Chemistry:Ibudilast

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Short description: Chemical compound
Ibudilast
Ibudilast.svg
Clinical data
Trade namesKetas, Pinatos, Eyevinal
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth (capsules),
topical (ophthalmic solution)
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC14H18N2O
Molar mass230.311 g·mol−1
3D model (JSmol)
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Ibudilast (development codes: AV-411 or MN-166) is an anti-inflammatory drug used mainly in Japan, which acts as a phosphodiesterase inhibitor, inhibiting the PDE4 subtype to the greatest extent,[1] but also showing significant inhibition of other PDE subtypes.[2][3]

Medical uses

In Japan , ibudilast oral capsules are approved for the treatment of asthma, and for improvement of dizziness secondary to chronic cerebral circulation impairment associated with sequelae of cerebral infarction.[4] Ibudilast ophthalmic solution is indicated for the treatment of allergic conjunctivitis and hay fever.[5]

It may have some use reducing methamphetamine,[6][7] opioid,[8] and alcohol[9] addiction.

Pharmacology

Ibudilast has bronchodilator, vasodilator[10] and neuroprotective effects,[11][12] and is mainly used in the treatment of asthma and stroke.[13] It inhibits platelet aggregation,[14] and may also be useful in the treatment of multiple sclerosis.[15]

Ibudilast crosses the blood–brain barrier and suppresses glial cell activation. This activity has been shown to make ibudilast useful in the treatment of neuropathic pain and it not only enhances analgesia produced by opioid drugs, but also reduces the development of tolerance.[16]

Pharmacodynamics

Ibudilast is principally a PDE4 inhibitor but has also been shown to act as an antagonist at the toll-like receptor 4 (TLR4).[17] This likely plays a large part in its effect, specifically its synergy with opioid drugs, its anti-inflammatory effect, and its own painkilling effect.[18] It is unknown if the PDE4-inhibiting properties potentiate the effects of TLR4 inactivation and/or vice versa, despite that some of their effects are shared, such as inflammation reducing properties.[19] TLR4 antagonists theoretically reverse the increase in pain and inflammation caused by most TLR4 agonists, which includes alcohol & many opiate or opioid drugs.[20]

References

  1. ↑ "Preferential inhibition of human phosphodiesterase 4 by ibudilast". Life Sciences 78 (23): 2663–2668. May 2006. doi:10.1016/j.lfs.2005.10.026. PMID 16313925. 
  2. ↑ "Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS". Brain Research 837 (1–2): 203–212. August 1999. doi:10.1016/s0006-8993(99)01666-2. PMID 10434004. 
  3. ↑ "The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family". European Journal of Pharmacology 538 (1–3): 39–42. May 2006. doi:10.1016/j.ejphar.2006.02.053. PMID 16674936. 
  4. ↑ "Ketas (ibudilast) Capsules 10 mg. Prescribing Information". Kyorin Pharmaceutical Co., Ltd.. http://www.kyorin-pharm.co.jp/prodinfo/medicine/pdf/KETAS_Capsules.pdf. 
  5. ↑ "Ketas (ibudilast) Eye Drops 0.01% Kisuri-no-Shiori (Drug Information Sheet)". Senju Pharmaceutical Co., Ltd.. http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1744. 
  6. ↑ "Cure for Meth Addiction?". 2013-04-03. http://www.huffingtonpost.com/2013/04/03/meth-addiction-cure-ucla-ibudilast_n_2863126.html. 
  7. ↑ "A comprehensive study to delineate the role of an extracellular vesicle-associated microRNA-29a in chronic methamphetamine use disorder". Journal of Extracellular Vesicles 10 (14): e12177. December 2021. doi:10.1002/jev2.12177. PMID 34913274. 
  8. ↑ "The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers". Addiction Biology 21 (4): 895–903. July 2016. doi:10.1111/adb.12261. PMID 25975386. 
  9. ↑ "Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence". Addiction Biology 20 (1): 38–42. January 2015. doi:10.1111/adb.12106. PMID 24215262. 
  10. ↑ "Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall". Cardiovascular Drug Reviews 19 (3): 215–225. Fall 2001. doi:10.1111/j.1527-3466.2001.tb00066.x. PMID 11607039. 
  11. ↑ "Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia". Neuropharmacology 46 (3): 404–411. March 2004. doi:10.1016/j.neuropharm.2003.09.009. PMID 14975696. 
  12. ↑ "Effects of ibudilast on hippocampal long-term potentiation and passive avoidance responses in rats with transient cerebral ischemia". Pharmacological Research 45 (4): 305–311. April 2002. doi:10.1006/phrs.2002.0949. PMID 12030794. 
  13. ↑ "Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat". Brain Research 992 (1): 53–59. November 2003. doi:10.1016/j.brainres.2003.08.028. PMID 14604772. 
  14. ↑ "Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells". Thrombosis Research 102 (3): 239–246. May 2001. doi:10.1016/s0049-3848(01)00258-4. PMID 11369417. 
  15. ↑ "Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis". Multiple Sclerosis 10 (5): 494–498. October 2004. doi:10.1191/1352458504ms1070oa. PMID 15471363. 
  16. ↑ "Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes". Expert Opinion on Investigational Drugs 16 (7): 935–950. July 2007. doi:10.1517/13543784.16.7.935. PMID 17594181. 
  17. ↑ "[Toll-like receptor 4: the potential therapeutic target for neuropathic pain]". Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae 34 (2): 168–173. April 2012. doi:10.3881/j.issn.1000-503X.2012.02.013. PMID 22776604. 
  18. ↑ "Evidence that opioids may have toll-like receptor 4 and MD-2 effects". Brain, Behavior, and Immunity 24 (1): 83–95. January 2010. doi:10.1016/j.bbi.2009.08.004. PMID 19679181. 
  19. ↑ "Phosphodiesterase 4 and its inhibitors in inflammatory diseases". Chang Gung Medical Journal 35 (3): 197–210. 2012-06-01. doi:10.4103/2319-4170.106152. PMID 22735051. 
  20. ↑ "Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice". International Review of Neurobiology 85: 207–219. 2009-01-01. doi:10.1016/S0074-7742(09)85016-2. PMID 19607972. 



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