A Novel Approach to Visualize Risk Minimization Effectiveness: Peeping at the 2012 UK Proton Pump Inhibitor Label Change Using a Rapid Cycle Analysis Tool.

INTRODUCTION: Evaluation of risk minimization (RM) actions is an emerging area of regulatory science, often without tools to rapidly and systematically assess their effectiveness. PURPOSE: The aim of this study was to evaluate whether chronographs, typically used for rapid signal detection in observational longitudinal databases, could be used to visualize RM effectiveness. We evaluated the UK Medicines and Healthcare products Regulatory Agency (MHRA) 2012 proton-pump inhibitors (PPIs) class-wide label change that warned of increased risk of bone fracture, advocated to limit duration of use, and recommended to treat those at risk for osteoporosis according to clinical guidelines. METHODS: The cohort consisted of adults aged 18 years and above prescribed one of the five PPIs available in the UK The Health Improvement Network (THIN) database through September 2015. Four chronographs were compared using drug episodes that started before (PRE) and after (POST) the 20 April 2012 MHRA warning; fracture and osteoporosis were evaluated separately. Chronographs show a measure of observed/expected events, the Information Component (IC) and 95% credibility interval (CI), calculated at monthly time intervals relative to the start date of a prescription, and summed to estimate IC over a 3-year period; IC > 0 indicates observed > expected events. We hypothesized that chronographs may assess RM effectiveness if stratified by PRE/POST an RM intervention such as a label change. RESULTS: There were 1,588,973 and 664,601 PPI users in the PRE and POST periods, respectively. We observed a 4.6% reduction in the proportion of long-term PPI episodes and a 4.1% reduction in the overall proportion of the THIN population using PPIs. Compared with the PRE chronographs, when both visually comparing and when examining the summed ICs for fracture in the POST period, a significant reduction was observed overall (IC = 0.024 [95% CI 0.015 to 0.33] PRE vs - 0.141 [95% CI - 0.162 to - 0.120] POST), suggesting less observed events than expected, and prior to PPI start, suggestive of strong channeling (IC = - 0.027 [95% CI - 0.037 to - 0.017] PRE vs - 0.291 [95% CI - 0.308 to - 0.274] POST). Results were qualitatively similar for osteoporosis. CONCLUSIONS: This pilot demonstrated a novel application of a visual, rapid analysis technique to assess RM effectiveness, and supported a hypothesis that prescribers altered some behaviors after the MHRA label change, such as channeling patients at risk of fracture or osteoporosis away from PPI use and potentially reducing fracture outcomes. Limitations include lack of confounding control and outcomes defined only by diagnosis code. Results demonstrate the potential to use large healthcare databases with chronographs to rapidly assess RM effectiveness, similar to signal detection in pharmacovigilance, and may help design more comprehensive RM evaluation studies.

Assessment of Radiometer Calibration with GPS Radio Occultation for the MiRaTA CubeSat Mission.

The Microwave Radiometer Technology Acceleration (MiRaTA) is a 3U CubeSat mission sponsored by the NASA Earth Science Technology Office (ESTO). The science payload on MiRaTA consists of a tri-band microwave radiometer and Global Positioning System (GPS) radio occultation (GPSRO) sensor. The microwave radiometer takes measurements of all-weather temperature (V-band, 50-57 GHz), water vapor (G-band, 175-191 GHz), and cloud ice (G-band, 205 GHz) to provide observations used to improve weather forecasting. The Aerospace Corporation's GPSRO experiment, called the Compact TEC (Total Electron Content) and Atmospheric GPS Sensor (CTAGS), measures profiles of temperature and pressure in the upper troposphere/lower stratosphere (∼20 km) and electron density in the ionosphere (over 100 km). The MiRaTA mission will validate new technologies in both passive microwave radiometry and GPS radio occultation: (1) new ultra-compact and low-power technology for multi-channel and multi-band passive microwave radiometers, (2) the application of a commercial off the shelf (COTS) GPS receiver and custom patch antenna array technology to obtain neutral atmospheric GPSRO retrieval from a nanosatellite, and (3) a new approach to spaceborne microwave radiometer calibration using adjacent GPSRO measurements. In this paper, we focus on objective (3), developing operational models to meet a mission goal of 100 concurrent radiometer and GPSRO measurements, and estimating the temperature measurement precision for the CTAGS instrument based on thermal noise. Based on an analysis of thermal noise of the CTAGS instrument, the expected temperature retrieval precision is between 0.17 K and 1.4 K, which supports the improvement of radiometric calibration to 0.25 K.

Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists.

Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.