BACKGROUND:

Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease.

OBJECTIVES:

To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy.

DESIGN:

Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms.

RESULTS:

Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities.

CONCLUSIONS:

Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA.

Executive summary available for free by visiting the document URL listed with this record.

RECORD STATUS:

None

CITATION:

National Institute for Clinical Excellence. Guidance on the use of riluzole (Rilutek) for the treatment of motor neurone disease London: National Institute for Clinical Excellence (NICE). Technology Appraisal Guidance 20. 2001

RECORD STATUS:

None

CITATION:

Garces K, Husereau D, Skidmore B, Turnbull J. Riluzole for the treatment of amyotryophic lateral sclerosis: an assessment of clinical efficacy and safety. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) 2003

Background: Riluzole retards striatal glutamate release and pathologic consequences in neurotoxic animal models of Huntington's disease (HD). Objective: To determine the dosage-related impact of riluzole on chorea in HD. Methods: An 8-week double-blind dose-ranging multicenter study of riluzole was conducted in 63 subjects (32 women, 31 men) with HD who were randomized to receive placebo, riluzole 100 mg/day, or riluzole 200 mg/day. The prespecified outcome measure was change in the total maximal chorea score of the Unified Huntington's Disease Rating Scale (UHDRS). Results: Fifty-six (89%) subjects completed the study. A reduction (p < 0.01) in chorea at 8 weeks was found using a linear trend test with dose. Comparing the groups individually, the reduction in chorea for the riluzole 200-mg/day group (-2.2 ± 3.3) was different (p = 0.01) from placebo (+0.7 ± 3.4), but the riluzole 100-mg/day group (-0.2 ± 2.9) was not. Riluzole did not improve other motor, cognitive, behavioral, or functional components of the UHDRS. Alanine aminotransferase was elevated in a dosage-dependent fashion (p = 0.01). Conclusions: Over 8 weeks of treatment, riluzole 200 mg/day ameliorated chorea intensity in HD without improving functional capacity or other clinical features of illness. Riluzole 200 mg/day was attended by reversible liver transaminase abnormalities that would require monitoring in long-term studies.

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of adults which preferentially attacks the neuromotor system. Riluzole has been used as the only approved treatment for amyotrophic lateral sclerosis since 1995, but its mechanism(s) of action in slowing the progression of this disease remain obscure. Searching PubMed for "riluzole" found 705 articles published between January 1996 and June 2009. A systematic review of this literature found that riluzole had a wide range of effects on factors influencing neural activity in general, and the neuromotor system in particular. These effects occurred over a large dose range (<1 μM to >1 mM). Reported neural effects of riluzole included (in approximate ascending order of dose range): inhibition of persistent Na(+) current = inhibition of repetitive firing < potentiation of calcium-dependent K(+) current < inhibition of neurotransmitter release < inhibition of fast Na(+) current < inhibition of voltage-gated Ca(2+) current = promotion of neuronal survival or growth factors < inhibition of voltage-gated K(+) current = modulation of two-pore K(+) current = modulation of ligand-gated neurotransmitter receptors = potentiation of glutamate transporters. Only the first four of these effects commonly occurred at clinically relevant concentrations of riluzole (plasma levels of 1-2 μM with three- to four-fold higher concentrations in brain tissue). Treatment of human ALS patients or transgenic rodent models of ALS with riluzole most commonly produced a modest but significant extension of lifespan. Riluzole treatment was well tolerated in humans and animals. In animals, despite in vitro evidence that riluzole may inhibit rhythmic motor behaviors, in vivo administration of riluzole produced relatively minor effects on normal respiration parameters, but inhibited hypoxia-induced gasping. This effect may have implications for the management of hypoventilation and sleep-disordered breathing during end-stage ALS in humans.

BACKGROUND:

The pleiotropic effects of riluzole may antagonize common mechanisms underlying chronic cerebellar ataxia, a debilitating and untreatable consequence of various diseases.

METHODS:

In a randomized, double-blind, placebo-controlled pilot trial, 40 patients presenting with cerebellar ataxias of different etiologies were randomly assigned to riluzole (100 mg/day) or placebo for 8 weeks. The following outcome measures were compared: proportion of patients with a decrease of at least 5 points in the International Cooperative Ataxia Rating Scale (ICARS) total score after 4 and 8 weeks compared with the baseline score; mean changes from the baseline to posttreatment ICARS (total score and subscores at 8 weeks); and occurrence of adverse events.

RESULTS:

Riluzole and placebo groups did not differ in baseline characteristics. The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 4 weeks (9/19 vs 1/19; odds ratio [OR] = 16.2; 95% confidence interval [CI] 1.8–147.1) and 8 weeks (13/19 vs 1/19; OR = 39.0; 95% CI 4.2–364.2). The mean change in the riluzole group ICARS after treatment revealed a decrease (<i>p</i> < 0.001) in the total score (−7.05 [4.96] vs 0.16 [2.65]) and major subscores (−2.11 [2.75] vs 0.68 [1.94] for static function, −4.11 [2.96] vs 0.37 [2.0] for kinetic function, and −0.74 [0.81] vs 0.05 [0.40] for dysarthria). Sporadic, mild adverse events occurred.

CONCLUSIONS:

These findings indicate the potential effectiveness of riluzole as symptomatic therapy in diverse forms of cerebellar ataxia. Classification of evidence: This study provides Class I evidence that riluzole reduces, by at least 5 points, the ICARS score in patients with a wide range of disorders that cause cerebellar ataxia (risk difference 63.2%, 95% CI 33.5%–79.9%). (PsycInfo Database Record (c) 2021 APA, all rights reserved)

AIMS:

The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence.

DESIGN:

A multi-arm, modified blinded, placebo-controlled design was used.

SETTING:

The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU). Participants: Participants met criteria for cocaine dependence during a 2-week screening period. Intervention: Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study. Measurements: Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period.

FINDINGS:

None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated.

CONCLUSIONS:

This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

La esclerosis lateral amiotrófica esporádica (sALS) es una enfermedad degenerativa para la que no existe tratamiento etiológico eficaz. El riluzole prolonga poco la sobrevida. La principal causa de muerte es la insuficiencia respiratoria. Uno de los tratamientos para esta última es la ventilación asistida no invasiva (NIV) con equipos de doble nivel de presión. El objetivo de este trabajo fue determinar el impacto en la sobrevida de estos enfermos combinando ventilación no invasiva y riluzole. Se evaluaron y siguieron durante 60 meses 97 pacientes con diagnóstico de sALS, según criterios definidos en El Escorial modificados, y fueron seguidos por 60 meses. Veintinueve pacientes recibieron NIV y 68 no (nNIV). En el grupo NIV la sobrevida media fue de 15.41 ± 7.78 meses vs. 10.88 ± 7.78 meses en nNIV (p= 0.028). La sobrevida media de los pacientes que recibieron riluzole (n=44) no fue diferente de la que no lo recibieron (n=53), aunque en el 4° y 5° mes los pacientes tratados con riluzole mostraron un escaso beneficio. Los pacientes que recibieron NIV y riluzole (n=18) tuvieron una sobrevida media de 16.61 ± 10.97 meses vs. 10.69 ± 7.86 meses para los que sólo recibieron tratamiento sintomático (n=42) (p= 0.021). La NIV prolongó significativamente la sobrevida en este grupo de pacientes. El riluzole, empleado como única terapéutica, no lo hizo. Los pacientes que combinaron los dos tratamientos tuvieron la mayor sobrevida.

RECORD STATUS:

None

CITATION:

Stewart A, Sandercock J, Bryan S, Hyde C, Barton P M, Fry-Smith A, Burls A. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review. Health Technology Assessment 2001; 5(2): 1-97