Riluzole

Amyotrophic lateral sclerosis

There has been some evidence to show that higher doses might produce more significant improvements in ALS patients but at almost £6 (US$10) per tablet it is at risk of being prohibitively expensive given the modest benefit to patients. One study in the Netherlands found that riluzole is metabolized differently by males and females, and its levels in plasma are decreased in patients who smoke cigarettes or take omeprazole. A Cochrane Library review states a 9% gain in the probability of surviving one year.

Psychiatric use

A number of recent case studies have indicated that riluzole may have clinical use in mood and anxiety disorders. It has been shown to have antidepressant properties in the treatment of refractory depression and act as an anxiolytic in obsessive-compulsive disorder and in generalized anxiety disorder.

Research

A clinical study on mice has shown riluzole to compensate for harmful glutamate levels and promote dendritic spine clustering in hippocampal circuits implicated in memory and emotion. Therefore, the drug may act as an effective treatment for age-related memory loss and other forms of cognitive decline. The effect of riluzole on glutamate dysfunction in humans with Alzheimer's disease is unknown; however, a clinical trial is taking place to investigate this.

Riluzole was also studied as a treatment for spinal muscular atrophy; however, efficacy was not observed.

A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223 is under development for the treatment of generalized anxiety disorder and mood disorders now by Biohaven Pharmaceuticals.

A prodrug of riluzole, designated as BHV-4157, is under investigation for spinocerebellar ataxia.

Adverse effects

Overdose

Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and methemoglobinemia. Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.

Contraindications

Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.

Interactions

CYP1A2 substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism.

Mechanism of action

Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons. Riluzole has also been reported to directly inhibit the kainate and NMDA receptors. However, the action of riluzole on glutamate receptors has been controversial, as no binding of the drug to any known sites has been shown for them. In addition, as its antiglutamatergic action is still detectable in the presence of sodium channel blockers, it is also uncertain whether or not it acts via this way. Rather, its ability to stimulate glutamate uptake seems to mediate many of its effects. In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals. These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves.

Synthesis

Riluzole can be prepared beginning with the reaction of 4-(trifluoromethoxy)aniline with potassium thiocyanate followed by reaction with bromine. Displacement of bromine atom by sulfur forms the thiazole ring to afford riluzole.