Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea

Abstract

The 'old favourites' used for treatment of inflammatory diseases, and hence, the original immunomodulators, include the glucocorticoids, azathioprine, methotrexate and hydroxyurea. Glucocorticoids are still one of the most effective anti-inflammatory agents because they work on several different intracellular processes and hence, block many components that contribute to inflammatory and immune responses. They bind to intracellular glucocorticoid receptors which transport them into the nucleus. Here the receptor/steroid complex may bind to many genes that interact with transcription factors including NFkappaB and AP-1, to inhibit their activation, thereby preventing activation of many genes encoding immune effector and pro-inflammatory cytokines. Also, protein kinases involved in intracellular signalling, are directly activated resulting in phosphorylation of various targets of which Annexin (AXA)-1 is critical in inhibiting biosynthesis of both purines and DNA. This results in reduced proliferation of B and T lymphocytes, reduced immune effector mechanisms and reduced recruitment of mononuclear cells including monocytes into sites of immune inflammation. Methotrexate also blocks DNA synthesis and hence cellular proliferation but also induces release of adenosine. This inhibits chemotaxis of polymorph neutrophils and release of critical cytokines such as TNF-alpha and Interleukins 6 and 8. Hydroxyurea also inhibits DNA synthesis with inhibitory effects on proliferation of lymphocytes and possibly kerationcytes. Even though many new agents with much greater selectivity are coming through into clinical use, this group of old agents still have an absolutely central position in the therapeutic armamentarium. Their value lies in the fact that they are not 'clean' drugs with narrow effects but they inhibit a wide range of mechanisms involved in immune and inflammatory processes.

Azathioprine in dermatology: The past, the present, and the future

“…Azathioprine has been shown to reversibly reduce the number of monocytes in circulation and tissue in a dose-dependent manner, with little effect on neutrophils. 25,40,41 Azathioprine has been reported to impair synthesis of gamma globulin in patients who have rheumatoid disorders with a mean reduction of immunoglobulin G synthesis by 33% and immunoglobulin M by 41%. 42 Also, in vitro and in vivo data suggest that long-term immunosuppression with azathioprine decreases the number of cutaneous Langerhans cells.…”

The impact of glutathione S–transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases

“…AZA is a prodrug which can be metabolized to 6ethioguanine nucleotides (6eTGN) to exert its immunosuppressive action. After oral administration, AZA is quickly absorbed from the digestive tract and does not cross the bloodebrain barrier (1). The oral bioavailability of AZA is about 27%e83%, and 88% of AZA converted to mercaptopurine by the catalytic action of glutathione Setransferases (GSTs).…”

Successful Treatment of Amegakaryocytic Thrombocytopenia with Azathioprine

“…The mechanism of action for azathioprine had been explored elsewhere. In brief, both T cell and B cell function are affected [14]. Its clinical efficacy for other autoimmune diseases (e.g.…”