Abstract 5958: Oral Administrations of a Novel Long-Acting Prostacyclin Analog with Thromboxane Synthase Inhibitory Activity Ameliorates Pulmonary Arterial Hypertension in Rats
Development of prostacyclin therapy has improved survival of pulmonary arterial hypertension (PAH) in clinical setting. However, this existing therapy still holds serious problems, including its short-term activity and difficulty in drug delivery. Therefore, we developed new long-acting prostacyclin agonist with thromboxane synthase inhibitory activity, ONO-1301, and examined the therapeutic efficacy after oral administration of ONO-1301 on rat monocrotaline (MCT) model of PAH. After subcutaneous injection of monocrotaline (MCT) or vehicle, male Wister rats (5wk, n=15) were randomized to receive repeated oral administration of ONO-1301 or vehicle twice a day for 24 days. Hemodynamic and histological analyses were performed on Day 25. In ONO-1301 treated MCT rats, significantly attenuated the increases in right ventricular systolic pressure (18.4% decrease, P<0.001), right ventricular hypertrophy (18.4% decrease in the ratio of right ventricular weight to body weight. P<0.01) and medial wall thickness of peripheral pulmonary arteries (31.2% decrease, P<0.001) compared to MCT rats given vehicle. Treatment with ONO-1301 significantly decreased urinary 11-dehydro thromboxane B2 (a metabolite of thromboxane, 24.0% decrease compared to control, P<0.001), indicating that administered ONO-1301 inhibited systemic thromboxane synthesis . We also investigated whether oral administration of ONO-1301 improved survival rate in MCT rats compared to clinically existing drugs. Kaplan-Meier survival curves demonstrated that oral administration of ONO-1301 signinicantly improved survival rate in MCT rats compared to vehicle, endothelin receptor blocker(Bosentan) and phosphodiesterase inhibitor(Sildenafil)(log-rank test ; P<0.05). In addition, for the assessment of late reversal, oral administration of ONO-1301 was started on day 1, day 7 or day 14 after MCT injection. Improved survival rates were found in all ONO-1301-treated groups compared to non-treated group (log-rank test ; P<0.01). Oral administration of ONO-1301 ameliorated PAH in rats. Our results indicate that ONO-1301 might be a promising oral drug for the treatment of PAH compared to clinically exsiting drugs.