Riluzole

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Riluzole
Systematic (IUPAC) name
6-(trifluoromethoxy)benzothiazol-2-amine
Clinical data
Trade namesRilutek®
AHFS/Drugs.commonograph
MedlinePlusa696013
Pregnancy cat.C - Risk Cannot Be Ruled Out [1]
Legal statusRx Only
Pharmacokinetic data
Half-life12 Hours [2]
Identifiers
CAS number1744-22-5 YesY
ATC codeN07XX02
PubChemCID 5070
IUPHAR ligand2326
DrugBankDB00740
ChemSpider4892 YesY
UNII7LJ087RS6F YesY
KEGGD00775 YesY
ChEMBLCHEMBL744 YesY
Chemical data
FormulaC8H5F3N2OS 
Mol. mass234.199 g/mol
 YesY (what is this?)  (verify)
 
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Riluzole
Systematic (IUPAC) name
6-(trifluoromethoxy)benzothiazol-2-amine
Clinical data
Trade namesRilutek®
AHFS/Drugs.commonograph
MedlinePlusa696013
Pregnancy cat.C - Risk Cannot Be Ruled Out [1]
Legal statusRx Only
Pharmacokinetic data
Half-life12 Hours [2]
Identifiers
CAS number1744-22-5 YesY
ATC codeN07XX02
PubChemCID 5070
IUPHAR ligand2326
DrugBankDB00740
ChemSpider4892 YesY
UNII7LJ087RS6F YesY
KEGGD00775 YesY
ChEMBLCHEMBL744 YesY
Chemical data
FormulaC8H5F3N2OS 
Mol. mass234.199 g/mol
 YesY (what is this?)  (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[edit]

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[edit]

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[edit]

ALS[edit]

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[edit]

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[edit]

  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. 
  4. ^ Wokke J (September 1996). "Riluzole". Lancet 348 (9030): 795–9. doi:10.1016/S0140-6736(96)03181-9. PMID 8813989. 
  5. ^ 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. 
  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. 
  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 (March 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. 
  9. ^ http://products.sanofi.us/rilutek/rilutek.html RILUTEK Prescribing Information
  10. ^ Miller RG, Mitchell JD, Lyon M, Moore DH (2007). "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)". In Miller, Robert G. Cochrane Database Syst Rev (1): CD001447. doi:10.1002/14651858.CD001447.pub2. PMID 17253460. 
  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. (January 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. 
  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 (September 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. 
  14. ^ Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM (December 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. 

External links[edit]