Riluzole Explained

Riluzole is a medication used to treat amyotrophic lateral sclerosis 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.

Medical use

Amyotrophic lateral sclerosis

Riluzole was approved in the United States for the treatment of ALS by the U.S. Food and Drug Administration (FDA) in 1995.[2] A Cochrane Library review states a 9% gain in the probability of surviving one year.[1]

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.[5] [6] Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.[7] The drug has also been shown to postsynaptically potentiate GABAA receptors via an allosteric binding site.[8] 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.[9] [10] 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.[11] [12] In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals.[13] 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.[14] [15]

Society and culture

Legal status

Riluzole was approved for medical use in the European Union in October 1996.[16]

Research

A number of case studies and randomized controlled trials have indicated that riluzole, which is neuroprotective and a glutamate modulator, may have use in mood and anxiety disorders.[17] [18] [19] However, it failed in trials of Huntington's disease and Parkinson's disease.[19]

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.[20] [21] However, further research, especially in human trials, is necessary to confirm these findings and establish riluzole's clinical efficacy for treating hearing loss.

A sublingual reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223[22] is under development for the treatment of generalized anxiety disorder and mood disorders by Biohaven Pharmaceuticals.[23] [24] A prodrug formulation of riluzole, troriluzole, has been researched as a potential treatment for several different conditions.[25] [26]

Notes and References

  1. Miller RG, Mitchell JD, Moore DH . Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) . The Cochrane Database of Systematic Reviews . 2012 . 3 . CD001447 . March 2012 . 22419278 . 7055506 . 10.1002/14651858.CD001447.pub3 .
  2. Book: 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 . 31644225 . https://livertox.nih.gov/Riluzole.htm .
  3. Web site: Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more. Medscape Reference. WebMD. February 18, 2014.
  4. Book: Rossi S . 978-0-9805790-9-3 . Australian Medicines Handbook . Adelaide . The Australian Medicines Handbook Unit Trust . 2013 . 2013 .
  5. Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T . Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels . The Journal of Pharmacology and Experimental Therapeutics . 282 . 2 . 707–714 . August 1997 . 9262334 .
  6. Bellingham MC . A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? . CNS Neuroscience & Therapeutics . 17 . 1 . 4–31 . February 2011 . 20236142 . 6493865 . 10.1111/j.1755-5949.2009.00116.x .
  7. Debono MW, Le Guern J, Canton T, Doble A, Pradier L . 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 . April 1993 . 7685290 . 10.1016/0014-2999(93)90147-a .
  8. He Y, Benz A, Fu T, Wang M, Covey DF, Zorumski CF, Mennerick S . Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function . Neuropharmacology . 42 . 2 . 199–209 . February 2002 . 11804616 . 10.1016/s0028-3908(01)00175-7 . 24194421 .
  9. Wokke J . Riluzole . Lancet . 348 . 9030 . 795–799 . September 1996 . 8813989 . 10.1016/S0140-6736(96)03181-9 . 208788906 .
  10. Kretschmer BD, Kratzer U, Schmidt WJ . Riluzole, a glutamate release inhibitor, and motor behavior . Naunyn-Schmiedeberg's Archives of Pharmacology . 358 . 2 . 181–190 . August 1998 . 9750003 . 10.1007/pl00005241 . 5887788 .
  11. Azbill RD, Mu X, Springer JE . Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes . Brain Research . 871 . 2 . 175–180 . July 2000 . 10899284 . 10.1016/S0006-8993(00)02430-6 . 23849619 .
  12. Dunlop J, Beal McIlvain H, She Y, Howland DS . Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis . The Journal of Neuroscience . 23 . 5 . 1688–1696 . March 2003 . 12629173 . 6741992 . 10.1523/JNEUROSCI.23-05-01688.2003 .
  13. Wang SJ, Wang KY, Wang WC . Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes) . Neuroscience . 125 . 1 . 191–201 . January 2004 . 15051158 . 10.1016/j.neuroscience.2004.01.019 . 35667296 .
  14. Yagupol'skii LM, Gandel'sman LZ . Missing . Zh. Obshch. Khim. . 33 . 2301 . 1963 .
  15. EP. 50551. Medicament containing 2-amino-6-trifluoro-methoxy benzothiazole. 1982-04-28. Pharmindustrie. Mizoule J .
    Mizoule J . US . 4370338 . 1983 . Pharmindustrie .
  16. Web site: Rilutek EPAR . European Medicines Agency (EMA) . 1 October 2020.
  17. Kawashima Y, Yamada M, Furuie H, Kuniishi H, Akagi K, Kawashima T, Noda T, Yamada M . Effects of riluzole on psychiatric disorders with anxiety or fear as primary symptoms: A systematic review . Neuropsychopharmacology Reports . 43 . 3 . 320–327 . September 2023 . 37463744 . 10496048 . 10.1002/npr2.12364.
  18. Grant P, Song JY, Swedo SE . Review of the use of the glutamate antagonist riluzole in psychiatric disorders and a description of recent use in childhood obsessive-compulsive disorder . Journal of Child and Adolescent Psychopharmacology . 20 . 4 . 309–315 . August 2010 . 20807069 . 2958461 . 10.1089/cap.2010.0009 .
  19. Zarate CA, Manji HK . Riluzole in psychiatry: a systematic review of the literature . Expert Opinion on Drug Metabolism & Toxicology . 4 . 9 . 1223–1234 . September 2008 . 18721116 . 2587133 . 10.1517/17425255.4.9.1223 .
  20. Üstün Bezgin S, Uygur KK, Gökdoğan Ç, Elmas Ç, Göktaş G . The Effects of Riluzole on Cisplatin-induced Ototoxicity . International Archives of Otorhinolaryngology . 23 . 3 . e267–e275 . July 2019 . 31360245 . 6660296 . 10.1055/s-0038-1676654.
  21. Ruel J, Wang J, Pujol R, Hameg A, Dib M, Puel JL . Neuroprotective effect of riluzole in acute noise-induced hearing loss . . 16 . 10 . 1087–90 . July 2005 . 15973153 . 10.1097/00001756-200507130-00011 . 29393000 .
  22. Web site: BHV 0223 – AdisInsight . Adisinsight.springer.com . 2016-05-20.
  23. Harris E . Industry update: the latest developments in therapeutic delivery. Therapeutic Delivery. 6. 6. 2015. 647–652. 2041-5990. 10.4155/tde.15.44. free.
  24. Web site: Terry . Mark . Biohaven Reports Positive Early Clinical Trial Results for Anxiety Drug . BioSpace . 16 August 2018 . 5 November 2023.
  25. van Roessel PJ, Grassi G, Aboujaoude EN, Menchón JM, Van Ameringen M, Rodríguez CI . Treatment-resistant OCD: Pharmacotherapies in adults . Comprehensive Psychiatry . 120 . 152352 . January 2023 . 36368186 . 10.1016/j.comppsych.2022.152352. 2445/192315 . free.
  26. Silk AW, Saraiya B, Groisberg R, Chan N, Spencer K, Girda E, Shih W, Palmeri M, Saunders T, Berman RM, Coric V, Chen S, Zloza A, Vieth J, Mehnert JM, Malhotra J . A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors . European Journal of Medical Research . 27 . 1 . 107 . July 2022 . 35780243 . 9250196 . 10.1186/s40001-022-00732-w. free.

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