In Pursuit of an Allosteric Human Tropomyosin Kinase A (hTrkA) Inhibitor for Chronic Pain.

Human ß-nerve growth factor (ß-NGF) and its associated receptor, human tropomyosin receptor kinase A (hTrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located hTrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective hTrkA allosteric inhibitor, 1. 1 was shown to be active against the full length hTrkA, showing preferential binding for the inactive kinase, and was confirmed through the X-ray of hTrkA···1 bound complex. 1 was also found to inhibit ß-NGF induced neurite outgrowth in rat PC12 cells. Daily oral administration of 1 improved the joint compression threshold of rats injected intra-articularly with monoiodoacetate over a 14-day period. The efficacy of 1 in a relevant chronic pain model of osteoarthritis coupled with in vitro confirmation of target mediation makes allosteric hTrkA inhibitors potential candidates for modulating pain.

Serotonin-Modulating Antidepressants and Risk of Bleeding after Trauma.

Serotonin-modulating antidepressants have been associated with increased risk of gastrointestinal bleeding and increased blood loss during elective surgery. This study sought to investigate the effect of preinjury selective-serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) use on transfusion requirements after trauma, and to evaluate whether resumption of SSRI/SNRI after trauma may worsen bleeding risk. This was a retrospective matched-cohort study evaluating patients with solid organ injury. Preinjury SSRI/SNRI users were matched to non-SSRI/SNRI users based on age, preinjury aspirin use, Injury Severity Score, and abdominal Abbreviated Injury Severity Score. The primary endpoint was transfusion requirement during hospitalization. The absolute need for transfusion was higher in SSRI/SNRI users throughout hospitalization (50.9% vs 37.3%, P = 0.02). After logistic multivariate analysis, SSRI/SNRI users were more likely to require transfusion at 24 hours (odds ratio (95% confidence interval): 2.73 (1.41, 5.29), P = 0.003), but this difference did not persist for overall hospitalization (odds ratio (95% confidence interval): 1.32 (0.74, 2.36), P = 0.35). Fewer patients restarted on SSRI/SNRI therapy within 72 hours required packed red blood cell transfusion compared with those who were restarted later or not at all (43.2% vs 60.3%; P = 0.04). Preinjury use of serotonin-modulating antidepressants led to an increased requirement of blood transfusions after solid organ injury. Although clinicians should weigh bleeding risk before reinitiation of SSRI/SNRI, the results of this study indicate that reasonable efforts to restart these medications after stabilization do not result in further risk for transfusion.

A high-fidelity simulation mannequin to introduce pharmacy students to advanced cardiovascular life support.

OBJECTIVE: To design and implement an advanced cardiac life support (ACLS) workshop featuring a human patient simulator (HPS) for third-year pharmacy students. DESIGN: The ACLS workshop consisted of a pre-session lecture, a calculation exercise, and a 40-minute ACLS session using an HPS. Twenty-four 5-member teams of students were assigned roles on a code team and participated in a ventricular fibrillation/pulseless ventricular tachycardia case. ASSESSMENT: Students completed an anonymous postactivity survey instrument and knowledge quiz. Most students who completed the ACLS workshop agreed they would like to participate in additional simulation activities and that the HPS experience enhanced their understanding of ACLS and the pharmacist responsibilities during an ACLS event (99.2% and 98.3%, respectively). However, the median score on the knowledge-based questions was 25%. CONCLUSION: Pharmacy students agreed HPS enhanced their learning experience; however, their retention of the knowledge learned was not consistent with the perceived benefits of HPS to education.