Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-04-08
2004-02-10
Wang, Shengjun (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C514S826000
Reexamination Certificate
active
06689748
ABSTRACT:
BACKGROUND INFORMATION
This invention relates to the treatment of diseases induced by biochemicals released from activated mast cells. More particularly, the invention relates to treatment of mast cell-induced diseases such as allergies, interstitial cystitis, inflammatory bowel disease, irritable bowel syndrome, and certain hyperproliferative diseases such as systemic mastocytosis with a proteoglycan without or with functionally synergistic flavonoids and/or heterocyclic antagonists of histamine receptors.
Mast cells are a normal component of connective and mucosal tissues and play an important role in allergy and inflammation. They are localized in the connective tissues, but also in the mucosa of the bladder, gastrointestinal tract, lung and nose, as well as in the skin and the meninges of the brain. They are located there because these tissues are the main entry points for infective organisms, allergens and other noxious chemicals that trigger the body's immune response.
Mast cells derive from the bone marrow and migrate into the tissues where they synthesize and can secrete numerous vasoactive, nociceptive and inflammatory mediators. (Galli, S. J.
N. Engl. J. Med
. 328:257, 1993). They are located perivascularly close to nerve endings and can be activated by a variety of neuroimmunoendocrine triggers. (Theoharides, T. C.
Int. J. Tissue React
. 18:1, 1996).
Mast cells are located at strategic points around capillaries and small blood vessels, where they are important in regulating the extent of constriction or dilation of the vessels including those which make up the blood-brain barrier, the protective lining of the brain which excludes toxic materials (Theoharides, T. C.,
Life Sciences
46:607, 1990).
Each mast cell contains up to 500 secretory granules, each storing more than 20 potent biological compounds. Mast cells secrete the contents of these granules (i.e., degranulate) when triggered by various specific and non-specific mechanisms, such as the allergic reaction involving immunoglobulin E (IgE) and antigen (Ag). Notable among non-allergic triggers are certain polysaccharides or monosaccharide-containing lectins such as dextran and concanavalin A (Baxter, J. H. et al,
Biochemical Pharm
. 27:497, 1978). Other known triggers include the neurotransmitter acetylcholine, various neuropeptides such as calcitonin-gene-related peptide (CGRP), corticotropin-releasing hormone (CRH), neurotensin (NT), substance P (SP), somatostatin and vasoactive intestinal peptide (VIP), as well as viruses, bacterial toxins, drugs (such as aspirin, morphine and curare), contrast media used in radiology, extreme heat, cold, solar radiation, hyperosmotic media and pressure (Theoharides, ibid.).
Compounds released by mast cell degranulation, collectively referred to as mediators or activators, include: histamine, kinins, prostaglandin D
2
and vasoactive intestinal peptide, which are vasodilatory, as well as serotonin, prostaglandin F
2
-alpha and leukotrienes, which are vasoconstrictive. In addition, cytokines, histamine, kinins and prostaglandins can cause pain directly, while enzymes that destroy proteins and phospholipids can cause tissue damage directly. Finally, cytokines can cause inflammation and regulate other biological responses (Galli, S. J., above).
The compounds released by the mast cells following degranulation are known to cause many biological responses which are part of the overall response of the body to invasion by infective organisms, allergens or other stressful stimuli. Degranulation will be defined herein as the release of any or all mediators from any or all secretory granules, whether in parallel, sequentially, differentially or selectively. Relevant examples of such responses are vasodilation and recruitment of inflammatory cells (e.g. leukocytes) from the circulation, tearing, nasal secretions, bronchoconstriction, itching of the skin, diarrhea or bladder pain.
Histamine and the other mediators are secreted from the granules of mast cells during degranulation. The histamine and other mediators then bind to specific receptors on the surface of endothelial cells on vessels, neurons or other tissues. Vasodilation and chemoattraction permits lymphocytes to leave the blood circulation and enter the tissue, where they cause additional mast cell degranulation and other responses. The process of degranulation continues, eventually involving many mast cells. It is important to note that there are no clinically available drugs with mast cell secretion inhibitory activity. Anti-histamines, properly known as histamine receptor antagonists, act only after histamine is released (Theoharides, T. C.,
Drugs
37:345, 1989). They neither block the secretion of histamine or other mediators nor the action of any other mediators. Disodium cromoglycate (cromolyn) is called a “mast cell stabilizer” and is available for rhinitis, asthma and food allergies, but its action is short-lived, it is only partially effective, it does not affect all mast cells and it is difficult to put in solution (Shapiro, G. G. et al.,
Pharmacotherapy
5:156, 1985).
The common form of interstitial cystitis (IC) is the “early” or non-ulcer variety with normal bladder capacity and the absence of inflammation. The role of mast cells in the bladder has acquired increased significance since it was shown that mast cells in this tissue can be activated with or without an increase in their numbers (Theoharides, T. C. et al.,
Sem. Urol
., 9:74, 1991). Moreover, acute immobilization stress results in bladder mast cell degranulation (Spanos et al.,
J. Urol
.,157:669, 1997).
Mucosal mast cells have also been implicated in irritable bowel syndrome (IBS) (Weston, A. P., et al.,
Digestive Diseases and Sciences
38:1590, 1993) where are increased in numbers and/or activated to various degrees. (Pang, X. et al.,
Urology
47:436, 1996). Moreover, histamine and prostaglandins have been involved in gastrointestinal permeability and related diarrhea syndromes. (Castaglluolo, I. et al.,
Am. J. Physiol
. 271:884, 1996). Recent studies have shown that acute stress by immobilization leads to gastrointestinal mast cell activation, a process blocked by pre-treatment with neutralizing antiserum to corticotropin releasing hormone (CRH) which is liberated under stress (Castaglluolo, I. et al., above). We further showed that CRH can induce mast cell degranulation and increased vascular permeability directly (Theoharides, T. C., et al.,
Endocrinology
139:403, 1998).
The term inflammatory bowel disease (IBD) is used to describe a variety of disorders. Crohn's disease, as well as various forms of infectious diarrhea, such as that due to
Clostridium difficile
which is called pseudomembranous colitis, are the most common forms of inflammatory conditions of the intestine. Recent evidence (discussed above) indicates that mast cells exist in the mucosa of the small intestine and that they are different from mast cells in other, especially connective tissues. Moreover, they have also been shown to be in close apposition to nerve endings, suggesting that they may be affected by the nervous system. In fact, gastrointestinal membranes are activated in Crohn's disease (Dvorak et al.,
Int. Arch. Allergy Immunol
., 98:158, 1992).
Mast cell secretion was shown to be stimulated by parathyroid hormone (PTH) in vitro (Tsakalos, N. D. et al.,
Biochemical Pharmacology
32:355, 1983). In addition, PTH was shown to increase mast cell accumulation in bone (Rockoff, S. D. et al.,
Calc. Tiss. Res
. 5:49, 1970). Molecules secreted from mast cells may increase bone resorption, leading to a net loss of bone loss, and eventually resulting in osteoporosis in susceptible individuals. In fact, osteoporosis was seen as the sole presentation of bone marrow mastocytosis in humans (Lidor, C., et al.,
Journal of Bone and Mineral Research
5:871-876, 1990). During an investigation of the bone response to calcium deficient diets over time, dramatic increases in the numbers of mast cells were observed in the metaphyseal region of tibia, which showed o
Blecher Melvin
Law Offices of Dr. Melvin Blecher
Theoharides Theoharis C.
Wang Shengjun
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