Bartoo, Anna

BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.

Abstract Shortages of antimicrobial agents rank second among all pharmaceutical classes. These shortages are persistent and increasing. The underlying reasons for shortages include manufacturing and quality issues, market economics, and changes in demand. Antimicrobial shortages compromise patient outcomes and increase treatment costs, contribute to antibiotic resistance, and may lead to increased adverse effects.

AbstractIntroductionActive engagement in research and scholarly output is challenging for pharmacists following residency training.ObjectivesTo determine the current structure of institutional support for pharmacy research, describe barriers to increasing staff research support and scholarly output, and benchmark best practices.MethodsA national survey was developed and distributed to the Vizient Consortium Director of Pharmacy listserv. The survey was conducted between October 2, 2019 and January 31, 2020 and incorporated 23 base questions assessing seven domains: financial support, study design/conduct support, interdisciplinary support, staff incentives, pharmacy research oversight, best practices, and barriers to research support.ResultsThe survey was distributed to 253 directors of pharmacy and 49 (19%) distinct responses were obtained. Most responders (71%) reported less than 25% of clinical staff were involved in research. Responses indicated most departmental research was driven by residents: 43% reported postgraduate year one (PGY1) and postgraduate year two (PGY2) residents were responsible for at least 75% of research projects. The greatest barriers to conducting research included time (72%), funding (33%), and knowledge/experience (32%). Research support included access to statisticians for data analysis (63%) or study design (57%), development of a pharmacy research committee (55%), and financial support or stipends (45%).ConclusionDespite institutional financial and educational support, the most commonly reported barriers to conducting pharmacy research were time, funding, and knowledge or experience of staff pharmacists.