48 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
Increased Migration of Monocytes in Essential Hypertension Is Associated with Increased Transient Receptor Potential Channel Canonical Type 3 Channels
Increased transient receptor potential canonical type 3 (TRPC3) channels have been observed in patients with essential hypertension. In the present study we tested the hypothesis that increased monocyte migration is associated with increased TRPC3 expression. Monocyte migration assay was performed in a microchemotaxis chamber using chemoattractants formylated peptide Met-Leu-Phe (fMLP) and tumor necrosis factor-α (TNF-α). Proteins were identified by immunoblotting and quantitative in-cell Western assay. The effects of TRP channel-inhibitor 2âaminoethoxydiphenylborane (2-APB) and small interfering RNA knockdown of TRPC3 were investigated. We observed an increased fMLP-induced migration of monocytes from hypertensive patients compared with normotensive control subjects (246±14% vs 151±10%). The TNF-α-induced migration of monocytes in patients with essential hypertension was also significantly increased compared to normotensive control subjects (221±20% vs 138±18%). In the presence of 2-APB or after siRNA knockdown of TRPC3 the fMLP-induced monocyte migration was significantly blocked. The fMLP-induced changes of cytosolic calcium were significantly increased in monocytes from hypertensive patients compared to normotensive control subjects. The fMLP-induced monocyte migration was significantly reduced in the presence of inhibitors of tyrosine kinase and phosphoinositide 3-kinase. We conclude that increased monocyte migration in patients with essential hypertension is associated with increased TRPC3 channels
Determination of trace elements in the human substantia nigra
''The gain in brain is mainly in the stain'' was long time a key sentence for research in neurodegenerative disease. However, for a quantification of the element concentrations (especially iron) in brain tissue, standard staining methods..