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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 -
Cell Research Apr 2020The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors,... (Review)
Review
The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.
Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Dimethyl Fumarate; Glycolysis; Humans; Immunomodulation; Immunosuppressive Agents; Inflammation; Metformin; Methotrexate; Sirolimus
PubMed: 32132672
DOI: 10.1038/s41422-020-0291-z -
Joint Bone Spine May 2019Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review,... (Review)
Review
Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple hypotheses to explain the mechanism of methotrexate efficacy in RA. These include folate antagonism, adenosine signaling, generation of reactive oxygen species (ROS), decrease in adhesion molecules, alteration of cytokine profiles, and polyamine inhibition amongst some others. Currently, adenosine signaling is probably the most widely accepted explanation for the methotrexate mechanism in RA given that methotrexate increases adenosine levels and on engagement of adenosine with its extracellular receptors an intracellular cascade is activated promoting an overall anti-inflammatory state. In addition to these hypotheses, we examine the mechanism of methotrexate in RA from the perspective of its adverse effects and consider some of the newer genetic markers of methotrexate efficacy and toxicity in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear explanation for the pathway and mechanism leading to methotrexate efficacy in RA, there may be a way to formulate more potent therapies with fewer side effects.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Female; Humans; Male; Methotrexate; Molecular Targeted Therapy; Prognosis; Reactive Oxygen Species; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 30081197
DOI: 10.1016/j.jbspin.2018.07.004 -
Drugs Nov 2017Intravenous (IV) and subcutaneous (SC) tocilizumab (RoActemra), an IL-6 receptor antagonist, are approved (± methotrexate) in numerous countries throughout the world,... (Review)
Review
Intravenous (IV) and subcutaneous (SC) tocilizumab (RoActemra), an IL-6 receptor antagonist, are approved (± methotrexate) in numerous countries throughout the world, for the treatment of adults with moderate to severe active rheumatoid arthritis (RA). Extensive clinical experience has firmly established the short- and long-term efficacy and safety of tocilizumab [monotherapy or in combination with conventional synthetic DMARDs (csDMARDs)] in adults with early-stage and longer-duration established RA. In the clinical trial and real-world settings, tocilizumab monotherapy or combination therapy provided rapid and sustained improvements in clinical and radiographic outcomes and health-related quality of life. The safety profile of tocilizumab is consistent over time and, in general, is consistent with that of other immunomodulatory agents. This narrative review, written from an EU perspective, summarizes the clinical use of IV and SC tocilizumab in RA. Given its low risk of immunogenicity, the flexibility of IV and SC administration and the convenience of the once-weekly, self-administered, SC regimen, tocilizumab provides an effective treatment for severe, active and progressive RA in adults not previously treated with methotrexate and an effective biologic first- or subsequent-line treatment for moderate to severe active RA in adults who have either responded inadequately to or were intolerant of previous therapy with ≥ 1 csDMARD or TNF inhibitor.
Topics: Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Methotrexate; Receptors, Interleukin-6
PubMed: 29094311
DOI: 10.1007/s40265-017-0829-7 -
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 -
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 -
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 -
Clinical Medicine (London, England) Sep 2019The chikungunya virus (CHIKV) infection epidemic has emerged as a significant public health concern in the last 10-15 years, especially in Asian and south American... (Review)
Review
The chikungunya virus (CHIKV) infection epidemic has emerged as a significant public health concern in the last 10-15 years, especially in Asian and south American countries. However, with ever-expanding tourism and migration, cases have now been reported in north America and Europe. CHIKV infection predominantly causes musculoskeletal symptoms with a chronic polyarthritis which may resemble autoimmune inflammatory arthritis. CHIKV infection should always be suspected in a returning traveller presenting with fever, skin rash and arthralgia. Though first reported in the last century, a series of epidemics since 2004 have substantially improved our knowledge. There has also been a significant increase in our understanding of the immunopathogenesis of chikungunya infection. This knowledge is being used in the development of new treatment strategies and preventive measures. In this narrative review, we discuss some of the recent advances in the epidemiology, immunopathogenesis, and management of CHIKV arthritis.
Topics: Antiviral Agents; Arthritis, Infectious; Chikungunya Fever; Chikungunya virus; Chronic Disease; Humans; Methotrexate
PubMed: 31530685
DOI: 10.7861/clinmed.2019-0035 -
Dermatologic Clinics Oct 2015This article reviews methotrexate and the more potent, related compound, pralatrexate, for the treatment of cutaneous T-cell lymphomas, including mycosis fungoides,... (Review)
Review
This article reviews methotrexate and the more potent, related compound, pralatrexate, for the treatment of cutaneous T-cell lymphomas, including mycosis fungoides, Sézary syndrome, and CD30+ lymphoproliferative disorders. Although these folate antagonists are traditionally viewed as antiproliferative cell cycle inhibitors, it is recognized that they inhibit DNA methylation, providing a rationale for their use as epigenetic regulators and cell proliferation inhibitors. The underlying mechanisms are outlined, key supporting data presented, followed by brief mention of recent mathematical modeling supporting the general superiority of combination therapy. Several novel examples involving folate antagonists are proposed.
Topics: Aminopterin; Antimetabolites, Antineoplastic; Apoptosis; DNA Methylation; Epigenesis, Genetic; Folic Acid Antagonists; Humans; Lymphoma, T-Cell, Cutaneous; Methotrexate; S Phase; Skin Neoplasms
PubMed: 26433846
DOI: 10.1016/j.det.2015.05.009