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目的:研究大剂量甲氨蝶呤治疗急性淋巴细胞白血病患儿对肝肾功能的影响。方法:2004年3月至2008年5月期间165例急性白血病住院患儿纳入研究,并分为2个组:3g/m2剂量组(119例)和5g/m2剂量组(46例)。3g/m2剂量组中男64例,女55例,平均年龄(104.88±21.40)月。5g/m2剂量组中男37例,女9例,平均年龄(101.57±20.43)月。给药方法:甲氨蝶呤先按3g/m2或5g/m2总剂量的1/6作为突击量于30min内静脉滴注,其余5/6剂量于23.5h内滴注完毕,同时给予5%碳酸氢钠注射液3～5ml/kg静脉滴注至甲氨蝶呤血浓度<0.1μmol/L和尿液pH值6～8时停用。每天给予2～3L/m2液体水化。给予甲氨蝶呤36h后静脉注射亚叶酸钙解救,其总量为甲氨蝶呤的3%～5%,分6～8次给予,每6h1次,首次剂量加倍;给予还原型谷胱甘肽0.6～1.2g/d,多烯磷脂酰胆碱232.5～465mg/d,均静脉滴注,连续给药10～14d。甲氨蝶呤给药后于24、36、48、72和96h测定其血浓度,记录甲氨蝶呤使用前和使用后2～7d及化疗结束后的肝肾功能,记录化疗开始后24h尿量和pH值。结果:5g/m2剂量组和3g/m2剂量组给药24、36、48h后甲氨蝶呤的血浓度分别为(130.99±67.23)μmol/L、(1.95±0.98)μmol/L、(2.13±3.03)μmol/L与(55.02±29.46)μmol/L、(1.22±0.75)μmol/L、(1.28±2.75)μmol/L,差异有统计学意义(P<0.01,P<0.05,P<0.05)。化疗过程中5g/m2剂量组与3g/m2剂量组的γ-GT、TBil、DBil值分别为(63.94±76.41)U/L、(24.87±42.91)μmol/L、(12.19±29.92)μmol/L与(40.72±35.34)U/L、(13.01±6.26)μmol/L、(4.39±2.59)μmol/L,差异均有统计学意义(均P<0.01);5g/m2与3g/m2剂量组的ALT、AST和ALP值分别为(187.29±171.18)U/L、(85.47±111.59)U/L、(141.71±69.24)U/L与(165.93±178.84)U/L、(73.45±82.42)U/L、(138.60±59.92)U/L,差异有统计学意义(均P<0.05)。2组的肾功能,治疗中与治疗前比较,以及治疗中2组间比较,差异均无统计学意义(P>0.05)。保肝治疗后,5g/m2与3g/m2剂量组的ALT、AST及ALP明显下降,分别为(47.86±37.84)U/L、(24.00±10.78)U/L、(115.40±34.43)U/L与(75.16±68.52)U/L、(32.78±27.65)U/L、(151.27±60.18)U/L,差异有统计学意义(均P<0.05)。5g/m2剂量组与3g/m2剂量组首日与次日液体排出量分别为(3673±974)ml、(4216±1189)ml与(3236±1039)ml、(3832±1134)ml,5g/m2剂量组的液体排出量高于3g/m2剂量组,差异有统计学意义(P<0.05)。尿pH值无明显改变。结论:大剂量甲氨蝶呤能致急性淋巴细胞白血病患儿肝损害,损害程度与剂量相关。应用还原型谷胱甘肽和多烯磷酯酰胆碱对肝脏有保护作用。
Objective: To study the effect of high dose methotrexate on liver and kidney function in children with acute lymphoblastic leukemia. Methods: From March 2004 to May 2008, 165 acute leukemia hospitalized children were enrolled and divided into two groups: 3g / m2 dose group (119 cases) and 5g / m2 dose group (46 cases). There were 64 males and 55 females in the 3g / m2 dose group with an average age of (104.88 ± 21.40) months. In the 5g / m2 dose group, there were 37 males and 9 females, with an average age of (101.57 ± 20.43) months. Dosage: Methotrexate by 3g / m2 or 5g / m2 total dose of 1/6 as a surprise dose within 30min intravenous infusion, and the remaining 5/6 dose within 23.5h infusion completed, given 5% Sodium bicarbonate injection 3 ~ 5ml / kg intravenous infusion methotrexate blood concentration <0.1μmol / L and urine pH 6 to 8 disabled. Give 2 ~ 3L / m2 liquid hydration daily. Give methotrexate 36h after intravenous leucovorin rescue, the total amount of methotrexate 3% to 5%, administered 6 to 8 times, every 6h1 times, the first dose doubled; give reduced glutathione Peptide 0.6 ~ 1.2g / d, polyene phosphatidylcholine 232.5 ~ 465mg / d, are intravenous infusion, continuous administration of 10 ~ 14d. Methotrexate after administration at 24,36,48,72 and 96h determination of blood concentration, record methotrexate before and after 2 ~ 7d and after the end of chemotherapy liver function, record the beginning of chemotherapy 24h urine Amount and pH. Results: The concentrations of methotrexate in the 5g / m2 and 3g / m2 groups were (130.99 ± 67.23) μmol / L, (1.95 ± 0.98) μmol / L and (P <0.01, P <0.05, P <0.05), and the difference was statistically significant (P <0.01, P <0.05) 0.05). The values of γ-GT, TBil and DBil in the 5g / m2 dose group and 3g / m2 dose group were (63.94 ± 76.41) U / L, 24.87 ± 42.91μmol / L and 12.19 ± 29.92μmol / L and (40.72 ± 35.34) U / L, (13.01 ± 6.26) μmol / L and (4.39 ± 2.59) μmol / L, respectively) The values of ALT, AST and ALP were (187.29 ± 171.18) U / L, (85.47 ± 111.59) U / L, (141.71 ± 69.24) U / L and (165.93 ± 178.84) U / L respectively) and (73.45 ± 82.42 ) U / L, (138.60 ± 59.92) U / L, the difference was statistically significant (all P <0.05). There was no significant difference in renal function between the two groups (P> 0.05), compared with before treatment, and between the two groups in treatment. After liver protection treatment, ALT, AST and ALP in 5g / m2 and 3g / m2 groups were significantly decreased (47.86 ± 37.84) U / L, (24.00 ± 10.78) U / L and (115.40 ± 34.43) U / L and (75.16 ± 68.52) U / L, (32.78 ± 27.65) U / L and (151.27 ± 60.18) U / L respectively. There were significant differences between the two groups (all P <0.05). The liquid excretion on the first day and the next day in the 5g / m2 and 3g / m2 groups were (3673 ± 974) ml, (4216 ± 1189) ml and (3236 ± 1039) ml, / m2 dose group liquid discharge higher than the 3g / m2 dose group, the difference was statistically significant (P <0.05). Urine pH no significant change. Conclusion: High dose methotrexate can cause liver damage in children with acute lymphoblastic leukemia, the degree of damage is dose-dependent. Application of reduced glutathione and polyene phosphatidylcholine have a protective effect on the liver.