Brauner R, Laks H, Drinkwater D C, Chaudhuri G, Shvarts O, Drake T, Bhuta S, Mishaly D, Fishbein I, Golomb G
Division of Cardiothoracic Surgery, University of California at Los Angeles School of Medicine, USA.
J Thorac Cardiovasc Surg. 1997 Jul;114(1):53-63. doi: 10.1016/S0022-5223(97)70117-X.
Inhibition of early myointimal proliferation may improve longterm patency of vein grafts, but the clinical use of many experimental drugs is limited by systemic toxicity. To determine whether this goal can be achieved by low-dose targeted drug administration, we constructed a polymeric system delivering verapamil and evaluated the effects on local and downstream vein graft morphology, neointimal smooth muscle cell proliferation, and vasomotor function.
Ethylene-vinyl acetate polymeric delivery systems were constructed, containing 2% verapamil by weight. These are flexible, biocompatible, and nonbiodegradable matrices, delivering the drug at a rate of 10 micrograms/day. The autologous external jugular vein was used to create a carotid artery bypass graft in hypercholesterolemic (n = 22) rabbits. Verapamil-containing matrices (n = 12) or plain polymers (control, n = 10) were wrapped around the proximal third of the veins after reperfusion. Graft vasomotor function was evaluated and was also compared with function of an additional group of normocholesterolemic vein grafts (n = 8).
Twenty-eight days after grafting, intimal index (intima/media thickness ratio) was 31% lower, neointima/original lumen surface ratio was 26% lower, and residual luminal area was 71% greater (4.00 +/- 1.2 mm2 versus 2.34 +/- 0.9 mm2, all p < 0.01) under verapamil matrices compared with control grafts. Neointimal smooth muscle cell content was reduced from 45.4% to 28.2%, and net neointimal smooth muscle cell thickness was reduced by 47% (30 microns vs 15.8 microns, both p < 0.01). Verapamil-treated segments distal to the matrices also showed significantly lower neointimal smooth muscle cell density and increased lumen size. Sensitivity to serotoin and vasomotor responses to serotonin, norepinephrine, and sodium nitroprusside in distal segments were significantly lower in verapamil-treated grafts than in controls.
Periadventitial controlled administration of verapamil below 1% of the systemic dose effectively inhibits myointimal hyperplasia in vein grafts. Local polymeric drug delivery may be readily applicable to coronary revascularization operations.
抑制早期肌内膜增殖可能会改善静脉移植物的长期通畅性，但许多实验药物的临床应用受到全身毒性的限制。为了确定通过低剂量靶向给药是否能实现这一目标，我们构建了一种递送维拉帕米的聚合物系统，并评估其对局部和下游静脉移植物形态、新生内膜平滑肌细胞增殖及血管舒缩功能的影响。
构建含2%（重量）维拉帕米的乙烯-醋酸乙烯酯聚合物递送系统。这些是柔性、生物相容性且不可生物降解的基质，以每天10微克的速率释放药物。使用自体颈外静脉在高胆固醇血症兔（n = 22）中创建颈动脉旁路移植物。再灌注后，将含维拉帕米的基质（n = 12）或普通聚合物（对照组，n = 10）包裹在静脉近端三分之一处。评估移植物血管舒缩功能，并与另一组正常胆固醇血症静脉移植物（n = 8）的功能进行比较。
移植后28天，与对照移植物相比，维拉帕米基质下的内膜指数（内膜/中膜厚度比）低31%，新生内膜/原始管腔表面积比低26%，残余管腔面积大71%（4.00±1.2平方毫米对2.34±0.9平方毫米，均p < 0.01）。新生内膜平滑肌细胞含量从45.4%降至28.2%，新生内膜平滑肌细胞净厚度减少47%（30微米对15.8微米，均p < 0.01）。基质远端经维拉帕米处理的节段也显示出新生内膜平滑肌细胞密度显著降低且管腔尺寸增大。维拉帕米处理组移植物远端节段对血清素的敏感性以及对血清素、去甲肾上腺素和硝普钠的血管舒缩反应均显著低于对照组。
维拉帕米外膜周围控制给药剂量低于全身剂量的1%可有效抑制静脉移植物中的肌内膜增生。局部聚合物药物递送可能很容易应用于冠状动脉血运重建手术。
