Riluzole

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Riluzole
Riluzole2DACS.svg
Riluzole ball-and-stick model.png
Systematic (IUPAC) name
6-(trifluoromethoxy)benzothiazol-2-amine
Clinical data
Trade names Rilutek
AHFS/Drugs.com monograph
MedlinePlus a696013
Licence data US FDA:link
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 (WHO)
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
Molecular mass 234.199 g/mol
  • FC(F)(F)Oc1ccc2nc(sc2c1)N
  • InChI=1S/C8H5F3N2OS/c9-8(10,11)14-4-1-2-5-6(3-4)15-7(12)13-5/h1-3H,(H2,12,13) YesY
  • Key:FTALBRSUTCGOEG-UHFFFAOYSA-N YesY
  (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][1]

Adverse effects

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

  • Nausea
  • Weakness
  • Decreased lung function

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

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  • 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. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 12.2 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  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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