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Single Injection of a Sustained-release Prostacyclin Analog Improves Pulmonary Hypertension in Rats

¹ Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka, Japan; ² Division of Cardiology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan; ³ Ono Pharmaceutical Co. Ltd., Research Headquarters, Osaka, Japan; ⁴ Department of Internal Medicine, National Cardiovascular Center, Osaka, Japan; ⁵ Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Osaka, Japan; and ⁶ Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan

Correspondence and requests for reprints should be addressed to Noritoshi Nagaya, M.D., Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail: nnagaya{at}ri.ncvc.go.jp

Rationale: Although prostacyclin is recognized as a therapeutic breakthrough for pulmonary hypertension, it needs continuous infusion because of its short action. Therefore, we developed a new drug delivery system for prostacyclin. We prepared ONO-1301MS, a novel sustained-release prostacyclin analog polymerized with poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres.

Objectives: We examined whether ONO-1301MS attenuates monocrotaline (MCT)-induced pulmonary hypertension in rats, and attempted to elucidate the underlying mechanisms responsible for the beneficial effects of ONO-1301MS.

Methods: After MCT injection, rats were randomized to receive a single subcutaneous injection of 100 mg/kg ONO-1301MS or vehicle.

Measurements and Main Results: We prepared ONO-1301MS, which was polymerized with PLGA to release ONO-1301 for 3 weeks. A single administration of ONO-1301MS achieved sustained elevation of its circulating level and plasma cyclic adenosine 3',5'-monophosphate level for 3 weeks, and attenuated an increase in a metabolite of thromboxane A₂ level. Rats had developed pulmonary hypertension 3 weeks after MCT injection; however, treatment with ONO-1301MS significantly attenuated the increases in right ventricular systolic pressure and right ventricular weight to body weight ratio. ONO-1301MS significantly inhibited hypertrophy of pulmonary arteries. Phosphorylation of extracellular signal-regulated protein kinase (ERK) in the lung was significantly increased in the control group, whereas this increase was markedly attenuated by treatment.

Conclusions: We developed a new drug delivery system for prostacyclin using PLGA and ONO-1301. A single injection of ONO-1301MS resulted in sustained activity for 3 weeks, and attenuated pulmonary hypertension, partly through its antiproliferative effect on vascular smooth muscle cells via inhibition of ERK phosphorylation.

Key Words: pulmonary hypertension • prostacyclin analog • sustained-release preparation • extracellular signal regulated kinase • poly(lactic-co-glycolic acid)

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although prostacyclin is recognized as a therapeutic breakthrough for pulmonary hypertension, it needs continuous infusion because of its short action. For patients with pulmonary hypertension, development of a sustained-release prostacyclin would be beneficial in terms of stable hemodynamics and quality of life. What This Study Adds to the Field A single injection of ONO-1301MS resulted in sustained activity for 3 weeks, and attenuated pulmonary hypertension in rats.