EFFECTS OF CHRONIC TREATMENT WITH INDOMETHACIN AT CLINICALLY RELEVANTDOSES ON INTESTINAL TISSUE 6-KETO PROSTAGLANDIN F1-ALPHA AND LEUKOTRIENE B-4 LEVEL IN RELATION TO GASTROENTEROPATHY

This study investigated the effects of indomethacin at clinically rele vant doses and its chronic usage on intestinal pathology, survival tim e and intestinal tissue 6-keto prostaglandin F-1 alpha and leukotriene B-4 level in rats during various periods with different doses. Indome thacin was administered ranging from 0.625 to 5 mg/kg. When used in do ses of 0.625 and 1.25 mg/kg, indomethacin caused no apparent intestina l lesions or death during a treatment period of 30 days. On the other hand, all rats died in 7 days when 5 mg/kg of indomethacin was given. Mortality rate reached 53.3% in seven days in the group where 3.75 mg/ kg indomethacin was given. The minimal dose of indomethacin, which ind uced intestinal ulcer and death, was 2.5 mg/kg. The main pathological findings were intestinal ulcers, but no macroscopic and microscopic ch anges were observed in the stomach. Intestinal tissue 6-keto prostagla ndin F-1 alpha and leukotriene B-4 levels were quantified by enzyme im munoassay after homogenisation and extraction of tissue. In dose-depen dent studies, only the dose of indomethacin, 3.75 mg/kg, significantly inhibited intestinal tissue 6-keto prostaglandin F-1 alpha levels dur ing seven days application period (197.39 +/- 24.26 vs 383.66 +/- 46.6 8 ng/g tissue, treatment vs control). 2.5 mg/kg of indomethacin caused no intestinal ulceration on 4th day, however it significantly inhibit ed intestinal tissue 6-keto prostaglandin F-1 alpha levels on 4th day in time-dependent studies (190.3 +/- 26.62 vs 383.66 +/- 46.68 ng/g ti ssue, treatment vs control). Neither dose-dependent nor time-dependent indomethacin administration changed intestinal tissue leukotriene B-4 level. The results of this study indicated that indomethacin produced enteropathy rather than gastropathy when used chronically in clinical ly relevant doses in rats. Inhibition of prostaglandin synthesis, whic h was estimated by quantification of intestinal tissue 6-keto prostagl andin F-1 alpha level, seemed not to be a prerequisite for its enterop athic effect.