For the treatment of amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease)
Riluzole, a member of the benzothiazole class, is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole extends survival and/or time to tracheostomy. It is also neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. The etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS the enzyme superoxide dismutase has been found to be defective.
Mode of Action:
The mode of action of riluzole is unknown. Its pharmacological properties include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release (activation of glutamate reuptake), 2) inactivation of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors.
Riluzole is extensively metabolized to six major and a number of minor metabolites, which have not all been identified to date. Metabolism is mostly hepatic, consisting of cytochrome P450_dependent hydroxylation and glucuronidation. CYP1A2 is the primary isozyme involved in N-hydroxylation; CYP2D6, CYP2C19, CYP3A4, and CYP2E1 are considered unlikely to contribute significantly to riluzole metabolism in humans.
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 Aug;282(2):707-14. Pubmed 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 Sep 1;58(5):424-8. Pubmed 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 Mar;59(3):310-3. Pubmed 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 Jan;161(1):171-4. Pubmed Mathew SJ, Manji HK, Charney DS: Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. Epub 2008 Jan 2. Pubmed Lamanauskas N, Nistri A: Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci. 2008 May;27(10):2501-14. Epub 2008 Apr 26. Pubmed
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