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Yale J Biol Med. 1996 May-Jun;69(3):233-43.

Current status of acid pump antagonists (reversible PPIs).

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Byk Gulden Pharmaceuticals, Konstanz, Germany.


The introduction of H2-receptor antagonists in the mid-1970s provided, for the first time, acceptable medical therapy for acid-related diseases. Their short duration of action and single receptor targeting, however, limited satisfactory treatment of patients. Today the control of gastric acid secretion can be effectively achieved by direct inhibition of the H+, K(+)-ATPase. Inhibition of the proton pump suppresses acid secretion independent of the route of stimulation. Two classes of drugs are able to inhibit the proton pump. First, the substituted benzimidazoles (proton pump inhibitors [PPIs]), which, due to their pKa of about 4, accumulate in the acidic secretory canaliculus of the stimulated parietal cell. Following conversion to a cationic sulfenamide, they react with cysteines on the extracytoplasmatic face of the H+, K(+)-ATPase subunit. Second, acid pump antagonists (APAs) acting by K(+)-competitive and reversible binding to the gastric proton pump, which is the final step for activation of acid secretion in the parietal cell. One possible class of APAs are imidazopyridines. BY841 was selected from this class and is chemically a (8-(2-methoxycarbonylamino-6-methyl-phenylmethylamino )-2,3-dimethyl-imidazo [1,2-a]-pyridine). In pharmacological experiments such as pH-metry in the conscious, pentagastrin-stimulated fistula dog, BY841 proved to be superior to both ranitidine and omeprazole by rapidly elevating intragastric pH up to a value of 6. The duration of this pH elevation in the dog was dose-dependent. As was predicted by the above-mentioned dog model, available clinical phase I data confirm dose-dependent pharmacodynamics of BY841 in man. Using both acid output and continuous 24-hr pH measurements, a pronounced antisecretory effect of BY841 has been found. Actually, a single 50 mg oral dose of BY841 immediately elevated intragastric pH to about 6. Higher doses caused a dose-dependent increase in duration of the pH-elevation, without any further increase in maximum pH values. Twice daily administration was more effective than once a day administration of the same daily dose. With both regimens, the duration of the pH-elevating effect of BY841 further increased upon repeated daily administration. This demonstrates lack of tolerance development, the latter being a well-known disadvantage of H2-receptor antagonists. In comparison with the standard dose of omeprazole, BY841 administered at a dose of 50 mg or 100 mg twice daily is markedly more effective on Day one of treatment, and both doses are at least as potent as omeprazole following repeated daily administration.

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