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

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metabolite of azathioprine, it is not known whether the agents are identical in activity. However, both can be used to reduce steroid dosage and enable remission induction in chronic active IBO.

Antibacterials are used quite widely in lBO, despite there being little evidence of benefit for most agents except in the perioperative period. The rationale for their use involves reduction of bacteria and bacterial antigens which may aggravate mucosal inflammation.

Metronidazole, which is both antimicrobial and immunosuppressive, is therapeutic in Crohn's disease.

In the future Hope for the future lies in better

understanding of the causes of IBO. 'Basic research exploring the genetics of I BD, the influence of genetics on the immune response and the initiating event(s) will lead to intenoentions that cannot be imagined at present, and the cure awaits elucidation of the cause.'

Areas for research inelude genetic determinations, evaluation of the effects of smoking and the roles of mucus and permeability. There appears to be some merit in the theory that the epithelial mucosa is starved of short chain fatty acids, and delivery of these acids is being evaluated.

Antigen processing dysfunction. possibly related to elass II major histocompatibility complex expression. is being evaluated as an aetiological factor and chloroquine and hydroxychloroquine are being studied with this mode of action in mind.

As with current therapies, most future therapies will probably focus on the prevention of the amplification of the immunological and inflammatory responses. Future therapies will hopefully be more specific, more potent and less toxic than current agents.

Cyelosporin and tsukobaenolide [FK 506; Fukisawa] are currently being studied for their immunological effects but their possible role is as yet unknown. The use of eicosanoids with the intention of reducing leukotriene B4 production is being evaluated. and preliminary data are encouraging.

Prevention of the production of free oxygen radicals with xanthine oxidase. oxygen radical removal with superoxide dismuthase or scavenging of free radicals with tocopherol may be useful. since prevention or depletion of free oxygen radicals in animal models has reduced inflammatory responses.

Other potential therapies include inhibition of complement activation and inhibition of substance P and other neuropeptides.

Hanauer SB. Inflammatory bowel disease revisited: newer drugs. Scandinavian Journal of Gastrocntcrology 25 (Suppl. 175): 97-106. Sep 1990 [108 referencesl ....

21 INPHARMA@200ct 1990 _