Riluzole was approved in the United States for the treatment of ALS by the U.S. Food and Drug Administration (FDA) in 1995.[3] A Cochrane Library review states a 9% gain in the probability of surviving one year.[2]
Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and methemoglobinemia.[1] Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.[1]
Contraindications
Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.[1]
Interactions
CYP1A2 substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism.[1]
Mechanism of action
Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.[6][7] Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.[8] The drug has also been shown to postsynaptically potentiate GABAA receptors via an allosteric binding site.[9] 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.[10][11] 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.[12][13] In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals.[14] 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.[15][16][17]
Riluzole synthesis
Society and culture
Legal status
Riluzole was approved for medical use in the European Union in October 1996.[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.[22][23] However, further research, especially in human trials, is necessary to confirm these findings and establish riluzole's clinical efficacy for treating hearing loss.
^"Riluzole". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. May 2018. PMID31644225.
^Debono MW, Le Guern J, Canton T, Doble A, Pradier L (April 1993). "Inhibition by riluzole of electrophysiological responses mediated by rat kainate and NMDA receptors expressed in Xenopus oocytes". European Journal of Pharmacology. 235 (2–3): 283–289. doi:10.1016/0014-2999(93)90147-a. PMID7685290.
^He Y, Benz A, Fu T, Wang M, Covey DF, Zorumski CF, et al. (February 2002). "Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function". Neuropharmacology. 42 (2): 199–209. doi:10.1016/s0028-3908(01)00175-7. PMID11804616. S2CID24194421.
^Wang SJ, Wang KY, Wang WC (January 2004). "Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes)". Neuroscience. 125 (1): 191–201. doi:10.1016/j.neuroscience.2004.01.019. PMID15051158. S2CID35667296.
