A NOVEL METHOD FOR THE PRECLINICAL ASSESSMENT OF RECTAL IRRITATION

The purpose of this study concerns a novel method for preclinical asse ssment of rectal irritation caused by suppositories introduced into th e rectum. Rectal irritation was assessed by the balloon method in fast ing conscious rats. This method is based on measuring rectal contracti ons due to possible irritation caused by the presence of drugs and adj uvants in the suppository. In control experiments (vehicle only), sign ificant rectal contractions were not observed in a range of pH 1.5-11. 0 and osmotic pressure 70-2000 mOsm kg(-1) H2O, respectively. On the o ther hand, strong contractions were observed after rectal administrati on of an aqueous solution of 50% glycerin, 100 mM sodium caprate or 25 mM sodium cholate. The intensity of contraction after rectal administ ration of sodium caprate or sodium cholate was dependent on the concen tration in the dosing solution. In addition, the effect of sodium capr ate and sodium cholate on rat rectal mucosa was investigated by optica l light microscopy. Although slight or moderate alteration such as the presence of mucinous substance in lumen and congestion, oedema and ha emorrhage of the rectal membrane 20 min after rectal administration, t here was no major damage to the rectal mucosa. There was a correlation between the median score for mucinous substance in lumen and mean int ensity of rectal contraction. For comparative purposes, defecating sen sations, pain, itch, burning sensations, and awareness of the presence of a foreign body after administration of suppositories containing 0, 1, 2 and 4% sodium caprate were examined in eight healthy volunteers. The defecating sensation in the human subjects correlated with the in tensity of rectal contraction in rats. The results suggest that rectal contraction in conscious fats could be a useful index for prediction of a defecating sensation in man.