Pulmonary-delivered Anticalin Jagged-1 antagonists reduce experimental airway mucus hyperproduction and obstruction.

Mucus hypersecretion and mucus obstruction are pathogenic features in many chronic lung diseases directly linked to disease severity, exacerbation, progression, and mortality. The Jagged-1/Notch pathway is a promising therapeutic target that regulates secretory and ciliated cell trans-differentiation in the lung. However, the Notch pathway is also required in various other organs.

Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children.

Background And Objective: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by insufficient levels of survival motor neuron (SMN) protein. Risdiplam (Evrysdi) increases SMN protein and is approved for the treatment of SMA. Risdiplam has high oral bioavailability and is primarily eliminated through hepatic metabolism by flavin-containing monooxygenase3 (FMO3) and cytochrome P450 (CYP) 3A, by 75% and 20%, respectively.

Relative bioavailability and food effect study of an oral suspension of alectinib in healthy volunteers using venipuncture and capillary microsampling.

Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK-positive non-small cell lung cancer, is being assessed in children with ALK-positive solid and central nervous system tumors. An ad hoc pediatric-friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, crossover, relative bioavailability, and food effect study evaluated alectinib administered as an oral suspension versus capsule formulation following conventional venipuncture and capillary microsampling.

A20 and the noncanonical NF-κB pathway are key regulators of neutrophil recruitment during fetal ontogeny.

Newborns are at high risk of developing neonatal sepsis, particularly if born prematurely. This has been linked to divergent requirements the immune system has to fulfill during intrauterine compared with extrauterine life. By transcriptomic analysis of fetal and adult neutrophils, we shed new light on the molecular mechanisms of neutrophil maturation and functional adaption during fetal ontogeny.

Chemical, Analytical and Pharmacokinetic Characterisation of RO7304898, an API Consisting of Two Rapidly Interconverting Diastereoisomers.

Purpose: Exploration of the chemical, analytical and pharmacokinetic properties of the API, RO7304898, an allosteric EGFR inhibitor, intended to be developed as a mixture of two rapidly interconverting diastereoisomers with composition ratio of approximately 1:1.

Methods: Assessment of diastereoisomer stereochemistry, interconversion rates, binding to EGFR protein, metabolic stability and in vivo PK in Wistar-Han rats was conducted.

Results: The two diastereoisomers of the API undergo fast interconversion at physiologically relevant pH and direct EGFR binding studies revealed diastereoisomer B to be the active moiety.