Search

Background: Glucagon-like peptide-1 (GLP-1)(7-36) amide is an intestinal incretin hormone which also inhibits gastric acid secretion in humans. Its mechanism of action is unclear, but it strongly inhibits vagally induced secretion (sham feeding), suggesting that it could influence vagal activity., Aim/methods: The effect of intravenous GLP-1 (7-36 amide) (1 pmol/kg/min) was studied on pentagastrin induced acid secretion in otherwise healthy subjects, previously vagotomised for duodenal ulcer (n = 8) and in a group of young (n = 8) and old (n = 6) healthy volunteers., Results: Pentagastrin increased acid secretion significantly in all three groups, but the plateau concentration in the vagotomised subjects was lower than in controls. Infusion of GLP-1 (7-36 amide) significantly inhibited acid secretion in the control groups (to 67 (SEM 6) and 74 (SEM 3)% of plateau concentrations in young and old controls, respectively) but had no effect in the vagotomised subjects. Differences in plasma concentrations of GLP-1 (7-36 amide), recovery of gastric marker, duodenal regurgitation, or Helicobacter pylori status could not explain the lack of effect. Blood glucose was lowered equally by GLP-1 (7-36 amide) in all subjects., Conclusion: The inhibitory effect of GLP-1 (7-36 amide) on acid secretion depends on intact vagal innervation of the stomach.

Helicobacter pylori infection may be associated with duodenal ulcer (DU) and accompanied by enhanced gastrin release but the mechanism of this H pylori related hypergastrinaemia in DU patients is unclear. Cholecystokinin (CCK) has been implicated in the feedback control of gastrin release and gastric acid secretion in healthy subjects. This study therefore investigated if CCK participates in the impairment of postprandial gastrin release and gastric secretion in six DU patients. Tests were undertaken with and without elimination of endogenous CCK by loxiglumide, a selective CCK-A receptors antagonist, before and after eradication of H pylori with triple therapy (omeprazole, amoxicyllin, bismuth). In H pylori positive DU patients, the post-prandial decline in pH (with median pH 3.5) was accompanied by a pronounced increment in plasma gastrin but the administration of loxiglumide did not affect significantly this postprandial rise in plasma gastrin and gastric pH profile. After eradication of H pylori, the plasma gastrin concentration was reduced while the median postprandial pH was significantly increased (median pH 4.3). The administration of loxiglumide resulted in significantly greater increase in postprandial plasma gastrin and greater decrease in pH (median pH 3.1) in these patients. This study shows that (a) infection with H pylori is accompanied by an enhanced gastrin release and gastric acidity in DU patients, (b) the failure of loxiglumide to affect plasma gastrin or gastric acid secretion in H pylori infected DU patients could be attributed, at least in part, to the failure of endogenous CCK to control gastrin release and gastric secretion by releasing somatostatin, and (c) the test with loxiglumide may be useful in the identification of patients with impaired feedback control of gastrin release and gastric secretion resulting from infection with H pylori.

The behaviour of basal and stimulated acid secretion, gastrin release, serum pepsinogen I, and gastric emptying of liquids was studied in 19 consecutive patients with Helicobacter pylori positive duodenal ulcer, over a follow up period of six months. Eleven patients were studied before and at three and six months after eradication with lansoprazole plus amoxicillin and tinidazole (case group), whereas the remainder, with persistent H pylori infection, were studied before and after three and six months from ulcer healing, thus constituting the control group. In the case group, three months after eradication, fasting serum pepsinogen I fell from (mean (SEM)) 91.9 (6.9) (pretreatment) to 72.2 (5.1) ng/l and the integrated gastrin response to a meal reduced from 11,470 (1174) (pretreatment) to 8130 (608) pg/ml/h (p < 0.05). Fasting serum gastrin concentrations and maximal acid output reduced significantly only six months after eradication. In contrast, no significant change of any of these measurements was seen in the control group either at three or six months from healing compared with the pretreatment values. Gastric emptying of liquids did not change over the entire period of follow up in both study groups. In conclusion, eradication of H pylori in duodenal ulcer patients is accompanied by a rapid fall in serum pepsinogen I and plasma gastrin concentrations, whereas a slight but significant reduction of maximal acid secretion takes place later on. In contrast, gastric emptying of liquids does not seem to be influenced by H pylori status.

The relation between Helicobacter pylori (H pylori) infection and fasting gastrin and pepsinogen-I and -II concentrations was evaluated in 278 volunteers without symptoms and the results were compared with the values obtained in 35 patients with duodenal ulcers. H pylori infection was determined with the 13C-urea breath test in subjects without symptoms and with endoscopy, biopsy (histology and culture), and quick urease test (CLO-test) in patients with duodenal ulcers. Gastrin and pepsinogen-I and -II concentrations were assayed with specific radioimmunoassay systems. The results clearly indicate that fasting gastrin and pepsinogen-I and -II concentrations were significantly higher in H pylori positive compared with H pylori negative subjects. Neither age nor sex affected basal gastrin and pepsinogen concentrations in H pylori negative subjects. Fasting gastrin, pepsinogen-I and -II concentrations in serum samples were similar in H pylori positive persons with no symptoms and those with duodenal ulcers suggesting that similar mechanisms are involved in increasing plasma concentrations of these variables in both populations. Hypergastrinaemia and hyperpepsinogenaemia are therefore probably secondary to active H pylori infection.

In the past five years 12 patients have been identified presenting with chronic duodenal ulcer (DU) disease and with no evidence of current or recent Helicobacter pylori (H pylori) infection. Four of them were taking regular non-steroidal anti inflammatory agents, one was subsequently found to have Crohn's disease of the duodenum, and one to have the Zollinger-Ellison syndrome. The remaining six patients with idiopathic DU disease were remarkable for their absence of the A1 blood antigen gene. Detailed studies of gastric function were performed in these six patients and compared with H pylori positive patients with DU and with healthy volunteers. The median integrated gastrin response in the patients with idiopathic DU (2810 (range 750-8750) ng/l min) was similar to that of the H pylori positive patients with DU (3355 (550-8725)) and higher than that of the H pylori negative healthy volunteers (560 (225-1125)). The median peak acid output in the patients with idiopathic DU (37 mmol/h, range 17-52) was similar to that of the H pylori positive patients with DU (40 (15-57)) and higher than that of the non-ulcer controls (22 (16-29)). The median percentage of a liquid meal retained in the stomach at 60 minutes was less in the patients with idiopathic DU (23 (15-33)) than in H pylori negative healthy volunteers (34 (30-53) p < 0.01). The median percentage of a solid meal retained at 60 minutes was less in the patients with idiopathic DU (54 (9-83)) than in either H pylori negative healthy volunteers (87 (49-95) p<0.01) or H pylori positive patients with DU (79 (51-100) p<0.01). In conclusion, three abnormalities of gastric function are prevalent in patients with H pylori negative idiopathic DU disease - hypergastrinaemia, increased acid secretion, and the one feature distinguishing them from H pylori positive patients with DU - rapid gastric emptying of both liquids and solids. Each of these abnormalities will increase the exposure of the duodenal mucosa to acid and thus explain its ulceration. The absence of the blood group A1 antigen gene is consistent with a genetic basis for the disturbed gastric function linked to the ABO blood group antigen genes.

Helicobacter pylori infection increases the serum concentration of gastrin, and this may be one of the mechanisms by which it predisposes to duodenal ulceration. Different forms of circulating gastrin were studied both basally and postprandially in 13 duodenal ulcer patients before and one month after eradication of H pylori. Three antisera that are specific for particular regions of the gastrin molecules were used. Gel chromatography indicated that > 90% of the circulating gastrin consisted of gastrin (G) 17 and G34 both before and after eradicating the infection. The basal median total immunoreactive gastrin concentration fell from 26 pmol/l (range 11-43) to 19 pmol/l (8-39) (p < 0.05), entirely because of a fall in G17 from 6 pmol/l (< 2.4-25) to < 2.4 pmol/l (< 2.4-23) (p < 0.001). The median (range) basal G34 values were similar before (15 pmol (2-36)) and after (10 pmol (2-30)) eradication. The median total immunoreactive gastrin concentration determined 20 minutes postprandially fell from 59 pmol/l (38-114) to 33 pmol/l (19-88) (p < 0.005), and again this was entirely the result of a fall in G17 from 43 pmol/l (9-95) to 17 pmol/l (< 2.4-52) (p < 0.001). The median postprandial G34 values were similar before (13 pmol/l, range 6-42) and after (15 pmol/l, range 6-30) eradication. Eating stimulated a noticeable rise in G17 but little change in G34, both in the presence and absence of H pylori. The finding that H pylori infection selectively increases G17 explains why the infection causes mainly postprandial hypergastrinaemia. G17 is increased selectively because H pylori predominantly affects the antral mucosa which is the main source of G17 whereas G34 is mainly duodenal in origin. This study also indicates that the increased concentration of gastrin in H pylori infection is the result of an increase in one of the main biologically active forms of the hormone.

Ranitidine bismuth citrate was compared with an equipotent dose of ranitidine, to determine whether the former, by an anti-Helicobacter pylori activity, would counteract the rise of gastrin resulting from ranitidine's gastric acid antisecretory activity. Twenty four men with duodenal ulcers were studied before and on the 8th day of dosing with either ranitidine bismuth citrate 800 mg twice daily or ranitidine 300 mg twice daily (double blind, randomised, parallel groups). Fasting and postprandial plasma gastrin and plasma pepsinogen I and II concentrations were measured, and a 13C-urea breath test was performed before and on the 8th day of dosing. The 13C-urea breath tests were positive in 21 patients before dosing and remained positive in nine of nine of the ranitidine dosed patients, whereas only two of 12 patients treated with ranitidine bismuth citrate remained positive. The expected rise in meal stimulated plasma gastrin with ranitidine was seen in the 12 patients who received ranitidine but, despite suppression of H pylori urease activity in 10 of 12 patients taking ranitidine bismuth citrate, there was no attenuation of the meal stimulated gastrin rise. There was no significant difference in the mean derived (4 hour) plasma pepsinogen I and II concentrations after dosing with ranitidine or ranitidine bismuth citrate.

The mechanism of the hypergastrinaemia associated with Helicobacter pylori infection is unknown. It may be an effect of the ammonia produced by the bacterium near the antral epithelial surface. We have examined the effect on serum gastrin of inhibiting H pylori urease activity with acetohydroxamic acid in six duodenal ulcer patients. On day 1 the fasted patients received placebo tablets at 8 am, a peptide meal at 10 am, and a 14C urea breath test at 11.30 am. The next day 750 mg acetohydroxamic acid was administered orally in place of the placebo. The median (range) 30 minute breath test value (dose/mmol CO2 X kg body wt X 100) was 152 (111-335) on day 1, but only 22 (14-95) the next day (p less than 0.03). Further studies performed in one subject confirmed that acetohydroxamic acid lowered the ammonium concentration and raised the urea concentration in gastric juice. The inhibition of urease activity and ammonia production did not result in a fall in the basal gastrin concentration or in the median integrated gastrin response to the peptide meal, which was 78 ng/1.h (range 21-222) on day 1 and 79 ng/1.h (33-207) the next day. Ten days after acetohydroxamic acid, the urea breath test values were similar to those before treatment. This study shows that the raised gastrin concentration in patients with H pylori infection is not directly related to the organism's urease activity. It also shows that temporary suppression of H pylori urease activity does not clear the infection.

It has been proposed that the hypergastrinaemia in subjects with Helicobacter pylori infection is caused by the action of the ammonia produced by the organism's urease activity on the antral G cells. To investigate this hypothesis we examined the effect on plasma gastrin of increasing the bacterium's ammonia production by infusing urea intragastrically to eight H pylori positive duodenal ulcer patients. After a 60 minute control intragastric infusion of dextrose solution at 2 ml/minute, a similar infusion containing urea (50 mmol/l) was continued for four hours. During the urea infusion, the median gastric juice urea concentration rose from 1.1 mmol/l (range 0.3-1.6) to 15.5 mmol/l (range 7.9-21.3) and this resulted in an increase in the ammonium concentration from 2.3 mmol/l (range 1.3-5.9) to 6.1 mmol/l (range 4.2-11.9) (p less than 0.01). This appreciable rise in ammonia production did not result in any change in the plasma gastrin concentration. The experiment was repeated one month after eradication of H pylori, at which time the median basal gastrin was 20 ng/l (range 15-25), significantly less than the value before eradication (30 ng/l range 15-60) (p less than 0.05). On this occasion, the gastric juice ammonium concentration was considerably reduced at 0.4 mmol/l (range 0.1-0.9) and the urea infusion did not raise the ammonium concentration or change the plasma gastrin concentration. In conclusion, augmenting H pylori ammonia production does not cause any early change in plasma gastrin.

Patients with hypergastrinaemic duodenal ulcer disease were studied to determine whether chronic moderate hypergastrinaemia produces hyperplasia of gastric enterochromaffin-like cells in man. Eight patients had peak postprandial plasma gastrin concentrations greater than 200 pmol/l, which is the 92nd percentile for patients with duodenal ulcer disease in this laboratory. The control group was eight patients with duodenal ulcers whose peak postprandial gastrin concentrations were less than 200 pmol/l. Basal and peak postprandial plasma gastrin concentrations were 107 (37) and 306 (66) pmol/l (mean (SEM] respectively in the hypergastrinaemic patients compared with 26 (4) and 137 (14) pmol/l respectively in the controls. There was no significant difference in the density of gastrin enterochromaffin-like cells between the two groups. The number of enterochromaffin-like cells per high power field was 53 (8) in the hypergastrinaemic patients compared with 50 (8) in the controls. We conclude that chronic moderate hypergastrinaemia does not produce hyperplasia of enterochromaffin-like cells in man. Our hypergastrinaemic group had plasma gastrin concentrations similar to, or greater than those reported during treatment with drugs such as omeprazole and histamine H2 receptor blockers.

Although various markers have been used in attempts to elucidate the mode of inheritance of duodenal ulcer, they have not significantly contributed to a clear understanding of the problem. In the present study total serum pepsinogen was used as a genetic marker and its concentrations were estimated in 100 ulcer patients and their family members up to three generations. Eighty three per cent of the ulcer patients had hyperpepsinogenaemia on a familial basis, and it followed an autosomal dominant mode of inheritance. Thus a large majority of ulcer patients have associated hyperpepsinogenaemia which forms a genetic basis of their disease. The remaining 17% ulcer patients did not have associated hyperpepsinogenaemia nor was the ulcer inherited by the family. Based on these observations we wish to suggest that duodenal ulcer associated with hyperpepsinogenaemia may be considered a genetic disease. This type may be termed 'primary duodenal ulcer'. In the remaining patients without hyperpepsinogenaemia or affected relatives the ulcer may be called 'secondary duodenal ulcer'. Thus total serum pepsinogen may be considered a reliable genetic marker in helping to delineate the genetic disorder from the non-genetic, thereby improving the predictive ability in duodenal ulcer.

Serum cholecystokinin (CCK) levels were measured in 10 patients with chronic duodenal ulcers, fasting and at intervals after two standard tests meals (300 ml of 40 mmol/1 phenylalanine solution), one given before and one during H2-receptor blockade with metiamide (200 mg four times a day). Fasting serum CCK levels were lower in all patients during treatment with metiamide (the mean level falling from 306-0 +/- 102-0 (SEM) to 82-1 +/- 23-6 pg/ml after treatment (p less than 0-01)). In contrast, peak serum CCK levels after the meal were not significantly different (7400 +/- 1141 pg/ml before treatment and 7569 +/- 1293 pg/ml on metiamide). We conclude that in duodenal ulcer patients CCK secretion under basal condtions may be in part dependent on stimulation of the small intestinal mucosa by gastric acid, but that, after an amino acid meal, gastric acid secretion is less important in determining the amount of CCK released.

Fasting serum pyridoxal was assayed by an automated microbiological system in 50 patients with endoscopically confirmed active peptic ulceration. Thirty patients had gastric ulceration, 14 had duodenal, four had pyloric canal ulceration, and two had both a gastric and a duodenal ulcer. Serum pyridoxal was below normal in 28 of the gastric ulcer group and in one of the duodenal ulcer group. No difference in the age, sex, drug, alcohol intake, or diet could be distinguished between those two groups.

The effects of omeprazole, a benzimidazole derivative, have been determined on the secretory responses to modified sham feeding and pentagastrin, and upon serum gastrin and pancreatic polypeptide concentrations in duodenal ulcer patients. Intragastric administration of omeprazole in doses of 2 and 6 mumol/kg produced, respectively, about 50% and 90% reduction in acid outputs in responses to modified sham feeding and pentagastrin without affecting serum gastrin and pancreatic polypeptide response to modified sham feeding.

Cigarette smoking has been linked with duodenal ulcer disease although the mechanism of this association is unclear. This study assessed basal gastric secretory response to acute smoking of smokers with an active duodenal ulcer; in addition the possible effects of chronic smoking on gastric secretory capacity, as expressed by pentagastrin stimulated gastric acid secretion and fasting serum pepsinogen I (PG I) concentrations, were investigated in patients with active duodenal ulcer, or non-ulcer dyspepsia. In 10 smokers with duodenal ulcer smoking four cigarettes during 40 minutes did not influence basal gastric secretion of acid and pepsin, or serum PG I and gastrin concentrations. In 136 patients with duodenal ulcer and 90 controls with non-ulcer dyspepsia, pentagastrin stimulated acid secretion and fasting serum PG I concentrations were significantly higher among habitual heavy smokers than among non-smokers. These findings suggest that in heavy smokers with duodenal ulcer acid- and pepsin-secreting cell function is not affected by acute cigarette smoking. By contrast, chronic cigarette smoking seems to be associated either with an increase of parietal- and chief-cell mass, or with an enhancement of their secretory capacity.

Gastric acid secretion, gastric emptying, fasting serum gastrin and the serum gastrin response to a meal were measured in duodenal ulcer patients before, and at least five days after completing prolonged treatment with cimetidine (1 or 2 g/day for four or eight weeks followed by 600 mg twice daily for six months). Fasting serum gastrin and the gastrin response were also measured during treatment. Compared with pretreatment values, fasting serum gastrin concentrations were raised both during and five to 31 days after stopping treatment (P less than or equal to 0.02). The integrated gastrin response and the rate of gastric emptying of the solid component of the meal were increased during treatment (P less than 0.001 and P less than 0.002 respectively) but returned to pretreatment levels after stopping therapy. No significant changes were observed in the basal or maximal acid outputs or the rate of emptying of the liquid component of the meal. The results imply that the hypergastrinaemia associated with long-term cimetidine therapy does not result in increased gastric acid secretion.

Plasma gastrin concentrations and gastric acid output after modified sham feeding were determined in 20 duodenal ulcer patients. Sham feeding produced an acid response corresponding to 40-68% of the maximal acid output after pentagastrin stimulation, with no significant increase of plasma gastrin concentrations. In eight patients proximal gastric vagotomy almost abolished the acid responses to both insulin hypoglycaemia and sham feeding. Sham feeding in the vagotomised patients did not change the gastrin concentrations in plasma. After pretreatment with benzilonium, an anticholinergic with minimal central nervous effects, plasma gastrin concentrations increased after sham feeding. The study confirms that sham feeding is a poor stimulus for gastrin release in duodenal ulcer patients and supports a cholinergic inhibition of gastrin release. Intravenous injection of benzilonium bromide in a dose close to 70 micrograms/kg, and atropine in the low dose of 30 micrograms/kg inhibited the acid response to sham feeding by about 65%. Atropine in a dose of 50 micrograms/kg virtually abolished the acid sham feeding response, possibly owing to ganglionic or central nervous blockade. Vagal activation of the acid secretory glands does not seem to involve a purely cholinergic neurotransmission.

Serum gastrin concentrations were measured in patients with duodenal ulcer and controls before, during, and after one-hour intravenous infusion of various doses of adrenaline (0.12 microgram to 6 microgram/min). Gastrin concentrations in the basal state were significantly increased in duodenal ulcer patients compared to controls. The maximal rise in serum gastrin concentrations was obtained at a dose of 4 microgram/min adrenaline in both groups of subjects, and the increase was significantly higher in duodenal ulcer patients than in controls. Adrenaline increased predominantly the gastrin III component (gastrin-17 like) in both duodenal ulcer patients and controls. The threshold level of adrenaline-induced gastrin release was significantly lower in duodenal ulcer patients: intravenous infusion of adrenaline in a dose of 0.12 microgram and 0.25 microgram/min increased serum gastrin concentrations 23 and 43%, respectively, but had no effect in controls. Rises in plasma adrenaline concentrations were similar in both groups of subjects in response to the various doses of adrenaline employed. Only the smallest dose of adrenaline (0.12 microgram/min) resulted in clearly physiological variations in plasma adrenaline concentrations. The results indicate that endogenous adrenaline may stimulate the secretion of gastrin during physiological conditions in patients with duodenal ulcer.

A dose response study of the effect on gastric acid secretion of synthetic human gastrin-17 in doses of 50,200, and 500 ng/kg/h was performed in eight healthy volunteers and in eight patients with duodenal ulcer. The study was repeated on a separate day during intravenous infusion of calcium gluconate (0.1 mmol Ca2+/kg/h). In healthy subjects the acid response to the combined infusion of synthetic human gastrin and calcium did not significantly exceed the response to synthetic human gastrin alone, in contrast with patients with duodenal ulcer in whom the combined infusion did significantly improve acid output compared with infusion of synthetic human gastrin alone. The dose of synthetic human gastrin required for half maximal acid response (D50) was reduced in both groups but significantly more in patients with duodenal ulcer. No difference in serum gastrin concentrations or in serum calcium concentrations were found. It is hypothesised that extracellular calcium plays a role in gastrin stimulated acid secretion in man and that patients with duodenal ulcer are more sensitive to this calcium dependent mechanism than non-duodenal ulcer subjects.

Plasma concentrations of prostaglandins E and F have been measured by radioimmunoassay in patients undergoing diagnostic upper intestinal endoscopy. The results fail to support a previously reported deficiency of plasma PGE in duodenal ulcer patients. Plasma prostaglandin concentrations failed to correlate with the parameters of gastric secretion studied; and were unaffected by histamine H2-receptor blockade or the activity of duodenal ulceration. During combined pentagastrin and insulin secretory studies there was a significant correlation between the outputs of PGE and acid into gastric juice.

Integrated postprandial serum gastrin levels were studied in a prospective series of 144 Chinese patients with duodenal ulcer in relation to sex, total body weight, age of onset and duration of ulcer symptoms, blood group status, and positivity for familial dyspepsia. Postprandial gastrin was unrelated to sex, total body weight, duration of symptoms, and blood group status. Patients whose onset age was in the first two decades (early onset group) had significantly higher postprandial gastrin than those with onset age in the 4th and 6th decades (P less than 0.01). This was found to be associated with the presence in the early onset group (n = 35) of a high proportion of patients with positive family history of ulcer dyspepsia (n = 24), in whom postprandial gastrin was significantly higher than those without such history (P less than 0.01). These results suggest that early onset patients who are positive for family history of ulcer dyspepsia segregate to form one subgroup of duodenal ulcer. They also offer a clue that familial hypergastrinaemia may be one marker for familial duodenal ulcer.

The effects of truncal vagotomy and parietal cell vagotomy on gastric acid secretion and plasma gastrin and pancreatic polypeptide release were studied in 28 duodenal ulcer patients under basal conditions and after modified sham feeding and infusion of pentagastrin (2 micrograms/kg/h). Before vagotomy gastric acid output in response to modified sham feeding was significantly higher than basal acid secretion in all subjects tested and reached about 45% of the pentagastrin maximum. No difference in the increase in acid response, or in the pancreatic polypeptide response to modified sham feeding was found between patients with high and low basal secretion. Plasma gastrin concentration was unaltered by modified sham feeding before and after truncal vagotomy or parietal cell vagotomy, although after vagotomy it tended to reach higher values than before this procedure. After truncal vagotomy, basal pancreatic polypeptide concentration was decreased and modified sham feeding-induced pancreatic polypeptide increment was completely eliminated. Four weeks after parietal cell vagotomy, the modified sham feeding-induced increment in plasma pancreatic polypeptide was significantly decreased and observed only in seven of 12 patients. Four to five years after parietal cell vagotomy all subjects responded to modified sham feeding with pancreatic polypeptide increment similar to that before vagotomy and in three of 12 patients acid response to modified sham feeding was seen. This study indicates that truncal vagotomy eliminates gastric acid and plasma pancreatic polypeptide responses to vagal excitation while parietal cell vagotomy abolishes gastric acid response and reduces temporarily the pancreatic polypeptide response to modified sham feeding (possibly because of transient impairment of the vagal innervation of the pancreas). (2) A high ratio of basal to maximal acid output in non-operated duodenal ulcer patients is not associated with a low acid response to modified sham feeding, nor with a high pancreatic polypeptide concentration, and (3) Restitution of the pancreatic polypeptide response to modified sham feeding five years after parietal cell vagotomy does not indication ineffective denervation of the parietal cells.

Gastric acid and serum gastrin, pancreatic polypeptide, and insulin responses to cephalic vagal stimulation were studied in eight patients with duodenal ulcer using modified sham-feeding for periods varying from four to 30 minutes. In addition, the maximal acid response to sham-feeding was compared with that induced by pentagastrin in 10 healthy subjects and 14 patients with duodenal ulcer. It was found that the gastric acid response to modified sham-feeding reached the maximal value after 15 minutes of sham-feeding and amounted to about 68% of the pentagastrin maximum. The serum pancreatic polypeptide response was also increased after modified sham-feeding and depended on the duration of this procedure, whereas gastrin and insulin responses were not significantly affected by modified sham-feeding. When the peak acid output induced by modified sham-feeding was normalised as percentage of the peak response to pentagastrin, it was similar in healthy subjects and in patients with duodenal ulcer; this indicates that the increased peak acid response to modified sham-feeding observed in patients with duodenal ulcer corresponded with their greater parietal cell mass rather than with increased vagal tone.

Gastric acid secretion, pepsin secretion, and fasting serum gastrin levels were measured in 23 patients with duodenal ulcer disease, divided into three groups which received either cimetidine 800 mg daily, cimetidine 1600 mg daily, or ranitidine hydrochloride 300 mg daily for eight weeks. Pentagastrin tests were carried out at intervals both before and after treatment. Each dose of cimetidine reduced acid secretion to 42% of control one week after starting therapy. Ranitidine reduced acid secretion to 33% of the pretreatment value. Acid secretion remained suppressed to these levels throughout treatment with each drug. Acid secretion returned to pretreatment levels in all patients one week after treatment and remained normal until the end of the study. Both drugs reduced pepsin, which fell to 64% and 61% (p less than 0.01) after 800 mg and 1600 mg cimetidine respectively and to 65% (p less than 0.005) with ranitidine after one week's treatment. Pepsin secretion remained at this reduced level in both cimetidine groups till the end of treatment. Pepsin levels fell to 50% at two weeks of therapy with ranitidine but stabilised at this level till the end of therapy. Cimetidine withdrawal was followed by a return towards pretreatment levels of pepsin secretion; but secretion remained significantly depressed (p less than 0.05) to the end of the study period. In the ranitidine-treated patients pepsin output returned to normal after drug withdrawal. Fasting gastrin levels rose during treatment with both drugs but failed to reach significant levels. After withdrawal of treatment fasting serum gastrin levels returned to normal in all three groups of patients.

In a double blind placebo controlled study the effect of calcitonin on gastric emptying and on serum concentrations of gastrin, insulin, glucose, calcium and phosphorus after a mixed solid-liquid meal was examined in eight patients with duodenal ulcer. Synthetic salmon calcitonin 415 pmol iv was given as a bolus followed by a 90 minute infusion to reach an overall dose of 62.25 pmol/kg. Gastric emptying of a radiolabelled meal was measured with a gamma camera. Calcitonin markedly delayed gastric emptying in all patients examined. The emptying index (Ix) decreased from 2.979 (0.397)/min after placebo to 0.896 (0.317)/min after calcitonin (p less than 0.001). Calcitonin did not affect significantly postprandial gastrin release: AUC0-90, 8768 (880) pg/l min (placebo) and 7807 (619) pg/l min (calcitonin). Postprandial insulin release was abolished by calcitonin -Auc0-90, 2258 (242) mU/l min (placebo) v 736 (131) mU/l min (calcitonin), p less than 0.001. Parallel to the suppression of insulin release was a steady increase in the serum glucose during calcitonin infusion, with the highest glucose concentration of 5.8 (0.53) mmol/l at the end of infusion of the hormone. Calcitonin did not change significantly serum calcium or phosphorus concentrations. A combination of a delaying effect on gastric emptying with the inhibition of gastric acid secretion elicited by calcitonin warrants further studies of calcinonin in the treatment of duodenal ulcer.

The absorption of carbenoxolone sodium has been studied in 15 patients with gastric ulcer and eight patients with duodenal ulcer treated for four weeks. Blood levels of carbenoxolone showed a log distribution, varied markedly between patients, and were significantly higher after Biogastrone tablets (300 mg/day) than after Duogastrone capsules (200 mg/day). Serum carbenoxolone levels were similar in patients taking Biogastrone tablets before or after meals, and in patients taking Biogastrone tablets or Duogastrone capsules with or without antacids following chronic administration. Serum carbenoxolone levels were similar in patients whose gastric ulcers had or had not healed after four weeks' treatment. Serum carbenoxolone was significantly higher in patients who developed oedema, and was significantly correlated with age and with fall in plasma potassium. Carbenoxolone may exert its metabolic effects systemically, but its ulcer-healing effects topically; additional studies are needed to test this hypothesis.

In normal, duodenal ulcer, and gastric ulcer subjects the two main forms of gastrin, G17 and G34, were estimated by radioimmunoassay in fasting serum and after feeding. Two antisera were used: one showing high specificity for G17, the other specific for the common COOH-terminus of G17 and G34 and so allowing estimation of G34 by difference. Basal G17 was similar in gastric ulcer, duodenal ulcer, and normal subjects and the increases of G17 after feeding were also similar in these groups. In contrast, basal G34 was similar in normal and duodenal ulcer subjects but raised in gastric ulcer subjects. After a meal the G34 concentration in both gastric and duodenal ulcer patients was significantly higher than normal. It is concluded that the higher post-prandial gastrin responses in peptic ulcer that have been previously described are due largely to increased G34.

Biopsy specimens have been taken from five standard sites in the stomach and from the duodenal bulb in order to investigate the association of gastritis and duodenitis with duodenal ulcer. Twenty patients with chronic duodenal ulcer were investigated in this manner and in addition had gastric secretion tests and a radio-immune assay of serum gastrin under differing conditions. The patients were then treated either by a truncal vagotomy and pyloroplasty (TVP) or by a highly selective vagotomy without a drainage procedure (HSV). All the investigations were repeated three months postoperatively. Duodenal ulcer was usually associated with gastriitis, although this varied in extent and severity from patient to patient. In nearly all the patients, gastritis was present at the pyloric end of the stomach and along the lesser curve. In more than half of the patients, gastritis was also present in the body of the stomach but the fundus was usually spared. Chronic duodenitis was found in the duodenal bulb in all these patients. After vagotomy there was a marked increase in both the extent and severity of the proximal gastritis in both treatment groups but the distal gastritis remain almost unchanged. There was little change in the incidence of duodenitis after vagotomy but its severity was lessened. No correlation was found between the peak acid output (PAO) in response to Histalog and the severity of the gastritis or the duodenitis either before or after operation, with one exception. The postoperative PAO was significantly less in those patients who developed a severe proximal gastritis after vagotomy. No relationship was found between the severity of the distal gastritis and the levels of serum gastrin. No correlation was found between either the basal or peak acid output and the corresponding serum gastrin levels before or after vagotomy.

Twenty four hour intragastric acidity was measured in five duodenal ulcer patients studied at least three times. The effects of different dosage regimens of intravenous omeprazole was compared with placebo. Mean intragastric acidity from 1000 to 0800 was 34.3 +/- 4.3 mmol/l on placebo. After omeprazole 80 mg at 0900 and 40 mg at 1700 mean acidity was 2.1 +/- 0.9 mmol/l and after omeprazole 80 mg at 0900 and 80 mg at 1700 it was 0.7 +/- 0.2 mmol/l. pH remained above 4.0 for about 80% of recordings with these regimens and for only 5% with placebo. Three of the five patients also received omeprazole 80 mg at 0900, 40 mg at 1700 and 40 mg at 0100 when pH remained above 4.0 for 90% of recordings with 99% inhibition of acidity. Omeprazole rapidly raised intragastric pH in all patients and maintained a gastric pH of greater than 4.0 for most of the time. Large doses of IV omeprazole were required compared with studies using the oral compound.

A one-hour infusion of 0.25 micrograms/kg urogastrone administered to seven patients with duodenal ulceration resulted in significant reduction of basal acid secretion (p less than 0.05) but was without significant effect on basal pepsin and intrinsic factor secretion or on serum gastrin concentration. In another group of five patients with duodenal ulceration a one-hour infusion of urogastrone was given on five successive days. On day 1 and 5 urogastrone was administered after establishing a plateau response to intravenous pentagastrin 1.2 micrograms/kg/h. A mean reduction of 65% in acid output during the urogastrtone infusion was seen on day 1 and this was maintained during the next hour. On day 5 the pentagastrin-stimulated acid output was less than on day 1 and a further significant decrease was noted after urogastrone. Pepsin and intrinsic factor output were also significantly inhibited. There was no change in fasting serum gastrin or urogastrone concentration.

The effectiveness of antacid maintenance therapy in preventing duodenal ulcer (DU) relapse was investigated. Two hundred and fifty one asymptomatic patients with healed DU were stratified into smokers and non-smokers and randomised to receive for one year either placebo, or Maalox TC three tablets (81 mmol) at bedtime (hs), or Maalox TC three tablets in the morning plus three tablets at bedtime (bd) (162 mmol), or cimetidine 400 mg at bedtime. A double dummy technique was used to render the study double blind. In 176 patients evaluable for efficacy, the cumulative relapse at one year was: placebo 57%; Maalox TC hs 39%; Maalox TC bd 23%; cimetidine 25%. Maalox TC bd and cimetidine were equally effective and superior to placebo (p less than 0.01) and bedtime Maalox TC (p less than 0.04). The benefit of treatment was significant for the overall sample and for the subgroup of smokers. The results for the non-smokers also supported efficacy for these two treatments but, perhaps because of small sample sizes, these comparisons were not significant. All 251 patients were assessed for safety. Approximately half the patients in each treatment group had adverse events, leading to withdrawal in three, seven, 12, and four patients on placebo, Maalox hs, Maalox bd, and cimetidine respectively. Diarrhoea occurred in 12 patients in Maalox TC bd and eight in each other group. Serum magnesium concentrations were unchanged; aluminium concentrations were higher than baseline at six and 12 months in both antacid groups and at 12 months in the cimetidine group but the differences were not significant. Maalox TC three tablets bd are as effective as cimetidine 400 mg at bedtime in reducing DU relapse and both are superior to placebo.

Amino acid induced acid and gastrin responses during intragastric titration at pH 2.5 and 5.5 were compared in normal subjects and duodenal ulcer patients with G-cell hyperfunction. The latter were identified on the basis of raised basal or maximal acid outputs and increased gastrin responses to feeding. In normal subjects the mixed amino acid meal stimulated only modest increases in serum gastrin, and the highest observed increase was about 30% that after a standard meal. In contrast, in the G-cell hyperfunction group the highest gastrin concentrations were similar to those after a standard meal. In the G-cell hyperfunction group the increment in serum gastrin at pH 2.5 expressed as a proportion of that at pH 5.5 was 0.29 indicating that the capacity of acid to inhibit gastrin release was well established in these patients. Acid secretory rates were close to maximal at both pH 2.5 and 5.5 during intragastric titration in the ulcer patients, but in normal subjects acid output was about 50% maximal at 2.5 and close to maximal at 5.5. The results suggest that the enhanced gastrin response to feeding in G-cell hyperfunction patients is because of increased sensitivity to amino acid stimulation rather than to diminished acid-inhibitory mechanisms.

Serum gastrin and gastric acid responses to a test meal of 10% peptone were measured in six duodenal ulcer patients using intragastric titration at pH levels ranging from 5.5 to 1.0. In this way the pH profile for inhibition of serum gastrin release and gastric acid secretion was established. A peptone meal adjusted to pH 5.5 produced gastric acid similar to the maximal response to histamine. A graded decrease of pH of the peptone meal to 1.0 resulted in the progressive inhibition of the gastric acid secretion and the concomitant suppression of the serum gastrin level. Exogenous secretin given in graded doses ranging from 0.25 to 2.0 U/kg-hr caused a dose-related inhibition of gastric acid secretion and the suppression of serum gastrin level. The results of the study indicate that gastric acid secretion and the rise in serum gastrin levels in response to an experimental meal are less when the gastric contents become more acid. The mechanism may involve release of secretin from the small intestine by acid.

Serum gastrin has been measured in 30 patients following selective gastric vagotomy. Basal serum gastrin was 52+/-5.7 pg/ml which was significantly lower than the corresponding level in 50 patients following truncal vagotomy (84+/-7.9 pg/ml). After a standard protein meal serum gastrin rose to 136+/-8.3 pg/ml at 60 minutes after the meal. The peak rise above basal levels was significantly lower than that achieved in patients who had undergone truncal vagotomy. These results complement our previous hypothesis that section of extragastric vagal fibres permits the release of additional gastrin above that expected with the diminution of acid secretion, and hence the decrease in inhibition of gastrin release from the antrum.

Serum gastrin has been measured by radioimmunoassay in normal subjects and patients with proven duodenal ulcer in response to insulin hypoglycaemia in conjunction with manoeuvres to decrease the intragastric acidity. Insulin hypoglycaemia alone caused a rise in the serum gastrin level from 5 +/- 1.0 to 49 +/- 2.9 pg/ml in duodenal ulcer and from 17 +/- 5.6 to 42 +/- 7.7 pg/ml in normals. With complete intragastric neutralization of acid and the same stimulus, the rise in duodenal ulcer was from 5 +/- 1.3 to 128 +/- 13.6 pg/ml and in normals from 13 +/- 2.6 to 84 +/- 2.6 pg/ml. These studies suggest an increased production rate of gastrin in response to vagal stimulation in duodenal ulcer, and indicate the precise role of acid inhibition in the control of gastrin release and support the concept of both an increased ;G cell' mass and parietal cell mass in duodenal ulcer. They have also offered an explanation of the variable vagal stimulation of gastrin release in normal subjects.

Fasting serum gastrin has been measured by radioimmunoassay in 72 patients with duodenal ulcer and compared with that in normals, patients with gastric ulcer, and with the Zollinger-Ellison syndrome. The mean (+/- SEM) gastrin levels were 15.7 +/- 1.5 pg/ml in the duodenal ulcer group, 32.1 +/- 4.3 pg/ml in normals, 118 +/- 18.1 pg/ml in gastric ulcer, and between 450 and 2,000 pg/ml in the Zollinger-Ellison syndrome. There were no difficulties in distinguishing simple ulcer from the Zollinger-Ellison syndrome as the presence of hyperchlorhydria in combination with hypergastrinaemia led to a confident diagnosis of the latter disease.The effect of protein, glucose, and cream feeding with and without atropine was also assessed in a group of these patients with duodenal ulcer. As in normals, there was no stimulation of gastrin release by either atropine alone, distilled water, glucose, or cream. However, protein alone produced a greater rise in serum gastrin levels compared with that in normals and prior atropinization augmented this response greatly in duodenal ulcer. This indicates an increased amount of releasable gastrin in the latter disease, the release of which, under basal conditions, is suppressed by the high acidity in the antrum.

A perfused rat stomach technique which can detect synthetic human gastrin I in amounts greater than 10 ng and measure by block assay amounts greater than 50 ng was used to study circulating gastrin-like activity in normal subjects, patients with peptic ulcer, and patients with the Zollinger-Ellison syndrome. No detectable activity was found in normal subjects or patients with gastric ulcer before or after meals. No activity was found in the fasting plasma of patients with duodenal ulcer but after meals activity could be detected in duplicate samples in seven of 20 patients. In nine proven cases of the Zollinger-Ellison syndrome, gastrin-like activity in the plasma ranged from 15 to 356 ng/ml. The gastrin-like content of two tumours was 6.4 and 29.1 mug/g of tissue. The significance of these findings in relation to immunoassay is described.

Following truncal vagotomy and anterior pylorectomy for duodenal ulcer, fasting serum gastrin levels were higher at 84 +/- 7.9 pg per ml than in unoperated patients with duodenal ulcer (16 +/- 1.5 pg per ml). In response to a standard protein meal, the peak serum gastrin achieved in the vagotomized group was 259 +/- 37.8 pg per ml at 75 minutes after ingestion, a much higher response than that obtained with a standard meal plus prior atropinization in the unoperated duodenal ulcer patients.These results suggest that truncal vagotomy allows release of gastrin which was previously inhibited with the vagi intact and the temporal characteristics of the response indicate that some of this gastrin is derived from an extragastric source. The results also exemplify the dependence of gastrin estimations as measured by this immunoassay on the acidity of the contents bathing the gastric antrum.