Agarwala S S, Bahnson R R, Wilson J W, Szumowski J, Ernstoff M S
Department of Medicine, University of Pittsburgh, Pennsylvania, USA.
Am J Clin Oncol. 1995 Jun;18(3):211-5. doi: 10.1097/00000421-199506000-00006.
Quinidine is known to inhibit p-glycoprotein and enhance the activity of vinblastine against cultured renal carcinoma cells. We have combined quinidine and vinblastine in a Phase I trial in patients with metastatic renal cell carcinoma. Twenty-three patients were entered. Prior treatment included nephrectomy (15 patients), radiation (1 patient) and interferons (8 patients). Cohorts of patients were treated at one of three quinidine dose levels (100, 200, and 400 mg); one patient received 300 mg. Quinidine was given orally 4 times daily starting 3 days prior to the first dose of vinblastine of 5 mg/m2 intravenously given once a week. Hematologic parameters, EKG, and quinidine levels were monitored weekly. Mean quinidine levels in each dose tier were 1.58, 2.59, and 4.24 micrograms/ml, respectively. The dose-limiting toxicity was leukopenia, which necessitated dose interruptions in 16 patients. The mean nadir WBC count (x 10(9)/L) was 3.47, 2.3, and 1.73 in each dose tier, respectively. Corresponding values for the mean maximum decrease in WBC count from baseline were 3.85, 5.86, and 6.53, respectively. There was a trend for leukopenia to become more severe with increasing doses of quinidine. Other toxicities included mild nausea and vomiting in all patients, and hypotension and paralytic ileus in one patient each. No cardiac toxicity was observed. One patient had a complete remission and 4 patients had stable disease. We conclude that quinidine and vinblastine may be administered together safely in a clinical setting, with leukopenia being dose-limiting. Further studies are needed to determine any therapeutic advantage over vinblastine alone.
已知奎尼丁可抑制P-糖蛋白，并增强长春碱对培养的肾癌细胞的活性。我们在转移性肾细胞癌患者中进行了一项奎尼丁和长春碱联合应用的I期试验。共纳入23例患者。先前的治疗包括肾切除术（15例患者）、放疗（1例患者）和干扰素治疗（8例患者）。患者队列接受三种奎尼丁剂量水平（100、200和400mg）之一的治疗；1例患者接受300mg治疗。奎尼丁在每周静脉注射一次5mg/m²长春碱的第一剂之前3天开始，每日口服4次。每周监测血液学参数、心电图和奎尼丁水平。每个剂量组的平均奎尼丁水平分别为1.58、2.59和4.24μg/ml。剂量限制性毒性为白细胞减少，16例患者因此需要中断剂量。每个剂量组的平均最低白细胞计数（×10⁹/L）分别为3.47、2.3和1.73。白细胞计数从基线的平均最大下降的相应值分别为3.85、5.86和6.53。随着奎尼丁剂量增加，白细胞减少有加重趋势。其他毒性包括所有患者均有轻度恶心和呕吐，1例患者出现低血压和麻痹性肠梗阻。未观察到心脏毒性。1例患者完全缓解，4例患者病情稳定。我们得出结论，在临床环境中，奎尼丁和长春碱可安全联合使用，白细胞减少为剂量限制性毒性。需要进一步研究以确定与单独使用长春碱相比是否有任何治疗优势。
