Acute Methotrexate Research Articles

CTNI-08. DOSE ADJUSTED TEDDI-R FOR PRIMARY CNS DIFFUSE LARGE B-CELL LYMPHOMA

Abstract We report our initial experience treating 4 patients with the dose adjusted TEDDI-R protocol as reported by Dunleavy et al in 2015. The median age was 63 years, 2 patients were male, median KPS 60. Two patients were newly diagnosed: one of these had inadequate renal function for methotrexate; and the other had experienced acute methotrexate leukoencephalopathy. Two patients were treated for their first recurrence, having progressed during therapy with the MT-R protocol; one of these received salvage WBRT prior to starting. The protocol consisted of temozolomide 90 mg/sq m IV, cycles 1-6, days 2-5; etoposide 45 mg/sq m/day IV cycles 1-6, Days 2-5; liposomal doxorubicin 40 mg/sq m IV, cycles 1-6, day 2; dexamethasone 10 mg PO bid, cycles 1-6, days 1-5; ibrutinib 560 mg qd starting 3 days before cycle 1, day 1, then 560 mg qd, cycles 1-6, days 1-10; rituximab 375 mg/sq m IV cycles 1-6, days 1-2; and cytarabine 70 mg via Ommaya reservoir, cycles 2-6, days,1 and 5. Aspergillosis prophylaxis with isavuconazonium 372 mg mg PO bid was used. Overall, only 1 patient completed all 6 planned cycles; the median number of cycles completed was 4.5. Both newly diagnosed patients died during therapy; one died after 1 cycle from CMV colitis, and the other after 5 cycles from tumor recurrence, pneumonia, and septic shock. One patient with recurrent disease achieved a complete response and went on to high dose chemotherapy and autologous bone marrow transplantation; the other had a partial response after 4 cycles but died from pulmonary embolism. Median PFS for the newly diagnosed patients was 177 days, and for the recurrent patients, 221 days. Median OS for the cohort was 242 days. These preliminary data suggest that the TEDDI-R protocol was relatively toxic, especially for patients with poor neurological function, but can be an effective salvage therapy after progression on methotrexate-based therapy.

Role of Vitamin C on methotrexate-induced nephrotoxicity in psoriasis context: A preclinical assessment

Methotrexate (MTX) is the most prescribed drug for systemic treatment of psoriasis. However, its clinical use is limited by its nephrotoxicity, which antioxidants can attenuate. This study evaluates the impact of vitamin C (vitC), a well-known antioxidant, on nephrotoxicity induced by high MTX doses in the context of psoriasis. To achieve this purpose, the kidney injury triggered by acute MTX exposure was established in an imiquimod-induced psoriasis-like mouse model. Mice were randomly divided into six groups: group 1 (control); group 2 (Imiquimod, IMQ), group 3 (IMQ+vitC 175 mg/kg/day); group 4 (MTX 20 mg/kg i.p); group 5 (IMQ+MTX 20 mg/kg) and group 6 (IMQ+MTX 20 mg/kg + vitC 175 mg/kg/day). The effects of these treatments were determined by considering the evolution of IMQ-induced skin lesions and serum creatinine levels. Moreover, histopathological analysis, lipid peroxidation, oxidative stress, and TNF-α production were determined in kidney tissue. Results showed that vitC attenuates renal damage in the context of IMQ-induced psoriasis. However, the opposite occurs when administered with IMQ+MTX, worsening skin psoriasis lesions and exacerbating acute renal tubular necrosis and oxidative DNA damage. These results establish new clues about the MTX-induced nephrotoxicity in the psoriasis context and the putative protective effects of vitC. It suggests that vitC supplementation could help attenuate the renal damage promoted by the psoriatic pathological environment. However, it should be avoided in psoriasis patients with renal dysfunction treated with MTX.

Acute Methotrexate Toxicity Managed with Leucovorin and Pegylated Granulocyte Colony-stimulating Factor: A Report of Two Cases and Review of Literature

Acute methotrexate (MTX) toxicity is most commonly due to overdose of the drug, which may be due to the patient's noncompliance to doctor's orders or physician's prescription error. Other causes include acute renal failure, concomitant use of other drugs, and genetic susceptibility. MTX toxicity presents with pancytopenia, mucositis, hepatotoxicity, pulmonary toxicity, and acute renal failure. Treatment involves a polypragmatic approach which includes vigorous hydration, urinary alkalinization, administration of leucovorin, and glucarpidase. Administration of granulocyte colony-stimulating factor should be considered in cases of severe neutropenia. Here, we present two cases of acute MTX toxicity in chronic plaque psoriasis presenting with ulceration of psoriatic lesions and mucosal ulceration successfully treated with leucovorin and pegylated granulocyte colony-stimulating factor (G-CSF). This case report demonstrates that G-CSF might be lifesaving by contributing to rapid reconstitution of leukopoiesis.

Methotrexate toxicity encountered in dermatology department: A retrospective study at tertiary care center in western India

Methotrexate (MTX) is considered a relatively safe drug when prescribed at dose ranging from 7.5mg-30mg per week. Severe acute toxicity is rare and present with mucositis, cutaneous ulceration and pancytopenia. Most cases occur as the result of inadvertent overdosing due to erroneously taking the drug daily. A retrospective study of 10 cases of acute methotrexate toxicity in patients attending the dermatology OPD at P. D. U govt. medical College and hospital, Rajkot during a period of 1 year was done. Out10 patients, 7 had both oral and cutaneous involvement, 4 had genital mucosal involvement while 2 cases had only oral ulcerations. Organ -specific toxicities includes pancytopenia in all cases, as well as hepatoxicity, renal toxicity, and GI toxicity in 3 patients. Additionally, cutaneous toxicity was observed in 6 cases. “Of the 10 patients, 2 recovered after stopping methotrexate with supportive care. The remaining 8 received injectable folinic acid, resulting in recovery for 6 patients, but 2 patients unfortunately died during treatment. Although MTX appears to be a safe and effective medication when used at low-dose, acute MTX toxicity can be a life threating emergency when comorbidities are not addressed. Sensitization amongst doctors, general practitioners and resident doctors is of paramount importance to identify possible MTX toxicity in earlies phases and in a way ensure earliest management.

Development of a Novel Methotrexate-Related Neurotoxicity Risk Score in Pediatric Acute Leukemia: A Report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Introduction: Methotrexate (MTX) chemotherapy is a critical component of contemporary pediatric acute lymphoblastic leukemia (ALL) treatment regimens. However, intrathecal (IT) and intravenous (IV) MTX can result in dose-limiting acute neurotoxicity, which has been associated with an increased risk of ALL relapse. Emerging data suggest the likelihood of MTX neurotoxicity is elevated in Latino patients and those diagnosed at older age or treated with high-dose MTX (> 1g/m2); however, there are no established methods for identifying those at greatest risk. Therefore, we used machine learning algorithms to develop a neurotoxicity risk prediction model in a diverse, multi-ethnic cohort of pediatric patients with ALL. Methods: The Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium enrolls patients diagnosed with ALL from six participating treatment centers in the Southwestern U.S. This interim analysis included pediatric patients (age <20 years) diagnosed and treated for ALL at Texas Children's Hospital (2005-2019). Individuals diagnosed with infant leukemia (<1 year of age) and/or with preexisting neurologic disease were excluded. We retrospectively reviewed medical records to identify clinical, sociodemographic, and Common Terminology Criteria for Adverse Events (CTCAE) grading of toxicities such as transaminitis and hyperbilirubinemia. Address information at the time of diagnosis was geocoded and aligned to the American Community Survey at the census-tract level to define residential social determinants of health (SDOH). Cases of MTX neurotoxicity were identified by manual review of records for any patient who underwent brain MRI imaging during ALL therapy. Cases of acute MTX neurotoxicity were defined following Ponte di Legno Delphi Consensus definitions as neurologic episodes (e.g., seizure, stroke-like symptoms, altered mental status) occurring within 21 days of IV or IT MTX with no other identifiable underlying cause. Demographic and clinical factors were compared between cases of acute MTX-related neurotoxicity and controls using logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI). The dataset was randomly split with 80% of observations used in the training stage and 20% reserved for testing. Random forest algorithms with boosting and down sampling were grown using 5-repeat, 10-fold cross validation to optimize tuning parameters. Model performance was evaluated using test and train error rate, area under the curve of the receiver operating characteristic (AUC-ROC), sensitivity, and specificity. Results: A total of 770 patients were eligible and met inclusion criteria. Patients were a mean age of 7.0 years at diagnosis, 54% male, 55% Latino and 45% treated with high-risk protocols. Acute MTX neurotoxicity developed in 134 (17.4%) of patients. In logistic regression models, neurotoxicity odds increased with older age at diagnosis (OR = 1.20, 95% CI: 1.15-1.26), Latino ethnicity (OR = 2.14, 95% CI: 1.38-3.38), treatment on high-risk protocols (OR=4.32, 95% CI: 2.75-6.99), obesity at diagnosis (vs normal weight, OR = 2.54, 95% CI: 1.51-4.22), and CTCAE grade 3 or higher transaminitis (OR = 2.02, 95% CI: 1.03-4.47) or hyperbilirubinemia (OR = 4.71, 95% CI: 1.21-18.41) during induction therapy. Overall, the random forest machine learning algorithm resulted in an AUC-ROC of 0.79 with an error rate of 0.26 in both the training and test sets. The overall sensitivity was 0.71, with a specificity of 0.67. Recognizing ethnic disparities in MTX neurotoxicity may exist, random forest models were generated stratifying on ethnicity (Figure 1), which yielded slightly better performance in non-Latino patients (AUC-ROC = 0.77) than Latino patients (AUC-ROC = 0.73). Conclusions: This interim analysis of data from the REDIAL Consortium demonstrates the potential utility of machine learning algorithms to develop a novel risk prediction model for acute MTX-related neurotoxicity. Efforts to expand this work within the larger REDIAL cohort (n>2,000) and incorporate inherited genetic data are ongoing. Ultimately, this work may inform efforts to preemptively risk-stratify patients and deliver targeted interventions to vulnerable individuals.

Neurologic Complications in Patients With Lymphoreticular Malignancy: A Descriptive Cohort Study.

The objectives of this study were to study the spectrum of neurologic complications in children with lymphoreticular malignancy (acute lymphoblastic leukemia, Hodgkin, and non-Hodgkin lymphoma) at diagnosis and during treatment and to determine the etiology of these complications. In this descriptive cohort study, conducted between November 2018 and March 2020, 204 children with a diagnosis of lymphoreticular malignancy were enrolled. The baseline investigations were done in all the cases. Those who developed neurological symptoms were evaluated with cerebrospinal fluid examination and radiologic and electrophysiologic studies as per indication and were managed according to standard management guidelines. Of the 204 patients, 30 (14.7%) developed neurological complications. The majority of these complications (n=20/30; 87%) occurred during the intensive chemotherapy period. Common complications included acute methotrexate neurotoxicity (n=7), vincristine-induced neurotoxicity (n=7), central nervous system (CNS) relapse (n=4), and posterior reversible encephalopathy syndrome (n=2). L-asparaginase-induced thrombosis (n=1), intramedullary compression syndrome (n=1), CNS infection (n=2), CNS hemophagocytic lymphohistiocytosis (n=1), and steroid-induced myopathy (n=1) were also observed. The complications resolved in 21/30 (70%) patients after receiving appropriate treatment while the neurological complication persisted in 2/30 (6.7%) patients. Three patients (10%) abandoned the treatment, and 4 (13.3%) patients expired. Neurologic complications in patients with lymphoreticular malignancy are quite variable, having common presenting symptoms but varying imaging abnormalities. By close follow-up and effective treatment, the morbidity and mortality of these complications can be minimized.

Ulcerations in Chronic Plaque Psoriasis: A Diagnostic Clue for Acute Methotrexate Toxicity

An elderly male patient, a known case of psoriasis vulgaris, presented with ulcerations in preexisting psoriatic lesions. The patient had fever with chills and severe pain and burning sensations in the lesions. There was a history of intramuscular methotrexate (Mtx) injection 15 mg followed by oral Mtx 7.5 mg once daily from next day for 5 days. Laboratory investigations revealed severe pancytopenia and abnormal renal and liver function tests. A diagnosis of acute Mtx toxicity was made and started treatment with intravenous leucovorin and subcutaneous granulocyte colony-stimulating factor (filgrastim) for 4 days. The patient responded to the treatment with improvement in skin lesions and laboratory parameters. The present case underlines the importance of patient counseling regarding the dosage schedule of the drugs and their adverse effects. The ulceration of preexisting lesions helps in early diagnosis, evaluation, and initiation of specific therapy.

Abstract 3636: Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Abstract Introduction: Methotrexate (MTX) is a key component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL). However, delivery of MTX is often interrupted by dose-limiting acute neurotoxicity, which manifests as seizures, stroke-like symptoms, or altered mental status. Because incidence and risk factors for MTX neurotoxicity are poorly defined, we evaluated clinical and demographic predictors of MTX neurotoxicity using the multi-ethnic REDIAL Consortium. Methods: The REDIAL cohort includes pediatric patients diagnosed with ALL at six treatment centers in the southwestern U.S. This interim analysis evaluated 756 patients age 1-21 years diagnosed with B-ALL (2005-2018). Electronic health records were reviewed to determine race/ethnicity (Latino, non-Latino White, non-Latino Black, or Other), body mass index, sex, age, and intravenous (IV) MTX dose. Applying Ponte di Legno criteria, acute MTX neurotoxicity was defined as neurologic episodes occurring <21 days from intrathecal or IV MTX, which resulted in MTX treatment modifications. The proportion of patients who experienced MTX neurotoxicity and corresponding 95% confidence interval (CI) was calculated overall and within the induction, post-induction, and maintenance treatment phases. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) for the association between clinical factors and MTX neurotoxicity. Results: The study population was 56.6% Latino, 52.8% male, 41.4% treated with >5g/m2 IV MTX, and diagnosed at a median age of 5 years. Overall, 15.5% (95% CI: 12.9-18.3%) of patients experienced neurotoxic events (n=117), including 1.9% (n=14, 95% CI: 1.0-3.1%) during induction, 13.0% (n=98, 95% CI: 10.7-15.6%) during post-induction, and 0.7% (n=5, 95% CI: 0.2-1.5%) during maintenance therapy. Ethnic differences were not statistically significant during induction or maintenance phases. Compared to non-Latinos, post-induction neurotoxicity was significantly more frequent among Latinos (aOR = 2.87, 95% CI: 1.68-5.10), with disparities observed during consolidation, interim maintenance and delayed intensification phases. Exposure to >5g/m2 IV MTX (aOR = 2.16, 95% CI: 1.08-3.24) and older age at diagnosis (aOR = 1.16, 95% CI: 1.08-1.24) were also associated with a significantly more post-induction neurotoxicity. No factors evaluated were significantly associated with neurotoxicity during induction and maintenance therapy. Conclusions: MTX neurotoxicity disproportionally affects Latino children during ALL post-induction therapy. Additional work is warranted to identify risk factors for neurotoxicity during induction and maintenance therapy as well as the specific clinical and host biological factors responsible for post-induction ethnic differences in MTX neurotoxicity. Citation Format: Austin L. Brown, Rachel D. Harris, Olga A. Taylor, Melanie B. Bernhardt, Juan C. Bernini, Rodrigo A. Erana, Timothy Griffin, Kenneth Heym, Van T. Huynh, Kathleen Ludwig, Avner Meoded, Sandi L. Pruitt, Philip J. Lupo, Karen R. Rabin, Michael E. Scheurer. Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3636.

Acute methotrexate toxicity in patients with psoriasis: case series

Acute methotrexate toxicity in patients with psoriasis: case series

Ethnic Disparities in Methotrexate Neurotoxicity among Children and Adolescents with Acute Lymphoblastic Leukemia

Abstract Purpose of study: To identify factors related to the increased risk of neurotoxicity in children with acute lymphoblastic leukemia (ALL) after treatment with the antifolate agent methotrexate (MTX), a critical component of curative protocols. Methods: We analyzed the incidence of and factors associated with acute MTX neurotoxicity (neurologic episode within 14d of dose that resulted in treatment modification) in a multi-site study of 280 (48% Latino) newly diagnosed (between 2012–2017) patients treated on recent pediatric ALL protocols. We examined the effects of genetic ancestry and single nucleotide variants in a subset of 190 patients with genotype data. Results: MTX neurotoxicity occurred in 22% of Latino compared to 7% of non- Latino patients; a nearly 2.5-fold increased risk after accounting for other clinical and demographic factors. Patients with neurotoxicity received fewer total MTX doses, and their risk for relapse was 2-fold higher than patients who did not experience neurotoxicity. We also found that 42% of our Latino patients who experienced a first neurotoxic event went on to have additional events, compared to only 21% of non-Latino patients. The proportion of genetic variation that co-segregates with Native American ancestry was overrepresented in individuals with MTX-related neurotoxicity (mean = 35%) vs without neurotoxicity (mean = 23%, p = 0.025). In multivariable models accounting for sex, age at diagnosis, and treatment risk group, every 10% increase in the proportion of Native American genetic ancestry was associated with a 16% increase in neurotoxicity incidence (HR = 1.16; 95% CI: 1.02–1.32). Our data also suggest that Latinos are at higher risk for first (OR = 3.51, p = 0.02) and subsequent (OR = 6.10, p = 0.04) neurotoxic events associated with a missense variant in TCF12, which is more common in admixed Latino (23%) compared to European (3%) or African (<1%) populations. Conclusions: MTX neurotoxicity is more common among Latino children and adolescents with ALL, compromises treatment efficacy, and may contribute to disparities in ALL relapse and survival. Our findings to date highlight that differences in inherited genetic variation, which segregate with ancestry, likely contribute to disparities in the incidence of treatment-related neurotoxicity.

Idiosyncratic Reaction to Single 7.5 mg Dose of Methotrexate

Methotrexate (MTX) is one of the most common systemic immunosuppressive agents prescribed in dermatology. MTX toxicity targets skin, gastrointestinal mucosa, kidney, liver, and bone marrow. Toxic effects of MTX presenting as hepatic, renal, pulmonary, and bone marrow disorders occur less frequently than the minor effects but may be life-threatening. Characteristic signs and symptoms of acute MTX toxicity are based on extent and severity of organ involvement. Here, we report a 55-year-old married male, known case of chronic plaque-type psoriasis presenting with reaction to single dose of tablet MTX 7.5 mg as advised by the dermatologist for his disease. On history and clinical examination, diagnosis of idiosyncratic reaction to single dose of tablet MTX 7.5 mg was made.

A Rational, Evidence-Based Approach to Methotrexate Poisoning

Our primary aim was to create a succinct yet thorough evidence-based review of the pharmacokinetics, pharmacodynamics, clinical presentation, evaluation, and treatment of methotrexate poisoning that may serve as a useful reference for practitioners and researchers. A significant amount of recent research has studied various aspects of intravenous high-dose methotrexate, particularly prevention and management of toxicity. Less substantial evidence exists concerning the management of intrathecal methotrexate overdoses, repeated oral ingestions, and the outcomes of acute oral methotrexate overdoses. Pharmacokinetics studies in children have highlighted the importance of body surface area for dosing and the monitoring of methotrexate concentrations to prevent complications after administration of intravenous high-dose methotrexate. Other studies have documented the efficacy of glucarpidase and leucovorin for some of these patients. Similarly, glucarpidase has been shown to be effective in case reports of intrathecal overdoses, even when administration is delayed. Recent retrospective reviews in adult and pediatric patients have shown that most acute oral overdoses of methotrexate rarely result in toxicity. However, chronic oral ingestions are more likely to develop toxic effects. This review generated management and treatment recommendations for various exposure types.

Toxic Epidermal Necrolysis-Like Lesions as Cutaneous Manifestation of Acute Methotrexate Toxicity.

Toxic Epidermal Necrolysis-Like Lesions as Cutaneous Manifestation of Acute Methotrexate Toxicity.

Acute methotrexate toxicity with severe cutaneous ulcerations in a patient of chronic plaque psoriasis

<p>Methotrexate continues to be one of the most widely used systemic immunosuppressive agents in chronic plaque psoriasis. In addition to the important well characterized adverse effects such as hepatotoxicity and myelosuppression, methotrexate may induce a number of mucocutaneous adverse events including methotrexate induced mucocutaneous ulcerations. We present a case of methotrexate induced severe cutaneous ulcerations in patient with chronic plaque psoriasis. 45 year old male known case of chronic plaque psoriasis on methotrexate therapy manifested as methotrexate toxicity leading to acute kidney injury with painful ulcerated plaques with active bleeding over previously psoriatic plaques over extremities and trunk with mucosal ulcerations responding effectively to leucovorin therapy. Dermatologists need to be alert to the possibility of cutaneous adverse events associated with methotrexate therapy especially ulcerations of psoriatic plaques. </p>

四肢の浸潤性紅斑が診断契機となったメトトレキサートによる急性毒性の 1 例

四肢の浸潤性紅斑が診断契機となったメトトレキサートによる急性毒性の 1 例

Systematic literature review investigating whether methotrexate causes chronic pulmonary fibrosis.

Methotrexate is a treatment widely used in many medical conditions. It is highly effective especially in conditions such as rheumatoid arthritis (RA) and psoriasis. Methotrexate is associated with a potentially fatal acute methotrexate pneumonitis. In regards to chronic lung complications, three case reports with a total of four patients have suggested a link between methotrexate and chronic lung fibrosis.1–3 Subsequent longitudinal studies have refuted this claim.4,5 The aim in this study is to undertake a systematic literature review to evaluate the published evidence on whether methotrexate causes chronic interstitial pulmonary fibrosis in humans. …

Systematic literature review investigating whether methotrexate causes chronic pulmonary fibrosis

Methotrexate is a treatment widely used in many medical conditions. It is highly effective especially in conditions such as rheumatoid arthritis (RA) and psoriasis. Methotrexate is associated with a potentially fatal acute methotrexate pneumonitis. In regards to chronic lung complications, three case reports with a total of four patients have suggested a link between methotrexate and chronic lung fibrosis.1–3 Subsequent longitudinal studies have refuted this claim.4,5 The aim in this study is to undertake a systematic literature review to evaluate the published evidence on whether methotrexate causes chronic interstitial pulmonary fibrosis in humans. …

Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose

Objective: Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose.Case Report: A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17.Discussion: Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate’s pharmacokinetics and the patient’s normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg.

Management of Patients with Acute Methotrexate Nephrotoxicity with High-Dose Leucovorin.

Acute kidney injury complicating high-dose methotrexate (HDMTX) therapy increases the risk for severe mucositis, myelosuppression, and death. It is unclear whether high-dose leucovorin and supportive therapy without the use of glucarpidase can reduce toxicity from HDMTX. The charts of all patients at Memorial Sloan Kettering Cancer Center whose methotrexate (MTX) drug levels at 48 or 72 hours after administration were 10 times or more the toxic level were reviewed between January 2000 and December 2011. Eighty-eight patients (median age 51 years, range 9-90 years) who received 100 courses of HDMTX were identified. Serum creatinine increased by 2-fold from baseline (median, range 1- to 10-fold), but all patients recovered kidney function. Serum levels of MTX were 69 μmol/L (median, range 2.2-400), 6.9 μmol/L (1.3-64), and 2.0 μmol/L (0.05-26) at 24, 48, and 72 hours, respectively, after administration. A statistically significant correlation existed between MTX levels at 48, 72, 96, and 120 hours after administration but not between 24 and 72 hours or subsequent time points. High-dose leucovorin was given in 81% of courses in accordance with institutional protocols in most cases. Myelosuppression was present in 42%; grade III or higher neutropenia in 29%, and thrombocytopenia in 25%. Infectious complications, oral mucositis, and diarrhea occurred in 21%, 17%, and 6% of patients, respectively. Five deaths occurred, none directly attributed to complications from MTX administration. Seven additional patients received glucarpidase at the discretion of a treating physician during the study period, and results are reported separately. Patients who had 100 episodes of HDMTX-associated acute kidney injury were treated with a strategy that only included usual supportive measures and high-dose leucovorin. No deaths were directly attributed to complications related to HDMTX. Glucarpidase, an expensive drug, may not be necessary for a significant number of patients.

Beneficial role of virgin coconut oil supplementation against acute methotrexate chemotherapy-induced oxidative toxicity and inflammation in rats

BackgroundMethotrexate (MTX) is a commonly used antineoplastic and anti-rheumatoid agent whose efficacy is limited by marked organ toxicities associated with oxidative stress. The study investigated beneficial effect of virgin coconut oil (VCO) supplementation on MTX-induced oxidative stress and inflammation in rats. MethodsRats were divided into 4 groups (n=6): Control, MTX (20mg/kg bw), VCO (5%)+MTX and VCO (15%)+MTX. The pre-treatment with VCO for 14 days was followed by single intraperitoneal injection of MTX and the rats were sacrificed after 3 days. Serum activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and levels of reduced glutathione (GSH) and malondialdehyde (MDA) were determined. Interleukin-6 (IL-6), C-reactive protein (CRP) and nitric oxide (NO) levels were also evaluated. ResultsMTX induced a distinct diminution in serum activities of oxidative stress markers (SOD, CAT, GPx and GSH), while lipid peroxidation considerably increased demonstrated by MDA level. Similarly, levels of IL-6, CRP and NO increased prominently in MTX control rats. The VCO supplementation markedly enhanced resistance to the MTX-induced biochemical alterations in rats. ConclusionVCO can be a useful adjuvant natural product in MTX chemotherapy by reducing oxidative stress and pro-inflammatory responses.