Biomedical subjects

S Postius

Publications and source records attributed to S Postius.

At least 19 recordsLinked to original sources

PubMed2001

Mutations of the Helicobacter pylori genes rdxA and pbp1 cause resistance against metronidazole and amoxicillin.

To investigate amoxicillin and metronidazole resistance of Helicobacter pylori, we compared putative resistance genes between resistant strains obtained in vitro and their sensitive parent strain. All metronidazole-resistant strains had rdxA mutations, and an amoxicillin-resistant strain had pbp1 and pbp2 mutations. By transforming PCR products of these mutated genes into antibiotic-sensitive strains, we showed that rdxA null mutations were sufficient for metronidazole resistance, while pbp1 mutations contributed to amoxicillin resistance of H. pylori.

Amino Acid Sequence↗

PubMed2001

Helicobacter pylori.

Explore the source record for details and available documents.

Gastrointestinal Diseases↗

PubMed2000

Animal pharmacology of reversible antagonism of the gastric acid pump, compared to standard antisecretory principles.

To define the basic antisecretory profile of a potassium-competitive antagonism of the gastric acid pump relative to other classes of acid-inhibitory drugs, they were compared to each other against all three major stimuli of acid secretion. Pumaprazole is an imidazo-pyridine derivative that was used in this investigation as an example of reversibly binding acid pump antagonists (APAs). It differs from covalently binding proton pump inhibitors (PPIs), such as omeprazole, both with respect to chemical structure and mode of interaction with the gastric H(+)/K(+)-ATPase (i.e., the acid or proton pump). The present data show that a single dose of pumaprazole is able to elevate intragastric pH in the dog with gastric fistula under pentagastrin or carbachol stimulation from pH 1 to about pH 7 while still displaying a dose-dependent, well-controlable duration of action of a few hours. Ranitidine at the same oral dose also shows a short duration of action, but combined with a far lower efficacy. By contrast, a single oral dose of the PPI omeprazole elevates intragastric pH for a longer time period, but this pH elevation is far lower compared to that of the APA. Regarding the less stringent parameter of inhibition of total acid output in the Heidenhain pouch dog, the modified Shay rat or the Ghosh-Schild rat, pumaprazole is, overall, slightly more efficacious than ranitidine. The M(1)-muscarinic antagonist pirenzepine is ineffective (against histamine stimulation) or far less effective than pumaprazole (against pentagastrin-stimulation), but as effective as pumaprazole against carbachol stimulation in the Ghosh-Schild rat. Basal acid output in the same model is more effectively inhibited by pumaprazole than by ranitidine. In conclusion, our data demonstrate the exceptional ability of a reversibly binding APA to elevate intragastric pH up to neutrality even upon a first administration while still displaying a limited, dose-dependent duration of action.

Animals↗

PubMed1998

The Helicobacter felis ftsH gene encoding an ATP-dependent metalloprotease can replace the Escherichia coli homologue for growth and phage lambda lysogenization.

Cloning and sequencing of an approximately 6.0-kb chromosomal DNA fragment from Helicobacter felis revealed five complete open reading frames. The deduced amino acid sequence of one ORF exhibited sequence similarity to the FtsH protein, an ATP-dependent metalloprotease, from various bacterial species. The encoded protein consists of 638 amino acid residues with a molecular mass of 70.2 kDa. The hydropathy profile of the FtsH protein predicted two N-terminal transmembrane regions that were confirmed experimentally. Insertion of ftsH into a new versatile expression vector resulted in overexpression of FtsH protein in Escherichia coli. In addition, the E. coli ftsH gene could be replaced by the H. felis homologue to allow reduced growth and tenfold increased lysogenization by temperate phage lambda.

ATP-Dependent Proteases↗

PubMed1998

The role of internal urease in acid resistance of Helicobacter pylori.

BACKGROUND & AIMS: The relative role of internal urease for acid protection of Helicobacter pylori is unknown. The aim of this study was to determine the comparative importance of internal and external urease under acidic conditions. METHODS: The pH optimum and measured Michaelis constant for urea of external urease and urease in intact bacteria at different medium pH (pHout) were measured using 14CO2 release from 14C-urea. The effect of urea on membrane potential and bacterial cytoplasmic pH was measured at different fixed pHout. 35S-methionine labeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of labeled proteins in the organism and medium measured protein synthesis at different pHout and mechanisms of urease externalization. RESULTS: External urease had activity between pH 5.0 and 8.5 and internal urease between pHout 2.5 and 6.5, and its Michaelis constant at pHout 7.5 was 300 mmol/L but at pHout 4.5 was 0.5 mmol/L, similar to free urease. The addition of 5 mmol/L urea to bacteria at fixed pHout from 3.0 to 6.0 elevated potential to about -105 mV and periplasmic pH to about pH 6.2. Protein synthesis occurred mainly between pH 6.5 and 8.0, and urease activity resulted in increased protein synthesis at acidic pH. The labeling pattern of intrabacterial and released protein was similar. CONCLUSIONS: Intracellular urease activity is regulated by external pH, defends against gastric acidity by increasing periplasmic pH and membrane potential, and stimulates protein synthesis at acidic pH. External urease is produced mostly by cell lysis.

Gastric Acid↗

PubMed1995

Properties of the reversible, K(+)-competitive inhibitor of the gastric (H+/K+)-ATPase, SK&F 97574. II. Pharmacological properties.

SK&F 97574 [3-Butryl-4-(2-methylamino)-8-(2-hydroxyethoxy) quinoline] is a potent, reversible inhibitor of the gastric (H+/K+)-ATPase. In an anaesthetised lumen-perfused rat preparation, it inhibited pentagastrin-stimulated gastric acid secretion with intravenous and intraduodenal inhibitory ED50 values of 2.40 mumol/kg and 4.43 mumol/kg, respectively. In the conscious fistula rat model, doses of 10 mumol/kg IV and 25 mumol/kg PO produced mean peak inhibitions of basal acid output of 91% and 97%, respectively. In these experiments, the duration of action of SK&F 97574 was much shorter than that of the covalent (H+/K+)-ATPase inhibitor, omeprazole. In the conscious Heidenhain pouch dog, SK&F 97574 inhibited histamine-stimulated gastric acid secretion after both intravenous and oral administration with ED50 values of 0.49 mumol/kg and 0.89 mumol/kg, respectively. In this model, duration of action studies showed that significant residual inhibition of acid secretion remained 8 hours after intravenous dosing with SK&F 97574 (producing peak inhibition of 92%). However, 24 hours after oral dosing of SK&F 97574 (10 mumol/kg), no significant inhibition remained. These data indicate that the duration of action of SK&F 97574 is longer than that of the histamine H2 receptor antagonists such as cimetidine, but shorter than that of covalent (H+/K+)-inhibitors such as omeprazole. Overall, the pharmacological properties of SK&F 97574 suggest that it could be a potentially useful clinical treatment for acid-related diseases.

Aminoquinolines↗

PubMed1995

Loss of circadian rhythm in luminal acidity of canine stomach by implantation of a gastric fistula.

One to four months after implantation of a gastric fistula, a circadian rhythm in gastric acidity could be demonstrated by use of the intragastric 24-hour pH-metry in dogs with the gastric fistula protruding on the left side of the upper abdomen. This circadian rhythm was found to be fully developed within 3 years, and it remained unchanged up to 5 years after implantation. It is characterized by a daytime intragastric median pH of about 2 and a nocturnal intragastric median pH of about 7. In contrast, a circadian rhythm did not develop within 5 months after instrumentation of the dogs with a gastric fistula protruding on the right side of the upper abdomen. Only 2 years after implantation of the fistula, an intragastric daytime median pH of about 2 and a nocturnal median pH of about 4 appeared. Four years after implantation, the circadian rhythm had evolved. The results show a delayed postoperative restoration of circadian rhythm in canine gastric acidity if a gastropexy occurs at an untolerated position. This may lead to unphysiological distensions in the gastric wall with subsequent continuous stimulation of acid secretion.

Abdominal Muscles↗

PubMed1992

Effect of acute and chronic acid suppression on plasma gastrin release in the rat.

The mechanisms by which administration of the H+,K(+)-ATPase inhibitor B 831-78 or intragastric perfusion with NaHCO3 induces plasma gastrin release were studied in the rat. Experiments were performed after a washout of residual intragastric contents in fasted animals provided with chronic gastric fistulae. Acute and chronic administration of B 831-78 elevated plasma gastrin dose-dependently up to 5-6 times above control levels, while the increase was only twofold with intragastric NaHCO3 infusion despite similar neutralization of gastric acidity. The profound hypergastrinaemia induced by the H+,K(+)-ATPase inhibitor, after both acute and chronic treatment, was completely prevented or reversed by intragastric perfusion with physiological amounts of acid (0.15 N HCl, 2.5 ml/h). The hypergastrinaemia was, however, largely resistant to high doses of atropine (4.3 mumol/kg) and of the M1 selective muscarinic antagonist telenzepine (10 mumol/kg). In contrast, the modest increase in plasma gastrin induced by gastric perfusion with NaHCO3 was completely suppressed by the high atropine dose and was attenuated by small doses of atropine or telenzepine (0.01 mumol/kg and 1 mumol/kg). These results demonstrate that, in the rat, blockade of the H+,K(+)-ATPase can potently induce gastrin release in the absence of a meal. Moreover, they suggest that interruption of the negative feedback between acid and gastrin release is the main mechanism through which this class of drugs releases gastrin in the rat. Since a similar degree of gastrin release cannot be achieved by alkalinization of gastric contents, additional hormonal or neural regulatory factors may contribute to the drug-induced hypergastrinaemia.

Adenosine Triphosphatases↗

PubMed1991

The novel proton pump inhibitor pantoprazole elevates intragastric pH for a prolonged period when administered under conditions of stimulated gastric acid secretion in the gastric fistula dog.

The duration of intragastric pH-elevation upon administration of the novel H+K(+)-ATPase inhibitor pantoprazole and its pharmacodynamic interaction with H2 receptor blockade was assessed in the gastric fistula dog using the intragastric 24 hour pH-metry. Gastric acid secretion was stimulated by s.c. pentagastrin infusion. Group A received i.v. saline (controls), group B once an i.v. bolus of pantoprazole and group C twice the H2-receptor antagonist famotidine. Group D received the doses of famotidine and pantoprazole used in groups B and C. The intragastric pH-elevating effect of pantoprazole was not prolonged but, in fact, significantly shortened by the pretreatment with famotidine. Moreover, this effect depended on the pretreatment-dose of famotidine. The results underline that substituted benzimidazoles like pantoprazole need to be chemically activated in the acidic compartment of the parietal cell to produce a sustained intragastric pH-elevation. With regard to the potential therapeutic implication of these observations it is speculated that pantoprazole may be most effective in patients with high gastric acid secretion but may display reduced duration of intragastric pH-elevation under conditions of low acid secretion when acid blockade is not required.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1990

Direct comparison between the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors, one M1-selective antimuscarinic and one H2 receptor antagonist in the rat.

A direct comparison of the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors (pantoprazole and omeprazole), one M1 antimuscarinic (telenzepine) and one H2 receptor antagonist (cimetidine) was performed in the rat. Gastric and duodenal ulcers were induced by local application of acetic acid and thereafter treated over 10 days by the test drugs. Overall and on a molar basis, ulcer healing was comparably accelerated by pantoprazole, omeprazole and telenzepine and less so by cimetidine. The same rank order was found with respect to the inhibition of gastric acid secretion in the modified Shay rat.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1990

BY 1023/SK&F 96022 INN pantoprazole, a novel gastric proton pump inhibitor, potently inhibits acid secretion but lacks relevant cytochrome P450 interactions.

The novel H+/K(+)-adenosine triphosphatase inhibitor (gastric proton pump inhibitor), BY 1023/SK&F 96022, was found to be more potent than omeprazole in some rat models and slightly less potent in a dog model. Overall, both compounds are of a similar potency and efficacy. BY 1023/SK&F 96022 exhibited a somewhat longer duration of the antisecretory action than omeprazole in the Ghosh-Schild rat. In the modified Shay rat, on the basis of equieffective doses in terms of the initial effect, both compounds had a comparable duration of action. However, the p.o./i.v. dose ratio upon acute administration was larger for omeprazole, possibly reflecting its lower stability in the acidic environment of the secreting stomach, compared to BY 1023/SK&F 96022. As in vivo, both compounds were equipotent to inhibit acid production in rabbit isolated fundic glands. However, omeprazole interacted with the 7-ethoxycoumarin dealkylase in vitro with high affinity (Ki = 38.5 mumol/l), in contrast to BY 1023/SK&F 96022 (Ki = 135 mumol/l). Compared to omeprazole, BY 1023/SK&F 96022 also showed less interaction with the cytochrome P450 enzyme hydroxylating ionazolac. Moreover, this difference between the two compounds was also found in the rat in vivo with respect to their interaction with diazepam. Thus, both compounds displayed a comparable antisecretory potency in vivo and in vitro but showed a different interference with cytochrome P450 in favor of less interaction by BY 1023/SK&F 96022.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1987

Gastric prostaglandin E2 release induced by aluminium hydroxide and aluminium hydroxide-containing antacids in rats. Effect of low doses and citric acid.

Suspensions of aluminium hydroxide or a commercial antacid containing aluminium hydroxide (Trigastril) was instilled intragastrically in rats in doses comparable to high and low human therapeutic doses (aluminium hydroxide, 125 mg and 12.5 mg/kg, respectively). Corresponding experiments were carried out with 0.6% citric acid added to the antacid suspensions. Prostaglandin E2 (PGE2) in the gastric content was analysed by radioimmunoassay 6 h after drug administration. Both high and low doses of aluminium hydroxide and Trigastril increased the concentration of PGE2 significantly. Citric acid did not significantly affect the antacid-induced PGE2 release except in combination with a low dose of aluminium hydroxide, with which a significant increase was seen. Release of PGE2 by low doses of antacids implies the possibility that enhanced cytoprotection may be involved in the mechanism by which antacids promote the healing of peptic ulcers.

Aluminum Hydroxide↗

PubMed1986

[Tetrahydroisoquinolines as components of H2-antagonists. 27. H2-antihistaminics].

In studies on structure-activity relationships of histamine H2-receptor antagonists, lamtidine-analogue derivatives of N-(3-hydroxyphenyl)guanidine and 5- and 7-hydroxy-tetrahydroisoquinoline were prepared and tested for their H2-antagonistic activity on the isolated guinea-pig atrium and on the histamine-stimulated acid secretion of the anaesthetized rat. A further aim of the investigations was to examine the influence of a lengthening of the side-chain as well as the substitution of the aminotriazole with other H2-antagonistic components, on the pharmacological data of the above-mentioned isoquinoline derivatives. All compounds made showed only little H2-antagonistic activity on the guinea-pig atrium. At the acid secretion a noticeable activity especially of the 7-hydroxy-tetrahydroisoquinoline isomers could be observed.

Animals↗

PubMed1986

Further evidence for gastroprotection induced by aluminium hydroxide in the rat.

The effect of aluminium hydroxide on the development of gastric mucosal lesions induced by microcirculatory disturbances was investigated in the rat. Aluminium hydroxide dose-dependently inhibited the serotonin-induced gastric damages. Carbachol give subcutaneously intensified the development both of ethanol-produced gastric erosions and of indometacin-induced lesions. Al(OH)3 was able to counteract the damaging effect of the compounds mentioned. The gastroprotective effect of Al(OH)3 may be explained by the release of vasodilating prostaglandins into the submucosa; and by the slight spasmolytic effect of aluminium that also contributes to the improvement of the mucosal blood supply.

Aluminum Hydroxide↗

PubMed1985

Evidence for an anaphylactic reaction-induced gastric acid secretion from the isolated stomach of the mouse.

Under in vitro circumstances, ovalbumin, administered serosally, caused a definite acid secretory response in the isolated whole stomach of sensitized mice. Acid secretion induced by challenge was inhibited by cimetidine or by pretreatment with disodium cromoglycate. It remained, however, unchanged by mepyramine or atropine. It is likely that a local histamine release caused by an anaphylactic reaction of type I might be involved in the pathogenesis of certain kinds of digestive diseases, i.e. peptic ulcer.

Anaphylaxis↗

PubMed1985

Prostaglandin formation by isolated gastric parietal and nonparietal cells of the rat.

Rat gastric cells isolated by pronase and subdivided by Percoll into 3 fractions (F1, F2, F3) were used to study prostaglandin E2 (PGE2) formation and, as an indirect measure of parietal cell H+ production, [14C]-aminopyrine uptake. Cells that had not been fractionated, with 20 to 25% parietal cells, contained at 0 degree C 1.7 +/- 0.35 (s.e.mean) ng PGE2 10(8) cells-1. During incubation at 37 degrees C these cells steadily synthesized up to 4.36 +/- 0.73 ng PGE2 10(8) cells-1 from endogenous substrate. Indomethacin in concentrations higher than 10(-6) mol 1(-1) inhibited this basal formation completely, but 10(-4) mol 1(-1) did not reduce the cellular PGE2 level below 1.4 +/- 0.2 ng 10(8) cells-1. Arachidonic acid in concentrations higher than 10(-5) mol 1(-1) evoked an abundant formation of PGE2, and 10(-4) mol 1(-1) built up a plateau of over 7.5 +/- 1.65 ng PGE2 10(8) cells-1 within 15 min. PGE2 formation in cell fractions increased significantly with the number of parietal cells per assay tube. Indomethacin (10(-8) to 10(-4) mol 1(-1] did not influence the histamine-stimulated uptake of [14C]-aminopyrine, while arachidonic acid (10(-5) to 10(-4) mol 1(-1] inhibited this process. PGE2 formation in response to arachidonic acid was prevented by indomethacin, but the inhibition of aminopyrine uptake by arachidonic acid could not be prevented by indomethacin. The data suggest that isolated gastric cells of the rat sustain constant PGE2 synthesis in vitro, which is more pronounced in parietal than in mucosal and chief cells. PGE2 may exert different effects within distinct gastric cell types.

Aminopyrine↗

PubMed1985

[C-2 basically substituted thiazoles with H2-antagonistic action. 21. H2-antihistaminics].

In studies on structure-activity relationships of histamine H2-receptor antagonists, C-2 basically substituted thiazoles were prepared and tested for their H2-antihistaminic activity on the isolated guinea-pig atrium and on the histamine stimulated acid secretion of the anaesthetized rat. As a basic substituent the dimethylaminomethyl group is especially suitable, while cyclic guanidines lead to lower H2-antagonistic activity.

Animals↗

PubMed1985

[Isohistamine and homologs as components of H2-antagonists. 22. H2-antihistaminics].

Starting with isohistamines and their homologues or from appropriately hydrogenated imidazo[1,2-c]pyrimidines, imidazo[1,2-c] [1,3]diazepines and -diazocines, H2-antihistaminics with cyanoguanidine and 2-nitro-1,1-ethenediamine structure were prepared and tested for their H2-antagonistic activity on the isolated guinea-pig atrium and on the histamine-stimulated acid secretion of the anaesthetized rat. While the cyanoguanidines 3a-c,f were weaker in comparison to cimetidine, or inactive, 12a-e,g-l, 17 and 19 possessed markedly stronger activity, whereby the activity reaches a maximal effect at the rat stomach when cyanoguanidine and imidazole ring are connected with a three-membered chain. The activity of the 2-nitro-1,1-ethenediamines 15b,h,l exceed that of the comparable cyanoguanidines at both test models.

Animals↗