A synergistic interaction between aspirin,or other non-steroidal anti-inflammatory drugs,and stress which produces severe gastric mucosal damage in rats and pigs

A synergistic interaction was observed in the development of damage to the gastric mucosa of rats following the administration of a single oral dose of 50 or 200 mg/kg body weight aspirinand exposure to brief periods of cold or restraint stress. Under the experimental conditions employed, the stressed (control) animals did not develop any visible signs of damage while the rats given only aspirin developed typical small erosions. However, the animals given aspirin and simultaneously exposed to stress developed a large number of deep ulcers and massive haemorrhage. Similar results were obtained in rats given a variety of non-steroidal anti-inflammatory drugs, but not with dextropropoxyphene—an analgesic devoid of ulcerogenic activity. In pigs, the chronic administration of aspirin and exposure to restraint stress resulted in the formation of deep crater-like ulcers. Only small focal lesions were found in the pigs given aspirin alone and no mucosal damage was evident in the pigs exposed only to stress. It appears that the aspirinplus stress synergism may be the basis for the formation of chronic gastric ulcers in humans.     

Immunomodulating Activity of Wy-41, 770 (5H-Dibenzo[A, D] Cyclohepten-5-Ylidene) Acetic Acid

The immunomodulatory effects of Wy-41,770 (5H-dibenzo[a,d)cyclohepten-5-ylidene)acetic acid, were compared to levamisole and indomethacin in several in vivo models. In the Jerne plaque assay, Wy-41,770 (1 and 100 mg/kg, p.o.) administered on day 1 after sensitization suppressed IgM plaque forming cells (PFC) while levamisole was active when given on days 1 and 2 after sensitization. In contrast, indomethacin administered on days 2 and 3 after sensitization increased PFC. In the rat experimental allergic encephalomyelitis (EAE) model, Wy-41,770 reduced limb paralysis at 10 and 100 mg/kg, p.o. when dosed before sensitization. Indomethacin was active too when predosed in the rat EAE model. In the methylated bovine serum albumin model (MBSA) delayed hypersensitivity (DH) model in mouse, Wy-41,770 (10 mg/kg, p.o.) given on day 1 prior to sensitization and day 2 after sensitization in subliminally sensitized animals augmented the DH response while inhibiting the subliminal DH response when administered at 6 hr after challenge. Levamisole showed similar activity in this subliminal model while indomethacin given 6 hr post challenge was inhibitory. All three drugs were inactive in mice normally sensitized to MBSA at the same drug regimens. In guinea pigs, subliminally sensitized to tuberculin, Wy-41,770 (10 and 100 mg/kg, p.0.) and levamisole augmented the DH response. No changes in DH response were observed for both drugs in normally sensitized guinea pigs. In the rat adjuvant arthritic model, Wy-41,770 (5 and 15 mg/kg, p.o.) inhibited day 16 uninjected paw edema and restored significantly the depressed proliferative responses to mitogen by spleen cells taken from the same arthritic rats at day 16. The moderate immunomodulatory activity of Wy-41,770 may contribute along with its antiinf lammatory activity, towards the treatment of arthritic diseases.     

Reactive oxygen metabolites and anti-oxidative defenses in aspirin-induced gastric damage in rats: Gastroprotection by Vitamin E

OBJECTIVE: It has been proposed that neutrophil infiltration and oxygen radicals may be the important prime events that lead to mucosal injury induced by aspirin. Vitamin E acts as a potent antioxidant, and is capable of scavenging free radicals. The aim of this study was to evaluate the oxygen metabolites and anti-oxidative defenses in acute gastric damage induced by aspirin and to find the effects of Vitamin E. METHODS: Ninety-six Wistar rats were divided into four groups of 24 rats each as follows: (1) the control group; (2) the ASA group that received 300mg/kg of ASA; (3) the Vitamin E plus ASA group and (4) the Vitamin E group that received Vitamin E (75 units) alone. At 3, 6, 9 and 24h after the drug administration, six rats were randomly selected from each group and gastric mucosal injury, prostaglandin E2, and the activities of myeloperoxidase, xanthine-oxidase, superoxide dismutase, glutathione peroxidase as well as glutathione level were measured and compared between the groups. RESULTS: Oral administration of ASA caused acute gastric erosions and an increase in myeloperoxidase activity. It also decreased prostaglandin E2, superoxide dismutase activity, glutathione peroxidase activity and glutathione level. Concomitant administration of Vitamin E and ASA restored all the changes toward the control levels. CONCLUSION: Free radicals and suppression of anti-oxidizing enzymes play important roles in gastric damage induced by aspirin. Increased myeloperoxidase activity suggests that activated neutrophils may be a major source of free radicals. Vitamin E protects against ASA-induced damage due to its anti-oxidizing activity.     

Effect of the COX-2 Selective Inhibitor L-745,337 on Inflammation and Organ Prostaglandin E2 (PGE2) Levels in Adjuvant Arthritic Rats

The anti-inflammatory activity of the cyclooxygenase-2 inhibitor, L745,337, was assessed in adjuvant arthritic rats (AA). The relationship between PGE₂ organ levels and drug activity or adverse effects was determined. Arthritic rats were orally treated for two weeks with L-745,337 (0.1, 1 and 5 mg/kg/day), indomethacin (1 mg/kg/day) or vehicle and paw swelling was determined. At the end of the study, samples from paw, stomach (wall and mucosa) and kidney were obtained from rats with or without treatment at high doses of L-745,337 or indomethacin and PGE₂ levels were determined. The L-745,337 anti-inflammatory effective-dose-50 was 0.4 mg/kg. Maximal anti-inflammation was obtained with L-745,337 or indomethacin at doses of 5 and 1 mg/kg respectively. L-745,337 showed anti-arthritic activity. No stomach ulcers appeared in either untreated or treated arthritic and healthy control rats. In AA rats, PGE₂ increased in paw, stomach wall, gastric mucosa and kidney. These levels were lower in all organs after both drugs but not below PGE₂ control levels.     

Effect of <Emphasis Type="Italic">Cannabis sativa</Emphasis> extract on gastric acid secretion,oxidative stress and gastric mucosal integrity in rats

Studies were conducted in pylorus-ligated rats to investigate the effect of Cannabis sativa extract on gastric acid secretion, experimental gastric ulcer and on oxidative stress and inflammatory markers in the gastric mucosa. C. sativa (5, 10 and 20 mg/kg, expressed as Δ⁹-tetrahydrocannabinol) was administered subcutaneously daily for 4 weeks prior to pylorus ligation and different treatments. Under basal conditions, pretreatment with cannabis extract at doses of 5 and 10 mg/kg increased gastric acid secretion and induced minimally visible gastric mucosal lesions in the 4 h pylorus-ligated rat. Malondialdehyde and nitric acid concentration increased, while reduced glutathione decreased by cannabis at doses of 5 and 10 mg/kg in gastric mucosa. TNF-α increased by cannabis extract at doses of 5 and 10 mg/kg but decreased following the high dose of 20 mg/kg. On the other hand, the gastric acid secretory responses stimulated by pentagastrin or carbachol (but not histamine) were inhibited in rats pretreated with cannabis extract. Under these conditions, cannabis decreased pepsin content after pentagastrin and carbachol but not histamine stimulation. Cannabis also decreased lipid peroxidation and nitric oxide content, and increased both reduced glutathione and catalase activity in mucosa. Moreover, cannabis decreased mucosal inflammation (level of TNF-α) and the development of gastric mucosal lesions. Cannabis administered for 1 month prior to pylorus-ligation and either acidified aspirin or ethanol (96 %) decreased the development of gastric mucosal damage in a dose-dependent manner, along with reduction in gastric acid output, gastric mucosal oxidative stress and inflammation (TNF-α). Sections of gastric mucosa stained with periodic acid Schiff showed increased mucus secretion by cannabis in basal conditions and after treatment with aspirin or ethanol. Results indicate that: (1) the effect of cannabis differs in basal conditions and after exposure of the gastric mucosa to high acid concentrations or other chemical noxious agents; (2) cannabis administered systemically exerts gastric mucosal protective effects against mucosal damage evoked by stimulation of gastric acid secretion, acidified aspirin or ethanol. These effects of cannabis are likely to involve inhibition of gastric acid and pepsin secretion, increased mucus, decreased oxidative stress and inflammation in gastric mucosa.     

An investigation of the effect of anti-inflammatory and anti-rheumatoid drugs in cell-mediated immune arthritis in guinea-pigs by microfocal radiography

Guinea-pigs were sensitized by intra-articular injection of M. tuberculosis (2.0 mg) into one knee joint and arthritis induced in the opposite knee 21 days later by intra-articular injection of antigen (0.2 mg). The time course off the arthritic changes was followed for 25 days by assessment of knee swelling and hind-limb flexion. Twenty-eight days after challenge the experiment was terminated and radiographic changes evaluated by means of a microfocal X-ray unit. The effect of treatment with the anti-rheumatic drugs, D-penicillamine (100 mg/kg by mouth), dexamethasone (0.1 mg/kg i.p.), aspirin (100 mg/kg by mouth), chloroquine phosphate (30 mg/kg by mouth) and sodium aurothiomalate (2 mg/kg i.m.) given daily from 10 days after sensitization until 28 days after challenge was assessed. Changes in joint swelling and hind-limb flexion were maximal 1-3 days after challenge. None of the drug treatments influenced these parameters. Microfocal radiography showed marked changes in arthritis animals of all X-ray parameters measured. It was possible readily to identify joint erosion, trabecular loss and associated osteoporosis, the latter occurring proximal to and relatively remote from the affected joint. None of the treatments prevented the radiographic changes but exacerbation of trabecular number in the area of the epiphysis was seen with aspirin and D-penicillamine and of trabecular density further up the shaft of the femur was seen with D-penicillamine. The changes with D-penicillamine may reflect the potentiation of cell-mediated hypersensitivity with this drug reported by other workers. It was concluded that the model is not suitable for the detection of clinically active anti-rheumatic drugs but that microfocal radiography provides a sensitive index for the assessment of joint damage in small animals.     

An investigation of the effect of anti-inflammatory and anti-rheumatoid drugs in cell-mediated immune arthritis in guinea-pigs by microfocal radiography.

Guinea-pigs were sensitized by intra-articular injection of M. tuberculosis (2.0 mg) into one knee joint and arthritis induced in the opposite knee 21 days later by intra-articular injection of antigen (0.2 mg). The time course off the arthritic changes was followed for 25 days by assessment of knee swelling and hind-limb flexion. Twenty-eight days after challenge the experiment was terminated and radiographic changes evaluated by means of a microfocal X-ray unit. The effect of treatment with the anti-rheumatic drugs, D-penicillamine (100 mg/kg by mouth), dexamethasone (0.1 mg/kg i.p.), aspirin (100 mg/kg by mouth), chloroquine phosphate (30 mg/kg by mouth) and sodium aurothiomalate (2 mg/kg i.m.) given daily from 10 days after sensitization until 28 days after challenge was assessed. Changes in joint swelling and hind-limb flexion were maximal 1-3 days after challenge. None of the drug treatments influenced these parameters. Microfocal radiography showed marked changes in arthritis animals of all X-ray parameters measured. It was possible readily to identify joint erosion, trabecular loss and associated osteoporosis, the latter occurring proximal to and relatively remote from the affected joint. None of the treatments prevented the radiographic changes but exacerbation of trabecular number in the area of the epiphysis was seen with aspirin and D-penicillamine and of trabecular density further up the shaft of the femur was seen with D-penicillamine. The changes with D-penicillamine may reflect the potentiation of cell-mediated hypersensitivity with this drug reported by other workers. It was concluded that the model is not suitable for the detection of clinically active anti-rheumatic drugs but that microfocal radiography provides a sensitive index for the assessment of joint damage in small animals.     

Protective Effects of Ginger against Aspirin-Induced Gastric Ulcers in Rats

We investigated the mechanism underlying the protective effects of ginger against gastric damage induced by aspirin in rats. Gastric mucosal lesions were produced by orally administering 200 mg/kg aspirin suspended in 1% carboxymethylcellulose solution to pyloric-ligated male Wistar rats. Ginger powder (200 mg/kg) markedly reduced the aspirin-induced gastric hemorrhagic ulcer area. The total acidity of gastric juice was not significantly influenced by aspirin or ginger. Ginger powder did not affect the aspirin-induced reduction in mucosal prostaglandin E₂ (PGE₂) content; however, it did ameliorate the aspirin-induced increases in mucosal activity of the inducible form of NO synthase (iNOS) and plasma tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels. In the next experiment, high and low doses of 6-gingerol and 6-shogaol were used instead of ginger powder in the same experimental model to examine their roles in the anti-ulcer mechanism of ginger. Both 6-gingerol and 6-shogaol reduced aspirin induced ulcer formation, mucosal iNOS and plasma TNF-α and IL-1β levels. In conclusion, ginger powder prevents the aspirin induced gastric ulcer formation by reducing mucosal iNOS activity and the plasma levels of inflammatory cytokines but does not affect gastric juice or acid production or mucosal PGE₂ content. This protective effect of ginger powder against gastric ulcers may be attributable to both gingerol and shogaol.     

Structural damage and changes in eicosanoid metabolites in the gastric mucosa of rats and pigs induced by anti-inflammatory drugs of varying ulcerogenicity

The object of the studies reviewed here has been to correlate the time-course of ultrastructural changes induced by oral administration of a range of non-steroidal anti-inflammatory (NSAI) drugs with effects on eicosanoid metabolism and drug absorption, so as to discriminate what biochemical/cellular and pharmacological factors account for their varying ulcerogenicity. Oral administration of highly ulcerogenic drugs (e.g. aspirin, diclofenac, indomethacin, piroxicam) to rats causes rapid damage to surface and gastric mucous cells, selective parietal cell damage, and extensive disruption of endothelial cells of submucosal microcapillaries (especially with aspirin) with accompanying extravasation of blood cell components. These changes are coincident with depressed levels of PGE2/6-keto-PGF1 alpha (measured by GC/MS or RIA) and uptake of the drugs (measured by scintillation counting or HPLC). Low ulcerogenic NSAI drugs (e.g. azapropazone, benoxaprofen and fenclofenac) causes very little damage to the surface mucosal cells. Azapropazone has been found to be well absorbed, and benoxaprofen and fenclofenac somewhat more slowly, so for the latter two drugs their low rate of absorption might also be a factor in their reduced ulcerogenicity. Aspirin, azapropazone and benoxaprofen have been shown to reduce 5-HETE levels (RIA), although the latter two drugs were more effective than aspirin. Thus, they result in the inhibition of PG production, by cyclo-oxygenase inhibition (with potential adverse effects from excess oxyradical and/or production of HETE's) with inhibition of the lipoxygenase pathway. The time-sequence of changes induced by single oral doses of indomethacin or other NSAI drugs on the ultrastructure and the prostanoid metabolism of the pig gastric mucosa parallelled those seen in the rat. Attempts to determine whether co-administration of NSAI drugs might reduce the inhibition of PG cyclo-oxygenase by more potent inhibitors (e.g. indomethacin) have been explored as a means for reducing the gastric ulcerogenicity of the latter. The results suggest that pharmacokinetic factors may largely account for the reduced ulcerogenicity of these drug mixtures.     

Role of neutrophils in indomethacin-induced gastric mucosal lesions in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause clinically important gastric damage by several mechanisms. In order to evaluate the role of neutrophil infiltration in lesion formation, tissue myeloperoxidase activities were assessed in different gastric layers of the stomach both in rats with normal neutrophil levels and in neutropenic rats. Sprague-Dawley rats were treated either with indomethacin (Indo; 25 mg/kg, s.c.) or the vehicle. A group of rats were made neutropenic by administration of methotrexate (MTX; 2.5 mg/kg i.p.) once a day for 3 days. The stomachs were removed for the determination of lesion index, glutathione, lipid peroxide levels, protein oxidation and tissue myeloperoxidase activities. MTX treatment appeared to reduce neutrophil infiltration significantly while producing insignificant effects on eosinophils and macrophages. Indo administration caused multiple gastric lesions and treatment with MTX significantly reduced lesion index. In rats treated with Indo, neither glutathione nor LP levels showed any significant changes but the protein oxidation was significantly higher than that of other groups. The MPO level of gastric mucosa was increased in Indo-treated rats and reversed by MTX pretreatment. The results of the present study indicate that neutrophil infiltration in the gastric mucosa of rats may be involved in the pathogenesis of NSAID-induced gastric mucosal injury, but no correlation was found between lesion formation and protein oxidation in the gastric mucosa.     

Mucosal lesions induced in the rat intestinal tract by the anti-inflammatory drug, Wy-41,770, a weak inhibitor of prostaglandin synthesis, contrasted with those from the potent prostaglandin inhibitor, indomethacin

The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 [5H-dibenzo(a,d)-cyclohepten-5-ylidine] was contrasted with the potent synthesis inhibitor, indomethacin, in rats to establish the relationship of inhibition of prostaglandin synthesis to the intestinal damage. Wy-41,770 induced superficial erosions only in the cecum 26 hr after a single oral dose of 250 or 500 mg/kg of the drug, progressing to ulcers after 5 days dosing with ultrastructural evidence of bacteria in the mucosa. Indomethacin (5 or 10 mg/kg po) induced mucosal erosions in the ileum, initially at 26 hr progressing to ulcers after 5 days. Fewer bacteria were seen in the ileal mucosa of indomethacin-treated rats. Both drugs reduced prostaglandin E in those regions of the intestine coincident with the known accumulation of these drugs at sites of mucosal injury. Site-specific intestinal damage from these 2 drugs is associated with inhibition of the synthesis of mucosal-protective prostanoids, followed by pronounced bacterial invasion through the damage mucosae with consequent appearance of local immuno-inflammatory reactions.     

The interrelationships between the lipid peroxidation, superoxide dismutase activity, development of gastric H+ secretion and gastric mucosal damage produced by intragastric administration of aspirin in pylorus-ligated rats

Gastric mucosal damage of pylorus-ligated rats was induced by the intragastric administration of aspirin at 200 mg/kg at the time of ligation. The animals were sacrificed at 0, 1, 2, 3, and 4 h after the treatment. The gastric lesions (ulcers) were counted and their severities were calculated, and the volume of gastric secretion and the H+ output were measured. The extent of lipid peroxidation was assessed by measuring the malondialdehyde (MDA) in the gastric mucosa, simultaneously with measurement of the activity of superoxide dismutase (SOD). It was found in these pylorus-ligated rats that: the number of visible gastric lesions was significantly higher 1 h after aspirin administration than at other times; the severity of gastric lesions increased significantly at the 3rd and 4th hour after administration of aspirin; the volume of gastric secretory responses increased gradually after administration of aspirin and to a higher extent than the H+ output; the H+ output was significantly less after aspirin administration than that after pylorus ligation only; the gastric mucosal SOD activity significantly increased 1 h after administration of aspirin, decreasing significantly and gradually thereafter; the tissue level of MDA remained unchanged 1 h after aspirin administration, decreasing significantly thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered susceptibility of arthritic rats to the gastric lesion-inducing effects of aspirin or ethanol and the antilesion effect of rioprostil

It is well known that nonsteroidal antiinflammatory agents produce gastric mucosal lesions in both laboratory animals and man. However, the effect of an arthritic condition on their susceptibility to ulcerogenic agents and on the efficacy of antiulcer agents is less definitive. As a model to explore these questions, the effect of oral administration of aspirin or ethanol on gastric lesion formation was examined in rats with or without established adjuvant-induced polyarthritis. In addition, the antilesion efficacy of rioprostil, a primary alcohol prostaglandin E₁ analog, was evaluated in both groups of rats. The results demonstrated that arthritic rats were more sensitive to the lesion-inducing effect of aspirin, but were more resistant to the lesion-inducing effect of ethanol when compared to normal rats. An increase in endogenous gastric prostaglandin production in arthritic rats may account for their relative resistance to ethanol. Aspirin inhibited the prostaglandin synthetic capacity of the stomach in both normal and arthritic rats, which may be responsible for eliminating the relative resistance of arthritic rats to gastric irritation. Rioprostil effectively prevented aspirin or ethanol-induced lesion formation in both arthritic and nonarthritic rats, but its potency against either irritant was decreased in arthritic rats.     

Anti-inflammatory/anti-pyretic salicylic acid esters with low gastric ulcerogenic activity

The methyl and some other esters of acetylsalicylic and salicylic acids and their derivatives were found to have much lower gastric ulcerogenic activity (when assayed in the stress-sensitized rat) compared with their corresponding acids. There was little or no loss in therapeutic potencies of these salicylate esters as determined by assessment of anti-inflammatory activity (against the carrageenan-induced oedema) and antipyretic activity (against yeast-induced fever in rats. The methyl ester of acetylsalicylic acid (=AME) was almost devoid of gastric irritancy/ulcerogenicity (as observed with acetylsalicylic acid) when given orally to pigs for 10 days. AME had appreciable anti-inflammatory activity in the adjuvant-arthritis model and at high doses (200 mg/kg t.i.d.) was without the lethal effects seen with acetylsalicylic acid. Moreover, no toxic effects were seen after long-term administration of 100–1000 mg/kg/day AME for 3–4 months.The results provide further evidence for the hypothesis that the carboxylic acid moiety of salicylates is a major factor in the gastric ulcerogenic activity of these drugs. The methyl esters of these salicylates may be considered as models for the development of pro-drugs and in some cases may be therapeutic alternatives to acetylsalicylic acid or salicylate.     

Analgesic and antiinflammatory effects of dipyrone in rat adjuvant arthritis model

Dipyrone, a pirazolone derivative, is a known analgesic drag with minor toxic effects associated with its administration. The aim of the present study was to determine the analgesic and antiinflammatory effects of dipyrone in a model of chronic inflammation (adjuvant-induced arthritis in rats). Hind-paw hyperalgesia was detected in arthritic rats from the 10th to the 16th day of observation. Edema development was maximum (twofold increase) at the 14th day of observation compared to control animals and reduced at the 16th day of observation. Dipyrone (1–50 mg/kg) dose-dependently reduced both hind-paw hyperalgesia and edema from arthritic rats. However, it was shown to be more potent as analgesic than antiinflammatory in the present model. In contrast, indomethacin (2 mg/kg) and dexamethasone (0.4 mg/kg) completely inhibited hind-paw hyperalgesia and edema development. Our results indicate that dipyrone reduced the hyperalgesia and edema in arthritic rats by a mechanism not involving release of prostaglandin-like substances. The possibility of dipyrone inducing analgesia in arthritic rats through a peripheral action supports the use of dipyrone as an alternative choice drug for the treatment of pain associated with arthritislike diseases in selected cases.     

Alterations in the gastro-intestinal functions during the development of adjuvant disease in rats

Gastric biliary and pancreatic secretions were examined in Lewis rats with adjuvant-induced polyarthritis. By application of the pylorus-ligation technique according to Shay for 4 h, a marked increase in gastric secretion was detected from day 11 to day 54 after adjuvant injection. The changes were manifest by a decrease of pH and an increase of secretory volume as well as total acid output. Maximum values were reached at the 23rd day with an acid secretion 4 times higher than in healthy animals. The enhanced hydrochloric acid secretion in adjuvant arthritic rats was confirmed with the aid of the gastric perfusion technique according to Ghosh and Schild and by the finding that the gastric contents of conscious arthritic rats under standard feeding conditions showed a statistically significant higher acidity (pH 2.5) than normal rats (pH 4.0).Adjuvant arthrltic rats with acute bile fistulas exhibited a basal and stimulated bile and pancreatic secretion like normal rats.The gastric mucosa of rats with adjuvant disease is highly sensitive to the irritant effect of gastric hypersecretion in the pylorus-ligation technique. The ulcer rate increases during the progress of the disease with a maximum of 70% at the 37th day. Normal rats with 4 h-pylorus ligation showed no macroscopically visible lesions. Increased sensitivity of the gastric mucosa against the ulcerogenic activity of non-steroidal anti-rheumatic drugs was demonstrated for aspirin and indomethacin. The etiological role of disease stress for the high susceptibility of the arthritic rat to gastric ulceration is discussed.To whom correspondence should be addressed.     

Strain-related susceptibility to nephrotoxicity induced by aspirin and phenylbutazone in rats

Single doses of aspirin induce scattered foci of necrosis of proximal tubules in some strains of rats, whereas acute or sub-acute administration of phenylbutazone causes renal papillary necrosis. Initially, using Sprague-Dawley rats of CFY and CD strains, it became clear that these rats were not as susceptible to these drugs as the literature suggested. Aspirin-induced necrosis was apparently sex-related, being seen in females but could be induced by hormone treatment in males. Male Wistar and Sprague-Dawley rats had reacted differently to administration of phenylbutazone for two weeks. Two experiments were performed with four rat strains: Wistar, Lister-Hooded, Sprague-Dawley, and Fischer-344. The rats were six weeks old at the start of the experiments. Five males and five females of each strain were gavaged with either a single dose of 1,000 mg/kg of aspirin or 200 mg/kg phenylbutazone once daily for four weeks. The drugs were suspended in methylcellulose, which was given to equal numbers of control male and female rats in each experiment. The rats were maintained under standard conditions. Blood and 18-hour overnight urine samples were collected prior to sacrifice. There were no strain-related differences in the types of renal lesions seen, however there were differences in the degrees of responses to the two drugs. With aspirin the female Fischer-344 rats were the most susceptible showing necrosis of proximal tubules of both kidneys and markedly elevated urinary protein concentration and gamma-GT activity. Other females showed less change. Male rats were affected only slightly and males of the Wistar strain were not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of etodolac on articular and bone pathology associated with adjuvant arthritis in rats: A comparison with aspirin and naproxen

The effect of treatment with the new anti-inflammatory drug etodolac on the articular and bone pathology associated with adjuvant arthritis in rats has been compared to the effects produced by aspirin and naproxen. Five measures of drug effect were made (changes in hind paw edema, body weight, normal hind leg function and articular damage as assessed by radiologic and histopathologic techniques). Drug treatment was initiated 16 days after adjuvant injection when arthritis was already established and continued for either 14 or 28 days. Etodolac produced a dose-related inhibition of all arthritic changes. Results from the radiologic study indicated that etodolac not only prevented the further development of articular damage by arthritis but actually caused a regression of these lesions established before drug treatment began. Similar results were obtained from the histopathologic study. Naproxen prevented the further development of arthritic damage but aspirin, although it decreased hind paw edema and increased body weight gains, had no significant effect on the articular damage produced by arthritis.     

Aspirin,prostaglandins and mucopolysaccharide/glycoprotein secretion

The object of the present study was to investigate the possibility that the ulcer-protective action of prostaglandins (PGs) in eliciting mucus discharge in the stomach could be due to their effect in enhancing the biosynthesis of mucus.Intraperitoneal injection of 2.5 mg/kg PGE₂, or the same dose of PGE₂ plus 200 mg/kg aspirin (p.o.), both failed to cause any statistically significant changes in the incorporation of radioactive sulphate into gastric mucus glycoproteins in vivo compared with controls. Aspirin, under these conditions, inhibits mucus synthesis and this effect may be related to the development of gastric mucosal damage by this drug. In contrast, PGE₂ administration reverses the gastric mucosal damage induced by aspirin so that the ulcer-protective effect of PGE₂ appears to be unrelated to mucus synthesis. PGE₂ (0.125–1.25 g/ml) inhibited oxygen consumption and¹⁴CO₂ output from 1-¹⁴C-, and 6-¹⁴C-glucose in rat gastric mucosal slices in vitro. Thus the absence of effect of PGE₂ on mucus biosynthesis may be due to an effect of this PG in reducing the capacity of the mucosa to yield energy (ATP) from the metabolism of glucose.     

Different effects of two types of H2-receptor antagonists, famotidine and roxatidine, on the mucus barrier of rat gastric mucosa

Compared with the aggressive factors, little attention has been paid to the mucosal defensive factors in ulcer therapy, and the role of the H2-receptor antagonists in gastric mucosal protection has not been well characterized. In the present study, the effects of different types of H2-receptor antagonists (famotidine and roxatidine) on rat gastric mucus cells were investigated using both biochemical and histological methods. Each drug (famotidine, 3 mg/kg; roxatidine, 100 mg/kg) was orally administered to rats by gavage once daily for 7 days. The biosynthesis and tissue content of mucin were compared in the gastric mucosa treated with each drug. Using anti-mucin monoclonal antibodies, the mucin content and immunohistochemical localization were also compared. Both the biosynthesis and the accumulation of gastric mucin were significantly decreased in the famotidine-treated rats, but not in the roxatidine. Both the content and the immunoreactivity of surface mucus cell-derived mucin were reduced by famotidine, while they were maintained in roxatidine-treated rat stomachs. There was no difference between the groups in the content and immunoreactivity of mucous neck cell-derived mucin. H2-receptor antagonists should be classified in relation to gastric surface mucus cell function, raising the possibility of more effective ulcer therapy.