Hooi, Peh Kheng; (1995) Actions of balsalazide and sulphasalazine on mast cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mode of action of sulphasalazine (SASP) and balsalazide (BSZ), therapeutic agents of inflammatory bowel disease (IBD), is not clear. This thesis describes studies of the pharmacological actions of SASP, BSZ, and cyclosporin A (CsA, an immunosuppressant), with particular reference to histamine release (HR) from mast cells. In acute rat colitis, topical pretreatment with BSZ and SASP showed marked prophylactic effect by reducing myeloperoxidase activity, tissue oedema, lactate dehydrogenase release, and HR. Oral treatment of chronic and active rat colitis showed some improvement with BSZ, but not with SASP. Secretagogues for HR showed differential effects on dispersed guinea pig rectocolonic mucosal cells (RCMC) and isolated rat peritoneal mast cells (RPMC). Deoxycholic acid evoked dose-dependent HR (partly cytotoxic). Peroxidase/H 2O2/halide system (free radical generating system) also induced HR from both cell types. This was inhibited by metabolites of BSZ and SASP, while parent molecules were less effective. CsA only inhibited the induced HR from RPMC, but not that from RCMC. Some studies of the signal transduction pathways involved in HR from RPMC showed that SASP and BSZ might have a mode of action different to that of CsA. The modulatory effect of both SASP and BSZ on HR by selected secretagogues studied showed tachyphylaxis. BSZ, SASP, and in some cases their metabolites were shown to stabilize erythrocyte membrane against various membrane labilizers. CsA had the opposite effect. This study demonstrated that BSZ and SASP share similar actions and efficacy, the parent molecules may not merely be pro-drugs, and their carrier moieties may contribute to the beneficial effect of both compounds. CsA was found to have different actions from both BSZ and SASP. The demonstration that IBD therapeutic agents show different pharmacological actions further indicates the involvement of multiple mechanisms in IBD pathogenesis. The study yields useful information which may lead to new, more effective, and less toxic approaches to treat IBD.

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