Riluzole

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Riluzole
Riluzole2DACS.svg
Riluzole ball-and-stick model.png
Clinical data
Trade namesRilutek, Teglutik
AHFS/Drugs.comMonograph
MedlinePlusa696013
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
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
CompTox Dashboard (EPA)
ECHA InfoCard100.124.754 Edit this at Wikidata
Chemical and physical data
FormulaC8H5F3N2OS
Molar mass234.199 g/mol g·mol−1
3D model (JSmol)
  (verify)

Riluzole is a medication used to treat amyotrophic lateral sclerosis. 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[edit]

Amyotrophic lateral sclerosis[edit]

Riluzole was approved in the United States for the treatment of ALS by the FDA in 1995.[3] A Cochrane Library review states a 9% gain in the probability of surviving one year.[2]

Adverse effects[edit]

Overdose[edit]

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[edit]

Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.[1]

Interactions[edit]

CYP1A2 substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism.[1]

Mechanism of action[edit]

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] These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves. Furthermore, riluzole ability to inhibit with an ATP-competitive mechanism the protein kinase CK1δ has been recently demonstrated.[15] 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[edit]

Riluzole can be prepared beginning with the reaction of 4-(trifluoromethoxy)aniline with potassium thiocyanate followed by reaction with bromine, forming the thiazole ring.[16][17][18]

Riluzole synthesis

Research[edit]

A number of recent case studies have indicated that riluzole may have use in mood and anxiety disorders.[19]

A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223[20] is under development for the treatment of generalized anxiety disorder and mood disorders now by Biohaven Pharmaceuticals.[21]

See also[edit]

References[edit]

  1. ^ a b c d e f g h i "PRODUCT INFORMATION RILUTEK® (riluzole) Tablets" (PDF). TGA eBusiness Services. sanofi-aventis australia pty ltd. January 6, 2009. Retrieved February 18, 2014.
  2. ^ a b Miller, RG; Mitchell, JD; Moore, DH (March 14, 2012). "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)". The Cochrane Database of Systematic Reviews. 3 (3): CD001447. doi:10.1002/14651858.CD001447.pub3. PMID 22419278.
  3. ^ "Riluzole".
  4. ^ "Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved February 18, 2014.
  5. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  6. ^ Song, JH; Huang, CS; Nagata, K; Yeh, JZ; Narahashi, T (August 1997). "Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 282 (2): 707–14. PMID 9262334.
  7. ^ Bellingham, MC (February 2011). "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. doi:10.1111/j.1755-5949.2009.00116.x. PMC 6493865. PMID 20236142.
  8. ^ 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". Eur. J. Pharmacol. 235 (2–3): 283–9. doi:10.1016/0014-2999(93)90147-a. PMID 7685290.
  9. ^ He, Y.; Benz, A.; Fu, T.; Wang, M.; Covey, D.F.; Zorumski, C.F.; Mennerick, S. (2002). "Neuroprotective agent riluzole potentiates postsynaptic GABAA receptor function". Neuropharmacology. 42 (2): 199–209. doi:10.1016/s0028-3908(01)00175-7. PMID 11804616.
  10. ^ Wokke, J (September 21, 1996). "Riluzole". Lancet. 348 (9030): 795–9. doi:10.1016/S0140-6736(96)03181-9. PMID 8813989.
  11. ^ Kretschmer BD, Kratzer U, Schmidt WJ (August 1998). "Riluzole, a glutamate release inhibitor, and motor behavior". Naunyn Schmiedebergs Arch. Pharmacol. 358 (2): 181–90. doi:10.1007/pl00005241. PMID 9750003.
  12. ^ Azbill, RD; Mu, X; Springer, JE (July 2000). "Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes". Brain Res. 871 (2): 175–80. doi:10.1016/S0006-8993(00)02430-6. PMID 10899284.
  13. ^ Dunlop, J; Beal McIlvain, H; She, Y; Howland, DS (March 1, 2003). "Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis". J. Neurosci. 23 (5): 1688–96. doi:10.1523/JNEUROSCI.23-05-01688.2003. PMID 12629173.
  14. ^ Wang, S.-J (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. PMID 15051158.
  15. ^ Bissaro, Maicol; Federico, Stephanie; Salmaso, Veronica; Sturlese, Mattia; Spalluto, Giampiero; Moro, Stefano (2018). "Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?". ChemMedChem. 13 (24): 2601–2605. doi:10.1002/cmdc.201800632. ISSN 1860-7187. PMID 30359484.
  16. ^ L. M. Yagupol'skii, L. Z. Gandel'sman, Zh. Obshch. Khim. 33, 2301 (1963), C.A. 60, 692a (1964).
  17. ^ J. Mizoule, EP 50551 ; idem, U.S. Patent 4,370,338 (1982, 1983 both to Pharmindustrie).
  18. ^ U.S. Patent 4,826,860
  19. ^ Grant, P; Song, JY; Swedo, SE (2010). "Review of the use of the glutamate antagonist riluzole in psychiatric disorders and a description of recent use in childhood obsessive-compulsive disorder". J Child Adolesc Psychopharmacol. 20 (4): 309–15. doi:10.1089/cap.2010.0009. PMC 2958461. PMID 20807069.
  20. ^ "BHV 0223 – AdisInsight". Adisinsight.springer.com. Retrieved May 20, 2016.
  21. ^ Harris, Elaine (2015). "Industry update: the latest developments in therapeutic delivery". Therapeutic Delivery. 6 (6): 647–652. doi:10.4155/tde.15.44. ISSN 2041-5990.

External links[edit]