View source for Riluzole

{{Short description|Medication used to treat amyotrophic lateral sclerosis}}
{{Use mdy dates|date=August 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| verifiedrevid = 464382551
| image = Riluzole2DACS.svg
| width = 200
| alt =
| image2 = Riluzole ball-and-stick model.png
| width2 = 200
| alt2 =
<!-- Clinical data -->
| tradename = Rilutek, Tiglutik, Exservan, others
| Drugs.com = {{drugs.com|monograph|riluzole}}
| MedlinePlus = a696013
| pregnancy_AU = B3
| ATC_prefix = N07
| ATC_suffix = XX02
| ATC_supplemental =
| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx Only
| legal_US_comment = <ref>{{cite web | title=Rilutek (riluzole) tablets, for oral useInitial U.S. Approval: 1995 | website=DailyMed   | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=798886 | access-date=August 26, 2024}}</ref><ref>https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020599Orig1s000rev.pdf {{Bare URL PDF|date=August 2024}}</ref>
| legal_EU = Rx Only
| legal_EU_comment = <ref name="Rilutek EPAR" />
| routes_of_administration = [[Oral administration|By mouth]]
<!-- Pharmacokinetic data -->
| bioavailability = 60±18%<ref name = TGA>{{cite web|title=PRODUCT INFORMATION RILUTEK® (riluzole) Tablets|work=TGA eBusiness Services|publisher=sanofi-aventis australia pty ltd|date=January 6, 2009|access-date=February 18, 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05951-3|format=PDF}}</ref>
| protein_bound = 97%<ref name = TGA/>
| metabolism = [[Hepatic]] ([[CYP1A2]])<ref name = TGA/>
| elimination_half-life = 9–15 hours<ref name = TGA/>
| excretion = Urine (90%)<ref name = TGA/>
<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 1744-22-5
| PubChem = 5070
| IUPHAR_ligand = 2326
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00740
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4892
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 7LJ087RS6F
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00775
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 744
<!-- Chemical data -->
| IUPAC_name = 6-(trifluoromethoxy)benzothiazol-2-amine
| C=8 | H=5 | F=3 | N=2 | O=1 | S=1
| smiles = FC(F)(F)Oc1ccc2nc(sc2c1)N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C8H5F3N2OS/c9-8(10,11)14-4-1-2-5-6(3-4)15-7(12)13-5/h1-3H,(H2,12,13)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FTALBRSUTCGOEG-UHFFFAOYSA-N
}}
'''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.<ref name="Coch">{{cite journal | vauthors = Miller RG, Mitchell JD, Moore DH | title = Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 3 | pages = CD001447 | date = March 2012 | pmid = 22419278 | pmc = 7055506 | doi = 10.1002/14651858.CD001447.pub3 }}</ref> 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.<ref>{{cite book | chapter = Riluzole | title = LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet] | location = Bethesda (MD) | publisher = National Institute of Diabetes and Digestive and Kidney Diseases | date = May 2018 | pmid = 31644225  | chapter-url= https://livertox.nih.gov/Riluzole.htm }}</ref> A [[Cochrane Library]] review states a 9% gain in the probability of surviving one year.<ref name = Coch/>
==Adverse effects==
* Very common (>10% frequency):<ref name="MSR">{{cite web|title=Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=February 18, 2014|url=http://reference.medscape.com/drug/rilutek-riluzole-343067#showall}}</ref> [[nausea]]; [[Asthenia|weakness]]; decreased [[lung function]]
* Common (1–10% frequency):<ref name="AMH">{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref> headache; dizziness; drowsiness; vomiting; abdominal pain; increased [[aminotransferase]]s
* Uncommon (0.1–1% frequency):<ref name = AMH/> [[pancreatitis]]; [[interstitial lung disease]]
* Rare (<0.1% frequency):<ref name = AMH/> [[neutropenia]]; allergic reaction (including [[angiooedema]], anaphylactoid reaction)
===Overdose===
Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and [[methemoglobinemia]].<ref name = TGA/> Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.<ref name = TGA/>
==Contraindications==
Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.<ref name = TGA/>
== Interactions ==
[[CYP1A2]] substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism.<ref name = TGA/>
==Mechanism of action==
Riluzole preferentially blocks [[Tetrodotoxin|TTX]]-sensitive [[sodium channel]]s, which are associated with damaged [[neuron]]s.<ref>{{cite journal | vauthors = Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T | title = Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 282 | issue = 2 | pages = 707–714 | date = August 1997 | pmid = 9262334 | url = http://jpet.aspetjournals.org/content/282/2/707.full.pdf }}</ref><ref>{{cite journal | vauthors = Bellingham MC | title = 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? | journal = CNS Neuroscience & Therapeutics | volume = 17 | issue = 1 | pages = 4–31 | date = February 2011 | pmid = 20236142 | pmc = 6493865 | doi = 10.1111/j.1755-5949.2009.00116.x }}</ref> Riluzole has also been reported to directly inhibit the [[kainate receptor|kainate]] and [[NMDA receptor]]s.<ref name="pmid7685290">{{cite journal | vauthors = Debono MW, Le Guern J, Canton T, Doble A, Pradier L | title = Inhibition by riluzole of electrophysiological responses mediated by rat kainate and NMDA receptors expressed in Xenopus oocytes | journal = European Journal of Pharmacology | volume = 235 | issue = 2–3 | pages = 283–289 | date = April 1993 | pmid = 7685290 | doi = 10.1016/0014-2999(93)90147-a }}</ref> The drug has also been shown to postsynaptically potentiate [[GABAA receptor|GABA<sub>A</sub> receptors]] via an allosteric binding site.<ref>{{cite journal | vauthors = He Y, Benz A, Fu T, Wang M, Covey DF, Zorumski CF, Mennerick S | title = Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function | journal = Neuropharmacology | volume = 42 | issue = 2 | pages = 199–209 | date = February 2002 | pmid = 11804616 | doi = 10.1016/s0028-3908(01)00175-7 | s2cid = 24194421 }}</ref> However, the action of riluzole on [[glutamate receptor]]s has been controversial, as no binding of the drug to any known sites has been shown for them.<ref>{{cite journal | vauthors = Wokke J | title = Riluzole | journal = Lancet | volume = 348 | issue = 9030 | pages = 795–799 | date = September 1996 | pmid = 8813989 | doi = 10.1016/S0140-6736(96)03181-9 | s2cid = 208788906 }}</ref><ref name="pmid9750003">{{cite journal | vauthors = Kretschmer BD, Kratzer U, Schmidt WJ | title = Riluzole, a glutamate release inhibitor, and motor behavior | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 358 | issue = 2 | pages = 181–190 | date = August 1998 | pmid = 9750003 | doi = 10.1007/pl00005241 | s2cid = 5887788 }}</ref> 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.<ref>{{cite journal | vauthors = Azbill RD, Mu X, Springer JE | title = Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes | journal = Brain Research | volume = 871 | issue = 2 | pages = 175–180 | date = July 2000 | pmid = 10899284 | doi = 10.1016/S0006-8993(00)02430-6 | s2cid = 23849619 }}</ref><ref>{{cite journal | vauthors = Dunlop J, Beal McIlvain H, She Y, Howland DS | title = Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis | journal = The Journal of Neuroscience | volume = 23 | issue = 5 | pages = 1688–1696 | date = March 2003 | pmid = 12629173 | pmc = 6741992 | doi = 10.1523/JNEUROSCI.23-05-01688.2003 }}</ref> In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals.<ref>{{cite journal | vauthors = Wang SJ, Wang KY, Wang WC | title = Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes) | journal = Neuroscience | volume = 125 | issue = 1 | pages = 191–201 | date = January 2004 | pmid = 15051158 | doi = 10.1016/j.neuroscience.2004.01.019 | s2cid = 35667296 }}</ref> Since [[CSNK1D|CK1δ]] plays a key role in [[TAR DNA-binding protein 43 |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.<ref>{{cite journal | vauthors = Yagupol'skii LM, Gandel'sman LZ | title = Missing | journal = Zh. Obshch. Khim. | volume = 33 | pages = 2301 | date = 1963 }}</ref><ref>{{Cite patent|country=EP|number=50551|title=Medicament containing 2-amino-6-trifluoro-methoxy benzothiazole|pubdate=1982-04-28|assign=Pharmindustrie|inventor = Mizoule J }}; {{cite patent | inventor = Mizoule J | country = US | number = 4370338 | gdate = 1983 | assign1 = Pharmindustrie }}</ref><ref>{{US patent|4826860}}</ref>
:[[File:Riluzole synthesis.png|thumb|left|500px|Riluzole synthesis]]{{clear-left}}
== Society and culture ==
=== Legal status ===
Riluzole was approved for medical use in the European Union in October 1996.<ref name="Rilutek EPAR">{{cite web | title=Rilutek EPAR | website=[[European Medicines Agency]] (EMA) | date=April 16, 2007 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/rilutek | access-date=October 1, 2020}}</ref>
==Research==
A number of [[Case study|case studies]] and [[randomized controlled trial]]s have indicated that riluzole, which is [[Neuroprotection|neuroprotective]] and a [[Glutamate (neurotransmitter)|glutamate]] modulator, may have use in [[Mood disorder|mood]] and [[anxiety disorder]]s.<ref name="pmid37463744">{{cite journal |vauthors=Kawashima Y, Yamada M, Furuie H, Kuniishi H, Akagi K, Kawashima T, Noda T, Yamada M |title=Effects of riluzole on psychiatric disorders with anxiety or fear as primary symptoms: A systematic review |journal=Neuropsychopharmacology Reports |volume=43 |issue=3 |pages=320–327 |date=September 2023 |pmid=37463744 |pmc=10496048 |doi=10.1002/npr2.12364}}</ref><ref>{{cite journal | vauthors = Grant P, Song JY, Swedo SE | title = Review of the use of the glutamate antagonist riluzole in psychiatric disorders and a description of recent use in childhood obsessive-compulsive disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 20 | issue = 4 | pages = 309–315 | date = August 2010 | pmid = 20807069 | pmc = 2958461 | doi = 10.1089/cap.2010.0009 }}</ref><ref name="pmid18721116">{{cite journal | vauthors = Zarate CA, Manji HK | title = Riluzole in psychiatry: a systematic review of the literature | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 4 | issue = 9 | pages = 1223–1234 | date = September 2008 | pmid = 18721116 | pmc = 2587133 | doi = 10.1517/17425255.4.9.1223 }}</ref> However, it failed in trials of [[Huntington's disease]] and [[Parkinson's disease]].<ref name="pmid18721116"/>
Riluzole has been investigated in rodent models for its potential ability to protect against [[noise-induced hearing loss]] (NIHL) and [[cisplatin]]-induced [[ototoxic]]ity. 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.<ref name="pmid31360245">{{cite journal |vauthors=Üstün Bezgin S, Uygur KK, Gökdoğan Ç, Elmas Ç, Göktaş G |title=The Effects of Riluzole on Cisplatin-induced Ototoxicity |journal=International Archives of Otorhinolaryngology |volume=23 |issue=3 |pages=e267–e275 |date=July 2019 |pmid=31360245 |pmc=6660296 |doi=10.1055/s-0038-1676654}}</ref><ref name="pmid15973153">{{cite journal |vauthors=Ruel J, Wang J, Pujol R, Hameg A, Dib M, Puel JL |title=Neuroprotective effect of riluzole in acute noise-induced hearing loss |journal=[[NeuroReport]] |volume=16 |issue=10 |pages=1087–90 |date=July 2005 |pmid=15973153 |doi=10.1097/00001756-200507130-00011 |s2cid=29393000 |url=}}</ref> 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<ref>{{cite web|url=http://adisinsight.springer.com/drugs/800043098 |title=BHV 0223 – AdisInsight |publisher=Adisinsight.springer.com |access-date=May 20, 2016}}</ref> is under development{{when|date=October 2020}} for the treatment of [[generalized anxiety disorder]] and [[mood disorder]]s by Biohaven Pharmaceuticals.<ref name="Harris2015">{{cite journal| vauthors = Harris E |title=Industry update: the latest developments in therapeutic delivery|journal=Therapeutic Delivery|volume=6|issue=6|year=2015|pages=647–652|issn=2041-5990|doi=10.4155/tde.15.44|doi-access=free}}</ref><ref name="Terry 2018">{{cite web |last=Terry |first=Mark |title=Biohaven Reports Positive Early Clinical Trial Results for Anxiety Drug |website=BioSpace |date=August 16, 2018 |url=https://www.biospace.com/article/biohaven-reports-positive-early-clinical-trial-results-for-anxiety-drug/ |access-date=November 5, 2023}}</ref> A [[prodrug]] formulation of riluzole, [[troriluzole]], has been researched as a potential treatment for several different conditions.<ref name="pmid36368186">{{cite journal |vauthors=van Roessel PJ, Grassi G, Aboujaoude EN, Menchón JM, Van Ameringen M, Rodríguez CI |title=Treatment-resistant OCD: Pharmacotherapies in adults |journal=Comprehensive Psychiatry |volume=120 |issue= |pages=152352 |date=January 2023 |pmid=36368186 |doi=10.1016/j.comppsych.2022.152352|hdl=2445/192315 |hdl-access=free}}</ref><ref name="pmid35780243">{{cite journal |vauthors=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 |title=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 |journal=European Journal of Medical Research |volume=27 |issue=1 |pages=107 |date=July 2022 |pmid=35780243 |pmc=9250196 |doi=10.1186/s40001-022-00732-w|doi-access=free}}</ref>
== See also ==
[[Utreloxastat]]
== References ==
{{Reflist}}
{{Other nervous system drugs}}
{{GABA metabolism and transport modulators}}
{{Glycine receptor modulators}}
{{Ion channel modulators}}
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[[Category:Benzothiazoles]]
[[Category:Drugs with unknown mechanisms of action]]
[[Category:Experimental anxiolytics]]
[[Category:GABA reuptake inhibitors]]
[[Category:Glycine receptor antagonists]]
[[Category:Trifluoromethyl ethers]]