Preclinical and clinical evidence for suppression of alcohol intake by apremilast

Abstract

Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a novel bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing, (i.e. FDA approved for psoriasis, low incidence of adverse events, excellent safety profile), and tested it using multiple animal strains and models, as well as in a human Phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models for stressfacilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment seeking individuals with AUD in a double blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.

Blood metabolomic profiling reveals new targets in the management of psychological symptoms associated with severe alcohol use disorder

“…In a randomized, double-blind, placebo-controlled trial, the phosphodiesterase inhibitor pentoxifylline associated with escitalopram showed greater reduction of depression scores compared to patients receiving escitalopram alone (27). In another study, Apremilast which is also a phosphodiesterase inhibitor, suppressed excessive alcohol drinking in AUD patients (28). Paraxanthine has a psychostimulant effect and can modulate dopamine release in the striatum (29).…”

Medications for treating alcohol use disorder: A narrative review

“…A six‐week clinical trial that aims to replicate the effects on alcohol consumption is currently underway (NCT05414240). Apremilast, also a PDE inhibitor, a target dosage of 90 mg/day of apremilast, was recently shown to reduce the number of drinks/day and the proportion of heavy drinking days in an 11‐day trial in non‐treatment‐seeking individuals with AUD (Grigsby et al, 2023).…”

“…Apremilast, also a PDE inhibitor, a target dosage of 90 mg/day of apremilast, was recently shown to reduce the number of drinks/day and the proportion of heavy drinking days in an 11-day trial in nontreatment-seeking individuals with AUD (Grigsby et al, 2023).…”

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

“…15 Currently, PDE4 inhibitors apremilast and ibudilast are undergoing clinical trials to treat AUD. 17,18 On the other hand, chronic alcohol consumption also resulted in the upregulation of hepatic PDE4 expression and the deficiency of cAMP signaling in hepatic tissues of patients, 19 and PDE4 inhibitor rolipram significantly reduced alcohol-induced hepatic steatosis and injury by reduced oxidative and endoplasmic reticulum stress. 19 These results indicate that PDE4 might serve as a novel target for both AUD and ALD treatment.…”

“…Many studies have confirmed that dysregulation of cAMP/PKA signaling has been implicated in the development of EtOH drinking behavior. , Moreover, intracellular signaling, mediated by secondary messenger cAMP, is an essential basis for genetic predisposition, reward characteristics, systemic toxicity, and relapse characteristics of compulsive alcohol consumption . Currently, PDE4 inhibitors apremilast and ibudilast are undergoing clinical trials to treat AUD. , On the other hand, chronic alcohol consumption also resulted in the up-regulation of hepatic PDE4 expression and the deficiency of cAMP signaling in hepatic tissues of patients, and PDE4 inhibitor rolipram significantly reduced alcohol-induced hepatic steatosis and injury by reduced oxidative and endoplasmic reticulum stress . These results indicate that PDE4 might serve as a novel target for both AUD and ALD treatment.…”