Inhibition of Clostridium difficile toxin A-induced colitis in rats by APAZA.
A new compound, APAZA, consisting of a molecule of 5-aminosalicylic acid linked to one molecule of 4-aminophenylacetic acid by an azo bond, was testedfor its ability to inhibit acute colitis in rats caused by Clostridium difficile toxin A. When administered chronically for 5 days in drinking water, APAZA significantly inhibited toxin A-induced myeloperoxidase activity, luminal fluid accumulation, and structural damage to the colon at doses of from 1 to 100 mg/kg x day. For comparison, sulfasalazine was administered in identical doses and was found to significantly inhibit toxin A-induced colitis only at the dose of 100 mg/kg x day. When 4-aminophenylacetic acid alone was administered chronically in drinking water, it also inhibited toxin A-induced colonic inflammation at a dose of 100 mg/kg x day. In order to determine if 4-aminophenylacetic acid has a direct anti-inflammatory effect on the colon rather than a systemic effect, 4-aminophenylacetic acid was administered acutely to surgically prepared isolated colonic segments by intraluminal injection in anesthetized rats 30 min before toxin A was injected. 4-Aminophenylacetic acid strongly and significantly inhibited toxin A-induced colitis in this experiment at doses as low as 10 microg/segment. It is concluded that APAZA is a potent inhibitor of toxin A-induced colonic inflammation in rats and that its constituent, 4-aminophenylacetic acid, is responsible for this increased protection against colitis compared to the 5-aminosalicylic acid component of sulfasalazine.
McVey
Douglas C
DC
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Liddle
Rodger A
RA
Riggs-Sauthier
Jennifer
J
Ekwuribe
Nnochiri
N
Vigna
Steven R
SR
D000704:Analysis of Variance; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001427:Bacterial Toxins; D001707:Biopsy, Needle; D016360:Clostridioides difficile; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D010648:Phenylacetates / Q000494:pharmacology*; D011336:Probability; D051381:Rats; D011919:Rats, Inbred Strains; D012680:Sensitivity and Specificity
D000814:Aniline Compounds; D001427:Bacterial Toxins; D010648:Phenylacetates; C109911:4-aminophenylacetic acid