Uçar A, Sak S D, Melli M
Department of Pharmacology, Medical Faculty of Ankara University, Turkey.
Inflammation. 1998 Jun;22(3):243-52. doi: 10.1023/a:1022354614385.
This study investigated the effects of indomethacin at clinically relevant doses and its chronic usage on intestinal pathology, survival time and intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 level in rats during various periods with different doses. Indomethacin was administered ranging from 0.625 to 5 mg/kg. When used in doses of 0.625 and 1.25 mg/kg, indomethacin caused no apparent intestinal 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 induced intestinal ulcer and death, was 2.5 mg/kg. The main pathological findings were intestinal ulcers, but no macroscopic and microscopic changes were observed in the stomach. Intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 levels were quantified by enzyme immunoassay after homogenisation and extraction of tissue. In dose-dependent studies, only the dose of indomethacin, 3.75 mg/kg, significantly inhibited intestinal tissue 6-keto prostaglandin F1 alpha levels during seven days application period (197.39 +/- 24.26 vs 383.66 +/- 46.68 ng/g tissue, treatment vs control). 2.5 mg/kg of indomethacin caused no intestinal ulceration on 4th day, however, it significantly inhibited intestinal tissue 6-keto prostaglandin F1 alpha levels on 4th day in time-dependent studies (190.3 +/- 26.62 vs 383.66 +/- 46.68 ng/g tissue, treatment vs control). Neither dose-dependent nor time-dependent indomethacin administration changed intestinal tissue leukotriene B4 level. The results of this study indicated that indomethacin produced enteropathy rather than gastropathy when used chronically in clinically relevant doses in rats. Inhibition of prostaglandin synthesis, which was estimated by quantification of intestinal tissue 6-keto prostaglandin F1 alpha level, seemed not to be a prerequisite for its enteropathic effect.
本研究调查了临床相关剂量的吲哚美辛及其长期使用对不同时期不同剂量大鼠肠道病理学、存活时间以及肠道组织6-酮前列腺素F1α和白三烯B4水平的影响。吲哚美辛的给药剂量范围为0.625至5mg/kg。当以0.625和1.25mg/kg的剂量使用时，吲哚美辛在30天的治疗期内未引起明显的肠道病变或死亡。另一方面，给予5mg/kg吲哚美辛时，所有大鼠在7天内死亡。给予3.75mg/kg吲哚美辛的组中，7天内死亡率达到53.3%。诱导肠道溃疡和死亡的吲哚美辛最小剂量为2.5mg/kg。主要病理表现为肠道溃疡，但在胃中未观察到宏观和微观变化。组织匀浆和提取后，通过酶免疫测定法定量肠道组织6-酮前列腺素F1α和白三烯B4水平。在剂量依赖性研究中，仅3.75mg/kg的吲哚美辛剂量在7天的应用期内显著抑制肠道组织6-酮前列腺素F1α水平（治疗组与对照组分别为197.39±24.26与383.66±46.68ng/g组织）。在时间依赖性研究中，2.5mg/kg的吲哚美辛在第4天未引起肠道溃疡，但在第4天显著抑制肠道组织6-酮前列腺素F1α水平（治疗组与对照组分别为190.3±26.62与383.66±46.68ng/g组织）。吲哚美辛的剂量依赖性和时间依赖性给药均未改变肠道组织白三烯B4水平。本研究结果表明，吲哚美辛在大鼠中以临床相关剂量长期使用时会产生肠病而非胃病。通过定量肠道组织6-酮前列腺素F1α水平估计的前列腺素合成抑制似乎不是其肠病效应的先决条件。
