Gemcitabine-Lipid Conjugate and ONC201 Combination Therapy Effectively Treats Orthotopic Pancreatic Tumor-Bearing Mice.

Gemcitabine (GEM) is a nucleoside analogue approved as a first line of therapy for pancreatic ductal adenocarcinoma (PDAC). However, rapid metabolism by plasma cytidine deaminase leading to the short half-life, intricate intracellular metabolism, ineffective cell uptake, and swift development of chemoresistance downgrades the clinical efficacy of GEM. ONC201 is a small molecule that inhibits the Akt and ERK pathways and upregulates the TNF-related apoptosis-inducing ligand (TRAIL), which leads to the reversal of both intrinsic and acquired GEM resistance in PDAC treatment.

Recent advances in drug delivery and targeting for the treatment of pancreatic cancer.

Despite significant treatment efforts, pancreatic ductal adenocarcinoma (PDAC), the deadliest solid tumor, is still incurable in the preclinical stages due to multifacet stroma, dense desmoplasia, and immune regression. Additionally, tumor heterogeneity and metabolic changes are linked to low grade clinical translational outcomes, which has prompted the investigation of the mechanisms underlying chemoresistance and the creation of effective treatment approaches by selectively targeting genetic pathways. Since targeting upstream molecules in first-line oncogenic signaling pathways typically has little clinical impact, downstream signaling pathways have instead been targeted in both preclinical and clinical studies.

Short-term exposure to JUUL electronic cigarettes can worsen ischemic stroke outcome.

Background: The short and long-term health effects of JUUL electronic cigarette (e-Cig) are largely unknown and warrant extensive research. We hypothesized that JUUL exposure could cause cerebrovascular toxicities impacting the progression and outcome of ischemic stroke comparable to tobacco smoke (TS) exposure.

Methods: We exposed male C57 mice to TS/JUUL vapor for 14 days.

In-Vivo and Ex-Vivo Brain Uptake Studies of Peptidomimetic Neurolysin Activators in Healthy and Stroke Animals.

Purpose: Neurolysin (Nln) is a peptidase that functions to preserve the brain following ischemic stroke by hydrolyzing various neuropeptides. Nln activation has emerged as an attractive drug discovery target for treatment of ischemic stroke. Among first-in-class peptidomimetic Nln activators, we selected three lead compounds (9d, 10c, 11a) for quantitative pharmacokinetic analysis to provide valuable information for subsequent preclinical development.

Effect of magnesium stearate surface coating method on the aerosol performance and permeability of micronized fluticasone propionate.

In this study, we evaluated the aerodynamic performance, dissolution, and permeation behavior of micronized fluticasone propionate (FP) and magnesium stearate (MgSt) binary mixtures. Micronized FP was dry mixed with 2% w/w MgSt using a tumble mixer and a resonant acoustic mixer (RAM) with and without heating. The mixing efficacy was determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis.