関: Methotrexate

関: methotrexate

WordNet

toxic antimetabolite that limits cellular reproduction by acting as an antagonist to folic acid; used to treat certain cancers and psoriasis and rheumatoid arthritis (同)methotrexate_sodium, amethopterin

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/05/23 10:26:10」(JST)

wiki en

Methotrexate (MTX), formerly known as amethopterin, is an antimetabolite and antifolate drug.^[6]^[7]

It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions.^[8] It acts by inhibiting the metabolism of folic acid via dihydrofolate reductase.^[6]

Methotrexate began to replace the more toxic antifolate aminopterin starting in the 1950s. The drug was originally synthesised by the Indian biochemist Yellapragada Subbarow and clinically developed by the American paediatrician Sidney Farber.^[9]^[10] It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.^[11]

Medical uses

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 a number of cancers including: breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, bladder, and trophoblastic neoplasms.^[8]

Autoimmune disorders

It is used as a disease-modifying treatment for some autoimmune diseases, including rheumatoid arthritis, juvenile dermatomyositis, psoriasis, psoriatic arthritis, lupus, sarcoidosis, Crohn's disease (although a recent review has raised the point that it is fairly underused in Crohn's disease),^[12] eczema and many forms of vasculitis.^[6]^[7] Although originally designed as a chemotherapy drug (using high doses), in low doses methotrexate is a generally safe and well tolerated drug in the treatment of certain autoimmune diseases. Because of its effectiveness, low-dose methotrexate is now first-line therapy for the treatment of rheumatoid arthritis. Weekly doses are beneficial for 12 to 52 weeks duration therapy, although discontinuation rates are as high as 16% due to adverse effects.^[13] Although methotrexate for autoimmune diseases is taken in lower doses than it is for cancer, side effects such as hair loss, nausea, headaches, and skin pigmentation are still common.^[6]^[14]^[15] Use of methotrexate together with NSAIDS is safe, if adequate monitoring is done.^[16]

Not everyone is responsive to treatment with methotrexate, but multiple studies and reviews showed that the majority of people receiving 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.^[17] Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes.^[18] It has also been used for multiple sclerosis.^[8]

Abortion

Methotrexate is an abortifacient and is commonly used to terminate pregnancies during the early stages, generally in combination with misoprostol. It is also used to treat ectopic pregnancies, provided the fallopian tube has not ruptured.^[8]^[19]

Molar pregnancy

Methotrexate with dilatation and curettage is used to treat molar pregnancy.

Administration

Methotrexate can be taken orally or administered by injection (intramuscular, intravenous, subcutaneous, or intrathecal).^[8] Oral doses are usually taken weekly, not daily, to limit toxicity.^[8] Routine monitoring of the complete blood count, liver function tests, and creatinine are recommended.^[8] Measurements of creatinine are recommended at least every 2 months.^[8]

Adverse effects

The most common adverse effects include: hepatotoxicity (liver damage), ulcerative stomatitis, low white blood cell count and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, dizziness, acute pneumonitis, rarely pulmonary fibrosis and kidney failure.^[6]^[8] Methotrexate is teratogenic (harmful to fetus) and hence not used in pregnancy (pregnancy category X).

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 leucoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.^[20]

Another little understood but serious possible adverse effect of methotrexate is neurological damage and memory loss. Neurotoxicity may result from the drug crossing the blood-brain barrier and damaging neurons in the cerebral cortex. Cancer patients who receive the drug often nickname these effects "Chemo brain" or "Chemo fog".^[21]

Drug interactions

Penicillins may decrease the elimination of methotrexate and thus increase the risk of toxicity.^[8] While they may be used together, increased monitoring is recommended.^[8] The aminoglycosides, neomycin and paromomycin, have been found to reduce GI absorption of methotrexate.^[22] Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity.^[22] Likewise retinoids and trimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively.^[22] Other immunosuppressants like ciclosporin may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity.^[22] NSAIDs have also been found to fatally interact with methotrexate in numerous case reports.^[22] Nitrous oxide potentiating the haematological toxicity of methotrexate has also been documented.^[22] Proton-pump inhibitors like omeprazole and the anticonvulsant valproate have been found to increase the plasma concentrations of methotrexate, as have nephrotoxic agents such as cisplatin, the GI drug, colestyramine and dantrolene.^[22] Caffeine may antagonise the effects of methotrexate on rheumatoid arthritis by antagonising the receptors for adenosine.^[4]

Mechanism of action

The coenzyme folic acid (top) and the anti-cancer drug methotrexate (bottom) are very similar in structure. As a result, methotrexate is a competitive inhibitor of many enzymes that use folates.

Methotrexate (green) complexed into the active site of DHFR (blue)

Methotrexate 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.^[23]^[24] The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate.^[23] Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis.^[23] Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.^[23]

For the treatment of rheumatoid arthritis, inhibition of DHFR is not thought to be the main mechanism, but rather multiple mechanisms appear to be involved including: the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine; inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells; selective down-regulation of B cells; increasing CD95 sensitivity of activated T cells; inhibition of methyltransferase activity, leading to (de)-activation of enzyme activity relevant to immune system function.^[25]^[26] Another mechanism of MTX is the inhibition of the binding of interleukin 1-beta to its cell surface receptor.^[27]

History

Image shows open bottle of methotrexate drug—one of the first chemotherapeutic drugs used in the early 1950s

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 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.^[28]Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia.^[29] 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.^[30] Wright's group were 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,^[31] and in 1960 Wright et al. produced remissions in mycosis fungoides.^[32]^[33]

References

^ "methotrexate - definition of methotrexate in English from the Oxford dictionary". OxfordDictionaries.com. Retrieved 2016-01-20.
^ "methotrexate". Merriam-Webster Dictionary.
^ "methotrexate". Dictionary.com Unabridged. Random House.
^ ^a ^b ^c ^d ^e ^f "Trexall, Rheumatrex (methotrexate) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 12 April 2014.
^ ^a ^b Bannwarth, B; Labat, L; Moride, Y; Schaeverbeke, T (January 1994). "Methotrexate in rheumatoid arthritis. An update.". Drugs 47 (1): 25–50. doi:10.2165/00003495-199447010-00003. PMID 7510620.
^ ^a ^b ^c ^d ^e Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
^ ^a ^b Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k "Methotrexate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
^ Mukherjee, S (16 November 2010). The Emperor of All Maladies: A Biography of Cancer. Simon and Schuster. ISBN 978-1-4391-0795-9.
^ Miller, DR (July 2006), "A tribute to Sidney Farber – the father of modern chemotherapy", British Journal of Haematology 134 (1): 20–26, doi:10.1111/j.1365-2141.2006.06119.x, PMID 16803563
^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ Herfarth HH, Long MD, Isaacs KL (2012). "Methotrexate: underused and ignored?". Digestive Diseases. 30 Suppl 3: 112–8. doi:10.1159/000342735. PMID 23295701.
^ Lopez-Olivo, MA (2014). "Methotrexate for treating rheumatoid arthritis". Cochrane Database of Systematic Reviews (6): Art. No.: CD000957. doi:10.1002/14651858.CD000957.pub2. Retrieved 18 October 2014.
^ Cronstein, B. N. (2005). "Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis". Pharmacological Reviews 57 (2): 163–172. doi:10.1124/pr.57.2.3. PMID 15914465.
^ American , Rheumatoid Arthritis Guidelines (2002). "Guidelines for the management of rheumatoid arthritis: 2002 update". Arthritis Rheum 46: 328–346. doi:10.1002/art.10148.
^ Colebatch, AN (2011). "Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD008872.pub2.
^ Weinblatt, ME (2013). "Methotrexate in rheumatoid arthritis: a quarter century of development." (PDF). Transactions of the American Clinical and Climatological Association 124: 16–25. PMC 3715949. PMID 23874006.
^ Marks JL, Edwards CJ (2 February 2012). "Protective effect of methotrexate in patients with rheumatoid arthritis and cardiovascular comorbidity" (PDF). Therapeutic Advances in Musculoskeletal Disease 4 (3): 149–157. doi:10.1177/1759720X11436239. PMC 3400102. PMID 22850632.
^ Mol, F.; Mol, B.W.; Ankum, W.M.; Van Der Veen, F.; Hajenius, P.J. (2008). "Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis". Human Reproduction Update 14 (4): 309–19. doi:10.1093/humupd/dmn012. PMID 18522946.
^ Scheinfeld, N (2006). "Three cases of toxic skin eruptions associated with methotrexate and a compilation of methotrexate-induced skin eruptions". Dermatology online journal 12 (7): 15. PMID 17459301.
^ Hafner, D (2009). "Lost in the Fog: Understanding "Chemo Brain"". Nursing 2009 39 (8): 42–45. doi:10.1097/01.nurse.0000358574.56241.2f.
^ ^a ^b ^c ^d ^e ^f ^g Brayfield, A, ed. (6 January 2014). "Methotrexate". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014.
^ ^a ^b ^c ^d Rajagopalan, P. T. Ravi; Zhang, Zhiquan; McCourt, Lynn; Dwyer, Mary; Benkovic, Stephen J.; Hammes, Gordon G. (2002). "Interaction of dihydrofolate reductase with methotrexate: Ensemble and single-molecule kinetics". Proceedings of the National Academy of Sciences 99 (21): 13481–6. doi:10.1073/pnas.172501499. PMC 129699. PMID 12359872.
^ Goodsell DS (August 1999). "The Molecular Perspective: Methotrexate". The Oncologist 4 (4): 340–341. PMID 10476546.
^ Wessels, JA; Huizinga, TW; Guchelaar, HJ (March 2008). "Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis." (PDF). Rheumatology 47 (3): 249–55. doi:10.1093/rheumatology/kem279. PMID 18045808.
^ Böhm I. Increased peripheral blood B-cells expressing the CD5 molecules in association to autoantibodies in patients with lupus erythematosus and evidence to selectively down-modulate them. Biomed & Pharmacother 2004;58:338 - 343
^ Brody M et al. Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. Eur J Clin Chem Clin Biochem. 1993;31(10):667-74
^ Bertino JR (2000). "Methotrexate: historical aspects". In Cronstein BN, Bertino JR. Methotrexate. Basel: Birkhäuser. ISBN 978-3-7643-5959-1. Retrieved November 21, 2009. ^{[page needed]}
^ Meyer, Leo M.; Miller, Franklin R.; Rowen, Manuel J.; Bock, George; Rutzky, Julius (1950). "Treatment of Acute Leukemia with Amethopterin (4-amino, 10-methyl pteroyl glutamic acid)". Acta Haematologica 4 (3): 157–67. doi:10.1159/000203749. PMID 14777272.
^ Wright, Jane C.; Prigot, A.; Wright, B.P.; Weintraub, S; Wright, LT (1951). "An evaluation of folic acid antagonists in adults with neoplastic diseases. A study of 93 patients with incurable neoplasms". J Natl Med Assoc 43 (4): 211–240. PMC 2616951. PMID 14850976.
^ Li, MC; Li, R; Spencer, DB (1956). "Effect of methotrexate upon choriocarcinoma". Proc Soc Exp Biol Med 93 (2): 361–366. doi:10.3181/00379727-93-22757. PMID 13379512.
^ Wright, JC; Gumport, SL; Golomb, FM (1960). "Remissions produced with the use of methotrexate in patients with mycosis fungoides". Cancer Chemother Rep 9: 11–20. PMID 13786791.
^ Wright, JC; Lyons, M; Walker, DG; Golomb, FM; Gumport, SL; Medrek, TJ (1964). "Observations on the use of cancer chemotherapeutic agents in patients with mycosis fungoides". Cancer 17 (8): 1045–1062. doi:10.1002/1097-0142(196408)17:8<1045::AID-CNCR2820170811>3.0.CO;2-S. PMID 14202592.

External links

National Rheumatoid Arthritis Society (NRAS) article on Methotrexate
Chembank entry on methotrexate
Methotrexate—general article from NIH
Methotrexate Injection MedlinePlus article from NIH
Patient Education - Methotrexate from American College of Rheumatology
U.S. National Library of Medicine: Drug Information Portal - Methotrexate

English Journal

Removal of the anti-cancer drug methotrexate from water by advanced oxidation processes: Aerobic biodegradation and toxicity studies after treatment.

Lutterbeck CA1, Baginska E2, Machado ÊL3, Kümmerer K4.
Chemosphere.Chemosphere.2015 Dec;141:290-6. doi: 10.1016/j.chemosphere.2015.07.069. Epub 2015 Aug 27.
Anti-cancer drugs are discussed as high risk substances in regard to human health and considered as problematic for the environment. They are of potential environmental relevance due to their poor biodegradability and toxicological properties. Methotrexate (MTX) is an antimetabolite that was introdu
PMID 26298026

Advances in Primary Central Nervous System Lymphoma.

Patrick LB1, Mohile NA2,3.
Current oncology reports.Curr Oncol Rep.2015 Dec;17(12):60. doi: 10.1007/s11912-015-0483-8.
Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma that is limited to the CNS. Although novel imaging techniques aid in discriminating lymphoma from other brain tumors, definitive diagnosis requires brain biopsy, vitreoretinal biopsy, or cerebrospinal fluid analys
PMID 26475775

Risk Factors, Pattern and Clinical Outcome of Acute Graft Versus Host Disease in Acute Leukemia Patients Undergoing Allogeneic Stem Cell Transplant.

Gupta A1, Punatar S1, Gawande J1, Mathew L1, Bagal B1, Kannan S2, Khattry N1.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion.Indian J Hematol Blood Transfus.2015 Dec;31(4):404-12. doi: 10.1007/s12288-014-0499-5. Epub 2015 Jan 7.
We sought to determine risk factors, pattern and outcome of acute graft versus host disease (aGVHD) in seventy-seven acute leukemia patients who underwent allogeneic stem cell transplant at our centre from January 2008 to March 2013. GVHD prophylaxis with cyclosporine-methotrexate or cyclosporine-my
PMID 26306063

Japanese Journal

Stereoselective Recognition of Amethopterin Enantiomers by the Rat Proton-Coupled Folate Transporter

Biological and Pharmaceutical Bulletin 38(4), 545-551, 2015
NAID 130005062275

Stereoselective Transport of Human His27- and Arg27-Reduced Folate Carrier

Biological and Pharmaceutical Bulletin 37(3), 439-446, 2014
NAID 130003390949

Stereoselective Transport of Amethopterin Enantiomers by the Proton-coupled Folate Transporter

Drug metabolism and pharmacokinetics 25(3), 283-289, 2010-06-25
NAID 10027582937

Related Pictures

Amethopterin - TerritorioScuola Amethopterin hydrate, 99%, ACROS AMETHOPTERIN HYDRATE, 95 | 6745-93-3 The Effect of L-carnitine on Amethopterin Methotrexate (Amethopterin; MTX) - patient Generic Amethopterin Emthexate Rheumatrex

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Methotrexate
Systematic (IUPAC) name
	(2S)-2-[(4-{[(2,4-Diaminopteridin-6-yl)methyl](methyl)amino}benzoyl)amino]pentanedioic acid
Clinical data
Pronunciation	i/ˌmɛθəˈtrɛkˌseɪt, ˌmiː-, -θoʊ-/
Trade names	Trexall, Rheumatrex
AHFS/Drugs.com	monograph
MedlinePlus	a682019
License	US FDA: Methotrexate;
Pregnancy	AU: D; US: X Contraindicated; ;
Administration	oral, IV, IM, SC, intrathecal
Legal status
Legal status	AU: S4 Prescription only; CA: ℞-only; UK: POM Prescription only; US: ℞-only; ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	60% at lower doses, less at higher doses.
Protein binding	35–50% (parent drug), 91–93% (7-hydroxymethotrexate)
Metabolism	Hepatic and intracellular
Biological half-life	3–10 hours (lower doses), 8–15 hours (higher doses)
Excretion	Urine (80–100%), faeces (small amounts)
Identifiers
CASRN	59-05-2
ATC code	L01BA01 (WHO) L04AX03 (WHO)
PubChem	CID 126941
IUPHAR/BPS	4815
DrugBank	DB00563
ChemSpider	112728
UNII	YL5FZ2Y5U1
KEGG	D00142
ChEBI	CHEBI:44185
ChEMBL	CHEMBL34259
Chemical data
Formula	C20H22N8O5
Molar mass	454.44 g/mol
	SMILES O=C([C@H](CCC(O)=O)NC(C1=CC=C(N(CC2=CN=C(N=C(N)N=C3N)C3=N2)C)C=C1)=O)O ;
	InChI InChI=1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1 ; Key:FBOZXECLQNJBKD-ZDUSSCGKSA-N ;
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英: [[]]
同: amethopterin
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同: amethopterin

[1] "methotrexate - definition of methotrexate in English from the Oxford dictionary". OxfordDictionaries.com. Retrieved 2016-01-20.

[2] "methotrexate". Merriam-Webster Dictionary.

[3] "methotrexate". Dictionary.com Unabridged. Random House.

[MSR-4] ^ ^a ^b ^c ^d ^e ^f "Trexall, Rheumatrex (methotrexate) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 12 April 2014.

[drugs94-5] Bannwarth, B; Labat, L; Moride, Y; Schaeverbeke, T (January 1994). "Methotrexate in rheumatoid arthritis. An update.". Drugs 47 (1): 25–50. doi:10.2165/00003495-199447010-00003. PMID 7510620.

[AMH-6] Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.

[BNF-7] Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.

[AHFS-8] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k "Methotrexate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.

[9] Mukherjee, S (16 November 2010). The Emperor of All Maladies: A Biography of Cancer. Simon and Schuster. ISBN 978-1-4391-0795-9.

[10] Miller, DR (July 2006), "A tribute to Sidney Farber – the father of modern chemotherapy", British Journal of Haematology 134 (1): 20–26, doi:10.1111/j.1365-2141.2006.06119.x, PMID 16803563

[11] "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.

[12] Herfarth HH, Long MD, Isaacs KL (2012). "Methotrexate: underused and ignored?". Digestive Diseases. 30 Suppl 3: 112–8. doi:10.1159/000342735. PMID 23295701.

[13] Lopez-Olivo, MA (2014). "Methotrexate for treating rheumatoid arthritis". Cochrane Database of Systematic Reviews (6): Art. No.: CD000957. doi:10.1002/14651858.CD000957.pub2. Retrieved 18 October 2014.

[14] Cronstein, B. N. (2005). "Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis". Pharmacological Reviews 57 (2): 163–172. doi:10.1124/pr.57.2.3. PMID 15914465.

[15] American , Rheumatoid Arthritis Guidelines (2002). "Guidelines for the management of rheumatoid arthritis: 2002 update". Arthritis Rheum 46: 328–346. doi:10.1002/art.10148.

[16] Colebatch, AN (2011). "Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD008872.pub2.

[17] Weinblatt, ME (2013). "Methotrexate in rheumatoid arthritis: a quarter century of development." (PDF). Transactions of the American Clinical and Climatological Association 124: 16–25. PMC 3715949. PMID 23874006.

[18] Marks JL, Edwards CJ (2 February 2012). "Protective effect of methotrexate in patients with rheumatoid arthritis and cardiovascular comorbidity" (PDF). Therapeutic Advances in Musculoskeletal Disease 4 (3): 149–157. doi:10.1177/1759720X11436239. PMC 3400102. PMID 22850632.

[pmid18522946-19] Mol, F.; Mol, B.W.; Ankum, W.M.; Van Der Veen, F.; Hajenius, P.J. (2008). "Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis". Human Reproduction Update 14 (4): 309–19. doi:10.1093/humupd/dmn012. PMID 18522946.

[20] Scheinfeld, N (2006). "Three cases of toxic skin eruptions associated with methotrexate and a compilation of methotrexate-induced skin eruptions". Dermatology online journal 12 (7): 15. PMID 17459301.

[21] Hafner, D (2009). "Lost in the Fog: Understanding "Chemo Brain"". Nursing 2009 39 (8): 42–45. doi:10.1097/01.nurse.0000358574.56241.2f.

[MD-22] ^ ^a ^b ^c ^d ^e ^f ^g Brayfield, A, ed. (6 January 2014). "Methotrexate". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014.

[Raja-23] Rajagopalan, P. T. Ravi; Zhang, Zhiquan; McCourt, Lynn; Dwyer, Mary; Benkovic, Stephen J.; Hammes, Gordon G. (2002). "Interaction of dihydrofolate reductase with methotrexate: Ensemble and single-molecule kinetics". Proceedings of the National Academy of Sciences 99 (21): 13481–6. doi:10.1073/pnas.172501499. PMC 129699. PMID 12359872.

[Goodsell-24] Goodsell DS (August 1999). "The Molecular Perspective: Methotrexate". The Oncologist 4 (4): 340–341. PMID 10476546.

[25] Wessels, JA; Huizinga, TW; Guchelaar, HJ (March 2008). "Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis." (PDF). Rheumatology 47 (3): 249–55. doi:10.1093/rheumatology/kem279. PMID 18045808.

[26] Böhm I. Increased peripheral blood B-cells expressing the CD5 molecules in association to autoantibodies in patients with lupus erythematosus and evidence to selectively down-modulate them. Biomed & Pharmacother 2004;58:338 - 343

[27] Brody M et al. Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. Eur J Clin Chem Clin Biochem. 1993;31(10):667-74

[Bertino2000-28] Bertino JR (2000). "Methotrexate: historical aspects". In Cronstein BN, Bertino JR. Methotrexate. Basel: Birkhäuser. ISBN 978-3-7643-5959-1. Retrieved November 21, 2009. ^{[page needed]}

[29] Meyer, Leo M.; Miller, Franklin R.; Rowen, Manuel J.; Bock, George; Rutzky, Julius (1950). "Treatment of Acute Leukemia with Amethopterin (4-amino, 10-methyl pteroyl glutamic acid)". Acta Haematologica 4 (3): 157–67. doi:10.1159/000203749. PMID 14777272.

[30] Wright, Jane C.; Prigot, A.; Wright, B.P.; Weintraub, S; Wright, LT (1951). "An evaluation of folic acid antagonists in adults with neoplastic diseases. A study of 93 patients with incurable neoplasms". J Natl Med Assoc 43 (4): 211–240. PMC 2616951. PMID 14850976.

[31] Li, MC; Li, R; Spencer, DB (1956). "Effect of methotrexate upon choriocarcinoma". Proc Soc Exp Biol Med 93 (2): 361–366. doi:10.3181/00379727-93-22757. PMID 13379512.

[32] Wright, JC; Gumport, SL; Golomb, FM (1960). "Remissions produced with the use of methotrexate in patients with mycosis fungoides". Cancer Chemother Rep 9: 11–20. PMID 13786791.

[33] Wright, JC; Lyons, M; Walker, DG; Golomb, FM; Gumport, SL; Medrek, TJ (1964). "Observations on the use of cancer chemotherapeutic agents in patients with mycosis fungoides". Cancer 17 (8): 1045–1062. doi:10.1002/1097-0142(196408)17:8<1045::AID-CNCR2820170811>3.0.CO;2-S. PMID 14202592.

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