Effect of Basal Gastric Acid Secretion on the Pharmacodynamics of Ranitidine

Twelve patients with inactive ulcer disease were administered placebo and ranitidine via bolus and continuous intravenous infusions, at doses ranging from 50 every 8 h, to 12.5 mg/h for 24 h. Gastric acid was collected for 20 min each h for 24 h, and ranitidine serum concentrations were measured ± every 2 h, during each of the six study periods. Cosinor analysis of gastric acid secretion during placebo treatment revealed a significant circadian rhythm in all subjects. Mesor acid output ranged from 1.7 to 11.6 mmol/h (mean 5.6 ± 2.8 mmol/h) and the amplitude ranged from 0.7 to 6.5 mmol/h (mean 2.8 ±1.6 mmol/h). Peak acid output (acrophase) occurred at 10 p.m. ± 3 h. A pharmacodynamic model, relating ranitidine serum concentration to hourly acid secretion, was derived, which incorporated the circadian change in basal acid output. Data for this fractional response model included basal acid secretion–as determined by time of day, measured acid secretion, and associated serum ranitidine concentration. The 50% inhibitory concentration (IC₅₀) for ranitidine ranged from 10-75 ng/ml, with a mean of 44 ng/ml. The variation in IC₅₀ and in basal acid secretion combined to produce a wide variation in the pharmacodynamic response to ranitidine. The model-predicted serum concentrations, required to maintain acid secretion at 0.1 mmol/h, ranged from 250 to 1550 ng/ml, at the time of peak evening acid secretion. Despite a constant degree of acid inhibition by ranitidine during the day, higher serum concentrations are required during times of peak acid output to maintain adequate suppression of hydrogen ion secretion.     

Gastric acid inhibitory profile of ebrotidine, a novel H2-receptor antagonist in humans.

This study was designed to assess the gastric secretory effects of ebrotidine, a novel H2 receptor antagonist, in humans. Three groups (A, B and C) of male subjects with normal gastric mucosa were used. Group A (6 subjects) was used to determine the dose-dependency of gastric inhibitory effect of ebrotidine on basal and pentagastrin-induced maximal acid output. Group B (8 subjects) was employed to examine the duration of the inhibitory effect of ebrotidine on basal and pentagastrin-induced acid secretion. In group C (6 subjects), the 24h pH-metry was assessed using intraluminal pH-electrode placed in the gastric corpus and connected to a portable recording unit. Single oral dose of ebrotidine (200, 400 or 800 mg) caused a dose-dependent reduction in basal and pentagastrin-induced acid secretion that at a dose of 800 mg amounted to about 89% and 93%, respectively. This inhibition was still observed after 6h and averaged 72% and 50%, respectively. After 12 and 24h upon the drug intake, both basal and pentagastrin-induced acid secretion returned to the control values. Single oral dose of ebrotidine (800 mg) caused a significant reduction in circadian acidity and resulted in a marked and significant reduction of intragastric acidity for about 6h upon the administration. This inhibition was accompanied by a transient increase in basal and postprandial gastrin levels. We conclude that ebrotidine is highly effective inhibitor of basal, pentagastrin-induced and circadian gastric acid secretion in humans.     

Oral PGE2 inhibits gastric acid secretion in man

The effect of oral prostaglandin E₂ (PGE₂) on gastric acid secretion was examined in healthy subjects. The gastic secretion was stimulated by a modified shamfeeding procedure. Each subject underwent one control test and three tests with intragastrically administered graded doses of PGE₂: 0.5, 1.0 and 2.0 mg.Oral PGE₂ significantly suppressed the peak and total acid response to vagal stimulation. The total acid output in controls was 27.5 ± 3.2 mol/90 min and 20.8 ± 2.8, 15.8 ± 2.2 (p<0.01) and 15.9±3.8 (p<0.005)mol/90 min in test series with 0.5, 1.0 and 2.0 mg PGE₂ respectively. The two higher doses were equally inhibitory to an average 40%. Gastric outputs on sodium and potassium in response to modified shamfeeding were reduced by PGE₂.In controls there was a significant release of plasma-gastrin in response to shamfeeding. Plasma-gastrin was apparently suppressed after the two lower doses of PGE₂ but 2.0 mg PGE₂ gave an elevation similar to controls.Thus the study demonstrates that the oral natural PGE₂ suppresses the gastric acid secretion in man. The absence of such an effect in prior studies has been one of the objections against an acid regulatory action of endogenously formed prostaglandins. The present results do not support this argument.     

Effect of Basal Gastric Acid Secretion on the Pharmacodynamics of Ranitidine

Twelve patients with inactive ulcer disease were administered placebo and ranitidine via bolus and continuous intravenous infusions, at doses ranging from 50 every 8 h, to 12.5 mg/h for 24 h. Gastric acid was collected for 20 min each h for 24 h, and ranitidine serum concentrations were measured ± every 2 h, during each of the six study periods. Cosinor analysis of gastric acid secretion during placebo treatment revealed a significant circadian rhythm in all subjects. Mesor acid output ranged from 1.7 to 11.6 mmol/h (mean 5.6 ± 2.8 mmol/h) and the amplitude ranged from 0.7 to 6.5 mmol/h (mean 2.8 ±1.6 mmol/h). Peak acid output (acrophase) occurred at 10 p.m. ± 3 h. A pharmacodynamic model, relating ranitidine serum concentration to hourly acid secretion, was derived, which incorporated the circadian change in basal acid output. Data for this fractional response model included basal acid secretion-as determined by time of day, measured acid secretion, and associated serum ranitidine concentration. The 50% inhibitory concentration (IC₅₀) for ranitidine ranged from 10-75 ng/ml, with a mean of 44 ng/ml. The variation in IC₅₀ and in basal acid secretion combined to produce a wide variation in the pharmacodynamic response to ranitidine. The model-predicted serum concentrations, required to maintain acid secretion at 0.1 mmol/h, ranged from 250 to 1550 ng/ml, at the time of peak evening acid secretion. Despite a constant degree of acid inhibition by ranitidine during the day, higher serum concentrations are required during times of peak acid output to maintain adequate suppression of hydrogen ion secretion.     

The effects of 11-methyl 16,16 dimethyl prostaglandin E2 on gastric acid secretion in man

11-Methyl 16,16 Dimethyl Prostaglandin E₂ (TM-PGE) was administered orally to man in dosages of 2.5, 5, 7.5 and 10 μg/kg. Maximal inhibition of basal secretion was 52 and 78% and submaximal histamine-stimulated secretion 45 and 70% for volume and acid output, respectively. Secretory inhibition was observed for approximately two hours after ingestion of the drug. No effect was observed on serum gastrin levels. Side effects occurred with equal frequency in the placebo and drug groups. TM-PGE is well tolerated and inhibits both basal and submaximal histamine-stimulated acid secretion in man. Further evaluation may prove it to be helpful in the clinical treatment of acid hypersecretory states and peptic ulcer disease.     

The role of prostaglandins in the regulation of gastric mucosal blood flow

It has been postulated that endogenous gastric prostaglandin activity contributes to the maintenance of non-stimulated gastric mucosal blood flow. Prostacyclin and PGE₂ increase mucosal blood flow in the non-stimulated canine stomach. Inhibition of prostaglandin synthesis by aspirin or indomethacin causes a reduction of 30% to 50% in non-stimulated gastric mucosal blood flow in dog and rat. These observations are consistent with the hypothesis that endogenous prostaglandin activity within the gastric mucosa contributes to the maintenance of its blood flow.Also it has been postulated that endogenous prostaglandins may, in part, mediate the vasodilation associated with stimulated gastric acid secretion. Exogenous prostacyclin and PGE₂ inhibit stimulated acid secretion while increasing mucosal blood flow. Indomethacin and aspirin-inhibited endogenous prostaglandin synthesis has been reported to increase stimulated acid secretion and reduce mucosal blood flow in anesthetized rat and dog. In gastric secretory fluid, prostaglandins have been detected during gastrin stimulation by some investigators and a dose response relationship between rate of secretion and fluid prostaglandin output has been observed. These observations are consistent with the hypothesis that endogenous prostaglandins may, in part, contribute to the regulation of mucosal blood flow during stimulated acid secretion. Further studies, directly measuring specific endogenous prostaglandins and their metabolic products within the gastric mucosa during stimulated and inhibited acid secretion will be necessary to prove or disprove this hypothesis.     

Effects of ethanol on gastric acid secretion and gastric mucosal cyclic AMP in the rat.

The effect of ethanol on the secretion of gastric acid and the content of cyclic AMP of the gastric mucosa was studied in rats. Intravenously, ethanol (10 to 800 mg/kg) had no effect on the output of acid. Upon local application into the stomach, ethanol (1 to 10%) caused a concentration-dependent inhibition of the output of gastric acid. The effect was evident within 5 min. At the concentration of 1 %,ethanol decreased the rate of acid secretion maximally by about 30%. At the concentration of 3 %, the maximal inhibition was about 70 %. At the concentration of 10 %, ethanol caused a total cessation of the output of acid within 20 to 60 min.Five and 25 min after the administration of 10 % ethanol into the stomach, the gastric mucosal content of cyclic AMP was decreased by approximately 50 %. Also in vitro, the mucosal content of cyclic AMP was decreased by ethanol within 5 min. The decrease was about 30 % with 2.5 % ethanol, approximately 60 % with 10 % ethanol, and approximately 45 % with 20 % ethanol. Alcohol inhibited the activity of the cyclic AMP phosphodiesterase of the gastric mucosa in a competitive manner. The K_i-value was 0.16 M which would correspond to an alcohol concentration of 9.1 % (v/v). Ethanol caused a concentration-dependent inhibition of the activity of the gastric mucosal adenyl cyclase. By 0.166 M (9.4 %) alcohol the inhibition was nearly 100 %.It is concluded that the ethanol-induced decrease of cyclic AMP in the gastric mucosa is due to a decreased formation of the nucleotide. The accompanying inhibition of the output of acid by ethanol is consistent with the view that cyclic AMP is an intracellular regulator of the gastric acid secretion. In view of the role of cyclic AMP in the control of the integrity of the cells, it is suggested that the ethanol-induced damage of gastric mucosa might also be, at least partly, due to the decreased mucosal content of cyclic AMP.     

Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus

Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg body weight) stimulated acid secretion. Motilin (0.1, 1.0, and 10 μg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 μg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 μg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 μg/kg BW) or ghrelin (1 μg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co-administration-induced acid output. In contrast, famotidine (a histamine H₂ receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. Our results also suggest that motilin and co-administration of motilin and ghrelin stimulate gastric acid secretion via the histamine-mediated pathway in suncus.     

The effects of 11-methyl 16,16 dimethyl prostaglandin E2 on canine gastric acid secretion

11-Methyl 16,16 Dimethyl Prostaglandin E₂ (TM-PGE₂) at peak effectiveness inhibited acid output stimulated submaximally by histamine in the dog by 95 and 84% when administered by the intravenous and oral routes, respectively. Inhibition of secretion was maintained for hours following intravenous administration while with the oral route, secretory inhibition was still present at the end of two hours after administration of the drug. The degree of inhibition of acid secretion caused by TM-PGE₂, its duration of action and the lack of side effects observed following administration of this drug makes it a suitable compound for evaluation as an anti-secretory agent in man.     

The influence of a new prostaglandin E2 analogue (FCE 20700) on gastric acid and pepsin secretion in the dog.

The effects of FCE 20700, a new prostaglandin E₂ analogue, on gastric acid and pepsin secretion stimulated by different secretagogues were studied in dogs. Intravenous FCE 20700 produced a significant inhibition of total acid output (TAO) induced by pentagastrin or histamine in gastric fistula (GF) dogs. This effect was short-lasting and mainly due to a reduction in the volume of gastric juice with little acid concentration change. TAO and pepsin output stimulated by 2-deoxy-D-glucose were simililarly inhibited by intravenous FCE 20700. In dogs chronically fitted with both GF and Heidenhain pouch (HP), intragastric FCE 20700 significantly inhibited TAO stimulated by pentagastrin or histamine from HP, while acid secretion from GF was not significantly affected. It is concluded that FCE 20700 possesses a weak antisecretory activity in dogs. Consequently the antiulcer effects of this prostaglandin derivative seem to be largely independent from its influence on gastric acid and pepsin secretion.     

Gastric secretion with feeding and restraint in conscious rhesus monkeys.

Four chair-housed rhesus monkeys (Macaca mulatta) were surgically prepared with vagally-innervated fundic gastric pouches. As in man, basal acid secretion was evident in all subjects. In response to a test meal, acid output rose twofold over basal values and remained elevated up to 6 h. Compared to control values, food-stimulated acid output was reduced significantly during periods of restraint.     

Aspirin changes the secretion rate and amino acid composition of human small intestinal mucin in subjects with ileal conduits

The effect of aspirin on the rate of secretion and amino acid composition of human ileal mucin was studied, using subjects with ileal conduits as a model system in which mucin secreted from the ileal conduit tissue is flushed out in the urine and can be measured and analysed. Aspirin (600 mg per day, administered orally) increased the daily mucin output by 37–104% in subjects by days 3 or 4, but thereafter the mucin output declined to below the baseline level by day 10. Mucin samples, purified from the ileal conduit urine during the control period and during aspirin administration, were compared. There were no discernible changes in the degree of polymerisation or the density, but during aspirin administration the amino acid composition was significantly changed, and in particular threonine and proline were enriched. One possible explanation, consistent with the compositional analyses, is that the N- and C-terminal regions of the mucin subunits have been cleaved off and lost during aspirin administration. The observed changes in mucin secretion may have implications for the mechanism of the toxic effects of aspirin on the small intestine by altering the barrier properties of the mucus layer.Abbreviations EGF epidermal growth factor - NSAID non-steroidal anti-inflammatory drug     

Effect of cyproheptadine administration on insulin secretion in acromegalic, diabetic and normal subjects.

The effect of cyproheptadine (Cypro) and Placebo administration on insulin secretion and glucose utilization following i.v. glucose (IVGTT) was evaluated in 8 normal, 7 diabetic and 8 acromegalic subjects. Five of the diabetic subjects had overt diabetes and two of the diabetic subjects had "chemical" diabetes (oral GTT). One of the acromegalic subjects had overt diabetes, while one had borderline glucose tolerance and six had normal glucose tolerance (oral GTT). Cypro increased insulin secretion in the acromegalic but not in the diabetic or normal subjects. Methysergide (Methyl) increased insulin secretion in acromegalic and diabetic subjects but not in normal subjects. Methy and Cypro both increased insulin secretion in the same acromegalic subjects. None of the three groups of subjects had a modification in insulin secretion following Placebo administration. Neither Placebo, Cypro or Methy altered the glucose utilization rate contant (KG). There was no change in insulin half life or tissue sensitivity to insulin from Cypro (normal and acromegalic subjects) or Methy (normal subjects) administration. Despite their increase in insulin secretion in response to serotonin antagonists, acromegalic subjects have normal urinary 5-hydroxyindoleacetic acid excretion and normal serum serotonin concentrations. Their response cannot therefore be attributed to a generalized overproduction of serotonin.     

Adenosine deaminase activity in the human duodenal mucosa in relation to gastric acid secretion.

Adenosine deaminase (ADA) activity was estimated in mucosal specimens obtained endoscopically from the duodenal bulb. Three groups of subjects were studied: 1. 9 patients with achlorhydria, 2. 12 subjects with normal gastric acid secretion, 3. 5 patients with hypersecretion. Enzyme activity was measured by determination of ammonia liberated from the substrate according to the Chaney and Marbach method. In patients with hypersecretion the ADA activity was lower than in those with achlorhydria (p less than 0.001) and normal acid secretion (p less than 0.02). A significant negative correlation between ADA activity in the duodenal bulb mucosa and basal and maximal gastric acid outputs was found. The present study seems to indicate a possible relationship between gastric acid secretion and duodenal ADA activity.     

Comparing binding of histamine and H2-antagonist with their effects on gastric acid secretion

A microsomal fraction from isolated frog gastric mucosa was used to study the binding of labeled histamine, labeled metiamide (a histamine H2-antagonist), and competition between labeled histamine and unlabeled metiamide. The separation of free from bound ligand was done by gel chromatography. The acid secretion was studied in frog gastric mucosa in vitro by a pH-stat method. The binding data could be interpreted in terms of two independent binding sites for both histamine and metiamide. However, the competition between histamine and metiamide does not support the independence of the sites. Moreover, the dissociation kinetics of labeled metiamide in the presence of unlabeled metiamide is non-monotone and, thus, indicates cooperativity. In the physiological studies, the dependence of the rate of acid secretion on histamine stimulation occurs within very narrow limits, which is the result of characteristics other than related to binding. However, the total amount of acid secreted caused by a pulse of histamine does indicate two sites, of which the high-affinity site is the more effective. Metiamide inhibition of acid secretion can be interpreted as an interaction between high-affinity sites of histamine and metiamide. Overall, studies involving physiological effects provide less precise data than the direct binding studies.     

The effect of 15 (R) 15 methyl prostaglandin E2 on gastric acid secretion in duodenal ulcer patients

The effect of synthetic analogue 15 (R) 15 methyl PGE₂ on basal and pentagastrin stimulated maximal acid output in 24 duodenal ulcer patients has been studied. The prostaglandin analogue in a single oral dose of 150 μg reduced both basal and maximum output. Basal acid output fell from a mean control value of 5.9 ± 1.5 mEq/hr to 2.1 ± 0.6 mEq/hr (p < 0.05) and maximum acid output from 32.1 ± 1.6 mEq/hr to 20.6 mEq/hr (p < 0.001). The volume of gastric secretion did not alter significantly in the basal state but fell significantly in the maximally stimulated state after prostaglandin administration.     

Fasting gastric pH of Japanese subjects stratified by IgG concentration against Helicobacter pylori and pepsinogen status

Background: The clinical significance of Helicobacter pylori antibody titer has been controversial, and the association between the extent of gastric atrophy or acid secretion and H. pylori antibody concentration has not been elucidated. Materials and Methods: Serum pepsinogen, H. pylori antibody concentration, and fasting gastric pH (as an indicator of acid secretion) were measured in 231 patients undergoing upper gastrointestinal endoscopy. “Atrophic” pepsinogen was defined as pepsinogen‐I < 70 ng/mL and pepsinogen‐I/II ratio <3. Other levels of pepsinogen were defined as “normal”. Fasting gastric pH was analyzed in subjects stratified by pepsinogen level and by H. pylori antibody concentration. Results: Helicobacter pylori antibody concentration showed no significant relationship with fasting gastric pH when all subjects were analyzed together. In H. pylori‐seronegative subjects, fasting gastric pH was within the normal range, irrespective of the extent of mucosal atrophy. In H. pylori‐seropositive subjects, H. pylori antibody concentration was positively correlated with fasting gastric pH in subjects with “normal” pepsinogen, but inversely correlated in those with “atrophic” pepsinogen. Particularly in subjects with low H. pylori antibody concentration and atrophic mucosa, a group reportedly at high risk of noncardia cancer, the most impaired acid secretion was shown among subjects with atrophic mucosa. Conclusions: The relationship between acid secretion and H. pylori antibody concentration differs depending on the presence of mucosal atrophy. Our findings provide a possible rationalization for measuring both serum pepsinogen levels and H. pylori antibody concentration in gastric cancer screening.     

Radioimmunoassay of main urinary metabolite of prostaglandin F2α in normal subjects

Radioimmunoassay of 5α,7α-dihydroxy-11-keto-tetranorprosta-1, 16-dioic acid, main urinary metabolite of prostaglandin F F_2α (PGE_2α-MUM), was performed in normal subjects. Twenty-four hours secretion of PGF_2α-MUM were 29.04 ± 9.73 μg in males and 18.22 ± 5.88 μg in females on an average. And an oral administration of aspirin resulted in the remarkable decrease of PGF_2α-MUM in both sexes.     

Peptide histidine valine-42 stimulates gastric acid secretion in man

The effect of peptide histidine valine-42 (PHV-42) on gastric acid secretion was studied in man. PHV-42 was infused into 5 healthy volunteers at a dose of 10 pmol/kg/min. This dose caused a significant stimulation of basal gastric acid and potassium output. there were no significant changes in circulating gastrin throughout the infusion. In 2 subjects with a background of submaximal pentagastrin stimulation, PHV-42 infusion at the same dose did not alter acid secretion in either subject. The previous observation that PHV-42 is found particularly in the stomach and the new finding that it stimulates basal gastric secretion suggest the possibility that PHV-42 could have a role in local control of acid secretion.     

β‐Cell Function Improvement After Biliopancreatic Diversion in Subjects With Type 2 Diabetes and Morbid Obesity

In subjects with obesity and type 2 diabetes mellitus (T2DM), biliopancreatic diversion (BPD) improves glucose stimulated insulin secretion, whereas the effects on other secretion mechanisms are still unknown. Our objective was to evaluate the early effects of BPD on nonglucose‐stimulated insulin secretion. In 16 morbid obese subjects (9 with T2DM and 7 with normal fasting glucose (NFG)), we measured insulin secretion after glucose‐dependent arginine stimulation test and after intravenous glucose tolerance test (IVGTT) before and 1 month after BPD. After surgery the mean weight lost was 13% in both groups. The acute insulin response during IVGTT was improved in T2DM after BDP (from 55 ± 10 to 277 ± 91 pmol/l, P = 0.03). A reduction of insulin response to arginine was observed in NFG, whereas opposite was found in T2DM. In particular, acute insulin response to arginine at basal glucose concentrations (AIR_basal) was reduced but insulin response at 14 mmol/l of plasma glucose (AIR₁₄) was increased. Therefore, after BPD any statistical difference in AIR₁₄ between NFG and T2DM disappeared (1,032 ± 123 for NFG and 665 ± 236 pmol/l for T2DM, P = ns). The same was observed for Slope_AIR, a measure of glucose potentiation, reduced in T2DM before BPD but increased after surgery, when no statistically significant difference resulted compared with NFG (Slope_AIR after BPD: 78 ± 11 in NFG and 56 ± 18 pmol/l in T2DM, P = ns). In conclusion, in obese T2DM subjects 1 month after BPD we observed a great improvement of both glucose‐ and nonglucose‐stimulated insulin secretions. The mechanisms by which BDP improve insulin secretion are still unknown.