GAL-160 increases CO2 chemosensitivity and reverses opioid-induced respiratory depression in rats (1092.14)

OIRD may result, at least in part, from decreased CO2 chemosensitivity. Previously, we reported that GAL-021 administered IV reverses OIRD and increases CO2 chemosensitivity in rats. GAL-021 IV has now been shown to attenuate OIRD in humans. Here we report on GAL-160, an orally bioavailable analog of GAL-021. In conscious rats, OIRD was induced with morphine (10 mg/kg, IV) and was evident as respiratory acidosis and hypoxemia using arterial blood gas analysis. GAL-160 (0.03 - 0.3 mg/kg/min X 30 min IV infusion) dose-dependently reversed the effects of morphine on breathing. The effects on CO2 chemosensitivity were evaluated in urethane anesthetized rats following biphasic IV infusion of GAL-160 (0.005 mg/kg/min X 15 min + 0.003 mg/kg/min X 60 min and 0.01 mg/kg/min X 15 min + 0.006 mg/kg/min X 60 min): regimens that do not stimulate ventilation. Minute volume was measured using tracheal spirometry at three levels of PaCO2: baseline (eucapnia), and +10 and +20 mmHg above baseline. CO2 chemosensitivity was ...