Analgesia and peripheral c-fiber modulation by selective Nav1.8 inhibition in rhesus.

Voltage-gated sodium (Nav) channels present untapped therapeutic value for better and safer pain medications. The Nav1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays.

2-Aminopyridines as Potent and Selective Na1.8 Inhibitors Exhibiting Efficacy in a Nonhuman Primate Pain Model.

Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Na1.8 sodium channel. Parallel library synthesis, guided by predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay.

Temporal, Seasonal, and Monthly Effects on Total Knee Arthroplasty Surgical Site Infection Rates.

Background: Deep surgical site infections (dSSI) following total knee arthroplasty (TKA) are associated with morbidity and poor outcomes. Although numerous patient and non-patient factors have been correlated with dSSI development, the temporal and seasonal variability of dSSI is unclear. The purpose of this study was to investigate the monthly and seasonal variability of dSSI rates following TKA.

Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.

Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype.