Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve.

As part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents produced changes in cardiovascular parameters and respiratory cessation.

An Exploratory Study Using Electronic Medical Records to Assess the Feasibility of Establishing Cohorts of Patients with Genetic Causes of Parkinson's Disease.

Background: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson's disease (PD).

Objective: To explore the use of the electronic medical records (EMRs) to identify participants with PD.

Methods: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2) and beta-glucocerebrosidase (GBA) variants.

Neurodegenerative Diseases: The Value of Early Predictive End Points.

Use of early predictive biomarkers of neurodegenerative disease in phase I clinical trials may improve the translation of novel drug therapies from preclinical development through late-stage studies. This article provides a categorical summary of promising biomarker approaches or clinical end points in molecular, cellular, metabolic, electrophysiological, or clinical function that can be used to predict or quantify the progression of neurodegenerative disorders and guide program support.

The PET tracer [C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [C]MK-6884 from rhesus monkeys to patients with Alzheimer’s disease (AD). [H]MK-6884/[C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo.