Ibudilast Explained

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 it also has significant affinity for PDE3, PDE10A, PDE11[17] . Ibudilast has also been shown to act as an antagonist at the toll-like receptor 4 (TLR4).[18] This likely plays a large part in its effect, specifically its synergy with opioid drugs, its anti-inflammatory effect, and its own painkilling effect.[19] 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.[20] TLR4 antagonists theoretically reverse the increase in pain and inflammation caused by most TLR4 agonists, which includes alcohol & many opiate or opioid drugs.[21]

Notes and References

  1. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K . 6 . Preferential inhibition of human phosphodiesterase 4 by ibudilast . Life Sciences . 78 . 23 . 2663–2668 . May 2006 . 16313925 . 10.1016/j.lfs.2005.10.026 .
  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 . 837 . 1–2 . 203–212 . August 1999 . 10434004 . 10.1016/s0006-8993(99)01666-2 . 7910607 .
  3. Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ . 6 . The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family . European Journal of Pharmacology . 538 . 1–3 . 39–42 . May 2006 . 16674936 . 10.1016/j.ejphar.2006.02.053 .
  4. Web site: Ketas (ibudilast) Capsules 10 mg. Prescribing Information. Kyorin Pharmaceutical Co., Ltd.. 3 October 2016. 30 August 2018. https://web.archive.org/web/20180830210732/http://www.kyorin-pharm.co.jp/prodinfo/medicine/pdf/KETAS_Capsules.pdf. dead.
  5. Web site: Ketas (ibudilast) Eye Drops 0.01% Kisuri-no-Shiori (Drug Information Sheet). Senju Pharmaceutical Co., Ltd.. 3 October 2016.
  6. Web site: Cure for Meth Addiction?. HuffPost. 2013-04-03.
  7. Chand S, Gowen A, Savine M, Moore D, Clark A, Huynh W, Wu N, Odegaard K, Weyrich L, Bevins RA, Fox HS, Pendyala G, Yelamanchili SV . 6 . 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 . 34913274 . 10.1002/jev2.12177 . 8674191 .
  8. Cooper ZD, Johnson KW, Pavlicova M, Glass A, Vosburg SK, Sullivan MA, Manubay JM, Martinez DM, Jones JD, Saccone PA, Comer SD . 6 . The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers . Addiction Biology . 21 . 4 . 895–903 . July 2016 . 25975386 . 4644513 . 10.1111/adb.12261 .
  9. Bell RL, Lopez MF, Cui C, Egli M, Johnson KW, Franklin KM, Becker HC . Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence . Addiction Biology . 20 . 1 . 38–42 . January 2015 . 24215262 . 4017009 . 10.1111/adb.12106 .
  10. 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 . 19 . 3 . 215–225 . Fall 2001 . 11607039 . 10.1111/j.1527-3466.2001.tb00066.x .
  11. Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Suzumura A . Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia . Neuropharmacology . 46 . 3 . 404–411 . March 2004 . 14975696 . 10.1016/j.neuropharm.2003.09.009 . 29284554 .
  12. 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 . 45 . 4 . 305–311 . April 2002 . 12030794 . 10.1006/phrs.2002.0949 .
  13. 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 . 992 . 1 . 53–59 . November 2003 . 14604772 . 10.1016/j.brainres.2003.08.028 . 24917936 .
  14. 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 . 102 . 3 . 239–246 . May 2001 . 11369417 . 10.1016/s0049-3848(01)00258-4 .
  15. 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 . 6 . Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis . Multiple Sclerosis . 10 . 5 . 494–498 . October 2004 . 15471363 . 10.1191/1352458504ms1070oa . 34072005 .
  16. 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 . 16 . 7 . 935–950 . July 2007 . 17594181 . 10.1517/13543784.16.7.935 . 22321634 .
  17. Gibson L.C., Hastings S.F., McPhee I., Clayton r.A., Darroch C.E., Mackenzie A., Mackenzie F.L., Nagasawa M., Stevens P.A., Macken‑ zie S.J.: The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur. J. Pharmacol., 2006; 538: 39‑42
  18. Jia ZJ, Wu FX, Huang QH, Liu JM . [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 . 22776604 . 10.3881/j.issn.1000-503X.2012.02.013 .
  19. Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR . 6 . Evidence that opioids may have toll-like receptor 4 and MD-2 effects . Brain, Behavior, and Immunity . 24 . 1 . 83–95 . January 2010 . 19679181 . 2788078 . 10.1016/j.bbi.2009.08.004 .
  20. Jin SL, Ding SL, Lin SC . Phosphodiesterase 4 and its inhibitors in inflammatory diseases . Chang Gung Medical Journal . 35 . 3 . 197–210 . 2012-06-01 . 22735051 . 10.4103/2319-4170.106152 . free .
  21. Komatsu T, Sakurada S, Katsuyama S, Sanai K, Sakurada T . Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice . International Review of Neurobiology . 85 . 207–219 . 2009-01-01 . 19607972 . 10.1016/S0074-7742(09)85016-2 .

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