Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Acyclic nitrogen double bonded to acyclic nitrogen – acyclic...
Patent
1996-07-11
1999-05-18
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...
514166, A61K31/63;31/615
Patent
active
059050730
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
1. Technical Field
This invention is related to colon cancer chemoprevention and chemotherapy.
2. Background Art
Colon cancer currently accounts for 11% of all deaths due to malignancy annually in the United States. With an incidence of 62 per 100,000 and a prevalence of 300 per 100,000, the disease is currently the third leading cause of death in men and the fourth leading cause of death in women. Colon cancer has a particularly poor five-year survival rate of less than 50%, due to the late stage at which diagnosis is generally made. The currently favored treatment, surgery combined with chemotherapy, has failed to increase this survival rate. What is needed is a safe and effective preventive therapy which could be initiated early in patient populations known to be at an increased risk of developing colon cancer.
Eicosanoids and Differentiated Functions of Gastrointestinal Cells. Eicosanoids are significant regulators of gastrointestinal epithelial cell growth, differentiation and function. Eicosanoid products of the prostaglandin series are known to induce mucus secretion (Beckel and Kauffman (1981) Gastroenterology 80:770-776) and the secretion of electrolytes and fluid (Miller (1983) Am. J. Physiol. 245:G601-G623). They also induce active transport (Bukhave and Rask-Madsen (1980) Gastroenterology 78:32-37) and increase the replicative capacity of the epithelium (Konturek et al. (1981) Gastroenterology 80:1196-1201). These responses result in the maintenance of a differentiated, protective barrier system of tightly joined epithelial cells whose apical surface are covered by a dense glyco-conjugate chemical buffer. In the stomach and upper duodenum such a barrier protects against the acidic and proteolytic environment elaborated for digestion, while in the colon it protects against the invasion of bacteria and toxins. It is therefore not surprising that exogenous, synthetic prostaglandins are actively cytoprotective (Whittle and Vane (1987) In: Johnson (ed.) PHYSIOLOGY OF THE GASTROINTESTINAL TRACT, Vol. 1, 2nd ed., New York: Raven Press, pp. 143-180) and have found therapeutic utility as secondary anti-ulcer treatments. The gastrointestinal ("GI") system has therefore evolved to actively produce and rely on a specific differentiated complement of eicosanoid products present in the local environment. As all eicosanoids are derived from the common precursor arachidonic acid, which is itself liberated from membrane phospholipids, GI mucosal cells have a relatively high basal level of arachidonate turnover initiated by the enzyme phospholipase A.sub.2 (PLA.sub.2).
The GI system is also a primary defense mechanism against environmental bacteria, antigens and toxins and must therefore also possess the ability to mount an aggressive and rapid inflammatory response. This response also relies upon eicosanoid products of both the prostaglandin (PG) series as well as the chemotactic leukotriene series (LTs) and results in the influx of blood-borne neutrophils, macrophages and immune cells in response to the activating agent. Each of these invading cells also brings with it a capacity to metabolize its own phospholipids as well as mucosal and luminal phospholipids by releasing inflammatory (secreted) PLA.sub.2 to amplify the release of arachidonic acid, which is then metabolized into both PGs and LTs.
Although the inflammatory cell infiltration confines and destroys the offending stimulus, the extent of damage due to inflammatory cell release products is significant. Neutrophils and macrophages release superoxide (O.sub.2.sup.-) (Kitahora et al. (1988) Dig. Dis. Sci. 33:951-955) as well as hydrogen peroxide (H.sub.2 O.sub.2) (Tauber and Babior (1985) Free Radic. Biol. Med. 1:265-307), and proteases (Ohlsson et al. (1977) Hoppe Seylers Z. Physiol. Chem 358:361-366). Where the resultant infiltration is extensive, significant denudation of the epithelial layer occurs with a subsequent compromise of the barrier function. Resolution of the inflammatory response is then required to regain final optimal epith
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Johnson Lorin K.
Sleisenger Marvin H.
Goldberg Jerome D.
Salix Pharmaceuticals, Inc.
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