Oral Administration of a Novel Long-Acting Prostacyclin Agonist With Thromboxane Synthase Inhibitory Activity for Pulmonary Arterial Hypertension

• Nakamura Atsuhiro

  Second Department of Internal Medicine, Nara Medical University Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute

• Nagaya Noritoshi

  Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute

• Obata Hiroaki

  Division of Cardiology, Niigata University Graduate School of Medical and Dental Science

• Sakai Katsuya

  Division of Tumor Dynamics and Regulation, Molecular & Cellular Targeting Translational Oncology Center, Cancer Research Institute, Kanazawa University

• Sakai Yoshiki

  Ono Pharmaceutical Co Ltd, Research Headquarters

• Yoshikawa Masanori

  Second Department of Internal Medicine, Nara Medical University

• Hamada Kaoru

  Second Department of Internal Medicine, Nara Medical University Department of Clinical Medicine, Faculty of Nursing, Nara Medical University

• Matsumoto Kunio

  Division of Tumor Dynamics and Regulation, Molecular & Cellular Targeting Translational Oncology Center, Cancer Research Institute, Kanazawa University

• Kimura Hiroshi

  Second Department of Internal Medicine, Nara Medical University

抄録

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. Methods and 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.  (Circ J 2013; 77: 2127–2133)<br>

収録刊行物

• Circulation Journal

  Circulation Journal 77 (8), 2127-2133, 2013

  一般社団法人 日本循環器学会

キーワード

• cAMP
• Hepatocyte growth factor
• Monocrotaline
• Pulmonary arterial hypertension
• Thromboxane synthase

詳細情報

• CRID: 1390001205103689472
• NII論文ID: 10031178685
• NII書誌ID: AA11591968
• DOI: 10.1253/circj.cj-13-0107
• COI: 1:CAS:528:DC%2BC3sXhsVSltbjK
• ISSN: 13474820
• ISSN: 13469843
• PubMed: 23676973
• Web Site: https://www.jstage.jst.go.jp/article/circj/77/8/77_CJ-13-0107/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2014298861
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• 抄録ライセンスフラグ: 使用不可