Riluzole

Riluzole
Systematic (IUPAC) name
6-(trifluoromethoxy)benzothiazol-2-amine
Clinical data
Trade names Rilutek
AHFS/Drugs.com monograph
MedlinePlus a696013
Licence data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability 60±18%[1]
Protein binding 97%[1]
Metabolism Hepatic (CYP1A2)[1]
Biological half-life 9-15 hours[1]
Excretion Urine (90%)[1]
Identifiers
CAS Number 1744-22-5 YesY
ATC code N07XX02
PubChem CID 5070
IUPHAR/BPS 2326
DrugBank DB00740 YesY
ChemSpider 4892 YesY
UNII 7LJ087RS6F YesY
KEGG D00775 YesY
ChEMBL CHEMBL744 YesY
Chemical data
Formula C8H5F3N2OS
Molar mass 234.199 g/mol
  (verify)

Riluzole (Rilutek) is a drug used to treat amyotrophic lateral sclerosis and is marketed by Sanofi Pharmaceuticals. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately two to three months.[2]

Medical use

Amyotrophic lateral sclerosis

There has been some evidence to show that higher doses might produce more significant improvements in ALS patients but at almost £6 (US$10) per tablet it is at risk of being prohibitively expensive given the modest benefit to patients. One study in the Netherlands found that riluzole is metabolized differently by males and females, and its levels in plasma are decreased in patients who smoke cigarettes or take omeprazole.[3] A Cochrane Library review states a 9% gain in the probability of surviving one year.[2]

Psychiatric use

A number of recent case studies have indicated that riluzole may have clinical use in mood and anxiety disorders.[4] It has been shown to have antidepressant properties in the treatment of refractory depression[5] and act as an anxiolytic in obsessive-compulsive disorder[6] and in GAD.[7]

Alzheimer's disease

A clinical study on mice has shown Riluzole to compensate for harmful glutamate levels and promote dendritic spine clustering in hippocampal circuits implicated in memory and emotion. Therefore, the drug may act as an effective treatment for age-related memory loss and other forms of cognitive decline.[8] The effect of riluzole on glutamate dysfunction in humans with AD is unknown, however a clinical trial is taking place to investigate this.[9]

Research

A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223 is under development for the treatment of generalized anxiety disorder and mood disorders now by Biohaven Pharmaceuticals.[10]

Adverse effects

Very common (>10% frequency):[11]

Common (1-10% frequency):[12]

  • Headache
  • Dizziness
  • Drowsiness
  • Vomiting
  • Abdominal pain
  • Increased aminotransferases

Uncommon (0.1-1% frequency):[12]

Rare (<0.1% frequency):[12]

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]

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]

Mechanism

Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.[13][14] Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.[15] 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.[16][17] 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.[18][19] In addition to its role in accelerating glutamate clearance from the synapse, Riluzole may also prevent glutamate release from presynaptic terminals.[20] These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves.

Synthesis

Riluzole synthesis:[21][22] U.S. Patent 4,826,860

It can be prepared by the reaction of 4-(trifluoromethoxy)aniline with potassium thiocyanate presumably to form the thiourea in situ; addition of bromine to the reaction mixture probably leads to bromination of the ortho position. Displacement of halogen by sulfun forms the thiazole ring to afford riluzole.


See also

References

  1. 1 2 3 4 5 6 7 8 9 "PRODUCT INFORMATION RILUTEK® (riluzole) Tablets" (PDF). TGA eBusiness Services. sanofi-aventis australia pty ltd. 6 January 2009. Retrieved 18 February 2014.
  2. 1 2 Miller, RG; Mitchell, JD; Moore, DH (14 March 2012). "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)." (PDF). The Cochrane Database of Systematic Reviews 3: CD001447. doi:10.1002/14651858.CD001447.pub3. PMID 22419278.
  3. ↑ van Kan, HJ; Groeneveld, GJ; Kalmijn, S; Spieksma, M; van den Berg, LH; Guchelaar, HJ (March 2005). "Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis." (PDF). British Journal of Clinical Pharmacology 59 (3): 310–3. doi:10.1111/j.1365-2125.2004.02233.x. PMC 1884790. PMID 15752377. Cite uses deprecated parameter |coauthors= (help)
  4. ↑ 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. 2010 August; 20(4): 309–315.
  5. ↑ Zarate CA, Jr; Payne, JL; Quiroz, J; Sporn, J; Denicoff, KK; Luckenbaugh, D; Charney, DS; Manji, HK (January 2004). "An open-label trial of riluzole in patients with treatment-resistant major depression.". The American Journal of Psychiatry 161 (1): 171–4. doi:10.1176/appi.ajp.161.1.171. PMID 14702270.
  6. ↑ Coric, V; Taskiran, S; Pittenger, C; Wasylink, S; Mathalon, DH; Valentine, G; Saksa, J; Wu, YT; Gueorguieva, R; Sanacora, G; Malison, RT; Krystal, JH (1 September 2005). "Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial.". Biological Psychiatry 58 (5): 424–8. doi:10.1016/j.biopsych.2005.04.043. PMID 15993857.
  7. ↑ Mathew, SJ; Amiel, JM; Coplan, JD; Fitterling, HA; Sackeim, HA; Gorman, JM (December 2005). "Open-label trial of riluzole in generalized anxiety disorder.". The American Journal of Psychiatry 162 (12): 2379–81. doi:10.1176/appi.ajp.162.12.2379. PMID 16330605.
  8. ↑ "Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering". Proceedings of the National Academy of Sciences of the United States of America. Retrieved 18 January 2015.
  9. ↑ "Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimers Disease". rucares.org. Retrieved 12 March 2015.
  10. ↑ 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.
  11. ↑ "Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 February 2014.
  12. 1 2 3 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  13. ↑ 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.
  14. ↑ 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. PMID 20236142.
  15. ↑ 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.
  16. ↑ Wokke, J (21 September 1996). "Riluzole.". Lancet 348 (9030): 795–9. doi:10.1016/S0140-6736(96)03181-9. PMID 8813989.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Dunlop, J; Beal McIlvain, H; She, Y; Howland, DS (1 March 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. PMID 12629173.
  20. ↑ 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.
  21. ↑ L. M. Yagupol'skii, L. Z. Gandel'sman, Zh. Obshch. Khim. 33, 2301 (1963), C.A. 60, 692a (1964).
  22. ↑ J. Mizoule, EP 50551; idem, U.S. Patent 4,370,338 (1982, 1983 both to Pharmindustrie).

External links

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