Cysteamine-induced Duodenal Ulcers Research Articles

Gene expression and gene therapy in experimental duodenal ulceration

Gastroduodenal ulceration is still poorly understood and changes in gene expression may provide new mechanistic insights. Previously, we demonstrated that angiogenic growth factors are potent ulcer healing agents, and the synthesis of bFGF, PDGF and VEGF is enhanced early in duodenal ulcer healing. The initial molecular event in duodenal ulceration seems to be the organ-specific early release of ET-1 in the pre-ulcerogenic stages after the administration of duodenal ulcerogen cysteamine in rats. We also briefly review here data from literature indicating a central role of ET-1 in gastroduodenal ulceration. After studying the involvement of immediate early genes (e.g. egr-1, Sp1) in ulcer development, we now investigated expression of other genes in the duodenal mucosa in the early stages of chemically induced duodenal ulceration in rats. Following a brief review of principles of gene expression and gene therapy, we review our preliminary gene expression studies, involving monitoring about 1200 genes which revealed about 160 signals and prominent changes in about 30 genes in the early stages of experimental duodenal ulceration. Cysteamine enhanced ET-B receptor gene expression in 30 min, while transcription factors (MAX, STAT 3) showed increased expression in 12 h. We recently also initiated gene therapy studies to enhance the local synthesis of PDGF and VEGF to accelerate duodenal ulcer healing, using a single dose of naked DNA (ND) or adenoviral (AV) vectors of VEGF and PDGF in rats with cysteamine-induced duodenal ulcers. Gene therapy with ND or AV of VEGF or PDGF significantly accelerated chronic duodenal ulcer healing, and increased levels of VEGF and PDGF were detected by Western blotting and ELISA in duodenal mucosa after both VEGF and PDGF gene therapy. Thus, gene expression studies provide new insights into the molecular mechanisms of duodenal ulceration and VEGF or PDGF gene therapy seems to be a new option to achieve a rapid ulcer healing.

Changes in expression and activity of phosphotyrosine phosphatase and phosphoser/Thr phosphatase during cysteamine-induced duodenal ulceration

Changes in expression and activity of phosphotyrosine phosphatase and phosphoser/Thr phosphatase during cysteamine-induced duodenal ulceration

Review article: transcription factors and growth factors in ulcer healing.

This review is focused on recent investigations demonstrating a pharmacological and pathophysiologic role in gastroduodenal ulceration for growth factors such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), as well as for transcription factors. Our experiments revealed accelerated healing, without decreased gastric acid secretion, of chronic cysteamine-induced duodenal ulcers in rats treated daily for 3 weeks with intragastric administration of bFGF, PDGF or VEGF. Our recent studies also indicate a pathophysiological role of endogenous growth factors in the natural history of experimental duodenal ulcer development and healing. More recently, we investigated the genetic regulation of these growth factors in experimental duodenal ulceration. Since gene expression is most effectively controlled by transcription factors, proteins that bind to cis-acting elements of DNA and guide the binding of polymerase II to start the transcription of specific mRNA, we tested the hypothesis that the expression of IEGs and their transcription factor products, such as Egr-1 and Sp1, might precede the increased synthesis of bFGF, PDGF and VEGF in duodenal ulcer healing. Indeed, the duodenal ulcerogen cysteamine, but not its nonulcerogen and toxic analogue ethanolamine, rapidly increased duodenal (but not gastric) mucosal levels of ET-1, which was followed by enhanced expression of Egr-1 and a decrease in Sp1 in the preulcerogenic stage of duodenal ulceration. These changes in levels of ET-1 and expression of transcription factors were also accompanied by increased expression of the CDK inhibitor p21. Thus, not only growth factors such as bFGF, PDGF and VEGF, but also transcription factors such as Egr-1 and Sp1 and the cell cycle regulator p21, may play a role in the natural history of experimental duodenal ulceration.

Characterization of antisecretory and antiulcer activity of CR 2945, a new potent and selective gastrin/CCK B receptor antagonist

The antigastrinic, antisecretory and antiulcer activities of CR 2945, ( R)-1-naphthalenepropanoic acid,β-[2-[[2-(8-azaspiro[4.5]dec-8-yl-carbonyl)-4,6-dimethylphenyl] amino]-2-oxoethyl], were investigated in vitro and in vivo in rats and cats. Its activities were compared with those of two gastrin/CCK B receptor antagonists, l-365,260 (3 R(+)- N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepin-3-yl)- N′-(3-methylphenyl)urea and CAM-1028 (4-[[2-[[3-(1 H-indol-3-yl)-2-methyl-1-oxo-2-[[[1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino-4-oxo-[1 S-1α,2β[ S′( S′)4α]]-butanoate- N-methyl- d-glucamine), of the histamine H 2 receptor antagonist, ranitidine, and the proton pump inhibitor, omeprazole. Cytosolic Ca 2+ elevation in rabbit parietal cells induced by gastrin (50 nM) was blocked by CR 2945 with an IC 50 value of 5.9 nM. CAM-1028 and l-365,260 showed similar activity. CR 2945 antagonized pentagastrin-stimulated gastric acid secretion in rats (ED 50=1.3 mg kg −1 i.v. and 2.7 mg kg −1 i.d.) and cats (1.6 mg kg −1 i.v.). CR 2945 was slightly less potent than the reference compounds after i.v. administration, whereas after intraduodenal (i.d.) administration, it was more potent than both ranitidine and omeprazole. In the rat, the gastrin antagonism exhibited by CR 2945 was reversible and competitive, with a pA 2 value of 7.33. CR 2945 had specific antigastrin activity, as it was unable to antagonize the gastric acid secretion stimulated by histamine or carbachol in rats up to the dose of 30 mg kg −1. CR 2945 was about as efficacious as ranitidine against the indomethacin- and ethanol-induced gastric ulcers and the cysteamine-induced duodenal ulcer in rats. On the contrary, l-365,260 was only slightly effective. These results suggest that CR 2945 might be a promising compound for the therapy of acid-related disorders, and that its clinical use could help clarify the therapeutic potential of gastrin/CCK B receptor antagonists in the gut.

Changes in transcription factors egr-1 and Sp-1 expression in the early stages of cysteamine-induced duodenal ulceration

Minimally invasive valve surgery has been associated with increased cerebrovascular complications. Our objective was to evaluate the incidence of cerebrovascular accidents in patients undergoing minimally invasive valve surgery.We retrospectively reviewed all the minimally invasive valve surgery performed at our institution from January 2009 to June 2012. The operative times, lengths of stay, postoperative complications, and mortality were analyzed.A total of 1501 consecutive patients were identified. The mean age was 73 ± 13 years, and 808 patients (54%) were male. Of the 1501 patients, 206 (13.7%) had a history of a cerebrovascular accident, and 225 (15%) had undergone previous heart surgery. The procedures performed were 617 isolated aortic valve replacements (41.1%), 658 isolated mitral valve operations (43.8%), 6 tricuspid valve repairs (0.4%), 216 double valve surgery (14.4%), and 4 triple valve surgery (0.3%). Femoral cannulation was used in 1359 patients (90.5%) and central cannulation in 142 (9.5%). In 1392 patients (92.7%), the aorta was clamped, and in 109 (7.3%), the surgery was performed with the heart fibrillating. The median aortic crossclamp and cardiopulmonary bypass times were 86 minutes (interquartile range [IQR], 70-107) minutes and 116 minutes (IQR, 96-143), respectively. The median intensive care unit length of stay was 47 hours (IQR, 29-74), and the median postoperative hospital length of stay was 7 days (IQR, 5-10). A total of 23 cerebrovascular accidents (1.53%) and 38 deaths (2.53%) had occurred at 30 days postoperatively.Minimally invasive valve surgery was associated with an acceptable stroke rate, regardless of the cannulation technique.

Antisecretory and antiulcer effect of T-330, a novel reversible proton pump inhibitor, in rats

The antisecretory and antiulcer effects of T-330 (2-[(2-dimethylaminobenzyl)sulfinyl]-1-(3-methylpyridine-2-yl)imidazole), a novel reversible proton pump inhibitor, were studied in rats. T-330 suppressed dibutyryl cyclic AMP-stimulated acid formation in isolated rat gastric mucosal cells with the IC 50 value of 0.57 μM. In chronic fistula rats, intravenous, intraduodenal and oral administration of T-330 inhibited pentagastrin-stimulated gastric acid secretion; the ED 50 values calculated from the peak inhibition were 0.36, 0.43 and 0.73 mg/kg, respectively. T-330 also reduced dimaprit-stimulated gastric acid secretion following its intraduodenal injection (ED 50 0.85 mg/kg). The antisecretory activities of T-330 following its intraduodenal and oral administration were 3–6- and 4–10-times more potent than those of omeprazole and ranitidine, respectively, while the duration of action of T-330 was apparently shorter than that of omeprazole and was almost equal to that of ranitidine. Oral or duodenal administration of T-330 inhibited the development of acid-related damage (water-immersion- and aspirin-induced gastric lesions, cysteamine-induced duodenal ulcers and reflux esophagitis) with equal or higher potency than omeprazole or ranitidine. Furthermore, T-330 prevented ethanol-induced gastric lesions. These findings indicate that T-330 exerts its antiulcer effect mainly via its potent antisecretory action and partly via its gastroprotective action.

Effect of quinacrine, a phospholipase A2 inhibitor on stress and chemically induced gastroduodenal ulcers.

Quinacrine, a phospholipase A2 inhibitor, has been studied for its ability to inhibit gastric secretion and to protect the gastric and duodenal mucosa against chemically and stress-induced ulcers. Acid secretion studies were undertaken in pylorus-ligated rats with and without quinacrine treatment. Experimental gastric lesions were induced by water-immersion restraint stress, indomethacin and 80% ethanol in rats; whereas duodenal ulcers were produced by treatment of rats with cysteamine. The level of nonprotein sulfhydryl compounds and gastric wall mucus were also measured in the glandular stomach of the rats following ethanol-induced gastric lesions. The results of this study demonstrate that quinacrine produces a dose-dependent inhibition of gastric acid secretion in rats. Pretreatment with quinacrine significantly attenuated the formation of stress-, indomethacin- and ethanol-induced gastric lesions. Quinacrine also protected intestinal mucosa against cysteamine-induced duodenal ulcers. The antiulcer activity of quinacrine was associated with appreciable inhibition of ethanol-induced depletion of nonprotein sulfhydryls and gastric wall mucus. These findings point towards the mediation of sulfhydryls in quinacrine-induced gastrointestinal cytoprotection. In conclusion, this study demonstrates that quinacrine possesses significant antiulcer and cytoprotective activity against various experimentally induced gastroduodenal lesions. Although the mechanism of action of quinacrine requires further evaluation, the experimental observations derived from this study may have future clinical relevance and therefore deserve to be investigated thoroughly.

The effect of the combination therapy with sucralfate and famotidine on experimentally induced duodenal ulcers in rats

The combination of sucralfate (SUC) and famotidine (FAM) at subtherapeutic dose on cysteamine-induced duodenal ulcers (3 x 250 mg/kg) in female rats was studied. Subtherapeutic doses were determined in the preliminary studies. They were 200 mg/kg SUC and 0.2 mg/kg FAM (twice a day). The macroscopic examination was done 24 hours after first application of cysteamine. The effectiveness of SUC and FAM combination in subtherapeutic doses was confirmed by decreased number (from 1.3 to 0.5), length (from 5.5 mm to 1.9 mm), severity of duodenal ulcers (from 3.4 to 1.2) and reduction of ulcerative index by 54.4%.

Endogenous zinc concentrations in cysteamine-induced duodenal ulcers in the rat.

Exogenously administered zinc compounds have been shown to possess anti-ulcer activity against a wide variety of ulcerogenic agents, both in laboratory animal models and in human peptic ulcer disease. However, a strong possibility exists that endogenous zinc may also play an important role during noxious events by various mechanisms. Therefore, the aim of this study was to focus on the changes of endogenous zinc serum and tissue concentrations in cysteamine-induced duodenal lesions. We used atomic absorption spectrophotometry to determine the tissue and serum concentrations of zinc in normal (control) rats and those with cysteamine-induced duodenal ulcers. The results obtained in this study indicated that the onset, development and spontaneous healing of ulcer lesions were associated with certain shifts in zinc serum and tissue concentrations. Prior to ulcer formation, a significant increase was noted in serum zinc values. With the onset of duodenal lesions, zinc serum concentrations significantly decreased, while there was a significant increase in duodenal tissue concentrations when compared to healthy control animals. Zinc tissue concentrations decreased and returned to starting values by the end of the first week of spontaneous healing. This decrease in zinc tissue concentration corresponded to the healing rate of the duodenal ulcers. Serum zinc concentrations also returned to starting values within the first week period. These observations indicate and confirm that zinc could play an important role in duodenal ulcer disease and represent a natural defense system in the body.

Basic fibroblast growth factor and PDGF in GI diseases

This chapter is focused on the relatively recent investigations demonstrating a pharmacological and pathophysiological role for bFGF and PDGF in ulcerative and inflammatory lesions in the upper and lower GI tract. Our initial animal model experiment revealed a potent healing of chronic cysteamine-induced duodenal ulcer in rats treated by intragastric administration of bFGF-w, the acid-resistant bFGF-CS23 or PDGF-BB without decreasing gastric acid secretion or concentration. Subsequently we and others have demonstrated that these peptides accelerate the healing of chronic gastric ulcers, chronic erosive gastritis and ulcerative colitis. Contrary to the potent ulcer healing properties of bFGF and PDGF, these growth factors exert no or modest acute gastroprotection. Nevertheless, new biochemical, molecular biological and immunohistochemical studies indicate that both bFGF and PDGF play a pathophysiological role in the natural history of ulcer healing.

The cytoprotective effects of zinc sulphate on cysteamine-induced duodenal ulcer in the rat: [formula omitted], V. Simicevic, M. Dodig, I. Rotkvic, M. Duvnjak, T. Brkic, M. Banic. Dept. of Gastroenterology, Clinical Hospital “Sestre Milosrdnice”, Zagreb, Croatia

The cytoprotective effects of zinc sulphate on cysteamine-induced duodenal ulcer in the rat: [formula omitted], V. Simicevic, M. Dodig, I. Rotkvic, M. Duvnjak, T. Brkic, M. Banic. Dept. of Gastroenterology, Clinical Hospital “Sestre Milosrdnice”, Zagreb, Croatia

Molecular and cellular basis of ulcer healing.

The high ulcer recurrence rates after treatment with antacids or antisecretory drugs illustrate the need for direct treatment of GI ulcers by stimulating repair and healing mechanisms. The molecular regulators of ulcer healing include polyamines and growth factors such as EGF, TGF-beta, bFGF and PDGF. Oral treatment of rats with bFGF or PDGF accelerated the healing of chronic cysteamine-induced duodenal ulcers without decreasing gastric secretion. We found that sucralfate binds bFGF in vitro and in vivo, and the elevated local concentration of this growth factor may contribute to the ulcer healing properties of sucralfate. Parallel treatment with bFGF + sucralfate resulted in synergistic healing of chronic duodenal ulcers and chronic gastritis. Rapid changes in mucosal concentration of bFGF and EGF receptors during ulceration suggest that these peptides play a role in the natural history of GI ulcers. Thus, treatment based on molecular and cellular mechanisms of ulcer healing allows a direct and efficient ulcer therapy.

4-Methoxyphenyl 4-(3,4,5-Trimethoxybenzyl)-1-Piperazineacetate Monofumarate Monohydrate (KB-5492), a New Anti-Ulcer Agent with a Selective Affinity for the Sigma Receptor, Prevents Cysteamine-Induced Duodenal Ulcers in Rats by a Mechanism Different from That of Cimetidine

Both KB-5492, a new anti-ulcer agent, and cimetidine, administered orally at 25-200 mg/kg, dose-dependently prevented cysteamine (400 mg/kg, s.c.)-induced duodenal ulcers in rats with ED50 values of 63 and 40 mg/kg, respectively. Anti-ulcer doses of cimetidine, but not KB-5492, inhibited gastric acid hypersecretion induced by cysteamine (400 mg/kg, s.c.). In contrast, anti-ulcer doses of KB-5492, but not cimetidine, increased duodenal HCO3- secretion in normal anesthetized rats. These findings suggest that KB-5492 prevents cysteamine-induced duodenal ulcers by stimulating duodenal HCO3- secretion, whereas cimetidine does so by inhibiting cysteamine-induced gastric acid hypersecretion.

Relationship between tissue calcium content and duodenal ulcer in the rat.

Since the effect of cellular calcium on cell injury has been in question, this study focused on the relationship between tissue calcium content and cysteamine-induced duodenal ulcer. Rats treated with cysteamine showed a high frequency and severity of duodenal ulcer, and the calcium content in the duodenal mucosa was elevated. Furthermore, the level of calcium content in duodenal mucosa was positively associated with the severity of the duodenal lesion. Whereas administration of calcium increased duodenal ulcerative response to cysteamine, verapamil afforded protection against ulceration. We conclude that calcium accumulation in duodenal mucosa is related to duodenal ulceration induced by cysteamine.

Effects of a new σ ligand, JO 1784, on cysteamine ulcers and duodenal alkaline secretion in rats

Background: The ulceroprotective effects of JO 1784 [(+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1 -ethyl-but-3-en-l-ylamine, hydrochloride], a new specific and highly selective σ ligand, were examined in rats. Methods: Different models of gastric ulcers (4-hour restraint stress, aspirin, ethanol, and taurocholate) and cysteamine-induced duodenal ulcers were used. The gastric acid secretion (4-hour Shay rat preparation) and the duodenal bicarbonate secretion were also studied. Results: JO 1784 elicited a potent protection against duodenal ulcers but had a weaker protective effect on any of the gastric ulceration models tested. It displayed no gastric antisecretory activity but induced a dose-dependent stimulation of duodenal bicarbonate secretion. Haloperidol, hexamethonium, tetrodotoxin, bivagotomy (but not atropine), and the intravenous but not intracerebroventricular administration of devazepide, a cholecystokinin A antagonist, inhibited the stimulatory effect of JO 1784. Conclusion: These results show that JO 1784, a selective σ ligand, is a potent protector of the duodenal mucosa. This activity may be related to its stimulating effect on bicarbonate secretion, which is driven through a complex nervous mechanism involving muscarinic synapses, vagal afferent fibers, and peripheral cholecystokinin receptors. This drug might open a new specific way in the treatment of duodenal ulcers.

On the biochemical background of cysteamine-induced duodenal ulceration in the rat.

In cysteamine-induced duodenal ulceration the endogenous prostacyclin level initially showed an elevation. This elevation later disappeared, and the endogenous prostacyclin level dropped to zero--that is, below the detection limit. During ulceration the mucosal DNA level decreased, a phenomenon that was directly proportional to ulceration. In the course of the ulcerative process in the duodenal mucosa a de novo protein synthesis took place. This process was most probably a mucus secretion and served as a protective reaction against damaging noxae. The mucosal cyclic adenosine 5'-monophosphate (cAMP) content increased in the so-called pre-ulcerative phase but later returned to the normal (physiologic) level. The changes in the cyclic guanosine 5'-monophosphate (cGMP) level were more pronounced than those of cAMP, and the final result was a decrease in the mucosal cAMP/cGMP ratio. In accordance with our previous results we conclude that a positive cAMP/cGMP 'shift' indicates antiulcerogenic, cytoprotective, reparative processes in the mucosa, whereas its decrease is connected to damaging noxae.

Cysteamine induced-duodenal ulcers are associated with a selective depletion in gastric and duodenal calcitonin gene-related peptide-like immunoreactivity in rats.

We have measured the endogenous levels of gastric and duodenal calcitonin gene-related peptide (CGRP)-, neurokinin A (NKA)-, galanin-vasoactive intestinal polypeptide (VIP)- and neuropeptide Y (NPY)-like immunoreactivity (li) in relation to cysteamine-induced gastric lesions and duodenal ulcers in rats. CGRP-li but not NKA-, galanin-, VIP- or NPY-li was decreased in gastric and duodenal samples following a single ulcerogenic dose of cysteamine (900 mg/kg p.o.). Temporal relationships of this phenomenon showed that CGRP-li was selectively decreased (stomach 45%, duodenum 68% as compared to controls, respectively after 24 h) concomitantly to the formation of acute gastric lesions and duodenal ulcers. Animals bearing healed ulcers 12 days after cysteamine, had gastroduodenal CGRP-li similar to control values. Pretreatment with the selective sensory neurotoxin capsaicin decreased gastroduodenal CGRP-li but not NKA-, galanin-, VIP- or NPY-li, showing that CGRP might be considered a marker of the afferent innervation of the gastroduodenal tract. The residual gastroduodenal CGRP-li levels in capsaicin-pretreated animals were not decreased by cysteamine administration, indicating that the effect of cysteamine is restricted to a peptide pool of primary afferent origin. Duodenal CGRP-li is selectively decreased by the duodenal ulcerogen cysteamine during the acute phase of ulcers formation and might be among the local mediators which afford protection against the ulcerogenic stimuli.

Functional and structural changes in the jejunum of the rat following cysteamine and stress-induced duodenal ulcer.

The effects of cysteamine and stress-induced duodenal ulcer on the functional and structural properties of the rat jejunum were investigated. The absorptive capacity of the jejunum was determined using alanine as the permeant solute and the single-pass perfusion technique. A statistically significant decrease (p < 0.01) in alanine absorption was observed after 8 h and 3 days of duodenal ulcer induction by stress and cysteamine respectively. However, alanine transport measured 7 days after cysteamine or stress ulcer induction showed no significant change from control values. Cysteamine and stress-induced duodenal ulcer did not show any significant change in water absorption across the jejunum when measured after 8 h, 3 and 7 days of ulcer induction. Microscopically, the jejunum of rats with 3-day cysteamine-induced ulcer exhibited diffuse type of apical derangements with excessive swelling of the villi and progressive degenerative changes. No such changes were noticed on the 7th day nor in the jejunum of the rats with stress-induced duodenal ulcer. The results suggest that cysteamine-induced duodenal ulcer produces an inhibition in the absorptive capacity of the jejunum which is time-dependent and reversible.

BAY P 1455, a thiazolylaminobenzimidazole derivative with gastroprotective properties in the rat

The antiulcer activity of BAY P 14551 a thiazolylaminobenzimidazole derivative, was evaluated in different experimental ulcer models and its antiulcer activity was compared to that of different reference drugs. The overall activity of the compound was equal to or more potent than that of reference antiulcer drugs, such as pirenzepine, cimetidine and carbenoxolone, but it was not as potent as rioprostil. The ED 50 values (expressed as μmol/kg p.o.) were 68 (confidence limits: 51–91) for indomethacin-induced ulcers, 21 (confidence limits: 13–31) for stress-induced ulcers and 1260 μmol/kg p.o. (confidence limits: 412–3800) for ulcers induced by absolute ethanol. The compound had no activity against cysteamine-induced duodenal ulcers and lost its cytoprotective activity in adrenalectomised rats. Since inhibition of gastric acid secretion was seen, if at all, only with the higher doses, the gastro-protective action of BAY P 1455 seemed not to be due to an antisecretory effect, but more likely to a gastroprotective action as hypothesised for prostaglandins.

Effects of a New Benzimidazole Derivative, NC-1300-O-3, on gastric Secretion and Gastroduodenal Lesions in Rats.

We examined the effects of a new compound, NC-1300-O-3 (2-[2-N-methyl-N-(2-methylpropyl) amino] benzylsulfinyl benzimidazole), on the gastric mucosal proton pump (H+, K(+)-ATPase) activity, gastric secretion and gastroduodenal lesions in rats. The compound potently inhibited the enzyme activity in a concentration-dependent manner, the IC50 being 5.3 x 10(-6) M at pH 6.0 and 1.4 x 10(-5) M at pH 7.4. NC-1300-O-3 markedly and persistently (for more than 24 hr) inhibited basal gastric secretion in male or female animals when administered by the p.o. route. The compound also significantly inhibited gastric secretion by the intraduodenal (i.d.), intragastric (after pylorus ligation) and i.p. routes, but only weakly by the s.c. route. Repeated p.o. administration of the compound for 1 week also significantly inhibited gastric secretion. Histamine-stimulated gastric secretion was also significantly inhibited by the i.d. administration of the compound. NC-1300-O-3, administered p.o., potently prevented water-immersion stress-, histamine-, indomethacin-, prednisolone- and compound 48/80-induced gastric lesions. In addition, it also significantly prevented the formation of gastric lesions induced by various necrotizing agents. Mepirizole- and cysteamine-induced duodenal ulcers were also prevented by the compound. The antisecretory and antilesion activities of NC-1300-O-3, administrated p.o., were not altered on its combination with 2% NaHCO3.