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。     

儿童急性白血病应用大剂量甲氨蝶呤严重并发症3例临床分析及文献复习

目的探讨儿童白血病（ALL）应用大剂量甲氨蝶呤（HD-MTX）严重并发症的临床特点、发生机制及预防处理措施。方法总结3例在本院确诊并按ALL治疗方案规范化疗的儿童急性淋巴细胞白血病应用HD．MTX后出现严重并发症病例的临床特点并复习文献。结果3例患儿均为学龄期儿童、急性淋巴细胞白血病应用HD．MTx（5g／m2）期间发生严重高甲氨蝶呤血症,治疗期间严密监测血药浓度,持续水化、碱化以及多种方式四氢叶酸钙解救但甲氨蝶呤排泄延迟,2～3周后血清甲氨蝶呤浓度仍明显高于中毒浓度,化疗后2周均合并严重骨髓抑制,2例出现表皮松解、1例消化道溃疡,均因继发感染及多脏器损害并发症死亡。结论甲氨蝶呤体内的代谢受到多种因素影响,持续高血药浓度可造成严重并发症,对儿童ALL应用HD．MTX应根据细胞免疫学表型、细胞遗传学及甲氨蝶呤静脉滴注后不同时段的血药浓度及药物代谢酶相关基因情况采用个体化治疗。     

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.     

Methotrexate levels and outcome in osteosarcoma

BACKGROUND: Peak serum concentrations of methotrexate (MTX) have been reported to correlate with outcome in osteosarcoma (OS). Modification of the MTX dose to achieve peak levels between 700 and 1,000 micromol/L has been recommended. The goal of the study was to assess whether there is a correlation between histologic necrosis of the tumor and/or prognosis with peak MTX serum concentration. PROCEDURE: Treatment included multi-agent adjuvant chemotherapy, including high-dose MTX (12 g/m2). Peak MTX levels were drawn following a 4-hr infusion. Histologic evaluation for percent necrosis was done at the time of definitive resection. RESULTS: The median peak MTX level (n = 52 patients) was 1,060 micromol/L (range: 410-4,700 micromol/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 micromol/L or higher. Response to pre-operative chemotherapy was: 18% Grade I necrosis, 35% Grade II, 31% Grade III, and 16% Grade IV. No significant association was found between the mean peak MTX levels and necrosis (P = 0.44). Event-free survival (EFS) for the 48 patients with non-metastatic disease at diagnosis was 76% at 4 years of follow-up, with no association between the mean peak MTX level and EFS (P = 0.24). CONCLUSIONS: The absence of a demonstrable correlation between peak MTX levels and histologic necrosis or EFS may suggest that most patients achieve therapeutic levels when MTX is given at a dose of 12 g/m(2). The significant degree of intra-patient variability in peak levels poses a dilemma for pharmacokinetic adjustment. Continued use of HD-MTX in all patients, rather than dose adapted therapy, may be justified.     

High-dose methotrexate therapy (6-8 g/m2) in childhood malignancies: clinical tolerability and pharmacokinetics

Five children, ages 2.5 to 12 years (mean 6.2 years), with acute lymphoblastic leukemia or non-Hodgkin's lymphoma were given 22 courses of high-dose methotrexate (HD-MTX) therapy (6-8 g/m2/24 h). No serious clinical complications were encountered, but stomatitis occurred after three (14%) of the courses. First-phase elimination half-lives (t1/2(alpha)) of MTX and 7-hydroxy-methotrexate (7-OH-MTX) after 21 infusions were 2.7 +/- 0.4 h and 6.5 +/- 1.8 h (mean +/- SD). In one course (4.5%) there was delayed systemic MTX elimination, with first-phase elimination half-lives (t1/2(alpha] for MTX and 7-OH-MTX of 4.2 and 9.9 h, respectively, and second-phase elimination half-lives (t1/2(beta)) of 43 and 58 h. Significant decreases in white blood cell count, increases in serum creatinine, and increases in alanine aminotransferase and/or aspartate aminotransferase during the first 2-6 days were present in five (23%), three (14%), and six (27%) of the courses, respectively. The regimen was tolerated well by the children.     

Plasma phenylalanine: Tyrosine ratios during high-dose methotrexate-citrovorum “rescue”

We have measured phenylalanine and tyrosine in the plasma of patients with osteogenic sarcoma undergoing chemotherapy with high-dose methotrexate (HDMTX) citrovorum factor rescue (CFR). During 14 treatments in six different patients, the phenylalanine to tyrosine ratio (PHE/TYR) at 21 to 38 hours was elevated over pretreatment levels. The observed increase in plasma phenylalanine is attributed to inhibition by MTX of the phenylalanine hydroxylase system of the liver, which is not folate-dependent and thus is not corrected by administration of CF. A post-infusion increase in PHE/TYR of 571% after 22 hours in one patient and of 410% after 30 hours in another were associated with marked MTX toxicity. The greatest increase in PHE/TYR seen in a patient who did not experience toxicity was was 249% in 21 hours. Thus, in this group of patients, there appears to be a correlation between evidence of clinical MTX toxicity and the magnitude of the percentage increase in PHE/TYR in the plasma, which indicates inhibition of a liver enzyme and thus reflects the intracellular concentration of MTX.     

Daily profiles of plasma phenylalanine and tyrosine in patients with osteogenic sarcoma during treatment with high-dose methotrexate-citrovorum rescue

Three adolescents and one child with osteosarcoma were studied during multiple courses of high-dose methotrexate, citrovorum factor rescue (HDMTX-CFR), with one adolescent treated intermittently over a period of 6 years. Plasma phenylalanine (Phe) and tyrosine (Tyr) were measured immediately before the infusion of MTX and then daily until serum MTX fell below 10(-7) M. At 24 hours, all showed marked increases in Phe and in the Phe/Tyr ratio. This suggests inhibition of dihydropteridine reductase (DHPR) which, in association with hepatic Phe hydroxylase, controls plasma concentrations of Phe. Inhibition of this enzyme system is not relieved by CFR. In the adolescent patients, although MTX levels in plasma declined steadily, Phe concentrations, which fell between 24 and 48 hours, rose to a new peak at 4-7 days. Possible reasons for this secondary increase are discussed. The patient with the longest exposure to HDMTX showed an increase in pretreatment Phe/Tyr ratios with time, suggesting damage to liver parenchymal cells not indicated by standard tests of liver function. Evaluation of plasma Phe during the course of HDMTX-CFR may permit assessment of intracellular concentrations of MTX or its metabolites in the liver without interference by CFR.     

High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance.

BACKGROUND: The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. PROCEDURE: Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. RESULTS: Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. CONCLUSIONS: These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.     

Severe methotrexate toxicity precipitated by intravenous radiographic contrast

Methotrexate (MTX), a widely used anticancer agent, and intravenous iodinated contrast used for radiographic studies can both cause acute renal failure. Their combined exposure may place patients at higher risk for renal failure. This report describes 2 pediatric patients with MTX toxicity precipitated by the use of intravenous radiographic contrast. One patient recovered with leucovorin rescue therapy, whereas the second patient responded to carboxypeptidase-G2. Both patients suffered MTX-related toxicities including myelosuppression and mucositis, but recovered full renal function and tolerated further high-dose MTX therapy. These cases suggest that intravenous iodinated contrast should be avoided in patients receiving high-dose MTX.     

High-dose cyclophosphamide-high-dose methotrexate with coordinated intrathecal therapy for advanced nonlymphoblastic lymphoma of childhood: results of a Pediatric Oncology Group study.

The Pediatric Oncology Group (POG) investigated a high-dose cyclophosphamide (CPM) high-dose methotrexate (MTX) regimen to determine therapeutic efficacy in confirmed advanced nonlymphoblastic non-Hodgkin's lymphoma (NHL) (stages III and IV) and B-cell acute lymphatic leukemia (B-ALL) in children. Another goal was to determine the comparative effectiveness of shortened maintenance treatment (2 versus 6 courses) in the study population. Systemic induction therapy included vincristine, prednisone, cyclophosphamide, and intermediate-dose MTX with leucovorin rescue. Superimposed intrathecal (IT) therapy included cytosine arabinoside for 2 successive days followed on day 3 by MTX. Intrathecal MTX was given 3 times during induction. At the end of induction, 2 days of triple (hydrocortisone, MTX, and cytosine arabinoside) therapy were given intrathecally (TIT). All patients then received a consolidation course of 4 doses of TIT, 2 doses of cyclophosphamide, and 4 more courses of vincristine and MTX with leucovorin rescue. Patients were then randomized to receive either 2 or 6 cycles of vincristine plus MTX with leucovorin rescue. The TIT was given with each cycle. Complete response rates by histology and Murphy stage (1) were as follows: undifferentiated lymphoma (DUL) stage III, 84/105 (80%): stage IV, 5/12 (42%); and other NHL [primarily large cell lymphoma (LCL)] stage III, 21/28 (75%); stage IV, 2/3 (67%). Event-free survival (EFS) at greater than 2 years was similar for patients with DUL and LCL, i.e., 65 and 61%, respectively. No significant difference in outcome was noted between patient groups receiving 2 or 6 maintenance treatments (p = .76). Treatment was notable for its modest toxicity following the early change to single-dose CPM therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Variability in dose intensity of high-dose methotrexate for nonmetastatic osteosarcoma

The authors evaluated their ability to maintain planned dosing schedules for high-dose methotrexate (HD-MTX) in patients with nonmetastatic osteosarcoma. Twenty-seven patients who received therapy according to 2 POG protocols (8651 and 9351), both of which included HD-MTX (12 g/m(2)/week for 2 consecutive weeks), between 1988 and 1998 were studied. Significantly fewer HD-MTX infusions were given on the second week to patients treated on POG 9351 (33 vs. 93%; p < .0001). The hydration guidelines were identical and there was no difference in peak serum MTX levels either within or between protocols. Differences in the administration of combination chemotherapy in 9351 compared to 8651 may have contributed to the increased toxicity associated with HD-MTX on 9351, although this is speculative. The use of HD-MTX should be carefully planned so that it does not decrease its dose intensity or that of other effective agents.     

Pharmacokinetics of HD-MTX in infants,children, and adolescents with non-B acute lymphoblastic leukemia

A retrospective pharmacokinetic analysis was done of methotrexate serum levels after high-dose treatment (HD-MTX, four cycles at two-week intervals of 5 g/sq.¹m. over 24 h i.v.) in children with non-B acute lymphoblastic leukemia (ALL) with the specific aim of seeking differences in patients of different ages, including infants under one year. A total of 122 children (seven infants aged 3 months-1 year, 26 children aged 1–3 years, 68 children aged 3–10 years and 21 adolescents aged 10–15 years) with normal liver and renal function, receiving consolidation therapy at the Pediatric Clinic of Monza between May 1988 and April 1992, were enrolled in this study. MTX was given as an intravenous infusion in 24 h and serum concentrations were measured up to at least 72 h after the start of infusion by an enzyme immunoassay (TDX Abbot, Dallas, TX) in order to modulate folinic acid rescue. Pharmacokinetic analysis of MTX levels according to a two-compartment open model indicated that, compared to all children up to 10 years old, in adolescents older than 10 years the drug reached higher concentrations in serum and was cleared at a lower rate. Steady-state levels and AUC were from 60% higher to more than double and the total clearance of the compound, expressed either per square meter surface area or per kg body weight, in each cycle was significantly lower in adolescents >10 years of age, sometimes being only one-third of the clearance in infants (0.2 vs. 0.6 1/h/kg and 6.6 vs. 10.7 1/h/sq.m). The relationship between each age and systemic clearance was highly significant as measured by regression analysis. Methotrexate systemic clearance progressively decreased as a function of age. Subsequent treatments did not induce changes in MTX pharmacokinetics. These data suggest that the better tolerance of HD-MTX in children may have a pharmacokinetic basis. The faster elimination of MTX in infants, who usually show the worst prognosis, suggests that full doses could be safely used in order to maximize the antileukemic effect without a high risk of toxicity. © 1995 Wiley-Liss, Inc.     

Methotrexate as relapse therapy for rhabdomyosarcoma

Four patients had a local relapse after standard therapy for rhabdomyosarcoma and were treated with high-dose 42-hour MTX infusions. All patients responded to this therapy, one patient had a complete, and two patients a partial remission. Long duration MTX infusion should be part of a combination chemotherapy for relapsed rhabdomyosarcomas.     

Low-dose methotrexate in the treatment of severe juvenile rheumatoid arthritis and sarcoid iritis.

OBJECTIVE: To assess the efficacy of low-dose oral methotrexate (MTX) therapy for children with severe iritis. METHODS: MTX in a weekly dose of 7.25 to 12.5 mg/m2 was administered orally to four patients (two with juvenile rheumatoid arthritis [JRA] and two with sarcoidosis) with severe iritis not adequately controlled by topical and systemic corticosteroid therapy. The treatment was initiated with half of the total dose and increased every 2 weeks until the final dose was reached. Iritis was graded from 0 to +4 according to the density of cells in the anterior chamber of the eye. RESULTS: There were three girls and one boy with a mean age of 10.5 years. Two patients were African American and two were Caucasian. The mean age at onset of iritis was 6 years. The mean duration of MTX therapy was 28.8 months. Significant improvement was noted in two of the four patients in ocular inflammation, demonstrated by reduction of cell density from +4 to +1. Two patients had a mild improvement of the iritis. However, corticosteroids were significantly reduced in all patients. One patient was completely off steroids within 30 months of MTX therapy. In the remaining three cases, the steroid dose was successfully tapered from 0.82 mg/kg/d to 0.15 mg/kg/d (mean doses) within a mean duration of 20 months. No side effects were observed with MTX therapy. CONCLUSION: Low-dose MTX therapy was effective and safe, and displayed steroid-sparing properties in four children with severe iritis.     

VARIABILITY IN DOSE INTENSITY OF HIGH-DOSE METHOTREXATE FOR NONMETASTATIC OSTEOSARCOMA

The authors evaluated their ability to maintain planned dosing schedules for high-dose methotrexate (HD-MTX) in patients with nonmetastatic osteosarcoma. Twenty-seven patients who received therapy according to 2 POG protocols (8651 and 9351), both of which included HD-MTX (12 g/m 2 /week for 2 consecutive weeks), between 1988 and 1998 were studied. Significantly fewer HD-MTX infusions were given on the second week to patients treated on POG 9351 (33 vs. 93%; p < .0001). The hydration guidelines were identical and there was no difference in peak serum MTX levels either within or between protocols. Differences in the administration of combination chemotherapy in 9351 compared to 8651 may have contributed to the increased toxicity associated with HD-MTX on 9351, although this is speculative. The use of HD-MTX should be carefully planned so that it does not decrease its dose intensity or that of other effective agents.     

Systemic inflammatory response related to cardiopulmonary bypass and its modification by methyl prednisolone: high dose versus low dose

The objective of our study was to investigate the safety and efficacy of high-dose methyl prednisolone (MP) in modifying the systemic inflammatory response (SIR) to cardiopulmonary bypass (CPB) and to compare its efficacy with low-dose MP in children undergoing cardiac surgery for congenital heart disease. Thirty children with congenital heart disease undergoing CPB were randomly assigned to two groups: group 1 (n = 15) received 30 mg/kg MP by an intravenous infusion for 30 minutes and group 2 (n = 15) received 2 mg/kg intravenously, before the onset of CPB. Postoperative clinical parameters were recorded, and serum interleukin (IL)-6 and 8 levels, acute phase reactants, and blood biochemistry were determined serially for both groups. In both groups plasma IL-6 and 8 levels were elevated above the preoperative levels at 2 and 24 hours after declamping. The peak levels were obtained at 2-hour samples. The difference between the two groups in terms of postoperative IL-6 and 8 levels was not statistically significant. C-reactive protein (CRP) levels and polymorphonuclear leukocyte counts, postoperative core temperature, duration of mechanical ventilation, period of stay in intensive care unit, oxygenation indices, and biochemical parameters of patients did not significantly differ in the two groups. Only 1 patient in group 1 had elevated liver enzymes, blood urea nitrogen, and creatinine in the postoperative period. No significant complications were observed due to treatment with high-dose MP. Although postoperative IL and CRP levels indicated a SIR in our patients, the clinical picture was apparently affected in only 1 patient and she was in the high-dose MP group. CPB initiates a SIR that is associated with an increase in neutrophil count, CRP, and IL-6 and 8 levels. High-dose (30 mg/kg) MP was not superior to low-dose (2 mg/kg) in blunting the SIR to CPB in pediatric patients undergoing open-heart surgery.     

大剂量甲氨蝶呤目标浓度个体化调整研究

目的 探讨大剂量甲氨蝶呤(MTX)24 h输注治疗儿童急性淋巴细胞白血病目标浓度个体化调整的方法.方法 本研究涉及24例患儿105个疗程,检测MTX开始输注后第1和第6小时的血药浓度,根据已建立的大剂量MTX群体药物动力学模型,推算出该疗程稳态血药浓度(CSS)的预测值.根据CSS预测值,于MTX开始输注后第8小时调整MTX输注速度和剂量.MTX输注后第23小时再检测血药浓度(CSS实测值).结果 为达目标浓度,17例(71%)患儿进行了剂量调整.45个疗程(43%)调整了剂量,42个疗程增加了剂量,3个疗程减少了剂量.早期阶段(诱导缓解和巩固治疗方案后的大剂量MTX的疗程)29个疗程中有16个疗程增加了剂量,1个疗程减少了剂量;维持阶段76个疗程中有26个疗程增加了剂量,2个疗程减少了剂量.最终有95个(90%)疗程的CSS实测值达目标范围,8个疗程小于目标范围,2个疗程大于目标范围.如果不调整剂量,仅有74个(70%)疗程的CSS(不调整)在目标范围.调整MTX剂量,与不调整相比,可以明显增加CSS实测值达目标范围的疗程数(χ2=13.366,P=0.000).在剂量不调整的60个疗程中,CSS实测值和CSS预测值有较好的直线相关性(r=0.487,P=0.000);CSS实测值与MTX输注后第6小时的血药浓度也有一定的直线相关性(r=0.389,P=0.002).105个疗程MTX的总清除率(CL)实测值是(7.01±2.06)L/(m2·h).在所有疗程间CL相差最大达4.4倍,同一患儿不同疗程间CL相差最大达2.9倍.CL与患儿的年龄、体重和总胆红素呈直线负相关,与血磷呈直线正相关;化疗早期阶段疗程的CL有高于维持阶段疗程的倾向(P均＜0.05).结论 105个疗程大剂量MTX化疗,疗程间CL差异最大达4.4倍,需要目标浓度个体化调整.通过检测MTX输注后第1和第6小时的血药浓度,调整MTX输注速度和剂量,最终90%疗程的CSS实测值达目标范围.早期阶段大剂量MTX化疗更需要目标浓度个体化调整.     

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。     

Recombinant human growth hormone treatment,using two dose regimens in children with chronic renal failure--a report on linear growth and adverse effects

The aim of this study was to study the efficiency and the adverse effects of 2 or 4 IU/m2/day of growth hormone (GH) in the first year and 4 IU/m2/day in the second. Of 29 growth-retarded children with chronic renal failure (CRF) (aged 3.4-15.1 years), 23 completed the first year of therapy, and 16 completed the second year. Height velocity SDS (HVSDS) increased in the first year in the low-dose group with 3.0, and 3.8 in the high-dose group. In the second year, HVSDS increased by 1.3 in the low-dose group and by 2.1 in high-dose group (p < 0.05). The IGF-I/IGFBP-3 ratio rose identically during the first year (p < 0.01). The retarded bone age did not advance inappropriately. The integrated insulin levels (AUC) increased significantly after 1 year of therapy in both groups. HbA1c, levels did not change. The number of adverse events was highest in the low-dose group, in which one patient developed overt insulin dependent diabetes mellitus. In conclusion, glucose metabolism should be monitored in children with CRF during rhGH-treatment. GH therapy in our patients resulted in a significant increase in height velocity with no inappropriate bone age progression and few serious adverse effects, all without relation to the dose of rhGH. The low start dose (2 IU/m2/ day) was of no advantage compared to the high dose.     

Cerebrospinal Fluid and Plasma Methotrexate Levels Following High-Dose Regimen Given as a 3-Hour Intravenous Infusion in Children with Nonhodgkin's Lymphoma

In the French non Hodgkin's lymphoma protocols, central nervous system prophylaxis is provided by high-dose methotrexate (HD-MTX), given as a 3-hour IV infusion of 3 g/m² MTX along with intrathecal MTX injection. The incidence of CNS relapse is less than 3%. We designed a study to evaluate the MTX transfer across the blood brain barrier in terms of cytotoxic concentrations, during these short-term infusions. Cerebrospinal fluid and plasma MTX levels were measured during 61 courses in 29 children with non Hodgkin's lymphoma; none of them had central nervous system disease. Samples were obtained either 4, 12, 18, or 24 hours after the start of HD-MTX IV infusion. A potentially cytotoxic MTX level (10^-6 M) was reached in all courses at 4 hours (median: 2.3 × 10^-6 M) and remained available in 8/16 courses at 12 hours (median: 1.0 × 10^-6 M) and in only 2/17 courses at 18 hours (median: 0.29 × 10^-6 M). Twenty-four hours after the start of HD-MTX IV infusion, CSF MTX level was always less than 10^-6 M. The plasma MTX levels were 260, 1.3, 1.0, and 1.7 × 10^-6 M at 4, 12, 18, and 24 hours, respectively. There was no correlation between plasma and CSF MTX levels. These data show that potentially cytotoxic MTX concentrations can be reached in CSF after a 3-hour IV infusion of 3 g/m² in every patient and remain available for at least 8 hours in half of them.