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Riluzole

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Riluzole
Clinical data
Trade namesRilutek®
AHFS/Drugs.comMonograph
MedlinePlusa696013
Pregnancy
category
  • C - Risk Cannot Be Ruled Out [1]
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life12 Hours [2]
Identifiers
  • 6-(trifluoromethoxy)benzothiazol-2-amine
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)
  • 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) checkY
  • Key:FTALBRSUTCGOEG-UHFFFAOYSA-N checkY
  (verify)

Riluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months.[citation needed]

It is marketed by Sanofi-Aventis with the brand name Rilutek.

Mechanism

Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.[3] This reduces influx of calcium ions and indirectly prevents stimulation of glutamate receptors.

However, the action of riluzole on glutamate receptors has been controversial, as no binding of the molecule has been shown on any known receptor.[4] In addition, as its antiglutamate 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.[5] [6]

Effects

In vitro, riluzole protects cultured neurons from anoxic damage, from the toxic effects of glutamic-acid-uptake inhibitors, and from the toxic factor in the CSF of patients with amyotrophic lateral sclerosis.[7]

In vivo, riluzole has neuroprotective, anticonvulsant, and sedative properties. In a rodent model of transient global cerebral ischemia, a complete suppression of the ischemia-evoked surge in glutamic acid release has been observed.[7]

Clinical use

ALS

While riluzole has been proven to slow down ALS, patients do not report any subjective improvement. Approximately 10% of patients experience side effects such as nausea and fatigue which lead them to discontinue treatment. Safety monitoring includes regular liver function tests and people with liver disease such as hepatitis should be monitored especially carefully.

In the UK riluzole has been available through the NHS since 1997 at a standard dosage of 50 mg twice daily. There has been some evidence to show that higher doses might produce more significant improvements in ALS patients but at £5 a tablet it is at risk of being prohibitively expensive given the modest benefit to patients. One study in the Netherlands found that riluzole is metabolised differently by males and females, and its levels in plasma are decreased in patients who smoke cigarettes or take omeprazole.[8] [9]

A Cochrane Library review states a 9% gain in the probability of surviving one year. In secondary analyses of survival at separate time points, there was a significant survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months.[10] There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. There were no data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients.

Antidepressant properties

A number of recent case studies have indicated that riluzole may have clinical use in mood and anxiety disorders.[11] It has been shown to have antidepressant properties in the treatment of refractory depression[12] and act as an anxiolytic in obsessive-compulsive disorder[13] and in GAD.[14]

References

  1. ^ http://www.drugs.com/pro/rilutek.html
  2. ^ http://www.drugs.com/pro/rilutek.html
  3. ^ Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T (1 August 1997). "Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels". J Pharmacol Exp Ther. 282 (2): 707–14. PMID 9262334.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Wokke J (1996). "Riluzole". Lancet. 348 (9030): 795–9. doi:10.1016/S0140-6736(96)03181-9. PMID 8813989. {{cite journal}}: Unknown parameter |month= ignored (help)
  5. ^ Azbill RD, Mu X, Springer JE (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b The pharmacology and mechanism of action of riluzole. http://www.ncbi.nlm.nih.gov/pubmed/8959995
  8. ^ van Kan HJ, Groeneveld GJ, Kalmijn S, Spieksma M, van den Berg LH, Guchelaar HJ (2005). "Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis". Br J Clin Pharmacol. 59 (3): 310–3. doi:10.1111/j.1365-2125.2004.02233.x. PMC 1884790. PMID 15752377. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ http://products.sanofi.us/rilutek/rilutek.html RILUTEK Prescribing Information
  10. ^ Miller RG, Mitchell JD, Lyon M, Moore DH (2007). Miller, Robert G (ed.). "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)". Cochrane Database Syst Rev (1): CD001447. doi:10.1002/14651858.CD001447.pub2. PMID 17253460.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ 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.
  12. ^ Zarate CA, Payne JL, Quiroz J; et al. (2004). "An open-label trial of riluzole in patients with treatment-resistant major depression". Am J Psychiatry. 161 (1): 171–4. doi:10.1176/appi.ajp.161.1.171. PMID 14702270. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Coric V, Taskiran S, Pittenger C, et al. currently a study is underway at the NIH in Bethesda using riluzol for the treatment of OCD by Dr Grant (2005). "Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial". Biol Psychiatry. 58 (5): 424–8. doi:10.1016/j.biopsych.2005.04.043. PMID 15993857. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM (2005). "Open-label trial of riluzole in generalized anxiety disorder". Am J Psychiatry. 162 (12): 2379–81. doi:10.1176/appi.ajp.162.12.2379. PMID 16330605. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

External links

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