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Methotrexate

Methotrexate (abbreviated MTX; formerly known as amethopterin) is an antimetabolite drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. more...

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History

Methotrexate originated in the 1940s when Sidney Farber at Children's Hospital Boston was testing the effects of folic acid on cancer. That inspired chemists at the drug company Lederle to start looking for antimetabolites resembling folic. The result was methotrexate, which was developed in 1948. Methotrexate gained FDA approval as an oncology drug in 1953.

Uses

Methotrexate was originally used, as part of combination chemotherapy regimens, to treat many kinds of cancers. It is still the mainstay for the treatment of many neoplastic disorders including acute lymphoblastic leukemia.

More recently it has come into use as a treatment for some autoimmune diseases, including psoriasis, psoriatic arthritis, rheumatoid arthritis (see disease-modifying antirheumatic drugs), and Crohn's disease. In the case of rheumatoid arthritis, parallel use with infliximab or etanercept has been shown to markedly improve symptoms. (Klareskog, et al., 2004)

Although not licensed for this indication, methotrexate is also sometimes used (generally in combination with misoprostol) to terminate early pregnancies, particularly ectopic pregnancies.

It can be taken orally or administered by injection (intramuscular, intravenous or intrathecal). Although daily preparations are occasionally used, most patients take weekly doses, which decreases the risk of certain side-effects.

Adverse effects

Possible side effects can include anemia, neutropenia, increased risk of bruising, and nausea. A small percentage of patients develop hepatitis, while there is an increased risk of pulmonary fibrosis.

The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed methotrexate "rescue") by using folinic acid supplements (not to be confused with folic acid).

Methotrexate is a highly teratogenic drug and categorized in Pregnancy Category X by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.

There is a risk of a severe adverse reaction if penicillin is prescribed alongside methotrexate.

Mode of action

Methotrexate competetively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that is part of the folate synthesis metabolic pathway. The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR. Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.

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Long-term tolerance of methotrexate administered as a steroid sparing agent for bronchial asthma: twelve years of experience
From CHEST, 10/1/05 by Amalia Moreno

PURPOSE: To evaluate the long-term tolerance of methotrexate (MTX) administered in a cohort of steroid-dependent asthmatic patients.

METHODS: Type of study: prospective, observational. Population: patients treated from 1992 to 2004 in our asthma clinic for steroid-dependent asthma (requirement of at least 7.5 nag per day of prednisolone for [greater than or equal to] than one year). Treatment: 10 mg per week of oral MTX + one weekly dose of folic acid the day after MTX intake. Instrumentation: blood analysis were performed at every three months including leukocyte differential count, CD4 and CD8 level, renal and hepatic function, immunoglobulin level (including IgG subclasses); sputum culture when infection and at the end of the follow-up; hepatic ultrasonography when an accumulated dose of 1,500 mg was reached or whenever hepatic function was altered.

RESULTS: 45 patients have been followed for a mean period of 91.3 [+ or -] 39.5 months (range 12-144). The mean accumulated dose of MTX was: 3,499 [+ or -] 2,207 mg (range: 470- 7,125). Hematology at entry: Leukocyte: 9,046 [+ or -] 2,470/mm3; CD4: 49.3 [+ or -] 7.1%; CD8: 25.0 [+ or -] 8%; Hct: 40.6 [+ or -]5.2%; Platelet count: 258,543 [+ or -]73,761/mm3; Mean Corpuscular Volume: 89.1 [+ or -] 3.9fL; GOT: 19 [+ or -] 7 U/L; IgA: 214+-113; IgM: 128 [+ or -] 90; IgE: 156 [+ or -] 331; IgG: 882 [+ or -] 344; IgG1: 554 [+ or -] 274; IgG2: 279 [+ or -] 133; IgG3: 69 [+ or -] 58; IgG4:24 [+ or -] 26 (mg/dL). No statistically significant changes were found during the follow-up. Side-effects: 4 patients showed mild elevation of hepatic enzymes that normalized after drug suppression (MTX could be reintroduced and ultrasonography was normal), one alopecia and one asthma. None sputum culture evidenced infection of Aspergillus, Nocardia or Pneumocystis.

CONCLUSION: 1) The concomitant administration of folic acid avoids macrocytic anemia. 2) Liver function should be monitored although seems to be infrequently affected. 3) After liver function recoveries, MTX can be reintroduced safely. 4) Immunity is not affected.

CLINICAL IMPLICATIONS: 1) Long-term administration of a low-weekly dose of MTX is safe. 2) The accumulated dose of 1,500 mg is not a therapeutic limitation.

DISCLOSURE: Christian Domingo, None.

Amalia Moreno MD Christian Domingo MD * Ricard Comet MD Manel Lujan MD Miguel Gallego MD Elisa Canturri MD Ana Galera RN Albert Marin MD Corporacio Parc Tauli, Sabadell, Spain

COPYRIGHT 2005 American College of Chest Physicians
COPYRIGHT 2005 Gale Group

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