Abstract
Pharmacological therapy for irritable bowel syndrome (IBS) has not been established. In order to find candidate drugs for IBS with diarrhea (IBS-D), we screened a compound library of drugs clinically used for their ability to prevent stress-induced defecation and visceral hypersensitivity in rats. We selected the bronchodilator aminophylline from this library. Using a specific inhibitor for each subtype of adenosine receptors (ARs) and phosphodiesterases (PDEs), we found that both A2BARs and PDE4 are probably mediated the inhibitory effect of aminophylline on wrap restraint stress (WRS)-induced defecation. Aminophylline suppressed maternal separation- and acetic acid administration-induced visceral hypersensitivity to colorectal distension (CRD), which was mediated by both A2AARs and A2BARs. We propose that aminophylline is a candidate drug for IBS-D because of its efficacy in both of stress-induced defecation and visceral hypersensitivity, as we observed here, and because it is clinically safe.
Highlights
Aminophylline was identified on the basis of its inhibition of both the visceromotor response (VMR) to colorectal distension (CRD) and wrap restraint stress (WRS)-induced fecal pellet output, as well as the available clinical data of its tolerability
Rolipram but not cilostazol suppressed the WRS-induced fecal pellet output in rats. These results suggest that the inhibitory effect of aminophylline on WRS-induced defecation is probably mediated by its inhibitory effect on both A2BARs and PDE4
Various types of drugs are prescribed for Irritable bowel syndrome (IBS)-D patients and several target proteins for IBS with diarrhea (IBS-D) drugs have been proposed, an appropriate pharmacological therapy has not yet been established
Summary
This strategy screens compounds with clinically beneficial pharmacological activity from a library of medicines that are already in clinical use to develop them for new indications The advantage of this strategy is the decreased risk of unexpected adverse effects in humans because the safety aspects of these drugs have already been well characterized[19]. It has been reported that inhibition of PDE4 suppresses stress-induced defecation[35] These results suggest that aminophylline (theophylline) may affect visceral hypersensitivity and stress-induced defecation in IBS-D patients and animal models either positively or negatively; no study to date has investigated these effects. We screened a compound library consisting of clinically available drugs for the ability of the drugs to prevent stress-induced defecation and visceral pain, and identified aminophylline as a potential candidate. On the basis of these results, we propose that aminophylline may be a candidate drug for IBS-D
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