拉扎罗类药物疗法（甲氨基色满：U83836E）可减轻静脉移植物内膜增生。

Davies M G, Dalen H, Barber L, Svendsen E, Hagen P O

Vascular Biology and Atherosclerosis Research Laboratory, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.

J Surg Res. 1996 Jun;63(1):128-36. doi: 10.1006/jsre.1996.0235.

The development of intimal hyperplasia is now recognized as a major impediment to graft patency and recent studies suggest that the infiltration of polymorphonucleocytes and oxygen free radical mediated injury are involved in the early development of intimal hyperplasia. This study examines the effect of a methylaminochroman, U83836E (Upjohn Company), a second generation lazaroid, in controlling the development of intimal hyperplasia and its associated smooth muscle cell physiological responses in an experimental model of vein bypass grafting. Twenty New Zealand White rabbits had a right carotid interposition bypass graft using the ipsilateral external jugular vein. Ten animals received chronic oral therapy with U83836E (10 mg/kg/day; begun 5 days before surgery and continued until harvest) and 10 control animals received vehicle only. All animals were sacrificed on the 28th postoperative day. Vein grafts were harvested either for morphology/videomorphometry (n = 6 per group) or for in vitro isometric tension studies (n = 4; four 5-mm rings per graft). The incorporation of [3H]thymidine into the cellular DNA of serum-stimulated rabbit aortic smooth muscle cells (passage 6th to 9th) was also assessed in the presence of increasing concentrations of U83836E (10(-9) to 10(-4) M). Treatment with U83836E produced a 41% decrease in overall mean intimal thickness in the U83836E-treated vein grafts compared to untreated vein grafts (P = 0.003). There were no differences in the medial thicknesses or luminal dimensions of the control and treated vein grafts. U83836E induced norepinephrine hypersensitivity in both jugular veins and vein grafts compared to controls. Other physiological contractile responses of the jugular veins and vein grafts were unaltered by U83836E. U83836E did not inhibit the in vitro [3H] thymidine incorporation in a dose-dependent manner until very high concentration when there was a significant and precipitous response with an IC(50) of 67 microM (114 microgram/ml) and a maximal inhibition of 97 +/- 2% (mean +/- SEM) at 80 microM (137 microgram/ml). Therapy with the methylaminochroman, U83836E, is beneficial in controlling the early development of intimal hyperplasia without significant changes in the physiological responses of the smooth muscle cells.

内膜增生的发展现已被认为是移植物通畅的主要障碍，最近的研究表明，多形核细胞的浸润和氧自由基介导的损伤参与了内膜增生的早期发展。本研究在静脉搭桥移植的实验模型中，检测了第二代拉扎罗类药物甲氨基色满U83836E（Upjohn公司）在控制内膜增生发展及其相关平滑肌细胞生理反应方面的作用。20只新西兰白兔用同侧颈外静脉进行右颈动脉间置搭桥移植。10只动物接受U83836E慢性口服治疗（10mg/kg/天；术前5天开始，持续至取材），10只对照动物仅接受赋形剂。所有动物在术后第28天处死。静脉移植物取材后用于形态学/视频形态测量（每组6只）或用于体外等长张力研究（每组4只；每个移植物取4个5mm的环）。在浓度不断增加的U83836E（10⁻⁹至10⁻⁴M）存在的情况下，还评估了[³H]胸腺嘧啶核苷掺入血清刺激的兔主动脉平滑肌细胞（第6至9代）细胞DNA中的情况。与未处理的静脉移植物相比，U83836E处理使U83836E处理的静脉移植物的总体平均内膜厚度降低了41%（P = 0.003）。对照和处理的静脉移植物的中膜厚度或管腔尺寸没有差异。与对照相比，U83836E在颈静脉和静脉移植物中均诱导了去甲肾上腺素超敏反应。U83836E未改变颈静脉和静脉移植物的其他生理收缩反应。直到非常高的浓度时，U83836E才以剂量依赖的方式抑制体外[³H]胸腺嘧啶核苷掺入，此时出现显著且急剧的反应，IC₅₀为67μM（114μg/ml），在80μM（137μg/ml）时最大抑制率为97±2%（平均值±标准误）。用甲氨基色满U83836E治疗有利于控制内膜增生的早期发展，而平滑肌细胞的生理反应无显著变化。