Inhibition of Clostridium difficile toxin A-induced colitis in rats by APAZA

• Published in: Digestive diseases and sciences Vol. 50; no. 3; pp. 565 - 573
• Main Authors: MCVEY, Douglas C, LIDDLE, Rodger A, RIGGS-SAUTHIER, Jennifer, EKWURIBE, Nnochiri, VIGNA, Steven R
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.03.2005; Springer Nature B.V
• Subjects: Analysis of Variance; Aniline Compounds - pharmacology; Animals; Bacterial Toxins; Biological and medical sciences; Biopsy, Needle; Bones, joints and connective tissue. Antiinflammatory agents; Clostridium difficile; Colitis - drug therapy; Colitis - pathology; Disease Models, Animal; Female; Immunohistochemistry; Male; Medical sciences; Pharmacology. Drug treatments; Phenylacetates - pharmacology; Probability; Rats; Rats, Inbred Strains; Sensitivity and Specificity; Prostaglandin-endoperoxide synthase; Animal model; Rat; Clostridiales; Bacteria; Intestinal disease; Salicylates; Inhibition; Enzyme; Rodentia; Clostridium difficile; 5-aminosalicylic acid; Enzyme inhibitor; Inflammation; Non steroidal antiinflammatory agent; Toxin; Vertebrata; Mammalia; Analgesic; Acids; Mesalazine; Animal; Clostridiaceae; Antipyretic; Digestive diseases; 4-aminophenylacetic acid; Oxidoreductases; Colitis
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-005-2476-1

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.