Riluzole was approved in the United States for the treatment of ALS by the U.S.Food and Drug Administration (FDA) in 1995.[6] ACochrane Library review states a 9% gain in the probability of surviving one year.[5]
Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma andmethemoglobinemia.[4] Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.[4]
Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.[4]
Riluzole preferentially blocksTTX-sensitivesodium channels, which are associated with damagedneurons.[9][10] Riluzole has also been reported to directly inhibit thekainate andNMDA receptors.[11] The drug has also been shown to postsynaptically potentiateGABAA receptors via an allosteric binding site.[12] However, the action of riluzole onglutamate receptors has been controversial, as no binding of the drug to any known sites has been shown for them.[13][14] 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.[15][16] In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals.[17] SinceCK1δ plays a key role inTDP-43 proteinopathy, a pathological hallmark of ALS, this could help to better decipher drug mechanism of action.
Riluzole can be prepared beginning with the reaction of 4-(trifluoromethoxy)aniline withpotassium thiocyanate followed by reaction with bromine, forming thethiazole ring.[18][19][20]
Riluzole has been investigated in rodent models for its potential ability to protect againstnoise-induced hearing loss (NIHL) andcisplatin-inducedototoxicity. These protective effects are believed to be caused by riluzole'santioxidant and anti-apoptotic properties, but other mechanisms, including modulation of glutamate signaling, are also being investigated.[24][25] 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.
^Kretschmer BD, Kratzer U, Schmidt WJ (August 1998). "Riluzole, a glutamate release inhibitor, and motor behavior".Naunyn-Schmiedeberg's Archives of Pharmacology.358 (2):181–190.doi:10.1007/pl00005241.PMID9750003.S2CID5887788.
^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.
