Obeticholic acid: A new light in the shadows treating portal hypertension?

Gracia‐Sancho, Jordi; Hernández‐Gea, Virginia; García‐Pagán, Juan Carlos

doi:10.1002/hep.27027

Cited by 3 publications

(6 citation statements)

References 13 publications

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“…For the purpose of our study, we performed detailed prestudy dose-finding experiments of acute OCA administration in two rat models of cirrhosis. We agree with GraciaSancho et al 2 that our experimental findings, although reproducible in two types of experimental cirrhosis, remain to be confirmed in patients with cirrhosis in which other PK issues might need to be addressed.…”

supporting

confidence: 90%

“…Whereas Gracia-Sancho et al 2 subscribed to and acknowledged our methodology, study design, and findings, Mookerjee et al touched on several points to which we would like to reply concisely.…”

Section: Replymentioning

confidence: 89%

“…We are glad that our recent article 1 has stimulated discussion on the role of the farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), in experimental portal hypertension and welcome the recent editorial by Gracia-Sancho et al 2 and letter to the editor by Mookerjee et al…”

Section: Replymentioning

confidence: 99%

“…It should be stressed that experimental studies in infected chimpanzees with HCV have emphasized the role of the innate immune system, namely, Kupffer cells (KCs), in clearance. 2 In this species, as well as in rodents or humans, it is taken for granted that KCs are equally abundant in males and females. In our opinion, differences in the number of KCs could also help explain the stronger viral clearance in females.…”

mentioning

confidence: 99%

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Verbeke

Trebicka²,

Laleman³

2014

Hepatology

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5-10 mg/kg in rodents over weeks. 3 The data from pharmacokinetic studies in humans would suggest that optimal tissue levels of OCA are not reached until 5-7 days of therapy, 2 and thus a 24-hour high-dose study is difficult to interpret.Finally, the interpretation of DDAH-2 being responsible for changes in eNOS function is likely erroneous. It is important to appreciate that there are two isoenzymes of DDAH: DDAH-1 predominantly in the liver and kidney accounting for over 80% of ADMA metabolism, and DDAH-2, located in the heart and vasculature with a role in promoting eNOS transcription, but little effect on ADMA.4 Therefore, the augmented DDAH-2 and improved ADMA metabolism post-OCA treatment in bile-ductligated (BDL) rats in the Verbeke et al. study is difficult to reconcile. Moreover, rodent models show increased hepatic DDAH-1 with FXR agonists, but there is no precedent for FXR agonism leading to increased hepatic DDAH-2 expression. 5In summary, whereas the Verbeke et al. study recapitulates important therapeutic effects of FXR agonists in portal hypertension, there are questions about study design and interpretation of mechanism pertaining to DDAH-2. Further studies are required to address concerns about the mechanism through which OCA reduces hepatic ADMA, and thereby portal pressure, in the BDL model.

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supporting

confidence: 90%

Section: Replymentioning

confidence: 89%

Section: Replymentioning

confidence: 99%

mentioning

confidence: 99%

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Verbeke

Trebicka²,

Laleman³

2014

Hepatology

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“…16 Obeticholic acid and synthetic bile acid receptor agonists are also currently being investigated in phase II and phase III trials in patient. [19][20][21] Because of the small molecular size and hydrophobicity of bile acid mimics, they are usually absorbed in the GI tract and inhibit the bile acid receptors or transporters which exist in the intestine, liver, bile duct and kidney. 16 However, bile acid receptors control a number of fundamental pathways in the liver and physiological process including energy metabolism, glucose homeostasis, and inflammation; these are essential for normal living and digesting.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Therapeutic Evaluation of Poly(acrylic acid)–tetraDOCA Conjugate as a Bile Acid Transporter Inhibitor

Park¹,

Al-Hilal

Jeong

et al. 2015

Bioconjugate Chem.

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Regulation of cholesterol and bile acid homeostasis has been attracting attention as a pharmaceutical target for the treatment of diseases, such as hypercholesterolaemia and type 2 diabetes. In recent years, small bile acid analogues have been developed for the purpose of apical sodium-dependent bile acid transporter (ASBT) inhibition. Here, we designed a novel hydrophilic ASBT inhibitor using oligomeric bile acid with a high affinity with ASBT. Polyacrylic acid-tetraDOCA conjugates (PATD) have the ability to bind to ASBT in order to induce hypocholesterolemic effects. Both the viability and the functionality of PATD were evaluated in vitro, showing that PATDs were effective in inhibiting the increases of cholesterol in the blood and oil in the liver induced by high fat diet (HFD). The results indicated that the newly developed biomaterials with oligomeric bile acids and a hydrophilic polymer are potent therapeutic agents for hyperlipidemia.

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