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Riluzole

Riluzole
Systematic (IUPAC) name
6-(trifluoromethoxy)benzothiazol-2-amine
Clinical data
Trade names Rilutek
AHFS/Drugs.com
MedlinePlus
Licence data US FDA:
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 60±18%[1]
Protein binding 97%[1]
Metabolism Hepatic (CYP1A2)[1]
Biological half-life 9-15 hours[1]
Excretion Urine (90%)[1]
Identifiers
CAS Registry Number  Y
ATC code N07
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEMBL  Y
Chemical data
Formula C8H5F3N2OS
Molecular mass 234.199 g/mol
 Y   

Riluzole (Rilutek) is a drug used to treat amyotrophic lateral sclerosis and is marketed by Sanofi Pharmaceuticals. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately two to three months.[2]

Contents

  • Medical use 1
    • Amyotrophic lateral sclerosis 1.1
    • Psychiatric use 1.2
    • Alzheimer's disease 1.3
  • Adverse effects 2
    • Contraindications 2.1
    • Interactions 2.2
    • Overdose 2.3
  • Mechanism 3
  • Synthesis 4
  • See also 5
  • References 6
  • External links 7

Medical use

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.[3] A Cochrane Library review states a 9% gain in the probability of surviving one year.[2]

Psychiatric use

A number of recent case studies have indicated that riluzole may have clinical use in mood and anxiety disorders.[4] It has been shown to have antidepressant properties in the treatment of refractory depression[5] and act as an anxiolytic in obsessive-compulsive disorder[6] and in GAD.[7]

Alzheimer's disease

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.[8] The effect of riluzole on glutamate dysfunction in humans with AD is unknown, however a clinical trial is taking place to investigate this.[9]

Adverse effects

Very common (>10% frequency):[10]

  • Nausea
  • Weakness
  • Decreased lung function

Common (1-10% frequency):[11]

  • Headache
  • Dizziness
  • Drowsiness
  • Vomiting
  • Abdominal pain
  • Increased aminotransferases

Uncommon (0.1-1% frequency):[11]

Rare (<0.1% frequency):[11]

Contraindications

Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.[1]

Interactions

CYP1A2 substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism.[1]

Overdose

Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and methemoglobinemia.[1] Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.[1]

Mechanism

Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.[12][13] Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.[14] 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.[15][16] 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.[17][18] In addition to its role in accelerating glutamate clearance from the synapse, Riluzole may also prevent glutamate release from presynaptic terminals.[19] These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves.

Synthesis

Riluzole synthesis: U.S. Patent 4,826,860

See also

References

  1. ^ a b c d e f g h i "PRODUCT INFORMATION RILUTEK® (riluzole) Tablets" (PDF). TGA eBusiness Services. sanofi-aventis australia pty ltd. 6 January 2009. Retrieved 18 February 2014. 
  2. ^ a b 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.  
  3. ^ 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.  
  4. ^ 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.
  5. ^ 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.  
  6. ^ 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.  
  7. ^ 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.  
  8. ^ "Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering".  
  9. ^ "Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimers Disease". rucares.org. Retrieved 12 March 2015. 
  10. ^ "Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 February 2014. 
  11. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.  
  12. ^ Song, JH; Huang, CS; Nagata, K; Yeh, JZ; Narahashi, T (August 1997). "Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels." (PDF). The Journal of Pharmacology and Experimental Therapeutics 282 (2): 707–14.  
  13. ^ Bellingham, MC (February 2011). "A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade?". CNS Neuroscience & Therapeutics 17 (1): 4–31.  
  14. ^ Debono MW, Le Guern J, Canton T, Doble A, Pradier L (April 1993). "Inhibition by riluzole of electrophysiological responses mediated by rat kainate and NMDA receptors expressed in Xenopus oocytes". Eur. J. Pharmacol. 235 (2-3): 283–9.  
  15. ^ Wokke, J (21 September 1996). "Riluzole.". Lancet 348 (9030): 795–9.  
  16. ^ Kretschmer BD, Kratzer U, Schmidt WJ (August 1998). "Riluzole, a glutamate release inhibitor, and motor behavior". Naunyn Schmiedebergs Arch. Pharmacol. 358 (2): 181–90.  
  17. ^ 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.  
  18. ^ 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.  
  19. ^ 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.  

External links

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