|Year : 2015 | Volume
| Issue : 3 | Page : 127-134
Acute methotrexate ingestions in adults: A review on ever-rising consumption of methotrexate since 1980s
Ranjita Santra(Dhali)1, Soumeek Choudhury2
1 Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
2 Department of Forensic Medicine, Burdwan Medical College, Burdwan, West Bengal, India
|Date of Web Publication||16-Jul-2015|
Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
To review the possible association between methotrexate (MTX) intake and increased toxicity. A MEDLINE literature search MEDLINE (1980-August 2014) was performed using the search terms MTX, antifolate, MTX toxicity, glucarpidase, and leucovorin. Additional references were identified from a review of literature citations. All English-language observational studies and case reports were considered. Methotrexate (meth" oh trex' ate) is an antifolate and antimetabolite that is used extensively in the therapy of leukemia, lymphoma, and several solid organ tumors. It also has potent activity against psoriasis and has immunomodulatory activity against inflammatory bowel disease and the inflammatory arthritidies. It exhibits a wide range of toxic effects profile. Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of MTX. In post marketing experience, overdose with MTX has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. Supporting care strategies, extracorporeal measures, and glucarpidase are some of the means to overcome MTX overdosage. At present, pharmacogenomics tends to contribute toward the emergence of adverse effects following the widespread use of MTX for various indications.
Keywords: Antimetabolites, glucarpidase, immunomodulation, leucovorin, methotrexate, overdosage, pharmacogenomics, post marketing phase, toxicity
|How to cite this article:|
Santra(Dhali) R, Choudhury S. Acute methotrexate ingestions in adults: A review on ever-rising consumption of methotrexate since 1980s. Int J Health Allied Sci 2015;4:127-34
|How to cite this URL:|
Santra(Dhali) R, Choudhury S. Acute methotrexate ingestions in adults: A review on ever-rising consumption of methotrexate since 1980s. Int J Health Allied Sci [serial online] 2015 [cited 2022 Jul 6];4:127-34. Available from: https://www.ijhas.in/text.asp?2015/4/3/127/160864
| Introduction|| |
Methotrexate (meth" oh trex' ate) is an antifolate and antimetabolite that is used extensively in the therapy of leukemia, lymphoma, and several solid organ tumors. It also has potent activity against psoriasis and has immunomodulatory activity against inflammatory bowel disease and the inflammatory arthritidies.
In 1947, a team of researchers led by Sidney Farber showed aminopterin, a chemical analog of folic acid developed by Yellapragada Subbarow of Lederle, could induce remission in children with acute lymphoblastic leukemia (ALL). The development of folic acid analogs had been prompted by the discovery that the administration of folic acid worsened leukemia, and that a diet deficient in folic acid could conversely produce improvement; the mechanism of action behind these effects was still unknown at the time. Other analogs of folic acid were in development, and by 1950, methotrexate (MTX) (then known as amethopterin) was being proposed as a treatment for leukemia. Animal studies published in 1956 showed the therapeutic index of MTX was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of MTX.
In 1951, Jane C. Wright demonstrated the use of MTX in solid tumors, showing remission in breast cancer. Wright's group was the first to demonstrate the use of the drug in solid tumors, as opposed to leukemias, which are a cancer of the marrow. Min Chiu Li et al. then demonstrated complete remission in women with choriocarcinoma and chorioadenoma in 1956 and in 1960 Wright et al. produced remissions in mycosis fungoides.
MTX is considered as a disease-modifying antirheumatic drug (DMARD) and used widely in rheumatoid arthritis and other autoimmune diseases. MTX acts by inhibition of folate metabolism, blocking dihydrofolic acid reductase, thereby inhibiting synthesis of purines and pyrimidines and decreasing DNA and RNA synthesis. Recent results suggest that MTX also leads to increase and release of adenosine, which may mediate its immunosuppressive activity. MTX utilizes several intercellular pathways to antagonize folate, which results in profound effects on rapidly dividing cells.  MTX was approved for use in cancer in the United States in 1955, for psoriasis in 1972, and rheumatoid arthritis in 1988 and is still widely used for these indications [Figure 1].
Penicillins may decrease the elimination of MTX and thus increase the risk of toxicity.  While they may be used together increased monitoring is recommended.  The aminoglycosides, neomycin, and paromomycin have been found to reduce gastrointestinal (GI) absorption of MTX.  Probenecid inhibits MTX excretion, which increases the risk of MTX toxicity.  Likewise, retinoids and trimethoprim have been known to interact with MTX to produce additive hepatotoxicity and hematotoxicity, respectively.  Other immunosuppressants like cyclosporine may potentiate MTX's hematologic effects, hence potentially leading to toxicity.  Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been found to fatally interact with MTX in numerous case reports.  Nitrous oxide potentiating the hematological toxicity of MTX has also been documented.  Proton-pump inhibitors like omeprazole and the anticonvulsant valproate have been found to increase the plasma concentrations of MTX, as have nephrotoxic agents such as cisplatin, the GI drug, cholestyramine, and dantrolene.  Caffeine may antagonize the effects of MTX on rheumatoid arthritis by antagonizing the receptors for adenosine. 
Common uses of MTX include treatment for a variety of cancers. It is also used for rheumatoid arthritis, ankylosing spondylitis, uveitis, organ transplantation, psoriasis, trophoblastic diseases, and therapeutic abortion. MTX regimens for chemotherapy and therapeutic abortions are administered parenterally. Intrathecally, MTX is available in variable doses (1-20 mg/kg). For the treatment of rheumatological conditions including psoriasis, rheumatoid arthritis, and ankylosing spondylitis, the adult dose is 7.5-15 mg orally per week. In past decades, isolated case reports of nonfatal toxic ingestion of MTX have been described. These cases did not have long-term sequelae. More recently, oral MTX use has increased in frequency and dosage. In Germany, oral MTX has become established as the most commonly used DMARD in the treatment of rheumatoid arthritis.  In the United States, a higher dose and early use of oral MTX for the treatment of inflammatory arthropathy has been used.  Recent case reports describe fatal outcomes from acute MTX ingestion after repeated ingestions.  However, most cases of adverse effects are with the parenteral administration or repeated oral ingestion. There are limited data on effects of acute ingestion of MTX in adults.  The objective of this review was to establish a possible association between acute MTX intake and increased adverse effects leading to toxicity.
| Methodology of review|| |
To capture as many relevant citations as possible, a wide range of medical, environmental, and scientific databases were searched to identify primary studies of the effects of MTX. The electronic searches were supplemented by hand searching of Index Medicus back to 1980. Furthermore, various internet engines were searched for web pages that might provide references. This effort resulted in 2242 citations from which relevant studies were selected for the review. Their potential relevance was examined, and 2100 citations were excluded as irrelevant. The full papers of the remaining 142 citations were assessed to select those primary studies in man that directly related to MTX intake in patients, comparing at least two groups. These criteria excluded 62 studies and left 80 in the review. They came from twenty-five countries, published in fourteen languages between 1980 and 2014. Of these studies, 65 were relevant to the question of safety, of which 40 used acute toxicity as an outcome. Data for this review work were extracted from MEDLINE literature search from 1980 to August 2014 using the MeSH terms provided by National Library of Medicine such as MTX, antimetabolites, antifolates, MTX toxicity, glucarpidase, leucovorin, post marketing studies, and pharmacogenomics. Additional references were identified from a review of literature citations. All English-language observational studies and case reports were considered.
| Hepatotoxicity|| |
MTX is well-known to cause serum aminotransferase elevations, and long-term therapy has been linked to the development of fatty liver disease, fibrosis, and even cirrhosis. The literature on MTX is extensive, but with great variability in rates of liver test and biopsy abnormalities at different doses, dose regimens, and durations of therapy. With high-dose intravenous MTX, serum alanine aminotransferase (ALT) levels can rise to 10-20 times the upper limit of normal within 12-48 h, but levels then fall rapidly to normal with only rare instances of jaundice or symptoms of liver injury. With long-term, low-to-moderate dose MTX therapy, elevations in serum ALT or aspartate aminotransferase values occur in 15-50% of patients, but are usually mild and self-limiting. Approximately 5% of patients have elevations greater than twice normal and these abnormalities resolve rapidly with discontinuation or dose modification but can resolve even with a continuation at the same dose level. The reported rate of ALT elevations during therapy has varied considerably, perhaps because of differences in frequency of determinations (every month vs. every 3, 6 or 12 months) and due to the timing of the blood sampling (whether just before or soon after the once weekly dose). Finally, coadministration of folic acid has been shown to decrease the frequency of serum enzyme elevations and now it is commonly used.
Long-term therapy with MTX has been associated with the development of fatty liver and hepatic fibrosis and in rare instances, portal hypertension and symptomatic cirrhosis. Symptoms are usually absent until cirrhosis is present, and liver tests are typically normal or minimally and transiently elevated. Routine monitoring of patients with regular liver biopsies done at 1-2 years intervals or with cumulative MTX doses of 1-10 g demonstrates that approximately 30% of patients develop mild-to-moderate histological abnormalities (fat, cellular unrest, mild inflammation, nuclear atypical) and 2-20% of patients develop some degree of hepatic fibrosis. Well-documented cases of cirrhosis arising during long-term MTX therapy have been reported, but cirrhosis is rare in prospective series, even with routine histological monitoring. Use of high doses and daily MTX dosing are particularly associated with the development of hepatic fibrosis and rates of cirrhosis of >20% after 5-10 years of treatment. 
| Mechanism of hepatic injury|| |
The mechanism of liver injury with MTX is believed to be a direct toxicity though inhibition of RNA and DNA synthesis in the liver and producing cellular arrest. MTX therapy has been shown to increase hepatic stellate cell numbers, but the mechanism by which fibrosis is induced has not been clearly elucidated. Concurrent therapy with folate has been shown to reduce the rate of serum enzyme elevations during low-dose MTX therapy.
| Pulmonary toxicity|| |
The clinical and radiologic manifestations of MTX generally reflect the underlying histopathologic processes and include nonspecific interstitial pneumonia (NSIP), bronchiolitis obliterans organizing pneumonia (BOOP), eosinophilic pneumonia, obliterative bronchiolitis, pulmonary hemorrhage, edema, hypertension, or veno-occlusive disease.  At radiography, NSIP appears as diffuse areas of heterogeneous opacity, whereas early computed tomography (CT) scans show diffuse ground-glass opacity and late CT scans show fibrosis in a basal distribution. BOOP appears on radiographs as heterogeneous and homogeneous peripheral opacities in both upper and lower lobes and on CT scans as poorly defined nodular consolidation, centrilobular nodules, and bronchial dilatation.  MTX-induced pulmonary drug toxicity occurs in 5-10% of patients. Symptoms typically manifest within months of starting therapy.  Knowledge of these manifestations and of the drug most frequently involved can facilitate diagnosis and institution of appropriate treatment. MTX-induced leukoencephalopathy (LEP) presents as focal area of restricted diffusion in deep periventricular white matter which is reversibly radiological on Diffusion-weighted magnetic resonance imaging (MRI) and corresponding apparent diffusion coefficient map, with parallel clinical outcome. Such changes in a deep cerebral white matter not necessarily indicate an irreversible cytotoxic injury. Alerting clinician to this potentially reversible condition can help facilitate appropriate management. Rollins et al.,  reported only 5 patients who had acute MTX neurotoxicity out of 194 children (age ranging from 12 to 15 years) diagnosed with pre B-cell ALL. They established a temporal relationship between the acute neurotoxicity and intrathecal administration of MTX and most often occurred 22-23 weeks into chemotherapy. Their stroke-like symptoms resolved within 24-36 h. Sandoval et al.,  also reported a 13-year-old female patient with acute MTX-induced neurotoxicity that occurred during consolidation phase for pre B-cell ALL, which showed restricted diffusion in bilateral centrum semiovale and splenium of corpus callosum. Clinically, she recovered completely within 2 h of onset. Three weeks after admission, her diffusion abnormalities normalized, with no postcontrast enhancement. Mckinney et al.,  reviewed 32 patients (age range 11-70 years) over an 8-year period diagnosed with medication-related toxic LEP with appearance of bilateral symmetric periventricular white matter reduced diffusion on initial MRI. Out of 32 patients, of toxic LEP due to various medications, MTX was the causative factor in 3 patients. Mahoney et al.,  reported 95 patients out of 1218 (7.8%) with acute MTX-induced neurotoxicity and described the majority of events being seizures. The increased incidence of MTX-LEP was due to increased cumulative exposure of intravenous MTX, increased MTX-leucovorin ratio, and choice and timing of intrathecal therapy. Inaba et al.  reported 7 out of 8 patients were more than 10-years-old, and 4 patients had delayed systemic MTX excretion requiring additional leucovorin. The tendency toward lower MTX clearance in adolescents may contribute to the age risk, there being no significant relation between MTX pharmacokinetic parameter and LEP.
| Osteonecrosis|| |
Osteonecrosis (death of bone) (latest reports from 205,403 patients) has been reported by people with osteoporosis, metastases to bone, multiple myeloma, breast cancer, and osteopenia. In 2014: 7192 people reported to have side effects when taking MTX sodium. Among them, 28 people (0.39%) have osteonecrosis. They amount to 0.01% of all the 205,390 people who have osteonecrosis in the United States [Figure 2] and [Table 1],[Table 2] and [Table 3]. 
|Figure 2: Trend of osteonecrosis in methotrexate sodium administration for various Indications|
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|Table 2: Age of people who have osteonecrosis on administration of MTX sodium|
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| Hematologic toxicity|| |
MTX can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia. In patients with malignancy and preexisting hematopoietic impairment, the drug should be used with caution, if at all. In controlled clinical trials in rheumatoid arthritis (n = 128), leukopenia (white blood cell <3000/mm 3 ) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm 3 ) in 6 patients, and pancytopenia in 2 patients. In psoriasis and rheumatoid arthritis, MTX should be stopped immediately if there is a significant drop in blood counts. In the treatment of neoplastic diseases, MTX should be continued only if the potential benefit warrants the risk of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy.
| Renal toxicity|| |
MTX may cause renal damage that may lead to acute renal failure. Nephrotoxicity is primarily due to the precipitation of MTX and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum MTX and creatinine levels are essential for safe administration.
| Skin|| |
Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome More Details, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal MTX administration. Reactions were noted after single or multiple, low, intermediate or high doses of MTX in patients with neoplastic and nonneoplastic diseases. There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports describing large series (n = 204, 248) of psoriasis patients treated with MTX. , Dosages ranged up to 25 mg/week and treatment was administered for up to 4 years. With the exception of alopecia, photosensitivity, and "burning of skin lesions" (each 3-10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear.
The approximate incidences of adverse reactions reported in pediatric patients with juvenile rheumatoid arthritis (JRA) treated with oral, weekly doses of MTX (5-20 mg/m 2 /week or 0.1-0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant NSAIDs, and some were also taking low doses of corticosteroids): Elevated liver function tests, 14%; GI reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, and 0.2%; rash. Although there is experience with dosing up to 30 mg/m 2 /week in JRA, the published data for doses above 20 mg/m 2 /week are too limited to provide reliable estimates of adverse reaction rates. 
| Overdosage of methotrexate|| |
Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of MTX. Leucovorin administration should begin as promptly as possible. As the time interval between MTX administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum MTX concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration, and urinary alkalinization it may be necessary to prevent the precipitation of MTX and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve MTX elimination. However, effective clearance of MTX has been reported with acute intermittent hemodialysis using a high-flux dialyzer.  In post marketing experience, overdose with MTX has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported.  Clinical trial results have revealed the number and organ-specific toxicities from 223 participants at the University of Alabama at Birmingham Folate and Immunex early rheumatoid arthritis trials. Each of the 223 subjects (193 Caucasians and 30 African - Americans) with rheumatoid arthritis who participated in one of the two clinical trials (University of Alabama at Birmingham folate trial and Immunex ERA trial) was prospectively evaluated for toxicity of MTX. In the former trial, all, 68% of the participants experienced some form of toxicity of MTX, most commonly nausea with indigestion (39%), diarrhea (14%), oral ulcers or stomatitis (11%), and rash (11%).  While in the latter trial, data on toxicity were obtained from all participants and defined categorically according to the common toxicity criteria of the National Cancer Institute. 96% of the MTX-treated participants experienced toxicity, most commonly nausea or indigestion (35.1%), skin rash or pruritus (21.2%), and fatigue or malaise or headache (19.1%). 
Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and GI reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, GI ulceration, GI bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. ,,
[Table 4] shows the interaction of other drugs with MTX, importance and toxicity, indications and management: ,,,,
| Discussion|| |
MTX was developed as an analog of folic acid, and many of the factors governing cellular handling of MTX are identical to those involved in folate metabolism. MTX is taken up by specific transporters into the cell where it interferes with the synthesis of purines and pyrimidines as well as blocks the conversion of homocysteine to methionine. Once inside the cell, MTX is polyglutamated, which confers both longevity on the polyglutamated metabolites and alters the spectrum of enzymes inhibited by the drug (Chabner et al., 1985); MTX polyglutamates inhibit AICAR transformylase, an enzyme involved in the de novo synthesis of purines, most potently (Allegra et al., 1985). The inhibition of AICAR transformylase by MTX polyglutamates is associated with the accumulation of AICAriboside and increased release of adenosine, which mediates many of the anti-inflammatory effects of MTX (Cronstein et al., 1991, 1993; Montesinos et al., 2000, 2003).
| Supportive care strategies|| |
In most patients with normal renal function, high-dose MTX (HDMTX) can be given safely with the use of several supportive care strategies. These include vigorous hydration and urinary alkalinization to enhance the solubility of MTX in the urine, as well as pharmacokinetically guided leucovorin rescue to protect against potentially lethal MTX toxicity.
| Extracorporeal measures|| |
Hemodialysis and hemoperfusion have been used in patients with toxic MTX levels and provide a means to remove MTX from the body despite acute kidney injury (AKI), while continuing leucovorin rescue to prevent MTX-toxicity. These extracorporeal strategies, however, involve physically removing MTX and require the placement of a dialysis catheter and in many cases - prolonged or repeated application, which adds to treatment-related morbidity in patients with delayed MTX elimination. For example, although high-flux hemodialysis clears a significant portion of circulating MTX from the plasma, this technique is associated with post dialysis plasma rebound. Plasmapheresis is another strategy that shows limited efficacy in the management of HDMTX-induced AKI. Regardless of the management strategy chosen, leucovorin rescue must be continued for patients with delayed MTX excretion. 
| Glucarpidase|| |
Glucarpidase (carboxypeptidase G2) was approved by the US Food and Drug Administration in January 2012 for the treatment of plasma MTX concentrations (>1 μm) in patients with delayed MTX clearance due to impaired kidney function despite standard leucovorin treatment. This agent is a recombinant form of bacterial carboxypeptidase that was developed to treat patients with delayed MTX elimination and MTX-induced renal impairment. The agent works by cleaving MTX into two inactive metabolites - DAMPA and glutamate - that are no longer toxic. Thus, glucarpidase provides an alternate, nonrenal route for clearing MTX in patients with renal dysfunction. 
As technology has progressed, it has become possible to pinpoint genetic factors that modulate response to various drugs, and MTX has received its share of attention. Identifying a genetic predisposition to a toxic reaction to a drug like MTX is much easier than pinpointing the factors that may predispose to a better response to the drug. Toxic reactions are discrete and easily identifiable, whereas therapeutic responses to MTX are often difficult to define; drug response in rheumatoid arthritis is generally a composite measure comprised of findings on physical examination (tender and swollen joints), laboratory results (C-reactive protein or erythrocyte sedimentation rates), and subjective responses (e.g. Modified Health Assessment Questionnaire, Physician's Global Response). Moreover, response to drug therapy in rheumatoid arthritis is clearly much better when the drug is started early in the course of the disease, regardless of the drug (Baumgartner et al., 2004). Thus, defining genetic factors that predispose to a better response to the drug is complex, and the genetic contribution may be different depending on when the drug is started in the course of the disease. Because of these problems, there is much more data available on the genetic factors that may predispose to MTX's toxicity than to its efficacy.
Clearly, a genetic test that predicted response to MTX would be greatly welcomed in the rheumatology community. One recent report has indicated that the A1298C polymorphism is associated with diminished efficacy of MTX (defined as requiring >10 mg/week MTX), although this was not confirmed in a subsequent study (Urano et al., 2002; Kumagai et al., 2003). In another recent study, an additive effect on MTX efficacy was demonstrated for polymorphisms in thymidylate synthase (involved in folate-dependent pyrimidine synthesis), AICAR transformylase, and RFC1 (the protein that transports MTX into the cell). Individuals with a polymorphism in more than one of these genes had a better response to MTX than those with none.  This was a small study, however, the role of these polymorphisms in MTX response requires further research.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]