Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury model
Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury model
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DOI：
10.1161/01.cir.0000124063.74526.be
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发表时间：
2004-03-30
期刊：
影响因子：
37.8
通讯作者：
Cho, MC
中科院分区：
文献类型：
--
作者：
Kim, DW;Kwon, JS;Cho, MC
背景 - 紫杉醇已被证明可以抑制有助于新内膜形成的血管平滑肌细胞迁移和增殖。本研究测试了新型紫杉醇口服制剂是否可以预防大鼠颈动脉损伤模型中的新内膜形成。方法和结果 - 损伤后对 40 只大鼠通过管饲法给予紫杉醇口服制剂（0、5、7.5 或 10 mg/kg）5 天。给予5、7.5和10mg/kg紫杉醇的峰值血浆水平分别为61+/-16、89+/-22和108+/-28nmol/L。受伤后 11 天评估治疗效果。口服紫杉醇5、7.5和10mg/kg治疗组的血管造影最小管腔直径分别为6.28+/-2.09、6.97+/-1.79和7.97+/-1.57AU，显着大于对照组（4.67+/-1.45AU）。口服紫杉醇组（5、7.5、10 mg/kg；0.05 +/- 0.05、0.04 +/- 0.03、0.05 +/- 0.03 mm(2)）与对照组（0.13 +/- 0.05 mm2）相比，新内膜形成显着减少。所有大鼠均存活至研究完成。受伤后 4 至 6 天内，10 mg/kg 组中只有 2 只动物出现体重减轻（约 10%）和稀便。在研究期间所有其他动物都显得健康。为了比较的目的，通过注射向15只大鼠施用紫杉醇的腹膜内制剂（0或2mg/kg）。我们证实腹腔注射紫杉醇也能有效抑制新生内膜形成。结论-紫杉醇口服制剂提供了抑制大鼠血管损伤增殖反应的有效方法。因此，紫杉醇的口服制剂可以预防人类再狭窄而没有明显的毒性。
Background - Paclitaxel has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal formation. This study tested whether novel oral formulations of paclitaxel can prevent neointimal formation in a rat carotid artery injury model.Methods and Results - Oral formulations of paclitaxel (0, 5, 7.5, or 10 mg/kg) were administered to 40 rats by gavage for 5 days after injury. The peak plasma levels of paclitaxel administered at 5, 7.5, and 10 mg/kg were 61 +/- 16, 89 +/- 22, and 108 +/- 28 nmol/L, respectively. Treatment effects were assessed 11 days after injury. The angiographic minimum luminal diameters of the oral paclitaxel groups treated at 5, 7.5, and 10 mg/kg were 6.28 +/- 2.09, 6.97 +/- 1.79, and 7.97 +/- 1.57 AU, and these were significantly larger than that of the control group (4.67 +/- 1.45 AU). The oral paclitaxel groups (5, 7.5, 10 mg/kg; 0.05 +/- 0.05, 0.04 +/- 0.03, 0.05 +/- 0.03 mm(2)) showed significant neointimal formation reductions versus the control group (0.13 +/- 0.05 mm2). All rats survived to study completion. Only 2 animals in the 10 mg/kg group experienced weight loss (approximate to10%) and loose stools between 4 and 6 days after injury. All other animals appeared healthy during the study. For comparison purposes, intraperitoneal formulations of paclitaxel (0 or 2 mg/kg) were administered by injection to 15 rats. We confirmed that the intraperitoneal administration of paclitaxel also effectively inhibited neointimal formation.Conclusions - Oral formulations of paclitaxel provide an effective means of inhibiting proliferative response to vascular injury in the rat. Thus, oral formulations of paclitaxel may prevent human restenosis without significant toxicity.