Experimental Peptic Ulcer Research Articles

Design and Optimization of Omeprazole-Curcumin-Loaded Hydrogel Beads Coated with Chitosan for Treating Peptic Ulcers.

This study aimed to formulate a pharmaceutical dosage form containing omeprazole (OMP) and curcumin (CURC) to treat experimental peptic ulcers. OMP and CURC were preliminarily complexed with hydroxypropyl-β-cyclodextrin for enhancing their solubilization. After that, the combined complex (CURC/OMP) was loaded to alginate beads to sustain their release and then coated with chitosan. Finally, we tested the anti-ulcerogenic impact of the best formula versus free OMP or OMP-only-loaded beads. The formulated spherical beads' diameter ranged from a minimum value of 1.5 ± 0.08 mm to 2.6 ± 0.24 mm; the swelling results ranged from 400.00 ± 8.5% to 800.00 ± 6.2%. The entrapment efficiency was in a range from 60.85 ± 1.01% to 87.44 ± 1.88%. The optimized formula (F8) showed a maximum EE% (87.44 ± 1.88%), swelling (800.00 ± 6.2%), and diameter in the range of 2.60 ± 0.24, with a desirability of 0.941. In the first hour following the administration of the free drug complex, 95% of OMP and 98% of CURC were released. This is unacceptable for medications that require a delayed release in the stomach. The initial drug release from hydrogel beads was 23.19% for CURC and 17.19% for OMP after 2 h and 73.09% for CURC and 58.26% for OMP after 12 h; however, after 24 h, 87.81% of CURC and 81.67% of OMP had been released. The OMP/CURC beads showed a more stable particle size (0.52 ± 0.01 mm) after 6 weeks. In conclusion, the OMP/CURC hydrogel beads give stronger anti-ulcer effectiveness compared to free OMP, CURC-only beads, and OMP-only-loaded beads, indicating a prospective application for managing peptic ulcers.

Acute and sub-chronic toxicity assessment and evaluation of the gastro-protective activity of polyherbal formulation \u201cMystomate4\xae\u201d against gastric ulcer in experimental laboratory animal

BackgroundUlcer remains a health challenge worldwide with antibiotics and proton pump inhibitors as major management therapy. The study investigated the acute, sub-chronic toxicity and gastrointestinal protective activity of a polyherbal formulation (Mystomate4®) used locally in Nigeria.MethodsOral LD50 and the sub-chronic toxicity test were determined in mice and rats. Mice were grouped into 8 groups of 8 mice each. They were dosed a graded concentration of the formulation (1.28, 2.56; 5.12; 10.24; 20.48; 40.96; 81.92; 163.84 g/kg body weight). The graded dose used was arrived at after an initial pilot study. Thereafter doses were chosen around the dose obtained from the pilot study. Animal were dosed orally and observed for sign of toxicity and number of death recorded after 24 h. The sub-chronic toxicity study was carried out for 3 months in rats at a dose of 2.5 and 5.0 g/kg body weight arrived at by titrating down the LD50 value after which some vital tissues were harvested and assessed for toxicity using relevant biomarkers. Anti-ulcer activity was evaluated in rats using ethanol, indomethacin and pylorus ligation induced ulcer models. Data were analysed with Graph Pad Prism version 5.0 using appropriate statistical method and significant level placed at p ≤ 0.05.ResultsThe acute toxicity study showed an LD50 result of 22,837.21 g/kg. The sub-chronic toxicity study resulted in a significant reduction in body weight due to significant decrease (p ≤ 0.05) in feed consumption. Biochemical analyses of the blood samples showed a significant increase (p ≤ 0.05) in creatinine and albumin level in the 2.5 mg/kg female group. ALT was significantly increased in all the treated rats except in 2 mg/kg female rats. Alkaline phosphatase significantly increased in high dosed male (HM) group while blood urea:creatinine ratio was significantly lowered in all the treated groups. There was a significant increase in serum TGL in all rats while LDL was significantly increased and decreased in HM and high dosed female (HF) respectively.ConclusionMystomate4® showed significant protection against ethanol and indomethacin-induced ulcer models but did not modify the gastric parameters in pylorus ligation-induced ulcer model. The polyherbal formulation is nontoxic with promising potentials for treating experimental peptic ulcer.

Gastroprotective effect of tarantula cubensis extract in the indomethacin-induced peptic ulcer model in rats

Aim: Gastric ulcers are the most common gastrointestinal disease, due to several factors in the industrialized world. They may also occur after many pharmacological agents, combined with gastroprotective agents such as proton pump inhibitors (PPI) or anti-acids, are used as a preferred approach to maintaining gastrointestinal health. Unexpected adverse effects in these combinations make natural products an important alternative option. Methods: Therefore, the main aim of this study is to investigate one natural compound, the Tarantula cubensis extract (TCE), in the experimental peptic ulcer model which was created by a single administration of indomethacin (40 mg/kg, body weight) to fed state Wistar-albino rats. The animals were pre-treated with two-doses of the TCE (0.2 ml/kg) before the indomethacin administration. After six hours, they were euthanized and the stomach tissue was isolated for biochemical and immunohistochemical analysis. Total antioxidant status/total oxidant status (TAS/TOS), prostaglandin E2 (PGE2), and nuclear factor kappa-B (NF-κB) levels were determined with ELISA in tissue homogenates. Caspase-3, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α), were visualized with immunohistochemistry in intact tissues. Results: Pre-treatment with TCE increased PGE2 levels and decreased total oxidative status (TAS/TOS). Additionally, TCE alleviated the increase of (NF-κB) levels due to the indomethacin administration. Histopathological and immunostaining results showed that TCE mitigated elevated immunoreactivity of the caspase-3, COX-2, iNOS, and TNF-α which were the results of the indomethacin administration. Conclusion: Our study demonstrated that pre-TCE treatment ameliorated indomethacin-induced peptic ulcers via antioxidant and anti-inflammatory actions.

Pomegranate bioactive constituents suppress indomethacine induced experimental peptic ulcer

Peptic ulcer disease, is the most common ulcer of the gastrointestinal tract. Several investigations have confirmed the role of oxidative stress in developmental peptic ulcers, possibly via the formation of free radicals. Currently due to several adverse effects of chemical drugs, herbal medicines are generally used in the treatment of peptic ulcer. The aim of this study was to evaluate the role of pomegranate juice on experimental gastric ulcer induced by indomethacin and exhibit its powerful antioxidant and anti-inflammatory properties. Forty male albino rats were used in this study and divided into four groups (control, pomegranate, peptic ulcer and treated) groups. Pomegranate and treated groups received 0.5 ml pomegranate juice/rat/day orally by gavage. After four weeks, liver and kidney functions were estimated, stomach malondialdehyde, superoxidedismutase, paraoxonase and total antioxidant capacity were determined by colorimetric methods. Serum interleukin-1 α was estimated by ELISA while, serum homocysteine was measured by high performance liquid chromatography (HPLC). Pomegranate supplementation significantly increased stomach total antioxidant, superoxide dismutase and paraoxonase levels concomitant with a reduction of malondialdhyde, interleukin-1 α and homocysteine values in treated group compared to peptic ulcer group. In conclusion, pomegranate seems to be a highly promising plant in protecting against the peptic ulcer through its antioxidant anti-inflammatory properties.

Effect of lapachol, a naphthaquinone isolated from Tectona grandis, on experimental peptic ulcer and gastric secretion

Lapachol, a naphthaquinone isolated from the roots of Tectona grandis given at a dose of 5 mg kg-1 p.o. twice daily for 3 days was found to have an anti-ulcerogenic effect on subsequently induced experimental gastric and duodenal ulcers in rats and guinea-pigs. Its action appears to be associated with an effect on the protein content of gastric juice, and it reversed aspirin-induced changes in peptic activity, protein and sialic acid.

On the specialities of the effect of several herbs on experimental peptic gastric ulcer

On the specialities of the effect of several herbs on experimental peptic gastric ulcer

Mucosal concentration of basic fibroblast growth factor in the healing process in human giant gastric ulcers.

Basic fibroblast growth factor (bFGF) is a key factor in the healing of human and experimental peptic ulcers, but the behavior of bFGF in human giant gastric ulcer remains to be determined. We determined the bFGF content in the rim of giant ulcers (bFGF rim) and in non-ulcerated mucosa located opposite the ulcer (bFGF opposite) before and during treatment. Biopsy specimens were endoscopically obtained from 31 patients with giant gastric ulcers and 17 patients with small ulcers before and 2, 4 and 8 weeks after treatment. The bFGF concentrations in the specimens were measured using a sandwich enzyme immunoassay. Before treatment, the bFGF rim and bFGF opposite concentrations were not associated with ulcer size. The bFGF rim concentration before treatment in the rapid healing group was higher than that in the slow healing group, but no significant difference in bFGF opposite concentrations were found between the two groups. The bFGF rim concentration in the rapid healing patients decreased during treatment, while the slow healing patients showed an inverse response. The bFGF opposite concentration did not change during treatment and bFGF rim concentrations in Helicobacter pylori-positive stomachs were significantly lower than those in H. pylori-negative stomachs. The bFGF rim concentration is not involved in the formation of giant gastric ulcers in humans. However, the bFGF rim concentration does appear to promote healing. The bFGF opposite concentration is not related to either the formation or healing of giant gastric ulcers.

Duodenal ulcer prevalence: experimental evidence for the possible role of dietary lipids.

Mapping the geographical distribution of duodenal ulcer in relation to staple diets, and experiments on animal peptic ulcer models suggested that the lipid fraction in certain foodstuffs had a protective effect which was most marked in the lipid obtained from Horse gram (Dolichos biflorus). Lipid obtained from stored polished rice or rice bran was ulcerogenic. Further animal experiments were designed to investigate the protective and healing effects of Horse gram lipid (HGL) against peptic ulceration. Three effects were investigated in rats: (i) the protective effect of HGL on peptic ulceration produced by using pyloric ligation in combination with South Indian diet or rice bran oil, or by cysteamine, alcohol or aspirin; (ii) the effect of HGL on mast cell degranulation in response to pyloric ligation and rice bran oil; and (iii) the healing effect of HGL on acute gastric ulceration produced by alcohol, on chronic gastric ulceration produced by topical acetic acid or on chronic duodenal ulcer following cysteamine. Horse gram lipid was shown to be protective and to promote ulcer healing in all the models used. Mast cell degranulation was inhibited. The experiments confirm the presence of a lipid in certain staple foods that have protective and healing properties in experimental peptic ulcer animal models. The differences in the prevalence of duodenal ulceration between different regions in some developing countries with a high prevalence of Helicobacter pylori infection might be explained by the presence or absence of protective lipids or ulcerogenic factors in the staple diet.

Increase of vgf mRNA in the dorsal vagal complex in brain and rats with experimental peptic ulcers

Increase of vgf mRNA in the dorsal vagal complex in brain and rats with experimental peptic ulcers

On the Absorption of Alendronate in Rats

Alendronate is an antiosteolytic agent under investigation for the treatment of a number of bone disorders. Since the compound is a zwitterion with five pKavalues and is completely ionized in the intestine at the physiological pH, absorption is poor; less than 1% of an oral dose is available systemically in rats. In the present studies, absorption was found to be predominantly in the upper part of the small intestine. Administration of buffered solutions of alendronate (pH 2–11) did not improve absorption. Whereas food markedly impaired the absorption of alendronate, EDTA enhanced absorption in a dose‐dependent manner. Pretreatment of rats with ulcerogenic agents, mepirizole, acetylsalicylic acid, or indomethacin, resulted in a 3–7‐fold increase in the oral absorption of alendronate. The absorption of phenol red, added as an indicator of intestinal tissue damage, was also increased in rats with experimental peptic ulcers. The enhanced absorption of alendronate observed in rats with experimental peptic ulcers was attributed to the alteration of the integrity of the intestinal membrane.

Gastric acid secretion and gastrin release in the baboon.

Significant species differences have been demonstrated in gastric physiology, a factor that limits extrapolation of animal data to man. Primate physiology is thought to be similar to that of man; however, gastric function has not been adequately documented in the primate. In the present study six baboons (body weight 25.5 +/- 1.8 kg) were trained to sit in a chair and gastric acid secretion and gastrin release was studied in conscious animals. Mean basal acid secretion was 1.3 +/- 0.1 mmol (H+)/hr. Maximum output after pentagastrin (12 micrograms/kg/hr) was 9.5 +/- 0.9 mmol (H+)/hr and 11.0 +/- 0.4 mmol (H+)/hr after histamine (40 micrograms/kg/hr). A statistically significant (by cosinor analysis) circadian rhythm was demonstrated for intragastric pH over 24 hr in fasted baboons (P less than 0.001). Mean basal serum gastrin level was 37.7 +/- 8.3 pg/ml. The integrated gastrin response after administration of a protein rich meal was 2.52 +/- 0.07 ng x min/ml and this increased to 5.17 +/- 0.18 ng x min/ml (P less than 0.05) following simultaneous administration of a meal with atropine (0.2 mg/kg) (P less than 0.05). Our results suggest that there is significant basal and stimulated acid secretion in the baboon; the amount of acid secreted is similar to that reported in man. Gastric pH demonstrated a circadian rhythm. Postprandial gastrin release was significantly enhanced by cotreatment with atropine. As the present findings are similar to those previously reported in man, the baboon may be a useful model for further studies in gastric physiology and experimental peptic ulceration.

Helicobacter pylori affects the quality of experimental gastric ulcer healing in a new animal model

Helicobacter pylori has been implicated in the genesis of human gastritis, dyspepsia, and peptic ulcers. However, its influence in the quality of experimental gastric ulcer healing has not been previously investigated. Standardized gastric fundic ulcers were produced in 50 male Sprague-Dawley rats (150–200 g) by a 4 mm in diameter focal, serosal application of 100% acetic acid. Thirty rats were administered 2 ml H. pylori suspension (urease producing, ATCC 43504) in normal saline (10 8 CFU/ml) 2×/day for 7 days. Twenty rats (controls) received 2 ml normal saline 2×/day for 7 days. Gastric ulcer surface area was measured under a dissecting microscope and mucosal specimens were obtained for qualitative and quantitative histology. No gross or microscopic duodenal abnormalities were identified at sacrifice. Ninety percent of control rats showed grossly and microscopically entirely healed ulcers. The remaining 10% showed partially reepithelialized ulcers (area, 0.78 to 1.77 mm 2; mean, 1.27 ± 0.7 mm 2). The grossly “healed” mucosa demonstrated marked dilatation of gastric glands lined with mature surface epithelial cells. Parietal cells were scanty (5–10% of all cells). One hundred percent of the H. pylori-exposed rats showed persistence of chronic active ulcers (area, 1.76 to 19.63 mm 2; mean, 8.95 ± 6.15 mm 2). The ulcer beds were infiltrated by acute and chronic inflammatory cells, abundant fibroblasts, and capillary networks. The raised ulcer borders were characterized by dilated glands lined by mature surface epithelial cells. Various special stains demonstrated the presence of H. pylori in the surface mucus and within the crypts. We conclude that (1) H. pylori delays healing of experimental gastric ulcers distorting the restoration of mucosal architecture and (2) this animal model is extremely useful for the study of the role of H. pylori in the healing of experimental peptic ulcers.

Administration of sucralfate prolongs survival of animals with experimental peptic ulceration

Ligation of the pig bile duct (BDL) results in 100% incidence of pars esophageal ulceration within 48 hours of the procedure. Usually such ulceration is uniformly fatal unless a highly selective vagotomy is performed simultaneously with the BDL. The administration of sucralfate to pigs with BDL prolonged their survival for up to 7 days, with evidence of healing of the ulcer on macroscopic and histologic observations. An increase in cell proliferation in the squamous epithelium of the ulcerated area was also seen in this sucralfate group. These features were not seen in controls, pigs with BDL only, or pigs with BDL and with magaldrate (Riopone), colloidal bismuth subcitrate (DeNol), or carbenoxolone. Analysis by Sepharose 2B gel filtration showed that there was no significant difference in the amounts of polymeric mucin in any group, with a wide scatter of the data seen especially for pigs in the untreated BDL-only group. This study suggests that sucralfate may enhance healing in this experimental pig ulcer model via a mechanism independent of the stimulation of mucus secretion. We propose that coating the mucosa with sucralfate provides a temporary substitute barrier that creates a microenvironment conducive to wound repair by mucosal proliferation.

P-554 - Effects of 3-hydroxy-2-methylimidazo[2, 1-b]benzothiazole(NIK-228) on gastric acid secretion and various experimental peptic ulcers in rats.

P-554 - Effects of 3-hydroxy-2-methylimidazo[2, 1-b]benzothiazole(NIK-228) on gastric acid secretion and various experimental peptic ulcers in rats.

Sucralfate in the prevention of porcine experimental peptic ulceration

Sucralfate is the first drug to be shown to prevent ulceration in bile duct-ligated pigs. Usually such ulceration is uniformly fatal. Seven pigs in each of four groups in this study received only saline, or sucralfate (1 g every six hours), famotidine (40 mg per day), or misoprostol (200 μg every six hours). A Foley catheter was placed into a gastrectomy after bile duct ligation. Similar groups of sham-operated pigs were also prepared. After 48 hours, all saline-, famotidine-, or misoprostol-treated pigs showed severe macroscopic ulceration, whereas only two of those treated with sucralfate showed minimal macroscopic ulceration. Until now, only highly selective vagotomy has reduced ulceration caused by bile duct ligation. The present results suggest that acid inhibition is not the only important factor in healing bile duct ligation-induced peptic ulceration.

種々の抗潰よう剤の実験潰ようにおける抗潰よう効果の評価

A retrospective bibliographical review was carried out to evaluate objectively the antipepticulcer activity of various agents in experimental animal models. In the present study, we selected benexate, cetraxate, clebopride, plaunotol, sofalcone, teprenone, and troxipide, which have been approved in Japan from 1979 to 1988, as enhancers of mucosal defense.Relationship between ulcer inhibition rate (UIR) and pharmacological effective oral dosewas examined in rats, as regards eight experimental peptic ulcer models. Most of theagents inhibited stress-, indomethacin-, and acetic acid-induced ulcer. It was found thatthe dose exhibiting the, pharmacological effect was remarkably different .among agents ineach model or among models in each agent. Therefore, the dose for UIR 50%, UIR50% (or UIR30% in acetic acid ulcer), which was calculated by the least-squares linear regressionanalysis of UIR versus logarithm of dose, was used as an index for the evaluation of eachinhibitory activity against ulceration. It was found that cetraxate was relatively. effectivein ethanol ulcer, plaunotol in stress and aspirin ulcer, and teprenone in indomethacin andethanol ulcer. Clebopride and plaunotol showed smaller UIR50% againststress ulcer, andteprenone and troxipide showed smaller UIR50% against indomethacin ulcer. Smaller UIR50% for ethanol ulcer was found with sofalcone and teprenone, and smaller .UIR30%for acetic acid ulcer was found with sofalcone. It is suggested that UIR50% (or UIR30%) may be a useful index for evaluating the preclinical anti-ulcer property and its rank orderamong various agents even in the absence of well-designed comparative studies.

The protective effect of meciadanol (O-methyl-3(+)-catechin) on experimental ulceration

Meciadanol, (O-methyl-3(+)-catechin), a histidine decarboxylase inhibitor was shown to have a marked protective action against experimental peptic ulceration in three rat models. The three methods used to induce ulceration were the instillation of absolute alcohol, pyloric ligation following an ulcerogenic South Indian diet and the instillation of rice bran oil into the stomach after pyloric ligation. Meciadanol was shown to reduce incidence, numbers and areas of ulceration and protected mast cells against degranulation and to preserve a normal vascular patterns. Furthermore, Meciadanol reduced gastric acid output and concentration in the pylorus ligation model. These results indicate that Meciadanol may be useful for the treatment of peptic ulcers in humans.

Effect of vagotomy, ?-tocopherol, and arachidene on lipid peroxidation in different parts of the gastorduodenal zone in rats with experimental peptic ulcer

Effect of vagotomy, ?-tocopherol, and arachidene on lipid peroxidation in different parts of the gastorduodenal zone in rats with experimental peptic ulcer

The ulcerogenic and protective action of rice and rice fractions in experimental peptic ulceration.

The ulcerogenic and protective effects of various rice fractions in the diet were studied in the pylorus ligated ulcer model in the rat. Oil present in rice and particularly rice bran becomes ulcerogenic on storage and in this model results in a significant increase in the median (range) numbers of ulcers from six (one to ten) to nine (six to 15) (P less than 0.05). The ulcerogenic effect of stored rice bran oil was reversed by cysteine which significantly reduced the ulcer incidence from 100% to 60% (P less than 0.005) and the numbers of ulcers from 26 (six to 70) to one (zero to four) (P less than 0.001). Fresh rice bran significantly reduced the numbers of ulcers from six (one to ten) to one (one to four) (P less than 0.05). Similarly, unmilled rice and freshly milled newly harvested rice was also shown to be protective in this model by significantly reducing the ulcer incidence from 87.5% to 50% and 0% respectively (P values less than 0.025) and the numbers of ulcers from three (zero to 17) to one (zero to one) and zero (zero to zero) respectively (P values less than 0.001). These results could in part explain the geographical distribution of duodenal ulceration, where the incidence is high in all the rice eating areas of the world, and provide a plausible hypothesis to explain the mechanism of dietary ulcerogenesis.

Serum pepsinogen levels in normal and experimental peptic ulcer rats measured by radioimmunoassay.

Antiserum to the rat pepsinogen (PG) purified by us was raised in the rabbit. We established a radioimmunoassay system for PG and measured the content of it in the digestive and urinary organs. Immunoreactive PG in serum was confirmed to be PG by high-performance liquid chromatography using an ion exchange column. Serum PG levels in pregnant or lactating rats were higher than normal. The maximum level during lactation was 6 or 7 times the normal value, and began to decrease from about the 16th day after delivery. Serum PG in infant rats was elevated along with the content of mucosal PG. In the measurement of serum PG levels in experimental peptic ulcer rats, no significant change was observed in Shay and cysteamine ulcers produced in the forestomach or/and the duodenum. However, serum PG levels rose significantly in rats with indomethacin, stress and ethanol ulcers, which represent injuries on the glandular portion.