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  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Clinical, Retrospective data, Journal, Real-world evidence:  Real-World Clinical Management of Patients with Primary Biliary Cholangitis-A Retrospective Multicenter Study from Germany. (Pubmed Central) -  Apr 7, 2021   
    The FXR agonist, OCA, ameliorated bacterial transloca- tion through affecting intestinal permeability, autophagy and immunity subsequently NASH-related events in a combined animal model of NASH and intestinal impairment through TLR4/TGF-beta1 suppression independently of PI3k/Akt. Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
  • ||||||||||  bezafibrate / Generic mfg.
    Review, Journal:  Primary biliary cholangitis. (Pubmed Central) -  Mar 30, 2021   
    Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.
  • ||||||||||  bile acid cholic acid (INT-777) / Intercept
    Journal:  Structural basis of GPBAR activation and bile acid recognition. (Pubmed Central) -  Mar 12, 2021   
    Here we report the cryo-electron microscopy structures of GPBAR-G complexes stabilized by either the high-affinity P395 or the semisynthesized bile acid derivative INT-777 at 3 Å resolution...Moreover, GPBAR undertakes an atypical mode of activation and G-protein coupling featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR involved in bile acid recognition and allosteric effects, but also suggests the presence of distinct connecting mechanisms between the ligand binding pocket and the G protein binding site in the GPCR superfamily.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Journal:  FXR activation prevents liver injury induced by Tripterygium wilfordii preparations. (Pubmed Central) -  Mar 12, 2021   
    Quantitative real-time PCR (QPCR) and western blot indicated that the above changes were accompanied by inhibition of farnesoid X receptor (FXR) signaling.Liver injury from TWT could be alleviated by treatment of the FXR agonist obeticholic acid (OCA) via activation of the FXR to inhibit the c-Jun N-terminal kinase (JNK) pathway and improve bile acid metabolism disorder by activating bile salt export pump (BSEP) and organic solute-transporter-β (OSTB). The data demonstrate that FXR signaling pathway plays a key role in Tripterygium wilfordii-induced liver injury, which could be alleviated by activated FXR.These results indicate that FXR activation by OCA may offer a promising therapeutic opportunity against hepatotoxicity from the preparations of Tripterygium wilfordii.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Preclinical, Journal:  The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice. (Pubmed Central) -  Mar 9, 2021   
    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.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Clinical, Journal, Real-World Evidence:  Real-world experience with obeticholic acid in patients with primary biliary cholangitis. (Pubmed Central) -  Mar 9, 2021   
    Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.
  • ||||||||||  Lipaglyn (saroglitazar) / Zydus Cadila, Ocaliva (obeticholic acid) / Intercept
    Review, Journal:  Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail. (Pubmed Central) -  Feb 20, 2021   
    Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic NASH patients...The search for an ideal drug or 'Holy Grail' within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for NASH which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Journal:  Emerging drugs for the treatment of primary biliary cholangitis. (Pubmed Central) -  Feb 4, 2021   
    The current guidelines and emerging therapies in phase 2, 3 and 4 clinical trials have been included.Expert opinion: The currently available therapies are effective, but their use has limitations and challenges and there is still significant unmet need. Although there have been promising therapeutic interventions in recent years, further research into personalising therapeutic strategies with available treatments and new agents is needed.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Preclinical, Journal:  FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR-B1-deficient mice fed a high-fat and high-cholesterol diet. (Pubmed Central) -  Jan 29, 2021   
    Obeticholic acid (OCA) activates the farnesoid X receptor (FXR) to lower circulating total cholesterol (TC) and high density lipoprotein-cholesterol (HDL-C) concentrations and to stimulate fecal cholesterol excretion in mice by increasing hepatic SR-B1 expression...However, OCA treatment of Sr-b1 KO mice fed a cholesterol-enriched diet reduced circulating cholesterol and increased fecal cholesterol output to comparable degrees to that of wild-type (WT) mice, and these effects were accompanied by substantial elevations of mRNA levels of Abca1, Abcg1, Abcg5, and Abcg8 in the ileum of Sr-b1 KO mice. Our studies suggest that FXR activation stimulates intestinal cholesterol excretion and reduces diet-induced hyperlipidemia through increased expression of ileal cholesterol transporters when hepatic SR-B1-mediated cholesterol movement is absent.
  • ||||||||||  Journal:  Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH). (Pubmed Central) -  Jan 28, 2021   
    EDP305, tropifexor, cilofexor, nidufexor, TERN.101, Px-104, EYP001, MET409...Efficacy of combining an FXR agonist with statins, CCR2, and ACC inhibitors is currently investigated. Identification of patient subsets would allow development of patients tailored therapy using a combination of drugs acting on different molecular mechanisms.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Review, Journal:  Review article: pathophysiology and management of primary biliary cholangitis. (Pubmed Central) -  Jan 12, 2021   
    PBC is a dynamic disease wherein current treatment goals have become appropriately ambitious. Goals of care should prioritise prevention of end-stage liver disease and amelioration of patient symptom burden for all.
  • ||||||||||  bile acid cholic acid (INT-777) / Intercept
    Journal:  Decreased Expression of TGR5 in Vogt-Koyanagi-Harada (VKH) Disease. (Pubmed Central) -  Jan 9, 2021   
    Goals of care should prioritise prevention of end-stage liver disease and amelioration of patient symptom burden for all. Our results show that a decreased TGR5 expression might contribute to the pathogenesis of VKH disease.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Journal:  Pyridoxal isonicotinoyl hydrazone inhibition of FXR is involved in the pathogenesis of isoniazid-induced liver injury. (Pubmed Central) -  Jan 7, 2021   
    HepaRG cells were treated with INH (10 mM) plus mixed bile acids (BA) and rats were treated with INH (60-600 mg/kg p.o.) or INH plus obeticholic acid (OCA, 10 mg/kg), a potent FXR agonist, for seven days...Liver total bile acids were significantly increased while FXR expression was not changed, but Shp mRNA levels were significantly decreased and Cyp7a1 mRNA was significantly increased, consistent with PIH acting as an FXR antagonist. In summary, PIH inhibition of liver FXR function leading to bile acid accumulation in hepatocytes may be an early pathogenesis event in INH-induced liver injury.
  • ||||||||||  bile acid cholic acid (INT-777) / Intercept
    Journal:  Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy (original article). (Pubmed Central) -  Jan 6, 2021   
    Moreover, GPS increased the TGR5 protein levels and promoted the interaction between IκBα and β-arrestin2, thereby inhibiting the reduction of IκBα and blocked NF-κB p65 nuclear translocation in the kidneys of STZ-induced diabetic mice. Collectively, these data suggested that GPS regulates the TGR5-β-arrestin2-NF-κB signalling pathway to prevent inflammation in the kidneys of diabetic mice, and ultimately ameliorates the pathological progression of diabetic renal fibrosis.
  • ||||||||||  Lacromid (bezafibrate) / Remedica
    Review, Journal:  Experimental Pharmacological Agents for the Treatment of Primary Biliary Cholangitis. (Pubmed Central) -  Dec 29, 2020   
    More recently, new pharmacological agents have been included in Phase 2 and Phase 3 trials: PPAR agonists, non-bile acid FXR agonists, anti-NOX agents, immunomodulators and mesenchymal stem cells transplantation. This review gives an overview on the current experimental pharmacological agents employed in the treatment of PBC.
  • ||||||||||  [VIRTUAL] Non-Alcoholic Steatohepatitis (NASH) Drug Pipeline Report September 2020 () -  Dec 26, 2020 - Abstract #ASHP2020ASHP_2853;    
    Due to the complexity of NASH pathophysiology, whether combinations of drugs may improve efficacy over single agents still remains to be studied. Currently available non-histological biomarkers have not consistently shown enough correlation to replace histological endpoints within clinical trials.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Clinical, Journal:  Obeticholic acid may increase the risk of gallstone formation in susceptible patients. (Pubmed Central) -  Dec 23, 2020   
    P2
    Our results show for the first time an enrichment of FGF19 in human bile after OCA treatment. In accordance with its murine homolog FGF15, FGF19 might trigger relaxation and filling of the gallbladder which, in combination with increased cholesterol saturation and BA hydrophobicity, would enhance the risk for gallstone development.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Preclinical, Journal:  Discovery and Optimization of Non-Bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis. (Pubmed Central) -  Dec 20, 2020   
    Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetics profiles, high liver distribution and preferable in vivo efficacy, indicating it is a potential candidate for the treatment of NASH or other FXR dependent diseases.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Journal, PARP Biomarker:  Obeticholic acid attenuates human immunodeficiency virus/alcohol metabolism-induced pro-fibrotic activation in liver cells. (Pubmed Central) -  Dec 17, 2020   
    We conclude that by suppressing oxidative stress and restoring proteasomal and lysosomal functions impaired by HIV and ethanol metabolism, OCA decreases accumulation of HIV in hepatocytes, leading to down-regulation of apoptosis in these cells. In addition, OCA reverses pro-fibrotic and inflammasome-related activation of HSC triggered by engulfment of HIV-containing apoptotic hepatocytes, potentially contributing to suppression of liver fibrosis development.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept, NN1213 / Novo Nordisk
    Trial completion date, Trial primary completion date:  Effect of Heavy Alcohol Consumption on Farnesoid X Receptor (FXR) Signaling (clinicaltrials.gov) -  Dec 8, 2020   
    P=N/A,  N=45, Recruiting, 
    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. Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Aug 2021
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Review, Journal:  The association of histological progression with biochemical response to ursodeoxycholic acid in primary biliary cholangitis. (Pubmed Central) -  Nov 21, 2020   
    Obeticholic acid is an approved second-line therapy for patients with PBC that are refractory to UDCA...Therefore, novel surrogate endpoints must be represented by parameters characterized by histological outcomes and treatment responses in PBC. In this review, we discuss the existing histological parameters and newly created factors to identify patients with PBC who are at a high risk of developing end-stage liver disease and, consequently, the potential need for additional treatments.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Biomarker, Journal:  Drug Therapies for Chronic Cholestatic Liver Diseases. (Pubmed Central) -  Nov 14, 2020   
    Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.