Abstract
The orally-active, anti-allergic, chromone drug, proxicromil, (6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-1-naphtho[2,3-b] pyran-2-carboxylate), produced an unexpectedly high incidence and severity of gastro-intestinal disorders in humans. These side-effects had not been predicted following a complete safety evaluation programme in animals. The purpose of the work described in the following chapters was to elucidate the mechanism by which proxicromil caused gastro-intestinal disorders in man, to determine whether the effect in humans could have been predicted from animal studies and, if so, to develop a simple but effective toxicity study that could be used with future drugs to predict their potential to induce this type of side-effect in humans. The gastrointestinal effects of proxicromil were found to be associated with delayed gastric emptying, and a method was developed in rats for demonstrating the potential of a candidate compound to cause an inhibition of gastric emptying. The method was shown to be reproducible and to detect the effect of 'standard' drugs such as codeine phosphate (decreases in gastric emptying) and metoclopramide (increases). A secondary screen used to evaluate drugs shown to be active in the primary test and to screen out false-positives was developed in marmosets. X-ray photography after a barium meal also demonstrated inhibition of gastric emptying. Proxicromil was shown to be a potent inhibitor of gastric emptying in both the rat primary screen and the marmoset secondary screen. Inhibition of gastric emptying was associated with a much lower and flatter plasma drug concentration v time course than was the case where inhibition did not occur. This effect has consequences on the relevance of toxicity studies in different species. From measurements of stomach pressure changes in spontaneously contracting rat stomachs and spontaneous contractions of rat fundic strip preparations, it was concluded that proxicromil had no direct effect on the musculature of the stomach. The drug was also shown to have no direct activity on the pyloric sphincter. An in situ preparation, developed to enable recordings of spontaneous contractions of the stomach to be made whilst retaining both nervous and blood supplies, showed that proxicromil had no effect when administered directly into the stomach. However when administered to the duodenum the drug induced a dramatic and immediate cessation of stomach contractions. It was demonstrated that the drug exerted its inhibitory activity on gastric emptying by a reflex mechanism initiated in the first 20 to 30 cm of the rat duodenum, that the effect occurred immediately when the compound reached the duodenum and that the duration of activity was related to the concentration of drug in the duodenum. The relative inhibitory activities of proxicromil on gastric emptying after oral and intravenous administration indicated that absorption was not necessary for activity. The time of onset of the activity, the lack of activity in rats with a common blood circulation to proxicromil treated animals, and the inhibitory effect of a local anaesthetic in the duodenum, all demonstrated that the drug exerted its inhibitory activity via a nervous rather than a hormonal pathway. It was demonstrated that the reflex was probably centrally-mediated via a non-cholinergic component of the vagus nerve. Structure-activity studies with a range of chromones and other drugs, from the completely inactive sodium cromoglycate to the very potent proxicromil, indicated that certain groupings on the chromone nucleus could be expected to increase or decrease the potential of a new chemical entity to induce similar gastro-intestinal disorders in humans. A positive correlation between inhibition of gastric emptying and sensory irritancy in the lung was demonstrated, indicating that the activity of proxicromil in the duodenum may be associated with its irritant properties. Thus the drug may initiate a reflex in the duodenum that has a physiological role in protecting the intestine from irritant or otherwise noxious substances.