New drug targets for alcoholic liver disease

Xu, Mingjiang; Chang, Binxia; Mathews, Stephanie; Gao, Bin

doi:10.1007/s12072-014-9516-x

Cited by 12 publications

(8 citation statements)

References 40 publications

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“…(35) It has been shown that IL-22 might overcome even the corticosteroid-mediated promotion of infection. (41,42) Therefore, in more severe AH (MELD score > 20), IL-22 could theoretically be used alone in a dose of 45 μg/kg or in combination with corticosteroids without increasing risk of infection. Interestingly, although the number of patients in the study was small and the follow-up period was only 42 days, the IL-22 agonist was associated with approximately 95% survival.…”

Section: Discussionmentioning

confidence: 99%

An Open‐Label, Dose‐Escalation Study to Assess the Safety and Efficacy of IL‐22 Agonist F‐652 in Patients With Alcohol‐associated Hepatitis

et al. 2020

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Background and Aims Interleukin‐22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol‐associated hepatitis (AH). F‐652 is a recombinant fusion protein of human interleukin‐22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F‐652 in patients with moderate and severe AH. Approach and Results A phase‐2 dose‐escalating study was carried out. F‐652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End‐Stage Liver Disease [MELD] scores: 11‐20) and severe AH (MELD scores: 21‐28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity‐matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half‐life of F‐652 following the first dose was 61‐85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day‐7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down‐regulated, and regeneration markers were up‐regulated at days 28 and 42. Conclusions F‐652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo‐controlled trials to test the efficacy of F‐652 in AH.

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Section: Discussionmentioning

confidence: 99%

An Open‐Label, Dose‐Escalation Study to Assess the Safety and Efficacy of IL‐22 Agonist F‐652 in Patients With Alcohol‐associated Hepatitis

et al. 2020

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“…So far there is no established drug available in the market that could cure ALD; however, for the management of ALD many drugs are available ( Table 4 ) [ 105 ]. Healthcare providers strongly believe that abstinence from alcohol is the best choice to prevent ALD.…”

Section: Treatment Approach Of Aldmentioning

confidence: 99%

Alcohol-associated liver disease: A review on its pathophysiology, diagnosis and drug therapy

et al. 2021

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Highlights Chronic intake of alcohol initiates a pathogenic process that involves the production of protein-aldehyde adducts, and release of cytokines. Involved gene polymorphisms may include alcohol dehydrogenase, cytochrome P4502E1, and those associated with alcoholism. Alcohol ingestion could be correlated to the risk of preterm births, there is no exact dose-response relationship. Oral drugs of pentoxifylline have reduced the severity of steatohepatitis in alcohol-use patients.

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“…Corticosteroids, which were first utilised in the early 1970s for the treatment of severe alcoholic liver disease, are still the only drugs currently used for the treatment of this disease. However, hormone therapy may lead to many negative side effects, including the inhibition of liver regeneration and the promotion of bacterial infections [21,22].…”

Section: Alcoholic Liver Injurymentioning

confidence: 99%

Interleukin 22 in Liver Injury, Inflammation and Cancer

Wu¹,

Min²,

Ge³

et al. 2020

Int. J. Biol. Sci.

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Interleukin 22(IL-22), a member of the IL-10 cytokine family and is an emerging CD4+Th cytokine that plays an important role in anti-microbial defense, homeostasis and tissue repair. We are interested in IL-22 as it has the double function of suppressing or encouraging inflammation in various disease models including hepatic inflammation. As a survival factor for hepatocytes, IL-22 plays a protective role in many kinds of liver diseases, such as hepatitis, liver fibrosis, or hepatocellular carcinoma (HCC) by binding to the receptors IL-22R1 and IL-10R2. Overexpression of IL-22 reduces liver fibrosis by attenuating the activation of hepatic stellate cell (the main cell types involved in hepatic fibrosis), and down-regulating the levels of inflammatory cytokines. Administration of exogenous IL-22 increases the replication of hepatocytes by inhibiting cell apoptosis and promoting mitosis, ultimately plays a contributing role in liver regeneration. Furthermore, treatment with IL-22 activates hepatic signal transducer and activator of transcription 3 (STAT3), ameliorates hepatic oxidative stress and alcoholic fatty liver, effectively alleviate the liver damage caused by alcohol and toxicant. In conclusion, the hepatoprotective functions and liver regeneration promoting effect of IL-22 suggests the therapeutic potential of IL-22 in the treatment of human hepatic diseases.

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New drug targets for alcoholic liver disease

Cited by 12 publications

References 40 publications

An Open‐Label, Dose‐Escalation Study to Assess the Safety and Efficacy of IL‐22 Agonist F‐652 in Patients With Alcohol‐associated Hepatitis

An Open‐Label, Dose‐Escalation Study to Assess the Safety and Efficacy of IL‐22 Agonist F‐652 in Patients With Alcohol‐associated Hepatitis

Alcohol-associated liver disease: A review on its pathophysiology, diagnosis and drug therapy

Interleukin 22 in Liver Injury, Inflammation and Cancer

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