Methotrexate In Children Research Articles

Prevention of toxicity in chemotherapy with high doses of methotrexate in children

Methotrexate (MTX) is a widely used anti-tumor drug, folic acid antagonists. The effectiveness of high doses (more than 1 g/m2) of MTX in a monotherapy or in a combination with other chemotherapeutic drugs has been proven in a treatment of a large spectrum of oncological diseases in children such as osteosarcoma, tumors of the central nervous system, lymphomas, acute lymphoblastic leukemia. The use of high doses of MTX is often fraughted with development of life-threatening complications such as MTX-induced acute kidney injury, neurotoxicity, myelosuppression. Currently developed recommendations for therapeutic monitoring and supportive care, including hyper-hydration, urine alkalization and leucovorin therapy, allow to reduce toxicity of MTX, but in some patients it is not always possible to prevent the development of complications. Cohort studies in order to identify risk factors for toxicity after high doses of MTX in children with different forms of cancer are limited, as well as comparing various types of supportive care regimens, including, infusion therapy. Studying of development mechanisms of MTX toxicity depending on background conditions will allow to improve existing recommendations and develop new and most effective standards of supportive therapy with respect to the individual specifics of patients.

Treatment of severe pediatric atopic dermatitis with methotrexate: A retrospective review.

Severe atopic dermatitis (AD) may require systemic immunomodulatory agents to control symptoms. A lack of evidence and guidelines for systemic AD therapy in children has led to variability in agents selected and uncertainty in their comparative efficacy and safety. Evaluation of the efficacy of methotrexate in children with severe AD was performed. We performed a retrospective chart review of 55 pediatric patients seen at Children's Hospital of Philadelphia that measured improvement using the Investigator's Global Assessment (IGA), a scale that rates AD symptoms from 0 to 5. About 76% of patients showed improvement with methotrexate. Mean baseline IGA of all patients was 4.18. After 6-9months of treatment, this improved to 2.94. There was additional improvement to a mean IGA score of 2.39 after 12-15months of treatment. At the final visit before each patient stopped methotrexate, the mean IGA score was 2.71. Approximately 50% of patients experienced minor side effects with gastrointestinal side effects the most common. In a diverse patient population, safety and efficacy of methotrexate was demonstrated. Significant improvement in IGA was noted for the majority after 6-9months of therapy with further improvement when continuing treatment to 12-15months. Methotrexate remains an important option for long-term symptom control with a favorable side effect profile and low cost.

Therapeutic role of methotrexate in pediatric Crohn's disease.

The main role of therapy in Crohn's disease (CD) is to achieve long-term clinical remission, and to allow for normal growth and development of children. The immunomodulatory drugs used for the maintenance of remission in CD include thiopurines (azathioprine and 6-mercaptopurine) and methotrexate (MTX). Development of hepatosplenic T-cell lymphoma in some patients with inflammatory bowel disease, treated with thiopurines only or in combination with anti-tumor necrosis factor agents, resulted in a growing interest in the therapeutic application of MTX in children suffering from CD. This review summarizes the literature on the therapeutic role of MTX in children with CD. MTX is often administered as a second-line immunomodulator, and 1-year clinical remission was reported in 25-69% of children with CD after excluding for the use of thiopurines. Initial data on MTX effectiveness in mucosal healing, and as a first-line immunomodulator in pediatric patients with CD, are promising. A definite conclusion, however, may only be made on the basis of additional research with a larger number of subjects.

Methotrexate for severe nummular eczema in children: Efficacy and tolerability in a retrospective study of 28 patients.

Nummular eczema in children is a chronic condition characterized by pruritic coin-shaped eczematous lesions that affect any part of the body and often become exudative. Mid- to high-potency topical corticosteroids are considered the mainstay treatment, but there are limited data on the use of systemic therapy for nummular eczema in children. The objective of the current study was to evaluate the efficacy and safety of methotrexate in children with severe nummular eczema. A retrospective review was undertaken of children with nummular eczema treated with methotrexate between January 2007 and May 2017. The records of 28 patients (24 male, 4 female) with a mean age at the beginning of treatment of 7.8±1.6years (95% confidence interval (CI)=6.1-9.4years) were reviewed. The median duration of treatment was 12.6±3.3 months (95% CI=9.2-16months), and 14 patients were still undergoing methotrexate therapy at the time of last review. Ten patients (35.7%) had complete or almost complete clearance of eczema (>90% improvement), 13 (46.4%) had marked improvement (50%-89%), four had mild improvement (<50%), and one failed methotrexate therapy. Gastrointestinal intolerance (21.4%) and a nonsignificant increase in liver enzymes (17.9%) were the most frequent side effects. No serious adverse events were noted. Methotrexate is an effective, well-tolerated treatment in children with moderate to severe nummular eczema that has failed to respond to conventional topical therapy.

Use of high doses of the methotrexate in children suffering from some form of cancer: specificities of the accompanying therapy, assessing the toxicity

Introduction. Methotrexate (MTX) is one of the most commonly used anti-tumor preparations which confirm it effectiveness against the large spectrum of the oncological diseases in children. Today the use of high doses of the MTX (g/m2 ) in the monotherapy or in combination with other chemotherapeutic agent is a standard of treatment of such nosology as osteosarcoma, tumors of the central nervous system (CNS), lymphomas, acute lymphoblastic leukemia. Despite of the developed recommendations on the fluid therapy, therapeutic monitoring, use of leukovorin which allowed to reduce the expected toxicity among some patients it is not always possible to prevent the development of complications. Ex post evaluation of different doses of schedule of the high-dose MTX is necessary in order to formulate new and effective treatment strategies with respect to the individual specifics of the patients. Materials and methods . During the period from October 2015 to February 2018, a patient cohort (n = 26) who received high-dose MTX therapy with the following nosology: osteosarcoma – 4, hemoblastosis – 11, and CNS – 11 tumors was evaluated. The average age of the patients was 7.3 years old; ratio of boys:girls – 2.25: 1. The used doses were ranged from 1 to 12 g/m 2 , the doses schedules ranged from 4 to 36 hours; the total number of courses during the observation period was 94; the average number of courses per patient was 3. In all cases, the level of MTX in the blood serum was monitored with correction of the dose of leucovorin according to international recommendations. Estimated toxicity parameters were the following: allergic reactions, skin and mucous membrane damage, neurologic disorders, myelosuppression, hepatic transaminase and creatinine growth. Results. Transitory toxicity was noted for 100 % of patients, of which clinically significant was in 62.7 % of cases. The development of complications that had required the use of antibacterial and blood transfusion therapy occurred after 36 courses of therapy (38.2 %), of wich in 24 cases (66.6 %) MTX was performed in combination with other antitumor agents. No cases of acute kidney injury were presented, there was no significant difference in creatinine level before and after high-dose MTX courses. The highest frequency of episodes of hepatotoxicity was noted in the group of patients diagnosed with “osteosarcoma”. After reduction the episodes of toxicity with the use of high-dose MTX, all patients continued programmed chemotherapy. Conclusions. Against the background of an adequate accompanying therapy (infusion therapy with alkalization of urine, pharmacodynamic monitoring, correction of the leucovorin dose), it is possible to achieve satisfactory tolerability of high doses of MTX. The combination of high doses of MTX with other antitumor drugs leads to a significant increase in the toxicity. Despite of the noted complications of therapy, continuation of treatment with the use of previous doses of MTX (does not require reduction) is possible, and a decrease in the rate of MTX removal is not always a predictor of episodes of the toxicity.

16. Clinical Factors Associated with Non-Response to Methotrexate in Children with Juvenile Idiopathic Arthritis: Results from the Childhood Arthritis Response to Treatment Consortium

16. Clinical Factors Associated with Non-Response to Methotrexate in Children with Juvenile Idiopathic Arthritis: Results from the Childhood Arthritis Response to Treatment Consortium

Adalimumab for treating childhood plaque psoriasis: a clinical trial evaluation

ABSTRACTIntroduction: Most systemic therapies have not been systematically investigated in moderate to severe childhood plaque psoriasis. Evidence on the efficacy and safety of systemic treatments is limited and therapeutic guidelines are lacking. Recently adalimumab, a fully human monoclonal antibody that binds tumor necrosis factor (TNF)- alpha, was investigated in childhood psoriasis. Adalimumab is licensed for many inflammatory conditions including chronic plaque psoriasis in adults.Areas covered: A randomized phase III study published provided favourable efficacy and safety data of adalimumab in childhood psoriasis. The active comparator was methotrexate. After 16 weeks of treatment, a PASI 75 score was achieved in 58% of patients within the adalimumab 0.8 mg/kg group compared with 32% of patients within the methotrexate group. Safety data gave no evidence of drug-related serious adverse events and no organ toxicity. This is the first randomised controlled study of either adalimumab or methotrexate in children and adolescents with psoriasis.Expert opinion: The aforementioned trial was the first to provide clinical data on adalimumab’s efficacy and safety in the short term when treating children and adolescents with psoriasis. Through the use of an active comparator, this study has opened the way for the future assessment of systemic therapies in children and adolescent with this condition.

Methotrexate for Severe Childhood Atopic Dermatitis: Clinical Experience in a Tertiary Center.

Atopic dermatitis (AD) affects up to 20% of children. Although the majority of patients are adequately controlled using emollients, topical corticosteroids, topical calcineurin inhibitors, or phototherapy, children with moderate to severe AD may require systemic treatment for control. The objective of the current study was to evaluate the efficacy and safety of methotrexate in children with severe AD attending a tertiary referral center. A retrospective chart review was undertaken of all children who received methotrexate for severe AD at our tertiary referral center from November 2010 to August 2015. Forty-seven children were started on methotrexate for AD during this period. The mean Investigator Global Assessment (IGA) at the 3- to 5-month follow-up improved from 4.25 to 2.8, with further improvement to 1.9 in the patients that continued therapy beyond 10months. Changes in the Children's Dermatology Life Quality Index (CDLQI) mirrored changes in the IGA, with improvement in the mean CDLQI from 14.4 at the start of the treatment to 7.5 at the 3- to 5-month follow-up. Further improvement in the CDLQI to 6.6 in patients who continued methotrexate beyond 10months confirmed continued improvement in disease control beyond medium-term therapy. The treatment was well tolerated. Methotrexate appears to be an effective, safe treatment for severe pediatric AD. Its therapeutic effects continue beyond the medium-term treatment period, as reflected by further improvement in IGA and CDLQI scores in patients who continued methotrexate therapy beyond 10months.

The Relationship of Polymorphism of RFC-I Gene on Methotrexate Serum Level and Related Toxicity in Pediatric Acute Lymphoblastic Leukemia

Introduction: Methotrexate is one of the most effective agents in chemotherapy regimens for childhood ALL. However, methotrexate has remarkable side effects, which causes complications in various tissues and organs of some patients under treatment of this drug. It is proved that genetic factors can determine methotrexate toxicity. The aim of this study is to evaluate the effect of RFC-I A80G polymorphism on toxicity and serum level of methotrexate in children affected by acute lymphoblastic leukemia. Methods: A80G polymorphism of RFC-I was genotyped with PCR-RFLP method in 69 ALL patients treated with methotrexate. The relation between RFC-I genotypes and serum level of methotrexate and toxicity were evaluated using HPLC method and common terminology criteria for adverse events (CTCAE) respectively. Results: In this study, frequency of allele A for A80G polymorphism was 42.8% in patients who were studied. In consolidation phase, allele A frequency in patients with hepatotoxicity was higher than patients with no hepatic event (P=0.03, OR=2.32, 95% CI=1.10-4.98). Nevertheless, there were not any association between the other types of toxicity and RFC-I genotypes. Also, there was no association between A80G genotypes and the serum level of methotrexate. Conclusion: Based on the obtained results, we concluded that allele A of A80G polymorphism of RFC-I gene is a risk factor for methotrexate hepatotoxicity in consolidation phase and the A80G polymorphism can be utilized for prediction of methotrexate toxicity and dose adjustment.

The Efficacy of Combination Therapy by Adalimumab with Methotrexate and of Monotherapy by Methotrexate for Children Suffering from Polyarticular Juvenile Idiopathic Arthritis

Background : The use of genetically engineered biological agents in patients with juvenile idiopathic arthritis (JIA) allows to achieve good results in treatment. However, their efficacy in patients refractory to basic antirheumatic drugs, requires further analysis. Objective : To study the efficacy and safety of the combination therapy by adalimumab with methotrexate and of the monotherapy by methotrexate in children with JIA. Methods : It was conducted a perspective (annual) comparative research with the analysis of the results of treating children with polyarticular seronegative JIA refractory to basic immunosuppressive therapy. The efficacy was assessed by ACRpedi criteria and by dynamics of values of cellular and humoral immunity indicators. Safety was determined by the number of adverse effects. Results : The combination therapy by methotrexate with adalimumab for children with JIA (n = 14) in a shorter time than the monotherapy by methotrexate (n = 17) induced arthritis remission. After 46 weeks of treatment, the remission of arthritis and the normalization of laboratory findings were reported in 6 (43%) patients treated by adalimumab with methotrexate, and in 3 (18%) children — methotrexate (p = 0.233); adverse effects — in 4 (29%) and 14 (82%) cases (p = 0.004), respectively. No serious adverse effects have been registered. Conclusion : The prescription of adalimumab in combination with methotrexate in children with JIA, refractory to basic immunosuppressive therapy, allows to achieve rapid remission of the disease while preserving the effect in a significant number of patients within 46 weeks of therapy.

Salivation in children during anticancer chemotherapy

The study aimed to assess the needs and options for salivation management in children treated with antileukemic chemotherapy. In a preliminary cross-sectional study the saliva flow rate and viscosity were evaluated in 75 leukemic children that received chemotherapy with methotrexate in low dose (44 people, 44 episode, group 1), or in high-dose (31 people, 42 episode, group 2), and in 25 healthy children (group 3). Then, 26 children were randomly divided into two groups in the 70 episodes course of high-dosed chemotherapy, and received acetylcysteine (A) or only standard oral management (S) for 1-10 day of treatment. Parameters of salivation and children performance (Lansky et al.) were evaluated. Mann-Whitney U-test was used for analysis. In group 1, 2 and 3 the flow rate (Me [LQ/HQ]) was 0.5 [0.3; 0.8]; 0.9 [0.6; 1.2] and 0.5 [0.3; 0.6] ml/min respectively (p1-3>0.05; p<0.01; p1-2<0.05). Viscosity levels in group 1, 2 and 3 were 2.75 [3.67; 3.67], 10.05 [5.3; 26.0] and 3.9 [2.7; 6.5] unites respectively (p1-3>0.05; p2, 3<0.01; p1, 2<0.01). In group A and S the flow rate was 2.7 [0.5; 4.1] and 0.4 [0.1; 2.2] ml/min (р<0.05); viscosity was 1.5 [1.2; 4.1] and 6.4 [5.3; 8.1] unites (р<0.001), performance Lansky index was 80 [65; 90] and 70 [60; 80] (р<0.01) respectively. Salivation dysfunction complicates the chemotherapy with high-dosed methotrexate in children: it is indicated by high viscosity combined with elevated flow rate. Acetylcysteine normalizes saliva viscosity and improves children's performance.

Effect of Intrathecal Methotrexate on CSF and RBC Folate Levels in Children Receiving Treatment for Acute Lymphoblastic Leukemia

Background: Children with acute lymphoblastic leukemia (ALL) receive multiple doses of intrathecal methotrexate during treatment. Methotrexate is a folate analogue that competitively inhibits dihydrofolate reductase leading to a decrease in purine and pyrimidine synthesis. The administration of methotrexate also leads to alterations of the methyl transfer pathway that may be determinants of toxicity and therapeutic response.Objective: To describe the changes of the methyl transfer pathway in CSF seen with sequential administration of intrathecal methotrexate in children receiving therapy for ALL.Methods: Children with ALL received age-based doses of intrathecal methotrexate on days 8, 29, 36, 43 and 50 of treatment. No oral or intravenous methotrexate was administered during the first 50 days of treatment. CSF and plasma samples were collected at the time of each intrathecal therapy. Concentration of 5-methyltetrahydrofolate (5-MTHF), 5,10-methylenetetrahydrofolate (5,10-MeTHF), betaine and choline were measured using reversed phase LC-MS/MS.1 Control samples were collected from patients with AML who were not exposed to any methotrexate.Results: 39 children with ALL and 7 with AML were included and contributed samples to our analysis. The mean baseline CSF 5-MTHF concentration (treatment day 8) measured in the ALL patients was 54.8 nM. The concentration of CSF 5-MTHF decreased to 34.4 nM (p<0.001) on treatment day 29, 21 days after receiving a single dose of intrathecal methotrexate. On treatment day 36, the CSF 5-MTHF was 56.7 nM, indicating a return to baseline levels. Despite repeated weekly administration, the concentration on treatment days 43 and 50 did not significantly change (Figure 1).Similar results were seen when CSF concentrations of 5,10-MeTHF were analyzed. The baseline mean 5,10-MeTHF concentration was 0.27 nM on treatment day 8 and this decreased to 0.13 nM 21 days later (p<0.001). By treatment day 36, mean CSF levels of 5,10-MeTHF were near baseline at 0.22 nM and no further significant changes in levels were seen on treatment days 43 or 50 (Figure 2).Day of TreatmentThe mean RBC 5-MTHF concentration was 641.9 nM on treatment day 8, 611.9 nM on day 29, 887.2 nM on day 36, 1197.3 nM on day 43 and 1063.3 nM on day 50. The mean RBC 5-MTHF on treatment days 43 and 50 was significantly increased when compared to baseline levels (p<0.001).As CSF folate is depleted and replenished during the first two months of treatment, other biochemical alterations of the methyl transfer pathway with the CSF were evaluated. Levels of CSF betaine steadily increased with ongoing intrathecal treatment while CSF choline did not change (Table 1).Table 1Changes in Folate Homeostasis During Therapy for ALL Through Treatment Day 50ControlDay 8Day 29Day 36Day 43Day 50pCSF 5-MTHF (nM)84.654.834.052.362.255.0<0.001CSF 5,10-MeTHF (nM)0.360.270.140.220.290.26<0.001CSF Betaine (µM)1.761.701.832.042.052.370.005CSF Choline (µM)2.272.272.292.382.442.590.665RBC 5-MTHF (nM)803.6641.9611.9887.21197.31063.3<0.001In the control group, the mean CSF 5-MTHF concentration was 84.6 nM. This was significantly increased compared to the concentrations seen in ALL patients at all timepoints, including baseline levels. The mean 5,10-MeTHF level for the control group was 0.36 nM. This was significantly different from ALL patients only on days 29 and 36 of treatment. There were no differences noted between CSF betaine and choline levels between ALL patients and controls.There were four patients with ALL who experienced neurotoxicity (grade 3 of higher) related to methotrexate. There were no differences in CSF 5-MTHF, 5,10-MeTHF, betaine or choline levels between patients that experienced neurotoxicity compared to those who did not.Conclusion: Children with ALL have a significant decrease in CSF 5-MTHF and 5,10-MeTHF levels following the initial administration of a single intrathecal dose of methotrexate. Despite additional intrathecal doses of methotrexate, these levels return to baseline by treatment day 36. This is accompanied by an increase in RBC 5-MTHF and CSF betaine. These data suggest that continued exposure of the CSF to methotrexate may induce systemic mechanisms of folate repletion.1 van Haandel L, et al. Rapid Commun Mass Spectrom 2012; 26(14):1617-30. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: an observational, cross-sectional study.

IntroductionMethotrexate (MTX) is a cornerstone of treatment in a wide variety of inflammatory conditions, including juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). However, owing to its narrow therapeutic index and the considerable interpatient variability in clinical response, monitoring of adherence to MTX is important. The present study demonstrates the feasibility of using methotrexate polyglutamates (MTXPGs) as a biomarker to measure adherence to MTX treatment in children with JIA and JDM.MethodsData were collected prospectively from a cohort of 48 children (median age 11.5 years) who received oral or subcutaneous (SC) MTX therapy for JIA or JDM. Dried blood spot samples were obtained from children by finger pick at the clinic or via self- or parent-led sampling at home, and they were analysed to determine the variability in MTXPG concentrations and assess adherence to MTX therapy.ResultsWide fluctuations in MTXPG total concentrations (>2.0-fold variations) were found in 17 patients receiving stable weekly doses of MTX, which is indicative of nonadherence or partial adherence to MTX therapy. Age (P = 0.026) and route of administration (P = 0.005) were the most important predictors of nonadherence to MTX treatment. In addition, the study showed that MTX dose and route of administration were significantly associated with variations in the distribution of MTXPG subtypes. Higher doses and SC administration of MTX produced higher levels of total MTXPGs and selective accumulation of longer-chain MTXPGs (P < 0.001 and P < 0.0001, respectively).ConclusionsNonadherence to MTX therapy is a significant problem in children with JIA and JDM. The present study suggests that patients with inadequate adherence and/or intolerance to oral MTX may benefit from SC administration of the drug. The clinical utility of MTXPG levels to monitor and optimise adherence to MTX in children has been demonstrated.Trial registrationISRCTN Registry identifier: ISRCTN93945409. Registered 2 December 2011.

The influence of detoxification agents on the intensity of side effects caused by medium-high doses of methotrexate in children with acute lymphoblastic leukemia: case series

SUMMARY Objective The treatment of childhood acute lymphoblastic leukemia (ALL) in Serbia is conducted according to protocol ALL IC BMF-2009. The therapy includes the application of cytostatic drugs methotrexate and 6-mercaptopurine, and drug detoxifying Calcium Folinate. At the moment, 80% of affected children could be cured with current treatment, but resistance to the therapy and its toxic effects remain serious clinical problems. The aim of the study was to investigate the influence of detoxification agents (Calcium Folinate, silymarin and ursodeoxycholic acid) on the side effects of methotrexate, applied in this protocol. Methods A modified acute toxicity form (GPOH) was used for side effects monitoring. The research included children with either standard or intermediate risk ALL in the consolidation therapy phase, who were hospitalised at the Institute for Child and Youth Health Care of Vojvodina in Novi Sad during the period from July 2010 to February 2011. Results The most frequent side effect after 40 applications of methotrexate in ten children was bone marrow depression. Methotrexate caused: leukopenia in 10 patients, thrombocytopenia in 5 patients; after the use of folic acid, platelet count grew in 8 patients, leukocyte in 2 patients. Less frequent side effects: an increase serum transaminase activity, the state of fever, bronchopneumonia, diarrhoea with mild cramps and hypercalcaemia. Conclusion The application of Calcium Folinate, silymarin and ursodeoxycholic acid prevented the occurrence of severe adverse effects caused by medium-high doses of methotrexate. Observed adverse effects were of mild to moderate intensity, reversible and did not significantly disturb the quality of life in treated patients.

Biochemical criteria of toxicity of therapy with high doses of methotrexate in children with osteosarcoma

Biochemical criteria of toxicity of therapy with high doses of methotrexate in children with osteosarcoma

Biochemical criteria of toxicity of therapy with high doses of methotrexate in children with osteosarcoma

Methotrexate (Mtx) is a cytotoxic drug from the group of antimetabolites, folic acid antagonists. High-dose (HD) Mtx in pediatric oncology are used for the treatment of osteosarcoma (OS), and other types of tumors. This therapy has allowed to achieve a five-year relapse-free survival rates up to 80 % in patients with OS. However, the high toxicity of Mtx is a serious constraint in achieving the maximum therapeutic effect, which in most cases poses the occurrence of side effects in patients on various organs and systems. Treatment should be under strict laboratory monitoring, primarily therapeutic drug monitoring the concentration of Mtx in serum. 246 children (boys – 125, girls – 121) aged 5 to 16 years with osteosarcoma (mean age 12.2 years) who were treated in N.N. Blokhin Russian Cancer Research Center from 2006 to 2013. Patients were conducted from 1 to 8 courses HD Mtx at a dose of 8 or 12 g/m2 , administered within 4 h of infusion on the background of alkaline prehydrate. Leucovorin was administered intravenously, every 6 hours, starting 24 h from the start of the Mtx infusion. 1137 courses of HD Mtx were conducted with FPIA method (analyzer TDx/Flx, Abbott, USA). The technique of monitoring of homocysteine (Hcy) in the blood serum by analyzer Vitros 5/1FS (Johnson & Johnson, USA) during the entire course of high-dose Mtx was tested. In groups calculated pharmacokinetic parameters Mtx were tested: area under the pharmacokinetic curve (MtxAUC), clearance of methotrexate (ClMtx), the elimination half-life (T1/2 ) and the total time of excretion (Ttotal). Normal excretion of Mtx was revealed at 1050 courses Mtx, corresponding to the following values: 4 h – 1109 ± 283 μmol/l; 24 h – 4,67 ± 0,95 μmol/l; 42 h – 0,38 ± 0.16 µmol/l; 48 h – less than 0,23 ± 0.04 µmol/l; 72 h of 0.07 ± 0,03 µmol/l; 96 h of 0.03 ± 0.01 µmol/l. At 87 courses identified delayed Mtx excretion, accounting for 7.6 % of all courses. In all measured parameters: hourly concentration of Mtx, Ttotal, MtxAUC, Clmtx, T1/2 , is obtained statistically significant differences between normal and delayed Mtx excretion. Patients in group of delayed excretion of methotrexate were characterized by the development of hepatotoxicity, there were also observed 4 cases of the occurrence of acute renal failure. Monitoring of biochemical parameters (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase) also revealed differences between the two groups – hepatotoxicity directly depended on MtxAUC, ClMtx and Ttotal, and the amplitude changes in activities of enzymes from course to course by increasing the number of course decreased. Our developed methodology of monitoring of Hcy in serum during the course of HD Mtx revealed that Hcy metabolic interconnected with Mtx – the higher the concentration of Mtx, the greater the amount of Hcy released into the blood. Hcy has a close metabolic relationship with Mtx – it can serve as a marker of the efficiency of suppression of the transformation of folates. During slow excretion of Mtx Hcy significantly increased in the blood, which also suggests that it can serve as a marker of pharmacodynamic effects of HD Mtx.

Genetic determinants for methotrexate response in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35–45% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA.

Procedural pain and patient-reported side effects with weekly injections of subcutaneous methotrexate in children with rheumatic disorders.

BackgroundDespite the widespread use of subcutaneous methotrexate in treating pediatric rheumatic disorders, the amount of pain associated with the injections has not been quantified. Our study aims 1) to quantify the amount of pain associated with subcutaneous injections of methotrexate, 2) to explore predictors of pain, 3) to determine the frequency of patient-reported clinical adverse effects of methotrexate, and 4) identify coping strategies of patients and caregivers.MethodsPatients aged 4–17 years with rheumatologic diseases who were receiving weekly subcutaneous methotrexate injections for at least 4 weeks were invited to participate in this prospective cohort study. They were trained to use the Faces Pain Scale – Revised (FPS-R) and Faces, Legs, Arms, Cry, Consolability (FLACC) tools to rate pain associated with the injections. All patients underwent focused interviews exploring their experiences with methotrexate injections.ResultsForty-one patients consented to the study. The mean age was 11.2 years (SD = 3.9 years) and 68% were female. Most patients were diagnosed with JIA (73%). Mean duration of methotrexate therapy was 2.5 years (SD = 2.1 yrs). All but one of the patients used methotrexate 25 mg/ml solution for injection in 1 cc or 3 cc syringe with 30 gauge ½” needle. Median amount of pain was 2/10 on the FPS-R and 1/10 on the FLACC. Higher intensity of pain was significantly associated with presence of side effects (p = 0.004), but not duration of therapy (p = 0.20) or age (p = 0.24). Most participants (61%) experienced at least one adverse effect; nausea (56%) and vomiting (34%) were the most common symptoms reported. Patients and caregivers reported using ice (34%), comfort positions (51%), rewards (49%), reassurance (54%), distraction (51%), and analgesic medications (22%) to cope with the injections.ConclusionSubcutaneous injections of methotrexate are associated with a mild amount of pain. Presence of side effects may amplify the amount of perceived pain. Clinicians can apply this knowledge when counseling patients and family members about methotrexate therapy.

Fractional model for pharmacokinetics of high dose methotrexate in children with acute lymphoblastic leukaemia

The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients.We applied two-compartment fractional model on 8 selected cases with the largest number (4–19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2–5g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post’s and Newton’s method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC.Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients.A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

Retrospective cohort study of methotrexate use in the treatment of pediatric Crohn's disease.

Methotrexate (MTX) use as an alternative to thiopurines in the treatment of Crohn's disease (CD) in children is increasing. This study was undertaken to assess safety and efficacy of MTX in children with CD. Patients treated with MTX with a minimum of 1-year follow-up were identified in the Pediatric IBD Collaborative Research Group Registry, a prospective inception cohort study started in 2002. The clinical efficacy and safety of MTX were analyzed retrospectively. Two hundred ninety patients treated with MTX were identified. One hundred seventy-two patients received at least 3 months of MTX without thiopurine or biologicals and had ≥1 year of follow-up. Eighty-one of 172 patients (47%) received MTX as first immunomodulator (IMM), of which 22 (27%) achieved ≥12 months of sustained clinical remission without surgery, thiopurine, biologicals, or corticosteroids. Those receiving MTX as second IMM achieved similar remission rate (35%, P = not significant). Fourteen percent received MTX as first IMM in 2002 and 60% in 2010 (P = 0.005). Disease location did not affect outcomes. MTX doses were equivalent in both groups. Fifteen percent of patients developed an alanine aminotransferase >60 international units/liter and 12% developed a white blood cell <4000 cells per microliter while on MTX. Only 4% of these discontinued MTX completely. A small group of 6 centers, which contributed only about one-third of patients with CD in the registry, contributed nearly two-thirds of the patients receiving MTX (P < 0.001). MTX use as first choice IMM is increasing in pediatric CD. MTX provided sustained clinical remission in nearly one-third of patients with minimal toxicity. There is large center-to-center variability in its use.