儿童急性淋巴细胞白血病治疗中甲氨蝶呤血药浓度和脑脊液浓度的相关性
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摘要
目的探讨儿童急性淋巴细胞白血病(ALL)大剂量甲氨蝶呤(HDMTX)治疗时甲氨蝶呤(MTX)血浆和脑脊液浓度的水平,以及同给药剂量、不良反应发生情况之间的关系。方法回顾性分析2015年1月-2017年1月在我院小儿血液科住院治疗的30名ALL患儿,共117例次HDMTX治疗。依据CCLG-ALL2008方案危险度分层,分成两组,A组:MTX为2g/m~2,B组:MTX为5g/m~2,进行多个时间点血药浓度和MTX开始后0. 5 h脑脊液药物浓度检测,对取得的药物浓度数据进行统计分析。结果 (1)B组患儿各时间点平均血药浓度和MTX开始后0.5 h脑脊液浓度均高于A组(P <0.05);(2)B组患儿骨髓抑制、肝功损害及口腔溃疡的发生率明显高于A组(P<0.05),其他不良反应的发生率差异无显著性(P>0. 05);两组患儿MTX开始后0.5h脑脊液药物浓度和血药浓度成正相关(P<0.01)。结论 (1)血浆和脑脊液MTX浓度同MTX给药剂量正相关。(2)MTX剂量越高,骨髓抑制、肝功损害、黏膜损害越严重,其他不良反应则无明显差异。(3)血药浓度决定MTX开始后0.5 h脑脊液浓度。
Objective To investigate the plasma and cerebrospinal fluid( CSF) concentrations of methotrexate(MTX) during the treatment of pediatric acute lymphoblastic leukemia(ALL) with high-dose methotrexate( HDMTX), discuss the relationship between plasma concentration, cerebrospinal fluid concentration, dosage and adverse reactions of methotrexate( MTX). Methods Retrospective analysis was performed on 30 children with ALL which totally had taken 117 cases of HDMTX treatment from January 2015 to January 2017. Patients were divided into two groups according to CCLG-ALL 2008 risk stratification, Group A : MTX dosage was 2 g/m~2, group B : MTX dosage was 5 g/m~2. Blood drug concentration was detected at multiple time points, and the drug concentration in cerebrospinal fluid was detected half hour after the infusion of MTX. All data obtained above were analyzed statistically. Results(1) The mean blood drug concentration of children in group B was higher than that in group A at each time point, and the cerebrospinal fluid concentration was higher than that in group A at half hour after the start of MTX(P <0. 05).(2) The incidence of bone marrow suppression, liver function damage and oral ulcer in group B was significantly higher than that in group A(P <0. 05), while the incidence of other adverse reactions was not significant different( P > 0. 05). There was a positive correlation between CSF drug concentration and blood drug concentration(P<0.01) at half hour after the start of MTX between the two groups. Conclusions(1) The concentration of plasma and CSF MTX was positively correlated with the dose of MTX administration.(2) The higher the MTX dose, the more serious the bone marrow suppression,liver function damage and mucosal damage were, and there was no significant difference in other adverse reactions.( 3) The drug concentration of cerebrospinal fluid at half hour after the start of MTX was positively correlated with the drug concentration of blood.
Objective To investigate the plasma and cerebrospinal fluid( CSF) concentrations of methotrexate(MTX) during the treatment of pediatric acute lymphoblastic leukemia(ALL) with high-dose methotrexate( HDMTX), discuss the relationship between plasma concentration, cerebrospinal fluid concentration, dosage and adverse reactions of methotrexate( MTX). Methods Retrospective analysis was performed on 30 children with ALL which totally had taken 117 cases of HDMTX treatment from January 2015 to January 2017. Patients were divided into two groups according to CCLG-ALL 2008 risk stratification, Group A : MTX dosage was 2 g/m~2, group B : MTX dosage was 5 g/m~2. Blood drug concentration was detected at multiple time points, and the drug concentration in cerebrospinal fluid was detected half hour after the infusion of MTX. All data obtained above were analyzed statistically. Results(1) The mean blood drug concentration of children in group B was higher than that in group A at each time point, and the cerebrospinal fluid concentration was higher than that in group A at half hour after the start of MTX(P <0. 05).(2) The incidence of bone marrow suppression, liver function damage and oral ulcer in group B was significantly higher than that in group A(P <0. 05), while the incidence of other adverse reactions was not significant different( P > 0. 05). There was a positive correlation between CSF drug concentration and blood drug concentration(P<0.01) at half hour after the start of MTX between the two groups. Conclusions(1) The concentration of plasma and CSF MTX was positively correlated with the dose of MTX administration.(2) The higher the MTX dose, the more serious the bone marrow suppression,liver function damage and mucosal damage were, and there was no significant difference in other adverse reactions.( 3) The drug concentration of cerebrospinal fluid at half hour after the start of MTX was positively correlated with the drug concentration of blood.
引文
1.顾龙君.儿童白血病.北京:人民卫生出版社,2017:3-7.
2. Chu E,ALLegra CJ, Antifolates Z,et al. Cancer chemotherapyand biotherapy:principle and practice. Philadelphia:Lippincot-Raven,1996:109-148.
3. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury.Mayo Clin Proc,2014,89:95-106.
4.王淑梅,孙路路,杨平,等.大剂量甲氨蝶呤注射剂化疗导致急性淋巴细胞白血病患儿白细胞减少的危险因素分析.中国临床药理学杂志,2016,32:1905-1907.
5.范芳,余炜,谢瑞祥,等.血药浓度监测下大剂量甲氨蝶呤24h滴注疗法延迟排泄分析.中国医院药学杂志,2016,36:115-119.
6.田应彪,陈泽慧,汪世明,等.甲氨蝶呤血药浓度检测在急性淋巴细胞白血病患儿化疗中的作用.中国实用儿科杂志,2008,23:797.
7. Tetef ML, Margolin KA,Doroshow JH,et al. Pharmacokinetics and toxicity of high-dose introvenous methotrexate in the treatment of leptomeningeal carcinomatosis. Cancer Chemother Pharmacol, 2000,46:19-26.
8. Shkalim Zemer V, Toledano H, Ash S, et al. Factors affecting the upper limit of the methotrexate(MTX)CSF levels achievable in children with brain tumors treated With high-dose intravenous MTX.J Pediatr Hematol Oncol,2016,38:544-548.
9.薛惠良,汤静燕,陈静,等.儿童急性淋巴细胞性白血病中枢神经系统浸润的防治.中国实用儿科杂志,2005,20:683-684.
10.中华医学会儿科学分会血液学组,《中华儿科杂志》编辑委员会.儿童急性淋巴细胞白血病诊疗建议(第四次修订).中华儿科杂志,2014,52:641-644.
11. CTCAE v4. 0, Common Terminology Criteria for Adverse Events[EB/OL].[2011/09/01] http://www. calgb. org/Public/meetings/presentations/2009/summer_group/cra_cont_ed/06a_CTCAE-Setser_062009. pdf.
12. Arend Stackelberg A, Hartmann R, B(u|¨)hrer C, et al. High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood, 2008, 111:2573-2580.
13. KaluZna E, Strauss E, Zajac-Spychala O, et al. Functional variants of gene encoding folate metabolizing enzyme and methotrexate-related toxicity in children with acute lymphoblastic leukemia. Eur J pharmacol,2015,769:93-99.
14. Fabresse N, Devictor B, Pissier C, et al. Plasma 7-hydroxymethotrexate levels versus methotrexate to predict delayed elimination in children receiving high-dose methotrexate. Ther drug monit,2018,40:76-83.
15.孟岩,梁筱灵,宪莹,等.大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的安全性与疗效分析.儿科药学杂志,2010,16:7-11.
16.马丹,代忠建,龙如洋,等.甲氨蝶呤血药浓度监测对治疗急性淋巴细胞白血病有效性与安全性的影响.重庆医学,2017,46:4394-4396.
17.王轶睿,王捷,安琳娜,等.甲氨蝶呤化疗常见不良反应的影响因素分析.中国临床药理学杂志,2016,32:138-140.
18.黎小妍,徐乐加.大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病血药浓度和不良反应分析.热带医学杂志,2012,12:367-369.
19.许宏,宋文琪.儿童急性淋巴细胞白血病治疗中甲氨喋呤血药浓度监测分析.中国新药与临床杂志,2010,29:675-678.
20. Niemann A, M(u|¨)hlisch J, Fr(u|¨)hwald MC, et al. Therapeutic drug monitoring of methotrexate in cerebrospinal fluid after systemic highdose infusion in children:can the burden of intrathecal methotrexate be reduced?. Ther drug monit,2010,32:467-475.
21.孙伟,马霖.大剂量甲氨蝶呤治疗儿童白血病的药动学研究.中国药学杂志,2002,37:431-133.
22.殷强.大剂量甲氨碟呤治疗白血病患儿的药代动力研究.黑龙江医药,2016,29:707-709.
23.唐茜,孙鲁宁,沈燕,等.HPLC法与EMIT法测定人血中甲氨蝶呤血药浓度差异分析.药学与临床研究,2015, 23:141-143.
2. Chu E,ALLegra CJ, Antifolates Z,et al. Cancer chemotherapyand biotherapy:principle and practice. Philadelphia:Lippincot-Raven,1996:109-148.
3. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury.Mayo Clin Proc,2014,89:95-106.
4.王淑梅,孙路路,杨平,等.大剂量甲氨蝶呤注射剂化疗导致急性淋巴细胞白血病患儿白细胞减少的危险因素分析.中国临床药理学杂志,2016,32:1905-1907.
5.范芳,余炜,谢瑞祥,等.血药浓度监测下大剂量甲氨蝶呤24h滴注疗法延迟排泄分析.中国医院药学杂志,2016,36:115-119.
6.田应彪,陈泽慧,汪世明,等.甲氨蝶呤血药浓度检测在急性淋巴细胞白血病患儿化疗中的作用.中国实用儿科杂志,2008,23:797.
7. Tetef ML, Margolin KA,Doroshow JH,et al. Pharmacokinetics and toxicity of high-dose introvenous methotrexate in the treatment of leptomeningeal carcinomatosis. Cancer Chemother Pharmacol, 2000,46:19-26.
8. Shkalim Zemer V, Toledano H, Ash S, et al. Factors affecting the upper limit of the methotrexate(MTX)CSF levels achievable in children with brain tumors treated With high-dose intravenous MTX.J Pediatr Hematol Oncol,2016,38:544-548.
9.薛惠良,汤静燕,陈静,等.儿童急性淋巴细胞性白血病中枢神经系统浸润的防治.中国实用儿科杂志,2005,20:683-684.
10.中华医学会儿科学分会血液学组,《中华儿科杂志》编辑委员会.儿童急性淋巴细胞白血病诊疗建议(第四次修订).中华儿科杂志,2014,52:641-644.
11. CTCAE v4. 0, Common Terminology Criteria for Adverse Events[EB/OL].[2011/09/01] http://www. calgb. org/Public/meetings/presentations/2009/summer_group/cra_cont_ed/06a_CTCAE-Setser_062009. pdf.
12. Arend Stackelberg A, Hartmann R, B(u|¨)hrer C, et al. High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood, 2008, 111:2573-2580.
13. KaluZna E, Strauss E, Zajac-Spychala O, et al. Functional variants of gene encoding folate metabolizing enzyme and methotrexate-related toxicity in children with acute lymphoblastic leukemia. Eur J pharmacol,2015,769:93-99.
14. Fabresse N, Devictor B, Pissier C, et al. Plasma 7-hydroxymethotrexate levels versus methotrexate to predict delayed elimination in children receiving high-dose methotrexate. Ther drug monit,2018,40:76-83.
15.孟岩,梁筱灵,宪莹,等.大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的安全性与疗效分析.儿科药学杂志,2010,16:7-11.
16.马丹,代忠建,龙如洋,等.甲氨蝶呤血药浓度监测对治疗急性淋巴细胞白血病有效性与安全性的影响.重庆医学,2017,46:4394-4396.
17.王轶睿,王捷,安琳娜,等.甲氨蝶呤化疗常见不良反应的影响因素分析.中国临床药理学杂志,2016,32:138-140.
18.黎小妍,徐乐加.大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病血药浓度和不良反应分析.热带医学杂志,2012,12:367-369.
19.许宏,宋文琪.儿童急性淋巴细胞白血病治疗中甲氨喋呤血药浓度监测分析.中国新药与临床杂志,2010,29:675-678.
20. Niemann A, M(u|¨)hlisch J, Fr(u|¨)hwald MC, et al. Therapeutic drug monitoring of methotrexate in cerebrospinal fluid after systemic highdose infusion in children:can the burden of intrathecal methotrexate be reduced?. Ther drug monit,2010,32:467-475.
21.孙伟,马霖.大剂量甲氨蝶呤治疗儿童白血病的药动学研究.中国药学杂志,2002,37:431-133.
22.殷强.大剂量甲氨碟呤治疗白血病患儿的药代动力研究.黑龙江医药,2016,29:707-709.
23.唐茜,孙鲁宁,沈燕,等.HPLC法与EMIT法测定人血中甲氨蝶呤血药浓度差异分析.药学与临床研究,2015, 23:141-143.