Riluzole is a medication used to treat amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. Riluzole delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months.[1] Riluzole is available in tablet and liquid form. A thin film version of riluzole which dissolves on the tongue (commercially known as Exservan or Emylif) is available in the United States and United Kingdom.[2]
Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.[4]
Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and methemoglobinemia.[4] Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.[4]
Interactions
CYP1A2 substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism.[4]
Mechanism of action
Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.[7][8] Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.[9] The drug has also been shown to postsynaptically potentiate GABAA receptors via an allosteric binding site.[10] 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.[11][12] 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.[13][14] In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals.[15] Since CK1δ plays a key role in TDP-43 proteinopathy, a pathological hallmark of ALS, this could help to better decipher drug mechanism of action.
Synthesis
Riluzole can be prepared beginning with the reaction of 4-(trifluoromethoxy)aniline with potassium thiocyanate followed by reaction with bromine, forming the thiazole ring.[16][17][18]
Riluzole has been investigated in rodent models for its potential ability to protect against noise-induced hearing loss (NIHL) and cisplatin-induced ototoxicity. These protective effects are believed to be caused by riluzole's antioxidant and anti-apoptotic properties, but other mechanisms, including modulation of glutamate signaling, are also being investigated.[25][26] However, further research, especially in human trials, is necessary to confirm these findings and establish riluzole's clinical efficacy for treating hearing loss.
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