Ignite Creation Date:
2024-10-26 @ 3:42 PM
Last Modification Date:
2024-10-26 @ 3:42 PM
Study NCT ID:
NCT06636227
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-03
Brief Title:
Diclofenac Dose Response Study
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Optimal Dosing Tolerability and Initial Efficacy of Diclofenac as a KMO Inhibitor in Individuals With Alcohol Use Disorder
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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
Detailed Description:
Alcohol use disorder AUD is a chronic condition for which current pharmacological treatments are only modestly effective 12 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 for AUD 34 To that end 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 Accumulating evidence suggests that chronic alcohol exposure produces dysregulation of the KP particularly as evidenced by altered levels of the metabolites kynurenic acid KYNA and quinolinic acid QUIN KYNA is an NMDA receptor and α7 nicotinic acetylcholine receptor nAChR antagonist that has neuroprotective and anticonvulsant properties 56 Conversely QUIN is an NMDA receptor agonist containing neurotoxic and convulsant properties 7-9 Both NMDA and α7nAChR are critically involved in addiction neurobiology For example α7nAChRs control glutamate release from cortical afferents to the nucleus accumbens and thereby modulate mesolimbic dopamine release in response to acute alcohol consumption and alcohol-related cues 10-12 Chronic alcohol exposure produces ametabolic shift away from KYNA and toward QUIN production and this imbalance is associated with various alcohol-related pathologies in animals and humans 11-14 Thus a medication that targets the KP to restore KYNA and attenuate QUIN levels may hold promise as an effective treatment for AUD
The enzyme kynurenine 3-monooxygenase KMO is increasingly understood to be a major gatekeeper of the KP and its production of KYNA KMO inhibition shifts the KP towards KYNA production in the brain 15 whereas KMO upregulation shifts the KP toward QUIN production Critically KMO inhibition in rodents decreases alcohol self-administration alcohol preference relapse to alcohol consumption and cue-induced reinstatement of alcohol-seeking 111216 These anti-alcohol effects were predominantly due to brain increases in KYNA which blocked alcohol-induced dopamine release in the nucleus accumbens shell through antagonism of α7nAChreceptors1112 KMO inhibition also reduced nicotine- and cannabinoid-induced extracellular dopamine release in the nucleus accumbens shell self-administration of nicotine and cannabinoids cue-induced nicotine and cannabinoid relapse behaviors and cocaine-seeking behavior like with alcohol these effects were also in part to KYNAs antagonism of α7nACh receptors 1117-19 These preclinical findings suggest increasing KYNA levels though KMO inhibition is a promising target for the treatment of AUD as well as other substances of misuse but medications with this pharmacological property have not been tested in humans
Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug NSAID and like all NSAIDs produces anti-inflammatory antipyretic and analgesic effects at least in part through inhibiting prostaglandin activity However it was recently discovered that diclofenac also potently inhibits KMO activity and that it may be the only FDA-approved medication with this pharmacological property 2021 Consistent with KMO inhibition diclofenac increases KYNA levels in the brain and peripheral tissue in rodents 2223 Thus diclofenac has a unique and promising pharmacological profile for AUD treatment However it remains unknown whether diclofenac increases KYNA levels in humans at approved safe dosages and if KMO inhibition in humans is a viable pharmacological target for treating AUD As diclofenac is currently available and used by millions of patients each year for other indications the repurposing of diclofenac for the treatment of AUD represents a fast and economically feasible approach to drug development
The first step in determining whether diclofenac can be repurposed for AUD is to determine whether the drug inhibits KMO at FDA-approved safe and tolerable doses Thus investigators propose to conduct a human laboratory pilot study to test whether diclofenac can increase KYNA in individuals with AUD An increase in KYNA would support the proposed pharmacological property of KMO inhibition Individuals with AUD n 24 will complete four sessions where they receive one of three doses of 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
The KP is a complex enzymatic cascade with each step producing biologically active metabolites that are critically involved in diverse physiological and pathological processes Accumulating evidence suggests that chronic alcohol exposure produces dysregulation of the KP particularly as evidenced by altered levels of the metabolites kynurenic acid KYNA and quinolinic acid QUIN KYNA is an NMDA receptor and α7 nicotinic acetylcholine receptor nAChR antagonist that has neuroprotective and anticonvulsant properties 56 Conversely QUIN is an NMDA receptor agonist containing neurotoxic and convulsant properties 7-9 Both NMDA and α7nAChR are critically involved in addiction neurobiology For example α7nAChRs control glutamate release from cortical afferents to the nucleus accumbens and thereby modulate mesolimbic dopamine release in response to acute alcohol consumption and alcohol-related cues 10-12 Chronic alcohol exposure produces ametabolic shift away from KYNA and toward QUIN production and this imbalance is associated with various alcohol-related pathologies in animals and humans 11-14 Thus a medication that targets the KP to restore KYNA and attenuate QUIN levels may hold promise as an effective treatment for AUD
The enzyme kynurenine 3-monooxygenase KMO is increasingly understood to be a major gatekeeper of the KP and its production of KYNA KMO inhibition shifts the KP towards KYNA production in the brain 15 whereas KMO upregulation shifts the KP toward QUIN production Critically KMO inhibition in rodents decreases alcohol self-administration alcohol preference relapse to alcohol consumption and cue-induced reinstatement of alcohol-seeking 111216 These anti-alcohol effects were predominantly due to brain increases in KYNA which blocked alcohol-induced dopamine release in the nucleus accumbens shell through antagonism of α7nAChreceptors1112 KMO inhibition also reduced nicotine- and cannabinoid-induced extracellular dopamine release in the nucleus accumbens shell self-administration of nicotine and cannabinoids cue-induced nicotine and cannabinoid relapse behaviors and cocaine-seeking behavior like with alcohol these effects were also in part to KYNAs antagonism of α7nACh receptors 1117-19 These preclinical findings suggest increasing KYNA levels though KMO inhibition is a promising target for the treatment of AUD as well as other substances of misuse but medications with this pharmacological property have not been tested in humans
Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug NSAID and like all NSAIDs produces anti-inflammatory antipyretic and analgesic effects at least in part through inhibiting prostaglandin activity However it was recently discovered that diclofenac also potently inhibits KMO activity and that it may be the only FDA-approved medication with this pharmacological property 2021 Consistent with KMO inhibition diclofenac increases KYNA levels in the brain and peripheral tissue in rodents 2223 Thus diclofenac has a unique and promising pharmacological profile for AUD treatment However it remains unknown whether diclofenac increases KYNA levels in humans at approved safe dosages and if KMO inhibition in humans is a viable pharmacological target for treating AUD As diclofenac is currently available and used by millions of patients each year for other indications the repurposing of diclofenac for the treatment of AUD represents a fast and economically feasible approach to drug development
The first step in determining whether diclofenac can be repurposed for AUD is to determine whether the drug inhibits KMO at FDA-approved safe and tolerable doses Thus investigators propose to conduct a human laboratory pilot study to test whether diclofenac can increase KYNA in individuals with AUD An increase in KYNA would support the proposed pharmacological property of KMO inhibition Individuals with AUD n 24 will complete four sessions where they receive one of three doses of 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None