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The Oncologist Dec 2016: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered... (Review)
Review
UNLABELLED
: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.
IMPLICATIONS FOR PRACTICE
High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.
Topics: Acute Kidney Injury; Antimetabolites, Antineoplastic; Bone Marrow; Chemical and Drug Induced Liver Injury; Crystallization; Humans; Leucovorin; Methotrexate; Mucositis; gamma-Glutamyl Hydrolase
PubMed: 27496039
DOI: 10.1634/theoncologist.2015-0164 -
Actas Dermo-sifiliograficas 2014Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until... (Review)
Review
Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until quite recently. We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability, efficacy, and ease of administration of the drug. The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis. Moreover, the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin, adalimumab, and infliximab.
Topics: Dermatologic Agents; Humans; Methotrexate; Psoriasis
PubMed: 23434058
DOI: 10.1016/j.ad.2012.11.017 -
Rheumatic Diseases Clinics of North... Nov 1997Because of methotrexate's well-documented efficacy in the treatment of rheumatoid arthritis, it is important that we understand the mechanism of action of this drug.... (Review)
Review
Because of methotrexate's well-documented efficacy in the treatment of rheumatoid arthritis, it is important that we understand the mechanism of action of this drug. There are two biochemical mechanisms by which methotrexate may modulate inflammation: (1) promotion of adenosine release and (2) inhibition of transmethylation reactions. Evidence is reviewed that favors the notion that the endogenous anti-inflammatory autocoid adenosine mediates the anti-inflammatory effects of methotrexate. This insight should aid in the design of new agents for the treatment of rheumatoid arthritis and other inflammatory diseases.
Topics: Adenosine; Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Methotrexate; Methylation
PubMed: 9361153
DOI: 10.1016/s0889-857x(05)70358-6 -
The Oncologist Jun 2006Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an... (Review)
Review
Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G(2) (CPDG(2)), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG(2) administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%-99.5%). The early administration of CPDG(2) in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations.
Topics: Antimetabolites, Antineoplastic; Humans; Leucovorin; Methotrexate; Neoplasms; Renal Insufficiency; gamma-Glutamyl Hydrolase
PubMed: 16794248
DOI: 10.1634/theoncologist.11-6-694 -
ARP Rheumatology Oct 2022Methotrexate (MTX) is an anti-folate drug with anti-proliferative and anti-inflammatory effects. MTX proved to be the most highly effective, fast-acting disease... (Review)
Review
BACKGROUND
Methotrexate (MTX) is an anti-folate drug with anti-proliferative and anti-inflammatory effects. MTX proved to be the most highly effective, fast-acting disease modifying anti-rheumatic drug (DMARD), being widely used for the treatment of rheumatoid arthritis (RA). This review aims to describe the main genetic variants identified concerning proteins that play a role in methotrexate's kinetics and efficiency profile.
METHODS
A literature review was conducted since January of 2000 until December 2020, by searching the PubMed and Embase bibliographic databases, employing the following MeSH terms: methotrexate, pharmacogenetics, pharmacokinetics, and rheumatoid arthritis. The search was limited to articles in English language. Two independent reviewers screened the titles and abstracts followed by a full-text review to assess papers regarding their eligibility. A total of 48 articles matched the research criteria and were analyzed.
RESULTS
Reduced folate carrier 1 (RFC1), a constitutively expressed folate transport protein that has high affinity for MTX is responsible, almost exclusively, for the transport of folate and MTX into the cell. The most studied variant of the gene is the 80G>A variant, mapped within exon 2, on chromosome 21. It seems to improve RA responses to MTX, clinical efficacy with long disease remission. ABC transporters are involved in the efflux of MTX from cells. An increased expression and function of these transporters should decrease MTX concentrations in target cells, resulting in lack of therapeutic response. ABCB1 3435 C/T is a high frequency polymorphism, significantly associated with RA good responses, symptom remission and reduced adverse events, due to MTX treatment. Thymidylate synthase (TYMS) is involved in thymidine synthesis. MTX decreases TYMS activity by inhibition and decreasing the access to tetrahydrofolate (THF) cofactors. The most common genetic variant of the TYMS gene consists of a 28 bp tandem repeat, with double and triple number of repeats (2R and 3R). The 3R allele genotype was associated with decreased efficacy and increased toxicity. The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme is indirectly inhibited by MTX. The most common SNPs of the MTHFR gene are C677T and A1298C. Both are associated with a decreased efficacy and an increased toxicity of MTX.
CONCLUSION
MTX response is affected by many gene variants; the effect of each variant separately is likely to be small. Additionally, gene-gene interaction seems to enhance the potential role of linkage disequilibrium. This shows the emerging need for a better gene characterization and to improve the knowledge about variants distribution according to ethnicity, to explain different responses to MTX at an individual level.
Topics: Humans; Methotrexate; Pharmacogenetics; Arthritis, Rheumatoid; Antirheumatic Agents; Polymorphism, Single Nucleotide; Folic Acid
PubMed: 35724450
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... Jun 2022Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about forty years and to date MTX remains the part of global standard of treatment... (Review)
Review
Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about forty years and to date MTX remains the part of global standard of treatment for RA. The efficacy of MTX in RA is the result of multiple mechanisms of action. In order to summarize the possible pharmacological mechanisms of MTX in the treatment of RA, this review will elaborate on folate antagonism, promotion of adenosine accumulation, regulation of inflammatory signaling pathways, bone protection and maintenance of immune system function.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Methotrexate
PubMed: 35658215
DOI: 10.1016/j.biopha.2022.113074 -
International Journal of Molecular... Oct 2019Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying... (Review)
Review
Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses-including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus-have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients' immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.
Topics: Adenosine; Alarmins; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis; Arthritis, Rheumatoid; Cytokines; Folic Acid; HMGB1 Protein; Humans; Immunity, Innate; Inflammation; Matrix Metalloproteinases; Methotrexate; NF-kappa B; Polyamines; Prostaglandins; Reactive Oxygen Species
PubMed: 31658782
DOI: 10.3390/ijms20205023 -
The European Respiratory Journal Feb 2021
Topics: Humans; Lung; Methotrexate
PubMed: 33574052
DOI: 10.1183/13993003.00079-2021 -
Hematology/oncology Clinics of North... Jun 2012This article focuses on the cellular, biochemical, and molecular pharmacology of antifolates and how a basic understanding of the mechanism of action of methotrexate,... (Review)
Review
This article focuses on the cellular, biochemical, and molecular pharmacology of antifolates and how a basic understanding of the mechanism of action of methotrexate, its cytotoxic determinants, mechanisms of resistance, and transport into and out of cells has led to the development of a new generation of antifolates, a process that continues in the laboratory and in the clinics. New approaches to folate-based cancer chemotherapy are described based on the targeted delivery of drugs to malignant cells.
Topics: Animals; Antimetabolites, Antineoplastic; Drug Resistance, Neoplasm; Folic Acid; Folic Acid Antagonists; Humans; Methotrexate; Molecular Targeted Therapy; Neoplasms
PubMed: 22520983
DOI: 10.1016/j.hoc.2012.02.002 -
Digestive Diseases (Basel, Switzerland) 2012For more than a decade, methotrexate has been known to be an effective therapeutic agent in the treatment of steroid-dependent active Crohn's disease. However,... (Review)
Review
For more than a decade, methotrexate has been known to be an effective therapeutic agent in the treatment of steroid-dependent active Crohn's disease. However, international data on medication utilization suggest that this drug is rarely used in clinical practice for an indication of Crohn's disease. This review investigates the potential reasons for the underuse of methotrexate in patients with inflammatory bowel diseases.
Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Methotrexate; Patient Preference; Treatment Outcome
PubMed: 23295701
DOI: 10.1159/000342735