Effect of sialoadenectomy and synthetic human urogastrone on healing of chronic gastric ulcers in rats.

The effect of extirpation of the submandibular glands, an exocrine organ for epidermal growth factor/urogastrone (EGF/URO), and the effect of oral administration of synthetic human (EGF/URO) on healing of chronic gastric ulcers in rats has been investigated. Removal of the submandibular glands delayed healing of chronic gastric ulcers when examined after 50, 100, and 200 days. Oral administration of synthetic human EGF/URO stimulated gastric ulcer healing when examined after 25 and 50 days of treatment. The effect of synthetic human EGF/URO was comparable with that of cimetidine. The combined administration of synthetic human EGF/URO and cimetidine further increased healing of gastric ulcers compared with administration of each substance. Neither synthetic human EGF/URO, nor removal of the submandibular glands had any influence on gastric acid secretion. This study showed that the submandibular glands influence healing of chronic gastric ulcers and suggest that EGF/URO participate in healing of chronic gastric ulcers in rats.     

Effects of a proton pump inhibitor,omeprazole, on gastric secretion and gastric and duodenal ulcers or erosions in rats

The effects of omeprazole, a proton pump inhibitor, on gastric secretion and gastric or duodenal ulcers or erosions in rats were studied. Omeprazole, given intraduodenally, dose-dependently inhibited the gastric secretion (volume, acid and pepsin output) of pylorus-ligated rats. The antisecretory activity of omeprazole at 100 mg/kg persisted for 14 hr after treatment. Acutely induced gastric ulcers or erosions such as Shay ulcers, water-immersion stress-, indomethacin-, aspirin-, or prednisolone-induced erosions were all markedly inhibited by oral or intraduodenal administration of 10–100 mg/kg of omeprazole. The development of duodenal ulcers and gastric erosions caused by mepirizole was also potently inhibited by omeprazole at 3–10 mg/kg given orally. Repeated administration of omeprazole, 200 mg/kg/day in two divided doses for 14 days, significantly accelerated the spontaneous healing of acetic acid-induced gastric ulcers. The mechanism by which omeprazole inhibits the development of acute ulcers and accelerates healing of preexisting ulcers appears to be mainly due to its potent and longlasting antisecretory activity. The antisecretory and antiulcer activities of omeprazole are equal to or exceed those of cimetidine, both in the maximum inhibitory response and ED₅₀ values.     

Effects of cimetidine on healing of chronic gastric and duodenal ulcers in dogs

The effects of cimetidine on healing of gastric and duodenal ulcers induced in mongrel dogs were studied. Gastric ulcers were produced by subserosal injection of acetic acid solution and duodenal ulcers by topical application of acetic acid on the serosal surface of the duodenum. Oral treatment with cimetidine, 450 mg/dog/day in three divided doses for 14 days, produced a remarkable acceleration of healing of duodenal ulcers but exerted little influence on gastric ulcers.     

Effects of prednisolone and human epidermal growth factor on angiogenesis in granulation tissue of gastric ulcer induced by acetic acid

In an attempt to elucidate the role of granulation vessels in the healing of gastric ulcer, healing and angiogenesis in granulation tissue of acetic acid ulcers were studied in rats. In addition, the effects of prednisolone and synthetic human epidermal growth factor (EGF) on angiogenesis and ulcer healing were investigated. The newly formed granulation vessels in the ulcer base were measured by means of a carmine dye infusion method. Prednisolone, administered subcutaneously at 40 mg/kg/day, significantly decreased angiogenesis in the ulcer base on the 10th day after ulcer production, and on the 30th day ulcer healing was found to be significantly delayed. In contrast, angiogenesis was significantly increased, and ulcer healing was enhanced by intragastric administration of 100 micrograms/kg/day of EGF. With combined administration of prednisolone and EGF, angiogenesis was significantly increased compared to that observed with prednisolone treatment alone. The authors conclude that suppression of angiogenesis by prednisolone is a delaying factor in gastric ulcer healing and that exogenous EGF promotes ulcer healing, partly through restoration of angiogenesis.     

Gastric ulcer treatment with intravenous human epidermal growth factor: A double-blind controlled clinical study

Abstract We introduced a double-blind controlled clinical study to compare intravenous human epidermal growth factor (hEGF) to cetraxate hydrochloride (CH), an antiulcer drug, for their healing effect on gastric ulcers. We also prospected an oral use of EGF on the basis of our experimental evidence. In the clinical trial, the rate of ulcer healing within 8 weeks was 77.9% (67/86) in patients receiving 6 μg EGF intravenously twice a week, being significantly greater than 51.7% (45/87) in those given CH. Taking together all aspects assessed including the healing rate, pain relief, blood examination and adverse reactions, we judged the hEGF to be a useful and safe antiulcer drug. In rats, 50 μg/kg mouse EGF (mEGF) and 2% hydroxypropyl cellulose (HPC) or 1.0 g/kg sucralfate given by gastric intubation significantly raised the residual mEGF levels in both gastric luminal content (HPC: x 30; sucralfate: x 300 as high as those in EGF alone) and tissue (HPC: x 60; sucralfate: x 100). In addition, the combined treatments significantly promoted healing of rat gastric ulcers whereas each agent alone had no significant effect as compared with control (saline). This indicated the beneficial effect on ulcers of oral administration of EGF with agents allowing it to remain at high levels in the stomach, whereas most reports suggested less effect of oral EGF on healing of gastroduodenal ulcers. Subsequent to the clinical study, evaluation of oral use of EGF may be expected as the next step in the treatment of ulcers. The experimental evidence above would possibly be a guide for such trial.     

A new model of duodenal ulcers induced in rats by indomethacin plus histamine

We standardized a new method for producing duodenal ulcers in rats by administering indomethacin plus histamine, and investigated the pathogenesis. Indomethacin (5 mg/kg) was first given subcutaneously to rats fasted for 24 h, and subsequently histamine dihydrochloride (40 mg/kg) was given subcutaneously three times, at 2.5-h intervals, beginning 30 min after injection of indomethacin. This combined treatment induced one or two round lesions (9.8 +/- 1.4 mm2) in the proximal duodenum at an incidence of 100%, and a few lesions in the corpus and antrum of the stomach as well. Indomethacin or histamine alone had no effect on either the duodenum or the stomach. The lesions in the duodenum and antrum were inhibited by oral cimetidine (3-100 mg/kg) and 16,16-dimethyl prostaglandin E2 (dmPGE2) (3-30 micrograms/kg) in a dose-related manner, whereas those in the corpus were inhibited only by cimetidine. Indomethacin alone had no effect on gastric acid secretion, but did potentiate the increase of acid secretion caused by histamine. Histamine did not affect duodenal HCO3-secretion, whereas indomethacin slightly inhibited the basal HCO3-secretion and completely blocked the acid-stimulated HCO3-secretion. Intraduodenally administered cimetidine (30 mg/kg) or dmPGE2 (30 micrograms/kg) significantly inhibited acid secretion or increased HCO3-secretion, respectively, and both reduced the amount of acid emptied into the duodenum after treatment with indomethacin plus histamine. These results indicate that the development of duodenal lesions induced by indomethacin plus histamine in rats is due to both an increase in gastric acid secretion and an impairment of acid-induced duodenal HCO3-secretion. This newly established model will be useful for studying the pathogenesis of duodenal ulcers and for screening antiulcer agents.     

Cimetidine. H2-receptor blockade in gastrointestinal disease

Cimetidine is an H2-receptor antagonist that is capable of marked suppression of gastric acid and pepsin secretion. Patients with active duodenal ulcer disease treated with cimetidine show improved rates of healing and symptom relief compared with placebo-treated controls. Peptic ulcer and diarrhea of Zollinger-Ellison syndrome and other acid hypersecretory states respond to cimetidine treatment, as may stress ulcers and steatorrhea of patients with pancreatic insuffficiency who have a suboptimol response to oral pancreatin. Effectiveness with gastric ulcer has been less convincing than with duodenal ulcer. In duodenal ulcer disease, cimetidine need not replace less expensive antacid therapy in most cases and is unlikely to replace definitive surgery for suitable candidates.     

Effect of antisecretory agents and vagotomy on healing of “chronic” cysteamine-induced duodenal ulcers in rats

Penetrated cysteamine-induced duodenal ulcers in rats have a very prolonged course of healing. In this study, it was investigated how much the healing of these ulcers is accelerated by some treatments. The treatments included omeprazole, cimetidine, and truncal vagotomy. In addition, the effect of omeprazole and cimetidine on gastric acid secretion was investigated in chronic gastric fistula rats. After 25 days of treatment, significantly more rats in the treated groups had healed ulcers than in the control group. There was little further improvement up to 100 days of treatment, and the difference between treated and untreated groups decreased. The morphology of healing ulcers in treated and untreated rats was also compared. In controls, there was a simultaneous regeneration of mucosa and the submucosal Brunner's glands from the edges of the ulcer, the slow proliferation rate of the latter probably being decisive for the prolonged healing. In the treated rats, the mucosa first regenerated with formation of crypts and low villi and subsequently, the Brunner's glands were formed by proliferation from the bottom of the crypts.     

Role of epidermal growth factor in healing of chronic gastroduodenal ulcers in rats

The healing of acetic acid-induced gastric and duodenal ulcers was examined together with biochemical indices of growth in gastric and duodenal mucosa in rats with intact or removed salivary glands after treatment with epidermal growth factor (EGF) or somatostatin, or both. After the extirpation of salivary glands, the healing rate of gastric and duodenal ulcerations was delayed and gastric content of immunoreactive EGF was reduced. This was accompanied by a significant decrease in the contents of deoxyribonucleic acid and ribonucleic acid in the gastric and duodenal mucosa. Repeated administration of EGF either subcutaneously or orally accelerated the healing of gastroduodenal ulcers in rats with intact salivary glands and completely reversed the delay in ulcer healing in sialoadenectomized animals. These effects were also accompanied by a significant increase in the growth parameters of gastric and duodenal mucosa. Administration of somatostatin, which prevented the growth-promoting action of subcutaneous EGF, resulted in a significant decrease in the EGF-stimulated healing of gastric and duodenal ulcerations in both intact and sialoadenectomized rats. Our findings suggest that cell proliferation is an important factor in healing of gastric and duodenal ulcerations and that EGF plays an important role in ulcer healing due to its mitogenic action.     

Ranitidine in the treatment of duodenal ulceration

In a randomized, double-blind, endoscopically controlled clinical trial, 40 patients with duodenal ulcer were treated with either ranitidine (320 mg/day) or cimetidine (800 mg/day) for 28 days. The rate of healing of the ulcers (ranitidine, 78%, cimetidine, 45%) did not differ significantly in the two treatment groups. In a subsequent 'open' study, ranitidine (150 mg twice daily) healed the ulcers of 79% of 19 patients treated for 28 days. Treatment with ranitidine was not associated with significant adverse reactions and had no lasting effect on gastric secretory capacity. Whereas basal levels of serum testosterone rose significantly during treatment with cimetidine, no such increase was observed during treatment with ranitidine. We conclude that ranitidine can effectively and safely heal duodenal ulcers.     

Effects of cimetidine on the healing and recurrence of duodenal ulcers and gastric ulcers

The effects of cimetidine on the healing and recurrence of duodenal ulcers and gastric ulcers were compared. The extent of the acid secreting areas was examined by the endoscopic Congo red methylene blue test. Using the extent of acid secreting areas gastric ulcers were classified into ulcers with and without extensive acid secreting areas. Duodenal ulcers were all associated with extensive acid secreting areas. The gastric acid outputs in the basal state and after maximal stimulation with gastrin were highest in duodenal ulcers, and lowest in gastric ulcers without extensive acid secreting areas. Cimetidine treatment significantly promoted the healing of duodenal ulcers and gastric ulcers with extensive acid secreting areas when compared with placebo, but not of the gastric ulcers without extensive acid secreting areas. Cimetidine also significantly diminished the recurrence of duodenal ulcers, but not gastric ulcers with and without extensive acid secreting areas. These findings indicate that in Japan cimetidine promotes the healing of duodenal and gastric ulcers associated with high gastric acid production and prevents recurrence of duodenal ulcers, but has little or no influence on the healing and recurrence of gastric ulcers associated with low acid secretion.     

Effects of cimetidine,a histamine H2-receptor antagonist,on various experimental gastric and duodenal ulcers

The effects of cimetidine, a new histamine H₂-receptor antagonist, on the development of experimental gastric and duodenal ulcers were studied. It was found that either by the oral, intraduodenal, or intraperitoneal route this agent had a marked inhibitory activity on stress-, aspirin-, indomethacin-, or histamine-induced gastric ulcers in rats and guinea pigs. The effects of cimetidine on stress-, aspirin-, and indomethacin-induced gastric ulcers were dose-dependent in many cases. Pylorus-ligation ulcers, reserpine-or serotonin-induced gastric ulcers were little influenced by cimetidine. Duodenal ulcers induced by continuous infusion of carbachol-histamine were significantly inhibited by a simultaneous infusion of cimetidine. An analysis of gastric contents in pylorus-ligated rats after stressing indicated a decreased volume and acid output as the result of intraduodenal cimetidine treatment. In contrast, cimetidine exerted little influence on gastric secretion in rats treated with aspirin or in guinea pigs treated with histamine. Thus, the mechanism of action of cimetidine in preventing gastric or duodenal ulcers is likely to occur by suppression of gastric secretory function in a duodenal ulcer model but by suppression of other unknown ulcerogenic factors in gastric ulcer models.     

Failure of a cytoprotective dose of arbaprostil to heal acute duodenal ulcers. Results of a multiclinic trial

Previous therapeutic trials with prostaglandins have shown them to be effective in healing duodenal ulcers when used at doses that are highly effective suppressors of gastric acid secretion. We undertook this trial to determine if a cytoprotective dose of arbaprostil (10 micrograms q.i.d. for 4 wk) would also be efficacious in this disease state. Eighty-two patients between the ages of 19 and 72 yr with endoscopically documented duodenal ulcers were entered into this randomized double-blind placebo-controlled trial. The patients were monitored with biweekly endoscopies and laboratory examinations, weekly interviews during the period when drug was administered, and a follow-up interview plus laboratory examinations 1 wk after drug administration was completed. No statistically significant differences between the arbaprostil and placebo treatment groups were found for ulcer healing rates, pain relief, antacid consumption, side effects, or laboratory examinations. It is presumed that this prostaglandin may not have sufficient duodenal cytoprotective capacity to effectively heal duodenal ulcers, or that some suppression of gastric acid secretion may be required to achieve significant clinical efficacy.     

Validity of kissing gastric ulcers induced in rats for screening of antiulcer drugs

Abstract We examined the validity of kissing gastric ulcers induced in rats by determining the effects of conventional antiulcer drugs. Gastric ulcers were produced by luminal application of 60% acetic acid (0.2 mL, 45 s) to an area clamped with a pair of forceps. The ulcers were evaluated as to either the ulcerated area (mm²) or ulcer index (ulcerated area x depth). The healing of kissing ulcers was significantly enhanced by 2 week treatment with oral omeprazole (10, 30 mg/kg per day), leminoprazole (30, 60 mg/kg per day) or cimetidine (300, 450 mg/kg per day). The rate of healing was > 50% to both the ulcerated area and ulcer index. Aluminium hydroxide (up to 1800 mg/kg per day) had no effect on ulcer healing on the ulcerated area, but it caused a significant reduction in the ulcer index. Gastric acid secretion was significantly inhibited by repeated administration of omeprazole, leminoprazole and cimetidine in a dose-dependent manner. Aluminium hydroxide significantly increased the pH of the gastric contents. The mechanism of action of these drugs appears to involve partly the inhibition of gastric acid secretion and neutralization of secreted acid. We conclude that kissing gastric ulcers are a sensitive ulcer model for the screening of antiulcer drugs.     

Helicobacter Pylori and Refractory Duodenal Ulcers: Cross-over Comparison of Continued Cimetidine with Cimetidine plus Antimicrobials

Objectives: To determine the distribution of Helicobacter pylori in the antral and duodenal mucosa of patients with duodenal ulcers refractory to 12 wk of treatment with cimetidine and to evaluate the effect of adding antimicrobial agents to cimetidine on the bealing of refractory duodenal ulcers. Methods: A randomized crossover comparison of continued 800 mg of cimetidine at night for 4 wk with cimetidine plus 500 mg of amoxycillin three times a day for the first 2 wk and 250 mg of metronidazole three times a day for the second 2 wk. H. pylori status in the gastric antral and duodenal mucosa was evaluated by histology and bacterial culture before and at the end of each treatment period. Results: Forty-eight patients were studied. Upon entry to the study, all patients had antral colonization with H. pylori . In the duodenum, active chronic duodenitis was present in 66%, duodenal gastric metaplasia in 33%, and H. pylori in 50%, similar proportions to patients with nonrefractory duodenal ulcers. Healing occurred in 70% (30 of 43) of patients during treatment with cimetidine plus antimicrobials but in only 21 % (6 of 28) during treatment with cimetidine alone ( P = 0.0003). In patients who received antimicrobials, neither clearance of H. pylori from the antrum (58% of patients) or duodenum (71% of colonized patients) nor eradication of H. pylori (33%) was significantly correlated with ulcer healing. Conclusions: The distribution of H. pylori in refractory duodenal ulcers is similar to nonrefractory ulcers, and the combination of amoxycillin and metronidazole with cimetidine increases the proportion of refractory duodenal ulcers, which heals.     

Effects of transdermal scopolamine, alone or in combination with cimetidine, on total 24 hour gastric acid secretion in patients with duodenal ulcer.

Transdermal scopolamine is an antimuscarinic preparation approved for use in the United States for prevention of motion sickness. A recent study using this drug (0.5 mg/patch) suggested that enough scopolamine was absorbed through the skin to reduce basal gastric acid secretion in patients with duodenal ulcer. We have compared the effect of transdermal scopolamine and oral cimetidine (400 mg twice daily) in seven men with chronic duodenal ulcer, both alone and in combination, on acid secretion throughout an entire 24 hour period in a placebo-controlled, randomised, double blinded cross over study. The effect of these drugs on basal, interprandial, and nocturnal gastric juice volume and hydrogen ion concentration also was measured. Transdermal scopolamine had no significant effect on mean 24 hour acid secretion (placebo, 409.4 mmol/day; scopolamine, 364.0 mmol/day) nor did it have a significant effect on gastric juice volume or hydrogen ion concentration. The combination of transdermal scopolamine plus cimetidine was not more effective than cimetidine alone in reducing total 24 hour acid secretion (mean, 231.8 versus 235.3 mmol/day) nor in reducing gastric juice volume or hydrogen ion concentration.     

Effect of cell proliferation on healing of gastric and duodenal ulcers in rats

The healing of acetic acid-induced gastric and duodenal ulcers was examined together with the biochemical indices of growth in gastric and duodenal mucosa in the following three groups of rats: (a) chow-fed, (b) fed an isocaloric liquid diet, (c) fed the liquid diet plus pentagastrin injections (250 micrograms/kg, 3 times/day). Animals received the diet regimen for 10 days from 1 day after induction of ulcer (day 0). Following the feeding regimens, serum gastrin levels, oxyntic gland mucosal DNA synthesis, and gastric secretory function were significantly lowered in the rats fed liquid diets. DNA synthesis in the duodenal mucosa was not different from the pre-ulcer levels. Pentagastrin significantly restored the DNA synthetic and gastric secretory activity of the liquid diet-fed rats toward the levels in the chow-fed group. In the latter group, a significant increase in DNA synthesis and levels of serum gastrin was found at day 6 (after 5 days feeding), which corresponded with a rapid, spontaneous healing of ulcers. Feeding rats liquid diet significantly delayed the healing of gastric, but not duodenal ulcers. Repeated administration of pentagastrin accelerated gastric ulcer healing in the liquid diet group toward the rate observed in the chow-fed group, but had no effect on the healing of duodenal ulcers. These results indicate that cell proliferation is an important factor in the healing of gastric ulcers.     

Results of short- and long-term cimetidine treatment in patients with juxtapyloric ulcers, with special reference to gastric acid and pepsin secretion

One hundred and seven patients with active juxtapyloric ulcers and a history of chronic ulcer disease were treated with cimetidine. After ulcer healing 67 patients were selected for medical management, testing the value of cimetidine maintenance treatment. Time to healing was shorter for patients with duodenal ulcers when compared with those with active prepyloric ulcers. Recurrences were fewer for patients with pure duodenal ulcer disease (DUD) when compared with those with active or previous prepyloric ulcer disease (PUD). Patients whose ulcers were slow to heal and those with active or previous prepyloric ulcers (PUD) required a higher dose of cimetidine for effective control of their disease. All patients with slowly healing ulcers (more than 6 weeks) relapsed with 400 mg cimetidine at night. Among patients with relapse 46% with DUD and 31% with PUD were controlled by increasing cimetidine to 400 mg twice daily. Tests of acid secretion were of no value in predicting the rate of ulcer healing or relapse rate. Pepsin secretion studies, however, were of predictive value for patients with DUD but of indeterminate value for patients with PUD. Long-term cimetidine produced a significant decrease in pentagastrin-stimulated pepsin secretion (without treatment) in both patients with and without relapse. No significant changes in acid secretion were observed. As a result of these studies we recommend a cimetidine maintenance dosage of 400 mg twice a day for all patients whose ulcers are slow to heal on 1 g cimetidine a day and in patients with prepyloric ulcer disease regardless of rate of healing.     

Metabolism of oral trefoil factor 2 (TFF2) and the effect of oral and parenteral TFF2 on gastric and duodenal ulcer healing in the rat

BACKGROUND: Trefoil factors (TFFs) are peptides produced by mucus-secreting cells in the gastrointestinal tract. A functional association between these peptides and mucus, leading to stabilisation of the viscoelastic gel overlying the epithelia, has been suggested. Both oral and parenteral administration of the peptides increase the resistance of the gastric mucosa. AIM: To study the effect in rats of oral and parenteral porcine trefoil factor 2 (pTFF2) on the healing of gastric and duodenal ulcerations and to clarify the distribution and metabolism of orally administered pTFF2 in the gastrointestinal tract. METHODS: Gastric ulcers were induced in female Sprague-Dawley rats by indomethacin and duodenal ulcers by mercaptamine. The rats were treated for up to seven days with oral or subcutaneous pTFF2. Ulcer size after treatment was assessed by stereomicroscopy after whole mount staining with periodic acid-Schiff stain. (125)I-labelled pTFF2 was given orally to rats, and tissues were investigated by gamma counting of samples and by autoradiography of paraffin embedded sections. RESULTS: pTFF2 accelerated gastric ulcer healing after both oral and subcutaneous administration. Duodenal ulcers were aggravated by both treatments. After oral administration of (125)I-pTFF2, intact peptide was recovered from the superficial part of the mucus layer in the stomach; it passed through the small intestine but was degraded in the caecum. Only a minor part of the labelled pTFF2 entered the colon and was excreted in the faeces. Most of the label was excreted in the urine. CONCLUSIONS: Oral as well as parenteral pTFF2 accelerates the healing of gastric ulceration and aggravates duodenal ulcers. Oral pTFF2 binds to the mucus layer of the stomach and the small intestine but does not reach the colonic mucosa.     

Acidic fibroblast growth factor accelerates the healing of acetic-acid-induced gastric ulcers in rats.

Acidic fibroblast growth factor (aFGF) was evaluated for the healing of acetic-acid-induced gastric ulcers in rats. The effect of aFGF on angiogenesis in the gastric ulcer bed was determined by the carmine dye infusion method, while its effect on gastric acid secretion was assessed in chronic gastric fistula rats. Oral treatment with aFGF, in the presence of heparin, reduced (ED50 value = 30.2 micrograms/kg/day) the acetic-acid-induced gastric ulcer area, when assessed 1 week later. aFGF was about 1,333-fold more potent than famotidine for healing such ulcers. At a dose of 200 micrograms/kg/day, aFGF increased the carmine density 3-fold and correspondingly reduced (80%) the gastric ulcer area. Thus, the ulcer healing effect of this agent involves angiogenesis in the gastric ulcer bed. This effect of aFGF appears to be unrelated to an inhibition of gastric acid secretion, as it was ineffective in chronic gastric fistula rats. In summary, oral aFGF significantly accelerates the healing of experimental gastric ulcers in rats. It may be a potent and effective agent for the treatment of peptic ulcers in humans.