Chemistry:Riluzole

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Short description: Medication used to treat amyotrophic lateral sclerosis
Riluzole
Riluzole2DACS.svg
Riluzole ball-and-stick model.png
Clinical data
Trade namesRilutek, Tiglutik, Exservan, others
AHFS/Drugs.comMonograph
MedlinePlusa696013
License data
Pregnancy
category
  • AU: B3
  • US: N (Not classified yet)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60±18%[1]
Protein binding97%[1]
MetabolismHepatic (CYP1A2)[1]
Elimination half-life9–15 hours[1]
ExcretionUrine (90%)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC8H5F3N2OS
Molar mass234.20 g·mol−1
3D model (JSmol)
  (verify)

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.[2] 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.[3] A Cochrane Library review states a 9% gain in the probability of surviving one year.[2]

Adverse effects

  • Very common (>10% frequency):[4] nausea; weakness; decreased lung function
  • Common (1–10% frequency):[5] headache; dizziness; drowsiness; vomiting; abdominal pain; increased aminotransferases
  • Uncommon (0.1-1% frequency):[5] pancreatitis; interstitial lung disease
  • Rare (<0.1% frequency):[5] neutropenia; allergic reaction (including angiooedema, anaphylactoid reaction)

Overdose

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]

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.[19][20][21] However, it failed in trials of Huntington's disease and Parkinson's disease.[21]

A sublingual reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223[22] is under development[when?] for the treatment of generalized anxiety disorder and mood disorders by Biohaven Pharmaceuticals.[23][24]

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.

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "PRODUCT INFORMATION RILUTEK® (riluzole) Tablets" (PDF). TGA eBusiness Services. sanofi-aventis australia pty ltd. January 6, 2009. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05951-3. 
  2. ↑ 2.0 2.1 "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)". The Cochrane Database of Systematic Reviews 2012 (3): CD001447. March 2012. doi:10.1002/14651858.CD001447.pub3. PMID 22419278. 
  3. ↑ "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. https://livertox.nih.gov/Riluzole.htm. 
  4. ↑ "Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/rilutek-riluzole-343067#showall. 
  5. ↑ 5.0 5.1 5.2 Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  6. ↑ "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. PMID 9262334. http://jpet.aspetjournals.org/content/282/2/707.full.pdf. 
  7. ↑ "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. doi:10.1111/j.1755-5949.2009.00116.x. PMID 20236142. 
  8. ↑ "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. doi:10.1016/0014-2999(93)90147-a. PMID 7685290. 
  9. ↑ "Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function". Neuropharmacology 42 (2): 199–209. February 2002. doi:10.1016/s0028-3908(01)00175-7. PMID 11804616. 
  10. ↑ "Riluzole". Lancet 348 (9030): 795–799. September 1996. doi:10.1016/S0140-6736(96)03181-9. PMID 8813989. 
  11. ↑ "Riluzole, a glutamate release inhibitor, and motor behavior". Naunyn-Schmiedeberg's Archives of Pharmacology 358 (2): 181–190. August 1998. doi:10.1007/pl00005241. PMID 9750003. 
  12. ↑ "Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes". Brain Research 871 (2): 175–180. July 2000. doi:10.1016/S0006-8993(00)02430-6. PMID 10899284. 
  13. ↑ "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. doi:10.1523/JNEUROSCI.23-05-01688.2003. PMID 12629173. 
  14. ↑ "Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes)". Neuroscience 125 (1): 191–201. January 2004. doi:10.1016/j.neuroscience.2004.01.019. PMID 15051158. 
  15. ↑ "Missing". Zh. Obshch. Khim. 33: 2301. 1963. 
  16. ↑ Mizoule J, "Medicament containing 2-amino-6-trifluoro-methoxy benzothiazole", EP patent 50551, published 1982-04-28; Mizoule J, US patent 4370338, issued 1983, assigned to Pharmindustrie
  17. ↑ U.S. Patent 4,826,860
  18. ↑ "Rilutek EPAR". https://www.ema.europa.eu/en/medicines/human/EPAR/rilutek. 
  19. ↑ "Effects of riluzole on psychiatric disorders with anxiety or fear as primary symptoms: A systematic review". Neuropsychopharmacology Reports 43 (3): 320–327. September 2023. doi:10.1002/npr2.12364. PMID 37463744. 
  20. ↑ "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. doi:10.1089/cap.2010.0009. PMID 20807069. 
  21. ↑ 21.0 21.1 "Riluzole in psychiatry: a systematic review of the literature". Expert Opinion on Drug Metabolism & Toxicology 4 (9): 1223–1234. September 2008. doi:10.1517/17425255.4.9.1223. PMID 18721116. 
  22. ↑ "BHV 0223 – AdisInsight". Adisinsight.springer.com. http://adisinsight.springer.com/drugs/800043098. 
  23. ↑ "Industry update: the latest developments in therapeutic delivery". Therapeutic Delivery 6 (6): 647–652. 2015. doi:10.4155/tde.15.44. ISSN 2041-5990. 
  24. ↑ Terry, Mark (16 August 2018). "Biohaven Reports Positive Early Clinical Trial Results for Anxiety Drug". https://www.biospace.com/article/biohaven-reports-positive-early-clinical-trial-results-for-anxiety-drug/. 
  25. ↑ "The Effects of Riluzole on Cisplatin-induced Ototoxicity". International Archives of Otorhinolaryngology 23 (3): e267–e275. July 2019. doi:10.1055/s-0038-1676654. PMID 31360245. 
  26. ↑ "Neuroprotective effect of riluzole in acute noise-induced hearing loss". NeuroReport 16 (10): 1087–90. July 2005. doi:10.1097/00001756-200507130-00011. PMID 15973153. 

External links



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