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。     

Biopterin and neurotransmitter amine metabolism in children with acute lymphoblastic leukemia receiving methotrexate therapy

To test the hypothesis that some of the neurologic sequelae of treatment for acute lymphoblastic leukemia (ALL) might be related to abnormalities in biopterin metabolism associated with methotrexate (MTX) therapy, total biopterin levels in cerebrospinal fluid (CSF) and plasma, and homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were measured in a cross-sectional study of 80 children with ALL. For comparison, biopterins were also measured in a group of children of similar age undergoing investigation for neurologic disease. In children with ALL studied before therapy, no significant difference was found between the means of plasma biopterin or CSF biopterin concentrations and the means in the control group. In children receiving MTX, plasma biopterin values were higher in the group given maintenance therapy than in children observed before treatment. CSF levels were significantly increased only in those patients who had completed 2 years of maintenance therapy. CSF concentrations of HVA and 5HIAA in patients with ALL who had received no treatment (median values 52 and 18 ng/ml, respectively) showed a wide scatter and were inversely related to age. In patients receiving MTX, concentrations of these metabolites were higher than in the untreated group, again reaching a peak in patients just completing 2 years of treatment (median HVA 110 ng/ml, 5HIAA 34 ng/ml). These results provide no support for the idea that neurotransmitter amine deficiency occurs in children with ALL receiving MTX, and indicate, rather, that amine and biopterin synthesis increases in such patients.     

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Background

Severe neurotoxicity has been observed after systemic high‐dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX‐induced alterations of the folate and methyl‐transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated.

Procedure

MTX, 5‐methyltetrahydrofolate, calcium folinate, S‐adenosylmethionine, and S‐adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high‐dose MTX (5 g/m²) followed by calcium folinate rescue (3 × 15 mg/m²) and/or intrathecal (8–12 mg) MTX. Two patients developed subacute MTX‐associated neurotoxicity. CSF was obtained by lumbal puncture 1–3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection.

Results

In non‐toxic patients, CSF concentrations of 5‐methyltetrahydrofolate and S‐adenosylmethionine were in the normal range 2 weeks after administration of high‐dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5‐methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S‐adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5‐methyltetrahydrofolate and S‐adenosylmethionine during or following toxicity. S‐adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non‐toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion.

Conclusion

Intrathecal MTX without folinate rescue as well as MTX‐associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl‐transfer pathway. Pediatr Blood Cancer 2009;52:26–32. © 2008 Wiley‐Liss, Inc.     

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.     

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.     

Comparative study on the pharmacokinetics of 7-hydroxy-methotrexate after administration of methotrexate in the dose range of 0.5-33.6 g/m2 to children with acute lymphoblastic leukemia

Concentrations of 7-hydroxy-methotrexate (7-OH-MTX) were determined in serum samples obtained after 266 infusions of methotrexate administered to 58 children with acute lymphoblastic leukemia. The dose of methotrexate (MTX) was in the range of 0.5-33.6 g/m2. Pharmacokinetic parameters (metabolic index, drug/metabolite ratio, half-life) of 7-OH-MTX and their relationship to the kinetics of methotrexate were analyzed. A great variability was observed in the extent and time-course of the metabolite formation. The concentration of the metabolite was higher than that of the parent compound at any examined time after the end of the 24 hours' infusion. The increase of 7-OH-MTX levels at the end of the methotrexate infusion was found to be proportionate to the increase of the dose of MTX. Males had significantly higher metabolite levels than did females (P less than 0.01) in the dose range of 0.5-8.0 g/m2. The age of the patients also significantly influenced the rate of the metabolite formation. The serial number of the treatment courses did not have effect on the metabolism of MTX. Dose dependency of the elimination half-life of the metabolite was found. Although a tendency was observed that patients in continuous complete remission had higher metabolite levels than those who relapsed, the difference was not significant. Further studies are needed to determine the clinical importance of 7-OH-MT.     

Oral mucositis and salivary methotrexate concentration in intermediate-dose methotrexate therapy for children with acute lymphoblastic leukemia

The relationship between salivary methotrexate (MTX) concentration and severity of oral mucositis after administration of MTX was investigated in six children with acute lymphoblastic leukemia. They received two administrations of MTX at 500 mg/m2 with one third given bolusly and the remainder by 24-hour continuous infusion. No significant difference among patients or administration session was observed in serum MTX concentration. Detectable concentrations of salivary MTX (greater than 0.01 microM) were observed during nine of the ten infusions. A concentration of 0.1 microM or more, apparently lasting at least 12 hours, was observed during one infusion and followed by severe mucositis. During two of the ten infusions for different patients, concentrations of 0.04 to 0.07 microM and 0.02 to 0.04 microM, apparently lasting at least 12 and 18 hours, respectively, were observed, followed by moderate mucositis. During the other seven infusions, either much shorter or no increase in salivary MTX concentration was observed, with only mild or no subsequent mucositis. Analysis by Kendall's rank method showed a statistical correlation between concentration at 6 hours of infusion and severity of oral mucositis. The findings suggest that the early secretion of MTX into saliva has a significant role in the development of oral mucositis in leukemic children.     

Randomized comparison of moderate-dose methotrexate infusions to oral methotrexate in children with intermediate risk acute lymphoblastic leukemia: A Childrens Cancer Group study

Methotrexate (MTX) infusions of 500–1,000 mg/m² over 24 hours may improve survival and prevent relapse in children with acute lymphoblastic leukemia (ALL). Childrens Cancer Group (CCG) Study 139 compared weekly oral methotrexate 20 mg/m²/week (oral MTX) to MTX 500 mg/m² infused over 24 hours (IV MTX) three times during consolidation and every 6 weeks during maintenance in 164 children with intermediate-risk ALL, i.e., those patients over age 1 year with white blood cell count 10,000 to 49,999/ml and no bulky extramedullary disease. Median follow-up for CCG-139 exceeded 75 months. Thirty-four events occurred among 80 patients receiving IV and oral MTX and 36 events among 84 patients receiving oral MTX. Two children died during induction and one did not enter remission. Remission induction rate is 98%. There have been 26 marrow relapses, 11 combined marrow and extramedullary relapses, 24 CNS relapses, and five testicular or other relapses. The frequency and distribution of relapses does not differ between the two regimens. For the entire group, overall event-free survival (EFS) at 6 years is 57.9% (standard deviation = 4.0%) and actuarial survival is 80.0% (standard deviation = 3.3%). Of the 29 patients with isolated extramedullary relapse, 18 survive free of a second event, a median of 42 months from relapse. In contrast to other trials, this trial does not show that IV MTX in this dose and schedule offers an advantage over standard therapy for this group of children. © 1996 Wiley-Liss, Inc.     

Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia

Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts of reduced tetrahydrofolates. Of 53 children with acute lymphoblastic leukemia (ALL) in maintenance treatment with MTX and 6-mercaptopurine (6-MP), 25 had received daily folic acid supplements in vitamin tablets containing 75-200 micrograms folic acid for at least the preceding 3-month period. Experimental data have shown that increased folate concentrations intracellularly inhibit MTX metabolism and toxicity. Therefore we found it relevant to investigate the extent to which folic acid supplements affect hematological tolerance to MTX and 6-MP in children during maintenance therapy for ALL. The erythrocyte folate (ery-folate) concentration was significantly higher in children who received extra folic acid than in those who did not (p less than 0.001). The ery-folate in MTX-treated children was only marginally reduced compared with the controls. The erythrocyte methotrexate (ery-MTX) concentration correlated with the weekly dose of MTX but not with any of the investigated hematological parameters. Children who received vitamin tablets containing folic acid had higher thrombocyte counts (p = 0.0056), higher leukocyte counts (p = 0.06), higher neutrophil counts (p = 0.05), and lower erythrocyte mean cell volumes (p = 0.05) than children who received no folic acid. We conclude that folic acid supplements of 75-200 micrograms/day affect the proliferative capacity of the bone marrow. Since none of the children was folate deficient as judged by the ery-folate, we recommend that vitamins given to children in maintenance treatment with MTX and 6-MP for ALL should not contain folic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical significance of non-renal elimination mechanisms of methotrexate (MTX)

Biliary MTX levels in one patient undergoing intermediate dose MTX therapy (500 mg/m2) were measured by HPLC. At the end of the 24 h infusion period they were found in the range of the corresponding serum levels. In one other patients undergoing high-dose MTX therapy (12 g/m2) MTX serum levels in the slow elimination phase were lowered by orally applicated cholestyramine. In one further patient who developed renal failure under high-dose MTX therapy total body clearance of MTX could be markedly improved by cholestyramine per os. The data presented, suggesting an appreciable biliary secretion of the drug in man, are discussed in view of the current concepts of enterohepatic circulation of MTX.     

Effect of cranial irradiation on the blood-cerebrospinal fluid and blood-brain barrier

The influence of fractionated cranial irradiation with 24 Gy on blood-CSF and blood-brain barrier permeability for methotrexate (MTX) and serum proteins was studied in young rabbits. In unirradiated control animals and 1, 4, 14 and 26 weeks following cranial irradiation MTX 57.5 mg/kg body weight was given by an infusion. 24 hours after the start of the MTX-infusion blood, CSF and brain was collected. MTX was measured by a radioimmunoassay, albumin and IgG by immunnephelometry. MTX in serum and brain tissue did not change significantly in the different groups before and after cranial irradiation. MTX in CSF was significantly higher 4 and 14 weeks following cranial irradiation compared to the unirradiated control group, demonstrating a significant blood-CSF barrier disturbance without blood-brain barrier disturbance. Increased MTX concentration were paralleled by significantly increased albumin concentrations in the CSF. IgG penetration across the blood-CSF barrier remained unchanged after irradiation.     

Cisplatin ototoxicity in children: a practical grading system

A long-term follow-up study was carried out to assess ototoxicity in children who had been treated for a malignant tumour with "standard dose" cisplatin (60-100 mg/m2 per course), and were at least 2 years from stopping treatment. The median age at diagnosis was 2 years 2 months (range 1 month to 13.5 years). On the basis of hearing assessment by pure-tone audiometry, a practical grading system of hearing loss from 0 to 4 is proposed. Moderate to severe high-frequency hearing loss (grade 2-4) was found in half the children and 10 require appropriate hearing aids. The risk of developing ototoxicity increased significantly with the cumulative cisplatin dose (P = 0.027), although there was considerable individual susceptibility. Serial follow-up testing, to a median of 4 years after completion of cisplatin treatment, showed no recovery of hearing in any of these children. We suggest careful monitoring of young children by a consultant audiological physician throughout treatment with cisplatin, particularly when doses of 400 mg/m2 and over have been reached. Alternative chemotherapy should be discussed if grade 2 ototoxicity develops.     

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.     

Chloramphenicol in paediatrics: current prescribing practice and the need to monitor

Two hundred and fifty-five neonates, infants and children, from 45 hospitals, who were receiving chloramphenicol therapy for serious infections were the subject of this study. Samples of serum and cerebrospinal fluid (CSF) were assayed for chloramphenicol and the patient's treatment regimens analysed. Less than 50% of neonates and 25% of infants received the recommended dose of chloramphenicol. In older children the recommended dose was used. Only 34% babies under 1 year of age and 50% older children had serum concentrations within the therapeutic range (15–25 mg/l). Thirty-one percent of neonates and infants had potentially toxic serum concentrations. Forty-three percent of neonates receiving chloramphenicol every 6h had subtherapeutic peak serum levels compared to 20% of those receiving the antibiotic every 12h. Concomitant administration of phenobarbitone or phenytoin had no effect on mean serum chloramphenicol levels. Serum concentrations of chloramphenicol were significantly higher in patients also receiving penicillin. CSF levels in 77 samples (39 patients) ranged from 1–60 mg/l. CSF from 44% patients contained less than 4 mg/l. Twelve neonates and infants (5.5%) suffered toxic side effects, four died. A further eight babies received an accidental 2- to 10-fold overdose and in three others an overdose was assumed following assay. No overdoses or toxic effects were reported in children over 1 year of age. Eight patients with impaired renal function had elevated serum levels and three showed toxic effects. In 22% patients dosage regimens were altered following assay. Even when the recommended dosage regimen for chloramphenicol is followed serum from all babies under 1 year of age should be assayed every 48–72 h if safe and effective levels are to be maintained.Abbreviations CSF cerebrospinal fluid - SAS statistical analysing system     

Intravenous pulse cyclophosphamide--a new regime for steroid resistant focal segmental glomerulosclerosis

OBJECTIVE: A prospective study was conducted to evaluate the role of intravenous pulse cyclophosphamide (IVCP) infusions in the management of children with steroid resistant (SR) idiopathic focal segmental glomerulosclerosis (FSGS). METHODS: The study group comprised of 20 consecutive children with idiopathic nephrotic syndrome secondary to FSGS who were SR. All of them were subjected to standard baseline investigations. They were started on monthly infusions of IVCP in a dose of 500-750 mg/m2. Adjunctive prednisolone was given in a dose of 60 mg/m2/day for 4 weeks followed by 40 mg/m2/alternate day for another 4 weeks and tapered off over next 4 weeks. RESULTS: The study group comprised of 15 boys and 5 girls with mean age of onset of disease of 5.5 +/- 3.5 years. Two of these children had chronic renal insufficiency prior to starting therapy. At the end of the study, after a mean duration of disease (since onset of NS) of 77 +/- 55 months, all 20 children had normal renal functions. After a mean follow up post IVCP therapy of 21.2 +/- 13.4 months, 13 of the 20 children (65%) had attained a complete remission. Of these, 10 children were infrequent relapsers, 2 frequent relapsers and 1 steroid dependent. The mean duration of remission following last dose of IVCP in these children was 12.5 +/- 11.9 months. Of the 7 children who continued to be proteinuric, 3 became edema free and have not required any albumin infusion or diuretics. One other died due to peritonitis 2 years after the last dose of IVCP. The mean total protein and serum albumin levels following the IVCP infusion were significantly higher than those prior to therapy (6.5+/-1.0 mg/dl Vs 5.0+/-0.8) (p=0.0004) and (3.5+/-0.7 g/dl Vs 2.3+/0.7) (p = 0.000007) respectively. The serum creatinine levels following IVCP therapy (0.8+/-0.2 mg/dl) were significantly lower than those prior to treatment (1.0+/-0.6 mg/dl) (p=0.02). The only side effects that were observed were transient nausea and vomiting during infusion (n=2) and alopecia (n=1). None of the children developed leukopenia or hemorrhagic cystitis. CONCLUSION: IVCP infusions appear to be safe, effective and economical therapeutic modality in steroid resistant children with idiopathic FSGS.     

Pharmacology of all-trans-retinoic acid in children with acute promyelocytic leukemia

BACKGROUND: Due to severe side effects in virtually all children treated with a standard dose of 45 mg/m(2)/day all-trans-retinoic acid (ATRA) for acute promyelocytic leukemia (APL) the AML-BFM study group reduced the dosage to 25 mg/m(2)/day. For the lack of data on the use of ATRA at this dosage in children with APL, the study group further decided to evaluate the pharmacokinetics and metabolism of ATRA in children. PROCEDURE: Twenty-three pharmacokinetic and metabolic profiles of ATRA were studied in 14 children (aged 0.9-18.4 years) with APL. Eleven plasma samples were collected over a period of 8 hr and analyzed for ATRA and its metabolites by high-performance liquid chromatography. RESULTS: Peak plasma concentrations of ATRA were characterized by wide interpatient variability (range: 28.6-513.0 nM). Compared to adults the same metabolic pathways were observed in children. Even though peak plasma concentrations were in the lower range of those considered effective in vitro, ATRA side effects, notably neurotoxicity, still required dose reduction, treatment break, or drug withdrawal in eight patients. In this small number of patients, neurotoxicity could not be related to age or any specific level of ATRA or metabolites in the plasma. Plasma concentrations of vitamin A, however, were significantly higher in those patients, who developed signs of neurotoxicity (P = 0.03, Mann-Whitney Rank Sum test). CONCLUSIONS: Considering the low plasma concentrations and the persistence of toxicity in spite of dose reduction intermittent dosing schedules might be considered as an alternative to further dose reduction of ATRA in the treatment of APL especially in children, who might be at risk of ATRA-induced neurotoxicity.     

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.     

Chloramphenicol pharmacokinetics in African children with severe malaria

The objective of this study was to determine if the current dosage regimen for chloramphenicol CAP administered to children with severe malaria SM for presumptive treatment of concomitant bacterial meningitis achieves steady state plasma CAP concentrations within the reported therapeutic range of 10-25 mg/l. Fifteen children (11 male, 4 female) with a median age of 45 months (range: 10-108 months) and having SM, were administered multiple intravenous doses (25 mg/kg, 6 hourly for 72 h) of chloramphenicol sodium succinate CAPS for presumptive treatment of concomitant bacterial meningitis. Blood samples were collected over 72 h, and plasma CAPS, CAP and CSF CAP concentrations determined by high performance liquid chromatography. Average steady state CAP concentrations were approximately 17 mg/l, while mean fraction unbound (0.49) and CSF/plasma concentration ratio (0.65) were comparable to previously reported values in Caucasian children. Clearance was variable (mean = 4.3 l/h), and trough plasma concentrations during the first dosing interval were approximately 6 mg/l. Simulations indicated that an initial of loading dose of 40 mg/kg CAPS, followed by a maintenance dose of 25 mg/kg every 6 h would result in trough CAP concentrations of approximately 10 mg/l and peak concentrations <25 mg/l throughout the treatment period. The current dosage regimen for CAP needs to include a loading dose of 40 mg/kg CAPS to rapidly achieve plasma CAP concentrations within the reported therapeutic range.     

High-dose methotrexate improves clinical outcome in children with acute lymphoblastic leukemia: St. Jude Total Therapy Study X

High-dose methotrexate (HDMTX, 1,000 mg/m2) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard-risk ALL: a leukocyte count less than 100 X 10(9)/L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone-vincristine-asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow-up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC (P = .049) or historical institutional control regimens (P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar (P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.     

Weekly dosing of carboplatin increases risk of allergy in children

BACKGROUND: Carboplatin (CBDCA) has been used increasingly to treat pediatric low-grade gliomas. Allergic reactions to CBDCA have been reported in 2% to 30% of children. The reason for this high incidence of allergy is unclear. METHODS: To determine the risk factors for CBDCA allergy, an historic cohort study was conducted for all children who received the drug during a 6-year period at the Lucile Salter Packard Children's Hospital at Stanford. The patients' medical records were reviewed for data on age, tumor type, CBDCA dose schedule, total number of doses, cumulative dosage, dose per treatment, other chemotherapy administered, and allergic reaction. RESULTS: Fifty-four children (mean age 7.2 years, 35 boys) were identified. Six children (11.1%) had an allergic reaction to CBDCA. All reactors had low-grade gliomas treated with weekly CBDCA and vincristine, with a dosage per treatment <500 mg/m2. Overall, six (75%) of eight children administered weekly CBDCA, 6 (46.2%) of 13 children with brain tumors, and 6 (40%) of 15 administered CBDCA dosage <500 mg/m2 manifested allergic reactions. Patients receiving more than five doses had significant risk for CBDCA allergy (relative risk [RR] = 11.8; 95% confidence interval [CI]: 1.5-94.1). Using logistic regression with multiple variables, weekly dose schedule was the most predictive covariate for allergic reaction (P < 0.000 1), and other factors were unrelated or redundant. CONCLUSIONS: Children with low-grade gliomas receiving CBDCA weekly are at significantly increased risk for CBDCA allergy. The repetitive, weekly dosing schedule of CBDCA appears to be a key risk factor for allergic reaction in brain tumor patients. The high frequency of allergy with weekly CBDCA warrants further consideration when planning future trials.