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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/06/19 16:00:34」(JST)
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| Clinical data | |
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| Trade names | Rilutek, Teglutik |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a696013 |
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| Bioavailability | 60±18%[1] |
| Protein binding | 97%[1] |
| Metabolism | Hepatic (CYP1A2)[1] |
| Biological half-life | 9-15 hours[1] |
| Excretion | Urine (90%)[1] |
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| ECHA InfoCard | 100.124.754 |
| Chemical and physical data | |
| Formula | C8H5F3N2OS |
| Molar mass | 234.199 g/mol |
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Riluzole (marketed as Rilutek and Teglutik) is a drug used to treat amyotrophic lateral sclerosis. Riluzole delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately two to three months.[2]
Riluzole is available in a tablet and liquid form. The liquid formulation may be more suitable for patients with swallowing difficulties.
Contents
- 1 Medical use
- 1.1 Amyotrophic lateral sclerosis
- 1.2 Psychiatric use
- 1.3 Research
- 2 Adverse effects
- 2.1 Overdose
- 3 Contraindications
- 3.1 Interactions
- 4 Mechanism of action
- 5 Synthesis
- 6 See also
- 7 References
- 8 External links
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 generalized anxiety disorder.[7]
Research
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 Alzheimer's disease is unknown; however, a clinical trial is taking place to investigate this.[9]
Riluzole was also studied as a treatment for spinal muscular atrophy;[10] however, efficacy was not observed.
A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223[11] is under development for the treatment of generalized anxiety disorder and mood disorders now by Biohaven Pharmaceuticals.[12]
A prodrug of riluzole, designated as BHV-4157, is under investigation for spinocerebellar ataxia.[13][14]
Adverse effects
- Very common (>10% frequency):[15] nausea; weakness; decreased lung function
- Common (1-10% frequency):[16] headache; dizziness; drowsiness; vomiting; abdominal pain; increased aminotransferases
- Uncommon (0.1-1% frequency):[16] pancreatitis; interstitial lung disease
- Rare (<0.1% frequency):[16] neutropenia; allergic reaction (including angiooedema, anaphylactoid reaction)
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]
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]
Mechanism of action
Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.[17][18] Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.[19] 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.[20][21] 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.[22][23] In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals.[24] These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves.
Synthesis
Riluzole can be prepared beginning with the reaction of 4-(trifluoromethoxy)aniline with potassium thiocyanate followed by reaction with bromine.[25][26][27] Displacement of bromine atom by sulfur forms the thiazole ring to afford riluzole.
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Riluzole synthesis
See also
- Pramipexole
References
- ^ 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.
- ^ 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 (3): CD001447. PMID 22419278. doi:10.1002/14651858.CD001447.pub3.
- ^ 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. PMC 1884790 . PMID 15752377. doi:10.1111/j.1365-2125.2004.02233.x.
- ^ Grant, P; Song, JY; Swedo, SE (2010). "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. 20 (4): 309–15. PMC 2958461 . PMID 20807069. doi:10.1089/cap.2010.0009.
- ^ 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. PMID 14702270. doi:10.1176/appi.ajp.161.1.171.
- ^ 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. PMID 15993857. doi:10.1016/j.biopsych.2005.04.043.
- ^ 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. PMID 16330605. doi:10.1176/appi.ajp.162.12.2379.
- ^ Pereira, Ana C.; Lambert, Hilary K.; Grossman, Yael S.; Dumitriu, Dani; Waldman, Rachel; Jannetty, Sophia K.; Calakos, Katina; Janssen, William G.; McEwen, Bruce S.; Morrison, John H. (2014). "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. 111 (52): 18733–18738. Bibcode:2014PNAS..11118733P. doi:10.1073/pnas.1421285111. Retrieved 18 January 2015.
- ^ "Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimers Disease". rucares.org. Retrieved 12 March 2015.
- ^ "Study to Evaluate the Efficacy of Riluzole in Children and Young Adults With Spinal Muscular Atrophy (SMA)". ClinicalTrials.gov. Retrieved 2016-05-20.
- ^ "BHV 0223 - AdisInsight". Adisinsight.springer.com. Retrieved 2016-05-20.
- ^ Harris, Elaine (2015). "Industry update: the latest developments in therapeutic delivery". Therapeutic Delivery. 6 (6): 647–652. ISSN 2041-5990. doi:10.4155/tde.15.44.
- ^ "Biohaven Receives FDA Investigational New Drug Application (IND) Approval for BHV-4157". Yahoo News. July 5, 2016.
- ^ "The Fox Chase Chemical Diversity Center Announces that the FDA has Completed its Review of FC-4157 (also known as BHV-4157) Investigational New Drug Application (IND) Filed on May 31, 2016 by Biohaven Pharmaceutical Holding Company Ltd". Fox Chase Chemical Diversity Center. July 5, 2016.
- ^ "Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 February 2014.
- ^ 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.
- ^ 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.
- ^ 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. PMID 20236142. doi:10.1111/j.1755-5949.2009.00116.x.
- ^ 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. PMID 7685290. doi:10.1016/0014-2999(93)90147-a.
- ^ Wokke, J (21 September 1996). "Riluzole.". Lancet. 348 (9030): 795–9. PMID 8813989. doi:10.1016/S0140-6736(96)03181-9.
- ^ Kretschmer BD, Kratzer U, Schmidt WJ (August 1998). "Riluzole, a glutamate release inhibitor, and motor behavior". Naunyn Schmiedebergs Arch. Pharmacol. 358 (2): 181–90. PMID 9750003. doi:10.1007/pl00005241.
- ^ 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. PMID 10899284. doi:10.1016/S0006-8993(00)02430-6.
- ^ 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. PMID 15051158. 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).
- ^ U.S. Patent 4,826,860
External links
- National Institute for Health and Clinical Excellence (NICE) guidelines for prescription of riluzole in the UK [1]
- Manufacturer's website [2]
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UpToDate Contents
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- 1. 筋萎縮性側索硬化症の病態修飾療法 disease modifying treatment of amyotrophic lateral sclerosis
- 2. 筋萎縮性側索硬化症の症状に基づくマネージメント symptom based management of amyotrophic lateral sclerosis
- 3. ハンチントン病：管理 huntington disease management
- 4. パーキンソン病に対する神経保護療法 neuroprotective therapy for parkinson disease
- 5. 小児および思春期における強迫性障害の治療 treatment of obsessive compulsive disorder in children and adolescents
English Journal
- Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial.
- UKMND-LiCALS Study Group.AbstractBACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS.
- Lancet neurology.Lancet Neurol.2013 Apr;12(4):339-45. doi: 10.1016/S1474-4422(13)70037-1. Epub 2013 Feb 27.
- BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS.METHODS: The li
- PMID 23453347
- Riluzole: what it does to spinal and brainstem neurons and how it does it.
- Cifra A, Mazzone GL, Nistri A.Source1Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy.
- The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.Neuroscientist.2013 Apr;19(2):137-44. doi: 10.1177/1073858412444932. Epub 2012 May 16.
- Amyotrophic lateral sclerosis (Lou Gehrig's disease) is a devastating neurodegenerative disorder for which the only licensed treatment is riluzole. Although riluzole clinical efficacy is rather limited, its use has important implications for identifying those parameters that might improve its clinic
- PMID 22596264
Japanese Journal
- Riluzole and Prognostic Factors in Amyotrophic Lateral Sclerosis Long-term and Short-term Survival: A Population-Based Study of 1149 Cases in Taiwan
- Lee Charles Tzu-Chi,Chiu Yi-Wen,Wang Kai-Chen,Hwang Chi-Shin,Lin Kuan-Hsiang,Lee I-Ta,Tsai Ching-Piao
- Journal of Epidemiology, 2013
- … Medical interventions, including noninvasive positive pressure ventilation (NIPPV), tracheotomy, gastrostomy, and riluzole, were included in time-dependent survival analysis.<BR>Results: Of the 1149 ALS patients, 438 (38.12%) died during follow-up. … Factors significantly associated with increased mortality were male sex, advanced age, rural residence, lower economic status, no tracheotomy, and no riluzole treatment. …
- NAID 130001913531
- Riluzole-induced Lung Injury in Two Patients with Amyotrophic Lateral Sclerosis
- Kakuta Takuya,Hirata Hirokuni,Soda Sayo,Shiobara Taichi,Watanabe Mineaki,Tatewaki Masamitsu,Fukushima Fumiya,Chibana Kazuyuki,Sugiyama Kumiya,Arima Masafumi,Koichi Honma,Fukuda Takeshi,Fukushima Yasutsugu
- Internal Medicine 51(14), 1903-1907, 2012
- … Riluzole has recently been proven as the first effective drug for the treatment of amyotrophic lateral sclerosis (ALS). … We report two rare cases of lung injury caused by riluzole therapy in patients with ALS. … A drug lymphocyte stimulation test (DLST) of peripheral blood or bronchoalveolar lavage cells was positive for riluzole. … To the best of our knowledge, this is the first report of riluzole-induced lung injury with positive DLST results. …
- NAID 130002062227
Related Links
- Riluzole: learn about side effects, dosage, special precautions, and more on MedlinePlus ... Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to riluzole.
- Before using riluzole: Some medical conditions may interact with riluzole. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you: if you are pregnant, planning to become ...
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