Methotrexate for

Rheumatoid arthritis (RA moderate to severe) In combination with methotrexate for reducing the signs and symptoms and inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA who have had an inadequate response to methotrexate. 

Fu KK, Phillips TL, Silverberg IJ, et al. Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer update of a Northern California Oncology Group randomized trial. J Clin Oncol 1987 5 1410-1418. 

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

Mechanism of Action An antidote to folic acid antagonists that may limit methotrexate action on normal cells by competing with methotrexate for the same transport processes into the cells Therapeutic Effect Reverses toxic effects of folic acid antagonists. Reverses folic acid deficiency. 

I I 3. The answer is c. (Hardman, pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydrofolate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2), which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

Infliximab is administered in combination with methotrexate for rheumatoid arthritis. A dose of 3 mg/kg is administered via intravenous infusion and is repeated after 2 and 6 weeks followed by the maintenance dose every 8 weeks. The recommended dose for Crohn s disease is 5 mg/kg. The side effects associated with the administration of infliximab include acute infusion reactions (fever, chills, chest pain, hypotension and rare anaphylaxis), increased risk of infection, production... 

Originally used in the treatment of malaria, the drugs chloroquine (Aralen) and hydroxychloroquine (Pla-quenil) have also been used to treat rheumatoid arthritis. In the past, these drugs have been used reluctantly because of the fear of retinal toxicity (see Adverse Side Effects ).25 There is now evidence, however, that these agents can be used safely, but they are only marginally effective when compared to other DMARDs. These drugs are therefore not usually the first choice, but they can be used in patients who cannot tolerate other DMARDs, or in combination with another DMARD (e.g., methotrexate) for more comprehensive treatment. 

Molloy, M., Tikly, M., Oed, C., Rosenbueg, R., Loew-Friedrich, I. (2000). A comparison of the efficacy and safety of Lefiunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 39, 655-665. 

METHOTREXATE PENICILLINS t plasma concentrations of methotrexate and risk of toxic effects of methotrexate, e.g. myelosuppression, liver cirrhosis, pulmonary toxicity Penicillins 1 renal elimination of methotrexate by renal tubular secretion, which is the main route of elimination of methotrexate. Penicillins compete with methotrexate for renal elimination. Displacement from proteinbinding sites may occur and is only a minor contribution to the interaction Avoid concurrent use. If concurrent use is necessary, monitor clinically and biochemically for blood dyscrasia, liver toxicity and pulmonary toxicity. Do FBCs and LFTs prior to concurrent treatment... 

METHOTREXATE AMINOSALICYLATES-SULFASALAZINE t risk of hepatotoxicity with sulfasalazine Additive hepatotoxic effects. Sulfasalazine also competes with methotrexate for renal elimination Monitor closely for symptoms of liver failure. Check LFTs at the beginning of treatment then weekly until stable, and repeat if there is clinical suspicion of liver disease... 

METHOTREXATE ANTIGOUT DRUGS -PROBENECID t methotrexate levels Probenecid 1 elimination of methotrexate renally by interfering with tubular secretion in the proximal tubule and also 1 protein binding of methotrexate (a relatively minor effect). Probenecid competes with methotrexate for renal elimination Avoid co-administration if possible if not possible, 1 dose of methotrexate and monitor FBC closely... 

Tubule obstruction. Given certain physicochemical conditions, crystals can deposit within the tubular lumen. Methotrexate, for example, is relatively insoluble at low pH and can precipitate in the distal nephron when the urine is acid. Similarly the uric acid produced by the metabolism of nucleic acids released during rapid tumour cell lysis can cause a fatal urate nephropathy. This was a particular problem with the introduction of chemotherapy for leukaemias until the introduction of allopurinol it is now routinely given before the start of chemotherapy to block xanthine oxidase so that the much more soluble uric acid precursor, hypoxanthine, is excreted instead. Crystal-nephropathy is also a... 

Methotrexate, for example, a folic acid antagonist, competitively inhibits dihydrofolate reductase, preventing the synthesis of tetrahydrofolic acid (the coenzyme that is important in synthesis of amino and nucleic acids). This drug also provides a cogent illustration of the need to exploit every possible... 

Baldus, W.P. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis the results of a pilot study. Hepatology 1995 22 1158-1162... 

Lindor, K.D., Jorgensen, RA., Anderson, M.L., Gores, G.J., Hofmann, A.F., LaRusso, NJ . UrsodeoxychoUc acid and methotrexate for primary sclerosing cholangitis a pilot study. Amer. J. Gastroenterol. 1996 91 511-515... 

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 22 of 29 patients (76%) who were treated with low-pulse doses of methotrexate for rheumatoid arthritis, liver biopsy specimens showed variability in liver cell nuclear size, glycogenated nuclei, and fatty change. Occasionally there was mild portal infiltration with lymphocytes. There were no significant differences in age, duration of treatment, or cumulative dose amongst the cases. Serial increases in serum transaminases and/or alkaline phosphatase activity and development of hypoalbuminemia during treatment were indicators of development of liver disease (54). 

In a meta-analysis of 636 patients from 15 studies, who took chronic low-dose methotrexate for rheumatoid arthritis or psoriasis, the risk of liver toxicity increased with cumulative dose and heavy alcohol intake (56). 

There was a characteristic clinical and histopathological spectrum of skin lesions, distinct from rheumatoid papules, in four patients who took low-dose methotrexate for acute flares of collagen vascular disease (71). These so-called methotrexate-induced rheumatoid papules developed shortly after methotrexate administration consisted of erythematous indurated papules mostly affecting the proximal Umbs, and disappeared after methotrexate was withdrawn or tapered. Histology showed inflammatory infiltrates of interstitiaUy arranged histiocytes and a few neutrophils, but no features of leukocjrtoclastic vasculitis. 

Severely ulcerated psoriatic plaques and acute extensive exfoliative dermatitis occurred in a 37-year-old man who had taken methotrexate for 5 years for psoriasis (74). 

In the context of a case of severe reactivation of recent sunburn after a single injection of methotrexate for ectopic pregnancy in a 40-year-old woman, the authors reviewed the literature on methotrexate photosensitivity (75). Photodermatitis reactivation is the only well-documented type of photosensitivity associated with methotrexate. It can occur if methotrexate is given at 2-5 days after excessive exposure to ultraviolet or X-radiation. 

A 51-year-old man with systemic sarcoidosis took methotrexate for 36 months and developed a large anal fissure with a diffuse polymorphic infiltrate containing large Epstein-Barr virus-positive lymphoid cells, similar to the classical B cell lymphoproliferative disorders that occur in immunosuppressed transplant recipients of solid organs (121). 

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