Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Patent
1991-07-22
1997-03-04
Housel, James C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
4241841, 530324, 530325, 530326, 530327, 530328, 530329, 530330, 530309, 514 12, 514 13, 514 14, 514 15, 514 16, 514 17, 514 18, C07K 500, A61K 3900, A61K 39385, A61K 3800
Patent
active
056076762
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Peptic ulcer disease exists in two forms, duodenal ulcers and gastric ulcers. Central to the cause of duodenal ulcers, is the production of excess stomach acid and pepsin and a rapid gastric emptying time. This results in an increase in duodenal exposure to secreted acid and enzymes, and in mucosal damage.
The second form of the disorder, gastric ulcer disease, may be caused by increased stomach acid and a breakdown of the complex stomach defenses that normally protect the gastric mucosa from acid damage. Although the two conditions have different etiologies, both benefit from a reduction in gastric acid secretion.
Because excess stomach acid is a central cause of ulcers, antacid preparations are commonly used as one method of treatment. This method merely neutralizes stomach acid after it is produced. Consequently, large quantities of antacids must be consumed on an ongoing basis to neutralize acid which is continually produced in the stomach. Antacids do not cure the disease because they do not affect the source of acid production.
Gastric acid is produced in a specialized stomach cell, the parietal cell. Parietal cells can be stimulated to secrete acid by acetylcholine, histamine and gastrin, upon the binding of each of these compounds with specific receptors on the surface of the cell. Of these the most potent stimulator of acid secretion is the peptide hormone gastrin.
Current approaches to the control and cure of peptic ulcers center upon devising drugs that inhibit the ability of one or more of these compounds to stimulate acid production or secretion. The most effective group of drugs approved for sale are the H2 antagonists (e.g. Tagamet.RTM. and Zantac.RTM.) which block the histamine H2 receptors on gastric parietal cells and inhibit acid secretion. These drugs, however, require relatively large doses on a daily basis and may induce several undesirable side effects. In cases where H2 antagonists have cured ulcers, relapses occur in almost 100% of cured individuals within a year of discontinuation of treatment. Other drugs have also exhibited problems, including low efficacy and unacceptable levels of toxicity. In the case the peptide hormone gastrin, no successful chemical antagonists have been identified.
Gastrin has several important functions in the gastrointestinal tract, the two most important being stimulation of acid secretion and stimulation of the growth of cells in the gastrointestinal tract. The hormone exists in at least two molecular forms, heptadecagastrin ("G.sub.17 ") and tetrateseracontagastrin ("G.sub.34 ") named according to the number of amino acid ("AA") residues in each molecule. G.sub.34 and G.sub.17 are identical in structure at the carboxy terminus, which is the binding site of the hormones with receptors. G.sub.17 constitutes the 17 carboxy terminal ("C-terminal") end residues of G.sub.34. G.sub.34 consists of the 17 C-Terminal end residues which comprise G.sub.17 and an additional different amino acid sequence of 17 amino terminal ("N-terminal") residues. When G.sub.34 is split by trypsin a G.sub.17 subunit and a non-hormonal 17 amino acid subunit results. Though G.sub.17 is usually obtained by trypsin cleavage of G.sub.34, each form may also be generated separately from its own prohormone.
Although G.sub.17 and G.sub.34 are thought to be equipotent on a molar basis as stimulator of acid release, G.sub.34 is most probably responsible for the stimulation of growth of the gastrointestinal mucosa and the maintenance of the basal acidity of the stomach. G.sub.34 is the principal form present during interdigestive periods. G.sub.34 has a serum half life approximately six times as long as G.sub.17 (40 minutes versus 6 minutes) and is produced in both the stomach and the duodenum. Alternatively, G.sub.17 is the primary stimulator of meal-induced gastric acid secretion. G.sub.17 is 1500 times more potent than histamine and makes up 90% of the antral (stomach) gastrin. G.sub.17 accounts for roughly 60%-70% of the gastrin-mediated acid release.
The pr
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Gevas Philip C.
Grimes Stephen
Karr Stephen L.
Littenberg Richard L.
Aphton Corporation
Housel James C.
Minnifield N. M.
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