Methotrexate

Chemotherapy Methotrexate was originally developed and continues to be used for chemotherapy, either alone or in combination with other agents. It is effective for the treatment of several cancers, including solid tumours of breast, head and neck, lung, bladder, as well as acute lymphocytic leukemias, non-Hodgkin's lymphoma, osteosarcoma, and choriocarcinoma and other trophoblastic neoplasms. It is also used in the treatment of aggressive fibromatosis (desmoid tumor). Autoimmune disorders Although originally designed as a chemotherapy drug, in lower doses methotrexate is a generally safe and well-tolerated drug in the treatment of certain autoimmune diseases. Methotrexate is used as a disease-modifying treatment for several autoimmune diseases in adults, including rheumatoid arthritis, and many forms of vasculitis. In children, it can be used for juvenile dermatomyositis, juvenile idiopathic arthritis, uveitis and localised scleroderma. Use of low doses of methotrexate together with NSAIDs such as aspirin or analgesics such as paracetamol is relatively safe in people being treated for rheumatoid arthritis, with appropriate monitoring. Methotrexate is also sometimes used in combination with other conventional DMARDs, such as sulfasalazine and hydroxychloroquine. Studies and reviews have found that most rheumatoid arthritis patients treated with methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many people receiving methotrexate, with the progression being completely halted in about 30% of those receiving the drug. Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions and strokes. Results of a systematic review exploring the comparative effectiveness of treatments of early rheumatoid arthritis show that treatment efficacy can be improved with combination therapy with anti-TNF or other biologic medications, compared with methotrexate monotherapy. Likewise, a 2016 study found the use of methotrexate, in combination with anti-TNF agents, is effective for the treatment of ulcerative colitis. Methotrexate has also been used for multiple sclerosis Atopic dermatitis Along with other immunosuppressants, methotrexate is used to treat severe atopic dermatitis (eczema). During pregnancy Methotrexate is an abortifacient and is used to treat ectopic pregnancies, provided the fallopian tube has not ruptured. Methotrexate with dilation and curettage is used to treat molar pregnancy. Rarely, it is used in combination with misoprostol to abort intrauterine pregnancies. Administration Methotrexate can be given by mouth or by injection (intramuscular, intravenous, subcutaneous, or intrathecal). ==Adverse effects==

The most common adverse effects include hepatotoxicity, stomatitis, blood abnormalities (leukopenia, anaemia and thrombocytopenia), increased risk of infection, hair loss, nausea, reduced appetite, abdominal pain, diarrhea, fatigue, fever, dizziness, drowsiness, headache, acute pneumonitis and renal impairment. Methotrexate can also cause mucositis. Methotrexate pneumonitis is a rare complication of therapy and appears to be reducing in frequency in most recent rheumatoid arthritis treatment trials. In the context of rheumatoid arthritis interstitial lung disease, methotrexate treatment may be associated with a lower incidence of ILD over time. Methotrexate is teratogenic and it is advised to stop taking it at least four weeks before becoming pregnant and it should be avoided during pregnancy (pregnancy category X) and while breastfeeding. Guidelines have been updated to state that it is safe for a male partner to take at any point while trying to conceive. Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route (directly into the cerebrospinal fluid), which include myelopathies and leukoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses. Another little-understood but serious possible adverse effect of methotrexate is neurological damage and memory loss. Drug interactions Penicillins may decrease the elimination of methotrexate and increase the risk of methotrexate toxicity. Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity. Vaccine interactions Taking methotrexate can reduce the effectiveness of vaccinations against various diseases, such as influenza and hepatitis A. It does this by blunting the immune response of the body to the vaccine. Methotrexate also dampens the immune response to COVID-19 vaccines, making them less effective. Pausing methotrexate for two weeks following COVID-19 vaccination may result in improved immunity. Not taking the medicine for two weeks might result in a minor increase of inflammatory disease flares in some people. ==Mechanism of action==

Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about 1000-fold that of dihydrofolate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. An additional mechanism is the inhibition of the binding of interleukin 1-beta to its cell surface receptor. Image:Methotrexate vs folate.svg|The coenzyme folic acid (top) and the anticancer drug methotrexate (bottom) are very similar in structure. As a result, methotrexate is a competitive inhibitor of many enzymes that use folates.|alt=The chemical structures of folic acid and methotrexate highlighting the differences between these two substances (amidation of pyrimidone and methylation of secondary amine) File:DHFR methotrexate.jpg|Methotrexate (green) complexed into the active site of DHFR (blue) ==History==

In 1947, a team of researchers led by Sidney Farber showed aminopterin, a chemical analogue of folic acid developed by Yellapragada Subbarao of Lederle, could induce remission in children with acute lymphoblastic leukemia. The development of folic acid analogues had been prompted by the discovery that the administration of folic acid worsened leukaemia, 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 analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia. Animal studies published in 1956 showed the therapeutic index of methotrexate was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of methotrexate. In 1951, Jane C. Wright demonstrated the use of methotrexate in solid tumors, showing remission in breast cancer. Wright's group was the first to demonstrate use of the drug in solid tumors, as opposed to leukemias, which are a cancer of the marrow. Min Chiu Li and his collaborators then demonstrated complete remission in women with choriocarcinoma and chorioadenoma in 1956, and in 1960 Wright et al. produced remissions in mycosis fungoides. == References ==