Novel targets for the pharmacotherapy of diarrhoea: a view for the millennium

Acute diarrhoea continues to carry a high morbidity and mortality worldwide. Intestinal infection is the major cause of acute diarrhoea although the prevalence of individual pathogens varies according to geographic location. In many countries in the industrialized world, reports of intestinal infections continue to increase; these are largely related to waterborne and foodborne outbreaks. Acute diarrhoea may be due to increased intestinal secretion, commonly as a result of infection with enterotoxin-producing organisms (enterotoxigenic Escherichia coli, Vibrio cholerae) or to decreased intestinal absorption from infection with organisms that damage the intestinal epithelium (enteropathogenic E. coli, Shigella sp., Salmonella sp.). Although oral rehydration therapy has reduced the mortality associated with acute diarrhoea, the diarrhoea attack rate remains unchanged and stool volume often increases during the rehydration process. The search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce stool volume has been going on for more than 20 years. Research during the past decade has highlighted the importance of neurohumoral mechanisms in the pathogenesis of diarrhoea, notably the role of 5-hydroxytryptamine, substance P, vasoactive intestinal polypeptide and neural reflexes within the enteric nervous system. Cholera toxin, E. coli enterotoxins and Clostridium difficile toxin A are known to invoke these mechanisms in diarrhoea pathogenesis. This new dimension of intestinal pathophysiology has already exposed possible novel targets for anti-secretory therapy, namely, 5-HT receptor antagonists, substance P antagonists and the possibility for potentiating the proabsorptive effects of endogenous enkephalins by use of enkephalinase inhibitors. There now seems to be a real possibility that anti-secretory therapy will become more widely available in the future.