Target-Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model-Informed Dose Selection for the First-in-Human Study of AVB-S6-500.

AVB-S6-500 neutralized growth arrest-specific 6 (GAS6) protein and effectively inhibited AXL signaling in preclinical cancer models. A target-mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) model was used to select first-in-human (FIH) doses for AVB-S6-500 based on predicted target (GAS6) suppression in the clinic. The effect of TMDD on AVB-S6-500 clearance was incorporated into a standard two-compartment model, providing parallel linear and nonlinear clearance.

Evaluation of Eluxadoline Effect on Cardiac Repolarization.

This study evaluated the effects of eluxadoline, a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, on cardiac repolarization. This evaluator-blinded, placebo- and positive-controlled, 4-period crossover study randomized healthy men and women to single oral doses of eluxadoline (therapeutic dose 100 mg or supratherapeutic dose 1000 mg), moxifloxacin 400 mg, or placebo. QT data were corrected using individual custom correction (QTcI).

Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline.

The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS-d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0-inf) ] by 4.4- and 1.

New models of Tetrahymena telomerase RNA from experimentally derived constraints and modeling.

The telomerase ribonucleoprotein complex ensures complete replication of eukaryotic chromosomes. Telomerase RNA (TER) provides the template for replicating the G-rich strand of telomeric DNA, provides an anchor site for telomerase-associated proteins, and participates in catalysis through several incompletely characterized mechanisms. A major impediment toward understanding its nontemplating roles is the absence of high content structural information for TER within the telomerase complex.

MiRNA profile associated with replicative senescence, extended cell culture, and ectopic telomerase expression in human foreskin fibroblasts.

Senescence is a highly regulated process that limits cellular replication by enforcing a G1 arrest in response to various stimuli. Replicative senescence occurs in response to telomeric DNA erosion, and telomerase expression can offset replicative senescence leading to immortalization of many human cells. Limited data exists regarding changes of microRNA (miRNA) expression during senescence in human cells and no reports correlate telomerase expression with regulation of senescence-related miRNAs.

Effect of locked-nucleic acid on a biologically active g-quadruplex. A structure-activity relationship of the thrombin aptamer.

Here we tested the ability to augment the biological activity of the thrombin aptamer, d(GGTTGGTGTGGTTGG), by using locked nucleic acid (LNA) to influence its G-quadruplex structure. Compared to un-substituted control aptamer, LNA-containing aptamers displayed varying degrees of thrombin inhibition. Aptamers with LNA substituted in either positions G5, T7, or G8 showed decreased thrombin inhibition, whereas LNA at position G2 displayed activity comparable to un-substituted control aptamer.