Highly potent and selective NaV1.7 inhibitors for use as intravenous agents and chemical probes.

The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.

Effect of laughter yoga on mood and heart rate variability in patients awaiting organ transplantation: a pilot study.

CONTEXT: Research shows that laughter has myriad health benefits, yet the medical community has not implemented it formally as a treatment. Patients awaiting organ transplantation have significant physical disabilities and are at risk for psychological distress. Attenuated heart rate variability (HRV) is a risk factor for a negative long-term outcome in some patients. OBJECTIVE: The study intended to evaluate the clinical utility of laughter yoga in improving psychological and physiological measures in outpatients awaiting organ transplantation. Positive results would indicate promising areas to pursue in a follow-up study. DESIGN: Six participants met for 10 sessions over 4 weeks. The research team measured each participant's heart rate, HRV, blood pressure (BP), and immediate mood before and after the laughter and control interventions. The team assessed participants' longer-term mood (anxiety and depression) at the study's initiation, after a no-treatment control week, and at the end of the study. SETTING: The study occurred at the Department of Surgery and Medicine at the University of Arizona Health Sciences Center, Tucson. PARTICIPANTS: Participants were patients awaiting transplants (three heart and three lung), two women and four men (ages 51-69 y). Participants had received no major surgery in the 3 months prior to the intervention, did not have a hernia or uncontrolled hypertension, and did not fall into the New York Heart Association function class 4. INTERVENTION: The 20-minute laughter intervention involved breathing and stretching exercises, simulated laughter (ie, unconditional laughter that is not contingent on the environment), chanting, clapping, and a meditation. The 20-minute control intervention involved the study's personnel discussing health and study-related topics with the participants. OUTCOME MEASURES: The research team measured BP, heart rate, and HRV and administered the Profile of Mood States, Beck Anxiety Inventory, and Beck Depression Inventory-II to evaluate immediate and longer-term mood. The team had planned quantitative statistical analysis of the data at the study's initiation but did not complete it because the number of enrolled participants was too low for the analysis to be meaningful. The team visually examined the data, however, for trends that would indicate areas to examine further in a follow-up study. RESULTS: Participants showed improved immediate mood (vigor-activity and friendliness) and increased HRV after the laughter intervention. Both the laughter and control interventions appeared to improve longer-term anxiety. Two participants awaiting a lung transplant dropped out of the study, and no adverse events occurred. CONCLUSION: This pilot study suggests that laughter yoga may improve HRV and some aspects of mood, and this topic warrants further research.