title: Oral administration of a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity for pulmonary arterial hypertension.
abstract: BACKGROUND
  Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity.
  
  
  RESULTS
  We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B2 and increased the plasma hepatocyte growth factor concentration.
  
  
  CONCLUSIONS
  Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor.
authors.affiliation: Second Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Nakamura
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Nagaya
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Obata
authors.forename: Katsuya
authors.initials: K
authors.lastname: Sakai
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sakai
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hamada
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D011464:Epoprostenol / Q000819:agonists*; D017228:Hepatocyte Growth Factor / Q000097:blood; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000652:urine; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D011725:Pyridines; C105488:ONO 1301; D013929:Thromboxane B2; D017228:Hepatocyte Growth Factor; C049235:11-dehydro-thromboxane B2; D016686:Monocrotaline; D011464:Epoprostenol; D013930:Thromboxane-A Synthase