Effects of esomeprazole on glutathione levels and mitochondrial oxidative phosphorylation in the gastric mucosa of rats treated with indomethacin

Proton pump inhibitors exert their preventive and healing effects on gastropathy induced by nonsteroidal anti-inflammatory drug (NSAIDs) by a dual action: the antisecretory and the antioxidant effect. The latter was investigated by using esomeprazole against indomethacin-induced gastric mucosa lesions in rats and assessed by a histomorphometric analysis. Treatment by intragastric gavage were 1% methocel as vehicle; esomeprazole 10, 30, or 60 μmol/kg; indomethacin 100 μmol/kg; and esomeprazole 10, 30, or 60 μmol/kg plus indomethacin 100 μmol/kg. The evaluation of glutathione (GSH) levels and respiratory chain complex activities [nicotinamide adenine dinucleotide, reduced (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome C reductase, cytochrome oxidase] was performed in the isolated gastric mucosa. Esomeprazole (10–60 μmol/kg) dose dependently reversed, up to complete recovery, the inhibitory effect of indomethacin on GSH levels (approximately 60% inhibition) and mitochondrial enzyme activities (inhibition ranging from 60% to 75%). Indomethacin-induced mucosal injuries were reduced by esomeprazole. Thus, in addition to inhibiting acid secretion, the gastroprotective effect of esomeprazole can be ascribed to a reduction in gastric oxidative injury.     

醋氨己酸锌对半胱胺大鼠溃疡模型的影响

用半胱胺在大鼠上引起非弥散性和弥散性十二指肠溃疡，并以雷尼替丁作为对照，研究了醋氨己酸锌对溃疡的预防作用和治疗作用。弥散性十二指肠溃疡有一个较长的愈合过程，在用醋氨己酸锌治疗５０ｄ后，溃疡受到极明显的抑制。对非弥散性十二指肠溃疡也表现了极好的预防作用。另外，对醋氨己酸锌各个剂量溃疡愈合的形态学也进行了比较，发现在不同的剂量时显示不同的损伤修复及愈合情况，明显地加速了受损处的上皮细胞、十二指肠腺及平滑肌细胞的增殖。     

A comparative study with indomethacin and combined indomethacin sodium-salicylate in rheumatoid arthritis.

A double-blind cross-over clinical trial was performed to compare clinical effectiveness of indomethacin (3 x 25 mg/day) alone to that of a combination of indomethacin + sodium-salycylate (3 x 25 mg/day and 3 x 250 mg/day, respectively) in rheumatoid arthritis. It was established that enteral blood loss was significantly reduced by combined treatment as determined by Cr51 labelled erythrocytes in comparison to that after treatment with indomethacin alone. Therapeutic effect was maintained in both groups, no significant disparities were observed. Occurrence of subjective complaints was less frequent in the combined treatment group. It was concluded that the combined preparation consisting of indomethacin and sodium-salicylate has a favourable effect in rheumatoid arthritis.     

Diamine oxidase activity in the duodenal mucosa of rats with cysteamine-induced ulceration.

Cysteamine administration to rats is followed by a high incidence of duodenal ulceration. The effect of cysteamine on the activity of diamine oxidase (DAO, histaminase) in the duodenal mucosa of the rat was investigated. Rats were injected subcutaneously with cysteamine on 2 successive days at doses of 10, 20 and 40 mg/100 g body weight and killed 24 h after the second dose. The results indicated that cysteamine at a dose of 40 mg/100 g body weight inhibited enzyme activity by about 27% (p less than 0.05). Lower doses of cysteamine did not significantly affect enzyme activity. In another experiment, rats were injected subcutaneously with either saline (control) or cysteamine at a single dose of 40 mg/100 g body weight and killed 4, 8, 12, 24, 48 and 60 h thereafter. The ulcerogen produced progressive reductions in enzyme activity, which were significant at 12 h (22% reduction) and 24 h (25% reduction). At 60 h, enzyme activity was not significantly different from that of control.     

Mechanism of action of cysteamine on duodenal alkaline phosphatase

A single s.c. injection of cysteamine-HCl, a potent duodenal ulcerogen, drastically decreased duodenal alkaline phosphatase (DAP) activity in mucosal cells. The effect was detectable 4 hr after the injection of cysteamine, it was the most prominent at 12 hr and lasted less than 24 hr after the ulcerogen administration. Under the same experimental conditions cysteamine did not affect alkaline phosphatase activity in the liver. Furthermore, ethanolamine, the toxic but nonulcerogenic derivate of cysteamine, had no effect on the DAP activity if given in equimolar quantities. Thus, the effect of DAP activity seems to be a property of the duodenal ulcerogen, related only to the target organ, i.e. duodenal mucosa. Since cimetidine administration and pylorus ligation, which both abolish HCl hypersecretion provoked by cysteamine, did not "protect" the enzyme from the depletion, it is hard to believe that gastric acid hypersecretion could be responsible for the enzyme depletion provoked by the ulcerogen. Dopamine metabolism disorders, induced by cysteamine administration in the brain and duodenal mucosa, are not causally related to DAP-depletion either. Cysteamine most probably inhibits the DAP activity by three different mechanisms, by one acting directly on the enzyme molecules and by two others acting indirectly, through its adrenocorticolytic and stresogenic effects.     

Effects of prostaglandin biosynthesis inhibitors and ouabain on duodenal mucosa and HCO3- secretion in rats

A single injection (s.c.) of prostaglandin biosynthesis inhibitors such as indomethacin (5 mg/kg), aspirin (200 mg/kg) and quinacrine (100 mg/kg) or a Na+.K+ ATPase inhibitor such as ouabain (10 mg/kg) significantly reduced the adaptive increase of HCO3- output caused by acid in the duodenum of anesthetized rats. These agents had no effect on basal duodenal HCO3- secretion and histamine-stimulated gastric acid secretion. Either of these agents, when given alone, had no effect on the duodenal mucosa of conscious rats, but produced damage in the proximal duodenum within 8 hr when given together with histamine (40 mg/kg X 3, s.c., every 2.5 hr). A significant relationship was found between the degrees of inhibition of acid-induced HCO3- output and the severity of duodenal lesions induced by these drugs (r = 0.8620, P less than 0.01). These results suggest that an impairment of the mechanisms related to acid-induced HCO3- secretion may be particularly relevant to the pathogenesis of duodenal lesions.     

Endogenous vasopressin damages duodenal mucosa during haemorrhagic shock in rats

The role of endogenous vasopressin was studied in the development of mucosal erosions induced by haemorrhagic shock in the duodenum of the rat. Ischaemia-reperfusion provoked duodenal haemorrhagic lesions and elevated circulating and intramucosal vasopressin level. This mucosal injury was significantly attenuated by a vasopressin pressor receptor antagonist. Moreover, in the vasopressin-deficient Brattleboro homozygous rat, mucosal injury induced by haemorrhagic shock was also reduced. By contrast, when the vasopressin agonist, lysin-vasopressin, was administered, significant aggravation of ischaemia-reperfusion-induced duodenal mucosal injury was seen. These findings indicate the aggressive role of endogenous vasopressin, via its pressor receptors, in the generation of duodenal mucosal stress erosions in haemorrhagic shock. This paper was presented at the Symposium on ‘Cell injury and protection in the gastrointestinal tract: from basic science to clinical perspectives’, October 8–11, 1995, Pécs, Hungary.     

Chronic fluoride toxicity: a scanning electron microscopic study of duodenal mucosa

The effects of chronic fluoride toxicity on duodenal mucosa of rabbits were investigated using scanning electronmicroscope on materials obtained from rabbits subjected to oral administration of sodium fluoride at the dose of 10 mg/kg body weight per day for a period of 24 months. Significant morphological abnormalities were observed in the mucosa of all the fluoride treated animals [n = 9] when compared to that of control rabbits. The surface of the microvilli of duodenal epithelium revealed a "cracked-clay" appearance in fluoride treated rabbits. Besides, abrasion on the villus surface due to epithelial cell degeneration was also noticed. Mucus probably coating the degenerated cells formed strands over the villi in fluoride treated animals.     

Effect of nitrofurans on duodenal ulceration induced by cysteamine or indometacin

The present experiments examined the protective effect of the nitrofuran drugs, furazolidone (FZ) and nitrofurazone (NF), on duodenal ulceration induced by cysteamine or indometacin in rats. FZ at oral doses of 25, 50 or 100 mg/kg for 2 consecutive days signficantly reduced, in a dose-dependent manner, the incidence and extent of cysteamine-induced ulceration. However, oral NF (100 mg/kg) given for 2 consecutive days had no significant effect on duodenal ulceration. The duodenal mucus content of rats was not significantly affected by either FZ or cysteamine treatments. FZ at an oral dose of 100 mg/kg for 2 consecutive days significantly reduced the incidence and extent of indometacin-induced ulceration. Smaller doses of 25 or 50 mg/kg had no significant effects.     

A comparative study of fenbufen and indomethacin in patients with rheumatoid arthritis.

A short-term, double-blind crossover study was completed in 29 patients with definite rheumatoid arthritis to compare the antirheumatic activity of indomethacin (100 mg/day) with that of fenbufen (800 mg/day). The patients were randomly allocated to two groups and treated for a period of 6 weeks with each of the drugs. Subjective and objective assessment of rheumatic activity showed that indomethacin produced significant improvement only in morning stiffness and walking time; however, following fenbufen a significant improvement in walking time, grip strength and joint swelling resulted. Both the observed and the patients assessed the fenbufen period as significantly better than the baseline and that following indomethacin.     

Effect of indomethacin on rats with Grollman hypertension

Grollman hypertension was produced in 15 Sprague-Dawley rats, and chronic 46-week hypertension was observed in these rats. Weekly subcutaneous injections of 1.44 mg indomethacin resulted in significant reduction of the systolic blood pressure 1 h after the injection (p less than 0.001). There was no change in the blood pressure following treatment with indomethacin in the 6 normotensive control rats. Light microscopic examinations revealed that adrenal and cardiac tissues were free of serious toxic indomethacin effects. Liver tissue examination showed slight degenerative changes in the indomethacin-treated animals.     

A comparative study of flurbiprofen and indomethacin in rheumatoid arthritis

Summary

A double-blind, crossover study was carried out in 30 patients with active, classical or definite rheumatoid arthritis to compare the effect of 200?mg flurbiprofen per day with that of 100?mg indomethacin per day. Patients received, at random, each drug for a period of 2 weeks separated by a week's wash-out period on placebo. Assessments were made before the start of the trial and at weekly intervals of pain, morning stiffness, grip strength, articular index, walking time, and finger joint size. Patients' preference for any particular treatment period was recorded at the end of the trial. Laboratory investigations were carried out before and during the trial. Both drugs show statistically significant improvement over baseline assessments, although there was little difference between the two active treatment periods. More patients preferred the treatment period with flurbiprofen, and this was probably related to the fewer side-effects which were reported with this drug.     

Impairment of acid-neutralizing capacity and lesion formation in the rat duodenum during hemorrhagic shock: comparative study with indomethacin

The effects of hemorrhagic shock (HE) on duodenal pH, acid-neutralizing capacity and mucosal tolerance to acid were investigated in anesthetized rats, and they were compared with those of indomethacin. HE was performed by bleeding from the carotid artery to reduce arterial blood pressure to about 55 mmHg (3 ml of bleeding per 200 g of body weight), and indomethacin was given s.c. in a dose of 5 mg/kg. Duodenal pH was determined in the outflow from the proximal duodenum (1.7 cm) which was perfused with 10(-4) M HCl, and acid-neutralizing capacity was measured by back-titration of the perfusate to pH 4.0 with 10 mM HCl. Under these conditions, duodenal pH was kept at around 6.0 as the result of neutralization in the loop (approximately 8 microEq/hr). Both HE and indomethacin significantly decreased the pH and acid-neutralizing capacity. Administration of 16,16-dimethyl prostaglandin E2 (16-dmPGE2: 30 micrograms/kg, s.c.) significantly increased both pH and acid-neutralizing capacity in normal and indomethacin-treated rats, but failed to affect these parameters in rats under HE conditions. When the duodenal loop was perfused with 50 mM HCl for 1.5 hr, both HE and indomethacin induced extensive damage in the mucosa. Pretreatment with 16-dmPGE2 significantly reduced the formation of duodenal lesions induced by indomethacin but not by HE. These results suggest that HE as well as indomethacin impaired duodenal acid-neutralizing capacity to reduce the tolerance to acid of the mucosa. The deleterious effects of HE on the mucosa may be mainly due to a decreased mucosal blood flow, but not due to a deficiency of endogenous prostaglandins.     

A comparative study of azapropazone and indomethacin in the treatment of rheumatoid arthritis

Summary

A double-blind crossover trial in 50 patients with rheumatoid arthritis was carried out to compare the clinical effectiveness of 800?mg. azapropazone per day with 100?mg. indomethacin per day. Blood plasma concentrations of azapropazone were also studied in 10 patients.

Patients received both drugs for a 3-week period, the order of treatment being determined at random. Although there were no marked differences in any of the objective measurements, patients' assessments of response to and preference for each drug treatment period suggested that azapropazone produced significant improvement compared to that with indomethacin. Plasma levels of azapropazone remained remarkably constant for each patient. Side-effects with both drugs were mild and transient, and there were no marked variations from normal in any of the laboratory parameters measured.     

A comparative study of flurbiprofen and indomethacin in rheumatoid arthritis.

A double-blind, crossover study was carried out in 30 patients with active, classical or definite rheumatoid arthritis to compare the effect of 200 mg flurbiprofen per day with that of 100 mg indomethacin per day. Patients received, at random, each drug for a period of 2 weeks separated by a weeks' wash-out period on placebo. Assessments were made before the start of the trial and at weekly intervals of pain, morning stiffness, grip strength, articular index, walking time, and finger joint size. Patients' preference for any particular treatment period was recorded at the end of the trial. Laboratory investigations were carried out before and during the trial. Both drugs shows statistically significant improvement over baseline assessments, although there was little difference between the two active treatment periods. More patients preferred the treatment period with flurbiprofen, and this was probably related to the fewer side-effects which were reported with this drug.     

A comparative gastroscopic study of lonazolac and indomethacin in healthy subjects

In 9 healthy volunteers the effects of a 14-day treatment with lonazolac 300 mg b.i.d. on gastric and duodenal mucosa have been endoscopically compared with those of indomethacin 75 mg b.i.d. in a double-blind placebo-controlled trial. Lonazolac and indomethacin induced significantly more gastric and duodenal mucosal injuries (1.9 +/- 0.4 and 1.7 +/- 0.3) compared to placebo (0.9 +/- 1.0) (p less than 0.05). The validity of different procedures in predicting the deleterious effects of nonsteroidal antiinflammatory drugs on the human upper gastrointestinal epithelium is discussed.     

半胱胺对小鼠疼痛感受的影响

INTRODUCTION Cysteamine (β-mercaptoethylamine) is a thiol com-pound whose biological activities have recently receivedgreat attention, and that can be found in animals whenacetyl coenzyme A is hydrolized by pantethinase.Clinically it has been used in the treatment ofacetaminophen poisoning and in the treatment ofnephropathic cystinosis. It was reported that cys-teamine depletes somatostatin in the stomach, duodenum,pancreas, gut and hypothalamus of rat. Cysteaminewas also found to deplete somatostatin in the brain     

Effects of indomethacin, piroxicam and selected prostanoids on gastric acid secretion by the rat isolated gastric mucosa

The effects of the cyclo-oxygenase inhibitors indomethacin and piroxicam have been investigated on histamine- and dibutyryl cyclic AMP-induced acid secretion in the rat isolated gastric mucosa. The relative potencies of a number of prostanoids as inhibitors of histamine-induced acid secretion were determined in an attempt to classify the prostaglandin receptor mediating this response. Indomethacin (8 X 10(-9) - 2.7 X 10(-6) M) and piroxicam (3 X 10(-6) M) potentiated the secretory responses elicited by histamine. This effect might be due to inhibition of the biosynthesis of antisecretory prostanoids. Indomethacin (2.7 X 10(-6) M) and piroxicam (3 X 10(-6) M) also potentiated the secretory response to dibutyryl cyclic AMP, but since prostaglandin E2 (PGE2, 10(-5) M) did not inhibit this secretory response, the mechanism of the potentiation may differ from that of histamine. The potency of the thromboxane mimetic U-46619 as an inhibitor of histamine-induced acid secretion was markedly reduced in the presence of indomethacin, suggesting that U-46619 may release endogenous antisecretory prostanoids. In the presence of indomethacin (2.7 X 10(-6) M) all the prostanoids tested produced concentration-related inhibitions of histamine-induced gastric acid secretion. PGE-analogues were the most potent compounds, the rank order of potency being 16, 16 dimethyl PGE2 greater than PGE2 greater than PGF2 alpha greater than U-46619 greater than PGD2 greater than PGI2. This order of potency is very similar to that obtained in smooth muscle preparations containing 'EP' receptors, suggesting that this receptor type also mediates inhibition of histamine-induced acid secretion in the rat.     

高锌对大鼠肠粘膜免疫的影响

为阐明高锌对肠粘膜免疫屏障结构和功能的影响及其机理 .采用建立正常锌和高锌大鼠模型 ,应用形态学手段结合免疫组化和图像分析方法 ,对大鼠肠道粘膜的超微结构 ,粘膜 Ig A的产生和含量作定位和定量研究 .结果表明第 4周末和第 7周末 ,高锌组血浆 ,红细胞膜和肠组织的锌含量明显高于正常锌组 ;高锌组光镜下肠粘膜未见异常改变 ,但是电镜下见肠道粘膜超微结构严重损害 ;第 7周末 ,Ig A浆细胞计数及其平均吸光度 ,以及粘液 Ig A水平均显著低于正常锌组 ( P<0 .0 1 ) .结果提示高锌可以引起肠道粘膜和 Ig A屏障结构损害 .