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Prolonged inflammation after spinal cord injury is detrimental to recovery. To find pharmacological modulators of the inflammation response, we designed a rapid drug screening paradigm in larval zebrafish followed by testing of hit compounds in a mouse spinal cord injury model.Methods: We used reduced il-1β linked green fluorescent protein (GFP) reportergene expression as a read-out for reduced inflammation in a screen of 1081compounds in larval zebrafish. Hit drugs were tested in a moderate contusion model in mice for cytokine regulation, and improved tissue preservation and locomotor recovery.Results: Three compounds robustly reduced il-1β expression in zebrafish.Cimetidine, an over-the-counter H2 receptor antagonist, also reduced the number of pro-inflammatory neutrophils and rescued recovery after injury in a zebrafish mutant with prolonged inflammation. Cimetidine action on il-1β expression levels was abolished by somatic mutation of H2 receptor hrh2b, suggesting specific action. In mice, systemic treatment with Cimetidine led to significantly improved recovery of locomotor behavior as compared to controls, accompanied by decreased neuronal tissue loss and a shift towards a pro-regenerative profile of cytokine gene expression.Conclusion: Our screen revealed H2 receptor signaling as a promising target forfuture therapeutic interventions in spinal cord injury. This work highlights the usefulness of the zebrafish model for rapid screening of drug libraries to identify therapeutics to treat mammalian spinal cord injury.

As an alternative to classical synthetic approaches for the production of betazole drug, a one-pot biocatalytic system for this pharmaceutical molecule from its alcohol precursor has been developed. An ω-transaminase, an alcohol dehydrogenase and a water-forming NADH oxidase for in situ cofactor recycling have been combined to catalyse this reaction, yielding 75% molar conversion in batch reactions with soluble enzymes. This multienzyme system was then co-immobilised through a newly established protocol for sequential functionalization of a methacrylate-based porous carrier to enable tailored immobilisation chemistries for each enzyme. This pluri-catalytic system has been set up in a continuous flow packed-bed reactor, generating a space–time yield of up to 2.59 g L−1 h−1 with 15 min residence and a constant supply of oxygen for in situ cofactor recycling through a segmented air–liquid flow. The addition of an in-line catch-and-release column afforded >80% product recovery., The primary amine of betazole is synthesised from an alcohol in a one-pot, continuous flow biocatalytic cascade, using a PBR hosting a multienzyme co-immobilised system with constant O2 supply for in situ cofactor recycling, yielding 2.59 g L−1 h−1.

Pyrazole is a five-membered aromatic heterocyclic ring with two adjacent nitrogen atoms C3H3N2H.The presence of this nucleus in pharmacological agents of various therapeutic categories gifts a broad spectrum of biological activities and pharmaceuticals that contain pyrazole like celecoxib (anti-inflammatory), CDPPB (antipsychotic), Rimonabant (anti-obesity), Difenamizole, (Analgesic), Betazole (H2 receptor agonist), Fezolamide (Antidepressant), etc… The pharmacological potential of the pyrazole fraction is proved in many publication where they synthesized and evaluated pyrazoles against several biological agents. The aim of this article review is to survey recent works linking pyrazole structures to anticancer activities corresponding to 9 different type of cancer.

Objective: The aim of this study was to identify alternative compounds to the tumor suppressor miR-375 using the connectivity map (CMAP) and to validate the antitumor effects of the identified drugs in esophageal squamous cell carcinoma (ESCC). Methods: Gene profiling of miR-375-treated TE2 and T.Tn cells was applied in order to search the CMAP database. Among the compounds identified using the CMAP, we focused on 8 drugs [(-)-epigallocatechin-3-gallate, metformin, rosiglitazone among others], excluding 2 drugs among the top 10 compounds. We evaluated whether these compounds possess tumor-suppressive functions in ESCC. Results: A cytotoxicity assay showed that the sensitivity of TE2 and T.Tn cells treated with the 8 compounds was evaluated based on IC50 values of 42.9 µM to 3.8 mM. A cell cycle analysis revealed that the percentage of TE2 and T.Tn cells incubated with 6 compounds in the G0/G1 phase or the G2/M phase increased by approximately 40-80%. A TUNEL assay showed that the percentages of apoptotic cells treated with almost all compounds were significantly increased (p < 0.05) compared with the control cells. Conclusion: The CMAP database is a useful tool for identifying compounds affecting the same molecular pathways, particularly products that are difficult to apply via practical approaches, such as microRNAs.

Achalasia surgical treatment alters the esophagogastric junction anatomy (cardiomyotomy plus fundoplication or esophagectomy and gastric pull-up), thus favoring a certain degree of gastroesophageal reflux. Gastric secretory and hormonal functioning is not completely known in chagasic patients. The aim of this study was to evaluate the gastric secretory and hormonal response in patients with end-stage chagasic achalasia compared with normal subjects. Gastric secretion and hormonal response were assessed by estimation of gastric acid secretion (GAS) in basal condition and after pentagastrin stimulation, basal serum gastrin, and serum pepsinogen (SP) in basal condition and after betazole hydrochloride (Histalog; Eli Lilly and Company, Indianapolis, IN, USA) stimulation in 27 patients with chagasic achalasia. The results were then compared with those of 24 normal subjects. In the chagasic group, the mean basal and stimulated GAS were significantly lower than in the control group (basal: 1.277 vs. 3.13, P = 0.002; stimulated: 15.9 vs. 35.8, P = 0.0001). Chagasic patients' SG levels showed a significantly higher basal value than the control group (83.3 vs. 36.8, P = 0.0001). There was a significant increase of SP after stimulation compared with the basal levels in both chagasic and control groups. Although the chagasic patients' SP values were higher than the controls, this difference was not statistically significant, either in basal and stimulated conditions (basal: 122.0 vs. 108.9, stimulated 120 min: 177.1 vs. 158.9). In patients with chronic Chagas' disease (ChD), although autonomic denervation does not suppress the strength of the gastric mucosal cells' secretory response to stimulation, it reduces GAS (parietal cell) without, however, affecting SP production (chief cells). On the other hand, the gastrin-producing cells have continuously been stimulated by low GAS.

Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

The stomach tube was first used to administer food and medication or to remove poisonous substances. Later, it served to aspirate the stomachs of patients with gastric retention. Chemical analysis of stomach contents after a meal was first suggested in 1871 and quickly became an important laboratory procedure as various test-meal stimuli and more flexible tubes were developed. Quantitative estimations of free and total acidity were made by titration with 0.01 mol/L sodium hydroxide and specific indicators. Pentagastrin has supplanted secretagogues such as histamine and betazole; meal stimulation, tubeless tests, and other tests of gastric secretion are no longer used clinically. Tests of gastric acid secretion have been used in the diagnosis of upper gastrointestinal lesions and to help select the type of surgical procedure for gastric and duodenal ulcers, but the tests have decreased in importance because of their limited diagnostic sensitivity and specificity. Today, fiberoptic endoscopy is replacing gastric analysis as well as radiologic examination.

Basal (BAO) and maximum (PAO) hydrochloric acid output after Histalog stimulation, basal pepsinogen (SPL-B), at 60 (SPL-60) and at 90 minutes (SPL-90), and basal gastrin (BG) levels were measured and compared in different gastric (GU) and duodenal (DU) ulcer sites.Fifty nine patients with peptic ulcer were grouped according to Johnson's classification for gastric ulcers: type I (15), type II (16) type III (12) GU and (16) DU. Fifteen normal subjects were studied as controls.The BAO was greater in the DU than in the control or GU groups. No significant difference was noted in the production of hydrochloric acid after stimulation with Histalog. The SPL-B, at 60 and at 90 minutes was higher in type II GU than in the DU group and controls. The SPL-60 was higher in type II GU patients than in type III GU. Basal gastrin was higher in group DU and types II and III GU compared to the type I GU patients and controls.The topographic criteria for differentiating peptic ulcers has low discrimination capacity based on comparison of mean values of HCl acid production, pepsinogen and gastrin serum levels both basal and after stimulation with Histalog due to heterogeneity of these variables in group studies. In these studies, peptic ulcers from different sites should not be grouped as distinct entities except for type II gastric ulcers.

To assess the effect of malnutrition on gastric acidity and gastric bacterial colonization, we studied 35 severely malnourished Bangladeshi children before (0 wk) and after (3 wk) they received nutritional rehabilitation for 3 wk. These results were compared with those obtained from a similarly examined group of 20 better-nourished Bangladeshi children. Gastric acid output, both basal and after betazole stimulation, was significantly lower in the malnourished group at 0 wk compared with the better-nourished children (p less than 0.01): basal 0.22 vs. 0.52 mEq HCl/h and stimulated 0.90 vs. 2.5 mEq HCl/h. Both the concentration of acid and the rate at which gastric juice was secreted were decreased in the malnourished group but serum gastrin levels were not significantly different. After 3 wk, the malnourished children had improved from 61% (+/- 9.0%; SD) to 81% (+/- 8.1%) of expected weight-for-height and were not significantly different than the better-nourished group (86% +/- 11%). Nevertheless, gastric acid concentration remained depressed in the 3-wk group, although the rate of gastric juice secretion equaled levels observed in the better-nourished group. None of the better-nourished children had detectable gram-negative bacterial colonization of their gastric juice. In contrast, 26 of 32 (81%) malnourished children at 0 wk were colonized--even after betazole stimulation, 11 of 33 (33%) gastric juice samples yielded viable organisms--suggesting that the decrease in gastric acid output greatly reduced the gastric acid barrier. Interestingly, only 9 of 20 (45%) better-nourished children had gastric juice with basal pH values below 4.0, suggesting that the gastric acid barrier may be an intermittent defense factor in Bangladeshi children.

We have developed a noninvasive test for gastric acid secretion based on the reaction of ingested magnesium metal with gastric acid to produce hydrogen gas, which is excreted in exhaled air and belches. This test was compared to the standard intubation test by performing both, on different days, in 36 adult Peruvian outpatients referred for gastric analysis; the correlation coefficient for this comparison was 0.71. The new test was repeated in nine subjects, and the resulting test-retest correlation coefficient was 0.83. The new test thus compares favorably with the standard intubation test. Because it is also noninvasive and should therefore be more acceptable to subjects, this new test may be useful for clinical evaluation and research studies on subjects in whom intubation would be difficult or unacceptable.

1 Amodiaquine was found to be a potent inhibitor in vitro of gastric histamine methyltransferase from human and canine corpus and from pig antrum. The ID50 for the enzyme, purified from pig antrum mucosa by ultracentrifugation and chromatography on DEAE-cellulose, was 2.5 muM. 2 In six dogs with Heidenhanin pouches the maximum secretory response to histamine (40 mug/kg i.m.) was augmented by i.m. injection of amodiaquine. The augmentation depended on the dose of amodiaquine, the optimum effect (40% increase in volume of gastric juice, 80% in acid output) being achieved with 2 mg/kg. The maximum secretory response to betazole was also enhanced by amodiaquine. 3 It was suggested that amodiaquine may enhance the histamine and betazole stimulated gastric secretion by an inhibition of gastric histamine methyltransferase in vivo.

1. The development of gastric secretory capacity of hydrochloric acid and pepsin (EC 3. 4. 23. 1) was studied in thirty-eight Large White x Landrace pigs from the litters of six sows (three pairs of two), 9–38 d of age. The pigs of each pair of sows were born within 24 h of each other. The pigs of a litter were paired according to sex and size and cross-fostered, i.e. one pig from each pair was allocated to each sow.2. One litter from each pair was reared entirely by the sow (milk-fed, MF) whereas the other litter was reared by the sow for 21 d, but was allowed access to solid food (210 g crude protein (nitrogen x 6.25)/kg) at 12 d and was entirely dependent on solid food after 21 d (creep-fed, CF).3. Following a 14–18 h fast, pigs were anaesthetized (Halothane–sodium pentobarbitone) and their stomachs perfused a a constant rate with Ringer solution. Gastric secretion was stimulated by intravenous infusion of betazole hydrochloride (Histalog) at 3 mg/kg per h for 2 h. Hydrochloric acid and pepsin were measured in the perfusate which was collected at 15-min intervals.4. There were significant positive correlations between stomach weight and body-weight for both MF and CF pigs. The slope of the regression line for CF pigs was significantly greater than that for MF pigs (P < 0.01).5. There were significant positive correlations between maximal acid output and stomach weight for both MF and CF pigs.6. There were significant positive correlations between maximal pepsin output and stomach weight for both MF and CF pigs. The slope of the regression line for CF pigs was significantly different from that for MF pigs (P < 0.01). There were also significant positive correlations between maximal pepsin output per unit stomach weight and stomach weight for both MF and CF pigs.7. The pattern of development of pepsin secretory capacity in both CF and MF pigs was different from that for acid secretion. Maximal outputs of acid per unit stomach weight for MF and CF pigs remained relatively constant. Maximal outputs of pepsin per unit stomach weight and per unit body-weight increased with age for both MF and CF pigs.8. The results indicate that pigs given access to solid food before weaning and weaned on to solid food have heavier stomachs and greater acid and pepsin secretory capacity than pigs fed entirely on sows' milk.

The gastric acid, pepsin, and secretory volume output in response to a mixed meal were measured in six patients with Zollinger-Ellison syndrome caused by a gastrin-producing tumour proved subsequently at surgery. The patients were all normocalcaemic, and none had previous abdominal surgery. In four of the six patients, ingestion of the meal markedly inhibited the gastric secretory output, which decreased to below fasting levels, returning later to basal values. In two other patients, whose fasting acid output was considerably lower, the secretory output increased after the meal, but some inhibiton of gastric secretion was also apparent for variable intervals of time. The serum gastrin concentration in all patients remained essentially unchanged or increased after the meal. Two patients were restudied after successful removal of the duodenal gastrin-producing tumour, and in each the normal gastric secretory and gastrin-releasing responses were completely restored. Our studies suggest that, in patients with the Zollinger-Ellison syndrome caused by a gastrinoma, physiological regulatory mechanisms triggered by food reduce the continuous stimulation of gastric secretion caused by their tumoural hypergastrinaemia.

We studied the effect of fat on meal-stimulated gastric acid and pepsin secretion, duodenal acid and pepsin load, and gastrin release in 10 duodenal ulcer (DU) patients and in 10 normal (N) subjects. Gastric acid and pepsin secretion and duodenal acid and pepsin load were measured at 20-min intervals for 140 min in response to two 500-ml equicaloric (400 kcal), equiosmolar (960 milliosmoles per liter), protein (10% wv) meals; one meal also contained 22 g of fat (5% vv), and the other contained 50 g of dextrose (10% wv). Duodenal acid and pepsin load were determined by a serial dilution indicator method, which was validated in vitro and in vivo. The fat-containing meal produced significant inhibition of gastric acid and pepsin secretion and of duodenal acid and pepsin load in both the DU and N groups. The degree of inhibition of gastric acid secretion (50%), duodenal acid load (55%), gastric pepsin secretion (approximately 55%), and duodenal pepsin load (approximately 55%) did not differ significantly in the DU and N groups. The fat meal significantly inhibited gastrin release in the N subjects, but not in the DU patients. The acid and pepsin responses to the fat or carbohydrate meal were not significantly greater in the DU compared to the N group in spite of greater betazole- or pentagastrin-stimulated responses in the DU group. We conclude: (1) fat-induced inhibition of gastric acid and pepsin secretion and duodenal acid and pepsin load is not defective in DU patients; (2) however, the ability of fat to inhibit gastrin release does appear to be defective in DU patients; and (3) meal-stimulated acid and pepsin secretion was similar in both the DU and N groups.

The role and importance of enterogastric secretion in the disposition and elimination of the weak base, meperidine (pKa 8.63), was studied after intravenous administration (50 mg) of the drug to 6 normal volunteers. Continuous collection of the gastric fluid over a 4-hr period demonstrated the establishment of high gastric fluid/plasma concentration ratios for meperidine (mean about 50, range, 10 to 200). However, the total amount of drug recovered, even after correction for incomplete collection, was only a small percentage of the administered dose. Under basal conditions a mean +/- SE of 1.9 +/- 0.3 mg, equivalent to 3.7% of the administered dose, was found in the total gastric aspirate. Stimulation of gastric secretion by subcutaneous injection of betazole (1.5 mg/kg) increased this recovery to 3.6 +/- 0.3 mg (7.2%) primarily due to the increase in gastric volumen output. Aspiration of the gastric fluid in either the basal or stimulated situation had no observable effect upon the plasma concentration/time profile of meperidine whether assessed by the terminal half-life, t 1/2 beta, or the plasma clearance; control values were 3.8 +/- hr and 1,190 +/- 130 ml/min, respectively. In 2 subjects "bile fluid" was also collected for 2.5 hr and found to contain less than 0.2% of the administered dose. Enterosystemic recycling is therefore of minor importance in the disposition and elimination of meperidine in man.

The use of Congo Red testing for adequacy of vagotomy in a variety of clinical situations is described. Its intraoperative use is presented for the first time, thus allowing the surgeon immediate documentation of the completeness of his vagotomy and hopefully averting incomplete vagotomy, the single most common cause of ulcer recurrence after vagotomy-pyloroplasty.

1. 1. Pertechnetate clearance (CTc) by the stomach before and after betazole stimulation was compared to regional measurements of gastric blood flow utilizing nuclide (Chromium-51 and Cerium-141) labeled microspheres in five piglets. 2. 2. Pertechnetate clearance closely correlated (correlation coefficient 0.926) with mucosal blood flow in the gastric corpus measured by the microsphere technique. Betazole increased blood flow in the corpus region by 100% but did not alter this relationship. Except in one experiment, microsphere blood flow valves in the antrum and fundus were unchanged by betazole and did not significantly correlate with pertechnetate clearance. 3. 3. Pertechnetate clearance appears to be a reliable method of determining gastric mucosal blood flow in experimental animals and may be considered as a noninvasive method for measuring such flow in humans.

To elucidate further the role of histamine in pituitary regulation, TRH and L-DOPA stimulation tests were performed with and without diphenhydramine, cimetidine, or betazole pre-treatment. Betazole blunted the GH response to L-DOPA and slightly enhanced the T3 response to TRH without altering the TSH or PRL increments. Neither diphenhydramine nor cimetidine had any acute effect on the hormonal responses examined. Histamine appears to play only a limited role in these aspects of human pituitary regulation.

40749 RP, a pyridyl-2-tetrahydrothiophene derivative, is known to be a potent inhibitor of the gastric acid response to pentagastrin, betazole and a meal. In 6 healthy young volunteers, a single oral dose of 2 mg.kg-1 greatly reduced the gastric acid secretory response to sham-feeding. By contrast, neither gastric pepsin nor the plasma PP response were altered by the drug. No change was observed in plasma gastrin, motilin, VIP or somatostatin concentrations. The results show that 40749 RP is also active on the pure vagus-stimulated gastric acid secretion. The lack of effect upon gastric pepsin and plasma PP suggests that 40749 RP is not likely to act on the basolateral cholinergic receptor and that it affects further cellular steps involved in hydrogen ion secretion.

We have developed a noninvasive test of gastric acid secretion for use in infants and young children. It is based on the reaction of ingested magnesium metal with gastric acid to produce hydrogen gas, which is excreted in exhaled air and belches. This test was compared to the standard intubation test by performing both, on different days, in 20 children (5-37 months of age) without known gastric disease. The results of the two tests compared well: correlation coefficients were 0.78, 0.75, or 0.72 when exhaled air was collected for a total of 56, 81, or 31 min, respectively. Because the test is noninvasive, it should be more acceptable to children and their parents than the intubation test and thus could be used to conduct studies which are currently impractical.

The effect of suggestion of relaxation in hypnosis on basal and betazole-stimulated gastric acid secretion was examined in four healthy female volunteers, susceptible to hypnosis. Acid output was measured by means of intragastric titration and a pH-sensitive telemetering capsule. Three series of experiments, each lasting 3 hr, were carried out: (a) After 1 basal hr administration of 1.7 mg per kg body weight betazole subcutaneously. (b) After the basal hour, administration of saline subcutaneously and induction of hypnosis. Relaxation was suggested for 1 hr; after this period, posthypnotic amnesia was suggested and the subject awakened. (c) Procedure as in series b; instead of saline, 1.7 mg per kg of body weight betazole subcutaneously. Each subject underwent six experiments, two of each series. A completely crossed four-factorial analysis of variance, accounting for treatment, time, replication, and subject factors was carried out. Suggestion of relaxation in hypnosis resulted in a significant reduction of unstimulated as well as betazole-stimulated acid secretion and in a decrease of gastric motility. Both effects were reversed after the termination of hypnosis. It is suggested that these effects originate in the central nervous system and are mediated via an alteration of the stimulating and/or inhibiting tone of the autonomic nervous system.

The effect of the gastric alkaline tide on serum-ionized calcium levels was determined in human subjects. Gastric acid seretion was stimulated by a standard steak meal, human synthetic gastrin, and betazole hydrochloride. Ionized calcium levels fell to a similar extent after each stimulus. The mean decrease in calcium ion concentration in all experiments was 5.4 % of the basal concentration. The fall in serum calcium ion concentration was highly correlated with the rise in serum pH. We speculate that increased formation of calcium bicarbonate complex in the serum as well as increased binding of ionized calcium by serum protein accounts for the surprisingly large effect of the alkaline tide on serum-ionized calcium levels.

In 6 dogs with gastric fistula, burimamide, a histamine analog which blocks H-2 histamine receptors, was given in a dose of 500 μg/kg-hr as a background to step-dose responses with histamine (2–100 μg/kg-hr) or with betazole (50–5000 μg/kg-hr). The drug did not change the histamineresponsive H, electrolyte, or pepsin secretion, but did competitively inhibit both H+ and electrolyte responses to betazole, and reduced pepsin secretion by 90%. Three of the dogs in studies using pentagastrin (0.1–5.0 μg/kg-hr) had marked reduction in pepsin output but no effect on H+ or electrolytes by burimamide. With 2-DG stimulation in 3 dogs (1 dose, 100 mg/kg), burimamide had no effect on H+ or pepsin secretion. Larger doses of burimamide, 1–5 mg/kg-hr, produced side effects, especially retching and diarrhea, which precluded studies of these doses.

Betazole, (β-(3-pyrazolyl)-ethylammonium), a very weak H2-receptor agonist of histamine is compared, in the semiempirical quantum chemical CNDO/2 approximation, to histamine. The molecular determinants responsible for the H2-activity, such as the conformation of the ethylammonium side chain, a negative global charge on the imidazole ring, the existence of a proton on the N-terminal, as well as the inversion of the tautomeric preference for the cationic and neutral forms are considered. It was determined that betazole fulfilled all of the above except for the tautomerism N3-H→N1-H. It is concluded that the proton transfer from N3 to N1 is an important and necessary step in the mechanism of action of the H2-receptor agonists of histamine.

Duodenal ulcer has not been observed in full-heritage Pima Indians, while gastric cancer is relatively frequent. To investigate possible underlying factors for this phenomenon, we determined gastric acid output, gastric emptying rate, and plasma levels of gastrin, pepsinogen I, and pepsinogen II in apparently healthy Pima Indians and in Caucasian controls. The Pimas had significantly lower basal and stimulated outputs of gastric acid and higher fasting and postprandial plasma gastrin concentrations than the Caucasians. Plasma pepsinogen I levels were similar in the two groups, but plasma pepsinogen II was significantly higher and the ratio of pepsinogen I to pepsinogen II was significantly lower in the Pima Indians. In addition, gastric emptying of acaloric liquid meal was significantly delayed in the Pimas. The results suggest that the absence of duodenal ulcer in Pima Indians may be related to low gastric acid production and a slow rate of gastric emptying in this population. The associated findings of hypergastrinemia, hyperpepsinogenemia II, and a low ratio of pepsinogen I to pepsinogen II suggest that the hypochlorhydria may reflect an increased prevalence of chronic gastritis in full-heritage Pima Indians. This, in turn, could represent a risk factor for the development of gastric cancer in this population.

Histamine N -methyltransferase (E.C., 2.1.1.8; HMT) has been purified approximately 200-fold with about 20 per cent yield from guinea pig brain. The purification steps involved centrifugation at 225,000 g for 12hr, calcium phosphate gel adsorption, DEAE-cellulose chromatography and final chromatography on hydroxylapatite. The enzyme obtained is the most highly purified brain HMT so far prepared. It is specific for histamine with a K m of (4.30 ± 0.14) × 10 −5 M; it fails to methylate norepinephrine, serotonin and betazole. a histamine analogue. The kinetics and mechanism of action of histamine N -methyltransferase were investigated. Initial velocity studies at low substrate concentrations suggested that this methyltransferase action proceeded through two half-reactions in a ping pong mechanism with the intermediate formation of a methylated enzyme. This type of mechanism was also supported by results of product inhibition studies, in which methylhistamine was found to inhibit the enzyme competitively with respect to S -adenosylmethionine and noncompetitively with respect to histamine. Several drugs and chemicals were found to inhibit the enzyme; they included mercurial diuretics, antimalarials, antihistaminics, local anesthetics and ethylamine derivatives. The inhibition by each of these compounds, usually at a concentration of 10 −4 M or lower, was competitive with respect to histamine and appeared to be mixed with respect to S -adenosylmethionine. These patterns of inhibition also have a strong support for the ping pong mechanism.

The ulcerogenic and secretogenic properties of betazole, (an H2 agonist), and/or reserpine on pig stomachs were studied. (1) Betazole (50 mg/body) and reserpine (0.02 mg/kg) were successively injected (i.m.) for 5–10 days into starved animals. Gastroesophageal ulcers, pathologically similar to naturally occurring ulcers were observed in all pigs (10/10), whether a nutrient solution (5% glucose, 1 litre/day) was supplied or not. In the starved pigs given either betazole or reserpine, only a small ulcer or erosion was observed. (2) In four pigs which were given commercial mash at a rate of 3% of body weight per day and killed on the 6th or 10th day of successive injections of both drugs, the incidence of ulcers was 2/4. (3) The gastric secretogenic effect of betazole and/or reserpine was confirmed in pigs with Heidenhain gastric pouches. (4) From these data, a new method for the experimental induction of pig gastroesophageal ulcers, by means of simultaneous injections of betazole and reserpine for 5 days under the nutrient (glucose solution) drinking condition, is proposed. The authors consider that this method may be superior to the repository histamine method, with respect to the absence of adverse effects, practical convenience and pathological and etiological similarities with naturally occurring ulcers.

A Heidenhain pouch usable for several months was constructed in a Landrace secondary SPF piglet. The behaviors of electrolytes and pepsin in the gastric juice induced by tetragastrin (TG) were studied in the piglet, in comparison with the dog. A high positive correlation was observed between H+ concentration and secretory volume. The same results were obtained by stimulation with betazole and carbamylcholine. The concentrations of Na+ and Ca++ decreased, but those of K+ and Cl- increased with an increase in volume. The concentrations of these 4 ions correlated highly with H+ concentration or volume. Mg++ concentration increased temporarily after the TG administration and decreased there after. This curious responste of Mg++ concentration was observed in the dog, as well as in the piglet, after administration with any other stimulant. Pepsin concentration increased temporarily after TG stimulation, then turned to be at a basal level, and increased slightly thereafter. The kinetics of electrolytes on the gastric juice in the pig seemed to resemble that in the dog.

A significant association has previously been found between a betazole-induced decrease in serum group I pepsinogen (PG I) levels and a low peak acid output (PAO) in symptomatic patients with vagotomy and gastric resection or a drainage procedure. This study compares the effect of betazole on serum PG I levels and gastric acid output in 245 unoperated patients (115 duodenal ulcer, 25 prepyloric ulcer, 32 gastric ulcer, 73 nonulcer) and in 73 symptomatic postoperative patients (15 subtotal gastric resection, 28 vagotomy and gastric resection, 30 vagotomy and drainage). A negative serum PG I response (2-hr serum PG I level less than 92% of basal) occurred in 10 (4.1%) of the unoperated patients and in 31(42.5%) of the postoperative patients. Seven (70%) of the former and 29 (93.5%) of the latter patients had a PAO of less than 10 mEq per hr, indicating that a negative serum PG I response is associated with a low PAO in both unoperated and postoperative patients. The PAO was greater than 10 mEq per hr in 93.1% of the 277 patients with a 2-hr serum PG I level of more, than 92% of basal. Additional studies revealed that neither aspiration of gastric juice nor perfusion of the stomach with acid altered the serum PG I response. This suggests that topical acid does not modulate the effect of betazole on serum PG I levels. Finally, a negative serum PG I response has been shown to be paradoxical, in that gastric pepsin levels have been found to increase over basal concurrently with the decrease in serum PG I levels.

The accumulation of paraquat by slices of rat lung has been shown to be inhibited in vitro by the addition of rat plasma. For a given concentration of plasma, inhibition was constant with time and the amount of inhibition increased with increasing concentration of plasma. This suggests that there are components of rat plasma which inhibit paraquat accumulation by rat lung slices in a concentration-dependent manner. An ultrafiltrate of plasma also inhibited paraquat uptake, indicating that the inhibitor is a small molecular weight compound. A number of endogenous amines including noradrenaline, 5-hydroxytryptamine and histamine have been shown to reduce the concentration of paraquat accumulated into lung slices, as have several other drugs including imipramine, propranalol, burimamide and betazole. The relevance of these findings to the prevention of paraquat accumulation by lung is discussed.

Rioprostil, a primary alcohol prostaglandin E1 analogue, inhibits gastric acid secretion, both in vivo and in vitro, and prevents the formation of experimentally-induced gastric lesions in rats and dogs. In vitro experimental evidence suggests that the mechanism of the gastric antisecretory activity of rioprostil involves inhibition of the membrane bound histamine-stimulated adenylate cyclase. In vivo, rioprostil inhibits gastric acid secretion in 4-h pylorus-ligated rats, in gastric fistula dogs stimulated by betazole, tetragastrin, bethanechol, or 2-deoxy-D-glucose, and in Heidenhain pouch dogs stimulated by food. Rioprostil can completely prevent macroscopically visible gastric lesions induced by a variety of noxious agents in rats, including 50% ethanol, aspirin, indomethacin, strong acid, strong base and hypertonic saline. In dogs, rioprostil, but not the H2-blockers cimetidine or ranitidine, totally prevents endoscopically visible gastric lesions induced by aspirin tablets or 60% ethanol, and accelerates the healing of established aspirin-induced gastric lesions from 20 days (vehicle control) to 6 days (33 micrograms/kg p.o., t.i.d.) or 11 days (3 micrograms/kg p.o., t.i.d.). The precise mechanism for the antigastrolesive activity of rioprostil is not known, but may involve increased mucus and bicarbonate secretion, maintaining or increasing gastric mucosal blood flow, increasing the rate of cellular restitution, or possibly antigastrin activity that has been demonstrated in dogs. In rats, rioprostil also prevents duodenal lesions induced by cysteamine, small intestinal lesions induced by indomethacin, and colonic lesions induced by ethanol. The antisecretory and antigastrolesive potency of rioprostil given transdermally to rats is similar to its potency when given systemically, although its diarrhoeagenic potential is lower when given topically compared to oral administration. When used in combination with several non-steroidal anti-inflammatory drugs (NSAIDs) in a model of arthritis in rats, rioprostil inhibits gastric lesion formation without interfering with the anti-inflammatory or analgesic potency of the NSAIDs. In addition, concomitant use of either antacid or cimetidine with rioprostil does not inhibit either the antisecretory or antigastrolesive potency of rioprostil, with the effect of the combination being additive. The doses required to inhibit formation of experimentally-induced gastric lesions in both rat and dog are lower than those required to inhibit gastric acid secretion. This separation of antigastrolesive from antisecretory activity distinguishes rioprostil from other non-prostanoid antisecretory agents, such as histamine H2- receptor antagonists, and establishes rioprostil as a 'selective antigastrolesive agent' (SAGA).(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of cimetidine, an H 2 histamine receptor blocker, on spontaneous locomotor activity and ethanol-produced narcosis was studied in the male mouse. The separate and combined effects of cimetidine, and histalog (betazol), an H 2 histamine receptor agonist, on voluntary intake of diluted ethanol solution by the rat were also determined. The in vitro effect of cimetidine on rat liver alcohol and aldehyde dehydrogenase was assayed. Cimetidine treatment was associated with an initial moderate increase in locomotor activity which was increased significantly as a function of time. The central depressant action of ethanol, as measured by duration of ethanol-mediated narcosis, was decreased by pretreatment with a single dose of cimetidine. The drug did not alter voluntary drinking of ethanol by the rat but antagonized histalog-produced aversion to ethanol selection when administered prior to histalog. Cimetidine, 3 × 10 −3 M concentration, inhibited rat liver aldehyde dehydrogenase but not alcohol dehydrogenase in vitro. The results indicate cimetidine-ethanol interaction and suggest the implication of histamine in some of the ethanol-elicited responses studied.

Misoprostol, a synthetic prostaglandin E 1 analog, has been found to be safe and effective for the treatment of peptic ulcer disease. This brief overview summarizes the gastric antisecretory effects of misoprostol in healthy human subjects using randomized, double-blind, placebo-controlled studies. Misoprostol effectively and dose-dependently inhibited basal gastric acid secretion at single dose of 50, 100 and 200 mcg/subject. Furthermore, misoprostol effectively inhibited meal-, histamine-, coffee- and tetragastrin-stimulated gastric acid secretion. The inhibition of meal-stimulated gastric acid secretion was not a consequence of the reduction of serum gastrin. In addition, misoprostol inhibited noctural gastric acid secretion. In these studies, the titratable acidity, volume, acid output and pepsin activity were inhibited by misoprostol. The extent of the secretory inhibition achieved with the 200 mcg dose of misoprostol was comparable to that of cimetidine administered at a 300 mg dose. The duration of the gastric antisecretory actions was in the order of 3 to 5 hours. We conclude that misoprostol is a potent inhibitor of gastric acid secretion in man.

Four dogs were prepared with an isolated, innervated antral pouch, a Heidenhain pouch, and a gastric fistula. Gastric secretion was stimulated by perfusion of the antrum with a suspension of liver powder or by betazole injection. Both methods of gastric stimulation increased acid and gastrin output from the gastric fistulas and Heidenhain pouches. There was a significant direct correlation between these two variables in the gastric juice of the gastric fistulas and Heidenhain pouches. We conclude from this study that gastrin in the gastric juice originates in the antrum or some extragastric source and is cleared from the blood by the fundic mucosa. Its rate of appearance in the gastric juice is directly related to the secretory activity of the parietal cells.

1. 1. The urinary bladder of the tortoise, Damonia subtrijuga, transported Na+ from mucosa to serosa, H+ from serosa to mucosa, and base from mucosa to serosa. 2. 2. The acid-base transporting system sometimes became unstable, reversing direction, moving acid or base across both bladder surfaces simultaneously, or showing oscillations of the pH of the mucosal bathing medium. These instabilities in the acid-base transporting system were without effect on the polarity of the Na+ transporting system. 3. 3. Factors that stimulated (betazole) or inhibited (acetazolamide) acid-base transport did so whether the polarity of such transport was normal, or was reversed.

We have studied the gastric response to an ordinary solid-liquid meal in 12 patients with active duodenal ulcer and 8 healthy volunteers. Our method employs gastric and duodenal markers to quantify acid, pepsin, and volume outputs in response to the meal, without manipulating intragastric pH. Intragastric volume, rate of gastric emptying, delivery of acid into the duodenum, and serum gastrin response were also measured simultaneously. On a separate day, peak acid output in response to betazole (1.5 mg per kg subcutaneously) was determined. Our results indicate an inappropriately prolonged gastric secretory response to meals in duodenal ulcer disease, without a concomitant increase in peak postprandial secretory rates or an increase in serum immunoreactive gastrin levels. Further, the stomach in duodenal ulcer disease did not "retain" the additional acid secreted in the later postprandial period, and abnormally high rates of acid delivery into the duodenum occurred. Our data are consistent with a dual defect in the duodenal mechanisms regulating both acid secretion and acid delivery into the duodenum.

To elucidate the relation of noninsulin-dependent (type II) diabetes mellitus to plasma levels of gastrin, pepsinogen I, and pepsinogen II, gastric acid secretion, and gastric emptying, we studied diabetic and nondiabetic obese Pima Indian subjects. Fasting and postprandial plasma gastrin concentrations were significantly higher (P less than 0.02) in diabetic than in nondiabetic subjects, but gastric acid outputs basally, after an acaloric liquid meal, and in response to betazole were similar in the two groups. Plasma pepsinogen I and pepsinogen II levels were also similar in both groups. A significant negative relation (r = -0.84; P less than 0.01) was found between basal gastrin levels and gastric acid production in nondiabetic Indians, but not in diabetic Pimas. The fractional gastric emptying rate of an acaloric liquid meal was significantly decreased in diabetic Pimas (P less than 0.01); and at least one test showing abnormal vagal function, as estimated by the Valsalva maneuver, heart rate changes between deep expiration and inspiration, and postural hypotension, was found in every diabetic subject. These findings suggest that hypergastrinemia in type II diabetes is not related to hypochlorhydria, but, instead, results from autonomic dysfunction with slow gastric emptying.

Prostaglandin E 1 and E 2 inhibit gastric secretion in vivo and in vitro under a variety of conditions. It is not known whether these compounds may play a role in normal gastric secretory physiology or in the pathophysiology of peptic ulcer disease. Six normal adults and six patients with documented duodenal ulcer disease were studied under basal conditions and during gastric secretory stimulation with betazole. Prostaglandin E in plasma and gastric juice was measured by radioimmunoassay. Prostaglandin E was significantly higher in the plasma of normal volunteers both in the basal state and during stimulation. Gastric juice prostaglandin E was also significantly higher in normal volunteers during the basal state but the difference disappeared during stimulation. The relative deficiency of prostaglandin E in the ulcer group may indicate a role for prostaglandins in the pathophysiology of gastric hypersecretion.

This report concerns gastric juice, plasma, and urinary levels of adenosine 3',5'-monophosphate (cAMP) in 27 subjects undergoing routine gastric analysis under maximum stimulation with betazole or pentagastrin. Cyclic AMP was measured by sensitive and specific radioimmunoassay. No increase in concentration of cAMP was noted in gastric juice, plasma, or urine following either betazole or pentagastrin stimulation. Betazole-stimulated human gastric acid secretion was associated with an increased cAMP output into the gastric juice (P less than 0.05). There was no change in cAMP output following pentagastrin stimulation. The peak acid output produced by pentagastrin and betazole was similar. The lack of increase in cAMP concentration lends support to the concept that cyclic AMP is not a primary mediator in the stimulation of gastric acid secretion by betazole or pentagastrin in the human. The physiologic significance of the increase in cAMP output following betazole stimulation remains unresolved.

Summary 2-Benzimidazolylurea (BIU) decreases gastric acid secretion. The antisecretive activity appears to be associated with antihistaminic and antimuscarinic effects. The antihistaminic activity of BIU appears from its inhibitory effects on betazole stimulated gastric acid secretion and from its inhibitory activity on the isolated guinea pig auricle stimulated by betazole. The antimuscarinic activity of BIU appears from several experiments: this molecule decreases gastric acid secretion stimulated by carbachol in rats, depresses the neostigmine-stimulated motility of duodenum in the anaesthetized cat, lessens the hypertonus of isolated guinea pig trachea caused by pylocarpine and also inhibits guinea pig ileum activity stimulated by acetylcholine. BIU probably depresses gastric acid secretion by interferring with both histamine and acetylcholine receptors.

The effect of cimetidine on gastric acid, pepsin, and intrinsic factor secretion was assessed in normal male subjects. Cimetidine (300 mg) completely inhibited acid, pepsin, and intrinsic factor concentration and output stimulated by betazole. In contrast, basal output of pepsin and intrinsic factor was not inhibited. We conclude that H2-receptor antagonists inhibit betazole stimulation of intrinsic factor output in addition to their well-known inhibition of acid secretion.

Intragastric calcium chloride perfusion (80 mM, 5 ml per min) caused a 3-fold increase in gastric acid output without a change in serum gastrin and serum calcium values. The acid response to intragastric calcium represented one-third of the maximal hourly output after betazole injection. This effect was suppressed by calcitonin, but not influenced by parathyroid hormone, without a change in serum gastrin and serum calcium values. Additional studies showed that perfusion of calcium into the duodenum, in an amount calculated to be the maximum leaked through the pylorus during the intragastric perfusion studies, did not cause gastric hypersecretion and gastrin release. These findings suggest that calcium can cause gastric hypersecretion by a direct effect on the parietal cell.

Because of the lower recurrence rate of ulceration when vagotomy is accompanied by antrectomy, we studied the effects of combining submucosal denervation of the antrum (antroneurolysis) with highly selective vagotomy (HSV). Chemical antroneurolysis (CANL) was performed by submucosal injection of 50% ethanol. In two gastric fistula dogs HSV produced a significant decrease in peak acid output (PAO) in response to 0.2 U/kg insulin (5.42 ± 0.46 → 3.32 ± 0.99 meq/15 min, P 0.92). CANL produced no change in maximum serum gastrin rise above basal in response to a test meal either in four pouch dogs (47.4 ± 2.54 → 40.9 ± 3.69 pg/ml, P > 0.13) or in four normal dogs (27.5 ± 3.41 → 33.8 ± 4.47 pg/ml, P > 0.16). Basal gastrins were also unchanged. In conclusion, we feel that CANL provides no significant advantage over HSV, while increasing its complexity.

Cyclic AMP and cyclic GMP concentrations were measured in suction biopsy specimens of gastric fundic and antral mucosa and in gastric juice in response to maximum stimulation by histamine (0.015 mg per kg per hr), betazole (1.5 mg per kg), and pentagastrin (6 μg per kg) in 14 normogastrinemic healthy subjects, in 46 patients with dyspepsia or peptic ulcer (PU) disease and normal serum gastrin levels, and in 14 patients with hypergastrinemia, including 8 with pernicious anemia (PA), 3 with Zollinger-Ellison (ZE) disease, and 3 with gastric carcinoma. No regional differences were noted in unstimulated gastric antral or fundic cyclic nucleotide content in normal subjects or patients. During secretagogue stimulation no significant changes in cyclic nucleotide concentrations were observed in antral or fundic mucosa of healthy subjects or patients. During basal hourly secretion, cyclic nucleotide concentration and output in gastric juice was relatively constant, suggesting a steady state of secretion. After secretagogue stimulation, the concentrations of cyclic AMP and cyclic GMP were reduced by at least 50% and correlated with the increased parietal volume output, suggesting a dilutional effect. There was no significant change in gastric juice cyclic nucleotide output except in PU subjects after betazole stimulation, in whom cyclic AMP production increased almost 2-fold. This change in gastric juice cyclic AMP appeared proportional to a greater parietal volume flow and did not reflect intracellular mucosal events. Similarly, a decreased concentration of cyclic AMP in the basal and stimulated gastric juice of ZE patients and a reduced cyclic AMP output in PA patients also appeared proportional to volume flow. The presence of cyclic AMP in unstimulated gastric juice in PA suggested, in part, a nonparietal origin for cyclic AMP, probably derived from interstitial fluid secretion or transmucosal exudation from plasma. It is concluded that intra- or extracellular gastric cyclic AMP or cyclic GMP concentrations are not modulated by secretagogue stimulation, circulating high gastrin levels, alteration in intraluminal pH, or increasing age. These studies fail to implicate cyclic nucleotides as intracellular mediators of stimulated gastric acid secretion in healthy subjects, PU disease PA, ZE disease or gastric carcinoma.

Two distinct hyperpolarizing responses are produced when histamine is iontophoretically applied onto the somal membranes of identified neurons within the cerebral ganglion of Aplysia: a biphasic response consisting of a rapid component (less than 5 sec) usually superimposed upon a slowly developing component; or a monophasic slowly developing response 5-20 sec in duration. The reversal potential values for the fast (typically -65 mV) and the slow (typically -89 mV) responses, and their shift to new values when the external potassium or chloride concentrations were altered, revealed that the fast and slow potentials are produced predominantly by conductance increases to chloride and potassium ions, respectively. The effects of histamine H1- and H2-receptor agonists and antagonists were studied to characterize the pharmacological properties of histamine receptors mediating these two ionically dissimilar hyperpolarizing responses. The slow potassium-dependent hyperpolarization could be mimicked by several histamine analogues; the most potent tested were the H1-receptor agonist, 2-methylhistamine, and the H2-receptor agonist, 4-methylhistamine. Neither of these agents mimicked the fast chloride-dependent histamine response. The slow potassium-dependent responses induced by histamine or histamine agonists were completely and reversibly blocked by the H2-receptor antagonist, cimetidine. By contrast, the slow potassium-dependent hyperpolarizations produced by iontophoretically applied acetylcholine or by dopamine to the same neurons were unaffected by cimetidine. Other H1 and H2 antagonists tested were either ineffective, or only partially blocked the slow hyperpolarizations in a non-selective manner. The fast chloride-dependent hyperpolarizations were not selectively antagonized by any of the H1 or H2 reagents tested, although they were effectively suppressed by tubocurarine and strychnine. These data indicate that two pharmacologically distinct histamine receptors mediate potassium- and chloride-dependent hyperpolarizations in Aplysia neurons. Neither of these receptors, however, could be classified as strictly H1 or H2 according to criteria presently used in non-neuronal tissues. The selectivity and reversibility of cimetidine indicate that this particular antihistaminic could be a valuable pharmacological tool for defining putative histaminergic synapses in Aplysia and perhaps other nervous systems.

The function of isolated human gastric glands has been studied in vitro by measuring the 14C-aminopyrine accumulation (RAP) in basal, unstimulated, conditions and after stimulation with different secretagogues. A microscale technique was used which enabled determinations of RAP in tissue obtained as gastroscopic biopsies. In addition, oxyntic-gland-containing mucosa was obtained at gastric resections for gastric or prepyloric ulcer disease. Histamine and cAMP derivative both induced maximal stimulation; RAP was approximately three times larger than in basal states. Carbachol induced a smaller but still significant stimulation. Pentagastrin did not increase RAP above the unstimulated level. Combinations of histamine and carbachol or pentagastrin did not induce a larger response than carbachol alone. The peak acid response to pentagastrin or betazole in vivo did not correlate with the maximum RAP in vitro.