Behavioral & Cognitive Disorders
Dementia associated with amyotrophic lateral sclerosis
Aug. 11, 2023
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ISSN: 2831-9125
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Riluzole is a member of the benzothiazole class and is believed to be a glutamate antagonist. Several other glutamate antagonists (such as dextromethorphan and branched-chain amino acids) have been tried previously for the treatment of amyotrophic lateral sclerosis but without any success. Riluzole is the first drug to be approved for the treatment of amyotrophic lateral sclerosis; it received United States Food and Drug Administration approval in 1995 and was launched in several countries in 1996.
Pharmacodynamics. The mode of action of riluzole is not known. The following pharmacologic properties may be related to its beneficial effect in amyotrophic lateral sclerosis:
• An inhibitory effect on glutamate release. | |
• Neuroprotective action of riluzole may be partly mediated by its increase of transporter-mediated glutamate uptake. | |
• Inactivation of voltage-dependent sodium channels. | |
• Ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. Riluzole has been shown to be neuroprotective in experimental models of neuronal injury involving excitotoxic mechanisms. Transcranial magnetic stimulation has shown that riluzole reduces cortical excitability in patients with amyotrophic lateral sclerosis. This finding supports the view that attenuation of glutamate-related excitotoxicity is an important factor contributing to the beneficial effect. Riluzole has protective effects on dopamine neurons in vitro against neuronal injuries induced by impairment of cellular energy metabolism and oxidative stress. These results provide a basis for exploring the neuroprotective potential of riluzole in Parkinson disease. | |
• Riluzole increased the amount and activity of heat shock factor 1 to boost the expression of heat shock proteins and glutamate transporter 1, providing neuroprotection under stress (15). | |
• Results of experimental studies on neurons and myotubes indicate that one of the mechanisms of riluzole's therapeutic effect might be increasing the glucose transport rate in cells affected by amyotrophic lateral sclerosis (05). | |
• A longitudinal study of the effect of riluzole therapy on cortical hyperexcitability in patients with amyotrophic lateral sclerosis by using transcranial magnetic stimulation combined with peripheral nerve function excitability found transient modulation of cortical and axonal hyperexcitability as compared with healthy controls, which accounted for modest clinical effectiveness (09). |
Pharmacokinetics. Important points are as follows:
• Riluzole is well absorbed following oral administration and has a bioavailability of 60%. | |
• Pharmacokinetics are linear over a dose range of 25 to 100 mg given every 12 hours. | |
• The mean elimination half-life is 12 hours after repeated doses. | |
• Riluzole is 96% bound to plasma proteins. | |
• Riluzole is metabolized to six major (and several minor) metabolites, some of which are pharmacologically active. Metabolism is mostly hepatic and consists of cytochrome P450-dependent hydroxylation and glucuronidation. | |
• Excretion of riluzole is mainly renal as glucuronides. |
Formulations. An oral liquid formulation, 5 mg/mL suspension, is now available and provides an important therapeutic option for patients with amyotrophic lateral sclerosis, as most of them are unable to swallow solid tablets due to disease-related dysphagia (06).
Delivery of riluzole to the brain. Entry of riluzole into the brain across the blood-brain barrier is restricted because it is a substrate of P-glycoprotein. A formulation of riluzole with lipid nanoparticles has been shown to improve delivery to the brain with greater efficacy than free riluzole in rats (03). Results of another animal experimental study indicate that nanoemulsion of riluzole for intranasal administration improves delivery to the brain and has the potential to reduce the dose of riluzole and avoid dose-related adverse events during treatment of amyotrophic lateral sclerosis (19).
Main evidence for the approval of riluzole was based on a prospective, randomized, double-blind, placebo-controlled trial (02). Riluzole appeared to slow the progression of amyotrophic lateral sclerosis and improve survival in patients with bulbar onset of the disease. Another double-blind, placebo-controlled, multicenter study was carried out to confirm these findings and to assess drug efficacy at different doses (14). The study confirmed that riluzole is well tolerated and lengthens survival of patients with amyotrophic lateral sclerosis. Efficacy and safety results suggest that a 100 mg dose of riluzole has the best benefit-to-risk ratio. Over an 18-month period, there was a 35% decreased risk of death with a 100 mg dose compared with placebo.
The Cochrane Review of controlled clinical trials concluded that riluzole is reasonably safe and probably prolongs median survival of patients with amyotrophic lateral sclerosis by about 2 to 3 months (18).
As of October 2021, 114 clinical trials of riluzole are listed on the United States government website: ClinicalTrials.gov. Only 62 of these are for amyotrophic lateral sclerosis and the rest are for other indications.
Riluzole is indicated for the treatment of amyotrophic lateral sclerosis.
• A randomized, double-blind, placebo-controlled trial has shown some benefit in patients with cerebellar ataxia (21). | |
• Riluzole has been reported as useful for the prevention of acute noise-induced hearing loss. | |
• Riluzole has been used to treat psychiatric conditions in children, particularly obsessive-compulsive disorder. The dose of riluzole used in children achieved serum concentration levels like those observed in adults (12). | |
• Autistic disorder. Riluzole, when used as an adjunctive therapy to risperidone, improved irritability in children with autism, but it also significantly increased appetite and weight gain (11). | |
• Even when applied after a transient excitotoxic stimulus, riluzole can provide effective prevention of secondary excitotoxic damage to premotoneurons in spinal cord injury, although not to motoneurons that remain very vulnerable (22). A phase I trial is evaluating the safety and pharmacokinetic profile of riluzole as a neuroprotective agent in patients with spinal cord injury (04; 08). | |
• A positive correlation has been observed between cognitive measures and regional cerebral glucose metabolism in a clinical trial, suggesting engagement of the glutamatergic system by riluzole. The findings support the main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole-treated group than in the placebo group and future larger and longer studies should test riluzole as a potential novel therapeutic intervention for Alzheimer disease (17). | |
• A double-blind, placebo-controlled randomized trial of riluzole on patients with early cervical myelopathy did not show a significant change in the clinical outcome and diffuse tensor imaging (20). | |
• In a systematic review and metaanalysis of placebo-controlled studies of riluzole on patients with neurodegenerative movement disorders, there was motor improvement in hereditary ataxia (16). | |
• Exploratory findings of a randomized, double-blind, placebo-controlled, parallel trial offer some evidence that riluzole augmentation of an SSRI or SNRI may selectively improve hyperarousal symptoms without changes in overall posttraumatic stress disorder symptoms, depression, anxiety, or disability (23). | |
• A clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures did not show any benefit of riluzole in minimizing neuropathy and suggests that it worsens neuropathy (24). |
Riluzole is contraindicated in patients with hypersensitivity to riluzole or any of the tablet components.
The aim of riluzole is to extend survival time of patients with amyotrophic lateral sclerosis. Riluzole is not a cure for amyotrophic lateral sclerosis, but the modest prolongation of survival that riluzole provides represents a first step forward in treating amyotrophic lateral sclerosis patients.
Most population studies that compared riluzole to riluzole-free patients with amyotrophic lateral sclerosis found significant differences in median survival between the two groups, ranging from 6 to 19 months, which is substantially longer than the 2- to 3-month survival benefit observed in the pivotal clinical trials of riluzole (01).
A 10-year observational study in Italy has evaluated the impact of riluzole and other therapeutic interventions on the survival of patients with amyotrophic lateral sclerosis in a setting that resembles clinical practice more closely than randomized controlled trials (10). Riluzole was shown to prolong life significantly longer than noninvasive ventilation and enteral nutrition.
Dosing of riluzole is 50 mg every 12 hours.
Riluzole should be used with caution in patients with hepatic and renal insufficiency.
Pediatric. The safety and efficacy of riluzole in this age group have not been established.
Geriatric. Age-related decreases in liver and kidney function may cause a decrease in clearance of riluzole. Otherwise, there are no differences in adverse effects between younger patients and those over the age of 65 years.
Pregnancy. Embryotoxicity has been observed in experimental animals given doses of riluzole equivalent to the maximum human therapeutic dose. No adequate and well-controlled studies have been conducted with pregnant women. Riluzole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Anesthesia. No special precautions.
No clinical studies have been done to determine drug interactions, but a potential interaction exists with hepatotoxic drugs and with those drugs that are highly bound to plasma proteins. Drugs that inhibit cytochrome P450 can increase the elimination of riluzole.
Commonly observed adverse events in clinical trials with riluzole were asthenia, nausea, abdominal pain, dizziness, and liver enzyme elevation. Most of these are dose-related. Riluzole treatment may be associated with mild blood pressure elevations. Riluzole may rarely cause neutropenia. Moderately severe acute pancreatitis has been associated with riluzole therapy (13). Two patients were reported to develop severe recurrent acute pancreatitis with portal vein thrombosis during treatment with riluzole (07).
Management. Most of the adverse effects usually disappear after reduction of dose or discontinuation of therapy.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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