Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-19
2004-08-10
Russel, Jeffrey Edwin (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S262000
Reexamination Certificate
active
06774128
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to methods for preventing or treating gastrointestinal (GI) disorders. In one aspect, the invention provides methods for treating the disorders by modulating nitric oxide (NO) signaling pathways particularly in GI neurons. Methods of the invention typically involve administering at least one compound that modulates the pathway by increasing one or more of NO activity or levels of neuronal nitric oxide synthase (nNOS). The invention has a wide spectrum of useful applications including treating a variety of gastropathies by administering a therapeutic amount of at least one ofinsulin or a phosphodiesterase (PDE) inhibitor such as sildenafil (Viagra™).
2. Background
Hypomotility is one feature of a wide spectrum of gastrointestinal (GI) disorders. For example, gastric hypomotility accompanied by delayed emptying has been described. Stasis impacting the intestine, for example, is also known. See generally McCallum, R. W.(1989) in
Gastrointestinal Disease,
4
th
ed. (Sleisenger, M. H. and Fordtran, J. S. eds.) W. B. Saunders Co., Philadelphia; and references cited therein.
Symptoms of most GI disorders generally include nausea, vomiting, heartburn, post-prandial discomfort and indigestion. In some instances, acid reflux within the GI tract can cause ulceration leading to internal bleeding and infection. The pain associated with many of the GI disorders can lead to costly and potentially life-threatening misdiagnoses of asthma or myocardial infarction. See Brunton, L. L. in
The Pharmacological Basis of Therapeutics,
8
th
ed. (Gilman, A. G et al. eds) McGraw-Hill, Inc. New York.
Particular diseases are associated with hypomotility or stasis in the GI tract. For example, diabetic neuropathy, anorexia nervosa, and achlorhydria are frequently accompanied by gastric hypomotility. Damage to the GI tract following surgical intervention, for instance, can result in substantial gastric stasis.
Current treatment of gastric hypomotility generally involves administration of a prokinetic agent, typically domperidone, cisapride, or metoclopramide. It has been reported however that such drugs do not always impact gastric stasis and may be associated with side-effects. See Brunton, L. L., supra.
Diabetes is a common disorder worldwide resulting in significant complications including GI dysfunction. gastrointestinal dysfunction. See Porse, D. and Halter, J. B. (1999) in
Diabetic Neuropathy
(Dyck, P. J. and Thomas, P. K, eds) W. B Saunders Co. Philadelphia, Pa.; and Poster, D. W. (1998) in
Harrison's Principles of Internal Medicine
(A. S. Fauci et al. eds) McGraw-Hill New York.
There have been attempts to study human diabetes by employing animal models. Such models include streptozotocin-induced (STZ-induced) diabetes and rodent mutants such as NOD (non-obese diabetic) mice.
There has been recognition that diabetic gastropathies involve perturbation in the normal relaxation of the pyloric sphincter; an organ that helps coordinate gastric emptying.
The NOS enzyme has attracted much attention. Under appropriate conditions, the enzyme produces nitric oxide (NO). See e.g., U.S. Pat. Nos. 5,439,938; 6,103,872; and 6,168,926 to S. H. Snyder et al. for general disclosure relating to NOS and NO. See also Zakhary, R. et al. (1997)
PNAS
(
USA
) 94: 14848.
There is almost universal recognition that NO functions as a neurotransmitter. There is emerging evidence that NO provides functions in the GI tract, particularly the intestine, stomach and pylorus. See e.g, Huang, P. L. et al. (1993)
Cell
75: 1273.
In particular, loss of pyloric nNOS has been associated with gastric outflow obstruction. NO has also been implicated in reducing of isolated pyloric pressure waves, altering distribution of liquid glucose within the stomach, slowing gastric emptying, and reducing stomach tone.
There have been problems establishing firm relationship between NO effects and GI function.
For example, there is belief that NO may inhibit gastric emptying in humans, although in some animal models, nNOS is thought to delay that process. In addition, it has been difficult to establish how nNOS expression is regulated, particularly in vivo. These and other drawbacks have impeded efforts to develop therapies that involve increasing or decreasing endogenous NO levels.
There is general understanding that cyclic guanosine monophosphate (cGMP) is an important cell messenger molecule. Enzymes termed phosphodiesterase (PDE) are primarily responsible for destroying cGMP, typically by catalyzing hydrolytic reaction between the cGMP and water. There have been reports of ten (10) PDE families with each have a distinctive tissue, cellular and subcellular distribution. Some PDE families are thought to prefer cyclic adenosine monophosphate (cAMP) as a substrate instead of cGMP.
Numerous PDE inhibitors have been disclosed. For example, PDE type III and IV inhibitors have been reported. See eg., U.S. Pat. Nos. 4,753,945; 4,837,239; 4,971,972; 5,091,431; 6,054,475; 6,127,363; and 6,156,753; as well as referenced cited therein. See also Komas et al. in
Phosphodiesterase Inhibitors
(1996) (Schudt et al. eds) Academic Press, San Diego, Calif.
Particular attention has focussed on inhibitors of type V PDE, one of the cGMP preferred enzymes. For example, certain of the inhibitors such as sildenafil (Viagra™) have been reported to treat male erectile dysfunction. See e.g, U.S. Pat. Nos. 6,100,270; 6,207,829 and references cited therein.
There has been much work addressing the biological action of insulin. See generally Kahn, C. R. et al in
The Pharmacological Basis of Therapeutics
, 8
th
ed. (Gilman, A. G et al. eds) McGraw-Hill, Inc. New York.
See also U.S. Pat. Nos. 4,916,212; 4,701,440; H245 filed on Jun. 27, 1984; U.S. Pat. Nos. 4,652,547; and 4,652,525 (disclosing a variety of insulin molecules).
It would be useful to have methods for treating gastrointestinal (GI) disorders that involve modulating nitric oxide (NO) signaling. It would be especially desirable to have methods for treating GI disorders that enhance or preferably restore normal NO signaling in the presence of pathological levels of neuronal nitric oxide synthase (nNOS).
SUMMARY OF THE INVENTION
The present invention generally includes methods for preventing or treating gastrointestinal (GI) disorders. In one aspect, the invention provides methods for treating the disorders by modulating nitric oxide (NO) signaling pathways particularly in GI neurons. Preferred invention methods involve administering at least one compound that modulates the pathways by increasing one or more of NO activity or levels of neuronal nitric oxide synthase (nNOS). The invention has a wide spectrum of useful applications including treating a variety of gastropathies by administering a therapeutic amount of at least one of insulin or a phosphodiesterase (PDE) inhibitor such as sildenafil (Viagra™).
We have discovered that by modulating NO signaling pathways in GI neurons it is possible to prevent or treat a wide spectrum of disorders. In particular, it has been found that particular NO signaling pathways are damaged in many mammalian GI disorders. Preferred invention methods generally prevent or treat such disorders by enhancing activity of certain identified molecules in the pathway, typically the NO molecule or the enzyme that facilitates production of that molecule ie., the nNOS enzyme. Preferred invention methods suitably increase and more preferably restore normal neuronal NO signaling, thereby helping to prevent, reduce the severity of, or eliminate symptoms associated with many GI disorders.
More particularly, we have found that many, if not all, GI disorders are associated with abnormal neuronal NO signaling. For example, and as will be discussed below, it is believed that many such disorders involve loss of key NO signaling molecules, particularly nNOS enzyme and the NO molecule. Downstream signaling pathways are thought to suffer from this loss. Without wishing to be bound to theory, that loss of
Ferris Christopher D.
Snyder Solomon H.
Watkins Crystal C.
Foley & Lardner LLP
Johns Hopkins University
Russel Jeffrey Edwin
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