Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 9-year-old male German Shepherd Dog was presented with the primary complaints of vomiting, profuse watery diarrhea, anorexia, and severe weight loss. The dog developed hematemesis and melena, which were unresponsive to treatment with an H2-receptor antagonist and a gastrointestinal protectant. A marked neutrophilia, panhypoproteinemia, hypokalemia, and mildly increased activities of alkaline phosphatase and alanine aminotransferase were the only relevant abnormalities found on a CBC, serum biochemical profile, and urinalysis. An exploratory laparotomy revealed several small nonresectable masses at the root of the mesentery, which were identified histologically as a neuroendocrine neoplasm. Immunohistochemical staining of the neoplasm was positive for gastrin and negative for insulin, glucagon, pancreatic polypeptide, and vasoactive intestinal polypeptide. Fasting serum gastrin concentrations were high. Zollinger-Ellison syndrome was diagnosed, and the dog was treated with omeprazole, an H+,K(+)-ATPase inhibitor. All clinical signs resolved, and the dog remains asymptomatic 2 years later. Omeprazole may be the gastric acid antisecretory drug of choice for dogs with gastrinoma.
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PMID:Omeprazole in a dog with gastrinoma. 947 Jan 66

Rabeprazole is a proton pump inhibitor with antisecretory properties. In vitro animal experiments have indicated that the inhibition of the proton pump by rabeprazole is partially reversible. Rabeprazole has 2- to 10-fold greater antisecretory activity than omeprazole in vitro. However, it dissociates more readily from H+,K(+)-ATPase than omeprazole, resulting in a shorter duration of action. In comparative clinical trials rabeprazole was significantly more effective than placebo, famotidine or ranitidine and as effective as omeprazole in the treatment of patients with erosive or ulcerative gastro-oesophageal reflux disease or gastric or duodenal ulcers. Healing rates with rabeprazole were independent of Helicobacter pylori status. Rabeprazole in combination with either clarithromycin and metronidazole or clarithromycin and amoxicillin or amoxicillin and metronidazole or clarithromycin for 7 days produced eradication of H. pylori in 100, 95, 90 and 63% of patients. The tolerability profile of rabeprazole 20mg once daily was similar to that of famotidine 20mg twice daily, ranitidine 150mg 4 times daily or omeprazole 20mg once daily in comparative trials. The adverse events reported with once daily administration of rabeprazole 20mg include malaise, nausea, diarrhoea, headache, dizziness and skin eruptions in 0.7 to 2.2% of patients.
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PMID:Rabeprazole. 950 45

In the rapidly increasing elderly population, diarrhoea as a result of drug therapy is an important consideration. The elderly consume a disproportionately large number of drugs for multiple acute and chronic diseases. Drugs can compromise both immune and nonimmune responses. Aging decreases the quality and proportion of T cells which in turn reduces the production of secretory IgA, the primary immune response of the gut. Acid production in the stomach decreases with increasing age and this compromise its vital 'self-sterilising' function, thus increasing the risk of diarrhoea due to viral, bacterial and protozoal pathogens. Other nonimmune defence mechanisms include the motility of the small intestine and the host-protective commensal bacteria of the colon. Drug induced hypomotility may result in bacterial overgrowth, deconjugation of bile salts and diarrhoea. Less commonly, diarrhoea may occur due to hypermotility because of a cholinergic-like syndrome. In the colon the host-protective commensal bacteria provide a powerful defence against pathogens. Disruption of this commensal population by antibiotic therapy may result in Clostridium difficile supra-infection which causes diarrhoea through toxin production. This is especially important in the elderly patient on chemotherapy for malignancy and those with multiple diseases. The organism responds to vancomycin, metronidazole and bacitracin. Metronidazole is the suggested drug of choice, with vancomycin reserved for relapses. Drugs also cause diarrhoea by interfering with normal physiological processes. Drugs impair fluid absorption by activating adenylate cyclase within the small intestinal enterocyte which increases the level of cyclic AMP. This causes active secretion of Cl- and HCO3-, passive efflux of Na+, K+ and water and inhibition of Na+ and Cl- into the enterocyte. Examples of these drugs (secretagogues) are bisacodyl, misoprostol and chenodeoxycholic acid (used to dissolve cholesterol gallstones). Drugs may also affect a second mechanism that regulates water and electrolyte transport, the Na+, K+ exchange pump. The energy for this pump is provided by the ATPase mediated breakdown of ATP. ATPase may be inhibited by digoxin, auranofin, colchicine and olsalazine. A number of drugs cause osmotic diarrhoea including antacids containing magnesium trisilicate or hydroxide. Lactulose is being used increasingly in compensated liver disease to increase protein tolerance and prevent hepatic encephalopathy. Sorbitol, an osmotic laxative agent also used in some liquid pharmaceutical preparations, induces diarrhoea by virtue of its osmotic potential. Another mechanism by which drugs cause diarrhoea is by mucosal damage of the small and large bowel. In the small intestine mucosal damage causes diarrhoea and fat malabsorption, as may occur with neomycin and colchicine. In the colon, for example, gold salts and penicillamine cause colitis of varying severity. Though the causes of diarrhoea are diverse, a drug-associated aetiology should always be considered and actively sought and addressed to prevent the complications of dehydration, electrolyte imbalance and undernutrition.
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PMID:Mechanisms of drug-induced diarrhoea in the elderly. 978 28

The aim of this study was to determine whether ionizing radiation modifies muscarinic regulation of intestinal mucosal function. Rats exposed to total body 8-Gy gamma-irradiation or sham irradiated were studied up to 21 days after irradiation. Basal and carbachol-stimulated short-circuit current (Isc) and transepithelial conductance (Gt) of stripped ileum were determined in Ussing chambers. Muscarinic receptor characteristics using the muscarinic antagonist [3H]quinuclidinyl benzilate and three unlabeled antagonists were measured in small intestinal plasma membranes together with two marker enzyme activities (sucrase, Na+-K+-ATPase). Enzyme activities were decreased 4 days after irradiation (day 4). Basal electrical parameters were unchanged. Maximal carbachol-induced changes in Isc and Gt were increased at day 4 (maximal DeltaIsc = 195.8 +/- 14.7 microA/cm2, n = 19, vs. 115.4 +/- 8.2 microA/cm2, n = 63, for control rats) and unchanged at day 7. Dissociation constant was decreased at day 4 (0.73 +/- 0.29 nM, n = 10, vs. 2.14 +/- 0.39 nM, n = 13, for control rats) but unchanged at day 7, without change in binding site number. Thus total body irradiation induces a temporary stimulation of cholinergic regulation of mucosal intestinal function that may result in radiation-induced diarrhea.
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PMID:Ionizing radiation stimulates muscarinic regulation of rat intestinal mucosal function. 984 70

The regulation of gene expression by nutrients plays an important role in the overall manifestations of nutritional deficiencies. Insufficient intakes of dietary micronutrients, such as zinc, produce profound effects in multiple organs and tissues. One of the major challenges, however, is to identify genes affected by changes in nutritional status. Differential display of mRNA has proved to be a valuable technique in meeting this challenge. In our ongoing search for genes responsive to dietary zinc, we compared small intestinal mRNA from rats that were fed zinc-deficient or -adequate diets using differential display to generate 3' anchored expressed sequence tags (EST). EST for intestinal mRNAs with altered expression due to zinc deficiency include two peptide hormones, intestinal fatty acid binding protein, intestinal alkaline phosphatase II, a proteasomal ATPase, cis-Golgi p28 and two subunits of the ubiquinone oxidoreductase. The EST for one of the hormones yielded the sequence for the 3' end of an mRNA encoding preprouroguanylin and was used to clone the remaining portion of the rat cDNA via 5' rapid amplification of cDNA ends. Northern blot analysis of RNA from rat intestine demonstrated that preprouroguanylin mRNA was 2.5-fold more abundant during zinc deficiency. Uroguanylin, a natriuretic peptide hormone, is an endogenous ligand for the same guanylate cyclase C that the Escherichia coli heat-stable enterotoxin (STa) binds when it causes secretory diarrhea by activating the cystic fibrosis transmembrane conductance regulator, thus altering fluid balance in the intestine. This suggests a mechanism whereby zinc deficiency could induce uroguanylin levels in the intestine and cause or potentiate diarrhea.
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PMID:Regulation of intestinal gene expression by dietary zinc: induction of uroguanylin mRNA by zinc deficiency. 1080 50

In normal human colon, water and sodium (Na+) absorption are directly related. Defective Na+ absorption may therefore be an important factor in the pathogenesis of diarrhea in ulcerative colitis (UC). Electrophysiological studies have revealed profound decreases in channel-mediated apical Na+ entry and Na(+)-K(+)-ATPase-mediated basolateral Na+ extrusion in surface epithelial cells in inflamed human distal colon. Recent molecular biological studies indicate that mucosal inflammation in UC leads to significant decreases in Na+ channel beta- and gamma-subunit expression in the apical membrane of surface colonocytes, with a marked reduction in the levels of beta- and gamma-subunit-specific mRNAs. In addition, basolateral expression of the Na(+)-K(+)-ATPase alpha 1-isoform is reduced along the surface cell-crypt cell axis in UC, although there is no change in the level of the corresponding mRNA. Diarrhea in ulcerative colitis is therefore related, at least in part, to a major defect in electrogenic Na+ absorption, which reflects changes in the levels of expression of critical subunits of both the apical Na+ channel and basolateral Na(+)-K(+)-ATPase.
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PMID:Diarrhea in ulcerative colitis. The role of altered colonic sodium transport. 1119 95

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of pantoprazole are reviewed. Pantoprazole is a gastric hydrogen-potassium adenosine triphosphatase (H+/K(+)-ATPase) inhibitor. It shares the same core structure as other currently available proton-pump inhibitors (PPIs). The FDA-labeled indication is the short-term treatment of erosive esophagitis. PPIs act by selectively inhibiting H+/K(+)-ATPase in the secretory canaliculus of the stimulated parietal cell. Understanding the pharmacodynamics of PPIs is more relevant than knowing their pharmacokinetics, since the duration of action depends on the rate of de novo proton-pump regeneration, not the duration of drug circulation in the body. Pantoprazole is well absorbed, undergoes little first-pass metabolism, and has an absolute bioavailability of approximately 77%. Pantoprazole has been evaluated in more than 100 clinical trials involving more than 11,000 patients. It is effective in treating erosive esophagitis and duodenal and gastric ulcers. It is also effective as adjunctive treatment with antimicrobials in patients infected with Helicobacter pylori. Pantoprazole has been shown to control acid production in Zollinger-Ellison syndrome. Pantoprazole is well tolerated. The most commonly reported adverse effects are headache, diarrhea, and abdominal pain. The recommended oral dosage for erosive esophagitis is 40 mg once a day for up to eight weeks. The recommended i.v. dose is 40 mg given over 15 minutes once a day in patients with gastroesophageal reflux disease who are unable to take oral medication. Pantoprazole appears to be as safe and effective as other PPIs in acid-related disorders.
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PMID:Pantoprazole. 1140 94

The colonic epithelium has both absorptive and secretory functions. The transport is characterized by a net absorption of NaCl, short-chain fatty acids (SCFA), and water, allowing extrusion of a feces with very little water and salt content. In addition, the epithelium does secret mucus, bicarbonate, and KCl. Polarized distribution of transport proteins in both luminal and basolateral membranes enables efficient salt transport in both directions, probably even within an individual cell. Meanwhile, most of the participating transport proteins have been identified, and their function has been studied in detail. Absorption of NaCl is a rather steady process that is controlled by steroid hormones regulating the expression of epithelial Na(+) channels (ENaC), the Na(+)-K(+)-ATPase, and additional modulating factors such as the serum- and glucocorticoid-regulated kinase SGK. Acute regulation of absorption may occur by a Na(+) feedback mechanism and the cystic fibrosis transmembrane conductance regulator (CFTR). Cl(-) secretion in the adult colon relies on luminal CFTR, which is a cAMP-regulated Cl(-) channel and a regulator of other transport proteins. As a consequence, mutations in CFTR result in both impaired Cl(-) secretion and enhanced Na(+) absorption in the colon of cystic fibrosis (CF) patients. Ca(2+)- and cAMP-activated basolateral K(+) channels support both secretion and absorption of electrolytes and work in concert with additional regulatory proteins, which determine their functional and pharmacological profile. Knowledge of the mechanisms of electrolyte transport in the colon enables the development of new strategies for the treatment of CF and secretory diarrhea. It will also lead to a better understanding of the pathophysiological events during inflammatory bowel disease and development of colonic carcinoma.
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PMID:Electrolyte transport in the mammalian colon: mechanisms and implications for disease. 1177 14

Genetic disorders of acid-base transporters involve plasmalemmal and organellar transporters of H(+), HCO3(-), and Cl(-). Autosomal-dominant and -recessive forms of distal renal tubular acidosis (dRTA) are caused by mutations in ion transporters of the acid-secreting Type A intercalated cell of the renal collecting duct. These include the AE1 Cl(-)/HCO3(-) exchanger of the basolateral membrane and at least two subunits of the apical membrane vacuolar (v)H(+)-ATPase, the V1 subunit B1 (associated with deafness) and the V0 subunit a4. Recessive proximal RTA with ocular disease arises from mutations in the electrogenic Na(+)-bicarbonate cotransporter NBC1 of the proximal tubular cell basolateral membrane. Recessive mixed proximal-distal RTA accompanied by osteopetrosis and mental retardation is associated with mutations in cytoplasmic carbonic anhydrase II. The metabolic alkalosis of congenital chloride-losing diarrhea is caused by mutations in the DRA Cl(-)/HCO3(-) exchanger of the ileocolonic apical membrane. Recessive osteopetrosis is caused by deficient osteoclast acid secretion across the ruffled border lacunar membrane, the result of mutations in the vH(+)-ATPase V0 subunit or in the CLC-7 Cl(-) channel. X-linked nephrolithiasis and engineered deficiencies in some other CLC Cl(-) channels are thought to represent defects of organellar acidification. Study of acid-base transport disease-associated mutations should enhance our understanding of protein structure-function relationships and their impact on the physiology of cell, tissue, and organism.
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PMID:Genetic diseases of acid-base transporters. 1182 92

IL-1beta is suspected to be involved in the diarrhea that always accompanies inflammatory bowel disease. This work was aimed at studying the in vivo effect of IL-1beta on the net absorption of fluid, Na(+) and Cl(-) from the rat colon, and at delineating its mechanism of action. Rats were injected i.p. with IL-1beta (1 mug/kg body weight) and the colon was perfused, four hours later, with Krebs-Ringer buffer. Net fluid absorption was calculated as the difference between the total volume of the buffer infused and collected per cm(2) of perfused intestine. Chloride in both buffers was determined by titration according to Mohr's method and net Cl- absorption was calculated in the same way. IL-1beta reduced the net absorption of water and chloride. The cytokine also reduced the percentage recovery of the Na(+)-K(+) ATPase activity in crude homogenates of membranes from surface and crypt colonic cells as revealed by the determination of inorganic phosphate released. In addition IL-1beta decreased the protein expression of the Na(+)-K(+) pump and increased that of the NaKCl(2) symporter. It is concluded that IL-1beta has a dual effect: it inhibits the Na(+)-K(+) pump and consequently NaCl absorption, and up-regulates the NaKCl(2) transporter and increases Cl(-) secretion. The ultimate effect of the two processes is a net decrease in Na(+)+ and Cl(-) absorption and an increase in water retention in the colon leading to the observed diarrhea in inflammatory bowel disease.
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PMID:The mechanism by which interleukin-1 beta reduces net fluid absorption from the rat colon. 1223 80


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