METHOTREXATE
Methotrexate
is another antimetabolite that has beneficial effects in a number of chronic
inflammatory diseases, including Crohn’s disease and rheumatoid arthritis , and
in cancer . Methotrexate may be given orally, subcutaneously, or
intramuscularly. Reported oral bioavailabil-ity is 50–90% at doses used in
chronic inflammatory diseases. Intramuscular and subcutaneous methotrexate
exhibit nearly complete bioavailability.
The principal
mechanism of action is inhibition of dihydrofolate reductase, an enzyme
important in the production of thymidine and purines. At the high doses used
for chemotherapy, methotrexate inhibits cellular proliferation. However, at the
low doses used in the treatment of inflammatory bowel disease (12–25 mg/wk),
the anti-proliferative effects may not be evident. Methotrexate may inter-fere
with the inflammatory actions of interleukin-1. It may also stimulate increased
release of adenosine, an endogenous anti-inflammatory autacoid. Methotrexate
may also stimulate apopto-sis and death of activated T lymphocytes.
Methotrexate
is used to induce and maintain remission in patients with Crohn’s disease. Its
efficacy in ulcerative colitis is uncertain. To induce remission, patients are
treated with 15–25 mg of methotrexate once weekly by subcutaneous injection. If
a satisfac-tory response is achieved within 8–12 weeks, the dose is reduced to
15 mg/wk.
At
higher dosage, methotrexate may cause bone marrow depres-sion, megaloblastic
anemia, alopecia, and mucositis. At the doses used in the treatment of
inflammatory bowel disease, these events are uncommon but warrant dose
reduction if they do occur. Folate supplementation reduces the risk of these
events without impair-ing the anti-inflammatory action.
In patients with
psoriasis treated with methotrexate, hepatic damage is common; however, among
patients with inflammatory bowel disease and rheumatoid arthritis, the risk is
significantly lower. Renal insufficiency may increase risk of hepatic
accumula-tion and toxicity.
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