The contribution of Na1.6 to the efficacy of voltage-gated sodium channel inhibitors in wild type and Na1.6 gain-of-function (GOF) mouse seizure control.

Background And Purpose: Inhibitors of voltage-gated sodium channels (Nas) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na channels as a means of informing the development of improved antiseizure drugs.

Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na1.

Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety Evaluation.

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or -thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors.

Clinical characteristics and treatment experience of individuals with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE): Findings from an online caregiver survey.

Purpose: SCN8A developmental epileptic encephalopathy (SCN8A-DEE) is a rare and severe genetic epilepsy syndrome characterized by early-onset developmental delay, cognitive impairment, and intractable seizures. SCN8A gene variants are associated with a broad phenotypic spectrum and variable disease severity. A caregiver survey, solicited by the advocacy group The Cute Syndrome Foundation (TCSF), was conducted to gather information on the demographics/disease presentation, seizure history, and treatment of patients with SCN8A-related epilepsies.

NBI-921352, a first-in-class, Na1.6 selective, sodium channel inhibitor that prevents seizures in gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na1.6 channels. Such a molecule provides a precision-medicine approach to target -related epilepsy syndromes (-RES), where gain-of-function (GoF) mutations lead to excess Na1.

Prior Work and Educational Experience Are Not Associated With Successful Completion of a Master's-Level, Distance Education Midwifery Program.

Introduction: In order to increase and diversify the midwifery workforce, admissions criteria for midwifery education programs must not contain unnecessary barriers to entry. Once accepted, students need to successfully complete the program. Many admissions criteria commonly used in midwifery education programs in the United States are not evidence based and could be unnecessary barriers to education.

Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability.

Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.

Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors.

Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption.