Imatinib Mesylate Has The Potential to Exert Its Efficacy by Down-Regulating The Plasma Concentration of Platelet-Derived Growth Factor in Patients With Pulmonary Arterial Hypertension
Imatinib Mesylate Has The Potential to Exert Its Efficacy by Down-Regulating The Plasma Concentration of Platelet-Derived Growth Factor in Patients With Pulmonary Arterial Hypertension
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DOI：
10.1536/ihj.51.272
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发表时间：
2010-07-01
影响因子：
1.5
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Hatano, Masaru;Yao, Atsushi;Nagai, Ryozo
近年来，血小板源性生长因子（PDGF）与肺动脉血管平滑肌细胞的异常增殖和迁移有关。甲磺酸伊马替尼（Imatinib meslylate）是一种PDGF受体拮抗剂，在一些人类病例和动物模型中已被报道显著改善肺动脉高压（PAH）。5例PAR患者（3例硬皮病相关PAH和2例特发性/家族性PAH）服用不少于2种PAH药物，用低剂量伊马替尼（100 mg/d）治疗24周。伊马替尼滴定至200 mg/天，除非观察到重大并发症。治疗前后分别行右心导管检查、运动心肺功能试验、呼吸功能试验及血浆PDGF-BB和血管内皮生长因子（VEGF）浓度测定。治疗12周后，血浆PDGF-BB水平显著降低（P = 0.04），而VEGF没有变化。尽管伊马替尼给药24周对血流动力学和运动能力没有显着影响，但2例血浆PDGF-BB水平高的患者显示出良好的初始反应，肺血管阻力降低超过15%。治疗12周后，肺一氧化碳弥散量显著改善（P < 0.01），这种改善趋势可持续24周（P = 0.05）。3例患者在伊马替尼治疗过程中出现肾功能不全，PAH患者PDGF-BB表达上调可被伊马替尼抑制，这可能也是其疗效的决定性因素之一。(Int Heart J 2010; 51：272-276）
Recently, platelet-derived growth factor (PDGF) has been implicated in the abnormal proliferation and migration of pulmonary artery vascular smooth muscle cells. Imatinib meslylate, a PDGF receptor antagonist, has been reported to dramatically improve pulmonary arterial hypertension (PAH) in some human cases as well as animal models.Five patients with PAR (3 scleroderma-associated PAH and 2 idiopathic/familial PAH) taking no less than 2 PAH agents were treated with low-dose imatinib (100 mg/day) for 24 weeks. Imatinib was titrated up to 200 mg/day unless major complications were observed. Before and after the treatment, right heart catheterization, cardiopulmonary exercise test, respiratory function test, and plasma concentration measurements of PDGF-BB and vascular endothelial growth factor (VEGF) were performed. Plasma PDGF-BB levels were significantly decreased after 12 weeks of treatment (P = 0.04), while VEGF did not change. Although 24 week administration of imatinib did not show a significant effect on hemodynamics and exercise capacity, 2 patients with high plasma PDGF-BB levels showed a good initial response of more than a 15% decrease in pulmonary vascular resistance. Diffusion capacity of the lung for carbon monoxide significantly improved after 12 weeks of treatment (P < 0.01) and this improvement tended to be sustained for 24 weeks (P = 0.05). Renal dysfunction was observed in 3 patients during imatinib therapy.The upregulated PDGF-BB in patients with PAH could be suppressed by imatinib treatment, and also seemed to be one of the determinant factors for its efficacy. (Int Heart J 2010; 51: 272-276)