Use of methotrexate in juvenile idiopathic arthritis.

Methotrexate (MTX) has transformed the outlook for children with juvenile idiopathic arthritis (JIA). Most of the evidence from uncontrolled clinical trials suggests that MTX is an effective agent for treating active JIA. Data from controlled clinical trials suggests that MTX has statistically significant effects on patient centred disability measures in JIA patients with active arthritis. Although we would like a much larger study directed evidence base for our use of the drug, the studies that have been done are sound and have been followed by a change in clinical expectations and advice that speak of qualitative evidence from clinical practice, confirming the scientifically acquired data. Randomised controlled multicentre trials using sufficient numbers of patients, including functional assessment and quality of life measures, are needed to confirm the long term efficacy and safety of MTX in JIA.     

Use of methotrexate in juvenile idiopathic arthritis

Methotrexate (MTX) has transformed the outlook for children with juvenile idiopathic arthritis (JIA). Most of the evidence from uncontrolled clinical trials suggests that MTX is an effective agent for treating active JIA. Data from controlled clinical trials suggests that MTX has statistically significant effects on patient centred disability measures in JIA patients with active arthritis. Although we would like a much larger study directed evidence base for our use of the drug, the studies that have been done are sound and have been followed by a change in clinical expectations and advice that speak of qualitative evidence from clinical practice, confirming the scientifically acquired data. Randomised controlled multicentre trials using sufficient numbers of patients, including functional assessment and quality of life measures, are needed to confirm the long term efficacy and safety of MTX in JIA.     

Methotrexat in der Behandlung der juvenilen idiopathischen Arthritis

Low-dose methotrexate (MTX) is an established disease-modifying antirheumatic drug (DMARD) for the treatment of both juvenile idiopathic arthritis (JIA) and rheumatoid arthritis of adults (RA). However, in common clinical praxis, indication and application of MTX-treatment as well as monitoring of the respective side effects are differently managed. At the end of the eighties MTX was prescribed only to children, who were refractory to traditional slow-acting agents. In different clinical studies it has been found that MTX is a very safe and effective drug for treatment of JIA and that it is well tolerated in children. The common dosages of MTX in pediatric rheumatology ranges from 5–15 once a week, max. 250 mg/m²/week (0,2–0,8 mg/kg/week). The dosages given to children can be much higher than this given to RA patients (7.5–15 mg/week). This difference in dosage may be due to a different pharmakokinetic in children. Frequent side effects of MTX-treatment in children are gastrointestinal symptoms, like nausea and vomiting besides elevated liver enzymes and stomatitis. Thus, the weekly low dose MTX presents compared to other diseases-modifying antirheumatic drugs a beneficial efficiency-toxicity ratio in the treatment of juvenile idiopathic arthritis.     

How to use medicines in children: principles of paediatric clinical pharmacology

Knowledge of drug administration in children and infants has significantly lagged behind that of adults. Despite several paediatric therapeutic mishaps that have been a catalyst for major regulatory reform, the majority of registered medicines do not have indications or dosing for children. This paper will briefly summarise key issues in paediatric pharmacology, including differences in prescribing for children, off-label and unlicensed prescribing and conduct of paediatric clinical trials. A particular emphasis will placed on the situation in Australia.     

Intratumoral methotrexate kinetics in a patient with intracranial anaplastic ependymoma

Little is known about intratumoral anticancer drug concentration in childhood brain tumors. We were able to measure methotrexate (MTX) tumor concentrations directly in a cystic anaplastic ependymoma. Cyst fluid was obtained by puncture of a subgaleal Rickham reservoir connected to a catheter in the tumor cyst. MTX concentrations were determined by fluorescence polarization immunoassay and compared to serum concentrations. Maximum MTX concentrations in tumor and CSF were found at the end of MTX infusion. Twenty-four hour after MTX infusion the mean tumor concentration was significantly higher than in the serum indicating MTX retention and accumulation in the tumor cyst. An AUC(tumor)/AUC(serum) ratio of 1.95 was obtained. In response to the applied multiagent chemotherapy the clinical condition of our patient improved and the tumor showed partial response on MRI. Cystic ependymomas might benefit from high dose MTX especially because of drug retention in the tumor cyst.     

Pediatric clinical pharmacology: an introduction to a series of educational papers

Drug therapy is a very powerful tool to improve the medical outcome of children. Despite this fact, pediatricians still commonly prescribe drug formulations that were developed for adults. In this series of educational papers related to pediatric clinical pharmacology, we aim to raise awareness on different aspects of clinical pharmacology in children, covering neonatal clinical pharmacology, formulation-related issues, ethical aspects of clinical research, pharmacovigilance, and training in pediatric clinical pharmacology. We want to illustrate the relevance of this re-emerging research field for the practicing clinician, although we are very much aware that these topics do not fully cover the multifaceted landscape of pediatric clinical pharmacology. We hope that many readers will reconsider their daily clinical practices and will be stimulated to collaborate to further improve pediatric drug therapy throughout Europe and beyond.     

急性淋巴细胞白血病治疗中大剂量甲氨蝶呤血药浓度影响因素分析

目的探讨大剂量甲氨蝶呤(HDMTX)在儿童急性淋巴细胞白血病(ALL)治疗中各时间点的血药浓度与患儿病理生理状态的关系,发现影响药物体内消除因素,为甲氨蝶呤群体药动学研究提供线索,为临床治疗提供依据。方法89例ALL患儿接受HDMTX化疗,观察内容包括患儿性别、年龄(按月)、体重、身高、体表面积、单位体表面积MTX用量、血药浓度、化疗前肝、肾功能、单位体表面积液体出量、对应PH等逐一进行对比,分析各因素对MTX消除影响。结果高剂量组在24h、36h、42h、48h时药物浓度显著高于低剂量组(P<0.05);体型偏瘦患儿药物体内消除明显快于体型偏胖者(P<0.05);单位体表面积液体出量高的患儿MTX排泄相对快,表现在42h,48h,72h,96h药物浓度明显低(P<0.05),统计48h药物浓度大于1.2μmol/L事件:低出量组33例,高出量组21例,有统计学差异(χ2=4.39)。液体排出量明显影响药物体内消除;血清蛋白偏高组24h、36h、48h、72h、96h血药浓度低于蛋白偏低组,在24h、36h、48h有统计学意义(P<0.05);患儿性别、年龄与血药浓度无相关性,不影响药物在体内的消除。结论甲氨蝶呤量、患儿体型、液体出量、肝功等明显影响MTX体内消除。     

Educational paper: Do we need neonatal clinical pharmacologists?

Effective and safe drug administration in young infants should be based on integrated knowledge concerning the evolving physiological characteristics of the infant who will receive the drug and the pharmacokinetic and pharmacodynamic characteristics of a given drug. Consequently, clinical pharmacology in neonates is as dynamic and diverse as the neonates we are entitled to take care of. Even more than median estimates, covariates of variability within the population are of clinical relevance. We aim to illustrate the complexity and the need for neonatal clinical pharmacology based on the gap between current and likely best clinical practice for two commonly administered compounds (aminoglycosides for infection and ibuprofen for patent ductus arteriosus) and one new compound (bevacizumab, to treat threshold retinopathy of prematurity). Progression has been made to render pharmacokinetic studies child size, e.g., low volume samples, optimal study design, and population pharmacokinetics. Challenges to further improve clinical pharmacology in neonates include, when appropriate, the validation of off-patent drug dosing regimens and of infant-tailored formulations. Knowledge integration, i.e., the use of available data to improve current drug use and to predict pharmacokinetics/pharmacodynamics for similar compounds is needed. Development of clinical research networks is helpful to achieve these goals.     

Central nervous system pharmacology of antileukemic drugs

The blood-brain barrier provides a pharmacologic sanctuary for leukemic cells within the central nervous system (CNS), protecting them from the cytotoxic effects of systemic antileukemic therapy. Attempts to overcome this problem have included specific CNS-directed treatment in the form of direct intrathecal drug injection, cranial irradiation, and alteration in the dose and schedule of systemic agents to enhance their CNS penetration. Use of these treatments and strategies has led to the effective prevention and control of meningeal leukemia. Intrathecal therapy, primarily with methotrexate or cytosine arabinoside, is a form of regional chemotherapy that can achieve very high drug concentrations at the target site [i.e., in the meninges and cerebrospinal fluid (CSF)] with a low total dose. Therefore, there is minimal systemic toxicity. The dose and schedules, clinical pharmacology, and toxicities of the commonly used intrathecal agents are discussed in detail in this article. Another approach to overcoming the limited penetration of antileukemic drugs into the CNS has been the use of high-dose systemic therapy. Methotrexate and cytosine arabinoside in high doses have produced favorable clinical responses in patients with overt meningeal disease, and pharmacokinetic studies have documented cytotoxic concentrations of these drugs within the cerebrospinal fluid. A clear understanding of the CNS pharmacology of the antileukemic drugs is required in order to use these agents in the safest and most efficacious manner for the treatment of meningeal leukemia.     

Cell-kinetics and biochemical pharmacology of methotrexate and 6-mercaptopurine in human malignant T-lymphoblasts.

The cell-kinetics and biochemical pharmacology of simultaneous and sequential combination treatment with 0.02 microM methotrexate (MTX) and 2 microM 6-mercaptopurine (6MP) were studied in MOLT-4 malignant T-lymphoblasts. The results were compared with our data from earlier studies of separate treatment with these antimetabolites. A synergistic effect of combination treatment could be demonstrated, based on the inhibition of purine de novo synthesis by both agents, on DNA and RNA synthesis, on the incorporation of 6-thioguanine nucleotides into DNA and RNA, and on inhibition of cell growth and clonal growth. The synergistic effects of combination treatment with MTX and 6MP will only be available in malignant lymphoblasts, and will be absent in normal bone marrow cells and normal lymphocytes, because the activity of purine de novo synthesis in these cells is absent or low. Based on the synergistic effects of MTX and 6MP and the good penetration of both agents in the cerebrospinal fluid, the Dutch Childhood Leukemia Study Group presently performs a randomized study during protocol M of the BFM/DCLSG-ALL-90 protocol comparing the results of 4 times each two weeks 24 hr intravenous administration of MTX (5 g/m2) versus intravenous MTX, immediately followed by 24 hr intravenous administration of 6MP (1.3 g/m2). The pharmacokinetics and intracellular biochemical pharmacology of 6MP in lymphocytes will be studied, comparing intravenous administration and low dose oral administration.     

Disposition of oral methotrexate in children with acute lymphoblastic leukemia and its relation to 6-mercaptopurine pharmacokinetics

We studied the disposition pharmacokinetics of methotrexate (MTX) given orally to 16 children with acute lymphoblastic leukemia (ALL) and its relation to the pharmacokinetics of 6-mercaptopurine (6MP) in the same children. There was an eightfold variability in area-under-concentration time-curve (AUC) of MTX achieved by the same dose. Excellent correlation existed between peak concentrations and AUC0----infinity (r = 0.95, P less than 0.001). Elimination T1/2 was between 1.34 and 5 hours (mean 2.16 +/- 0.23 hr, mean +/- SE). A weak correlation existed between AUC achieved by 1 mg/m2 MTX and patients' age or body weight. Weak but significant correlation existed between AUC achieved by 1 mg/m2 of MTX vs. 6MP (r = 0.54, P less than 0.05). In 13/16 patients peak concentrations were achieved at 60 minutes. There was a significantly larger AUC of 6MP achieved by a standardized dose in longer therapy (greater than 15 mo) vs. short therapy (less than 12 mo) (462 +/- 75 and 246 +/- 58 ng.ml-1.min.mg-1.m2, P less than 0.025). No statistical differences in AUC of MTX were found between short and long therapy. The large interpatient variability in MTX pharmacokinetics supports the possibility that differences in absorption and/or clearance of the drug may affect the clinical response. Because of the excellent correlation between peak and AUC of MTX, and because 3 measurements, at 30, 60, and 90 minutes will almost invariably identify the peak, this measurement can be used to estimate AUC for purpose of correlation with clinical outcome.     

Evaluation of Serious Adverse Events in Patients Treated with Protocols Including Methotrexate Infusions

During the period 1979 to 1992 we treated 141 children for various malignant diseases with protocols including methotrexate (MTX) infusions in doses ranging from 0.5 to 33.6 g/m². During a total of 922 courses, there were no fatal complications associated with MTX treatment. Serum MTX concentration and pharmacokinetic data were monitored continuously during the infusions. In this study, we evaluated the occurrence of serious untoward reactions to MTX infusions. Impaired renal function with delayed drug elimination was seen in seven patients, all boys, especially after short infusion times. All recovered completely without any serious clinical symptoms. In three leukemia patients who later died from resistant disease, we observed lute neurological disturbances and computer tomography (CT) brain scan abnormalities. Pharmacokinetic data from the patients with complications are described and confirm that serial MTX concentration monitoring is the most important early indicator of renal toxictty.     

Ratio of methotrexate to folate uptake by lymphoblasts in children with B-lineage acute lymphoblastic leukemia: a pilot study

PURPOSE: Methotrexate (MTX) remains one of the most effective drugs for the treatment of children with acute lymphoblastic leukemia (ALL). Because MTX and 5-methyltetrahydrofolate (5CH3THF) share uptake and metabolic pathways, the efficacy of MTX is likely to depend not only on its metabolism but also on how well folate is accumulated by lymphoblasts. The authors' goal was to compare in vitro folate and antifolate uptake in B-lineage lymphoblasts from patients who remained in continuous complete remission (CCR) and those in whom relapse occurred. PATIENTS AND METHODS: Twenty-four children with B-lineage ALL were studied at diagnosis (n = 20) or relapse (n = 4). Lymphoblasts obtained by bone marrow aspiration were incubated for 24 hours in vitro with 0.05 microM 5CH3[3H]THF or 1 microM [3H]MTX. RESULTS: As of July 1999, 16 patients studied at diagnosis remained in CCR at a median follow-up of 45 months after achieving remission. Two of the patients studied at relapse are in second CCR; the remaining two died from progressive disease. The median uptake of neither [3H]MTX nor 5CH3[3H]THF differed significantly between the 16 patients in first CCR studied at diagnosis and the 4 patients studied at relapse. However, the median ratio of [3H]MTX:5CH3[3H]THF uptake differed significantly for patients who remained in first CCR versus patients studied at relapse. CONCLUSIONS: The uptake of [3H]MTX in relation to 5CH3[3H]THF by leukemic lymphoblasts in vitro may correlate positively with treatment outcome in children with B-lineage ALL. A larger study of homogeneously treated patients is necessary to confirm these results.     

Successful Carboxypeptidase G2 Rescue in Delayed Methotrexate Elimination Due to Renal Failure

We report on an 18.5-year-old woman with osteosarcoma and delayed methotrexate (MTX) elimination due to renal failure after high-dose MTX, in whom rescue with high doses of folinic acid caused intolerable side effects. In this life-threatening clinical situation, the patient was rescued by the administration of recombinant carboxypeptidase G₂, a bacterial enzyme that rapidly hydrolyzes MTX into inactive metabolites. This is the first report on the successful clinical use of this alternative catabolic route for the elimination of MTX.     

Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney function

BACKGROUND: The present investigation was intended to further clarify the mechanisms involved in renal dysfunction following high-dose methotrexate (HD-MTX) treatment. PATIENTS AND METHODS: Fifty eight predominately pediatric patients [39 male, 19 female; mean age 12.3 years (range 2.2-34.1)] suffering from acute lymphoblastic leukemia (ALL, n = 28), Non Hodgkins lymphoma (NHL, n = 13), osteosarcoma (n = 8), malignant brain tumor (n = 6), or an ALL relapse (n = 3), were prospectively examined. In the course of 220 infusions of HD-MTX, glomerular and tubular renal function was determined by measuring proteinuria and glomerular filtration rate (GFR), as well as renal excretion of alpha-1-microglobulin (AMG) and N-acetyl-beta-D-glucosaminidase (NAG). It was investigated whether there were differences in MTX toxicity in dependence on the administered dose (1, 5, or 12 g/m(2) BSA), on the combination with other cytostatic agents (ifosfamide or cyclophosphamide), on the metabolism of MTX into 7-OH-MTX, and on pre-treatment with MTX. RESULTS: The administration of HD-MTX has no direct tubulotoxic effect. The disturbance in glomerular function was dose dependently and indicated by an increase in proteinuria as well as by a decrease in GFR; all changes were completely reversible and did not correlate to the metabolism of MTX to 7-OH-MTX. Increasing the number of MTX therapeutic cycles did not increase the nephrotoxicity of MTX. CONCLUSION: MTX is not directly tubulotoxic. Its side effects on glomeruli are usually without clinical relevance.     

Reversible acute methotrexate leukoencephalopathy: atypical brain MR imaging features

Background: Unusual acute symptomatic and reversible early-delayed leukoencephalopathy has been reported to be induced by methotrexate (MTX). Objective: We aimed to identify the occurrence of such atypical MTX neurotoxicity in children and document its MR presentation. Materials and methods: We retrospectively reviewed the clinical findings and brain MRI obtained in 90 children treated with MTX for acute lymphoblastic leukaemia or non-B malignant non-Hodgkin lymphoma. All 90 patients had normal brain imaging before treatment. In these patients, brain imaging was performed after treatment completion and/or relapse and/or occurrence of neurological symptoms. Results: Of the 90 patients, 15 (16.7%) showed signs of MTX neurotoxicity on brain MRI, 9 (10%) were asymptomatic, and 6 (6.7%) showed signs of acute leukoencephalopathy. On the routine brain MRI performed at the end of treatment, all asymptomatic patients had classical MR findings of reversible MTX neurotoxicity, such as abnormal high-intensity areas localized in the deep periventricular white matter on T2-weighted images. In contrast, the six symptomatic patients had atypical brain MRI characterized by T2 high-intensity areas in the supratentorial cortex and subcortical white matter (n=6), cerebellar cortex and white matter (n=4), deep periventricular white matter (n=2) and thalamus (n=1). MR normalization occurred later than clinical recovery in these six patients. Conclusions: In addition to mostly asymptomatic classical MTX neurotoxicity, MTX may induce severe but reversible unusual leukoencephalopathy. It is important to recognize this clinicoradiological presentation in the differential diagnosis of acute neurological deterioration in children treated with MTX.     

Successful high-dose methotrexate chemotherapy in a patient with acute lymphocytic leukemia who developed acute renal failure during the initial treatment

Methotrexate (MTX) is a key drug in the chemotherapy for childhood acute lymphocytic leukemia (ALL). It is essential in the treatment of such areas as the central nervous system (CNS) and reproductive organs. High-dose chemotherapy is applied for this purpose to obtain an effective plasma concentration in the target organs.There are three major mechanisms of nephrotoxicity related with MTX. One is that induced by allergic reaction, which usually appears as interstitial nephritis. In this case MTX is contraindicated. Another is direct pharmacological toxicity against renal tubules. The third is precipitation of MTX, which plugs the renal tubules. The latter two are consequently dose dependent, and are usually associated with high-dose chemotherapy. To prevent these nephrotoxicities, hydration and alkalinization of the urine are performed to accelerate the urinary excretion and avoid the precipitation of MTX.     

Lung function in adolescents receiving high-dose methotrexate.

Methotrexate (MTX) has been implicated as a cause of interstitial pneumonitis and/or fibrosis, but the mechanism by which the drug causes these processes is not known. The purpose of this study was to determine whether patients receiving high-dose MTX developed a consistent decrease in pulmonary function, which would implicate a role for total dose of MTX received in the pathogenesis of the lung toxicity. Pulmonary function studies, including spirometry, plethysmography, and diffusing capacity at two levels of alveolar PO2, were performed in 38 adolescents treated for osteogenic sarcoma. The patients were divided into three groups including 12 patients (group 1) studied before and during therapy, 15 patients (group 2) studied during therapy, and 11 patients (group 3) studied after completion of treatment. While total dose received at the time of the study varied from 0 to 256 gm/sq m, pulmonary function showed no change, with one exception. A mild restrictive defect and decrease in diffusing capacity due to unilateral pleural and diaphragmatic disease, whose relationship to MTX therapy is uncertain, developed in one patient. MTX, when administered in high dose to young patients by the described protocol, causes no dose-related decrease in pulmonary function.     

非甾体类消炎药联合甲氨蝶呤治疗全身型幼年特发性关节炎疗效观察

目的探讨非甾体类消炎药(NSAIDs)联合甲氨蝶呤(MTX)治疗全身型幼年特发性关节炎(SO-JIA)的疗效。方法分析比较32例SO-JIA患儿以NSAIDs联合MTX治疗后临床症状的变化,关节炎病情改善评估参照美国风湿病学会推荐的类风湿性关节炎改善标准。结果32例患儿治疗后,体温恢复正常27例,退热有效率为84.4%(27/32例),5例加用糖皮质激素后热退;31例关节炎症状改善,有效率为96.9%(31/32例),1例加用来氟米特后关节炎症状缓解。停药观察3例,复发1例。结论SO-JIA诊断确立后应尽早予NSAIDs联合MTX治疗,NSAIDs能较好地退热及减轻关节症状,MTX可有效持续改善关节炎症。糖皮质激素不作为首选退热用药。     

大剂量甲氨蝶呤治疗急性淋巴细胞白血病

目的研究3g/m2和5g/m2甲氨蝶呤(MTX)治疗急性淋巴细胞白血病(ALL)的血、脑脊液MTX浓度和不良反应。方法ALL患儿43例共接受98例次MTX3g/(m2·次)或5g/(m2·次)治疗,对两剂量组进行MTX血药质量浓度、脑脊液浓度及不良反应比较。结果1.MTX44、66h血药质量浓度与23hMTX血药质量浓度明显相关(P<0.05);2.不同个体间及同一个体不同时间使用同一给药方案血药质量浓度、脑脊液浓度水平差异较大;3.两剂量组不良反应发生率无明显差异(P>0.05),骨髓抑制、肝功能损害的MTX血药质量浓度无明显差异(P>0.05)。结论对于标危、高危ALL分别采用3、5g/(m2·次)的剂量是合理的,无严重不良反应发生。