Riluzole

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Abstract
Riluzole, a benzothiazole, affects neurons by 3 mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitatory amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels. It has demonstrated neuroprotective activity in vivo and in vitro. Results from 2 randomised double-blind placebo-controlled trials in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) have demonstrated that riluzole can extend survival and/or time to tracheostomy. After 18 months, the relative risk of death or tracheostomy with riluzole 100 mg/day was reduced by 21%. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second, larger trial. Riluzole had no effect on any other functional or secondary variable. Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. Elevated alanine aminotransferase levels were observed in 10.6 versus 3.8% of patients treated with riluzole 100 mg/day versus placebo, leading to treatment withdrawal in 3.8 versus 2.1% of patients. In conclusion, riluzole is the first drug that has been shown to have an effect on survival in patients with ALS. Although the effect of riluzole was modest, it has allowed some insight into the pathogenesis of ALS from which future gains may be made. Amyotrophic lateral sclerosis (ALS; motor neuron disease) is characterised by progressive muscular weakness caused by degeneration of both upper and lower motor neurons. Sensory, autonomic and oculomotor neurons are almost completely unaffected. Patients usually die of respiratory failure within a median of 3.5 years. Both sporadic and familial types of ALS occur. The familial form of the disease has been linked to mutations in the gene encoding Cu/Zn-dependent superoxide dismutase. A number of hypotheses to explain the pathogenesis of ALS have been proposed but the precise cause of this disorder is unknown. Riluzole has 3 distinct effects on neurons. At micromolar concentrations, it inhibits both the release of excitatory amino acids and N-methyl-D-aspartate (NMDA) receptor-mediated events; these effects of riluzole may occur as a result of activation of a G protein-dependent process. Riluzole also stabilises the inactivated state of voltage-dependent sodium channels at low micromolar concentrations. Riluzole has demonstrated neuroprotective effects in vitro and in vivo. In vitro, riluzole caused partial reversal of the effects of various neurotoxins in CNS cell culture or tissue slices. In a transgenic mouse model of ALS, riluzole significantly extended survival by 11%, although it had no effect on disease onset. Riluzole has also demonstrated neuroprotective effects in animal models of ischaemia and other neurodegenerative diseases. Riluzole has an average oral bioavailability of approximately 60%. Peak blood concentrations and the area under the concentration-time curve are reduced by about 45 and 20%, respectively, after a high fat meal. Steady-state plasma con-centrations of riluzole are reached within 5 days, and the drug is 96% plasma protein bound. Riluzole is extensively metabolised (hydroxylation by cytochrome P450 1A2 and glucuronidation) in the liver. The drug has 6 major and several other minor metabolites, some of which may be pharmacologically active. The mean elimination half-life of riluzole after multiple doses is 12 hours. After administration of [14C]-riluzole as a single dose, 90% of radioactivity is recovered in the urine and 5% in the faeces over a 7-day period. The efficacy of riluzole in patients with probable or definite ALS has been investigated in 2 randomised placebo-controlled double-blind trials. The primary efficacy outcome was tracheostomy-free survival assessed by intention-to-treat analysis. In the first trial, riluzole 100 mg/day was associated with a significantly higher rate of tracheostomy-free survival than placebo at both 12 (74 vs 58%) and 21 (49 vs 37%) months. This survival advantage was confirmed in the second, larger study (74 vs 63% at 12 months and 57 vs 50% at 18 months). At 18 months, the relative risk of tracheostomy or death with riluzole 100 mg/day was 0.79 (p = 0.076). Results obtained with riluzole 200 mg/day were similar to those with the 100 mg/day dosage. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second trial. Riluzole had no effect on any other functional or secondary variable. Adverse events reported more commonly with riluzole than placebo were nausea, vomiting, diarrhoea, anorexia, asthenia, dizziness and circumoral paraesthesia. Treatment withdrawal was necessary in 14% of riluzole 100 mg/day recipients and 11 % of placebo recipients in one trial. Elevated alanine aminotransferase levels (> 3 times the upper normal limit) were reported in 10.6% of riluzole 100 mg/day recipients compared with 3.8% of placebo recipients, leading to treatment withdrawal in 3.8 and 2.1% of patients, respectively. Marked neutropenia has been reported in 3 patients of approximately 4000 treated with riluzole. In patients with ALS, riluzole 50mg should be taken every 12 hours at least 1 hour before or 2 hours after food. Riluzole should be administered with care in patients with evidence or a history of abnormal liver function and/or renal dysfunction and also in elderly patients, in whom hepatic or renal function may be compromised by age. Serum transaminases should be monitored during riluzole therapy and frequent monitoring is recommended in those who develop elevated transaminase levels. Riluzole (2-amino-6-trifluoromethoxybenzothiazole) is loosely termed a glutamate antagonist which has anticonvulsant, sedative and neuroprotective properties (fig. 1). Although much of the clinical research into the potential applications of this agent is at an early stage, riluzole has been tested in 2 large trials for the treatment of patients with amyotrophic lateral sclerosis (ALS; motor neuron disease). This review focuses on the use of riluzole in patients with ALS.