Research advances in obeticholic acid and fibrates in treatment of primary biliary cholangitis with poor response or intolerance to ursodeoxycholic acid / 临床肝胆病杂志

Poor response or intolerance to ursodeoxycholic acid may occur in the treatment of primary biliary cholangitis (PBC), and after switch to obeticholic acid or fibrates alone or in combination, poor response or intolerance is also observed in some treatment regimens. Clinical studies on obeticholic acid and fibrates will gradually solve these issues, and obeticholic acid/fibrates combined with ursodeoxycholic acid is safe and effective in PBC patients without advanced liver cirrhosis.

The mechanism and research progress of obeticholic acid in the intervention of non-alcoholic fatty liver disease / 国际药学研究杂志

Non-alcoholic fatty liver disease(NAFLD)is a relatively common chronic liver disease with imbal- anced lipid metabolism, and its incidence is increasing year by year. NAFLD is closely related to bile acid excretion, ab- normal bile acid synthesis and liver fibrosis. Farnesolid X receptor(FXR)regulates bile acid transport, inhibits bile acid synthesis and resists liver fibrosis. Obeticholic acid is a targeted drug for the treatment of NAFLD targeting the farnesol X receptor, which can effectively regulate fat metabolism and blood sugar balance. This review summarizes the mechanism and research progress of obeticholic acid intervention in NAFLD, and provides a theoretical basis for its foundamental re- search and clinical application.

Determination of obeticholic acid in rat plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) / 药学学报

A simple and sensitive method was developed for quantitation of obeticholic acid in rat plasma with liquid chromatography-tandem mass spectrometry (LC-MS/MS). After liquid-liquid extraction by methyl tert-butyl ether, the chromatographic separation was carried out on an ACE Excel 2 Super C18 column (50 mm×2.1 mm ID, 1.7 μm) with a gradient mobile phase consisting of acetonitrile and 2 mmol·L-1 ammonium formate at a flow rate of 0.2 mL·min-1. The quantitation analysis was performed using multiple reaction monitoring (MRM) at the specific ion transitions of m/z 418.9[M-H]-→401.2 for obeticholic acid and m/z 469.0[M-H]-→ 425.2 for glycyrrhetinic acid (internal standard) in the negative ion mode with electrospray ionization (ESI) source. This validated LC-MS/MS method yielded a good linearity over the range of 5 -5 000 ng·mL-1 with the lower limit of quantitation (LLOQ) of 5 ng·mL-1. The intra and inter-assay precisions (RSD) were all less than 9.82% and the accuracy (RE) was within ±6.90%. The extraction recovery of obeticholic acid was from 85.4% to 88.5%, and the matrix effect of obeticholic acid ranged from 78.9% to 82.5%. Stability test suggest that obeticholic acid in rat plasma was stable for 24 h on workbench, up to 1 month at -70℃, and after three cycles of freeze-thaw. Extracted samples were stable for more than 24 h in an auto-sampler at 6℃. The precision was less than 7.25%, and the accuracy was within ±11.2%, after being diluted 10 times by blank rat plasma. The method has been successfully applied to a pharmacokinetic study of obeticholic acid in rats following oral administration at the dose of 2.5 mg·kg-1.

Synthesis of obeticholic acid and optimization of the preparation process / 国际药学研究杂志

Objective To synthesize obeticholic acid and optimize the preparation process. Method Obeticholic acid was synthesized from (E) -3α-hydroxyl-6-ethylidene-7-keto-5β-cholane-24-acid via the reactions in cluding the double bound hydrogenation, inversion of α-ethyl′s configuration, and stereospecific reduction of the carbonyl group. Results The structures of the compounds were confirmed by1 H NMR, 13 C NMR and MS data. The preparation process was optimized, with the overall yield about 69％.Conclusion An industrial process for the preparation of obeticholic acid has been developed, available for the safety and quality control as well as the quality improvement of final products, which could meet the registration requiremens of Center for Drug Evalution (CDE).

Progression in the diagnosis and treatment of Bile acid diarrhea / 医学研究生学报

Bile-acid diarrhoea(BAD)is a common cause of chronic diarrhoea,resulting from the excess amounts of bile acids enter the colon.The understanding of people about the cause of this diarrhea is still relatively limited for a variety of reasons.Clin-ically,75SeHCAT is the first-line diagnostic test,Other diagnostic tests including the measurement of serum 7α-hydroxy-4-cholesten-3-one(C4)、serum fibroblast growth factor 19(FGF19)、fecal bile acids and the empirical treatment of bile acid sequestrants(BAS). First-line treatment is with BAS for BAD,primarily cholestyramine,Newer BAS such as colestipol and colesevelam have fewer side effects. Obeticholic acid(OCA),as a new drug,maybe have a significant future.This article gives an overview on the etiology,pathogen-esis、diagnosis and treatment progress of BAD.

Role of Farnesoid X Receptor in Treatment of Primary Biliary Cholangitis / 胃肠病学

Primary biliary cholangitis (PBC)is a commonly seen cholestatic liver disease.Currently,ursodeoxy-cholic acid (UDCA)is the only drug approved for the effective treatment of PBC.However,up to 40% of PBC patients had poor response to UDCA.Farnesoid X receptor (FXR)can inhibit the synthesis of bile acid,regulating the transport of bile acid and playing a role in anti-hepatic fibrosis.This article reviewed the role of FXR in treatment of PBC.

Pharmacotherapy for primary biliary cholangitis: basic concepts and research advances / 临床肝胆病杂志

Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease of unknown etiology characterized by highly specific anti-mitochondrial antibody in serum and immune-mediated non-pyogenic destructive infection in the small intrahepatic bile ducts,which can lead to portal inflammation and fibrosis and finally progress to liver cirrhosis and liver failure.At present,ursodeoxycholic acid (UDCA) is the only drug approved for the treatment of PBC with a recommended dose of 13-15 mg · kg-1 · d-1.There are significant improvements in the survival rate of patients achieving biochemical response after UDCA treatment.However,about 40％ of PBC patients do not respond to UDCA,and such patients have a risk of disease progression and are in urgent need of other drugs.With reference to recent clinical studies and guidelines,this article summarizes the basic concepts and latest advances in pharmacotherapy for PBC,as well as the perspectives of new drugs in clinical trials,in order to bring new hopes to PBC patients with poor response to UDCA.

Advances in the treatment of primary biliary cholangitis / 中华肝脏病杂志

Primary biliary cholangitis (PBC) is an autoimmune liver disease mainly involving intrahepatic interlobular bile ducts and can progress to liver fibrosis, liver cirrhosis, and even liver failure. Ursodeoxycholic acid (UDCA) is the first-line therapeutic drug for PBC and can delay disease progression, but as high as 40% of patients have suboptimal response to UDCA. Obeticholic acid, a farnesoid X receptor agonist, has been approved by FDA in May 2016 for patients who have no response to UDCA treatment or cannot tolerate such treatment. Other drugs such as fibrates, glucocorticoids, immunosuppressants, biological agents, and mesenchymal stem cells are gradually used in clinical practice and bring new hope to patients with refractory PBC.

Bile Acid Nuclear Receptor Farnesoid X Receptor: Therapeutic Target for Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver, occurring when fat is accumulated in the liver without alcohol consumption. NAFLD is the most common liver disorder in advanced countries. NAFLD is a spectrum of pathology involving hepatic steatosis with/without inflammation and nonalcoholic steatohepatitis with accumulation of hepatocyte damage and hepatic fibrosis. Recent studies have revealed that NAFLD results in the progression of cryptogenic cirrhosis that leads to hepatocarcinoma and cardiovascular diseases such as heart failure. The main causes of NAFLD have not been revealed yet, metabolic syndromes including obesity and insulin resistance are widely accepted for the critical risk factors for the pathogenesis of NAFLD. Nuclear receptors (NRs) are transcriptional factors that sense environmental or hormonal signals and regulate expression of genes, involved in cellular growth, development, and metabolism. Several NRs have been reported to regulate genes involved in energy and xenobiotic metabolism and inflammation. Among various NRs, farnesoid X receptor (FXR) is abundantly expressed in the liver and a key regulator to control various metabolic processes in the liver. Recent studies have shown that NAFLD is associated with inappropriate function of FXR. The impact of FXR transcriptional activity in NAFLD is likely to be potential therapeutic strategy, but still requires to elucidate underlying potent therapeutic mechanisms of FXR for the treatment of NAFLD. This article will focus the physiological roles of FXR and establish the correlation between FXR transcriptional activity and the pathogenesis of NAFLD.

Nuevas estrategias farmacológicas para el tratamiento del hígado graso no alcohólico / New pharmacological strategies for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) represents an increasing health problem in Chile and worldwide. In some cases NAFLD presents with a progressive form that can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Current pharmacological therapies (pioglitazone and vitamin E) show limited response and are associated to significant adverse effects. During recent years several novel and promising pharmacological therapies have been developed to prevent fibrosis, liver cirrhosis and reduce liver related deaths. The present article summarizes some of these promising strategies, including reported efficacy in clinical trials and associated adverse effects. Hopefully in the near future these new therapies will help to improve NAFLD management and reduce liver related complications.

El hígado graso no alcohólico (HGNA) es un creciente problema de salud pública en Chile y el mundo. En un subgrupo de sujetos, el HGNA puede presentarse con un fenotipo de daño hepático progresivo que puede evolucionar a fibrosis progresiva, cirrosis y carcinoma hepatocelular. Las estrategias farmacológicas actuales (pioglitazona y vitamina E) presentan eficacia limitada y no están exentas de efectos adversos. Durante los últimos años se han desarrollado múltiples estrategias farmacológicas novedosas y promisorias que buscan evitar la progresión hacia cirrosis y reducir la mortalidad de causa hepática. El presente artículo resume los principales nuevos fármacos, los efectos beneficiosos reportados y sus efectos adversos. Es de esperar que en un futuro próximo estas terapias permitan cambiar el pronóstico de nuestros pacientes con HGNA.