Riluzole

drugbox
IUPAC_name = 6-(trifluoromethoxy)benzothiazol-2-amine




CAS_number = 1744-22-5
ATC_prefix = N07
ATC_suffix = XX02
ATC_supplemental =
PubChem = 5070
DrugBank = APRD00145
C=8 | H=5 | F=3 | N=2 | O=1 | S=1
molecular_weight = 234.199 g/mol
bioavailability =
protein_bound =
metabolism =
elimination_half-life =
pregnancy_category =
legal_status =
routes_of_administration = 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 two months.

It is marketed by Aventis Pharmaceuticals Inc with the brand name Rilutek.

Mechanism of action

Riluzole has several actions:
* Sodium channel blockade
* High-voltage calcium channel blockade
* N-methyl-D-aspartate (NMDA)/glutamate receptor antagonism
* Glutamate transporter activation

Riluzole preferentially blocks TTX-S sodium channels, which are associated with damaged neurons (Song "et al" 1997). This reduces influx of calcium ions and indirectly prevents stimulation of glutamate receptors. Together with direct glutamate receptor blockade, the effect of the neurotransmitter glutamate on motor neurons is greatly reduced.

However, the action of Riluzole on Glutamate receptors has been controversial, as no binding of the molecule has been shown on any known receptor (Wokke 1996). 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 potent glutamate uptake activator activity seems to mediate many of its effects (Azbill "et al" 2000; Dunlop "et al" 2003).

tudies of efficacy

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 (Miller RG "et al" 2005). 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.

Clinical use

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 50mg 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 (van Kan "et al" 2005).

A number of recent case studies have also indicated that riluzole may have clinical use in mood and anxiety disorders. It has been shown to have antidepressant properties in the treatment of refractory depression (Zarate "et al" 2004) and as an anxiolytic in Obsessive-compulsive disorder (Coric "et al" 2005) and in GAD (Mathew "et al" 2005).

References

* Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T. "Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels" J Pharmacol Exp Ther 1997;282:707-14. [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=9262334&db=pubmed&url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9262334 Fulltext] PMID 9262334.
* Wokke J. "Riluzole" Lancet. 1996 Sep 21;348(9030):795-9 [http://www.ncbi.nlm.nih.gov/pubmed/8813989?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]
* Azbill RD, Mu X, Springer JE. Brain Res. 2000 Jul 21;871(2):175-80 [http://www.ncbi.nlm.nih.gov/pubmed/10899284?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]
* Dunlop J, Beal McIlvain H, She Y, Howland DS. J Neurosci. 2003 Mar 1;23(5):1688-96
* Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, Saksa J, Wu YT, Gueorguieva R, Sanacora G, Malison RT, Krystal JH. "Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial." Biol Psychiatry 2005. PMID 15993857.
* Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM. "Riluzole in generalized anxiety disorder: an open-label trial." Am J Psychiatry 2005; 162:2379-2381.
* Miller RG, Mitchell JD, Lyon M, Moore DH. "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)." The Cochrane Database of Systematic Reviews 2002;2:CD001447. DOI [http://dx.doi.org/10.1002/14651858.CD001447 10.1002/14651858.CD001447] .
* van Kan HJ, Groeneveld GJ, Kalmijn S, Spieksma M, van den Berg LH, Guchelaar HJ. "Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis." Br J Clin Pharmacol 2005;59:310-3. PMID 15752377.
* Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK. "An open-label trial of riluzole in patients with treatment-resistant major depression." Am J Psychiatry 2004;161:171-4. [http://ajp.psychiatryonline.org/cgi/content/full/161/1/171 Fulltext] . PMID 14702270.

External links

* National Institute for Health and Clinical Excellence (NICE) guidelines for prescription of riluzole in the UK [http://www.nice.org.uk/page.aspx?o=14491]
* [http://www.alsinfo.com/index.jsp Riluzole] (manufacturer's website)
* [http://www.meds-help.com/riluzole/ Riluzole] (patient information)