Ulcer formation and cytoprotection by acetazolamide

Acetazolamide, a carbonic anhydrase inhibitor, was administered orally and subcutaneously to rats. Acetazolamide increased the gastric ulcerogenicity of indomethacin, but inhibited gastric ulcers produced by acidified aspirin. When administered alone to fasted rats, it did not produce gastric ulcers. Acetazolamide was also cytoprotective for the stomach (it reduced dose dependently the number of gastric necrotic lesions caused by absolute ethanol given orally) and for the small intestine (it prevented dose dependently intestinal lesions produced by administration of a high dose of indomethacin). Acetazolamide did not prevent the antiulcer effect of PGE2 (against aspirin-induced ulcers) nor the cytoprotective effect of 16,16-dimethyl PGE2 (against ethanol-induced gastric lesions). The degree of gastric cytoprotection increased with time after a single administration of acetazolamide; the optimal effect occurred 60 and 90 min after oral and subcutaneous administration, respectively. Pretreatment with indomethacin completely prevented the cytoprotective effect of acetazolamide; this suggests that the cytoprotective effect may be mediated by endogenous release of prostaglandins by the stomach. All the effects of acetazolamide reported here were observed after either oral or subcutaneous administration. The mechanism by which acetazolamide influences ulcer formation and is cytoprotective is unknown.     

Effects of orally administered human epidermal growth factor on natural and delayed healing of acetic acid-induced gastric ulcers in rats

We examined the effects of orally administered human epidermal growth factor (hEGF) on healing of acetic acid-induced gastric ulcers in rats. hEGF, given twice daily at 30 and 100 micrograms/kg for 2 weeks or at 100 micrograms/kg for 4 weeks to rats with ulcers, had no effect on natural healing or the gastric secretion, delayed one caused by indomethacin. Oral hEGF had no effect on basal histamine-stimulated gastric secretion, and stomach weight. These results indicate that oral hEGF has no biological activity on the pathophysiology of the stomach.     

Gastric antral ulcers produced by the combined administration of indomethacin with 2-deoxy-D-glucose in the rat

The influence of 2-deoxy-D-glucose (2DG) on indomethacin ulcers was studied in rats. 2DG (200 mg/kg i.v.) produced large round ulcers in the lesser curvature of the antrum and aggravated lesions of the corpus 6 h after treatments in indomethacin (40 mg/kg i.p.)-treated rats. Insulin (5 units/kg i.v.) also produced gastric antral ulcers similarly to 2DG. Antral ulcers were revealed rather clearly 48 h after the administration of indomethacin and 2DG when the corpus lesion index was reduced. 2DG or insulin had only a slight influence on the severity of other experimental gastric ulcers. Peripheral gastric secretagogues, bethanechol (1 mg/kg s.c. X 2) or histamine (10 mg/kg s.c. X 2) did not produce antral ulcers at the gastric secretory dose in the indomethacin-treated rats. High doses of atropine (1.0 and 10 mg/kg s.c.) prevented gastric antral ulcers. The combined administration of indomethacin with 2DG produced gastric antral ulcers similar to human gastric ulcers in rats. The combination of gastric acid secretion, vagus nerve stimulation and some other factors may be involved in gastric antral ulcers produced in rats.     

Effect of unmodified eel calcitonin on gastric acid secretion and gastric ulcers in the rat.

A new peptide, eel calcitonin (eCT), synthesized to the sequence of calcitonin (CT) extracted from the ultimo branchial bodies of eels, is now on the market in some countries for clinical use in the treatment of Paget's disease of bone and in the prophylaxis or treatment of certain osteoporoses. We have now studied the effect of eCT on the inhibition of gastric acid secretion and protection against experimentally induced gastric ulcers in rats as other CTs have previously been shown to have such effects. EelCT shows a dose dependent inhibition of gastric acid secretion, both volume and concentration of acid - dose range 100-900 ng/Kg injected subcutaneously. Central administration is also effective at a dose of 100 ng/rat. There is no published evidence for a direct effect of CTs in the stomach and there is considerable speculation on possible mediating pathways. Somatostatin may be involved in the inhibitory effect of eCT on gastric acid secretion because when administered both centrally or peripherally eCT is ineffective in rats depleted of somatostatin by pretreatment with cysteamine. However, other mechanisms must also be involved as eCT has no preventive effect against gastric ulcers induced by ethanol but has a high index of protection against ulcers induced by cold restraint stress or indomethacin.     

Protective effects of nedocromil sodium and sodium cromoglycate on gastroduodenal ulcers: a comparative study in rats

Stabilization of mast cells plays a key mechanism to protect gastrointestinal tract from injury. This study presents a comparative evaluation of mast cell stabilizers nedocromil sodium (NDS) and sodium cromoglycate (SCG) in experimental gastric and duodenal ulcers in rats. Wistar rats of either sex were used in this study. Both NDS and SCG, in the doses of 10, 30 and 100 mg/kg were given intraperitoneally for gastric secretion studies and by gavage for antiulcer studies. Acid secretion studies were undertaken in pylorus-ligated rats. Gastric lesions were induced by water immersion restraint stress (WIRS), indomethacin and ethanol whereas duodenal ulcers were produced by cysteamine. The level of glutathione (GSH) and gastric wall mucus were measured in glandular stomach of rats following ethanol-induced gastric lesions. SCG was more effective than NDS in preventing WIRS- and indomethacin-induced gastric lesions whereas reverse was true in ethanol- and cysteamine-induced ulcers. All the 3 doses of SCG offered almost equal protection against WIRS-induced gastric lesions whereas only medium and high dose of NDS provided significant protection in this model of ulcer. NDS significantly inhibited cysteamine-induced duodenal ulcers whereas SCG failed to do so. Pretreatment with NDS or SCG significantly and dose-dependently protected gastric mucosa against ethanol-induced injury, while the former drug appeared to be more effective. The cytoprotective effects of these two drugs were accompanied by the attenuation of ethanol-induced depletion of gastric wall mucus and GSH. The differential effects of NDS and SCG against various gastric lesions rationalize the possible benefits of a combined therapy (NDS+SCG) for the treatment of complex gastroduodenal ulcers. Received 29 April 2006; revised: 26 May 2006; accepted: 26 May 2006     

Antiulcer and gastroprotective effects of solon, a synthetic flavonoid derivative of sophoradin. Role of endogenous prostaglandins

Solon is a synthetic isoprenyl flavonoid derived from sophoradin which is isolated from the root of an ancient Chinese plant. Solon was administered orally or intraperitoneally to rats. It inhibited dose dependently gastric ulcers produced by acidified aspirin, water immersion and restraint stress. Solon was also gastroprotective for the stomach as it reduced dose dependently the gastric necrotic lesions induced by absolute ethanol given orally. The degree of gastroprotection decreased with time, the optimal effects occurring 60-90 min after oral administration. Pretreatment with indomethacin partly prevented the gastroprotective effects of Solon. When given alone to fasted rats, Solon increased dose dependently the mucosal content of prostaglandins (PG), suggesting that the protective effects of this drug may be mediated at least in part by endogenous PG.     

Gastroprotective effects of the insulin sensitizers rosiglitazone and metformin against indomethacin‐induced gastric ulcers in Type 2 diabetic rats

1. Gastric ulcers are common in Type 2 diabetic patients. Of all drugs used in the treatment of Type 2 diabetes, the insulin sensitizers thiazolidinediones (e.g. rosiglitazone) and metformin exhibit additional effects in ameliorating oxidative stress and inflammation, rendering them attractive candidates for the prevention of gastric ulcer in Type 2 diabetes. Thus, the aim of the present study was to evaluate the gastroprotective effects of rosiglitazone and metformin against indomethacin‐induced gastric ulcer in Type 2 diabetic and non‐diabetic rats. 2. Diabetes was induced by a single injection of streptozotocin (60 mg/kg, i.p., dissolved in 0.1 mol/L cold citrate buffer, pH 4.5), 15 min after administration of 120 mg/kg, i.p., nicotinamide. Three weeks after the successful induction of diabetes, rats were subjected to pyloric ligation and then injected immediately with 30 mg/kg, i.p., indomethacin. Three hours after indomethacin administration, rats were killed and gastric injury was evaluated. Ranitidine (50 mg/kg) was used as a reference drug and was administered in a single oral dose 1 h before indomethacin injection, as were rosiglitazone (3 mg/kg) and metformin (500 mg/kg). 3. Both rosiglitazone and metformin exhibited gastroprotective effects, as evidenced by significant decreases in the ulcer index, free and total acid output in gastric juice and gastric mucosal malondialdehyde concentrations, with concomitant increases in gastric juice pH (only with rosiglitazone), mucin concentrations, gastric mucosal concentrations of nitric oxide and catalase activity compared with untreated diabetic rats. Conversely, rosiglitazone and metformin had no effect on peptic activity and gastric mucosal prostaglandin E₂ content, particularly in the diabetic group, compared with the untreated groups. 4. In conclusion, rosiglitazone and metformin protect Type 2 diabetic rats against indomethacin‐induced gastric ulceration, most possibly via antisecretory actions, enhanced mucosal protection and anti‐oxidant activity. Rosiglitazone seems to be provide superior gastroprotection to metformin.     

A comparative study on the activity of lansoprazole, omeprazole and PD-136450 on acidified ethanol- and indomethacin-induced gastric lesions in the rat

1. The proton pump inhibitors lansoprazole (LP) and omeprazole (OP) and the cholecystokinin (CCK)-receptor antagonist PD-136450 (PD) provide a broad spectrum of activities in their ability to inhibit gastric acid secretion and protect the stomach against ulcerogens. In the present study, we investigated the protective effects of these compounds against gastric ulcers induced by acidified ethanol (AE) and indomethacin. 2. Both AE (60% ethanol in 150 mmol/L HCl, 1 mL/rat) and indomethacin (30 mg/kg) produced gastric haemorrhagic lesions in the rat 1 and 6 h after oral administration, respectively. 3. The gastric mucosal protective effects of LP (1-20 mg/kg), OP (0.5-10 mg/kg) and PD (1-20 mg/kg), administered either orally or subcutaneously (s.c.) 30 min before the administration of AE or indomethacin, were dose dependent against both models of ulcer induction. 4. To determine whether the cytoprotective effect of LP, OP and PD (each 10 mg/kg) was mediated by endogenous prostaglandins (PG), indomethacin (10 mg/kg, s.c.) was administered 15 min before AE to inhibit prostanoids biosynthesis. Indomethacin reduced the cytoprotective effects of OP, but not LP, administered either orally or s.c. Indomethacin reduced the cytoprotective effect of PD administered orally, although the effect was much less significant than when PD was administered s.c. The results exclude the role of PG in mediating the protective effects of LP, whereas the possibility exists for PG to have a role in mediating the protective effects of OP and PD. 5. To investigate the possible involvement of endogenous nitric oxide (NO) in the cytoprotective action of LP, OP and PD, we treated rats with a selective inhibitor of NO synthesis, namely NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg, s.c.). Administration of L-NAME 15 min prior to LP, OP or PD (each 10 mg/kg) orally or s.c. and challenge with AE or indomethacin did not significantly increase the degree of the ulcer index and L-NAME was not able to antagonize the protective effects of LP, OP and PD, thus excluding the role of NO in mediating the protective effects of these drugs. However, the effects of PD in reducing the indomethacin-induced ulcer index were less significant in the presence than the absence of L-NAME (P < 0.05 vs P < 0.001, respectively), suggesting a role for NO. 6. In conclusion, the results of the present study suggest that LP and OP are equally effective against AE- as well as indomethacin-induced gastric ulcers and were more potent than PD in protecting the stomach against ulcer formation. Lansoprazole, OP and PD bring about their cytoprotective action through the reduction of acid secretion and some other unknown mechanisms. However, OP and PD may exert their cytoprotective action through PG and NO pathways.     

Gastroprotective Effect of Oxalis corniculata (Whole Plant) on Experimentally Induced Gastric Ulceration in Wistar Rats

The objective of the present study was to investigate the antiulcer activity of methanol extract of Oxalis corniculata (whole plant) using pylorus ligation and indomethacin-induced gastric ulceration in Wistar rats. The extract was preliminary evaluated for acute oral toxicity test using Organisation for Economic Co-operation and Development guidelines 423. Further, it was studied for antiulcer potential at the dose levels of 125, 250 and 500 mg/kg. Ranitidine was used as a standard drug (100 mg/kg). Acid secretory parameters like gastric volume, pH, total acidity and free acidity were measured in pylorus ligation model, whereas numbers of ulcers, ulcers score and ulcer index was measured in pylorus ligated and indomethacin treated rats. Pretreatment of test extract significantly (p<0.05) decreased the gastric volume, total acidity, free acidity and increase in the pH of the gastric fluid in pylorus-ligated rats. It also showed significant (p<0.05) decrease in number of ulcers, ulcers score and ulcer index in pylorus ligated and indomethacin treated rats. Results of the study suggest that, the methanol extract of Oxalis corniculata possesses significant antisecretory and antiulcer effects and justify the traditional usage of this herb to treat peptic ulcers.     

Influence of Indomethacin Amphoteric Gel on Gastric Ulcerogenicity and Absorption of Indomethacin in Rats

Indomethacin is a potent and efficacious antiinflammatory agent. However, a limiting side effect is its ability to cause gastric ulceration. This study was designed to investigate the effects of an amphoteric gel on the gastric ulcerogenicity and pharmacokinetics of indomethacin. Oral administration (5 mg/kg) in a suspension and a gel formulation were compared to an intravenous (iv) formulation of indomethacin in rats. The iv formulation administered to rats produced large severe ulcers in some rats but not in others. In contrast, the oral suspension produced small ulcers in all rats. The difference in toxicities is attributed to a centrally mediated action as a result of high plasma levels of indomethacin following iv administration, compared to locally mediated action with the suspension, resulting from local high concentrations of indomethacin on the apical epithelial surface because of the presence of indomethacin crystals. Oral administration of the gel formulation did not result in any gastric ulceration and improved the bioavailability of indomethacin to 115.5%, compared with 68.2% for the suspension. The reduced gastrointestinal toxicity of indomethacin in the gel was attributed to the gel's ability to dissolve indomethacin, preventing the localized high concentration observed with the suspension and possibly providing a gastric protectant phospholipid. The gel formulation doubled the oral bioavailability and the t _max of indomethacin compared to the suspension but did not affect the half-life. The results indicate that the local irritant effect of indomethacin, in rats, can be reduced by appropriate formulation design and suggest that the ulcerogenicity index for indomethacin can be improved by the use of an amphoteric gel formulation.     

The effects of some nonsteroidal anti-inflammatory drugs on experimental induced gastric ulcers in rats

Celecoxib is a frequently used nonsteroidal anti-inflammatory drug (NSAID) in the treatment of rheumatoid arthritis and osteoarthritis. It selectively inhibits cyclooxygenase II (COX-2) enzyme which is responsible for the production of proinflammatory prostanoids. It has been proposed that since it does not significantly inhibit COX-1, an isoenzyme responsible for the production of cytoprotective prostanoids, celecoxib has fewer side effects in the stomach. Dipyrone which is a drug with potent analgesic activity has no significant inhibitory effect on COX. In this sudy, the effects of celecoxib and dipyrone on experimentally induced gastric ulcers in rats were compared with respect to different parameters. In the first experiment, in an attempt to identify the best dose for both drugs, a histamin-induced gastric ulcer model was used and each drug was administered at 5, 25 and 100 mg/kg doses, and ulcer index, acidity and mucus secretion were measured in the stomach. The best dose was determined to be 5 mg/kg for both drugs. Celecoxib was found to delay ulcer healing when compared to dipyrone especially when ulcer index was used as measure. In the second experiment, ulcer index, acidity, mucus secretion, and the levels of myeloperoxidase (MPO), lipid peroxide (MDA), non-protein sulfhydryl groups (NP-SH), and prostaglandin E₂ (PGE₂) were investigated in the stomach of rats with gastric ulcers induced by histamine, stresss and diethyldithiocarbamate (DDC). While celecoxib increased the ulcer index in stress-induced ulcer, dipyrone decreased the index in DDC-induced ulcer. Celecoxib also caused a significant increase of gastric mucus secretion in histamine-induced ulcer model. Gastric lipid peroxidation was significantly increased by dipyrone in the control group without gastric ulcer induction, whereas it was significantly increased by celecoxib in the histamine-induced and stress-induced ulcer groups. Dipyrone promoted a decrease in gastric NP-SH levels in the control group with stress-induced ulcer. With respect to gastric MPO activity, dipyrone caused a decrease in the histamine-induced ulcer group but it caused an increase in the stress-induced and DDC-induced ulcer groups. Gastric PGE₂ levels in the control group without gastric ulcer induction were not affected by celecoxib while they were increased by dipyone. In conclusion, celecoxib prompted the formation of experimentally induced gastric ulcers more than did dipyrone. The study was supported by Osmangazi University Research Funds. Received 8 February 2007; revised 6 March 2007; accepted 13 April 2007     

Gastroprotective effects of bitter principles isolated from Gentian root and Swertia herb on experimentally-induced gastric lesions in rats

Gentianae Radix, the dried root and rhizoma of Gentiana lutea L. (Gentianaceae), has long been used as a remedy for liver and stomach inflammation, eye troubles, etc. In this paper, the gastroprotective effects of the methanol extract of Gentian root (GM) were studied using different gastric lesion models. In pylorus-ligated rats, administration of GM in the duodenum suppressed gastric juice secretion and total acid output in a dose-dependent manner. Oral or duodenum administration of GM showed significant protection against acute gastric ulcer induced by aspirin plus pylorus ligation, water-immersion restraint stress-induced ulcers, and gastric mucosal injury induced by ethanol. Furthermore, four secoiridoid glycosides, amarogentin (A1), gentiopicroside (A2), amaroswerin (A3), and swertiamarin (A4), were obtained from Gentian root or Swertia herb, and their protective effects against stress-induced ulcers and ethanol-induced gastric mucosal injury were evaluated. The doses required for 50% inhibition (ID₅₀) of A1, A3, and A4 on stress-induced ulcers were calculated to be 5.76, 2.58, and 167 mg/kg respectively. The protective effect of A2 at 250 mg/kg was 26.5%. On ethanol-induced gastritis, 5.0 mg/kg of A1 and A3 showed remarkable suppressive effects (33.7 and 45.4%, respectively), and 20 mg/kg of A4 exhibited a suppressive effect (30.8%). The effects of A1, A3, and A4 on ethanol-induced gastric lesions were canceled by 5.0 mg/kg indomethacin pretreatment. These results suggest that the therapeutic effects of Gentian root on gastric lesions are associated with enhanced mucosal defensive factors via the prostaglandin pathway in the cell membrane, and that secoiridoid glycosides contribute to this activity.     

Inhibitory Effects of ECQ on Indomethacin-Induced Gastric Damage in Rats

We investigated inhibitory effects of extract containing quercetin-3-O-β-D-glucuronopyranoside (ECQ) extracted from Rumex Aquaticus Herba on indomethacin-induced gastric damage in Rats. Gastritis was induced in male Sprague-Dawley rats (200~220 g) by oral administration of indomethacin at a dose of 40 mg/kg. One hour before administration of indomethacin, animals were orally pretreated with ECQ at doses of 0.3, 1, 3 or 10 mg/kg. Six hours after indomethacin administration, the rats were sacrificed and the stomach was excised and opened along the greater curvature, and the surface area of gastric lesion was measured using optical microscope. Superoxide dismutase (SOD), catalase (CAT), myeloperoxidase (MPO) activities and malondialdehyde (MDA) levels were measured by ELISA. Western blot analysis was performed to detect protein expression of SOD-2. Linear hemorrhagic mucosal lesions were observed in the stomach 6 hours after oral administration of indomethacin. Pretreatment with ECQ significantly reduced the severity of the lesions in a dose-dependent manner. It also inhibited the reductions in SOD and CAT activities and SOD expression by the indomethacin-induced gastric damage. In addition, the pretreatment with ECQ significantly suppressed the elevation of the MPO activity and the MDA levels induced by indomethacin. These results suggest that ECQ has the inhibitory effects via antioxidative action against indomethacin-induced gastritis in rats.     

Anti-Ulcerogenic Evaluation of the Persian Tooth Brush Tree (Salvadora Persica)

The effect of the lyophilized decoction of Salvadora persica on ulceration induced by ethanol, indomethacin and cold restraint stress was investigated in rats. Pre-treatment tests in rats revealed that the extract possessed significant protective action against ulcers induced by ethanol or stress. The protective effect was not altered by indomethacin, administered as a prostaglandin biosynthesis inhibitor. Salvadora persica shows some increase in gastric mucus with a certain diminution in the ulcer index in cold stress-induced ulcers. However, the drug failed to heal ethanol and indomethacin-induced ulcers.     

Role of endogenous glucocorticoids in the healing of gastric erosions and chronic gastric ulcers in rats

To investigate the role of endogenous glucocorticoids in the healing of gastric lesions, we compared the healing of indomethacin- or cold-restraint-induced gastric erosions as well as aceticacid-induced ulcers in sham-operated rats, adrenalectomized rats and adrenalectomized rats with corticosterone replacement. Adrenalectomy was performed immediately after the formation of gastric erosions (4 h after indomethacin administration or 6 h after the onset of cold-restraint stress) or chronic ulcers (in 3 days after ingestion of acetic acid into the luminal side of the stomach). All ulcerogenic stimuli caused an increase in corticosterone production. Adrenalectomy created corticosterone deficiency and delayed the healing of gastric erosions and chronic ulcers. Replacing corticosterone reversed the deleterious effect of adrenalectomy on healing of gastric damage in adrenalectomized rats. These results suggest that glucocorticoids participate in natural healing processes of injured gastric mucosa. The data obtained also indicate that participation of glucocorticoid in the healing of gastric lesions is more evident under prostaglandin deficient conditions.     

Gastric cytoprotective anti-ulcerogenic actions of hydroxychalcones in rats.

The preventive effects of hydroxychalcone derivatives on ulcer formation induced by severe necrotizing agents such as 60% ethanol in 150 mM HCl (HCl-ethanol) and 0.2 N NaOH in rats were examined. Among the compounds tested, 2',4'-dihydroxychalcone gave the strongest activity in both experimental models and protected the gastric mucosa from the insult of either necrotizing agent at oral doses ranging from 1 to 10 mg/kg, as evidenced by a dose-related reduction in the ulcer index. The mucosal protective activity of 2',4'-dihydroxychalcone was not affected by pretreatment with indomethacin (5 mg/kg, s.c.). To investigate the detailed mechanism of the mucosal protective action of 2',4'-dihydroxychalcone, its inhibitory effects on the decrease in the hexosamine content from the gastric mucus induced by HCl-ethanol were studied by using it in combination with a dye, Alcian blue. As a result, 2',4'-dihydroxychalcone at an oral dose of 10 mg/kg inhibited the decrease in the dye-recovery from the gastric mucus induced by HCl-ethanol. PGE2 at an oral dose of 0.1 mg/kg exhibited a similar action. These results established that 2',4'-dihydroxychalcone is a potent cytoprotective agent similar to PGE2 effectively preventing gastric ulcer formation induced by strong necrotizing agents and seems to suggest that this compound protects the stomach against its own peptic secretions by reinforcement of gastric resistances. In fact, 2',4'-dihydroxychalcone prevented ulcer formation induced by water-immersion stress in rats and also showed a marked enhancement of the healing of acetic acid-induced gastric ulcers in rats.     

EFFECTS OF PROSTAGLANDIN D2 AND OMEPRAZOLE ON INDOMETHACIN-INDUCED GASTRIC ULCERS IN RATS

1. The mechanism of indomethacin-induced gastric ulcers was investigated by measuring tissue prostaglandins (PG) levels. 2. The effects of PGD2 and omeprazole, an H+ pump inhibitor, were also estimated. 3. Four kinds of PG--6-keto PGF1 alpha, PGF2 alpha, and PGD2--in rat gastric mucosa were measured by high performance liquid chromatography. 4. All PG levels decreased 1 h after oral administration of 2 mg/kg indomethacin, although they recovered considerably 24 h after administration. No gastric ulcers were observed throughout the experiments in rats treated with 2 mg/kg indomethacin. 5. All PG were not detected 1 h, and even 24 h after administration of 12 mg/kg indomethacin. Over 6 h after administration, gastric ulcers were observed. 6. Premedication with omeprazole prevented ulcer formation, although it did not improve gastric mucosal PG levels. Administration of PGD2 also reduced ulcer formation, and considerable amounts of PGD2 in gastric mucosa were detected. 7. It can be concluded that H+ is a determining factor in the genesis of indomethacin-induced gastric ulcers and that persistent decreases in tissue PG levels also participate in ulcer formation.     

Effects of 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride on acute gastric lesions, acid secretion in rats and on some hemodynamic parameters in cats

The effectiveness of 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (AN12) on acute ulcer models and gastric acid secretion in rats was compared with the action of the histamine H2-receptor antagonist roxatidine (R). AN12 or R given orally, produced significant, dose-dependent decreases in stress- and indomethacin-induced ulcers. The ED50 value of AN12 and R were 0.40 (0.27-0.60) and 13.27 (9.13-19.29) mg/kg, respectively, for stress ulcers and 0.68 (0.17-2.61) and 25 mg/kg, respectively, for indomethacin ulcers. The length and number of ethanol-provoked gastric damages were significantly reduced by R (50 and 100 mg/kg p.o.) but not by AN12 (0.5-2 mg/kg p.o.). In pylorus-ligated rats, AN12 (2 mg/kg p.o.) and R (50 and 100 mg/kg p.o.) significantly inhibited basal gastric acid secretion, increased pH and decreased acidity. The influence of AN12 (2 mg/kg) on the volume of stomach juice was close to that of R (100 mg/kg), AN12 (0.1-1.0 mg/kg i.v.) did not significantly affect the hemodynamics of anesthesized cats. It is suggested that the influence of some CNS amine neurotransmitters may be included in part, in the effects of AN12.     

Influence of clonidine and a new related imidazoline derivative (tizanidine) on rat gastric mucosa

The effects of a novel imidazoline derivative (tizanidine) on experimental ulcers and glycoproteins in the gastric mucosa and juice of rats were examined and compared with that of clonidine. Tizanidine and clonidine inhibited indomethacin ulcer and aspirin ulcers. Tizanidine, however, did not influence stress ulcer while clonidine showed an inhibitory effect. Although tizanidine and clonidine did not increase glycoproteins in the gastric mucosa, they prevented aspirin-induced changes of glycoproteins in the gastric mucosa and juice, as well as aspirin-induced gastric ulcers. The results suggest that, as with clonidine, tizanidine inhibits drug-induced gastric ulcers and that tizanidine-mediated gastric mucosal protection may prevent gastric ulcers induced by anti-inflammatory agents.     

Effects of pantoprazole on ulcer healing delay associated with NSAID treatment

Nonsteroidal anti-inflammatory drugs delay gastric ulcer healing, and the ability of proton pump inhibitors to counteract this detrimental effect is debated. This study evaluates the effects of pantoprazole on experimental gastric ulcer healing in the presence of indomethacin. Rats with acetic-acid-induced gastric ulcers were orally treated for 3 or 7 days with pantoprazole (15 mumol/kg/day) or famotidine (20 mumol/kg/day), alone or in combination with indomethacin (3 mumol/kg/day). Ulcerated tissues were processed to assess ulcer area, malondialdehyde, proliferating cell nuclear antigen (PCNA) and cleaved caspase-3. Experiments on pylorus-ligated rats indicated that pantoprazole and famotidine were employed at equivalent inhibitory doses on gastric acid secretion (-67.9% and -64.5%, respectively). Indomethacin delayed ulcer healing both at days 3 and 7 (+22 and +35 mm(2) vs control ulcer, respectively). At day 3, pantoprazole was more effective than famotidine in promoting ulcer healing in indomethacin-treated animals (-53.6 and -31.6 mm(2) vs indomethacin, respectively). Malondialdehyde levels and caspase-3 activation in ulcers were increased by indomethacin (+79% and +3.7 folds vs control ulcer, respectively), and these effects were counteracted by pantoprazole (-77.9% and -3.5 folds vs indomethacin, respectively), but not famotidine. Increments of ulcer PCNA expression (+2.5 folds vs normal) were enhanced further by pantoprazole or famotidine, alone or in combination with indomethacin (+8.6 and +10.3 folds vs normal, respectively). Similar results were obtained after 7-day treatments of ulcerated animals with test drugs. It is concluded that, along with acid suppression, pantoprazole exerts acid-independent effects on ulcer healing, which can be ascribed to a decrease in tissue oxidation and apoptosis.