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

• Published in: American journal of respiratory and critical care medicine 2008-01, Vol.177 (2), p.195-201
• Main Authors: Obata, Hiroaki, Sakai, Yoshiki, Ohnishi, Shunsuke, Takeshita, Satoshi, Mori, Hidezo, Kodama, Makoto, Kangawa, Kenji, Aizawa, Yoshifusa, Nagaya, Noritoshi
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antihypertensive Agents - administration & dosage; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Delayed-Action Preparations; Disease Models, Animal; Drug Compounding; Drug delivery systems; Efficiency; Electron microscopes; Epoprostenol - agonists; Extracellular Signal-Regulated MAP Kinases - drug effects; Extracellular Signal-Regulated MAP Kinases - metabolism; Hemodynamics - drug effects; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - physiopathology; Injections, Subcutaneous; Intensive care medicine; Kinases; Male; Medical sciences; Microspheres; Monocrotaline; Morphology; Phosphorylation; Pneumology; Polylactic acid; Polyvinyl alcohol; Pulmonary arteries; Pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacokinetics; Rats; Rats, Wistar; Smooth muscle; Thromboxane-A Synthase - antagonists & inhibitors
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200703-349OC

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. 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. After MCT injection, rats were randomized to receive a single subcutaneous injection of 100 mg/kg ONO-1301MS or vehicle. 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 A(2) 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. 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.