|Trade names||Rilutek, Teglutik|
|ATC code||N07XX02 (WHO)|
|Biological half-life||9-15 hours|
|Chemical and physical data|
|Molar mass||234.199 g/mol|
|3D model (Jmol)||Interactive image|
Riluzole (Rilutek, Teglutik) is a drug used to treat amyotrophic lateral sclerosis. These are marketed by Sanofi Pharmaceuticals and Martindale Pharma respectively. Riluzole delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately two to three months.
Riluzole is available in tablet (Rilutek, riluzole) and liquid (Teglutik) form. The liquid formulation may be more suitable for patients with swallowing difficulties.
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. A Cochrane Library review states a 9% gain in the probability of surviving one year.
A number of recent case studies have 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 and act as an anxiolytic in obsessive-compulsive disorder and in GAD.
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. The effect of riluzole on glutamate dysfunction in humans with AD is unknown, however a clinical trial is taking place to investigate this.
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.
- Very common (>10% frequency): nausea; weakness; decreased lung function
- Common (1-10% frequency): headache; dizziness; drowsiness; vomiting; abdominal pain; increased aminotransferases
- Uncommon (0.1-1% frequency): pancreatitis; interstitial lung disease
- Rare (<0.1% frequency): neutropenia; allergic reaction (including angiooedema, anaphylactoid reaction)
Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.
Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and methemoglobinemia. Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.
Mechanism of Action
Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons. Riluzole has also been reported to directly inhibit the kainate and NMDA receptors. 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. 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. In addition to its role in accelerating glutamate clearance from the synapse, Riluzole may also prevent glutamate release from presynaptic terminals. These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves.
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 sulfur forms the thiazole ring to afford riluzole.
- "PRODUCT INFORMATION RILUTEK® (riluzole) Tablets" (PDF). TGA eBusiness Services. sanofi-aventis australia pty ltd. 6 January 2009. Retrieved 18 February 2014.
- Miller, RG; Mitchell, JD; Moore, DH (14 March 2012). "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)." (PDF). The Cochrane Database of Systematic Reviews. 3: CD001447. doi:10.1002/14651858.CD001447.pub3. PMID 22419278.
- 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." (PDF). British Journal of Clinical Pharmacology. 59 (3): 310–3. doi:10.1111/j.1365-2125.2004.02233.x. PMC . PMID 15752377.
- 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.
- Zarate CA, Jr; Payne, JL; Quiroz, J; Sporn, J; Denicoff, KK; Luckenbaugh, D; Charney, DS; Manji, HK (January 2004). "An open-label trial of riluzole in patients with treatment-resistant major depression.". The American Journal of Psychiatry. 161 (1): 171–4. doi:10.1176/appi.ajp.161.1.171. PMID 14702270.
- Coric, V; Taskiran, S; Pittenger, C; Wasylink, S; Mathalon, DH; Valentine, G; Saksa, J; Wu, YT; Gueorguieva, R; Sanacora, G; Malison, RT; Krystal, JH (1 September 2005). "Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial.". Biological Psychiatry. 58 (5): 424–8. doi:10.1016/j.biopsych.2005.04.043. PMID 15993857.
- Mathew, SJ; Amiel, JM; Coplan, JD; Fitterling, HA; Sackeim, HA; Gorman, JM (December 2005). "Open-label trial of riluzole in generalized anxiety disorder.". The American Journal of Psychiatry. 162 (12): 2379–81. doi:10.1176/appi.ajp.162.12.2379. PMID 16330605.
- "Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering". Proceedings of the National Academy of Sciences of the United States of America. Retrieved 18 January 2015.
- "Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimers Disease". rucares.org. Retrieved 12 March 2015.
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- 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.
- Wang, S.-J (January 2004). "Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes)". Neuroscience. 125 (1): 191–201. doi:10.1016/j.neuroscience.2004.01.019.
- L. M. Yagupol'skii, L. Z. Gandel'sman, Zh. Obshch. Khim. 33, 2301 (1963), C.A. 60, 692a (1964).
- J. Mizoule, EP 50551 ; idem, U.S. Patent 4,370,338 (1982, 1983 both to Pharmindustrie).
- National Institute for Health and Clinical Excellence (NICE) guidelines for prescription of riluzole in the UK 
- Manufacturer's website