Gastric protection by nocloprost against aspirin damage in humans. Possible role of epidermal growth factor.

Ten healthy young male subjects took part in a double-blind, placebo-controlled crossover study to assess the effects of nocloprost on gastric microbleeding and endoscopic mucosal injury induced by the administration of aspirin (2.5 g). In addition, basal and pentagastrin-induced gastric acid and pepsin secretion and salivary and plasma contents of epidermal growth factor (EGF) were measured after placebo plus aspirin or nocloprost plus aspirin treatment in these subjects. Nocloprost (100 micrograms/dose) significantly reduced spontaneous gastric microbleeding and almost completely prevented gastric mucosal injury induced by aspirin. Nocloprost failed to affect basal and pentagastrin-stimulated gastric acid and pepsin secretion but increased significantly the salivary outputs and plasma concentrations of EGF. In conclusion, nocloprost is effective in preventing gastric injury by aspirin even at a non-antisecretory dose, and this protection may involve an excessive release of EGF.     

Effect of ranitidine gastroduodenal mucosal damage induced by nonsteroidal antiinflammatory drugs

The effect of ranitidine in preventing mucosal damage caused by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated for eight weeks in a prospective study of 144 patients requiring NSAIDs. Patients with normal endoscopic findings were randomly assigned to receive either ranitidine 150 mg twice daily or placebo for eight weeks, along with either ibuprofen, indomethacin, naproxen, sulindac, or piroxicam. Duodenal damage was significantly less in the ranitidine group compared with the placebo group by weeks 4 and 8 (P0.01). Duodenal ulcers did not develop in any patients on ranitidine (0/57) compared with 4/49 patients (8%) on placebo (P=0.02). No significant difference was found between treatment groups with respect to gastric damage; 6/60 (10%) in the ranitidine group compared with 6/50 (12%) in the placebo group developed gastric ulcers. These findings suggest that acid suppression is of greater importance for mucosal protection in the duodenum than in the stomach, where other defense mechanisms may be operative. While ranitidine is an effective prophylaxis for NSAID-induced damage in the duodenum, further studies are needed to define specific risk groups and to assess the potential usefulness of more complete acid suppression in preventing gastric mucosal damage.     

Increased gastric juice epidermal growth factor after non-steroidal anti-inflammatory drug ingestion.

Epidermal growth factor (EGF), present in saliva and gastric juice, is a potent mitogen and an important element of mucosal defence. Changes in salivary and gastric juice epidermal growth factor in response to non-steroidal anti-inflammatory drug (NSAIDs) ingestion were measured to assess the role of EGF in gastric mucosal adaptation to NSAIDs. Patients with arthritis underwent endoscopy with collection of saliva and gastric juice for EGF measurement, before and two weeks after continuous NSAID ingestion. During this period patients also received either the prostaglandin analogue misoprostol or placebo in addition to their NSAID. In the misoprostol group (n = 5) there was no observed mucosal damage and no change in either salivary or gastric juice EGF. In the placebo group (n = 10) three patients developed erosions. Salivary EGF did not change (mean (SEM) 3.02 (0.54) ng/ml v 2.80 (0.41) ng/ml) but gastric juice EGF increased from 0.42 (0.12) ng/ml to 0.69 (0.14) ng/ml (p < 0.05). This increased EGF could contribute to the increased cellular proliferation observed during NSAID ingestion and may represent an important mechanism underlying gastric mucosal adaptation.     

Correlation between basal acid output and daily ranitidine dose required for therapy in Barrett's esophagus

We prospectively evaluated basal gastric acid secretion in 42 consecutive patients with Barrett's esophagus to determine the optimal dose requirement for an H₂-receptor antagonist in relation to the gastric acid secretory status of each patient. All patients with Barrett's esophagus had pyrosis and 31 of the 42 patients had erosive esophagitis. Mean extension of Barrett's epithelium was 6.9 cm (range 2–17 cm). Mean basal acid output for the patients with Barrett's esophagus was 8.0±5.2 meq/hr, which was significantly different compared to a group of 65 normal subjects with mean basal acid output of 3.0 ±2.7 meq/hr (P<0.001). There was no correlation between basal acid output and extension of Barrett's epithelium. All patients with Barrett's esophagus were treated with ranitidine, with 24 requiring standard-dose (300 mg/day) and 18 requiring increased doses (mean 1170 mg/day, range 600–2400 mg/day) for complete healing of esophagitis and disappearance of pyrosis. There was a significant correlation between basal acid output and daily ranitidine dose required for therapy (r=0.52,P<0.001). Fifteen of the 42 patients with Barrett's esophagus (36%) had gastric acid hypersecretion. There was a significant association between gastric acid hypersecretion defined as a basal acid output of greater than 10.0 meq/hr and a requirement for increased daily ranitidine doses (greater than 300 mg/day) (P<0.0002). No side effects occurred with any of these high doses of ranitidine. We conclude that as a group, patients with Barrett's esophagus have significantly higher basal acid outputs than normal subjects and many require increased therapeutic doses of ranitidine. Furthermore, there is a significant correlation between basal acid output and therapeutic daily ranitidine dose and a significant association between gastric acid hypersecretion and the requirement for increased daily ranitidine doses.     

Epidermal Growth Factor in Gastric Ulcer Healing by Nocloprost,a Stable Prostaglandin E2 Derivative

Background: The gastroprotective and ulcer-healing properties of prostaglandins, especially in gastric ulcers induced by non-steroidal anti-inflammatory drugs, are well established. Ulcer healing is an active process of filling the mucosal defect with migrating and proliferating epithelial cells combined with angiogenesis in granulation tissue at the ulcer bed. Growth factors, especially epidermal growth factor (EGF) and transforming growth factor alpha (TGFa) are crucial in the regulation of the reconstruction of damaged mucosal structures. Methods: In this double-blind, randomized, prospective study 40 patients with gastric ulcer were treated with nocloprost, a stable prostaglandin E₂ derivative, or with ranitidine. All subjects underwent endoscopy before and after 4 and 8 weeks of anti-ulcer therapy. During endoscopy mucosal biopsies were performed for determination of EGF content in gastric mucosa at the ulcer margin and in the intact mucosa. Additionally, EGF output in saliva and its plasma concentrations were determined in all subjects before and during the treatment. Results: The gastric ulcer healing rate after 4 weeks was significantly higher in patients treated with nocloprost than in those treated with ranitidine (63% versus 39%, respectively). At initial examination the EGF content in the gastric mucosa obtained from the ulcer edge was significantly higher than that in the intact mucosa. There was a significant increase in the EGF content in both the ulcer margin and the intact mucosa in subjects treated with nocloprost but not in patients under treatment with ranitidine. Similarly, patients treated with nocloprost had significantly higher EGF output in saliva and higher EGF concentration in plasma throughout the anti-ulcer therapy. Conclusion: Nocloprost is superior to ranitidine in the treatment of chronic gastric ulcers, and these effects could be due, at least in part, to higher expression and mucosal content of EGF in the ulcer area.     

Basal acid output and gastric acid hypersecretion in gastroesophageal reflux disease

The purpose of this study was to evaluate possible differences in basal gastric acid secretion with regard to severity of gastroesophageal reflux disease. Basal acid output was determined by nasogastric suction in 228 patients with gastroesophageal reflux disease who received upper gastrointestinal endoscopy and were diagnosed with either pyrosis alone (N = 98), erosive esophagitis with or without pyrosis (N = 87), or Barrett's esophagus (N = 43). Mean basal acid output for the 228 patients with gastroesophageal reflux disease was 6.5 ± 5.6 meq/hr, which was significantly different from 65 normal subjects with a mean basal acid output of 3.0 ± 2.7 meq/hr (P < 0.0001). Compared to normal subjects, mean basal acid outputs significantly differed for patients with pyrosis (P < 0.05), esophagitis (P < 0.01), and Barrett's esophagus (P < 0.01). There was also a significant difference in mean basal acid output between the patients with pyrosis and Barrett's esophagus (P < 0.01). Nineteen of the 98 patients with pyrosis (19%), 24 of the 87 patients with esophagitis (28%), and 15 of the 43 patients with Barrett's esophagus (35%) had gastric acid hypersecretion (basal acid output greater than 10.0 meq/hr). One hundred forty-six patients with gastroesophageal reflux disease were treated with ranitidine in doses that resulted in complete healing of esophagitis and disappearance of pyrosis. Ninety-three patients responded to ranitidine 300 mg/day; however, 53 patients required increased dose of ranitidine (mean 1205 mg/day, range 600–3000 mg/day). There was a significant correlation between basal acid output and daily ranitidine dose required for therapy for the 146 patients with gastroesophageal reflux disease (r = 0.53,P = 0.0001). Furthermore, a significant association was also found between the presence of gastric acid hypersecretion and the requirement for increased doses of ranitidine (greater than 300 mg/day) (P = 0.00001). These results indicate that there is a subset of patients with gastroesophageal reflux disease who do have idiopathic gastric acid hypersecretion. Moreover, these patients have an apparently higher requirement for medication dosage in order to achieve therapeutic efficacy.     

Preventive Effects of Rebamipide on NSAID-Induced Gastric Mucosal Injury and Reduction of Gastric Mucosal Blood Flow in Healthy Volunteers

The precise mechanisms of acute damage and the role of gastric mucosal blood flow in gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) remain uncertain. The aim of this study was to evaluate the preventive effect of rebamipide on gastric mucosal injury and reduction of gastric mucosal blood flow (GMBF) after ibuprofen administration. Twenty healthy volunteers were randomized two groups. The rebamipide group took ibuprofen, 1800 mg/day, and rebamipide, 100 mg t.i.d., for 7 days. The placebo group took ibuprofen, 1800 mg/day. The numbers of gastric ulcer subjects were three in the placebo group and zero in the rebamipide group. The mean modified Lanza score after ibuprofen administration was significantly higher in the placebo group than the rebamipide group (2.9±1.7 vs. 1.3±1.0, respectively; P=0.032). The GMBF of the placebo group was significantly decreased at antrum from baseline, from 2.8±0.5 to 2.0±0.5 tissue perfusion units (P=0.005). There was no difference in GMBF change in the rebamipide group. Gastric mucosal injury was correlated with GMBF reduction in antrum (r=−0.677, P=0.001). In conclusion, it is suggested that the decrease in GMBF may have been associated with NSAID-induced gastric mucosal injury, and rebamipide may have prevented NSIAD-induced gastric mucosal injury by maintaining GMBF in healthy subjects.     

Mealtime versus nighttime acid inhibition

This study was carried out in order to compare the effects of mealtime and bedtime regimens of ranitidine on gastric acidity. Fifteen duodenal ulcer pateints in clinical remission were randomized to receive in single-blind fashion either placebo, ranitidine 300 mg at night (2200 hr) or ranitidine 150 mg three times a day given before each of the three daily meals (1800, 0800 and 1200 hr). Over 24 hr, the two active treatments produced a significantly greater acid inhibition than placebo, while the single daily regimen was superior to the three times a day regimen of ranitidine in terms of both rise in pH values (P<0.001) and duration of action expressed as time spent obove 3.0 pH units (P<0.05). The analysis of these two parameters during fractioned periods of the circadian cycle showed that the three divided doses of ranitidine were more effective during the daytime (P<0.01) and the evening (P<0.001), whereas the bedtime dose of ranitidine was superior during the night (P<0.0001). Thus a short-lasting antisecretory action, which is, however, capable of fully controlling the hihg acidity of postprandial periods, might be the key to understanding the results of several recent clinical trials in which the suppression of daytime gastric acidity has been shown to promote similar or even faster duodenal ulcer healing rates than the suppression of nocturnal acidity.     

Salivary and gastric epidermal growth factor in patients with Zollinger-Ellison syndrome: its protective potential

OBJECTIVE: Evidence is accumulating that epidermal growth factor (EGF) is a major molecule contributing to the maintenance of the integrity of the upper alimentary tract mucosa before and after injury by acid and pepsin. Patients with Zollinger-Ellison Syndrome (ZES) typically have hypersecretion of acid and pepsin; however, the concentration and rate of secretion of salivary and gastric EGF that could counteract these potentially aggressive factors are unknown. Accordingly, this study was conducted to determine whether EGF affords mucosal protection in ZES patients. METHODS: The concentration and output of salivary (sEGF) and gastric epidermal growth factor (gEGF) were measured in eight patients with ZES and the results compared to those in 17 patients with nonulcer dyspepsia (NUD), serving as a control group. All patients had normal esophageal and gastric mucosa as determined by endoscopy. Total saliva was collected during 1-h parafilm- and 1-h pentagastrin/parafilm-stimulated conditions, as well as basal and pentagastrin-stimulated gastric juice. The concentration and output of EGF were determined by radioimmunoassay. RESULTS: The concentration of EGF in saliva collected from ZES patients after parafilm chewing was significantly higher compared to that in NUD patients (4.61 +/- 0.59 vs 2.75 +/- 0.50 ng/ml, p < 0.05). The concentration of EGF in saliva collected after pentagastrin stimulation in ZES patients was also significantly higher than in NUD patients (4.37 +/- 0.73 vs 2.22 +/- 0.37 ng/ml, p < 0.05). Salivary EGF output during parafilm chewing in ZES and NUD were similar (68 +/- 6.4 vs 109 +/- 25.2 ng/h). Salivary EGF output after administration of pentagastrin in ZES and NUD was also similar (66 +/- 6.1 vs 132 +/- 45.4 ng/h). Basal EGF output in the gastric juice of patients with ZES was 3-fold higher than in patients with NUD (801 +/- 73 vs 271 +/- 32 ng/h, p < 0.01). Pentagastrin-stimulated EGF output was similar in both groups (705 +/- 92 vs 675 +/- 168 ng/h). CONCLUSIONS: Patients with ZES have a significantly higher EGF concentration in saliva and EGF output in basal gastric juice. This elevated content of salivary and gastric EGF in ZES patients may play a protective role in preventing the development of reflux esophagitis and gastric ulcer under the impact of gastric acid and pepsin hypersecretion.     

Gastric adaptation to aspirin and Helicobacter pylori infection in man

Abstract The relationship between Helicobacter pylori infection and aspirin (ASA)-induced gastropathy and gastric adaptation to ASA remains unclear. We compared gastric damage and adaptation after repeated exposures to ASA in the same subjects without H. pylori infection and those infected by H. pylori before and after eradication of this H. pylori. Twenty-four volunteers in two groups (A and B), without H. pylori infection (group A) and with H. pylori infection (group B) before and after H. pylori eradication, were given ASA 2 g/day or placebo for 14 days. Mucosal damage was evaluated by endoscopy and gastric microbleeding; mucosal prostaglandin (PG) E₂ generation and luminal transforming growth factor (TGF)α were determined on days 0,3,7 and 14 of the ASA course. In all subjects, ASA-induced gastric damage reached a maximum on day 3. In H. pylori-positive subjects this damage was maintained at a similar level up to the 14th day of observation. Following H. pylori eradication, the damage was significantly lessened at day 14, as revealed by both endoscopy and microbleeding, and was accompanied by increased mucosal release of TGFα. Prostaglandin E₂ generation was significantly higher in H. pylori-positive subjects than after H. pylori eradication, but ASA treatment resulted in greater than 90% reduction of this generation independent of H. pylori status. Gastric adaptation to ASA is impaired in H. pylori-positive subjects but eradication of this bacterium restores this process.     

Indomethacin-induced gastroduodenal damage is not affected by cotreatment with ranitidine

A randomized, double-blind, placebo-controlled study was conducted to determine whether concomitant administration of ranitidine reduces gastroduodenal mucosal damage associated with 1 week of indomethacin treatment. One hundred ten subjects with acute musculoskeletal conditions and who received indomethacin 150 mg/day completed the trial: 55 were treated with ranitidine 150 mg b.i.d. and 51 subjects received placebo b.i.d. Endoscopic gastric and duodenal injury were assessed before and after one week of treatment. There was no statistically significant difference in the percentage of patients with gastroduodenal damage or in the severity of the lesions in both treatment groups. Ranitidine did not ameliorate indomethacin-induced gastrointestinal symptoms and there was no correlation between upper gastrointestinal symptoms and endoscopic findings.     

Ranitidine therapy in patients with idiopathic gastric acid hypersecretion

One hundred twenty-four patients with idiopathic gastric acid hypersecretion (basal acid output greater than 10.0 meq/hr) were prospectively evaluated and treated with ranitidine twice a day. Fifty-four patients (44%) required standard doses of ranitidine 300 mg/day for adequate treatment, and the other 70 patients (56%) required increased doses of ranitidine (mean 994 mg/day, range 600–3000 mg/day). Mean basal acid outputs for these two groups were 14.0 and 16.6 meq/hr, respectively, which were not significantly different. Nevertheless, there was a significant correlation between basal acid output and daily ranitidine dose required for therapy (r=0.18,P=0.05). The duration of ranitidine therapy consisted of: <1 year (N=46), 1 year (N=16), 2 years (N=19), 3 years (N=22), 4 years (N=15), 5 years (N=6). Only five patients required progressive increases in ranitidine during the time of treatment, which consisted of an average of 0.5 dose adjustments per year. No side effects occurred with any of these high doses of ranitidine. These results indicate that, as in Zollinger-Ellison syndrome, ranitidine is effective therapy for patients with idiopathic gastric acid hypersecretion; however, markedly increased doses as large as 3000 mg/day may be required.     

Comparison of omeprazole and ranitidine in treatment of refractory gastroesophageal reflux disease in patients with gastric acid hypersecretion

Secretion of gastric acid and volume, serum gastrin concentration, and ambulatory 24-hr esophageal pH monitoring were evaluated prospectively in 12 patients with idiopathic gastric acid hypersecretion (basal acid output greater than 10.0 meq/hr) undergoing treatment for refractory chronic long-standing pyrosis. Treatment lasted six months and consisted of three months of ranitidine (mean 2150 mg/day, range 1200–3000 mg/day), followed by three months of omeprazole (mean 33 mg/day, range 20–60 mg/day). Both ranitidine and omeprazole significantly reduced gastric acid output (P<0.001) and gastric volume output (P<0.001) compared to a basal evaluation and resulted in complete disappearance of pyrosis. Total reflux time (percent 24 hr intraesophageal pH less than 4) was significantly reduced by ranitidine (P<0.02) and omeprazole (P<0.001) compared to basal evaluation; however, the effects of omeprazole were significantly greater than ranitidine (P<0.05). Omeprazole caused a significant increase in serum gastrin concentration compared to both basal and ranitidine (P<0.05). Endoscopically documented erosive esophagitis was present in nine of the 12 patients, and seven of the 12 patients had Barrett's epithelium. All 12 patients had complete resolution of pyrosis and healed esophagitis by six months, but no significant endoscopic regression was observed in the extent of Barrett's epithelium. No side effects occurred with these high doses of ranitidine or omeprazole. These results indicate that high-dose ranitidine and omeprazole are effective therapy for refractory gastroesophageal reflux disease. However, with omeprazole, total reflux times are reduced more than with ranitidine, often into the normal range. That marked reduction of gastric acid secretion with omeprazole, which greatly reduces total reflux times, accounts for the significant elevation of serum gastrin concentration seen during omeprazole therapy.     

Influence ofHelicobacter pylori on gastric mucosal adaptation to naproxen in man

Our objective was to determine whetherH. pylori influences gastric mucosal injury and adaptation caused by naproxen. Twenty-four healthy volunteers, 12H. pylori-positive and 12H. pylori-negative, were given a 28-day course of naproxen 500 mg twice a day. They were each gastroscoped to assess gastric mucosal damage and mucosal blood flow before and at 1, 7, and 28 days during treatment. Maximal gastric mucosal damage (median grade+IQR) occurred during the first 24 hr in both groups and was of similar magnitude (H. pylori-positive: 2.5, 2.0–3.0P<0.01;H. pylori-negative: 2.0, 1.0–3.0P<0.01). This damage was associated with a fall in antral but not corpus mucosal blood flow. With continued NSAID administration, gastric damage resolved confirming adaptation (H. pylori-positive 1.0, 0–2.0,H. pylori-negative: 1.0, 0–1.0) and antral mucosal blood flow returned to baseline in both groups by day 28. These observations suggest that initial gastric mucosal injury is not influenced byH. pylori colonization and adaptation occurs regardless of its presence.     

Comparison between Ranitidine and Omeprazole for Protection against Gastroduodenal Damage Caused by Naproxen

Acute gastroduodenal injury is commonly associated with the use of nonsteroidal anti-inflammatory drugs. The mechanism of injury is not well understood. The objectives of this study were to evaluate the protective effect of two drugs that give different degrees of acid inhibition against naproxen-induced gastroduodenal injury. Fifteen volunteers aged 22–28 years underwent pre- and post-treatment gastroduodenoscopies during three treatment periods (that is, six examinations), and mucosal injury was graded on a Lanza scale ranging from 0 to 4. The subjects placebo, 150 mg ranitidine twice daily, or 40 mg omeprazole in a double-blind, random-order design for 7 days. Plain naproxen, 500 mg twice daily, was given on days 3–7. The mean injury score for the stomach during placebo treatment was 1.53, and ranitidine gave 44% and omeprazole 40% reduction compared with placebo, which did not reach statistical significance. About 70% of the stomach injury was located in the antrum. The mean injury score during placebo for the duodenum was 1.93, and ranitidine gave 80% and omeprazole 90% reduction (p = 0.004). In conclusion, a correlation between different degrees of acid suppression and a protective effect on the gastroduodenal mucosa could not be shown. The study suggests that acid plays a major role in acute naproxen-induced injury to the duodenal mucosa, and a moderate acid reduction is adequate for protection. In the stomach acid seems to play a minor role in the mucosal injury, but physicochemical contact with naproxen in the antrum and a cyclooxygenase inhibition are of greater importance.     

Impact of Smoking Cessation on Salivary Function in Healthy Volunteers

Background: Salivary bicarbonate and epidermal growth factor (EGF) have an important protective role in the oesophagus. The effect of smoking cessation on these aspects of salivary function is unknown. Methods: Salivary bicarbonate secretion and EGF output were measured before and after attempted smoking cessation in 28 healthy volunteers. Urinary cotinine excretion was used to assess compliance. Results     

Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: A controlled study in normal subjects

Background & Aims: Proton pump inhibitors administered twice daily do not provide complete nocturnal acid suppression. Acid breakthrough, or decrease in intragastric pH to <4 for an hour or longer, occurs in three quarters of normal subjects and patients at night. We compared the effect of a third dose of omeprazole at bedtime with that of a dose of ranitidine at bedtime on residual nocturnal acid secretion in patients receiving omeprazole twice daily. Methods: Twelve volunteers underwent overnight intragastric pH monitoring after 7 days of treatment with omeprazole, 20 mg twice daily, followed by different treatment supplements at bedtime: placebo; additional omeprazole, 20 mg; ranitidine, 150 mg; and ranitidine, 300 mg. Results: Additional omeprazole at bedtime reduced the percentage of time with intragastric pH of <4 from 48% to 31% (P < 0.005) compared with omeprazole twice daily with placebo at bedtime. Ranitidine at bedtime reduced this parameter more, 5% with 150 mg and 6% with 300 mg (P <0.01 vs. omeprazole twice daily plus bedtime). Results for percentage of time with intragastric pH <3 were similar. Eleven subjects had acid breakthrough with placebo at bedtime; 7 with omeprazole at bedtime (P = NS); 4 with ranitidine, 150 mg at bedtime; and 3 with ranitidine, 300 mg at bedtime (P < 0.05, ranitidine vs. placebo). Conclusions: Bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion in patients receiving omeprazole twice daily. This finding suggests that fasting breakthrough nocturnal acid secretion in patients receiving omeprazole twice daily is most likely histamine related.GASTROENTEROLOGY 1998;115:1335-1339     

Transforming Growth Factor Alpha and Epidermal Growth Factor in Protection and Healing of Gastric Mucosal Injury

Transforming growth factor alpha (TGF) and epidermal growth factor (EGF) present in the gastric mucosa are polypeptides with similar biologic activity. This study compares the activity of TGF and EGF in the protection against injury by 100% ethanol and stress and in healing of acute gastric ulcerations. TGF and EGF (12.5-100 μg/kg-h) infused subcutaneously 30 min before and during ethanol or stress decreased mucosal lesions dose-dependently. The ID₅₀ for ethanol- and stress-induced lesions after TGF were 40 and 70 μg/kg-h and after EGF 60 and 100 ug/kg-h. TGF and EGF infused subcutaneously into intact rats inhibited gastric acid secretion but did not affect the gastric blood flow or mucosal generation of prostaglandin E₂ (PGE₂). Both TGF and EGF also significantly enhanced the healing of stress-induced lesions and the restoration of DNA synthesis. Ethanol and stress reduced blood flow in the oxyntic mucosa by 68% and 51%, respectively, and this effect was partially reversed by EGF and TGF. Pretreatment with indomethacin (5 mg/kg intraperitoneally), which reduced mucosal generation of PGE₂ by 85%, decreased in part the protection by TGF and EGF against ethanol-induced damage and virtually abolished the protective action of these peptides against stress-induced injury. We conclude therefore that 1) TGF and EGF show similar and comparable gastroprotective activity against ethanol- and stress-induced damage; 2) the protection by TGF and EGF is accompanied by an increase in gastric blood flow which appears to be an essential factor in gastroprotection; 3) mucosal PG is necessary for manifestation of the protective activity of TGF and EGF against acute gastric damage; and 4) TGF and EGF enhance the healing of gastric lesions, possibly via stimulation of DNA synthesis and cell proliferation.     

Distribution and release of epidermal growth factor in man.

Epidermal growth factor (EGF) is localised in man to salivary and Brunner's glands. It is present in large concentrations in saliva and duodenal contents but the mechanisms of its release have been little studied. This study carried out on four groups of healthy subjects was designed to determine the distribution and the release of immunoreactive EGF (IR-EGF) in salivary, gastric, duodenal, and pancreatic secretions. Under basal conditions, the concentrations of IR-EGF in salivary, gastric, duodenal and pancreatic secretions were; 2.7 (0.4), 0.42 (0.12), 21 (5) and 8.5 (1.2) ng/ml, respectively. Chewing of Parafilm* significantly increased salivary but not gastric or duodenal EGF output while atropinisation led to the reduction in basal salivary and duodenal EGF output without affecting the increment in EGF release induced by chewing. Cigarette smoking caused a marked reduction in basal salivary and duodenal EGF output. Infusion of pentagastrin increased salivary and duodenal EGF output and this was blocked by the addition of somatostatin. Injection of secretin lead to an increase in pancreatic output of EGF. We conclude that in man the major sources of EGF are salivary glands, duodenum, and pancreas and that the release of EGF remains under neurohormonal control.