法尼醇X受体激动剂奥贝胆酸

奥贝胆酸是一种治疗原发性胆汁性肝硬化和非酒精性脂肪肝的新型候选药物,由美国Intercept制药公司研发,其机制主要是通过激动法尼醇X受体,调节相关基因,影响胆汁酸的合成、分泌、转运和吸收。临床研究表明,对熊去氧胆酸不能完全耐受的患者,通过服用奥贝胆酸能够明显改善碱性磷酸酶和血清胆红素的水平,提示奥贝胆酸的临床效果可能优于现有药物熊去氧胆酸。将从奥贝胆酸的药物概况、相关背景、合成路线、药理作用、临床前及临床试验研究以及安全性评价方面进行简述。     

基于FARES数据库的奥贝胆酸不良反应真实世界研究

目的 基于美国FDA不良事件报告系统(FARES)数据库中收录的不良事件数据,分析研究奥贝胆酸相关不良事件的风险信号,为临床安全用药提供参考。方法 收集2016年5月27日-2023年6月30日美国FARES数据库中奥贝胆酸相关的不良事件报告,提取报告数排名前50位不良事件报告,采用报告比值法(ROR)挖掘奥贝胆酸不良反应风险信号。结果 共收集奥贝胆酸相关不良事件报告数5 800例,不良事件报告数前5位依次为瘙痒、乏力、恶心、关节痛、死亡。对报告数排名前50位不良事件进行药物不良反应风险信号分析,检测出36个不良反应风险信号,主要累及胃肠系统(6个)、皮肤及皮下组织(5个)、生化检查(5个)、神经系统(4个)、肝胆系统(4个);发现了13个说明书中未记载的阳性信号,强度排名前5位的依次是药物漏用、腹胀、皮肤干燥、记忆损伤和失眠。结论 根据奥贝胆酸不良事件的真实世界数据系统、全面地分析了其潜在的不良反应风险,提示临床予以关注及进一步进行安全性评价,为有效开展药学监护和临床合理用药提供参考依据。     

奥贝胆酸对2型糖尿病KKAy小鼠的糖脂稳态影响

目的:研究奥贝胆酸(obeticholic acid,OCA)对自发性2型糖尿病KKAy小鼠的抗糖尿病作用.方法:将KKAy小鼠随机分为对照组(Control)和奥贝胆酸组(OCA,10 mg·kg-1),每组9只,ig给药,qd,连续6周.实验期间检测小鼠的体重、摄食量、摄水量、血糖、血脂、糖化血红蛋白和胰岛素水平,...     

Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver condition evolving in a proportion of patients into nonalcoholic steatohepatitis (NASH), an aggressive form of NAFLD associated with increased cardiovascular mortality and significant risk of progressive liver disease, including fibrosis, cirrhosis and hepatocellular carcinoma. At present, no specific therapies for NASH exist. In this review, we examine the evidence supporting activation of the farnesoid X receptor (FXR), a nuclear hormone receptor regulated by bile acids (BAs), for the treatment of NASH. We also discuss the potential of the semi-synthetic BA derivative obeticholic acid (OCA), a first-in-class FXR agonist, as a safe and effective drug to address this significant unmet medical need.     

FXR modulators for enterohepatic and metabolic diseases

ABSTRACT

Introduction: Farnesoid X receptor (FXR), a nuclear receptor mainly expressed in enterohepatic tissues, is a master for bile acid, lipid and glucose homeostasis. Additionally, it acts as a cell protector with unclear mechanism but may be implicated in combating against inflammation, fibrosis and cancers. FXR is thus accepted as a promising target particularly for the enterohepatic diseases, and numerous FXR modulators have been patented and developed.

Areas covered: This review provides an update on the development of FXR modulators for enterohepatic diseases and offers an in-depth perspective on new strategies for the development of novel FXR modulators.

Expert opinion: Despite the development of numerous FXR modulators, which culminated in the successful launch of obeticholic acid (OCA), it remains a matter of debate on how the function of FXR should be exploited for therapeutic purposes. The improvement for obesity achieved by either FXR agonists or antagonists is still in confusion. Whether the side effect of pruritus induced by OCA could be exempted for non-steroidal FXR agonists needs further validation. Apart from the development of conventional FXR ligands, emerging evidence support that restoration of FXR protein level may represent a new strategy in targeting FXR for enterohepatic and metabolic diseases.     

The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice

The disorder of bile acid metabolism is a common feature during pregnancy, which leads to adverse birth outcomes and maternal damage effects. However, the cause and therapy about the disorder of bile acid metabolism are still poor. Microbial infection often occurs in pregnant women, which can induce the disorder of bile acid metabolism in adult mice. Here, this study observed the acute effect of lipopolysaccharide (LPS) on maternal bile acid of pregnant mice at gestational day 17 and the protective effect of obeticholic acid (OCA) pretreatment, a potent agonist of bile acid receptor farnesoid X receptor (FXR). The results showed LPS significantly increased the level of maternal serum and disordered bile acids components of maternal serum and liver, which were ameliorated by OCA pretreatment with obviously reducing the contents of CA, TCA, DCA, TCDCA, CDCA, GCA and TDCA in maternal serum and DCA, TCA, TDCA, TUDCA, CDCA and TCDCA in maternal liver. Furthermore, we investigated the effects of OCA on LPS-disrupted bile acid metabolism in maternal liver. LPS disrupted maternal bile acid profile by decreasing transport and metabolism with hepatic tight junctions of bile acid in pregnant mice. OCA obviously increased the protein level of nuclear FXR and regulated its target genes involving in the metabolism of bile acid, which was characterized by the lower expression of bile acid synthase CYP7A1, the higher expression of CYP3A and the higher mRNA level of transporter Mdr1a/b. This study provided the evidences that LPS disrupted bile acid metabolism in the late stage of pregnant mice and OCA pretreatment played the protective role on it by activating FXR.     

Emerging therapies for the treatment of nonalcoholic steatohepatitis: A systematic review

To describe the mechanism, efficacy, and safety of novel agents that have reached phase 3 clinical trials for the treatment of biopsy-proven nonalcoholic steatohepatitis (NASH). A literature search was conducted using the PRISMA guidelines of MEDLINE databases (1990 to October 2020) with the following MeSH terms: NASH, nonalcoholic liver disease, fatty liver, liver diseases, steatohepatitis, liver fibrosis; combined with obeticholic acid, FXR agonist, cenicriviroc, CCR5 receptor antagonist, elafibranor, PPAR, selonsertib, ASK-1 inhibitor, resmetirom, THR-β receptor, arachidyl amido cholanoic acid (Aramchol™), and SCD-1 modulator. Results were verified via clinicaltrials.gov, Google Scholar, and Google. Articles were included if the medications of interest had ongoing or completed phase 3 trials in biopsy-proven NASH with outcomes directly related to NASH resolution. Eleven studies were identified involving obeticholic acid (OCA), elafibranor, cenicriviroc, Aramchol, and resmetirom. Two agents have reported data from phase 3 trials: OCA and elafibranor. OCA demonstrated safety and efficacy in NASH with a primary end point of improvement or NASH resolution; a new drug approval has been submitted. Elafibranor failed to show efficacy in NASH in the preliminary report from the RESOLVE-IT trial; however, the study is being extended to reassess outcomes. The remaining agents demonstrated positive results in phase 2b studies and have initiated phase 3 trials. With projections for increased prevalence of patients with NASH and the current lack of treatment options, novel agents with targeted mechanisms could potentially change the treatment landscape. The manufacturer of OCA is first to submit a new drug application for the treatment of NASH. These novel agents may fill a pharmacotherapy gap in patients with NASH and possibly prevent progression to advanced liver disease.     

Emerging and future therapies for nonalcoholic steatohepatitis in adults

Introduction: Nonalcoholic steatohepatitis (NASH) is a disease of increasing prevalence with morbidity and mortality closely related to cardiovascular disease, malignancies and cirrhosis. Despite the need for pharmacological treatment and intense research in the field, there is currently no approved agent for NASH.

Areas covered: There are medications shown to improve hepatic steatosis, including thiazolidinediones, vitamin E and pentoxifylline. However, hepatic fibrosis, the hard prognostic end-point for NASH, has shown little improvement with pharmaceutical intervention. Long-term use of thiazolidinediones has provided a marginal effect on fibrosis, whereas obeticholic acid, a farnesoid X receptor, showed to improve fibrosis, but further data are needed. There are currently many novel agents under investigation, including glucagon-like peptide-1 analogs, sodium glucose co-transporters and peroxisome proliferator-activated receptor-γ selective modulators, whose preliminary results have been promising.

Expert opinion: Given the multifactorial pathogenesis of NASH, it is rational to consider multiple treatments rather than monotherapy as a more promising approach. Although, it remains to be shown, targeting more than one pathogenetic ‘hit’ of the disease may provide more efficacious management. Furthermore, the establishment of a noninvasive index for long-term follow-up of NASH patients will facilitate treatment guidance by reducing the need for multiple liver biopsies.     

Obeticholic acid and budesonide for the treatment of primary biliary cirrhosis

Introduction: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of adults. Treatments are needed when patients have incomplete response to ursodeoxycholic acid (UDCA).

Areas covered: Discoveries of the key role played by bile acids (BAs) and nuclear receptors (NRs) in regulating liver and metabolic homeostasis have led to promising therapeutic approaches in liver diseases. A PubMed search for the recent literature on NRs in liver disease was conducted. In particular, obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist that has an important role in the enterohepatic circulation of BAs. Preliminary studies of OCA in patients with PBC have demonstrated marked biochemical improvement when administered in combination with UDCA and alone. Pruritus is the most common side effect, limiting treatment at higher doses. Budesonide is a glucocorticoid receptor/pregnane X receptor (PXR) agonist also involved in BA synthesis, metabolism and transport. Studies with budesonide have shown positive effects of short-term combination therapy in selected patients with early stage disease and overlapping features of autoimmune hepatitis.

Expert opinion: Though larger studies are needed, preliminary results of agents targeting FXR and PXR have been encouraging, particularly in subsets of patients with PBC and may mark a new therapeutic era.     

Obeticholic acid alleviate lipopolysaccharide-induced acute lung injury via its anti-inflammatory effects in mice

Acute lung injury (ALI) is a common disease that may result in acute respiratory failure and death. However, there are still no effective treatments for ALI. Several studies have shown that farnesoid X receptor (FXR) has an anti-inflammatory effect. We investigated the effects of obeticholic acid (OCA), an agonist of FXR, on Lipopolysaccharide (LPS)-induced ALI in mice. Sixty male mice were randomly divided into six groups, and orally administered with or without OCA once daily for 3 consecutive days before LPS (1.0 mg/kg). Animals were sacrificed at 0 h, 2 h or 6 h after LPS. As expected, OCA enhanced pulmonary FXR activity. OCA prevented LPS-induced ALI. Additional experiment showed that OCA alleviated LPS-induced up-regulation of pulmonary pro-inflammatory and chemokine genes. Moreover, OCA also repressed LPS-induced the release of TNF-α and KC in serum and bronchoalveolar lavage fluid. In contrast, OCA further up-regulated LPS-induced the expression of Il-10, an anti-inflammatory cytokine. Further study showed that OCA inhibited LPS-evoked NF-κB signaling in the lungs. OCA attenuated LPS-induced ERK1/2, JNK, p38 and Akt phosphorylation in the lungs. Overall, these results suggest that OCA prevent LPS-induced ALI may be through enhancing pulmonary FXR activity and then blockading several inflammatory signaling pathways.     

Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy

Primary bile acids were reported to augment secretion of chemokine (C‒X‒C motif) ligand 16 (CXCL16) from liver sinusoidal endothelial cells (LSECs) and trigger natural killer T (NKT) cell-based immunotherapy for liver cancer. However, abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control. Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation, we proposed a strategy using nanoemulsion-loaded obeticholic acid (OCA), a clinically approved selective farnesoid X receptor (FXR) agonist, for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy. The OCA-nanoemulsion (OCA-NE) was prepared via ultrasonic emulsification method, with a diameter of 184 nm and good stability. In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells. As a result, OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model, which performed much better than oral medication of free OCA. Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-γ, as well as increased NKT cell populations inside the tumor. Overall, our research provides a new evidence for the antitumor effect of receptors for primary bile acids, and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy     

Farnesoid X receptor modulators 2014-present: a patent review

Introduction. The nuclear receptor FXR regulates the expression of genes involved in bile acids, glucose and lipid homeostasis. For its role as guardian of metabolism, FXR has been identified a promising pharmacological target in liver bile acid and lipid accumulation, such as cholestasis and non-alcoholic fatty liver disease (NAFLD). The field of FXR research is extremely competitive with a large number of patents and articles published in the last decades identifying promising hit compounds.

Areas covered. The present review summarizes recent patent activity (2014-to date) filing for synthetic and natural FXR ligands, including bile acid derivatives and non-steroidal compounds, alongside their in vitro and in vivo efficacy as well as their therapeutic applications.

Expert opinion. While the first FXR agonist, obeticholic acid, has gained approval, significant safety issues have been emerged. Today is unclear whether these safety issues are class related or restricted to the bile acid scaffold of this agent. Despite the significant number of patent applications claiming steroidal and non-steroidal FXR agonists, several questions on their therapeutic potential in cholestasis and NASH remain open leaving a space for the development of novel compounds.     

Advances in pharmacotherapy for primary biliary cirrhosis

Introduction: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive.

Areas covered: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids.

Expert opinion: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.     

Current and promising therapy for primary biliary cholangitis

Introduction: Primary biliary cholangitis is a chronic, cholestatic liver disease that may progress to cirrhosis with complications of end-stage liver disease. Approved treatment options include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) but novel therapies are being investigated.

Areas covered: In this review, the authors describe the current pharmacotherapy for the treatment of primary biliary cholangitis (PBC) and for management of side effects such as pruritus and fatigue based on the currently available literature.

Expert opinion: Patients diagnosed with PBC should be offered treatment with UDCA at 13–15 mg/kg per day if liver enzymes are elevated. If they do not meet the defined criteria of response, adjunctive therapy should be considered. This may include OCA at 5 mg per day for patients without cirrhosis or investigational therapy. Management of the most common side effects, pruritus, and fatigue, is nuanced and includes lifestyle modifications as well as pharmacological approaches. Several tools such as the Mayo Risk Score and GLOBE are available for prognostic modeling. Ultimately, patients with PBC may end up requiring liver transplantation and referral to a transplant center may also be needed.     

高尿酸血症与缺血性卒中及其药物治疗

全球多项研究显示,高尿酸血症是缺血性脑卒中的独立危险因素之一,血尿酸水平升高可增加脑卒中的发生率和死亡率。高尿酸血症与缺血性卒中的危险因素(高血压、糖尿病、高血脂、动脉粥样硬化等)共同促进缺血性脑卒中的发生。对高尿酸血症的治疗已经从急性期治疗转变为强调长期控制血尿酸达标,预防各种合并症。高尿酸血症的治疗包括调整饮食结构、改变生活方式、积极控制与血尿酸升高相关的危险因素、避免应用血尿酸升高的药物、碱化尿液等。降低血尿酸的药物包括增加尿酸排泄的药物、抑制尿酸合成药物、辅助降尿酸药。如果引起血尿酸增高的原因不能去除,需要长期降尿酸治疗。     

Biliary,fecal and plasma deoxycholic acid in rabbit,hamster, guinea pig,and rat: comparative study and implication in colon cancer

Bile acids are believed to play a role in the etiology of colorectal cancer, and high fecal excretion of secondary bile acids was correlated with increased incidence of colon cancer. Recently, it was also reported that there is an increase in plasma of the secondary bile acid, deoxycholic acid in men with colorectal adenomas. Since deoxycholic acid is formed in the colon and absorbed into the portal systemic circulation, it was suggested that the blood concentration of this bile acid reflects the level of exposure of colonic cells to deoxycholic acid. The objective of this study was to investigate whether plasma deoxycholic acid level represents the fecal content of this bile acid in several animal species with different bile acid composition and deoxycholic acid contribution to the bile acid pool. Eight rabbits, hamsters, guinea pigs, and rats were used in this study. Blood samples and feces were collected on days 1, 3, 5 and 7. Bile samples were obtained only on day 7. The plasma, fecal and biliary bile acids were analyzed by gas chromatography-mass spectrometry. Bile acid composition and deoxycholic acid content varied greatly between the animal species studied. There was a variation in the concentration of total bile acids in the plasma and feces obtained at different times during the experiments, however, the bile acids profile remained constant throughout the study. The data obtained shows that although plasma bile acid profile was not similar to fecal bile acids profile, however, there was a significant correlation between the level of plasma and fecal deoxycholic acid. Plasma deoxycholic acid concentration might be a reliable biomarker for the degree of exposure of colon cells to this bile acid, and may be useful in further studies on the role of secondary bile acids in colon carcinogenesis.     

Simultaneous analysis of glycyrrhizin, paeoniflorin, quercetin, ferulic acid, liquiritin, formononetin, benzoic acid and isoliquiritigenin in the Chinese proprietary medicine Xiao Yao Wan by HPLC

A high performance liquid chromatography coupled with photodiode-array detection method was developed for simultaneous determination of glycyrrhizin, paeoniflorin, benzoic acid, quercetin, ferulic acid, formononetin, liquiritin and isoliquiritigenin in the Chinese proprietary medicine "Xiao Yao Wan" (XYW). The analysis was performed by reverse phase gradient elution, using an aqueous mobile phase (containing 0.1% phosphoric acid) modified by acetonitrile and detection made simultaneously at four wavelengths. The method was validated for accuracy, precision and limits of detection and quantification. Ten batches of XYW obtained from different pharmaceutical companies were analyzed and found to contain different amounts of the eight bioactive markers. This method could be used for quality assessment of this herbal medicine.     

RP-HPLC法测定熊去氧胆酸胶囊中熊去氧胆酸及有关物质的含量

目的建立反相高效液相色谱法(RP-HPLC)测定熊去氧胆酸胶囊中熊去氧胆酸、胆酸、鹅去氧胆酸及胆石酸的含量。方法使用Diamonsil C18色谱柱(200 mm×4.6 mm,5μm),流动相为乙腈-0.03 mol·L-1磷酸溶液(体积比为40∶60),流速为1.4 mL·min-1,检测波长为205 nm,柱温为35℃。结果熊去氧胆酸胶囊中熊去氧胆酸、胆酸、鹅去氧胆酸及胆石酸在25 min内洗脱并基线分离。熊去氧胆酸、胆酸、鹅去氧胆酸及胆石酸的线性范围分别为0.80²00.00、0.45200.00、0.45¹10.00、0.30110.00、0.30⁷0.00和0.3070.00和0.30⁸0.00 mg·L-1,平均回收率分别为99.7%、99.3%、98.7%和99.1%,RSD分别为1.30%、1.47%、1.87%和1.95%(n=3)。结论 RP-HPLC可用于同时测定熊去氧胆酸胶囊中熊去氧胆酸、胆酸、鹅去氧胆酸及胆石酸的含量,可应用于熊去氧胆酸胶囊胶囊制剂的质量控制。     

Functional activity of a monocarboxylate transporter, MCT1, in the human retinal pigmented epithelium cell line, ARPE-19

The purpose of this study was to identify and characterize the functional activity of monocarboxylic acid transporter 1 (MCT1) on the human retinal pigmented epithelium (RPE) cell line, ARPE-19, and to evaluate whether the cell line can function as an in vitro screening tool for intravitreally administered drugs/prodrugs targeted to the MCT1 expressed in RPE. Uptake studies were carried out at 37 degrees C, for 30 s, with ARPE-19 cells. [(14)C]l-Lactic acid was selected as a substrate for this transporter. Uptake of [(14)C]L-lactic acid by ARPE-19 cells was found to exhibit saturable kinetics (K(m) = 3.1 +/- 0.6 mM and V(max) = 63.1 +/- 4.1 pmol/min/mg of protein). Monocarboxylic acids, such as benzoic acid, salicylic acid, and pyruvic acid, inhibited the uptake of [(14)C]L-lactic acid whereas di- and tricarboxylic acids, such as phthalic, succinic, and citric acids, did not demonstrate any inhibitory effect. Uptake was stereospecific where D-lactic acid was less effective in inhibiting [(14)C]L-lactic acid uptake than unlabeled L-lactic acid. ELISA indicated the expression of only MCT1, MCT4, and MCT8 isoforms by ARPE-19 cells. Increase in [(14)C]L-lactic acid uptake was observed as the uptake medium pH was lowered from 7.4 to 5.0. Moreover, inhibition of [(14)C]L-lactic acid uptake was observed in the presence of the protonophore 2,4-dinitrophenol. Uptake was significantly decreased in the presence of sodium azide, ouabain, p-chloromercuribenzoic acid (pCMBA), N-ethylmaleamide, dithiothreitol, and p-chloromercuribenzene sulfonate (pCMBS). However, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and L-thyroxine did not inhibit [(14)C]L-lactic acid. RT-PCR studies and sequence analysis of the PCR product confirmed the expression of MCT1 by ARPE-19 cells. Our results indicate that MCT1 is functionally active and is the only MCT isoform involved in the apical uptake of monocarboxylates by ARPE-19 cells. This cell line may thus be used as an effective screening tool for intravitreally administered drugs/prodrugs targeted toward MCT1 expressed on the RPE.