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Indian Journal of Pharmacology 2022
Topics: Methotrexate; Hydroxides; Lethal Dose 50
PubMed: 36537409
DOI: 10.4103/ijp.ijp_899_21 -
British Journal of Haematology May 2009Due to the development of neurological toxicity and resistance to methotrexate (MTX), other antifolates have been evaluated for its potential replacement in the...
Due to the development of neurological toxicity and resistance to methotrexate (MTX), other antifolates have been evaluated for its potential replacement in the treatment of childhood acute lymphoblastic leukaemia (ALL). Aminopterin (AMT) has been suggested to provide clinical advantages over MTX and other antifolates. AMT activity, compared with MTX, was evaluated in ALL and lymphoma preclinical models. The minimum survival fraction at the range of concentrations tested was lower with AMT than with MTX in 3 out of 15 cell lines. Both AMT and MTX significantly extended the event-free survival of mice bearing 3 out of 4 xenografts with equivalent activity.
Topics: Aminopterin; Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; Female; Folic Acid Antagonists; Humans; Inhibitory Concentration 50; Lymphoma; Methotrexate; Mice; Mice, SCID; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Regression Analysis; Xenograft Model Antitumor Assays
PubMed: 19298590
DOI: 10.1111/j.1365-2141.2009.07631.x -
Cell Jan 2019With the advent of more successful chemotherapies, the number of cancer survivors continues to increase. Unfortunately, many of these patients will exhibit long-term...
With the advent of more successful chemotherapies, the number of cancer survivors continues to increase. Unfortunately, many of these patients will exhibit long-term sequelae from their treatments, including serious cognitive deficits that impair daily function. In this issue of Cell, Gibson et al. (2019) demonstrate that chemotherapy-related cognitive impairment is orchestrated by microglia.
Topics: Cognition Disorders; Cognitive Dysfunction; Humans; Methotrexate
PubMed: 30633904
DOI: 10.1016/j.cell.2018.12.027 -
The Oncologist 2012A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change... (Review)
Review
BACKGROUND
A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change based on the accumulating evidence for a possible drug-drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors (PPIs).
METHODS
The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database of spontaneous adverse event reports and the published literature were searched for cases reporting an interaction between methotrexate and PPIs.
RESULTS
A search of the AERS database and existing literature found several individual case reports of drug-drug interactions and three additional supportive studies that suggest potential underlying mechanisms for the interaction.
CONCLUSION
There is evidence to suggest that concomitant use of methotrexate (primarily at high doses) with PPIs such as omeprazole, esomeprazole, and pantoprazole may decrease methotrexate clearance, leading to elevated serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In several case reports, no methotrexate toxicity was found when a histamine H2 blocker was substituted for a PPI. Based on the reviewed data, the FDA updated the methotrexate label to include the possible drug-drug interaction between high-dose methotrexate and PPIs. Physicians should be alerted to this potential drug-drug interaction in patients receiving concomitant high-dose methotrexate and PPIs.
Topics: Adverse Drug Reaction Reporting Systems; Drug Interactions; Drug Labeling; Humans; Methotrexate; Proton Pump Inhibitors; United States; United States Food and Drug Administration
PubMed: 22477728
DOI: 10.1634/theoncologist.2011-0431 -
Arthritis Research & Therapy Aug 2011High expression of folate receptors is characteristic for the effector cell population of synovial macrophages in synovial inflammation. A new drug conjugate, EC0746,...
High expression of folate receptors is characteristic for the effector cell population of synovial macrophages in synovial inflammation. A new drug conjugate, EC0746, targets the folate inhibitor aminopterin to folate receptors. In vitro studies show that this conjugate acts antiproliferatively and inhibits cytokine production by macrophage cell lines. Moreover, it shows strong anti-arthritic effects in the rat model of adjuvant-induced arthritis in vivo. Toxicity of aminopterin was reduced 40-fold by using equimolar doses of the drug conjugate. In conclusion, this new treatment approach has the potential to further improve the most successful principle of folate inhibition in the treatment of arthritis.
Topics: Aminopterin; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Female; Folic Acid; Folic Acid Antagonists
PubMed: 21861856
DOI: 10.1186/ar3392 -
Advances in Therapy Mar 2016Methotrexate (MTX) is still considered the drug of choice in rheumatoid arthritis (RA) management. Comparing subcutaneous (MTX SC) and oral (MTX OR) routes of... (Review)
Review
UNLABELLED
Methotrexate (MTX) is still considered the drug of choice in rheumatoid arthritis (RA) management. Comparing subcutaneous (MTX SC) and oral (MTX OR) routes of administration is important to optimize the everyday therapeutic strategy in the real-life setting. This review summarizes scientific evidence currently available on this topic. As shown by pharmacokinetic studies, at the same dose level, bioavailability of MTX SC is significantly higher and less variable than that of MTX OR. This difference is even more pronounced for medium-to-high dosages (i.e., >15 mg/week). With regard to clinical response (Disease Activity Score-28, American College of Rheumatology Criteria), randomized, double-blind studies and retrospective or longitudinal analyses in real-life settings showed that MTX SC is more effective than MTX OR. This is true both in MTX-naive patients with early RA, and in patients who switch from MTX OR to MTX SC due to previous treatment failure, lack of efficacy and/or adverse events. Finally, MTX SC has a better tolerability profile than MTX OR, with fewer gastroenterological side effects. Delaying the use of more expensive biological therapies by switching from MTX OR to MTX SC in non-responders might provide cost savings, with relevant implications in the management of patients with RA.
FUNDING
Alfa Wassermann.
Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Humans; Injections, Subcutaneous; Methotrexate
PubMed: 26846283
DOI: 10.1007/s12325-016-0295-8 -
Drug Metabolism and Disposition: the... Apr 2014This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate... (Review)
Review
This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.
Topics: Aminopterin; Animals; Drug Resistance, Neoplasm; Folic Acid; Folic Acid Antagonists; Humans; Methotrexate; Neoplasms; Proton-Coupled Folate Transporter; Reduced Folate Carrier Protein
PubMed: 24396145
DOI: 10.1124/dmd.113.055723 -
Nature Jul 2018Clinical use of the anticancer drug methotrexate can be limited by its high toxicity. It emerges that a diet rich in the amino acid histidine increases the effectiveness...
Clinical use of the anticancer drug methotrexate can be limited by its high toxicity. It emerges that a diet rich in the amino acid histidine increases the effectiveness of methotrexate treatment and lowers toxicity in mice.
Topics: Histidine; Humans; Methotrexate; Mutation; Neoplasms; Research
PubMed: 30030511
DOI: 10.1038/d41586-018-05573-4 -
Oncology (Williston Park, N.Y.) Jul 1995Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include... (Review)
Review
Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include decreased drug transport into cells; decreased polyglutamation, leading to increased drug efflux from cells; decreased drug affinity for folate-dependent enzymes; mutations of dihydrofolate reductase (DHFR), a key enzyme required for the maintenance of adequate intracellular reduced folate levels that is inhibited by methotrexate; and increased expression of the DHFR protein. Promising antifolate compounds undergoing clinical testing as anticancer agents include trimetrexate (which was recently approved by the FDA for the treatment of Pneumocystis carinii pneumonia), edatrexate, piritrexim, Tomudex, and lometrexol. The mechanisms of action, dosage, pharmacokinetics, clinical toxicity, and antitumor activity of these drugs are profiled.
Topics: Aminopterin; Antimetabolites, Antineoplastic; Antineoplastic Agents; Drugs, Investigational; Folic Acid Antagonists; Humans; Neoplasms; Pyrimidines; Quinazolines; Thiophenes; Trimetrexate
PubMed: 8924375
DOI: No ID Found -
Nature Reviews. Gastroenterology &... May 2021
Topics: Bacteria; Humans; Methotrexate; Pharmaceutical Preparations
PubMed: 33692569
DOI: 10.1038/s41575-021-00437-1