Diclofenac Dose Response Study

Summary

The development of efficacious medications for AUD remains a high research priority with current emphases on identifying novel molecular targets and efficiently screening new compounds. Pharmacological modulation of the kynurenine pathway (KP) represents a promising novel target for AUD. The KP is a complex enzymatic cascade with each step producing biologically active metabolites that are critically involved in diverse physiological and pathological processes. Chronic alcohol exposure produces dysregulation of the KP, particularly as evidenced by decreased levels of the neuroprotective metabolite kynurenic acid (KYNA) and increased levels of the neurotoxic metabolite quinolinic acid (QUIN). This metabolic shift is associated with various alcohol-related pathologies in animals and humans. Thus, a medication that targets the KP to restore KYNA and attenuate QUIN levels may be an effective treatment for AUD. The enzyme kynurenine 3- monooxygenase (KMO) is a major gatekeeper of the KP and resultant KYNA levels. KMO inhibition shifts the KP towards KYNA production in brain and away from QUIN production. Critically, KMO inhibition in rodents, through its increase in brain KYNA levels, decreases alcohol self-administration, preference, cue-reactivity, and relapse behaviors. However, KMO-inhibitors have not been tested in humans because of presumed lack of availability. Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug that was recently discovered to inhibit KMO activity. Consistent with KMO inhibition, diclofenac increases KYNA levels in the brain and periphery of rodents. However, it remains unknown whether diclofenac increases KYNA levels and affects alcohol-related behaviors in humans at approved, safe dosages. Investigators propose to conduct a human laboratory pilot study to test whether diclofenac can increase KYNA in individuals with AUD, and if so, which of 3 doses (50, 75, or 100 mg) most effectively increases KYNA. Individuals with AUD (n = 24) will complete four sessions where they receive diclofenac (50, 75, or 100 mg) or placebo. Investigators will examine increases in KYA levels and will also assess QUIN levels, alcohol craving, and negative mood.

Timeline

Start

2024-12-01

Primary completion

2026-05-31

Completion

2026-08-31

Publications

• Background Rover S, Cesura AM, Huguenin P, Kettler R, Szente A. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J Med Chem. 1997 Dec 19;40(26):4378-85. doi: 10.1021/jm970467t.
• Background Leclercq S, Schwarz M, Delzenne NM, Starkel P, de Timary P. Alterations of kynurenine pathway in alcohol use disorder and abstinence: a link with gut microbiota, peripheral inflammation and psychological symptoms. Transl Psychiatry. 2021 Oct 1;11(1):503. doi: 10.1038/s41398-021-01610-5.
• Background Vengeliene V, Cannella N, Takahashi T, Spanagel R. Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse. Psychopharmacology (Berl). 2016 Sep;233(18):3449-59. doi: 10.1007/s00213-016-4384-9. Epub 2016 Jul 30.
• Background Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012 Jul;13(7):465-77. doi: 10.1038/nrn3257.
• Background Litten RZ, Falk DE, Ryan ML, Fertig J, Leggio L. Advances in Pharmacotherapy Development: Human Clinical Studies. Handb Exp Pharmacol. 2018;248:579-613. doi: 10.1007/164_2017_79.
• Background Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction. 2013 Feb;108(2):275-93. doi: 10.1111/j.1360-0443.2012.04054.x. Epub 2012 Oct 17.
• Background Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One. 2014 Feb 10;9(2):e87366. doi: 10.1371/journal.pone.0087366. eCollection 2014.

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