Muller D W, Topol E J, Abrams G D, Gallagher K P, Ellis S G
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0022.
J Am Coll Cardiol. 1992 Aug;20(2):460-6. doi: 10.1016/0735-1097(92)90118-7.
The study was performed to test the hypothesis that high local, intramural concentrations of antineoplastic agents at the site of balloon injury inhibit vascular smooth muscle cell proliferation without systemic toxicity.
The predominant mechanism for recurrent stenosis after coronary balloon angioplasty is neointimal thickening due to medial smooth muscle cell proliferation. The clinical use of potent antiproliferative agents to prevent restenosis has been limited by the potential for severe systemic side effects. Local therapy with these agents may be effective and free of systemic complications.
After bilateral balloon angioplasty of the carotid arteries of 14 juvenile farm pigs, the dilated arterial segments were treated locally with methotrexate (6.25 mg/ml, total dose 25 mg) or 0.9% saline solution through a perforated balloon catheter. The animals were then killed 30 days after balloon injury to determine the effects of this therapy on neointimal thickness. In an additional six animals, tritium-labeled methotrexate was used to determine the concentration and duration of detectability of methotrexate in the wall of the treated arteries and in the systemic circulation.
Two hours after drug instillation the concentration of labeled drug was greater than 1,000-fold greater in the wall of the treated artery than in circulating blood, and this ratio remained between 50 and 100 for at least 7 days. Despite this difference, the mean intimal thickness 30 days after the procedure was similar in the 10 methotrexate-treated arteries and the 18 saline-treated arteries (59 +/- 30 vs. 56 +/- 25 microns, p = 0.6). The morphologic appearance of the neointima was similar in each group and suggested an important role for mural thrombus in the genesis of the intimal thickening.
Treatment with intramural methotrexate, delivered through a perforated balloon catheter at the selected concentration and total dose, failed to prevent intimal thickening after balloon injury. Nonetheless, the perforated balloon catheter appears to be a promising means of delivering a high local concentration of drugs with potentially life-threatening systemic side effects. The optimal concentrations and combinations of candidate drug therapies warrant further evaluation.
进行本研究以检验以下假设，即球囊损伤部位局部壁内高浓度的抗肿瘤药物可抑制血管平滑肌细胞增殖且无全身毒性。
冠状动脉球囊血管成形术后再狭窄的主要机制是由于中膜平滑肌细胞增殖导致的内膜增厚。强效抗增殖药物预防再狭窄的临床应用因严重全身副作用的可能性而受到限制。这些药物的局部治疗可能有效且无全身并发症。
对14头幼年农场猪的双侧颈动脉进行球囊血管成形术后，通过带孔球囊导管对扩张的动脉节段局部给予甲氨蝶呤（6.25毫克/毫升，总剂量25毫克）或0.9%盐溶液。然后在球囊损伤后30天处死动物，以确定该治疗对内膜厚度的影响。在另外6只动物中，使用氚标记的甲氨蝶呤来确定甲氨蝶呤在治疗动脉壁和体循环中的浓度及可检测持续时间。
药物注入后两小时，治疗动脉壁内标记药物的浓度比循环血液中的浓度高1000倍以上，且该比值至少7天保持在50至100之间。尽管存在这种差异，但在10条接受甲氨蝶呤治疗的动脉和18条接受盐水治疗的动脉中，术后30天的平均内膜厚度相似（分别为59±30微米和56±25微米，p = 0.6）。每组内膜的形态学表现相似，提示壁内血栓在内膜增厚形成中起重要作用。
通过带孔球囊导管以选定的浓度和总剂量进行壁内甲氨蝶呤治疗，未能预防球囊损伤后的内膜增厚。尽管如此，带孔球囊导管似乎是一种有前景的输送高局部浓度药物的手段，这些药物可能具有危及生命的全身副作用。候选药物治疗的最佳浓度和组合值得进一步评估。
