side effects. RESULTS: Intent-to-treat analyses (N = 74) of the primary outcome (CAPS for DSM-IV) showed no significant between-group difference in change in overall PTSD symptoms (F = 0.64, P = .422), with a small effect size (d = 0.25). There was clinically significant within-group improvement in overall PTSD symptoms in both groups, with a greater mean (SD) decrease in CAPS score in the riluzole group (-21.1 [18.9]) than in the placebo group (-16.7 [17.2]). Exploratory analyses of PTSD symptom clusters showed significantly greater improvement on hyperarousal symptoms in the riluzole group as measured by the PTSD Checklist-Specific-Subscale D (d = 0.48) and near-significant findings on the CAPS Subscale D. Riluzole augmentation was not superior to placebo on change in depression, anxiety, or disability severity. CONCLUSIONS: Although preliminary, the exploratory findings of this study offer some evidence that riluzole augmentation of an SSRI or SNRI may selectively improve PTSD hyperarousal symptoms without changes in overall PTSD symptoms, depression, anxiety, or disability. Additional investigation of the mechanism of the efficacy of riluzole for hyperarousal symptoms is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02155829.

Glutamatergic and GABAergic reactivity and cognition in 22q11.2 deletion syndrome and healthy volunteers: A randomized double-blind 7-Tesla pharmacological MRS study.

AIMS: 22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning. Glutamatergic pathways have been linked with cognition and are hypothesized to be disrupted in 22q11.2DS patients, possibly 'shifting' the excitatory (glutamate)/inhibitory (GABA) balance. Hence, the glutamate/GABA balance may constitute a target for pharmacological treatment. We aimed to examine alterations of glutamate/GABA metabolites in 22q11.2DS in vivo using riluzole, a compound with glutamate/GABA-modulating action, as pharmacological challenge. METHODS: Seventeen 22q11.2DS patients and 20 matched healthy controls were enrolled in this randomized double-blind placebo-controlled crossover study. Glutamate and glutamine concentrations in the anterior cingulate cortex (ACC) and striatum, as well as ACC GABA concentrations were obtained after placebo and after a single dose of 50 mg riluzole using 7-Tesla magnetic resonance spectroscopy (MRS). Within the 22q11.2DS group, the relationship between metabolite concentrations and cognition was examined. RESULTS: No group differences were found in ACC and striatal metabolite concentrations following placebo. Riluzole numerically decreased ACC (η2= 0.094) but not striatal glutamate concentrations as well as ACC GABA concentrations (η2= 0.176) in all subjects. In both regions, riluzole did not alter glutamine concentration. No interaction effects were found. Although not significant after Bonferroni correction, ACC glutamate concentrations were inversely correlated with cognitive functions in 22q11.2DS patients. DISCUSSION: We did not demonstrate altered ACC and striatal metabolite concentrations in 22q11.2DS. Nevertheless, these results suggest that glutamate and GABA can be modulated with a single dose of riluzole. Possibly, riluzole may have memory-enhancing effects in 22q11.2DS. Future studies should examine the long-term effects of riluzole on cognition.

Emerging Drugs for the Treatment of Amyotrophic Lateral Sclerosis: A Focus on Recent Phase 2 Trials.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving both upper and lower motor neurons and resulting in increasing disability and death 3-5 years after onset of symptoms. Over 40 large clinical trials for ALS have been negative, except for Riluzole that offers a modest survival benefit, and Edaravone that modestly reduces disease progression in patients with specific characteristics. Thus, the discovery of efficient disease modifying therapy is an urgent need. AREAS COVERED: Although the cause of ALS remains unclear, many studies have demonstrated that neuroinflammation, proteinopathies, glutamate-induced excitotoxicity, microglial activation, oxidative stress, and mitochondrial dysfunction may play a key role in the pathogenesis. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of therapy. Ongoing phase 2 clinical trials aimed to interfere with these pathophysiological mechanisms are discussed. EXPERT OPINION: This review describes the challenges that the discovery of an efficient drug therapy faces and how these issues may be addressed. With the continuous advances coming from basic research, we provided possible suggestions that may be considered to improve performance of clinical trials and turn ALS research into a 'fertile ground' for drug development for this devastating disease.

Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma.

OBJECTIVE: Glutamatergic signaling significantly promotes proliferation, migration, and invasion in glioblastoma (GBM). Riluzole, a metabotropic glutamate receptor 1 inhibitor, reportedly suppresses GBM growth. However, the effects of combining riluzole with the primary GBM chemotherapeutic agent, temozolomide (TMZ), are unknown. This study aimed to investigate the efficacy of combinatorial therapy with TMZ/riluzole for GBM in vitro and in vivo. METHODS: Three GBM cell lines, T98G (human; O6-methylguanine DNA methyltransferase [MGMT] positive), U87MG (human; MGMT negative), and GL261 (murine; MGMT positive), were treated with TMZ, riluzole, or a combination of both. The authors performed cell viability assays, followed by isobologram analysis, to evaluate the effects of combinatorial treatment for each GBM cell line. They tested the effect of riluzole on MGMT, a DNA repair enzyme causing chemoresistance to TMZ, through quantitative real-time reverse transcription polymerase chain reaction in T98G cells. Furthermore, they evaluated the efficacy of combinatorial TMZ/riluzole treatment in an orthotopic mouse allograft model of MGMT-positive GBM using C57BL/6 J mice and GL261 cells. RESULTS: Riluzole displayed significant time- and dose-dependent growth-inhibitory effects on all GBM cell lines assessed independently. Riluzole enhanced the antitumor effect of TMZ synergistically in MGMT-positive but not in MGMT-negative GBM cell lines. Riluzole singularly suppressed MGMT expression, and it significantly suppressed TMZ-induced MGMT upregulation (p < 0.01). Furthermore, combinatorial TMZ/riluzole treatment significantly suppressed tumor growth in the intracranial MGMT-positive GBM model (p < 0.05). CONCLUSIONS: Riluzole attenuates TMZ-induced MGMT upregulation and enhances the antitumor effect of TMZ in MGMT-positive GBMs. Therefore, combinatorial TMZ/riluzole treatment is a potentially promising novel therapeutic regimen for MGMT-positive GBMs.

Riluzole-loaded nanoparticles to alleviate the symptoms of neurological disorders by attenuating oxidative stress.

Purpose: The objective of the research undertaken was to develop the Riluzole (RIZ) nanoparticles drug delivery system using Transferrin (Tf) as a ligand in the brain.Method: RIZ-loaded chitosan nanoparticles and RIZ-Tf chitosan (CS) nanoparticles (RIZ CSNPs and RIZ-Tf CSNPs) were formulated and compared for particles size, size distribution, encapsulation efficiency, and surface morphology, respectively. The in vitro drug release, permeation, pharmacokinetic, biochemical, and pharmacodynamic experiments were done to assess the improvement in in vivo fate and efficacy of RIZ.Results: The size of optimized RIZ CSNPs was found to be 173.6 ± 2.23 nm and polydispersity index (PDI) of 0.264 ± 0.002 while that of RIZ-Tf CSNPs was 207 ± 2.49 nm and 0.406 ± 0.002. In vitro release was found to be 86.15 ± 7.316% and 91.1 ± 5.836%, respectively, while permeability coefficient was found to be 4 × 10-2 and 4.2 × 10-2 cm/s for RIZ CSNPs and RIZ-Tf CSNPs. The biochemical analysis studies revealed that oxidative stress was significantly decreased in case of RIZ CSNPs and RIZ-Tf CSNPs (p < 0.01) treated groups. The antianxiety effect and the memory restoration were evident in pharmacodynamic studies (p < 0.05) of the prepared formulations.Conclusion: The results of pharmacokinetic studies demonstrated the remarkable brain delivery of RIZ-Tf CSNPs through intranasal route as compared to the RIZ solution.

A Pharmacokinetic Bioequivalence Study Comparing Sublingual Riluzole (BHV-0223) and Oral Tablet Formulation of Riluzole in Healthy Volunteers.

Orally administered riluzole extends survival in patients with amyotrophic lateral sclerosis, although it has significant shortcomings (eg, adverse events, dysphagic patients) that limit its utility. BHV-0223 is a Zydis-based orally disintegrating formulation of riluzole designed for sublingual administration that addresses the limitations of conventional tablets. This study assessed the bioequivalence between 40-mg BHV-0223 and standard 50-mg oral riluzole tablets, and the food effect on BHV-0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV-0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration-time curve (AUC) from time zero to time of last nonzero concentration (AUC0-t ) (89.9%; confidence interval [CI], 87.3%-92.5%), AUC from time zero to infinity (AUC0-∞ ) (89.8%; CI, 87.3%-92.4%), and maximum observed concentration (112.7%; CI, 105.5%-120.4%) all met bioequivalence criteria (80%-125%). Subsequently, 67 subjects received BHV-0223 under fed conditions. The geometric mean ratios of AUC0-t (91.2%; CI, 88.1-94.3%), and AUC0-∞ (92.0%; CI, 89.0-95.1%) were similar, but maximum observed concentration ratios were not within bioequivalence criteria. BHV-0223 was well tolerated. This study demonstrated that 40-mg sublingual BHV-0223 is bioequivalent to 50-mg oral riluzole tablets.

Osteosarcoma growth suppression by riluzole delivery via iron oxide nanocage in nude mice.

Osteosarcomas are the most commonly occurring malignant bone cancer in young individuals. The survival rate of patients with metastatic osteosarcoma is low and has been stagnant for over two decades. We previously demonstrated that the glutamate release inhibitor, riluzole inhibits osteosarcoma cell growth. Towards the development of more effective therapy, we investigated the delivery of riluzole in human metastatic osteosarcoma xenografts in mice. We compared the efficacy of riluzole delivery by intraperitoneally injecting either free riluzole or riluzole released via two different shapes of iron oxide nanoparticles (nanocage or nanosphere) of size 15±2.5 nm. We monitored tumor size using Vernier calipers and bioluminescence assay and found a significant reduction in tumor size in the riluzole­treated groups when injected, either in free form or via nanoparticles, compared to the control groups (PBS, nanosphere or nanocage). Importantly, nanocage­delivered riluzole was most effective in reducing tumor size in the xenograft nude mice. While riluzole delivery induced apoptosis in tumor tissues in all three groups of riluzole­treated animals, it was highest in tumors from the nanocage­delivered riluzole group. Therefore, we conclude that riluzole is an effective drug to reduce tumor size in osteosarcoma and the efficacy of riluzole as a apoptotic and tumor­reducing drug is enhanced when delivered via nanocage.

Riluzole Oral Suspension: Bioavailability Following Percutaneous Gastrostomy Tube-modeled Administration Versus Direct Oral Administration.

PURPOSE: During amyotrophic lateral sclerosis progression, up to 85% of patients develop dysphagia. Riluzole oral suspension 50 mg/10 mL is bioequivalent to riluzole 50-mg film-coated tablets administered orally under fasting conditions. Here, we compare the bioavailability of a single 50-mg dose of riluzole oral suspension via intragastric tube, a proxy for percutaneous endoscopic gastrostomy administration, with that of oral administration in healthy volunteers under fasting conditions. Secondary objectives included the plasma pharmacokinetic and safety profiles of each administration route. METHODS: This was a single-center, single-dose, open-label, randomized, 2-period, 2-sequence, crossover bioequivalence/bioavailability study. Healthy volunteers were randomized to riluzole oral suspension 50 mg/10 mL either via nasogastric tube or orally, with a 5-day washout before crossover. FINDINGS: A total of 32 subjects were randomized (safety population); 30 were eligible for pharmacokinetic analysis. The ratios (nasogastric tube/oral) of the geometric least squares means and the geometric 90% CIs of AUC0-t, AUC0-inf, and Cmax were calculated to be 90.60% (85.66%-95.82%), 90.43% (85.47%-95.67%), and 96.99% (89.40%-105.23%), respectively, indicating bioequivalence. No significant differences in Cmax, Tmax, Kel, and t1/2el between treatments were found. Overall, riluzole oral suspension was well tolerated. No deaths or other serious adverse events were reported. IMPLICATIONS: In this study, riluzole oral suspension was bioequivalent when administered intragastrically and orally in healthy subjects under fasting conditions. Both administration methods were well tolerated. These results show that intragastric administration of riluzole oral suspension may provide an important formulation option in people with amyotrophic lateral sclerosis who have a percutaneous endoscopic gastrostomy tube.

Longer-term open-label study of adjunctive riluzole in treatment-resistant depression.

BACKGROUND: While riluzole has been investigated for the treatment of depression, little is known about its longer-term efficacy and optimal treatment duration in treatment-resistant depression (TRD). The objective of this study is to characterize the longer-term outcome of adjunctive riluzole therapy for TRD in an open-label extension of an 8-week acute treatment trial. METHODS: The data from 66 patients with TRD who received adjunctive riluzole in a 12-week open-label extension phase were analyzed. Response rates (⩾50% reduction in the Mongomery-Asberg Depression Rating Scale [MADRS] score), relapse rates (a MADRS score of ⩾22 in patients who had previously achieved response), and adverse events were examined in patients who had achieved response at the end of the acute phase and those who had not. RESULTS: Among acute phase responders, the maintained response rate was 66.7% (8/12) and the relapse rate was 8.3% (1/12). In acute phase non-responders, the response rate was 24.1% (13/54). The most commonly reported adverse event was fatigue (9.1%). Three cases were considered serious adverse events; vomiting (n = 1), shortness of breath (n = 1), and aborted suicide attempt (n = 1). LIMITATIONS: This longer-term study was open-label and uncontrolled. The sample size was relatively small. CONCLUSIONS: Longer-term adjunctive riluzole appears relatively well tolerated and beneficial for maintaining previous response. Additionally, approximately one fourth of patients who did not respond to 8-week antidepressant treatment might respond if treated with riluzole for 12 weeks. Those findings warrant further investigation because adjunctive riluzole could represent an option for treatment of depression when standard antidepressants have failed.

Riluzole effectively treats psychotic symptoms and improves cognition in 22q11.2 deletion syndrome: A clinical case.

22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a hemizygous microdeletion on the long arm of chromosome 22 and is associated with a high risk for psychosis and cognitive impairment. One of the genes located in the deleted region of 22q11DS is Proline Dehydrogenase (PRODH) which is important for conversion of proline to glutamate. Glutamate is the primary excitatory neurotransmitter and is involved in the pathophysiology of psychosis as well as in cognition. Excessive concentrations are toxic. Possibly, neuroprotective drugs modulating glutamatergic neurotransmission could be effective in treating psychotic symptoms and cognitive enhancement in patients with 22q11DS. Riluzole is a potent anti-glutamatergic drug that reduces glutamatergic neurotransmission. Here we report acute (single dose) and long-term effects of riluzole on glutamate and GABA levels in the anterior cingulate cortex (ACC) and striatum (measured with magnetic resonance spectroscopy, 1H-MRS) as well as on psychotic symptoms and cognitive functioning in a medication-free 23-year old woman with 22q11DS. Patient presented with frequent auditory and visual hallucinations and mild paranoid ideas. The 1H-MRS measurements showed that after a single dose riluzole (50 mg), glutamate in the ACC and striatum was reduced whereas striatal GABA increased compared to baseline. Strikingly, hallucinations and paranoia disappeared. Therefore, riluzole treatment was initiated and patient was followed up after 18 months of treatment. At follow-up, patient reported no hallucinations or paranoia and several cognitive functions were improved. Furthermore, glutamate concentrations in the ACC and striatum decreased whereas GABA concentrations increased in the striatum but decreased in the ACC. These results suggests that riluzole may be an effective treatment option for psychotic symptoms and cognitive enhancement in 22q11DS. Results warrant replication in a bigger sample.

Degradable and Injectable Hydrogel for Drug Delivery in Soft Tissues.

Injectable hydrogels are promising platforms for tissue engineering and local drug delivery as they allow minimal invasiveness. We have here developed an injectable and biodegradable hydrogel based on an amphiphilic PNIPAAm- b-PLA- b-PEG- b-PLA- b-PNIPAAm pentablock copolymer synthesized by ring-opening polymerization/nitroxide-mediated polymerization (ROP/NMP) combination. The hydrogel formation at around 30 °C was demonstrated to be mediated by intermicellar bridging through the PEG central block. Such a result was particularly highlighted by the inability of a PEG- b-PLA- b-PNIPAAm triblock analog of the same composition to gelify. The hydrogels degraded through hydrolysis of the PLA esters until complete mass loss due to the diffusion of the recovered PEG and PNIPAAm/micelle based residues in the solution. Interestingly, hydrophobic molecules such as riluzole (neuroprotective drug) or cyanine 5.5 (imaging probe) could be easily loaded in the hydrogels' micelle cores by mixing them with the copolymer solution at room temperature. Drug release was correlated to polymer mass loss. The hydrogel was shown to be cytocompatible (neuronal cells, in vitro) and injectable through a small-gauge needle (in vivo in rats). Thus, this hydrogel platform displays highly attractive features for use in brain/soft tissue engineering as well as in drug delivery.

Riluzole for treatment of men with methamphetamine dependence: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Riluzole is a glutamate regulator and effective in treatment of neuropsychiatric conditions. AIMS: We assessed riluzole for treatment of methamphetamine dependence. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, male outpatients with methamphetamine dependence who were 18-65 years old received either 50 mg riluzole ( n=34) or placebo ( n=54) twice daily for 12 weeks. Patients were excluded in case of comorbid serious medical conditions or neurologic disorders, comorbid psychiatric disorders other than methamphetamine dependence requiring specific treatment interventions, simultaneous positive urine test result for substances of abuse other than methamphetamine, smoking >3 days per week, simultaneous consumption of medications which are contraindicated or have interaction with riluzole. RESULTS: Concerning primary outcomes, the cumulative mean number of attended weekly visits was higher in the riluzole arm compared with the placebo arm approaching a statistically significant difference (riluzole, median (range)=13.00 (2.00-13.00); placebo=4.00 (2.00-13.00); Mann-Whitney U=505.00, p-value=0.073), and the weekly measured rate of positive methamphetamine urine test results was significantly lower in the riluzole arm by the end of the study (riluzole=1 (5.00%), placebo=9 (45.00%), p-value=0.004). Patients in the riluzole arm experienced significantly greater improvement on all the craving, withdrawal, and depression measures regarding mean score changes from baseline to endpoint. No significant difference was detected between the two arms in terms of incidence of adverse events. CONCLUSION: Future randomized clinical trials are needed to investigate proper dosing strategy in a more inclusive sample.

Combined Applications of Repurposed Drugs and Their Detrimental Effects on Glioblastoma Cells.

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is a malignant primary brain tumor with high rates of recurrence. This study aimed to investigate the effect of repurposed drug combinations on GBM. MATERIALS AND METHODS: Viability of U87 MG and 11ST patient-derived GMB cell lines, after valproic acid, tranylcypromine or riluzole alone, in different combinations, as well as combined with standard temozolomide chemotherapy was examined using the MTT assay. Proliferation, mRNA level of tissue factor pathway inhibitor 2 (TFPI2), and cell invasion were evaluated using anti-Ki-67 antibody staining, reverse transcriptase-polymerase chain reaction and xCELLigence system. RESULTS: The strongest effect on cell viability was achieved by the combination of riluzole with valproic acid (U87MG: 27.2%, 11ST: 25.99%). Tranylcypromine significantly enhanced the effect of temozolomide when used in combination, as did valproic acid. The normally high proliferation of GBM significantly declined under treatment with valproic acid with tranylcypromine (p=0.01). Finally, we observed reduction of invasion comparing single tranylcypromine to its combination with valproic acid or riluzole. CONCLUSION: These results support the idea that combinations of drugs could increase the treatment efficiency of GBM.

Rational design and development of a stable liquid formulation of riluzole and its pharmacokinetic evaluation after oral and IV administrations in rats.

Enterally administered riluzole is currently being investigated in a Phase II/III clinical trial for the treatment of acute spinal cord injury (SCI). Many SCI patients suffer from severe motor dysfunction and exhibit swallowing difficulties and cannot swallow riluzole tablets. The purpose of the present study was to develop a liquid solution formulation of riluzole, which can be administered more easily to this patient population with the capability to adjust the dose if needed. Riluzole was solubilized using water miscible organic solvents, namely, polyethylene glycol 400, propylene glycol and glycerin. A Central Composite Design (CCD) approach was used to develop an optimum co-solvent composition that can solubilize the entire 50 mg dose of riluzole in 5 ml. A three-factor five-level design was employed to investigate the effects of composition of co-solvents on riluzole solubility. The selected optimum formulation consists of 15% v/v PEG 400, 20% v/v propylene glycol and 10% v/v glycerin, with riluzole concentration of 10 mg/ml. The optimum composition was assessed for stability at different temperatures. Satisfactory stability was obtained at room temperature and 4 °C (t90 of 17 and 35 months, respectively). The optimum formulation of riluzole was suitable for both oral and intravenous administrations. Single dose pharmacokinetic studies of the optimum formulation by oral and IV routes were evaluated in rats, using commercially available Rilutek® tablets as a reference. The co-solvent formulation was well tolerated both orally and intravenously. In comparison to the commercial tablet, the co-solvent formulation had a faster rate of absorption and more sustained plasma levels with a significantly longer elimination half-life. Higher concentrations of riluzole in brain and spinal cord were achieved from co-solvent formulation as compared to tablet. The riluzole solution formulation is stable and offers advantages of ease of administration, consistent dosing, rapid onset and longer duration of action, better availability at site of action which can be extremely beneficial for the therapy in SCI patients.

Mecasin treatment in patients with amyotrophic lateral sclerosis: study protocol for a randomized controlled trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes paralysis of limb, swallowing, and breathing muscles. Riluzole, the Food and Drug Administration-approved drug for ALS, provides minimal benefit, prolonging patient life by only 2-3 months. Previous studies have found a neuro-protective and anti-neuroinflammatory effect of Mecasin, with retrospective studies providing suggestive evidence for a beneficial effect of Mecasin. The aim of this study was to develop a protocol to determine the proper dosage of Mecasin. METHODS: This is a phase II-A, multi-center, randomized study with three arms. Thirty-six patients with ALS will be randomly assigned to one of three groups, each receiving the standard treatment with 100 mg of riluzole in addition to one of 1.6 g of Mecasin, 2.4 g of Mecasin, or a placebo. The Primary outcome is the Korean version of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised result after 12 weeks of treatment. Secondary outcomes include results of the Short Form Health Survey-8, Medical Research Council Scale, Visual Analogue Scale for Pain, Hamilton Rating Scale for Depression, Fatigue Severity Scale, Patient Global Impression of Change, pulmonary function test, forced expiratory volume in 1 s and its ratio to forced vital capacity, creatine kinase, and body weight. The frequencies of total adverse events and serious adverse events will be described and documented. The trial protocol has been approved by the Institutional Review Board of the Wonkwang University Gwangju and Sanbon Hospital (2016-5-4 and 2016-34-01, respectively). An Investigational New Drug status (30731) was granted by the Korea Food and Drug Administration. DISCUSSION: This trial will aim to identify the optimal dosage of Mecasin. Additionally, it will test the efficacy and safety of Mecasin in conjunction with standard treatment, riluzole, for alleviating the functional decline in patients with ALS. TRIAL REGISTRATION: Korean National Clinical Trial Registry CRIS; KCT0001984 . Registered on 28 July 2016.

Verapamil and riluzole cocktail liposomes overcome pharmacoresistance by inhibiting P-glycoprotein in brain endothelial and astrocyte cells: A potent approach to treat amyotrophic lateral sclerosis.

Riluzole is currently one of two approved medications for the treatment of amyotrophic lateral sclerosis (ALS). However, brain disposition of riluzole, as a substrate of P-glycoprotein (P-gp), is limited by the efflux transporters at the blood-brain barrier (BBB). We propose to develop a liposomal co-delivery system that could effectively transport riluzole to brain cells by reducing efflux pumps with a P-gp inhibitor, verapamil. Riluzole and verapamil cocktail liposomes were prepared by lipid film hydration. The average particle size of cocktail liposomes was 194.3 ±â€¯6.0 nm and their polydispersity index (PDI) was 0.272 ±â€¯0.017. The encapsulation efficiencies of verapamil and riluzole in the cocktail liposomes were 86.0 ±â€¯1.4% and 85.6 ±â€¯1.1%, respectively. The drug release from cocktail liposomes after 8 h in PBS at 37 °C was 78.4 ±â€¯6.2% of riluzole and 76.7 ±â€¯3.8% of verapamil. The average particle size of liposomes did not show significant changes at 4 °C after three months. Verapamil cocktail liposomes inhibited P-gp levels measured by western blotting in dose and time-dependent manners in brain endothelial bEND.3 cells. Increased drug efflux transporters were detected in bEND.3 and astrocytes C8D1A cells, promoted by tumor necrosis factor (TNF-α) or hydrogen peroxide (H2O2). Restored accumulations of riluzole and fluorescent dye rhodamine 123 were observed in bEND.3 cells after treatments with cocktail liposomes. It indicated that inhibitory potential of co-delivery liposome system towards P-gp could mediate the transport of both P-gp substrates. Verapamil and riluzole co-loaded liposomes may be used to overcome pharmacoresistance of riluzole for improving ALS therapy.

Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis (ALS) may be a relevant factor leading to motor neuron damage. This randomized, double-blind, three-way crossover, placebo-controlled study evaluated peripheral motor nerve excitability testing as a biomarker of hyperexcitability and assessed the effects of riluzole and retigabine in 18 patients with ALS. We performed excitability testing at baseline, and twice after participants had received a single dose of either 100 mg riluzole, 300 mg retigabine, or placebo. Between- and within-day repeatability was at least acceptable for 14 out of 18 recorded excitability variables. No effects of riluzole on excitability testing were observed, but retigabine significantly decreased strength-duration time-constant (9.2%) and refractoriness at 2 ms (10.2) compared to placebo. Excitability testing was shown to be a reliable biomarker in patients with ALS, and the acute reversal of previously abnormal variables by retigabine justifies long-term studies evaluating the impact on disease progression and survival.

Two Decades-Long Journey from Riluzole to Edaravone: Revisiting the Clinical Pharmacokinetics of the Only Two Amyotrophic Lateral Sclerosis Therapeutics.

The recent approval of edaravone has provided an intravenous option to treat amyotrophic lateral sclerosis (ALS) in addition to the existing oral agent, riluzole. The present work was primarily undertaken to provide a comprehensive clinical pharmacokinetic summary of the two approved ALS therapeutics. The key objectives of the review were to (i) tabulate the clinical pharmacokinetics of riluzole and edaravone with emphasis on absorption, distribution, metabolism and excretion (ADME) properties; (ii) provide a comparative scenario of the pharmacokinetics of the two drugs wherever possible; and (iii) provide perspectives and introspection on the gathered clinical pharmacokinetic data of the two drugs with appropriate conjectures to quench scientific curiosity. Based on this review, the following key highlights were deduced: (i) as a result of both presystemic metabolism and polymorphic hepatic cytochrome P450 (CYP) metabolism, the oral drug riluzole exhibited more inter-subject variability than that of intravenous edaravone; (ii) using various parameters for comparison, including the published intravenous data for riluzole, it was apparent that edaravone was achieving the desired systemic concentrations to possibly drive the local brain concentrations for its efficacy in ALS patients with lesser variability than riluzole; (iii) using scientific conjectures, it was deduced that the availability of intravenous riluzole may not be beneficial in therapy due to its fast systemic clearance; (iv) on the contrary, however, there appeared to be an opportunity for the development of an oral dosage form of edaravone, which may potentially benefit the therapy option for ALS patients by avoiding hospitalization costs; and (v) because of the existence of pharmaco-resistance for the brain entry in ALS patients, it appeared prudent to consider combination strategies of edaravone and/or riluzole with suitable P-glycoprotein efflux-blocking drugs to gain more favorable outcomes in ALS patients.