Ibudilast

Ibudilast
Clinical data
Trade names Ketas, Pinatos, Eyevinal
AHFS/Drugs.com International Drug Names
Routes of
administration		 By mouth (capsules),
topical (ophthalmic solution)
ATC code R03DC04 (WHO)
Legal status
Legal status
  • Rx-only (JP)
Identifiers
CAS Number 50847-11-5 YesY
PubChem (CID) 3671
IUPHAR/BPS 7399
DrugBank DB05266 N
ChemSpider 3543 N
UNII M0TTH61XC5 N
KEGG D01385 YesY
ChEMBL CHEMBL19449 N
ECHA InfoCard 100.164.881
Chemical and physical data
Formula C14H18N2O
Molar mass 230.31 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

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]

Ibudilast has bronchodilator, vasodilator[4] and neuroprotective effects,[5][6] and is mainly used in the treatment of asthma and stroke.[7] It inhibits platelet aggregation,[8] and may also be useful in the treatment of multiple sclerosis.[9]

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.[10]

It may have some use reducing methamphetamine[11] and alcohol[12] addiction.

Ibudilast is listed as being an antagonist at the toll-like receptor 4 (TLR4)[13] This likely play an immense part in its effect, specifically its synergy with opioid drugs, its anti-inflammatory effect, and its own painkilling effect.[14] 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.[15]

TLR4 antagonists theoretically reverse the increase in pain and inflammation caused by most TLR4 agonists, which include many opiate and opioid drugs.[16]

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.[17] Ibudilast ophthalmic solution is indicated for the treatment of allergic conjunctivitis and hay fever.[18]

References

  1. ↑ Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K. Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sciences. 2006 May 1;78(23):2663-8.
  2. ↑ Suzumura A, Ito A, Yoshikawa M, Sawada M. Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Research. 1999 Aug 7;837(1-2):203-12.
  3. ↑ Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. European Journal of Pharmacology. 2006 May 24;538(1-3):39-42.
  4. ↑ Kishi Y, Ohta S, Kasuya N, Sakita S, Ashikaga T, Isobe M. Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall. Cardiovascular Drug Reviews. 2001 Fall;19(3):215-25.
  5. ↑ Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Jacob Linder, Suzumura A. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology. 2004 Mar;46(3):404-11.
  6. ↑ Yoshioka M, Suda N, Mori K, Ueno K, Itoh Y, Togashi H, Matsumoto M. Effects of ibudilast on hippocampal long-term potentiation and passive avoidance responses in rats with transient cerebral ischemia. Pharmacological Research. 2002 Apr;45(4):305-11.
  7. ↑ Wakita H, Tomimoto H, Akiguchi I, Lin JX, Ihara M, Ohtani R, Shibata M. Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. Brain Research. 2003 Nov 28;992(1):53-9.
  8. ↑ Rile G, Yatomi Y, Qi R, Satoh K, Ozaki Y. Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells. Thrombosis Research. 2001 May 1;102(3):239-46.
  9. ↑ Feng J, Misu T, Fujihara K, Sakoda S, Nakatsuji Y, Fukaura H, Kikuchi S, Tashiro K, Suzumura A, Ishii N, Sugamura K, Nakashima I, Itoyama Y. Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. Multiple Sclerosis. 2004 Oct;10(5):494-8.
  10. ↑ Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opinion on Investigational Drugs. 2007 Jul;16(7):935-50.
  11. ↑ http://www.huffingtonpost.com/2013/04/03/meth-addiction-cure-ucla-ibudilast_n_2863126.html?utm_hp_ref=mostpopular#slide=more268305
  12. ↑ http://onlinelibrary.wiley.com/doi/10.1111/adb.12106/abstract
  13. ↑ Jia, Ze-jun; Wu, Fei-xiang; Huang, Qing-hai; Liu, Jian-min (2012-04-01). "[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. doi:10.3881/j.issn.1000-503X.2012.02.013. ISSN 1000-503X. PMID 22776604.
  14. ↑ Hutchinson, Mark R.; Zhang, Yingning; Shridhar, Mitesh; Evans, John H.; Buchanan, Madison M.; Zhao, Tina X.; Slivka, Peter F.; Coats, Benjamen D.; Rezvani, Niloofar (2010-01-01). "Evidence that opioids may have toll like receptor 4 and MD-2 effects". Brain, behavior, and immunity. 24 (1): 83–95. doi:10.1016/j.bbi.2009.08.004. ISSN 0889-1591. PMC 2788078Freely accessible. PMID 19679181.
  15. ↑ Jin, S.-L. Catherine; Ding, Shiau-Li; Lin, Shih-Chang (2012-06-01). "Phosphodiesterase 4 and its inhibitors in inflammatory diseases". Chang Gung Medical Journal. 35 (3): 197–210. ISSN 2309-835X. PMID 22735051.
  16. ↑ Komatsu, Takaaki; Sakurada, Shinobu; Katsuyama, Sou; Sanai, Kengo; Sakurada, Tsukasa (2009-01-01). "Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice". International Review of Neurobiology. 85: 207–219. doi:10.1016/S0074-7742(09)85016-2. ISSN 0074-7742. PMID 19607972.
  17. ↑ "Ketas (ibudilast) Capsules 10 mg. Prescribing Information" (PDF). Kyorin Pharmaceutical Co., Ltd. Retrieved 3 October 2016.
  18. ↑ "Ketas (ibudilast) Eye Drops 0.01% Kisuri-no-Shiori (Drug Information Sheet)". Senju Pharmaceutical Co., Ltd. Retrieved 3 October 2016.
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