Single injection of a sustained-release prostacyclin analog improves pulmonary hypertension in rats
Single injection of a sustained-release prostacyclin analog improves pulmonary hypertension in rats
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DOI：
10.1164/rccm.200703-349oc
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发表时间：
2008-01-15
影响因子：
24.7
通讯作者：
Nagaya, Noritoshi
中科院分区：
文献类型：
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作者：
Obata, Hiroaki;Sakai, Yoshiki;Nagaya, Noritoshi
理由：虽然前列环素是公认的治疗肺动脉高压的突破，但由于其作用时间短，需要持续输注。因此，我们开发了一种新的前列环素给药系统。我们制备了一种新型的丙环素类似物ONO-1301MS，它与聚（D， l -乳酸-羟基乙酸）（PLGA）微球聚合。目的：我们研究ONO-1301MS是否能减轻MCT诱导的大鼠肺动脉高压，并试图阐明ONO-1301MS有益作用的潜在机制。方法：大鼠注射MCT后，随机分为皮下注射ONO-1301MS 100 mg/kg或载药组。实验结果：制备ONO-1301MS，与PLGA聚合后释放ONO-1301，释放时间为3周。单次给药ONO-1301MS可使其循环水平和血浆环腺苷3′，5′-单磷酸水平持续升高3周，并减弱血栓素A代谢产物(2)水平的升高。注射MCT后3周大鼠出现肺动脉高压；然而，ONO-1301MS治疗显著降低了右心室收缩压和右心室重量与体重比的升高。ONO-1301MS明显抑制肺动脉肥大。在对照组中，肺细胞外信号调节蛋白激酶（ERK）的磷酸化显著增加，而这种增加在治疗后明显减弱。结论：利用PLGA和ONO-1301构建了一种新的前列环素给药系统。单次注射ONO-1301MS可导致持续3周的活性，并减轻肺动脉高压，部分原因是其通过抑制ERK磷酸化对血管平滑肌细胞具有抗增殖作用。
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 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.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.