Medicines Methotrexate

Strand, V., Cohen, S., Schiff, M., et al. (1999) Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Archives of Internal Medicine. 159, 2542-2550. 

Bathon, J.M., Martin, R.W., Fleischmann, R.M., et al. (2001) A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. New England Journal of Medicine. 343,1586-1593. 

Kumagai, K., Hiyama, K., Oyama, T., Maeda, H., and Kohno, N. (2003) Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. International Journal of Molecular Medicine. 11, 593-600. 

Another group of inhibitors prevents nucleotide biosynthesis indirectly by depleting the level of intracellular tetrahydrofolate derivatives. Sulfonamides are structural analogs of p-aminobenzoic acid (fig. 23.19), and they competitively inhibit the bacterial biosynthesis of folic acid at a step in which p-aminobenzoic acid is incorporated into folic acid. Sulfonamides are widely used in medicine because they inhibit growth of many bacteria. When cultures of susceptible bacteria are treated with sulfonamides, they accumulate 4-carboxamide-5-aminoimidazole in the medium, because of a lack of 10-formyltetrahydrofolate for the penultimate step in the pathway to IMP (see fig. 23.10). Methotrexate, and a number of related compounds inhibit the reduction of dihydrofolate to tetrahydrofolate, a reaction catalyzed by dihydrofolate reductase. These inhibitors are structural analogs of folic acid (see fig. 23.19) and bind at the catalytic site of dihydrofolate reductase, an enzyme catalyzing one of the steps in the cycle of reactions involved in thymidylate synthesis (see fig. 23.16). These inhibitors therefore prevent synthesis of thymidylate in replicating... 

At this stage, an assessment is made as to whether the medicine that could result is likely to be palliative or disease-modifying . Diseasemodifying drugs (DMD) are those which directly and beneficially deflect the natural history of the disease. Nonsteroidal anti-inflammatory drugs and methotrexate are examples of each of these in patients with rheumatoid arthritis. Then probability of one or the other can alter economic assessments of the research program, and lead to a go-no-go decision in some cases. 

Furst, D. E., Sherrer, Y, Fleischmann, R. M., Block, J., Rutstein, J., and Stamler, D. (1999). Efficacy of FK506 in rheumatoid arthritis (RA). A 6 month dose-ranging study in RA patients failing methotrexate (MTX). Presented at 1999 annual scientific meeting, American College of Rheumatology, Boston. Internal medicine (in submission). 

Sanchez-Reus mi, Iniesta MP and Ribas B (1988) Metallothionein induction by methotrexate in liver and intestinal mucosa. In Schramel P and Bratter P, eds. Trace Elements in Analytical Chemistry and Medicinal Biology, Vol. 5, pp. 437-443. Walter de Gruyter Co., Berlin-New York... 

Treatment of psoriasis with new biologies costs in the range of 25,000- 45,000 per year as compared with 2200 for methotrexate and 3000- 5000 per year for phototherapy. The cost of erythropoietin for renal dialysis is 10,000 per year and for cancer patients 1000 per month of treatment. New vaccines are priced in the 200- 400 range. Xigris is priced at 6800 per injection and drug-coated stents at over 3000. The European government-funded healthcare systems and insurance companies try to delay and limit access to costly new medicines and try to negotiate lower prices. 

The Committee on Safety of Medicines/Medicines Control Agency. Blood ( crasias and other ADRs with low-dose methotrexate. Current Problems (1997) 23,12. 

Sostman HD, Matthay RA, Putman GE. Methotrexate-induced pneumonitis. Medicine 1976 55 371-388. 

ViUa-Forte A, Clark TM, Gomes M, et al. Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis a 12-year single-practice experience. Medicine (Baltimore) 2007 86(5) 269 277. 

The next seven Chapters involve polymers with potential anti-tumor and other medicinal properties. Chapter 11 (Carraher Strothers) deals with the release of methotrexate and/or chloroplatinate while Chapter 12 (Gebelein, et al.) describes the release of 5-fluorouracil from a biodegradable polymer. Chapter 13 (Matsuzaki, et al.) reviews much research on polysaccharides that have anti-tumor properties, and this theme is enhanced in Chapter 14 (Carraher, et al.) which describes tin-modified polysaccharides. The use of nucleic acid analogs in chromatography is the main theme of Chapter 15 (Inaki, et al.), but these same materials also have potential anti-tumor properties. Poly(ICLC), Chapter 16 (Levy Bever) is also a nucleic acid analog with some anti-tumor potential. Finally, Chapter 17 (Trombley, et al.) covers polymers with anti-tumor and other medical properties. 

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