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1.
Scand J Gastroenterol Suppl ; (234): 3-9, 2001.
Article in English | MEDLINE | ID: mdl-11768559

ABSTRACT

Gastric proton-pump inhibitors (PPIs) are prodrugs. Their acid activation at pH 1.0 inside the canaliculus of a parietal cell should be fast relative to their serum elimination rate. Actually, all PPIs display chemical activation half-lives at pH 1.0 of a few minutes at the most, while being eliminated from serum with a half-life of about 1 h. This is the main reason they show similar antisecretory efficacies on a milligram basis. It is in line with about 5% to 15% higher healing rates in GERD, DU and GU when 40 mg is compared to 20 mg of either omeprazole or pantoprazole. The comparably large biological variation between patient samples explains why some studies show statistically significant differences between the two doses, while others do not. However, it would matter to the individual patient if s/he was the one additionally healed by a 40 mg dose within a defined treatment period. Chemical activation of PPI prodrugs is unwanted in weakly acidic tissue compartments such as lysosomes or secretory granules. However, the ratio of the serum elimination half-life (availability at the target) to the chemical activation half-life at a critical pH 5.0 is reversed only with pantoprazole. when compared to pH 1.0 (i.e. the ratio is < 1 at pH 5.0 and > 1.0 at pH 1.0). This is the basis of the high pH selectivity of pantoprazole. In contrast, rabeprazole is activated at pH 5.0 almost as quickly as it is at pH 1.0 and much faster than it is eliminated from serum. This unwanted reactivity of rabeprazole at pH 5.0 does not contribute to the antisecretory action at pH 1.0 and results in poor pH selectivity. Omeprazole and lansoprazole lie in between, as they are activated, at pH 5.0, about as quickly as they are eliminated from serum. The above activation rates refer to room temperature. At 37 degrees C. the activation rates of all PPIs further increase, by about the same factor of between 3 and 4. This renders their differential pH selectivities even more critical for drug safety. Biological consequences have been reported in the literature. It has been claimed that a dose of 40 mg of the S-enantiomer of omeprazole (esomeprazole) results in 10%-15% higher healing rates in GERD patients, compared to 20 mg omeprazole racemate. The same difference is found when the two doses of omeprazole racemate are compared to each other. This is not surprising, as the chiral PPI prodrug is converted by acid into an achiral cyclic sulfenamide which only then reacts with the proton pump. There is therefore no pharmacodynamic argument in favour of any single enantiomer formulation of any PPI. Moreover, potential pharmacokinetic differences between the enantiomers seem to be of little if any importance in the patient.


Subject(s)
Enzyme Inhibitors/pharmacology , Omeprazole/analogs & derivatives , Parietal Cells, Gastric/drug effects , Proton Pump Inhibitors , 2-Pyridinylmethylsulfinylbenzimidazoles , Benzimidazoles/administration & dosage , Benzimidazoles/pharmacokinetics , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Esomeprazole , Half-Life , Humans , Hydrogen-Ion Concentration , Lansoprazole , Omeprazole/administration & dosage , Omeprazole/pharmacokinetics , Pantoprazole , Prodrugs , Rabeprazole , Sulfoxides/administration & dosage , Sulfoxides/pharmacokinetics
2.
Pharmacology ; 60(4): 179-87, 2000 May.
Article in English | MEDLINE | ID: mdl-10828742

ABSTRACT

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.


Subject(s)
Benzimidazoles/pharmacology , Gastric Acid/metabolism , Parietal Cells, Gastric/drug effects , Proton Pump Inhibitors , Animals , Dogs , Female , Histamine H2 Antagonists/pharmacology , Male , Muscarinic Antagonists/pharmacology , Parietal Cells, Gastric/metabolism , Pirenzepine/pharmacology , Ranitidine/pharmacology , Rats , Rats, Sprague-Dawley
3.
Biochem Biophys Res Commun ; 272(1): 242-50, 2000 May 27.
Article in English | MEDLINE | ID: mdl-10872834

ABSTRACT

We have isolated two highly homologous but distinct rat sulfotransferase cDNAs termed ratSULT1C2 and ratSULT1C2A encoding polypeptides of 297 amino acids each. The amino acid sequence of ratSULT1C2 is 84% identical to the human SULT1C2 and 81% identical to a rabbit SULT1C2 sulfotransferase. ratSULT1C2 and ratSULT1C2A are 92% identical but differ in 22 amino acids. The majority of these amino acid substitutions in ratSULT1C2A is not found in the human and rabbit SULT1C2, which identifies ratSULT1C2 as the orthologue of these sulfotransferases, whereas SULT1C2A is a closely related but distinct enzyme. ratSULT1C2 and 2A sulfotransferases do not sulfonate steroids, dopamine, acetaminophen, or alpha-naphthol, but only p-nitrophenol. Prokaryotically expressed ratSULT1C2A is less active than ratSULT1C2. ratSULT1C2/2A mRNAs are abundant in kidney and less abundant in stomach and liver. The enzymes are expressed as 34-kDa polypeptides in rat kidney, liver, and stomach. In addition, a 28-kDa cross-reacting polypeptide is found in kidney only. Immunohistochemistry revealed expression of ratSULT1C2/2A in the epithelial cells of the proximal tubules of the kidney, bile duct epithelia, hepatocytes, and the epithelium of the gastric mucosal glands. Although the cDNA predicted amino acid sequence identifies both sulfotransferases as cytosolic enzymes, in tissue sections, in the kidney cell line NRK 52, and in transiently transfected BHK cells a considerable fraction of the enzyme was found in a granular perinuclear compartment. Costaining with a lysosomal marker in gastric mucosa tissue sections and cultured cells identifies these structures as lysosomes.


Subject(s)
Sulfotransferases/genetics , Sulfotransferases/metabolism , Amino Acid Sequence , Animals , Base Sequence , Cell Line , Cricetinae , DNA Primers/genetics , DNA, Complementary/genetics , DNA, Complementary/isolation & purification , Gene Expression , Humans , Immunohistochemistry , Kidney/enzymology , Lysosomes/enzymology , Molecular Sequence Data , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rabbits , Rats , Sequence Homology, Amino Acid , Species Specificity , Sulfotransferases/chemistry , Tissue Distribution , Transfection
4.
Pharmacology ; 59(2): 57-77, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10450061

ABSTRACT

The present review will verify by intra-study rank orders, and their comparison between studies, that the different gastric proton pump inhibitors (PPIs) display similar dose-response relationships with similar potencies and efficacies on a milligram basis, i.e., at the same milligram doses. This is in line with their basic pharmacology which suggests that, primarily, the serum AUCs of the free pro-drugs and their chemical activation half lives at pH 1 relative to their serum elimination half lives determine the efficacies of PPIs. According to the literature, these drug characteristics are similar for all PPIs. Although PPIs have been introduced into the therapy of acute peptic ulcer disease at different daily, oral doses of 20 mg (omeprazole and rabeprazole), 30 mg (lansoprazole) and 40 mg (pantoprazole), the data suggest that the optimal dose of lansoprazole, omeprazole and pantoprazole, with respect to the acute treatment of peptic ulcers and moderate to severe gastroesophageal reflux disease (GERD), is about 30-40 mg daily. The data base of rabeprazole appears to be too small at present to make any definite statement. Lower daily doses of the PPIs of about 15-20 mg are sufficient in less severe cases of GERD and in maintenance therapy. It appears that different dose recommendations were based on different strategies to balance optimal drug dosage and safety, rather than on real differences in milligram-related efficacies.


Subject(s)
Anti-Ulcer Agents/pharmacokinetics , Duodenal Ulcer/drug therapy , Gastroesophageal Reflux/drug therapy , Proton Pump Inhibitors , Stomach Ulcer/drug therapy , 2-Pyridinylmethylsulfinylbenzimidazoles , Anti-Ulcer Agents/administration & dosage , Anti-Ulcer Agents/therapeutic use , Benzimidazoles/administration & dosage , Benzimidazoles/pharmacokinetics , Benzimidazoles/therapeutic use , Dose-Response Relationship, Drug , Humans , Lansoprazole , Omeprazole/administration & dosage , Omeprazole/analogs & derivatives , Omeprazole/pharmacokinetics , Omeprazole/therapeutic use , Pantoprazole , Sulfoxides/administration & dosage , Sulfoxides/pharmacokinetics , Sulfoxides/therapeutic use
5.
Drugs Today (Barc) ; 35(10): 753-64, 1999 Oct.
Article in English | MEDLINE | ID: mdl-12973370

ABSTRACT

Pantoprazole sodium is a substituted benzimidazole derivative which controls acid secretion by inhibition of gastric H(+)/K(+)-ATPase. The prodrug pantoprazole accumulates in the acidic space of the parietal cell where it is converted to the pharmacologically active principle, a thiophilic cyclic sulfenamide. The pH-dependent activation profile, i.e., activation at pH 1 versus activation at pH 4-6, is more favorable for pantoprazole than for the other proton pump inhibitors (PPIs) currently available. In vitro, pantoprazole interferes less potently than omeprazole with biological targets not related to gastric acid secretion. The gastric target sites for the pantoprazole sulfenamide are the cysteines 813 and 822 of the catalytic subunit of the H(+)/K(+)-ATPase. In contrast to omeprazole, the two binding sites are located right at the proton channel. In rats, dogs and humans, pantoprazole produces marked and prolonged inhibition of both basal and stimulated acid secretion. Overall, its antisecretory potency is equal to that of omeprazole. Antiulcer activity has been demonstrated for pantoprazole in two rat models. As seen with H(2)-receptor antagonists and other PPIs, pantoprazole causes an increase in serum gastrin concentration which reflects the degree of gastric acid inhibition. Pantoprazole is mainly metabolized by CYP3A4 and 2C19, but displays a lower affinity for these phase I cytochrome P450 enzymes than omeprazole. In contrast to the latter, pantoprazole is further conjugated with sulfate by the hepatic phase II metabolism. These two differences may explain why pantoprazole does not interfere with the metabolism of any other drug thus far tested in humans.

6.
Immunobiology ; 199(1): 14-22, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9717664

ABSTRACT

Interleukin-15 is a recently discovered cytokine which is functionally similar to IL-2. In order to learn more about possible targets for modulation of the expression of IL-15 we investigated the expression of IL-15 mRNA and protein in the A549 (human lung carcinoma) cell line. Constitutive expression of IL-15 mRNA was detected in A549 cells. Treatment with TNF-alpha or IL-1 beta (10 ng/ml each) induced an about 2-fold increase of IL-15 mRNA; IFN-gamma induced significant effects only at 100 ng/ml. Stimulation with a combination of TNF-alpha and IFN-gamma was not superior to stimulation with TNF-alpha alone. EGF, KGF and the combination thereof were without effects. IL-15 protein was detected in cellular lysates of unstimulated cells and was increased by stimulation with TNF-alpha or IL-1 beta. No significant amounts of IL-15 protein were detected in cellular supernatants.


Subject(s)
Fibroblast Growth Factors , Interferon-gamma/pharmacology , Interleukin-15/biosynthesis , Interleukin-1/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Epidermal Growth Factor/pharmacology , Fibroblast Growth Factor 10 , Fibroblast Growth Factor 7 , Growth Substances/pharmacology , Humans , Interleukin-15/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Recombinant Proteins/pharmacology , Tumor Cells, Cultured
7.
Pharmacology ; 56(2): 57-70, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9494064

ABSTRACT

Gastric proton pump inhibitors (PPIs) are substituted benzimidazole prodrugs that require an acid-induced activation. Its rate depends on the reactivity of the molecule relative to the environmental pH and determines the drug's tissue selectivity. Factors affecting the exposure of moderately acidic tissues to the activated PPI are the area under the serum concentration-time curve (AUC), serum protein binding, the partition coefficient logP and the serum elimination half-life relative to the chemical activation half-life at a critical tissue pH of about 5. These parameters have therefore been determined in a comparative fashion in the present study. The data shows that pantoprazole is less likely to undergo unwanted activation at moderately acidic targets as opposed to the parietal cell, compared to omeprazole. Actually, although 40 mg pantoprazole (steady state) gave a slightly higher serum AUC of the total parent compound than 40 mg omeprazole (10.5 vs. 7.1 micromol x h x l[-1]), a higher serum protein binding of pantoprazole versus omeprazole (98 vs. 96%) reversed the AUC values for the free drug in favor of a lower value for pantoprazole (0.19 vs. 0.28 micromol x h x l[-1]). It is the free parent compound that equilibrates across cell membranes to be activated in acidic tissue compartments. At pH 5.1, the activation half-life of pantoprazole was 4.7 versus 1.4 h for omeprazole, the latter being in the order of the common serum elimination half-life determined in an intraindividual comparison (1.24 vs. 1.25 h). Thus, pantoprazole is eliminated faster from blood than it is activated at a pH of about 5, while omeprazole is as quickly activated at this pH as it is eliminated from blood. Biological in vitro experiments confirmed that pantoprazole displays a lower liability to interfere with unwanted biological targets. This has been demonstrated in vitro for inhibition of both renal Na+/K+-ATPase, lysosomal acidification and the production of reactive oxygen species by neutrophils.


Subject(s)
Benzimidazoles/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Gastric Mucosa/drug effects , Proton Pump Inhibitors , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Animals , Benzimidazoles/blood , Benzimidazoles/chemistry , Biological Availability , Dogs , Drug Stability , Enzyme Inhibitors/chemistry , Gastric Acid/metabolism , Gastric Mucosa/metabolism , Half-Life , Humans , Hydrogen-Ion Concentration , Male , Omeprazole/pharmacokinetics , Pantoprazole , Protein Binding , Rabbits , Sulfoxides/pharmacokinetics
8.
Biotechnol Bioeng ; 57(2): 238-44, 1998 Jan 20.
Article in English | MEDLINE | ID: mdl-10099199

ABSTRACT

The gene for the integral membrane protein glycophorin A (GPA) was cloned in frame to the 5' end of the antibiotic resistance gene, neomycin phosphotransferase II (NPT). Protein expression was achieved in Escherichia coli as well as in mammalian cells. In case of Chinese hamster ovary cells (CHO) the resistant populations were analyzed 2 weeks after transfection; the amount of GPA-NPT fusion protein produced was constant from experiment to experiment. Neomycin resistance was directly correlated with GPA expression, thus allowing the direct selection for a stable GPA-expressing cell population without the need of a cloning step. The amount of GPA-NPT produced was further increased by weakening the specific NPT enzymatic activity via site-directed mutagenesis. Detection was simplified by the fact that all different fusion proteins could be detected by the same anti-NPT antibody. This approach may be also applicable to other membrane proteins.


Subject(s)
Glycophorins/genetics , Kanamycin Kinase/genetics , Animals , Base Sequence , Biotechnology , CHO Cells , Cloning, Molecular , Cricetinae , DNA, Complementary/genetics , Escherichia coli/genetics , Gene Expression , Genetic Vectors , Glycophorins/biosynthesis , Humans , Kanamycin Kinase/biosynthesis , Kanamycin Resistance/genetics , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , Transformation, Genetic
9.
Eur J Biochem ; 248(3): 814-9, 1997 Sep 15.
Article in English | MEDLINE | ID: mdl-9342233

ABSTRACT

Phospholamban (PLN) was expressed in Escherichia coli as a protein fusion with glutathione S-transferase (GST). GST-PLN was mostly present in the insoluble protein fraction and accounted for approximately 50% of total insoluble protein. Attempts to suppress inclusion body formation or to use GST as an affinity-purification tag failed. A successful purification method is based on preparative SDS/PAGE and electrodialysis. From 1 g cells we typically purified 13.5 mg fusion protein with a PLN content of 2.8 mg. We genetically inserted an enterokinase (EK) protease site just in front of the PLN sequence and demonstrated the proteolytical liberation of PLN from the carrier protein. The approach described represents a substantial advancement in PLN expression and purification.


Subject(s)
Calcium-Binding Proteins/isolation & purification , Myocardium/chemistry , Recombinant Fusion Proteins/isolation & purification , Animals , Blotting, Western , Calcium-Binding Proteins/chemistry , Calcium-Binding Proteins/genetics , Dimerization , Dogs , Electrophoresis, Polyacrylamide Gel , Enteropeptidase/genetics , Enteropeptidase/metabolism , Escherichia coli/genetics , Gene Expression , Glutathione Transferase/genetics , Oligodeoxyribonucleotides/chemistry , Plasmids/genetics , Recombinant Fusion Proteins/chemistry , Sarcoplasmic Reticulum/chemistry
10.
Gut ; 36(6): 813-8, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7615265

ABSTRACT

Muscarinic receptors stimulate the secretion of acid pepsinogen and mucous in gastric mucosa. Whether muscarinic receptors are involved in the pathogenesis of benign gastric disease is unknown. Receptor changes in these conditions were therefore sought. An autoradiographic technique was developed to determine quantitatively muscarinic receptors in microtome sections of biopsy specimens obtained during gastroscopy. Muscarinic receptor density was mean (SEM) 18.4 (1.2) fmol/mg protein in the corpus and 8.9 (0.7) fmol/mg protein in the antrum (n = 53). Neither chronic nor active gastritis was associated with receptor changes in the antrum but chronic gastritis was associated with a receptor loss in the corpus. Patients with acute or recent duodenal or antral ulcers (n = 23) had significantly higher levels of muscarinic receptors in the corpus than controls (n = 25) (22.2 (1.5) v 16.9 (1.7) fmol/mg protein respectively (p < 0.025). These results suggest that muscarinic M3 receptor is overexpressed in duodenal ulcer disease and may play a part in its pathogenesis.


Subject(s)
Gastric Mucosa/metabolism , Peptic Ulcer/metabolism , Receptors, Muscarinic/metabolism , Stomach Diseases/metabolism , Acute Disease , Age Factors , Aged , Chronic Disease , Female , Gastritis/metabolism , Gastritis/pathology , Humans , Male , Middle Aged , Sex Factors , Stomach Diseases/pathology
11.
Br J Pharmacol ; 114(4): 739-44, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7773532

ABSTRACT

1. In a voltage clamp setting (Ussing chamber), the antidiarrhoeal drug, loperamide (Lop) slightly augmented prostaglandin E1 (PGE1) plus theophylline-stimulated net chloride secretion above control values at low concentrations (10(-10) and 10(-9) M) but inhibited it at higher concentrations (10(-6) and 10(-5) M). The apparently weak prosecretory action component of Lop was turned into a clear cut antisecretory effect by pretreatment with 2 x 10(-7) M naloxonazine plus 10(-7) M CTOP-NH2 (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2), two selective mu opioid receptor antagonists. This indicates a prosecretory effect of loperamide at mu opioid receptors. The antisecretory effect of low Lop concentrations, uncovered by mu opioid receptor blockade, was prevented by additional blockade of kappa opioid receptors by 5 x 10(-9) M nor-binaltorphimine (nor-BNI). 2. The nonselective opioid antagonist, naloxone, at 10(-6) M did not significantly reduce either PGE1 plus theophylline-stimulated net chloride secretion in Lop-free controls or the antisecretory action of Lop. By contrast, the partial agonist ethylketocyclazocine (EKC), which activates kappa but blocks mu opioid receptors, concentration-dependently inhibited PGE1 plus theophylline-stimulated net chloride secretion without any consistent prosecretory action component. Nor-BNI at 5 x 10(-8) M significantly blocked the antisecretory action of EKC. 3. It is concluded that, in the guinea-pig colonic mucosa under the present conditions, mu opioid receptors mediate enhancement and kappa opioid receptors inhibition of PGE1-stimulated net chloride secretion by low Lop concentrations. The two opposite actions are largely masked by superimposition. An opioid receptor-independent mechanism of action contributes to the antisecretory effect of Lop at high concentrations.


Subject(s)
Colon/drug effects , Loperamide/pharmacology , Receptors, Opioid, mu/drug effects , Alprostadil/pharmacology , Amino Acid Sequence , Animals , Chlorides/metabolism , Colon/metabolism , Dose-Response Relationship, Drug , Ethylketocyclazocine/pharmacology , Guinea Pigs , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Loperamide/administration & dosage , Male , Molecular Sequence Data , Naloxone/analogs & derivatives , Naloxone/pharmacology , Naltrexone/administration & dosage , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Patch-Clamp Techniques , Receptors, Opioid, delta/antagonists & inhibitors , Somatostatin/administration & dosage , Somatostatin/analogs & derivatives , Somatostatin/chemistry , Somatostatin/pharmacology , Theophylline/administration & dosage , Theophylline/pharmacology
12.
Digestion ; 56(6): 443-54, 1995.
Article in English | MEDLINE | ID: mdl-8536813

ABSTRACT

The novel antiulcer drugs omeprazole, lansoprazole, and pantoprazole are members of the class of substituted benzimidazoles. They potently inhibit the gastric proton pump by a common mechanism which depends on the acid-induced conversion of the parent compounds to the pharmacologically active principles: thiophilic cyclic sulfenamides. This transformation takes place in the luminal compartment of the secreting parietal cell. However, while the three proton pump inhibitors belong to the same chemical class, their two ring systems bear different functional substituents. This leads to essential modification of the physiochemical, metabolic, and pharmacokinetic properties of these drugs, possibly resulting in differences in tissue selectivity and thereby, in the long term, drug safety. Both preclinical and clinical data have accumulated that point to advantages of pantoprazole related to the above parameters: pantoprazole shows a higher stability at moderately acidic pH values and less inhibitory potential against cytochrome P450 than the other two drugs. In addition, pantoprazole displays linear pharmacokinetics with a high bioavailability.


Subject(s)
Anti-Ulcer Agents/pharmacology , Benzimidazoles/pharmacology , Omeprazole/analogs & derivatives , Omeprazole/pharmacology , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Anti-Ulcer Agents/chemistry , Anti-Ulcer Agents/pharmacokinetics , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors , Gastric Acid/metabolism , Humans , Lansoprazole , Omeprazole/chemistry , Omeprazole/pharmacokinetics , Pantoprazole , Sulfoxides/chemistry , Sulfoxides/pharmacokinetics
13.
Life Sci ; 53(13): 1061-8, 1993.
Article in English | MEDLINE | ID: mdl-8103566

ABSTRACT

The present voltage-clamp data from guinea pig colonic mucosa indicate that mu opioid receptors both enhance and inhibit net chloride secretion stimulated by PGE1 plus theophylline. Actually, enhancement by the mu opioid agonist DAGO (0.2 nmol/l) declines and finally turns into inhibition with increasing net chloride secretion observed in control preparations taken from the same animals. Moreover, inhibition by the mu opioid antagonist CTOP-NH2 (100 nmol/l) increases with increasing inhibition (or decreasing enhancement) by the mu opioid agonist DAGO. Thus, the mu opioid agonist DAGO and the mu opioid antagonist CTOP-NH2 display opposite effects on net chloride secretion only to a limited degree but otherwise show parallel, either stimulatory or inhibitory, effects. To explain this complex function of mu opioid receptors in the control of net chloride secretion, a working hypothesis is being proposed.


Subject(s)
Chlorides/metabolism , Intestinal Mucosa/metabolism , Receptors, Opioid, mu/physiology , Alprostadil/pharmacology , Amiloride/pharmacology , Amino Acid Sequence , Animals , Colon/metabolism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalins/pharmacology , Guinea Pigs , In Vitro Techniques , Intestinal Mucosa/drug effects , Male , Molecular Sequence Data , Receptors, Opioid, mu/antagonists & inhibitors , Receptors, Opioid, mu/drug effects , Somatostatin/analogs & derivatives , Somatostatin/pharmacology , Theophylline/pharmacology
14.
Eur J Pharmacol ; 230(2): 235-7, 1993 Jan 12.
Article in English | MEDLINE | ID: mdl-8093687

ABSTRACT

On the basis of the novel concept of a dual prosecretory/antisecretory intestinal opioid system, a voltage-clamp experiment was performed with guinea-pig colonic mucosa, and net anion (Cl-) secretion was measured after stimulation with prostaglandin E1 (PGE1) plus theophylline. Synergism between kappa-opioid receptor agonism by U69593 and mu-opioid receptor antagonism by CTOP-NH2 (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) was observed.


Subject(s)
Benzeneacetamides , Chlorides/metabolism , Colon/drug effects , Pyrrolidines/pharmacology , Receptors, Opioid, mu/antagonists & inhibitors , Somatostatin/analogs & derivatives , Amiloride/pharmacology , Amino Acid Sequence , Analgesics/pharmacology , Animals , Colon/metabolism , Drug Synergism , Guinea Pigs , Male , Molecular Sequence Data , Mucous Membrane/drug effects , Mucous Membrane/metabolism , Receptors, Opioid, kappa/drug effects , Somatostatin/pharmacology
15.
Aliment Pharmacol Ther ; 6(2): 195-206, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1318089

ABSTRACT

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.


Subject(s)
Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastrins/metabolism , Adenosine Triphosphatases/antagonists & inhibitors , Animals , Atropine/pharmacology , Dose-Response Relationship, Drug , Female , Gastric Mucosa/enzymology , Gastric Mucosa/metabolism , Gastrins/blood , H(+)-K(+)-Exchanging ATPase , Hydrogen-Ion Concentration , Muscarinic Antagonists , Parasympatholytics/pharmacology , Pirenzepine/analogs & derivatives , Pirenzepine/pharmacology , Pyloric Antrum/drug effects , Pyloric Antrum/enzymology , Pyloric Antrum/metabolism , Rats , Rats, Inbred Strains , Time Factors
16.
J Biol Chem ; 266(36): 24573-9, 1991 Dec 25.
Article in English | MEDLINE | ID: mdl-1840597

ABSTRACT

In the eubacterium Escherichia coli the genes for the ribosomal proteins L13 and S9 form an operon consisting of two genes. The corresponding operon of the archaebacterium Haloarcula marismortui (Halobacterium marismortui was recently reassigned to the genus Haloarcula [Oren, A., Ginzburg, M., Ginzburg, B. Z., Hochstein, L. I., and Volcani, B. E. (1990) Int. J. Syst. Bacteriol. 40, 209-210] and is now called Haloarcula marismortui) which is presented here, is much larger encoding three ribosomal proteins (HL29, HmaL13, HmaS9), a tRNA(Leu), the glycolytic enzyme enolase (HmaEno), a putative membrane protein (OrfMSG), and two not yet identified open reading frames (OrfMMV, OrfMNA). The nucleotide sequence of 3931 base pairs has been established. Northern analysis revealed the existence of a polycistronic mRNA (3.7 kilobases) demonstrating that the transcription of a gene of the glycolytic pathway is coupled to the transcription of ribosomal protein genes. Upstream of the first gene of the operon (tRNA(Leu)) a promoter structure typical for the extreme halophilic archaebacteria was detected and downstream of the last gene (OrfMSG) a terminator structure was present. As shown by S1-nuclease mapping, a tRNA-mRNA transcript as well as the mRNA alone was present in vivo. The transcriptional start point and the tRNA-mRNA cleavage point are shown to be almost identical to the 5' and 3' ends, respectively, of the putative mature tRNA. The C-terminal part of the OrfMSG protein shows a significant similarity to the vertebrate laminin receptor protein.


Subject(s)
Halobacterium/genetics , Membrane Proteins/genetics , Operon , Phosphopyruvate Hydratase/genetics , RNA, Transfer, Leu/genetics , Ribosomal Proteins/genetics , Bacterial Proteins/genetics , Base Sequence , Blotting, Northern , DNA, Bacterial , Escherichia coli/genetics , Genes, Bacterial , Molecular Sequence Data , Nucleic Acid Hybridization , RNA, Messenger/genetics , Restriction Mapping , Ribosomal Protein S9 , Sequence Homology, Nucleic Acid , Transcription, Genetic
17.
J Auton Pharmacol ; 11(5): 337-42, 1991 Oct.
Article in English | MEDLINE | ID: mdl-1684182

ABSTRACT

1. Highly controversial claims have been put forward in the literature as to the involvement of either M1 or non-M1 muscarinic receptors in the field (vagal) stimulation of gastric acid secretion. This mini-review considers three available sets of data obtained in the mouse isolated, lumen-perfused stomach. 2. While pA2 values seemed to favour non-M1 receptors, a comparison between M1 selective versus non-selective antagonists on the one hand and field stimulation versus bethanechol stimulation on the other clearly pointed to M1 receptors being involved. 3. In the present review we discuss a novel experimental approach supporting the latter concept of M1 receptors. This novel approach provides a simple though provocative way to deal with the particular difficulties in determining pA2 values in the acid-secreting gastric mucosa. It is based on the rank order in the effects of different antagonists relative to their receptor type-dependent affinities, when employed at a fixed concentration, rather than on their pA2 values.


Subject(s)
Gastric Acid/metabolism , Gastric Mucosa/chemistry , Receptors, Muscarinic/metabolism , Animals , Atropine/pharmacology , Bethanechol , Bethanechol Compounds/pharmacology , Dicyclomine/pharmacology , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Guinea Pigs , In Vitro Techniques , Mice , Parasympatholytics/pharmacology , Pirenzepine/pharmacology , Regression Analysis
18.
Naunyn Schmiedebergs Arch Pharmacol ; 344(3): 360-7, 1991 Sep.
Article in English | MEDLINE | ID: mdl-1720510

ABSTRACT

The influence of four opioid antagonists on short circuit current (Isc), transepithelial potential difference (Pdo) and tissue conductance (Gt) in the guinea pig colonic mucosa was investigated in vitro under both basal and PGE1 plus theophylline-stimulated conditions. The experiments aimed at identifying the opioid receptor type(s) endogenously activated to control chloride secretion. Under blockade of sodium-dependent Isc by amiloride (100 mumol/l), net anion secretion was regarded to equal the lumen-negative shift in Isc upon addition of 1 mumol/l PGE1 plus 100 mumol/l theophylline. It was significantly elevated by 100 nmol/l of the kappa-selective antagonist nor-binaltorphimine (nor-BNI). This augmenting effect was totally abolished in amiloride-free buffer or by omission of chloride. 1 mumol/l TTX completely prevented the effect of both PGE1 plus theophylline and nor-BNI. Both the kappa agonist U 69593 (10 nmol/l) and the calcium channel agonist Bay K 8644 (1 mumol/l) significantly depressed net anion secretion stimulated by PGE1 plus theophylline. Nor-BNI at 10 nmol/l prevented the suppressive effect of both Bay K 8644 and U 69593. This suggests release of endogenous opioids by the calcium channel agonist Bay K 8644 and competition between the kappa agonist U 69593 and the kappa antagonist nor-BNI. In contrast to the kappa antagonist nor-BNI, the mu antagonist CTOP-NH2 at 100 nmol/l significantly impaired, while the mu-selective agonist DAGO at 0.2 nmol/l augmented, net anion secretion stimulated by PGE1 plus theophylline. The effect of CTOP-NH2 was abolished in chloride-free buffer.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Benzeneacetamides , Chlorides/physiology , Endorphins/physiology , Intestinal Mucosa/metabolism , Receptors, Opioid/physiology , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Alprostadil/pharmacology , Amiloride/pharmacology , Amino Acid Sequence , Analgesics/pharmacology , Animals , Endorphins/metabolism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalins/pharmacology , Gluconates/pharmacology , Guinea Pigs , Intestinal Mucosa/drug effects , Male , Membrane Potentials/drug effects , Molecular Sequence Data , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists , Pyrrolidines/pharmacology , Receptors, Opioid, delta , Receptors, Opioid, kappa , Receptors, Opioid, mu , Somatostatin/analogs & derivatives , Somatostatin/pharmacology , Tetrodotoxin/pharmacology , Theophylline/pharmacology
19.
Biochimie ; 73(6): 657-68, 1991 Jun.
Article in English | MEDLINE | ID: mdl-1764513

ABSTRACT

Approximately 40 ribosomal proteins from each Halobacterium marismortui and Bacillus stearothermophilus have been sequenced either by direct protein sequence analysis or by DNA sequence analysis of the appropriate genes. The comparison of the amino acid sequences from the archaebacterium H marismortui with the available ribosomal proteins from the eubacterial and eukaryotic kingdoms revealed four different groups of proteins: 24 proteins are related to both eubacterial as well as eukaryotic proteins. Eleven proteins are exclusively related to eukaryotic counterparts. For three proteins only eubacterial relatives-and for another three proteins no counterpart-could be found. The similarities of the halobacterial ribosomal proteins are in general somewhat higher to their eukaryotic than to their eubacterial counterparts. The comparison of B stearothermophilus proteins with their E coli homologues showed that the proteins evolved at different rates. Some proteins are highly conserved with 64-76% identity, others are poorly conserved with only 25-34% identical amino acid residues.


Subject(s)
Geobacillus stearothermophilus/chemistry , Halobacterium/chemistry , Ribosomal Proteins/chemistry , Ribosomal Proteins/isolation & purification , Amino Acid Sequence , Isoelectric Point , Molecular Sequence Data , Molecular Weight , Sequence Homology, Nucleic Acid
20.
Naunyn Schmiedebergs Arch Pharmacol ; 343(1): 7-13, 1991 Jan.
Article in English | MEDLINE | ID: mdl-2030745

ABSTRACT

1. The muscarine receptor mediating electrically-stimulated acid secretion in the mouse isolated stomach was characterized using a variety of muscarine receptor antagonists confirming the M1 nature of the antagonist effect of telenzepine. 2. Field stimulation (7 V, 10 Hz, 0.5 ms) resulted in a plateau acid secretion over at least 90 min which was completely blocked by either 1 mumol/l TTX or H2 receptor antagonists (100 mumol/l cimetidine or 10 mumol/l lupitidine). Ranitidine, which is known to potently inhibit mucosal acetylcholine esterase, was ineffective. Compound 48/80 at 100 mumol/l, which depletes mucosal histamine stores, initially mimicked electrical stimulation but subsequently prevented it from inducing acid secretion. 3. 10 muscarine receptor antagonists with differing relative affinities for M1, M2 and M3 receptors were introduced at 1 mumol/l to inhibit electrically-stimulated acid secretion. The percentages inhibition were plotted against binding affinities of the antagonists at either M1, M2 or M3 binding sites. A statistically significant correlation between functional and binding data was detected only when based on M1 affinities. 4. It is concluded that field stimulation, which probably mimicks vagal drive, results in muscarinic M1 receptor activation on paracrine cells to release histamine. Histamine then stimulates parietal cells to secrete acid. Hence, according to the present and our previous data, telenzepine inhibits acid secretion under these conditions by blocking M1 receptors at least partially located on histamine-releasing paracrine cells.


Subject(s)
Acetylcholine/physiology , Gastric Acid/metabolism , Gastric Mucosa/metabolism , Histamine/physiology , Muscarinic Antagonists , Parasympatholytics/pharmacology , Pirenzepine/analogs & derivatives , Stomach/drug effects , Alkaloids/metabolism , Alkaloids/pharmacology , Animals , Anti-Ulcer Agents/metabolism , Anti-Ulcer Agents/pharmacology , Electric Stimulation , Furans , Histamine/metabolism , Histamine/pharmacology , Mice , Naphthalenes , Parasympatholytics/metabolism , Piperidines/metabolism , Piperidines/pharmacology , Pirenzepine/metabolism , Pirenzepine/pharmacology , Stomach/innervation , Stomach/physiology , Stomach/ultrastructure , Thiazepines/metabolism , Thiazepines/pharmacology , Vagus Nerve/physiology , p-Methoxy-N-methylphenethylamine/pharmacology
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