Pharmacology and Mechanism of Action

Cure Arthritis Naturally

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MTX is currently the cornerstone of drug treatment for RA. It is increasingly employed as the first DMARD used (24). It can be given orally or subcutaneously, because there is considerable variation in oral absorption (25). MTX was first used in RA and psoriatic arthritis in the early 1960s; however, the higher dose regimes used then were associated with significant and serious toxicity. As a result, it is now used in a low-dose weekly regime of 7.5-25 mg per week. MTX is taken up into cells via the reduced folate carrier and is poly-glutamated. Polyglutamation prolongs the intracellular half-life (26). Although originally believed to mediate its effect by inhibition of folate metabolism, it has become increasingly clear that this is not its only mechanism of action (26,27). MTX inhibits a number of essential enzymes, such as thymidylate synthase, dihydrofolate reductase (leading to an inhibition of pyrimidine and purine metabolism), and aminoamidazole carboxamide ribonucleotide transformylase (AICAR) (Fig. 2) (28,29). This leads to release of adeno-sine, which inhibits leucocyte migration and, acting via the A2a and A3 receptors, has potent anti-inflammatory actions (30).

Methotrexate Mode Action Flowchart

Figure 2 Overview of the mechanisms by which methotrexate mediates its anti-inflammatory effects in rheumatoid arthritis and related disorders. Key enzymes inhibited by MTX are highlighted in gray boxes. Abbreviations: DHF, dihydrofolate; MTX, methotrexate; THF, tehrahydrofolate; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide.

Figure 2 Overview of the mechanisms by which methotrexate mediates its anti-inflammatory effects in rheumatoid arthritis and related disorders. Key enzymes inhibited by MTX are highlighted in gray boxes. Abbreviations: DHF, dihydrofolate; MTX, methotrexate; THF, tehrahydrofolate; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide.

Clinically, MTX is capable of significantly reducing joint inflammation and retarding radiographic progression (31). Clinical trials confirm that ACR20 responses to low-dose MTX range from 44% to 65%, (9,10,32). In addition, MTX is relatively well tolerated, and many patients are able to remain on MTX for long periods of time. Wolfe et al. (33) found that the median time to discontinuation of MTX was 4.25 years, compared with two years for other DMARDs. Pincus et al. (15) also confirmed that over a five year period, "drug survival" times for MTX were superior to other DMARDs.

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