#6489 UNI-494 DOES NOT SIGNIFICANTLY AFFECT RAT RESPIRATORY FUNCTION

Abstract

Abstract Background and Aims Nicorandil, a selective mitochondrial ATP-sensitive potassium channel activator, may be beneficial for several disease states, including acute kidney injury. However, its clinical use is limited by serious gastrointestinal side effects and rapid absorption and elimination. UNI-494, a novel nicorandil prodrug designed to improve its pharmacologic properties, may increase the short half-life and improve the safety profile of nicorandil. We present safety results from a safety pharmacology study evaluating the effects of UNI-494 on respiratory function in a rat model. Method The effects of UNI-494 on respiratory function (peak inspiratory and expiratory flow, inspiratory and expiratory time, minute volume, and respiratory rate) were evaluated using whole body plethysmography test in 4 groups of male Wistar Han rats (n = 8 per group). In addition to a control group, 3 test groups were administered doses of 2, 20, or 200 mg UNI-494/kg. Airway function parameter data generated were acquired using specialized EMKA Technologies software (IOX version 2.9.5; DATANLYST version 2.6.1) connected to Emka plethysmographic equipment. Recordings were taken 3 hours before and 4 hours after administration of the control and test items. Effects were reported at 0, 10, 15, 20, 30, 60, 90, 120, 180, and 240 minutes after administration. Results UNI-494 had no relevant effects on rat respiratory function over the 240-minute test period at any dose (2, 20, or 200 mg UNI-494/kg). There were small but insignificant differences in peak inspiratory and expiratory flow (Figure 1, 2), minute volume, respiratory rate, and inspiratory and expiratory time between the control group and the 200 mg UNI-494/kg group. Conclusion Rat respiratory function was not significantly affected by UNI-494. Future studies should continue to evaluate the safety and efficacy of this novel drug.