Activities of 4 chiral congeners PCB91, 95, 132, and 149 and their respective 4- and 5-hydroxy (-OH) derivatives toward rabbit skeletal muscle GW4869 molecular weight ryanodine receptor (RyR1) are investigated using [H-3]ryanodine binding and SR Ca-2 flux analyses. Although 5-OH metabolites have comparable activity to their respective parent in both assays, 4-OH derivatives are unable to trigger Ca-2 release from SR microsomes in the presence of Ca-2-ATPase activity. PCB95 and derivatives are investigated using single channel voltage-clamp and primary murine embryonic muscle cells (myotubes). Like

PCB95, 5-OH-PCB95 quickly and persistently increases channel open probability (p(o) bigger than .9) by stabilizing the full-open channel state, whereas 4-OH-PCB95 transiently enhances p(o). Ca-2 imaging of myotubes loaded with Fluo-4 show that acute exposure to PCB95 (5M) potentiates ECC and caffeine responses and partially depletes SR Ca-2 stores. Exposure to 5-OH-PCB95 (5 M) increases cytoplasmic Ca-2, leading to 4SC-202 rapid ECC failure in 50% of myotubes with the remainder retaining negligible responses.

4-OH-PCB95 neither increases baseline Ca-2 nor causes ECC failure but depresses ECC and caffeine responses by 50%. With longer (3h) exposure to 300nM PCB95, 5-OH-PCB95, or 4-OH-PCB95 decreases the number of ECC responsive myotubes by 22%, 81%, and 51% compared with control by depleting SR Ca-2 and/or uncoupling ECC. NDL-PCBs and their 5-OH and 4-OH metabolites differentially influence RyR1 channel activity and ECC in embryonic skeletal muscle.”
“Background and Objective Vandetanib is a selective inhibitor of vascular endothelial check details growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140];

omeprazole (proton pump inhibitor) or ranitidine (histamine H-2-receptor antagonist; both NCT01539655). Methods Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg +/- vandetanib 800 mg, midazolam 7.5 mg +/- vandetanib 800 mg, or digoxin 0.25 mg +/- vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1-4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics.