Riluzole

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Riluzole
Riluzole2DACS.svg
Riluzole3DanBS.gif
Systematic (IUPAC) name
6-(trifluoromethoxy)benzothiazol-2-amine
Clinical data
Trade namesRilutek
AHFS/Drugs.commonograph
MedlinePlusa696013
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) Rx Only (US)
RoutesOral
Pharmacokinetic data
Bioavailability60±18%[1]
Protein binding97%[1]
MetabolismHepatic (CYP1A2)[1]
Half-life9-15 hours[1]
ExcretionUrine (90%)[1]
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
Riluzole2DACS.svg
Riluzole3DanBS.gif
Systematic (IUPAC) name
6-(trifluoromethoxy)benzothiazol-2-amine
Clinical data
Trade namesRilutek
AHFS/Drugs.commonograph
MedlinePlusa696013
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) Rx Only (US)
RoutesOral
Pharmacokinetic data
Bioavailability60±18%[1]
Protein binding97%[1]
MetabolismHepatic (CYP1A2)[1]
Half-life9-15 hours[1]
ExcretionUrine (90%)[1]
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 (Rilutek) is a drug used to treat amyotrophic lateral sclerosis marketed by Sanofi-Aventis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately two to three months.[2]

Medical use[edit]

Amyotrophic lateral sclerosis[edit]

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[edit]

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]

Adverse effects[edit]

Very common (>10% frequency):[8]

Common (1-10% frequency):[9]

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

Uncommon (0.1-1% frequency):[9]

Rare (<0.1% frequency):[9]

Contraindications[edit]

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

Interactions[edit]

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

Overdose[edit]

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

Mechanism[edit]

Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.[10][11] However, the action of riluzole on glutamate receptors has been controversial, as no binding of the molecule has been shown on any known receptor.[12] 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.[13][14] In addition to its role in accelerating glutamate clearance from the synapse, Riluzole may also prevent glutamate release from presynaptic terminals.[15] These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves.

References[edit]

  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. doi:10.1002/14651858.CD001447.pub3. PMID 22419278. 
  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. doi:10.1111/j.1365-2125.2004.02233.x. PMC 1884790. PMID 15752377. 
  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. doi:10.1176/appi.ajp.161.1.171. PMID 14702270. 
  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. doi:10.1016/j.biopsych.2005.04.043. PMID 15993857. 
  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. doi:10.1176/appi.ajp.162.12.2379. PMID 16330605. 
  8. ^ "Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 February 2014. 
  9. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  10. ^ 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. PMID 9262334. 
  11. ^ 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. doi:10.1111/j.1755-5949.2009.00116.x. PMID 20236142. 
  12. ^ Wokke, J (21 September 1996). "Riluzole.". Lancet 348 (9030): 795–9. doi:10.1016/S0140-6736(96)03181-9. PMID 8813989. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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[edit]