Looking for clues to future therapies in response to traditional agents in IBD
'All of our current medical therapies for I BD [inflammatory bowel disease] interrupt the amplification of immunoregulatory or inflammatory sequences rather than impacting on a primary, initiating process.' The initiating factors of the inflammatory response are not known, but intestinal permeability. abnormal usage of short chain fatty acids and inadequate antigen-processing mechanisms may be involved.
Salicylates It has now been recognised that the efficacy of
sulfasalazine largely results from a topical effect of its mesalazine component. Recognition of this has led to the production of topical delivery systems of mesalazine and targetted oral delivery systems which release mesalazine to its site of action with minimal systemic effects. Also possible now, are the delivery of high doses of mesalazine in refractory cases and the provision of maintenance therapy. However, the relationship between dosage and maintenance or remission-inducing effects has not been fully defined and comparative responses to the various formulations require further elucidation. Moreover, the long term adverse effects of high dose therapy are not well known and the mode of action remains a mystery.
Investigations into the mode of action of salicylates have identified cyelo-oxygenase inhibition and consequent reduction of leukotriene B4 production, impairment of neutrophil function and oxygen radical scavenging as contributors to the effect. Corticosteroids, immunosuppressants and antimicrobials
While corticosteroids and corticotrophin have traditionally been mainstays of therapy in acute exacerbations of IBO. thev are ineffective as maintenance therapy. The nonspecific action of corticosteroids on the immunological and inflammatorv mechanisms accounts for the adverse as w"ell as the therapeutic effects of these agents. Since the isolation of I predominant mechanism for the action of corticosteroids in IBO is unlikclv. future research seems likelv to focus on the development of targetted topi~ally active agents with few systemic effects.
The immunosuppressive agents azathioprine and mercaptopurine are now used in dosages lower than those required for true immunosuppression, with the result that pancreatitis. not bone marrow suppression, is the most severe adverse effect usually encountered. These agents have slow onsets of action of up to 6 months, an observation consistent with reduction of natural killer cell and nonmajor histocompatibility complex restricted T cell activities. Although mercaptopurine is a