Howell S B, Chu B B, Wung W E, Metha B M, Mendelsohn J
J Clin Invest. 1981 Apr;67(4):1161-70. doi: 10.1172/jci110130.
18 patients with malignant effusions were treated with continuous intraperitoneal, intrapleural, or intrapericardial infusion of methotrexate (MTX) 30 mg/m2 per d combined with simultaneous intravenous administration of leucovorin at a dose rate calculated to yield an equimolar concentration in the serum. In the serum the geometric mean steady-state MTX concentration was 0.95 microM, whereas it was 24 microM in the peritoneal, 213 microM in the pleural, and 434 microM in the pericardial cavities. Mean clearance was 6.6 ml/min from the peritoneal cavity, 2.6 ml/min from the pleural cavity, and 0.14 ml/min from the pericardial cavity. Leucovorin provided sufficient protection to allow the duration of infusion to be escalated from 24 to 120 h before myelosuppression was encountered. Marrow thymidylate synthetase activity was inhibited by an average of 46% compared to 86% inhibition in malignant cells in the effusions. Flow cytometric analysis showed no perturbation of the cell cycle phase distribution of marrow cells. All eight of the evaluable patients have responded: three received no other form of therapy, five also received systemic hormonal or chemotherapy. This study demonstrated that tumors confined to third space body fluids can be given very high concentration x time exposures to MTX with minimal systemic toxicity.
18例恶性积液患者接受了甲氨蝶呤（MTX）30mg/m²每日持续腹腔内、胸腔内或心包腔内输注，同时静脉给予亚叶酸钙，剂量按计算能使血清中达到等摩尔浓度。血清中甲氨蝶呤几何平均稳态浓度为0.95微摩尔，而腹腔内为24微摩尔，胸腔内为213微摩尔，心包腔内为434微摩尔。腹腔清除率平均为6.6毫升/分钟，胸腔为2.6毫升/分钟，心包腔为0.14毫升/分钟。亚叶酸钙提供了足够的保护，使输注时间在出现骨髓抑制前从24小时延长至120小时。骨髓胸苷酸合成酶活性平均受抑制46%，而积液中恶性细胞受抑制86%。流式细胞术分析显示骨髓细胞的细胞周期阶段分布未受干扰。所有8例可评估患者均有反应：3例未接受其他形式治疗，5例还接受了全身激素或化疗。本研究表明，局限于第三间隙体液中的肿瘤可以接受高浓度乘以时间的甲氨蝶呤暴露，全身毒性最小。
