32 research outputs found
Openâlabel, clinical trial extension:Twoâyear safety and efficacy results of seladelpar in patients with primary biliary cholangitis
SummaryBackgroundSeladelpar is a potent and selective peroxisome proliferatorâactivated receptorâÎŽ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to antiâcholestatic, antiâinflammatory and antiâpruritic effects.AimsTo evaluate the longâterm safety and efficacy of seladelpar in patients with PBC.MethodsIn an openâlabel, international, longâterm extension study, patients with PBC completing seladelpar leadâin studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10âmg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for nonâalcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2âyears.ResultsThere were no serious treatmentârelated adverse events observed among 106 patients treated with seladelpar for up to 2âyears. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2âyears of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67âĂâULN, â„15% decrease in ALP, and total bilirubin â€ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2.ConclusionsSeladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017â003910â16.</jats:sec
Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis
BACKGROUND: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-ÎŽ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects.
AIMS: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC.
METHODS: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10âmg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2âyears.
RESULTS: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2âyears. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2âyears of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67âĂâULN, â„15% decrease in ALP, and total bilirubin â€ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2.
CONCLUSIONS: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year
Dissimilarity in the occurrence of Bifidobacteriaceae in vaginal and perianal microbiota in women with bacterial vaginosis
Paraelectric and ferroelectric phases of betaine phosphite: structural, thermodynamic, and dielectric properties
Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice.
Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinurie in mice, is related to the single nucleotide polymorphism (SNP) C6418T of the prkdc gene encoding for the DNA repair enzyme DNA-PKcs. In addition, plasminogen (plg) has been reported to play a role in glomerular damage. Here, we investigated the interdependence of both factors for the development of DIN. Genotyping confirmed the SNP of the prkdc gene in C57BL/6 (prkdcC6418/C6418) and 129S1/SvImJ (prkdcT6418/T6418) mice. Intercross of heterozygous 129SB6F1 mice led to 129SB6F2 hybrids with Mendelian inheritance of the SNP. After doxorubicin injection, only homozygous F2 mice with prkdcT6418/T6418 developed proteinuria. Genetic deficiency of plg (plg-/-) in otherwise susceptible 129S1/SvImJ mice led to resistance to DIN. Immunohistochemistry revealed glomerular binding of plg in plg+/+ mice after doxorubicin injection involving histone H2B as plg receptor. In doxorubicin resistant C57BL/6 mice, plg binding was absent. In conclusion, susceptibility to DIN in 129S1/SvImJ mice is determined by a hierarchical two hit process requiring the C6418T SNP in the prdkc gene and subsequent glomerular binding of plasminogen