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  • ||||||||||  Ocaliva (obeticholic acid) / Intercept, Lacromid (bezafibrate) / Remedica
    [VIRTUAL] Obeticholic acid but not bezafibrate treatment improves cholestasis-induced cognitive decline (Poster Area) -  May 30, 2020 - Abstract #EASLILCI2020EASL-ILC-I-509;    
    Consistent with our previous studies, OCA therapy attenuates fibrogenesis and prevents cognitive symptoms in cholestatic BDL mice. Our data suggests that the cognitive effects of OCA are through a direct FXR-mediated effect rather than an indirect effect through reduced cholestasis.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    [VIRTUAL] Therapeutic Targeting of Bile Acid Metabolism Ameliorates Liver Ischemia/Reperfusion Injury (Virtual) -  May 29, 2020 - Abstract #ATC2020ATC_205;    
    In a murine liver partial warm ischemia model (60m and 90m), we treated mice with FXR agonist 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064) or obeticholic acid (OCA) either 1h prior to the onset of ischemia (pretreatment, 1 dose) or starting at 24h post reperfusion (posttreatment 1 dose/day x3) to determine its effect on the activation or the resolution of liver IRI, respectively... Phamacological activation of FXR protects livers from IRI by up-regulating SHP in KCs to inhibit liver proinflammatory response.
  • ||||||||||  bile acid cholic acid (INT-777) / Intercept
    [VIRTUAL] Study on the Mechanism of Activating Macrophages TGR5 on Glucose Metabolism during Pregnancy () -  May 18, 2020 - Abstract #ADA2020ADA_3210;    
    Activation of TGR5 in BMDM can effectively inhibit the macrophage polarization to M1, including inhibiting inflammatory factors expression and secretion. Moreover, activation of TGR5 can inhibit macrophage chemokine expression and secretion, cell migration and can upregulate PC1/3 expression.
  • ||||||||||  bile acid cholic acid (INT-777) / Intercept
    [VIRTUAL] Study on the Mechanism of Activating Macrophages TGR5 on Glucose Metabolism during Pregnancy () -  May 18, 2020 - Abstract #ADA2020ADA_2011;    
    Activation of TGR5 in BMDM can effectively inhibit the macrophage polarization to M1, including inhibiting inflammatory factors expression and secretion. Moreover, activation of TGR5 can inhibit macrophage chemokine expression and secretion, cell migration and can upregulate PC1/3 expression.
  • ||||||||||  bile acid cholic acid (INT-777) / Intercept
    Journal:  Activation of TGR5 receptor reduces damage of ET-1 on H9C2 cardiomyocytes by activating Nrf2. (Pubmed Central) -  May 18, 2020   
    Moreover, activation of TGR5 can inhibit macrophage chemokine expression and secretion, cell migration and can upregulate PC1/3 expression. Activation of TGR5 receptor may reduce the damage of ET-1 on H9C2 cardiomyocytes by activating Nrf2 and its downstream antioxidant genes HO-1, NQO-1 and Txnrd-1.
  • ||||||||||  INT-767 / Intercept, elafibranor (GFT505) / Genfit
    Preclinical, Journal:  Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH. (Pubmed Central) -  May 17, 2020   
    In conclusion, in-depth analyses of liver homogeneity demonstrated that drug-induced improvement in liver biopsy-assessed histopathology is representative for overall liver effects assessed using stereology. Importantly, these findings reveal how changes in whole-liver mass should be considered to provide a deeper understanding of apparent drug treatment efficacy in preclinical NASH studies.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Trial primary completion date:  Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients (clinicaltrials.gov) -  May 14, 2020   
    P2,  N=20, Recruiting, 
    Importantly, these findings reveal how changes in whole-liver mass should be considered to provide a deeper understanding of apparent drug treatment efficacy in preclinical NASH studies. Trial primary completion date: Jun 2020 --> Sep 2020
  • ||||||||||  Review, Journal:  Semisynthetic bile acids: a new therapeutic option for metabolic syndrome. (Pubmed Central) -  May 13, 2020   
    This review summarizes and critically evaluates the key chemical modifications of bile acids resulting in development of novel semisynthetic derivatives as well as the current status of their preclinical and clinical evaluation in metabolic syndrome treatment, so far lacking in the scientific literature. Taking into account the balance between therapeutic benefits and potential adverse effects associated with specific structure and mechanism of action, recommendations for future studies are proposed.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Preclinical, Journal:  Gypenosides regulate farnesoid X receptor-mediated bile acid and lipid metabolism in a mouse model of non-alcoholic steatohepatitis. (Pubmed Central) -  May 8, 2020   
    At the end of week 10, HFD-fed mice were randomly divided into HFD, HFD plus Gyp, and HFD plus obeticholic acid (OCA, FXR agonist) groups and were given the corresponding treatments for 4 weeks...Further, HFD-induced alterations in the expression genes involved in bile acid and lipid metabolism, such as CYP7A1, BSEP, SREBP1, and FASN, were significantly alleviated. Gyp can improve liver lipid and bile acid metabolism in a mouse model of NASH, and these effects may be related to activation of the FXR signaling pathway.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Review, Journal:  Precision medicine in primary biliary cholangitis. (Pubmed Central) -  May 6, 2020   
    The introduction of obeticholic acid in 2016 as a second-line treatment, together with the creation and validation of several biochemically based scores to stratify the risk of progressive disease, has opened up the need to redefine clinical practice by changing the actual paradigm...The availability of a second line disease-modifying drug and new molecules in 2 or 3 phase trial, make this an exciting time for the PM initiative in PBC. In this review we describe the current risk stratification tools and we track a possible path toward the application of precision medicine in clinical daily life.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    BIOCHEMICAL RESPONSE TO OBETICHOLIC ACID IN PRIMARY BILIARY CHOLANGITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS. () -  May 4, 2020 - Abstract #DDW2020DDW_7127;    
    Our study confirms that a 3-month therapy of 10 mg of OCA results in a significant reduction in baseline ALP levels along with all the other liver enzymes in PBC patients when used as a monotherapy or in combination with UDCA. Since biochemical response has been proven to predict clinical outcomes in PBC patients, our findings suggest that OCA use could result in better transplant-free survival and liver-related outcomes in these patients.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    OBETICHOLIC ACID IMPROVES HEPATIC FIBROINFLAMMATION AS ASSESSED BY MULTIPARAMETRIC MRI: INTERIM RESULTS OF THE REGENERATE TRIAL () -  May 4, 2020 - Abstract #DDW2020DDW_5555;    
    Treatment with OCA resulted in dose-dependent improvements in cT1 and liver fat content measured noninvasively by multiparametric MRI, which may be consistent with histologic improvements in steatohepatitis and fibrosis, as well as in serum-based noninvasive markers of steatohepatitis and fibrosis (Anstee 2019). 1The REGENERATE Month 18 interim analysis results are based on surrogate endpoints considered reasonably likely to predict clinical benefit and longer-term OCA treatment effect on clinical outcomes has not yet been demonstrated; the study is ongoing through outcomes to characterize OCA’s clinical benefit.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    EFFECTS OF BILE ACIDS ON METABOLIC PROFILE IN OBESE ANIMAL MODEL () -  May 4, 2020 - Abstract #DDW2020DDW_5038;    
    The second study compared the two groups of HFD, HFD + UDCA for 5 weeks to confirm reproducibility, and as another control, HFD + obeticholic acid(FXR agonist; Ocaliva®) was added...In conclusion, weight gain due to high fat diet may be slowed down by bile acids. However, It is not likely to be due to microbial changes in the intestinal tract but is likely to be involved in the direct effect of body metabolism of bile acids
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Journal:  Obeticholic acid ameliorates Valproic acid-induced Hepatic Steatosis and Oxidative Stress. (Pubmed Central) -  Apr 23, 2020   
    Constitutive activation of the farnesoid X receptor reduces PPARγ hepatic expression and induces hepatic antioxidant activity. The variability in FXR expression level/activity, for instance in individuals carrying loss-of-function genetic variants of the FXR gene, could contribute to valproic acid pharmacokinetic and toxicokinetic profile.
  • ||||||||||  acarbose / Generic mfg.
    Preclinical, Journal:  Acarbose improves health and lifespan in aging HET3 mice. (Pubmed Central) -  Apr 22, 2020   
    Three other interventions were also tested: ursolic acid, 2-(2-hydroxyphenyl) benzothiazole (HBX), and INT-767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose-control drugs in humans.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Review, Journal:  Primary biliary cholangitis: pathogenesis and therapeutic opportunities. (Pubmed Central) -  Apr 22, 2020   
    Substantial progress has been made in patient risk stratification with the goal of personalized care, including early adoption of next-generation therapy with licensed use of obeticholic acid or off-label fibrate derivatives for those with insufficient benefit from ursodeoxycholic acid, the current first-line drug...Immunotherapy remains a challenge, with a lack of target definition, pleiotropic immune pathways and an interplay between hepatic immune responses and cholestasis, wherein bile acid-induced inflammation and fibrosis are dominant clinically. The management of patient symptoms, particularly pruritus, is a notable goal reflected in the development of rational therapy with apical sodium-dependent bile acid transporter inhibitors.
  • ||||||||||  Triglide (fenofibrate) / Vectura, Shionogi
    Journal:  Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPARα. (Pubmed Central) -  Apr 12, 2020   
    Moreover, formononetin attenuated ANIT-induced inflammatory response by inactivating JNK inflammation pathway in PPARα dependent manner. Taken together, our study demonstrates that formononetin ameliorates hepatic cholestasis by upregulating expression of SIRT1 and activating PPARα, which is an important anti-cholestatic mechanism of formononetin.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Journal:  SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. (Pubmed Central) -  Apr 10, 2020   
    Here we report that prophylactic but not therapeutic administration of obeticholic acid (OCA) prevents hepatic stellate cell (HSC) activation and fibrogenesis...Therapeutic coadministration of OCA and SUMOylation inhibitors drastically impedes liver fibrosis induced by CCl, bile duct ligation, and more importantly NASH. In conclusion, we propose a promising therapeutic approach by combining SUMOylation inhibitors and FXR agonists for liver fibrosis.
  • ||||||||||  Firsocostat (GS-0976) / Gilead, Ocaliva (obeticholic acid) / Intercept, cilofexor (GS-9674) / Gilead
    Review, Journal:  Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis. (Pubmed Central) -  Mar 24, 2020   
    Another farnesoid X receptor agonist, cilofexor, in combination with firsocostat, an acetyl-CoA carboxylase inhibitor, improved hepatic steatosis, liver stiffness, liver function tests and serum fibrosis markers, without causing pruritus after 12 weeks of treatment. In conclusion, current evidence regarding the effect of farnesoid X receptor agonists on hepatic histology in patients with NASH is promising, but several safety issues need further evaluation.
  • ||||||||||  Ocaliva (obeticholic acid) / Intercept
    Journal:  miR-22 inhibition reduces hepatic steatosis via FGF21 and FGFR1 induction. (Pubmed Central) -  Mar 21, 2020   
    Our novel data revealed that the metabolic silencing effect of miR-22 occurs as a result of reductions in metabolic stimulators, which likely contribute to the development of fatty liver. Consistent with this finding, an miR-22 inhibitor effectively reversed both alcohol- and diet-induced fatty liver; miR-22 inhibition is a promising therapeutic option which could be used in combination with obeticholic acid.