Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-12-22
2003-09-23
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S051000
Reexamination Certificate
active
06624150
ABSTRACT:
TECHNICAL FIELD
This invention relates to a method of regulating mucus secretions and fluid transport in the gastrointestinal system of a patient by administering purinergic receptor agonists such as certain uridine, adenine, or cytidine 5′-di- and triphosphates, dinucleoside polyphosphates and their analogs thereof.
BACKGROUND OF THE INVENTION
There are many situations where it is therapeutically desirable to increase the amount of mucin secretion, bicarbonate secretions, and/or degree of hydration in gastrointestinal systems. The gastrointestinal system operates principally to extract energy and metabolic building blocks from the nutrient materials presented to it. The digestive tract includes the buccal cavity (primary salivary glands), esophagus, stomach, small intestine, large intestine, rectum, and ancillary organs (pancreas, liver and gall bladder). When the mucosal barrier is impaired in the digestive tract, it results in diseases such as dry mouth, gastro-esophageal reflux disease, peptic ulcer, inflammatory bowel disease, etc. Abnormal fluid and electrolytic transport in the lower gastrointestinal tract results in disorders such as constipation and diarrhea.
Mucus is a viscous material that coats many epithelial surfaces and is secreted into fluids such as saliva. It is composed chiefly of mucins and inorganic salts suspended in water. Mucus adheres to many epithelial surfaces, where it serves as a diffusion barrier against contact with noxious substances (e.g. gastric acid, digestive enzymes and bacteria) and as a lubricant to minimize shear stresses. Such mucous coatings are particularly prominent on the epithelia of the gastrointestinal, respiratory and genital tracts. Mucous is also an abundant and important component of saliva, giving it virtually unparalleled lubricating properties. Mucus-secreting cells such as goblet cells are abundant in the epithelium of the gastrointestinal tracts. Numerous submucosal mucous glands are scattered along the esophagus and especially accumulated below the upper and above the lower esophageal sphincters. Many of the acinar epithelial cells in salivary glands secrete mucus. The major structural molecules of the mucus layer are mucins, which are a family of large, heavily glycosylated proteins. The dense “sugar coating” of mucins gives them considerable water-holding capacity and makes them resistant to proteolysis, which may be important in maintaining mucosal barriers.
Bicarbonate secretion plays an important role in the maintenance of mucosal health in the gastrointestinal tract. The production of bicarbonate and mucus by the esophagus in response to local acidification provides an inherent mechanism for resisting acid-induced damage. The secretion of salivary protective factors, including bicarbonate, as well as bicarbonate secreted from esophageal submucosal glands, are important in preventing esophageal mucosal injury associated with gastrointestinal reflux disease. Mucosal bicarbonate also provides an important mechanism for protection against acid damage in the proximal duodenum, in which adherent mucus provides a stable protective layer supporting surface neutralization of acid by mucosal bicarbonate. [Nucleotides stimulate bicarbonate secretion in guinea pig pancreatic duct (Ishiguro el al 1999, J. Physiol. 519 Pt 2:551-558) and CFTR knockout mouse gall bladder epithelium (Clarke et al. 2000, Am. J Physiol. Gastrointest. Liver Physiol. 279:G132-138)].
Proper regulation of fluid and electrolytic absorption and secretion at appropriate regions along the gastrointestinal system is required for normal digestive function. Impairment of fluid transport leads to a variety of disorders, including constipation and diarrhea. Constipation is associated with a delay in the transit of fecal matter through the large intestine. The increased resident time of feces in the large intestine leads to increased fluid absorption by the colonic epithelium, and results in dehydration of feces and the subsequent production of dry, hard feces in the descending colon. Conversely, diarrhea results from rapid movement of fecal matter through the large intestine, resulting from either increased fluid secretion in the small intestine or by reduced fluid absorption in the colon.
Xerostomia, commonly known as dry mouth, results from the underproduction of saliva. Dry mouth is caused by radiation treatment or diseases that damage salivary glands and decrease salivary flow. Gastroesophageal reflux disease is the condition where the degree of exposure of esophageal mucosa to gastric contents is greater than normal. The most common manifestation is heartburn. Pharmacological treatment involves the use of H2 antagonists (e.g., Tagamet®, Zantac®, Pepcid®, Axid®) and proton pump inhibitors such as Prilosec® or Prevacid®, for treatment of acute disease. Peptic ulcer diseases include gastric ulcer, pyloric channel ulcer and duodenal ulcer. Ulceration results from a complex interplay of acid and chronic inflammation induced by
Helicobacter pylori
infection. Patients with duodenal ulcers have high acid secretion. Increased acid secretion causes changes in the wall of the duodenum, setting the stage for invasion by
H. pylori
. Drugs for treating peptic ulcer diseases include Histamine-2 (H2) blockers (Tagamet®, Zantac®, Axid®, Pepcid®, etc.), sucralfate, proton pump inhibitors, and antacids. Inflammatory bowel disease is classified into two types: ulcerative colitis and Crohn's disease. Ulcerative colitis affects the colon/rectum and involves the mucosa or the innermost lining of the colon wall. Crohn's disease is a transmural disease involving all layers of the bowel and may involve any part of the gut, from mouth to anus. Medical treatment of inflammatory bowel disease includes aminosalicylates and corticosteroids. Corticosteroids have substantial long-term toxicity. As an alternative to conventional therapies, medical researchers have sought to develop new treatments for gastrointestinal diseases.
The following references disclose the role of mucus integrity and mucin secretion in some diseases of the gastrointestinal tract. Rhodes et al. (
Gut,
26:1312-1318 (1985)) suggested that colonic mucus undergoes continual desulphation and desialation in vivo as a result of faecal enzyme activity; altered susceptibility of colonic mucus may be important in the pathogenesis of colonic disease. Somasundaram et al. (
Clin. Exp. Pharmacol. Physiol.,
14:309-318 (1987)) report that the integrity of the gastric mucosa and its ability to secrete mucus are essential for protection of gastric mucosa against ulceration induced by aggressive factors active in any stress situation. Desai et al. (
J. Pharm. Pharmacol.
47:734-738 (1995)) showed that SKF 38393, a specific dopamine D1-receptor agonist, was effective in preventing gastric and duodenal ulceration in rats. Sarosiek et al. (Digestion, 56 Suppl. 1 :15-23 (1995)) reported that the rate of secretion of esophageal mucin, EGF and PGE2, under the impact of HC1/pepsin in patients with reflux esophagitis, was significantly impaired. Saitoh et al. (
Dig. Dis. Sci.
41:1768-1774 (1996)) showed that compared with healthy subjects, the total yields of mucin from ulcerative colitis patients were low due to a deficiency of neutral mucin, whereas those from Crohn's disease patients were high due to high-molecular weight mucin. Sarosiek et al. (
Gastroenterology,
10:675-681 (1996)) suggest that an increase in the secretion rate of inorganic and organic protective components in saliva may be useful to the treatment of gastroesophageal reflux disease. Zeeh (
Gastroenterology,
110:1 077-1083 (1996)) reported that administration of keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats. Abbas et al. (
Indian J Exp. Biol.
36:182-186 (1998)) report that the antiulcerogenic effect of GABA and baclofen may be due to their predominant effects on mucosal defensive factors like enhanced mucin secretion and decreased cell shedding or mucosal damage. Nath et al. (
Clin.
Cowlen Matthew
Pendergast William
Peterson Ward M.
Rideout Janet L.
Shaver Sammy Ray
Fay Zohreh
Halluin Albert P.
Howrey Simon Arnold & White , LLP
Inspire Pharmaceuticals Inc.
Kung Viola T.
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