Mucositis methotrexate

The rapidly proliferating cells of the GI tract make them susceptible to the effects of chemotherapy. Mucositis is the inflamed, ulcerated mucosa of the mouth, esophagus, and lower GI tract that may result in infection and pain with subsequent decreased fluid and nutritional intake. Methotrexate, 5-FU, etoposide, and doxorubicin are the chemotherapy agents most commonly associated with mucositis. Patients should be instructed on good oral mouth care and use saline rinses several... 

There are certain histologic subtypes of diffuse, aggressive NHL that respond less well to treatment with conventional regimens such as CHOP. Burkitt s lymphoma, lymphoblastic lymphoma, mantel cell lymphoma, and primary CNS lymphoma are examples of disease that benefit from more intensive therapy. Regimens such as hyper-CVAD, which alternate cycles of hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone with high-dose cytarabine and methotrexate, often are substituted for CHOP. Intrathecal therapy with methotrexate is indicated with documented CNS infiltration of tumor or involvement of the sinuses. The recent appreciation of the etiology of Helicobacter pylori in the etiology of peptic ulcer disease and the association between colonization and mucosal-associated lymphoma (MALT) has spurred... 

Methotrexate -antifolate antimetabolite cell cycle dependent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hepatotoxicity—more common in high-dose therapy -CNS toxicity—dizziness, malaise, blurred vision, encephalopathy -nephrotoxicity—including acute renal failure, particularly at high doses... 

Methotrexate, an antimetabolite, is indicated for moderate to severe psoriasis. It is particularly beneficial for psoriatic arthritis. It is also indicated for patients refractory to topical or UV therapy. Methotrexate can be administered orally, subcutaneously, or intramuscularly. The starting dose is 7.5 to 15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk. Adverse effects include nausea, vomiting, mucosal ulceration, stomatitis, malaise, headache, macrocytic anemia, and hepatic and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by giving oral folic acid 1 to 5 mg/day. Methotrexate should be avoided in patients with active infections and in those with liver disease. It is contraindicated in pregnancy because it is teratogenic. 

Mucositis (toxicity) from methotrexate (methylene tetrahydrofolate reductase TT variant)... 

Folic acid is used as an adjunct to methotrexate therapy to limit methotrexate-induced side-effects such as mucositis and stomatitis. 

Methotrexate is an antimetabolite of folic acid and has immunosuppressant properties. It inhibits the enzyme dihydrofolate reductase that is required for the synthesis of purines and pyrimidines. It is used in malignant disease, Crohn s disease, rheumatic disease and psoriasis. Folic acid is given with methotrexate to reduce the occurrence of side-effects particularly the risk of mucositis. 

For immunosuppressive effects methotrexate is most frequently used in RA but also azathioprine and cyclosporin are employed. Methotrexate doses for this indication can be lower than those used for cancer chemotherapy but significant toxicity such as nausea, cytopenias and mucosal lesions, and with longterm therapy slowly progressive hepatotoxicity may still be seen. 

Nausea and mucosal ulcers are the most common toxicities. Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (< 1%). Liver toxicity is not related to serum methotrexate concentrations, and liver biopsy follow-up is only recommended every 5 years. A rare hypersensitivity-like lung reaction with acute shortness of breath is documented, as are pseudolymphomatous reactions. The incidence of gastrointestinal and liver function test abnormalities can be reduced by the use of leucovorin 24 hours after each weekly dose or by the use of daily folic acid, although this may decrease the efficacy of the methotrexate. This drug is contraindicated in pregnancy. 

Methotrexate Inhibits DHFR inhibits TS inhibits de novo purine nucleotide synthesis Breast cancer, head and neck cancer, osteogenic sarcoma, primary central nervous system lymphoma, non-Hodgkin s lymphoma, bladder cancer, chorioca rcinoma Mucositis, diarrhea, myelosuppression with neutropenia and thrombocytopenia... 

At higher dosage, methotrexate may cause bone marrow depression, 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 impairing the antiinflammatory action. 

Purine analogs and antimetabolites, eg, 6-mercaptopurine, methotrexate Mechanism uncertain may promote apoptosis of immune cells Generalized suppression of immune processes Moderately severe to severe Crohn s disease and ulcerative colitis GI upset, mucositis myelosuppression purine analogs may cause hepatotoxicity, but rare with methotrexate at the low doses used... 

Methotrexate 2.5-5 mg/d orally (Rheumatrex) 10 mg intrathecally (Folex) once or twice weekly Mucositis, diarrhea, bone marrow depression with leukopenia and thrombocytopenia... 

Two-thirds of patients treated with cyclophosphamide orally for 4 months plus intravenous 5-fluorouracil and methotrexate for breast cancer developed Barrett s epithelium (16), perhaps as a result of esophagitis, rather than through mucosal re-epithelialization by undifferentiated stem cells (17). 

In a double-blind, placebo-controlled study of the safety and efficacy of methotrexate therapy combined with glucocorticoids in patients with giant cell arteritis over 24 months, adverse events were defined as a new diagnosis of any condition during treatment (39). The combination of methotrexate plus prednisolone reduced the number of relapses and improved the course of the disease. Methotrexate was withdrawn in three patients who had adverse events that were clearly drug-related. One had leukopenia, anemia, and mucositis, one developed pancytopenia, and one oral ulcers. These patients were not taking folic acid or folinic acid supplements. 

A 61-year-old woman inadvertently took a high dose of methotrexate (10 mg/day) for psoriasis, and developed mucosal ulcers after 3 months. One month later, methotrexate (20 mg/week) was restarted, but she developed... 

Dexamethasone increased the hepatotoxicity of methotrexate in 57 children with brain tumors (137). The hepatotoxicity was not related to differences in serum concentrations and was independent of bone marrow toxicity or mucositis. 

Common side effects seen with methotrexate include mucositis, leukopenia, thrombocytopenia, and anemia. At normal doses, methotrexate is primarily excreted unchanged... 

The toxicity of antimetabolites is, as expected, due to their incorporation into the metabolism of normal cells, which is nearly identical to that of the malignant cells that they were designed to injure. The normal cells injured most severely are the rapidly proliferating cells of the bone marrow, the lymphoid system, and the GI epithelium. Thus, the common toxicities are bone marrow depression, nausea and vomiting, diarrhea, and mucositis. Cytarabine and pentostatin can cause conjunctivitis. Capecitabine and prolonged use of fluorouracil or cytarabine can cause cerebellar ataxia and the hand-foot syndrome, that is, palmar-plantar erythrodysesthesia or acral erythema. Pentostatin and high-dose methotrexate can cause renal toxicity. 

Methotrexate inhibits DNA synthesis by decreasing avail-ability of pyrimidine nucleotides. Methotrexate competitively inhibits the enzyme dihydrofolate reductase, thus decreasing the concentrations of the tetrahydrofolate essential to the methylation of the pyrimidine nucleotides and consequently the rate of pyrimidine nucleotide synthesis. Leucovorin, a folate analog, is used to rescue host cells from methotrexate inhibition as a synthetic substrate for dihydrofolate reductase, leucovorin administration allows resumption of tetrahydrofolate-dependent synthesis of pyrimidines and reinitiation of DNA synthesis. Methotrexate is a nonspecific cytotoxin, and prolongation of blood levels appropriate to killing tumor cells may lead to severe, unwanted cytotoxic effects such as myelosuppression, gastrointestinal mucositis, and hepatic cirrhosis. 

Ruiz-Arguelles GJ, Coconi-Linares LN, Garces-Eisele J et al (2007) Methotrexate induced mucositis in acute leukemia patients is not associated with the MTHFR C677T allele in Mexico. Hematology 12 387-391... 

Corticosteroids and adrenocorticotropic hormone have been widely used for the treatment of ulcerative cohtis and Crohn s disease, given parenterally, orally, or rectally. Corticosteroids are believed to modulate the immune system and inhibit production of cytokines and mediators. It is not clear whether the most important steroid effects are systemic or local (mucosal). Budesonide is a corticosteroid that is administered orally in a controlled-release formulation. The drug undergoes extensive first-pass metabolism, so systemic exposure is thought to be minimized. Immunosuppressive agents such as azathioprine, mercaptopurine (a metabolite of azathioprine), methotrexate, or cyclosporine are sometimes used for the treatment of IBD. ... 

Methotrexate 7.5-15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk Anemia, leukopenia, thrombocytopenia, hepatotoxicity, gastrointestinal upset, nausea, vomiting, mucosal ulceration, stomatitis, malaise, headaches, pulmonary toxicity... 

Methotrexate is associated with nausea and vomiting as well as mucosal ulceration, stomatitis, malaise, headaches, macrocytic anemia, and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by administering oral folic acid in doses of 1 to 5 mg/day. 

A 32-year-old female is being treated with methotrexate for a recently diagnosed choriocarcinoma of the ovary, and presents with complaints of oral mucosal ulcers. The patient recalls being advised not to take folate-containing vitamins during therapy. An uncomplicated surgical exploration was performed 5 weeks ago with removal of the affected ovary. The patient has been taking methotrexate for 2 weeks and has never had any of the above symptoms before. On examination, patient was afebrile and appeared ill. Several mucosal ulcers were seen in her mouth. The patient also had some upper abdominal tenderness. Her platelet count is decreased at 60,000/mm (normal 150,000 to 450,000/mm3). 

Methotrexate Cytotoxic to lymphocytes HematoLoxidty, mucositis, crystalluria... 

Methotrexate (CCS) Antimetabolite—inhibits DHF reductase (S phase) Leukemias, lymphomas, breast CA RA, psoriasis BMS, mucositis, crystal] aria leucovorin (folinic acid) rescue... 

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