Obeticholic Acid for Primary Biliary Cholangitis

Floreani, Annarosa; Gabbia, Daniela; Martin, Sara De

doi:10.3390/biomedicines10102464

Cited by 19 publications

(12 citation statements)

References 54 publications

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“…The recommended dose of OCA is 5-10mg, with incidence of pruritus increased with dose ( 125 ). The FDA issued a new warning in 2021that OCA use in PBC patients with advanced cirrhosis should be restricted due to risk of serious liver injury ( 126 ). A combination of UDCA and OCA provided satisfactory clinical outcomes for patients inadequately responded to UDCA monotherapy ( 127 ), while add-on therapy with OCA and bezafibrate improved the prognostic markers of difficult-to-treat PBC ( 128 ).…”

Section: Targeting Bile Acid Metabolismmentioning

confidence: 99%

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

Yang

Rojas

et al. 2023

Front. Immunol.

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Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by cholestasis, biliary injuries, liver fibrosis, and chronic non-suppurative cholangitis. The pathogenesis of PBC is multifactorial and involves immune dysregulation, abnormal bile metabolism, and progressive fibrosis, ultimately leading to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are currently used as first- and second-line treatments, respectively. However, many patients do not respond adequately to UDCA, and the long-term effects of these drugs are limited. Recent research has advanced our understanding the mechanisms of pathogenesis in PBC and greatly facilitated development of novel drugs to target mechanistic checkpoints. Animal studies and clinical trials of pipeline drugs have yielded promising results in slowing disease progression. Targeting immune mediated pathogenesis and anti-inflammatory therapies are focused on the early stage, while anti-cholestatic and anti-fibrotic therapies are emphasized in the late stage of disease, which is characterized by fibrosis and cirrhosis development. Nonetheless, it is worth noting that currently, there exists a dearth of therapeutic options that can effectively impede the progression of the disease to its terminal stages. Hence, there is an urgent need for further research aimed at investigating the underlying pathophysiology mechanisms with potential therapeutic effects. This review highlights our current knowledge of the underlying immunological and cellular mechanisms of pathogenesis in PBC. Further, we also address current mechanism-based target therapies for PBC and potential therapeutic strategies to improve the efficacy of existing treatments.

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Section: Targeting Bile Acid Metabolismmentioning

confidence: 99%

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

Yang

Rojas

et al. 2023

Front. Immunol.

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“…OCA is the only registered agent for second-line treatment in PBC patients UDCA-intolerant and/or UDCA nonresponders for whom a 12 month-treatment has not produced any benefit [ 192 ]. It has been examined in PBC patients with inadequate response to UDCA and has shown promising results [ 165 ].…”

Section: Current Treatments In Pbc and Pscmentioning

confidence: 99%

Selected Aspects of the Intricate Background of Immune-Related Cholangiopathies—A Critical Overview

Kasztelan-Szczerbińska

Rycyk-Bojarzynska

Szczerbinska

et al. 2023

Nutrients

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Primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are rare immune-related cholangiopathies with still poorly explained pathogenesis. Although triggers of chronic inflammation with subsequent fibrosis that affect cholangiocytes leading to obliteration of bile ducts and conversion to liver cirrhosis are unclear, both disorders are regarded to be multifactorial. Different factors can contribute to the development of hepatocellular injury in the course of progressive cholestasis, including (1) body accumulation of bile acids and their toxicity, (2) decreased food intake and nutrient absorption, (3) gut microbiota transformation, and (4) reorganized host metabolism. Growing evidence suggests that intestinal microbiome composition not only can be altered by liver dysfunction, but in turn, it actively impacts hepatic conditions. In this review, we highlight the role of key factors such as the gut–liver axis, intestinal barrier integrity, bile acid synthesis and circulation, and microbiome composition, which seem to be strongly related to PBC and PSC outcome. Emerging treatments and future therapeutic strategies are also presented.

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“…In recent years, the structural modification of CDCA has led to the production of agonists targeting FXR, such as obeticholic acid (OCA, 2 ), which has an agonistic activity of up to 100 nM [ 6 ]. OCA has received approval as a treatment option for primary biliary cholangitis (PBC) [ 7 ]. In addition, while it is under a phase III clinical investigation for NASH therapy [ 8 ], it also showed reverse effects as a full agonist, including liver damage [ 9 , 10 , 11 ] and hyperlipidemia [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Structure Optimization of 12β-O-γ-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist/Modulator for NASH Therapy

Bao

Niu

et al. 2023

Pharmaceuticals

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The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12β-O-(γ-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure–activity relationship (SAR) and identified the most potent compound, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg·Kg−1) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of 10b extends into the H11–H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12β-alkonate. These findings suggest that 12-glutamyl OA derivative 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH).

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Obeticholic Acid for Primary Biliary Cholangitis

Cited by 19 publications

References 54 publications

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

Selected Aspects of the Intricate Background of Immune-Related Cholangiopathies—A Critical Overview

Structure Optimization of 12β-O-γ-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist/Modulator for NASH Therapy

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