ATPase inhibitors, gastric

For control of gastric acid secretion, the H2 antagonists have encountered competition from the potent -ATPase inhibitors such as... 

Gastric H,K-ATPase inhibitors Potassium competitive acid blockers... 

ATC A02BC02 A02BD04 Use antisecretory, gastric HYK -ATPase inhibitor... 

GABA, heterocyclic analogues, 22 (1985) 67 GABAa receptor ligands, 36 (1999) 169 Gas-liquid chromatography and mass spectrometry, 12 (1975) 1 Gastric H /K -ATPase inhibitors, 31 (1994) 233... 

For the specific pharmacological assessment of inhibitors of gastric acid secretion, like H2-blockers, anticholinergics, H+/K+-ATPase inhibitors, this method reveals valid results with respect to the antisecretory potential of the candidate compound. Limitations of this methods with respect to safety pharmacological assessment of candidate compounds are (1) only parenteral administration of the candidate compound, preferentially i.v., is feasible and should be preferred, and (2) only antisecretory putative side effects can be investigated this method is of limited relevance to study secretory side effect potential of candidate compounds. 

Herling and Bickel (1986) showed that gastric acid secretion in stomach-lumen perfused rats can be stimulated in vivo on the subreceptor level by IBMX (phosphodiesterase inhibitor) and forskolin (non-receptor activation of the adenylate cyclase). H+/K+-ATPase inhibitors and H2-antagonists show, according to their different modes of action, also a different inhibitory profile in this assay. 

Gastric acid secretion can be pharmacologically inhibited by specific antagonists of the stimulatory receptors (histamine-Hj, muscarine-Mi/Mj, gastrin), by agonists to inhibitory receptors (prostaglandin, somatostatin), by carbonic anhydrase inhibitors, and by HVK -ATPase inhibitors. 

In contrast to the different types of receptor antagonists, omeprazole, the first HVK -ATPase inhibitor used clinically, causes a comparable inhibition of stimulated gastric acid secretion irrespective of the kind of stimulation Figure 4.3). Acid secretion can be induced in the rat perfused stomach-lumen model by an initial injection of isobutyl-methylxanthine (IBMX, a phosphodiesterase inhibitor) followed by an infusion of forskolin (direct stimulation of adenylate cyclase). This kind of stimulation represents an... 

H2-receptor antagonists are quite effective in some peptic acid disorders (duodenal ulcers, gastric ulcers), whereas their effectiveness in others is less apparent (Zollinger-Ellison syndrome, gastrooesophageal reflux disease) [22]. For such conditions, prolonged and potent reduction of acid secretion caused by H /K -ATPase inhibitors is necessary and results in superiority of omeprazole over H2-receptor antagonists [25, 26]. 

The effect of gastric HVK -ATPase inhibitors on enzyme activity (ATP cleavage) can be studied in vitro with partly purified HVK -ATPase preparations [27]. This assay has been used more effectively to study the mechanism of action of H /K -ATPase inhibitors in detail than to study the structure-activity relationship of such inhibitors [28]. Since HVK -ATPase inhibitors of the omeprazole-type need acid activation and the enzyme assay should be performed at neutral pH values, a pre-incubation period at the lowest possible pH of about 6 was used to initiate the acidic conversion of the test compound into its active principle. This reflects more the chemical instability of the test compound at neutral pH values than its effect during conditions of much higher acidity within the secretory cannaliculus of the parietal cell during acid secretion. Many chemically labile inhibitors are therefore very active in this test system. However, they do not cause an inhibition in more complex test systems and, therefore, are without any practical usefulness [28]. 

Proton transport studies in intact gastric vesicles, which form a pH gradient similar to in vivo conditions, are more suitable for studying the mechanism of action, acid-conversion and structure-activity relationship of H /K -ATPase inhibitors [29-31]. 

The structure-activity relationship of HVK -ATPase inhibitors of the omeprazole type is based on the balance between chemical stability at neutral pH values and acid-induced conversion into the active sulphenamide. Derivatives, which are too unstable at neutral pH, are very active in the test assay of partly purified HVK" -ATPase. This assay has been performed at pH 7.4 after preincubation at pH 6 of the enzyme protein with the derivative to be tested. The high activity was therefore the result of the conversion of the derivative in solutions of neutral pH values and this does not reflect the situation of high acidity within the secretory compartment of the parietal cell [28]. The derivatives which are very unstable at neutral pH do not inhibit gastric acid secretion in vivo because their transformation had already occurred prior to the active principle reaching the target enzyme. Chemically very stable derivatives do not show any inhibitory effect either in vitro or in vivo. 

Systematic synthesis was carried out by Smith Khne French to identify freely reversible, noncovalent inhibitors of gastric H /K -ATPase with a mode of action comparable with SCH 28080. It was expected that gastric HVK -ATPase inhibitors with a shorter duration of action could be of therapeutic interest [155, 156]. This research resulted in the selection of compound SK F 96067 [157] Figure 4.10). 

It has recently been suggested that stimulation of gastric acid secretion across the apical membrane of the gastric parietal cell predominantly reflects the insertion of an active potassium and chloride transporter/ channel rather than direct activation of HVK -ATPase. However, the mechanisms involved in and Cl transport into the gastric parietal cell are still controversial. The presence of a Cl channel in the apical membrane has been confirmed by using established d channel blockers. In vitro in rabbit isolated gastric parietal cells, 9-anthracene carboxylate and the more potent diphenylamine-2-carboxylate inhibit gastric acid formation concen-tration-dependently irrespective of the kind of stimulation [181]. Thus Cl channel blockers can be defined as indirect HVK -ATPase inhibitors. 

GASTRIC PROTON PUMP INHIBITOR, a (H /K ) ATPASE INHIBITOR. It can be used as an ANTIULCEROGENIC in the treatment of gastric ulcers and other gastric acid-related gastrointestinal disorders. It can be used in combination with amoxicillin for eradication of gastric Helicobacter pylori infection. Larafen ketoprofen. 

GASTRIC PROTON PUMP INHIBITOR, a (HVK ) ATPASE INHIBITOR. 

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