大剂量甲氨喋呤治疗小儿白血病毒副作用的观察和预防
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摘要
目的观察大剂量甲氨喋呤(high-dose methotrexate,HD-MTX)治疗小儿急性淋巴细胞白血病(ALL)产生的毒副作用,研究其预防措施。
方法40例ALL患儿接受150例次HD-MTX(每次3.0g/m~2)治疗,经综合预防措施后,观察临床症状、体征和实验室指标,总结HD-MTX副作用发生的种类、发生率及临床疗效,并比较充分水化与未充分水化者粘膜炎、皮疹发生率及白细胞、血小板、谷草转氨酶、肌酸肌酶-MB的变化。
结果胃肠道反应、肝功能损害、口腔粘膜炎、骨髓轻度抑制是HD-MTX常见的不良反应,未充分水化者其口腔粘膜炎、皮肤过敏反应的发生率较充分水化者高(P＜0.05),而白细胞、血小板下降,谷草转氨酶升高均较充分水化组明显(P＜0.05),肌酸肌酶-MB两组比较无明显差异(P＞0.05)。
结论充分水化碱化,适宜四氢叶酸钙解救,可有效降低HD-MTX毒副反应的发生率。
AIM: To observe the toxic side effects of high-dose methotrexate(HD-MTX) on acute lymphoblastic leukenia(ALL), and to investigate the measures for preventing complications.
METHODS: 40 children with ALL received 150 times HD-MTX treatment (3.0g/m~2,every time).The comprehensive measures for preventing complications were taken after chemotherapy. The clinical symptoms and the main toxic side effects were observed, and compare with the rate of mucositis and skin rash, the variation of WBC、PLT、ALT and CK-MB between adequate and inadequate hydration children.
RESULTS: Gastrointestinal reaction, hepatic damage, dental ulcer, slight depression of bone marrow were the common adverse effects of HD-MTX. Compare to adequate hydration children, the incidence rate of mucositis and skin rash were higher, the variation of WBC、PLT were decreased significantly, and the variation of ALT were increased significantly in inadequate hydration ones (P<0.05). As for CK-MB, there was no significantly variance between inadequate hydration and adequate hydration children (P>0.05).
CONCLUSION:Adequate hydration and alkalihization, correct calcium folinate rescue can reduce effectually the rate of the toxic side effects of HD-MTX .
方法40例ALL患儿接受150例次HD-MTX(每次3.0g/m~2)治疗,经综合预防措施后,观察临床症状、体征和实验室指标,总结HD-MTX副作用发生的种类、发生率及临床疗效,并比较充分水化与未充分水化者粘膜炎、皮疹发生率及白细胞、血小板、谷草转氨酶、肌酸肌酶-MB的变化。
结果胃肠道反应、肝功能损害、口腔粘膜炎、骨髓轻度抑制是HD-MTX常见的不良反应,未充分水化者其口腔粘膜炎、皮肤过敏反应的发生率较充分水化者高(P＜0.05),而白细胞、血小板下降,谷草转氨酶升高均较充分水化组明显(P＜0.05),肌酸肌酶-MB两组比较无明显差异(P＞0.05)。
结论充分水化碱化,适宜四氢叶酸钙解救,可有效降低HD-MTX毒副反应的发生率。
AIM: To observe the toxic side effects of high-dose methotrexate(HD-MTX) on acute lymphoblastic leukenia(ALL), and to investigate the measures for preventing complications.
METHODS: 40 children with ALL received 150 times HD-MTX treatment (3.0g/m~2,every time).The comprehensive measures for preventing complications were taken after chemotherapy. The clinical symptoms and the main toxic side effects were observed, and compare with the rate of mucositis and skin rash, the variation of WBC、PLT、ALT and CK-MB between adequate and inadequate hydration children.
RESULTS: Gastrointestinal reaction, hepatic damage, dental ulcer, slight depression of bone marrow were the common adverse effects of HD-MTX. Compare to adequate hydration children, the incidence rate of mucositis and skin rash were higher, the variation of WBC、PLT were decreased significantly, and the variation of ALT were increased significantly in inadequate hydration ones (P<0.05). As for CK-MB, there was no significantly variance between inadequate hydration and adequate hydration children (P>0.05).
CONCLUSION:Adequate hydration and alkalihization, correct calcium folinate rescue can reduce effectually the rate of the toxic side effects of HD-MTX .
引文
[1]中华学会儿科学会分会血液组,中华儿科杂志编辑委员会.小儿急性淋巴细胞白血病诊疗建议.中华儿科杂志,1999,37(5):305.
[2]叶辉,顾龙君.大剂量甲氨蝶呤治疗急性淋巴细胞白血病的研究进展。中华血液学杂志,1999,20(2):110-112。
[3]卢燕。甲氨蝶呤在儿童急性淋巴细胞白血病的应用进展。继续医学教育,2001,15(2):48-49。
[4]刘彬.大剂量甲氨蝶呤治疗小儿急性淋巴细胞白血病进展.儿科药学杂志,2006,12(2):59-61.
[5]Fisgin T,Yarali N,Kara A,et al.Hemostatic side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia.Pediatr Hematol Oncol,2004,21(1):77-83.
[6]浦杰.大剂量甲氨蝶呤防治中枢神经系统白血病研究进展.华夏医学,2006,19(6):1298-1299。
[7]Hashimoto H,Kubota M,Shimizu T,et al.Effect of high-dose methotrexate on plasma hypoxanthine and uridine levels in patients with acute leukemia or non-Hodgkin lymphoma in childhood.Leukemia.1992,6(11):1199-1202.
[8]Odoul F,Le Guellec C,Lamagnere JP,et al.Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukemia using a population pharmacokinetic approach.Fundam Clin Pharmacol,1999,13(5):595-604.
[9]田菊,宋金霞孙立荣.双通路同时水化碱化降低甲氨喋呤-四氢叶酸化疗毒副作用.南方护理学报,2004,11(1):49.
[10]Krause AS,Weihrauch MR,Bode U,et al.Carboxypeptidase-G2 rescue in cancer patients with delayed methotrexate elimination after high-dose methotrexate therapy.Leuk Lymphoma.2002,43(11):2139-2143.
[11]夏焱,薛红漫等。大剂量甲氨蝶呤治疗急淋白血病的副作用观察及对策。中国小儿血液,2002;7(2):58.
[12]殷慧君主编。小儿急性白血病化学治疗.北京:科学出版社,1996:125-129.
[1] Moe PJ. High-dose methotrexate in childhood acute lymphoblastic leukemia : a pilot study. Acta Pediatr, 1997, (5): 155-162.
[2] Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy . Clin Chem, 1996, 42(8): 1322-1329.
[3] Henderson GB,Suresh MR,Vitols KS,et al.Transport of folate compounds in L1-10 cells: kinetic evidence that folate infux proceeds via the high-affinity transport system for 5-methyterahydrofolate and methorexate.Cancer Res,1986,46:1639-1643.
[4] Wolfrom C,Hartmann R,Fengler R,et al.Randomized comparison of 36-hour intermediate-dose versus 4-hour high-dose methotrexate infusion for remission induction in relapsed childhood acute lymphoblastic leukemia. J ClinOncol,1993,11:827-833
[5] Synold TW,relling V,boyett JM,et al. Blast cell methotrexate-polyglutamate accumulation in vivo differs by lin-ease, ploidy, and methotrexate dose in acute lymphoblast leukemia.J Clin Invest, 1994,94: 1996-1999.
[6] Evans WE , Schell MJ , Pui CH. MTX clearance is more important for intermediate-risk ALL. J Clin Oncol, 1990 , 8 :1115-1119.
[7] Masson E , Relling MV , Synold TW, et al. Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. J Clin Invest ,1996 ,97 : 73-80.
[8] Kompdmcn S. Prophylaxis in acute lymphoblastic leukemia. Cancer, 1982, 50: 1031-1038.
[9] Reiterf A , Scfrappe M , Ludwigw D, et al. Chemo-therapy in 1998 unselected ch ildhood acute lymphoblastic leukem ia patients. Resalts and condusions of the multicenter trialA 11BFM 86. Blood, 1994, 84: 3122-3129.
[10] Conter V , Arico M , Vatsccchlm G, et al. Extended in tranthecalmetho trexate may replace cranial irradiation for prevention of CNS relapse in Children with intermediaterisd acute lymphoblastic leukemia reatedith Berin-Frankfurt-Munster-Basedintensive Chemo therapy. J Clin Onco 1, 1995, 13:2497-2501.
[11] Wang JJ , Freeman AI , Sinks LF. Treatment of acute lymphoblastic leukemia by high-dose intravenous methotrexate .Cancer Res , 1976 , 36 : 1441-1444.
[12] Brouwers P , Moss H , Reaman G, et al. Central nervous system preventive therapy with systemic high-dose methotrexate versus cranial irradiation and intrathecal methotrexate longitudinal comparison of effects of treatment on intellectual function of children with acute lymphoblastic leukemia. Proc Am Soc Clin Oncol, 1988 , (7): 176.
[13] Galpin AJ , Schuetz JD , Masson E , et al. Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B2 lineage versus T2 lineage leukemia lymphoblastas :mecharusms for lineage differences in methotrexate polyglutamylation and cytotoxicuy . Mol Pharmacol, 1997 ,52:155-163.
[15] Evans WE , Crom WR , Abromowitch M, et al. Clinical pharmacology of cancer chemotherapy in children . Pedia Clin North Am , 1989 , 36(5): 1203.
[16] Fisgin T, Yarali N , Kara A , et al. Hemostatic side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol, 2004 ,21(1): 77-83.
[17] Hashimoto H , Kubota M, Shimizu T, et al. Effect of high-dose methotrexate on plasma hypoxanthine and uridine levels in patients with acute leukemia or non-Hodgkin lymphoma in childhood. Leukemia. 1992,6(11): 1199-1202.
[18] Odoul F , Le Guellec C , Lamagnere JP, et al. Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukemia using a population pharmacokinetic approach. Fundam Clin Pharmacol, 1999 ,13 (5): 595-604.
[19]叶辉,顾龙君.大剂量甲氨蝶呤治疗急性淋巴细胞白血病的研究进展.中华血液学杂志,1999,20(2):110-112.
[20]田菊,宋金霞,孙立荣.双通路同时水化碱化降低甲氨喋呤-四氢叶酸化疗毒副作用。南方护理学报,2004,11(1):49.
[21]Krause AS,Weihrauch MR,Bode U,et al.Carboxypeptidase-G2rescue in cancer patients with delayed methotrexate elimination after high-dose methotrexate therapy.Leuk Lymphoma.2002,43(11):2139-2143.
[22]Dagdemir A,Yildirim H,Aliyazicioglu Y,et al.Does vitamin A prevent high-dose methotrexate induced D-xylose malabsorption in children with cancer.Support Care Cancer,2004,12(4):263-267.
[23]夏焱,薛红漫,方建培,等。大剂量甲氨蝶呤治疗急性淋巴细胞白血病的副作用观察及对策.中国小儿血液,2002,7(2):56。
[24]钱文王景,薛国菊,周凤珍,等.高效液相色谱法和荧光偏振免疫法测定甲氨蝶呤血药浓度的相关性。深圳中西医结合杂志,2003,13(4):262-263.
[25]Raimondi SC,Pui CH,Head D,et al.Heterogeneity of hyperdiploid(51267)childhood acute lymphoblastic leukemia.Leukemia (Baltimore),1996,10:213-224.
[2]叶辉,顾龙君.大剂量甲氨蝶呤治疗急性淋巴细胞白血病的研究进展。中华血液学杂志,1999,20(2):110-112。
[3]卢燕。甲氨蝶呤在儿童急性淋巴细胞白血病的应用进展。继续医学教育,2001,15(2):48-49。
[4]刘彬.大剂量甲氨蝶呤治疗小儿急性淋巴细胞白血病进展.儿科药学杂志,2006,12(2):59-61.
[5]Fisgin T,Yarali N,Kara A,et al.Hemostatic side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia.Pediatr Hematol Oncol,2004,21(1):77-83.
[6]浦杰.大剂量甲氨蝶呤防治中枢神经系统白血病研究进展.华夏医学,2006,19(6):1298-1299。
[7]Hashimoto H,Kubota M,Shimizu T,et al.Effect of high-dose methotrexate on plasma hypoxanthine and uridine levels in patients with acute leukemia or non-Hodgkin lymphoma in childhood.Leukemia.1992,6(11):1199-1202.
[8]Odoul F,Le Guellec C,Lamagnere JP,et al.Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukemia using a population pharmacokinetic approach.Fundam Clin Pharmacol,1999,13(5):595-604.
[9]田菊,宋金霞孙立荣.双通路同时水化碱化降低甲氨喋呤-四氢叶酸化疗毒副作用.南方护理学报,2004,11(1):49.
[10]Krause AS,Weihrauch MR,Bode U,et al.Carboxypeptidase-G2 rescue in cancer patients with delayed methotrexate elimination after high-dose methotrexate therapy.Leuk Lymphoma.2002,43(11):2139-2143.
[11]夏焱,薛红漫等。大剂量甲氨蝶呤治疗急淋白血病的副作用观察及对策。中国小儿血液,2002;7(2):58.
[12]殷慧君主编。小儿急性白血病化学治疗.北京:科学出版社,1996:125-129.
[1] Moe PJ. High-dose methotrexate in childhood acute lymphoblastic leukemia : a pilot study. Acta Pediatr, 1997, (5): 155-162.
[2] Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy . Clin Chem, 1996, 42(8): 1322-1329.
[3] Henderson GB,Suresh MR,Vitols KS,et al.Transport of folate compounds in L1-10 cells: kinetic evidence that folate infux proceeds via the high-affinity transport system for 5-methyterahydrofolate and methorexate.Cancer Res,1986,46:1639-1643.
[4] Wolfrom C,Hartmann R,Fengler R,et al.Randomized comparison of 36-hour intermediate-dose versus 4-hour high-dose methotrexate infusion for remission induction in relapsed childhood acute lymphoblastic leukemia. J ClinOncol,1993,11:827-833
[5] Synold TW,relling V,boyett JM,et al. Blast cell methotrexate-polyglutamate accumulation in vivo differs by lin-ease, ploidy, and methotrexate dose in acute lymphoblast leukemia.J Clin Invest, 1994,94: 1996-1999.
[6] Evans WE , Schell MJ , Pui CH. MTX clearance is more important for intermediate-risk ALL. J Clin Oncol, 1990 , 8 :1115-1119.
[7] Masson E , Relling MV , Synold TW, et al. Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. J Clin Invest ,1996 ,97 : 73-80.
[8] Kompdmcn S. Prophylaxis in acute lymphoblastic leukemia. Cancer, 1982, 50: 1031-1038.
[9] Reiterf A , Scfrappe M , Ludwigw D, et al. Chemo-therapy in 1998 unselected ch ildhood acute lymphoblastic leukem ia patients. Resalts and condusions of the multicenter trialA 11BFM 86. Blood, 1994, 84: 3122-3129.
[10] Conter V , Arico M , Vatsccchlm G, et al. Extended in tranthecalmetho trexate may replace cranial irradiation for prevention of CNS relapse in Children with intermediaterisd acute lymphoblastic leukemia reatedith Berin-Frankfurt-Munster-Basedintensive Chemo therapy. J Clin Onco 1, 1995, 13:2497-2501.
[11] Wang JJ , Freeman AI , Sinks LF. Treatment of acute lymphoblastic leukemia by high-dose intravenous methotrexate .Cancer Res , 1976 , 36 : 1441-1444.
[12] Brouwers P , Moss H , Reaman G, et al. Central nervous system preventive therapy with systemic high-dose methotrexate versus cranial irradiation and intrathecal methotrexate longitudinal comparison of effects of treatment on intellectual function of children with acute lymphoblastic leukemia. Proc Am Soc Clin Oncol, 1988 , (7): 176.
[13] Galpin AJ , Schuetz JD , Masson E , et al. Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B2 lineage versus T2 lineage leukemia lymphoblastas :mecharusms for lineage differences in methotrexate polyglutamylation and cytotoxicuy . Mol Pharmacol, 1997 ,52:155-163.
[15] Evans WE , Crom WR , Abromowitch M, et al. Clinical pharmacology of cancer chemotherapy in children . Pedia Clin North Am , 1989 , 36(5): 1203.
[16] Fisgin T, Yarali N , Kara A , et al. Hemostatic side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol, 2004 ,21(1): 77-83.
[17] Hashimoto H , Kubota M, Shimizu T, et al. Effect of high-dose methotrexate on plasma hypoxanthine and uridine levels in patients with acute leukemia or non-Hodgkin lymphoma in childhood. Leukemia. 1992,6(11): 1199-1202.
[18] Odoul F , Le Guellec C , Lamagnere JP, et al. Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukemia using a population pharmacokinetic approach. Fundam Clin Pharmacol, 1999 ,13 (5): 595-604.
[19]叶辉,顾龙君.大剂量甲氨蝶呤治疗急性淋巴细胞白血病的研究进展.中华血液学杂志,1999,20(2):110-112.
[20]田菊,宋金霞,孙立荣.双通路同时水化碱化降低甲氨喋呤-四氢叶酸化疗毒副作用。南方护理学报,2004,11(1):49.
[21]Krause AS,Weihrauch MR,Bode U,et al.Carboxypeptidase-G2rescue in cancer patients with delayed methotrexate elimination after high-dose methotrexate therapy.Leuk Lymphoma.2002,43(11):2139-2143.
[22]Dagdemir A,Yildirim H,Aliyazicioglu Y,et al.Does vitamin A prevent high-dose methotrexate induced D-xylose malabsorption in children with cancer.Support Care Cancer,2004,12(4):263-267.
[23]夏焱,薛红漫,方建培,等。大剂量甲氨蝶呤治疗急性淋巴细胞白血病的副作用观察及对策.中国小儿血液,2002,7(2):56。
[24]钱文王景,薛国菊,周凤珍,等.高效液相色谱法和荧光偏振免疫法测定甲氨蝶呤血药浓度的相关性。深圳中西医结合杂志,2003,13(4):262-263.
[25]Raimondi SC,Pui CH,Head D,et al.Heterogeneity of hyperdiploid(51267)childhood acute lymphoblastic leukemia.Leukemia (Baltimore),1996,10:213-224.