45 research outputs found
Alteration in P-glycoprotein Functionality Affects Intrabrain Distribution of Quinidine More Than Brain EntryâA Study in Rats Subjected to Status Epilepticus by Kainate
This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20Â mg/kg quinidine over 30 min or 4Â h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7Â h after the start of the infusion. Effect of pretreatment with tariquidar (15Â mg/kg, administered 30Â min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the bloodâbrain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the bloodâbrain barrier is altered at 1Â week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level
Elevated risk of infection with SARS-CoV-2 Beta, Gamma, and Delta variants compared with Alpha variant in vaccinated individuals
The extent to which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) break through infection- or vaccine-induced immunity is not well understood. We analyzed 28,578 sequenced SARS-CoV-2 samples from individuals with known immune status obtained through national community testing in the Netherlands from March to August 2021. We found evidence of an increased risk of infection by the Beta (B.1.351), Gamma (P.1), or Delta (B.1.617.2) variants compared with the Alpha (B.1.1.7) variant after vaccination. No clear differences were found between vaccines. However, the effect was larger in the first 14 to 59 days after complete vaccination compared with â„60 days. In contrast to vaccine-induced immunity, there was no increased risk for reinfection with Beta, Gamma, or Delta variants relative to the Alpha variant in individuals with infection-induced immunity.</p