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===Autoimmune disorders===
===Autoimmune disorders===
It is used as a treatment for some [[autoimmune diseases]], including [[rheumatoid arthritis]], [[juvenile dermatomyositis]], [[psoriasis]], [[psoriatic arthritis]], [[systemic lupus erythematosus|lupus]], [[sarcoidosis]], [[Crohn's disease]] (although a recent review has raised the point that it is fairly underused in Crohn's disease<ref>{{cite journal | author = Herfarth HH, Long MD, Isaacs KL | title = Methotrexate: underused and ignored? | journal = Digestive Diseases | volume = 30 Suppl 3 | pages = 112–8 | year = 2012 | pmid = 23295701 | doi = 10.1159/000342735 }}</ref>), [[eczema]] and many forms of [[vasculitis]].<ref name = AMH/><ref name = BNF>{{cite book | last1 = Joint Formulary Committee | first1 = | last2 = | first2 = | last3 = | first3 = | title = British National Formulary (BNF) | language = | volume = | year = 2013 | url = | isbn = 978-0-85711-084-8 | editor1-last = | edition = 65 | editor1-first = | oclc = | editor2-link = | location = London, UK | series = | chapter = | editor3-last = | trans_title = | quote = | orig-year = | editor2-last = | editor3-first = | authorlink1 = | authorlink2 = | authorlink3 = | publisher = Pharmaceutical Press | editor3-link = | work = | editor2-first = | editor1-link = }}</ref> 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. 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.<ref name = AMH>{{cite book | title = Australian Medicines Handbook | year = 2013 | publisher = The Australian Medicines Handbook Unit Trust | isbn = 978-0-9805790-9-3 | edition = 2013 | place = Adelaide | editor = Rossi, S }}</ref><ref>{{cite journal | last1 = Cronstein | first1 = B. N. | title = Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis | journal = Pharmacological Reviews | volume = 57 | issue = 2 | pages = 163–172 | year = 2005 | pmid = 15914465 | doi = 10.1124/pr.57.2.3 }}</ref><ref>American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines (2002) Guidelines for the management of rheumatoid arthritis: 2002 update. ''Arthritis Rheum'' 46: 328-346.</ref> 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.<ref>{{cite journal|last=Weinblatt|first=ME|title=Methotrexate in rheumatoid arthritis: a quarter century of development.|journal=Transactions of the American Clinical and Climatological Association|year=2013|volume=124|pages=16–25|pmid=23874006|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715949/pdf/tacca124000016.pdf|format=PDF|pmc=3715949}}</ref> 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]].<ref>{{cite journal | author = Marks JL, Edwards CJ | title = Protective effect of methotrexate in patients with rheumatoid arthritis and cardiovascular comorbidity | journal = Therapeutic Advances in Musculoskeletal Disease | volume = 4 | issue = 3 | pages = 149–157 | date = 2 February 2012 | pmid = 22850632 | pmc = 3400102 | doi = 10.1177/1759720X11436239 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400102/pdf/10.1177_1759720X11436239.pdf | format = PDF }}</ref> It has also been used for [[multiple sclerosis]], but is not approved for this use by the U.S. [[Food and Drug Administration]].<ref name=AHFS/>
It is used as a treatment for some [[autoimmune diseases]], including [[rheumatoid arthritis]], [[juvenile dermatomyositis]], [[psoriasis]], [[psoriatic arthritis]], [[systemic lupus erythematosus|lupus]], [[sarcoidosis]], [[Crohn's disease]] (although a recent review has raised the point that it is fairly underused in Crohn's disease<ref>{{cite journal | author = Herfarth HH, Long MD, Isaacs KL | title = Methotrexate: underused and ignored? | journal = Digestive Diseases | volume = 30 Suppl 3 | pages = 112–8 | year = 2012 | pmid = 23295701 | doi = 10.1159/000342735 }}</ref>), [[eczema]] and many forms of [[vasculitis]].<ref name = AMH/><ref name = BNF>{{cite book | last1 = Joint Formulary Committee | first1 = | last2 = | first2 = | last3 = | first3 = | title = British National Formulary (BNF) | language = | volume = | year = 2013 | url = | isbn = 978-0-85711-084-8 | editor1-last = | edition = 65 | editor1-first = | oclc = | editor2-link = | location = London, UK | series = | chapter = | editor3-last = | trans_title = | quote = | orig-year = | editor2-last = | editor3-first = | authorlink1 = | authorlink2 = | authorlink3 = | publisher = Pharmaceutical Press | editor3-link = | work = | editor2-first = | editor1-link = }}</ref> 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 between 5mg and 25mg is beneficial for 12 to 52 weeks duration therapy although discontinuation rates are as high as 16% due to adverse effects.<ref>{{cite journal|last1=Lopez-Olivo|first1=MA|title=Methotrexate for treating rheumatoid arthritis|journal=Cochrane Database of Systematic Reviews|date=2014|issue=6|page=Art. No.: CD000957.|doi=10.1002/14651858.CD000957.pub2.|url=http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000957.pub2/abstract|accessdate=18 October 2014}}</ref> 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.<ref name = AMH>{{cite book | title = Australian Medicines Handbook | year = 2013 | publisher = The Australian Medicines Handbook Unit Trust | isbn = 978-0-9805790-9-3 | edition = 2013 | place = Adelaide | editor = Rossi, S }}</ref><ref>{{cite journal | last1 = Cronstein | first1 = B. N. | title = Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis | journal = Pharmacological Reviews | volume = 57 | issue = 2 | pages = 163–172 | year = 2005 | pmid = 15914465 | doi = 10.1124/pr.57.2.3 }}</ref><ref>American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines (2002) Guidelines for the management of rheumatoid arthritis: 2002 update. ''Arthritis Rheum'' 46: 328-346.</ref> 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.<ref>{{cite journal|last=Weinblatt|first=ME|title=Methotrexate in rheumatoid arthritis: a quarter century of development.|journal=Transactions of the American Clinical and Climatological Association|year=2013|volume=124|pages=16–25|pmid=23874006|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715949/pdf/tacca124000016.pdf|format=PDF|pmc=3715949}}</ref> 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]].<ref>{{cite journal | author = Marks JL, Edwards CJ | title = Protective effect of methotrexate in patients with rheumatoid arthritis and cardiovascular comorbidity | journal = Therapeutic Advances in Musculoskeletal Disease | volume = 4 | issue = 3 | pages = 149–157 | date = 2 February 2012 | pmid = 22850632 | pmc = 3400102 | doi = 10.1177/1759720X11436239 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400102/pdf/10.1177_1759720X11436239.pdf | format = PDF }}</ref> It has also been used for [[multiple sclerosis]], but is not approved for this use by the U.S. [[Food and Drug Administration]].<ref name=AHFS/>


===Abortion===
===Abortion===

Revision as of 18:00, 18 October 2014

"Amethopterin" redirects here. For Not to be confused with aminopterin, see Amethopterin (disambiguation).

{{Drugbox | Watchedfields = changed | verifiedrevid = 464193974 | IUPAC_name = (2S)-2-[(4-{[(2,4-Diaminopteridin-6-yl)methyl](methyl)amino}benzoyl)amino]pentanedioic acid | image = Methotrexate skeletal.svg | width = 320 | image2 = Methotrexate3DanBS.gif | width2 = 230

| tradename = Trexall | Drugs.com = Monograph | MedlinePlus = a682019 | licence_US = Methotrexate | pregnancy_AU = D | pregnancy_US = X | legal_AU = S4 | legal_CA = Rx-only | legal_UK = POM | legal_US = Rx-only | routes_of_administration = oral, IV, IM, SC, intrathecal

| bioavailability = 60% at lower doses, less at higher doses.[1] | protein_bound = 35-50% (parent drug),[1] 91-93% (7-hydroxymethotrexate)[2] | metabolism = Hepatic and intracellular[1] | elimination_half-life = 3-10 hours (lower doses), 8-15 hours (higher doses)[1] | excretion = Urine (80-100%), faeces (small amounts)[1][2]

| CASNo_Ref =  checkY | CAS_number_Ref =  checkY | CAS_number = 59-05-2 | ATC_prefix = L01 | ATC_suffix = BA01 | ATC_supplemental = L04AX03 (WHO) | PubChem = 126941 | DrugBank_Ref =  checkY | DrugBank = DB00563 | ChemSpiderID_Ref =  checkY | ChemSpiderID = 112728 | UNII_Ref =  checkY | UNII = YL5FZ2Y5U1 | KEGG_Ref =  checkY | KEGG = D00142 | ChEBI_Ref =  checkY | ChEBI = 44185 | ChEMBL_Ref =  checkY | ChEMBL = 34259

| C=20 | H=22 | N=8 | O=5 | molecular_weight = 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 = 1/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 | StdInChI_Ref =  checkY | StdInChI = 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 | StdInChIKey_Ref =  checkY | StdInChIKey = FBOZXECLQNJBKD-ZDUSSCGKSA-N }} Methotrexate (INN, AAN, BAN and USAN) /mɛθ[invalid input: 'ɵ']ˈtrɛkseɪt/, abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug.[3][4] It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions.[5] It acts by inhibiting the metabolism of folic acid.[3] 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.[6][7]

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.[8]

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.[5]

Autoimmune disorders

It is used as a 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[9]), eczema and many forms of vasculitis.[3][4] 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 between 5mg and 25mg is beneficial for 12 to 52 weeks duration therapy although discontinuation rates are as high as 16% due to adverse effects.[10] 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.[3][11][12] 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.[13] 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.[14] It has also been used for multiple sclerosis, but is not approved for this use by the U.S. Food and Drug Administration.[5]

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.[5][15]

Administration

Methotrexate can be taken orally or administered by injection (intramuscular, intravenous, subcutaneous, or intrathecal).[5] Oral doses are taken weekly, not daily, to limit toxicity.[5] Routine monitoring of the complete blood count, liver function tests, and creatinine are recommended.[5] Measurements of creatinine are recommended at least every 2 months.[5]

Adverse effects

The most common adverse effects include: 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.[3][5]

Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route, which include myelopathies and leucoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.[16]

Drug interactions

Penicillins may decrease the elimination of methotrexate and thus increase the risk of toxicity.[5] While they may be used together increased monitoring is recommended.[5] The aminoglycosides, neomycin and paromomycin, have been found to reduce GI absorption of methotrexate.[17] Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity.[17] Likewise retinoids and trimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively.[17] Other immunosuppressants like ciclosporin may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity.[17] NSAIDs have also been found to fatally interact with methotrexate in numerous case reports.[17] Nitrous oxide potentiating the haematological toxicity of methotrexate has also been documented.[17] 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.[17] Caffeine may antagonise the effects methotrexate on rheumatoid arthritis by antagonising the receptors for adenosine.[1]

Mechanism of action

The similar structure of dihydrofolic acid and methotrexate suggests that methotrexate is a competitive inhibitor
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.[18][19] The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate.[18] Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis.[18] 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.[18]

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; increasing CD95 sensitivity of activated T cells; inhibition of methyltransferase activity, leading to (de)-activation of enzyme activity relevant to immune system function.[20]

History

See also: History of cancer chemotherapy
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 Subbarow 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.[21] Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia.[22] 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.[23] 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 et al. then demonstrated complete remission in women with choriocarcinoma and chorioadenoma in 1956,[24] and in 1960 Wright et al. produced remissions in mycosis fungoides.[25][26]

References

  1. ^ a b c d e f "Trexall, Rheumatrex (methotrexate) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 12 April 2014.
  2. ^ 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.
  3. ^ 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.
  4. ^ a b Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. {{cite book}}: Cite has empty unknown parameter: |trans_title= (help)
  5. ^ a b c d e f g h i j k "Methotrexate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  6. ^ Mukherjee, S (16 November 2010). The Emperor of All Maladies: A Biography of Cancer. Simon and Schuster. ISBN 978-1-4391-0795-9.
  7. ^ 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
  8. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  9. ^ Herfarth HH, Long MD, Isaacs KL (2012). "Methotrexate: underused and ignored?". Digestive Diseases. 30 Suppl 3: 112–8. doi:10.1159/000342735. PMID 23295701.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ 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. {{cite journal}}: Check |doi= value (help)
  11. ^ 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.
  12. ^ American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines (2002) Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 46: 328-346.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ Goodsell DS (August 1999). "The Molecular Perspective: Methotrexate". The Oncologist. 4 (4): 340–341. PMID 10476546.
  20. ^ 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.
  21. ^ Bertino JR (2000). "Methotrexate: historical aspects". Methotrexate. Basel: Birkhäuser. ISBN 978-3-7643-5959-1. Retrieved November 21, 2009. {{cite book}}: Unknown parameter |editors= ignored (|editor= suggested) (help)[page needed]
  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
  26. ^ 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

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