NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.

Continence Promotion and Successful Aging: The Role of the Multidisciplinary Continence Clinic.

Incontinence is a common yet under-recognized issue that impacts quality of life, especially for older adults in whom there is often a multifactorial etiology. A retrospective chart review was performed on a representative sample of patients seen at our multidisciplinary continence clinic in Vancouver, Canada from January to December 2017 inclusive. Initial assessment was performed by the nurse continence advisor (NCA) or geriatrician depending on the source of referral. The pelvic floor physiotherapist (PFP) could then be consulted based on perceived need. The average age at assessment was 76 years old (range 29⁻102), with 82% of patients ≥65 years and 27% ≥85 years old. The majority of patients were referred for bladder incontinence (72%), with the remaining patients referred for bowel incontinence (28%) or pessary care (7%). Referrals came from a variety of sources including physicians (62%), nurses (22%), allied health care providers (12%) and self-referral (5%). Multimorbidity was common, with 40% of patients having a Charlson Comorbidity Index ≥6. The same proportion of patients (40%) were on ≥5 prescription medications. Many patients were functionally dependent for either instrumental activities of daily living (52%) or activities of daily living (25%). Non-pharmacologic treatments were commonly recommended, with the majority of patients counselled on lifestyle changes (88%) and taught Kegel exercises (70%). For patients seen by the geriatrician, modifications were made to non-continence medications in 50% of cases and medical comorbidities were optimized in 39% of cases. In terms of pharmacologic therapy, over-the-counter (OTC) medications were initiated in 45% of patients whereas continence-specific prescription medications were started in 17% of patients. A multidisciplinary continence clinic can play an important role in promoting successful aging by assessing and treating medical causes of incontinence in medically complex older adults.