Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-12-20
2002-10-15
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S048000, C514S263100, C435S007200, C435S004000
Reexamination Certificate
active
06465441
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the modulation of human mast cell activation by compounds which modulate adenosine 5′-triphosphate (ATP) binding to ATP receptors (P2-purinoceptors) on the cells. The invention further relates to the treatment of disorders characterized by undesirable mediator release from stimulated mast cells, particularly immunologically stimulated lung mast cells. The invention also relates to methods for in vitro screening of candidate therapeutic agents for treating such disorders.
BACKGROUND OF THE INVENTION
Mast Cells
Mast cells comprise a normal component of the connective tissue that plays an important role in immediate (type I) hypersensitivity and inflammatory reactions by secreting a large variety of chemical mediators from storage sites in their granules upon stimulation. Mast cells, and their circulating counterparts the basophils, possess surface receptors known as Fc&egr;RI. The receptors are specific for antibody &egr; heavy chains.
The event that initiates immediate hypersensitivity is the binding of antigen to IgE on the mast cell or basophil surface. Both cell types are activated by cross-linking of Fc&egr;RI molecules, which is thought to occur by binding multivalent antigens to the attached IgE molecules.
Mast cells may also be activated by mechanisms other than cross-linking Fc&egr;RI, such as in response to mononuclear phagocyte-derived chemocytokines, to T cell-derived cytokines and to complement-derived anaphylatoxins. Mast cells may also be recruited and activated by other inflammatory cells or by neurotransmitters which serves as links to the nervous system.
When antigen binds to IgE molecules attached to the surface of mast cells, a variety of mediators are released which give rise to increased vascular permeation, vasodilation, bronchial and visceral smooth muscle contraction, and local inflammation. In the most extreme form of immediate hypersensitivity reaction known as anaphylaxis, mediators released from mast cells can restrict airways to the point of asphyxiation. So-called atopic individuals, who are prone to develop strong immediate hypersensitivity responses, may suffer from asthma, hay fever or chronic eczema. These individuals possess higher than average plasma IgE levels.
Antigens that elicit strong immediate hypersensitivity reactions are known as allergens. Allergy afflicts twenty percent of the United States population.
Immediate hypersensitivity results from the following sequence of events: production of IgE by B cells in response to antigen, binding of the IgE to Fc&egr;RI on the surface of mast cells, interaction of re-introduced antigen with the bound IgE and activation of the mast cells and release of mediators. Antigen binding can be simulated by polyvalent anti-IgE or by anti-Fc&egr;RI antibodies. Such antibodies can activate mast cells from atopic as well as non-atopic individuals, whereas allergens activate mast cells only in atopic persons.
Mediators released from mast cells may be divided into two broad classes, pre-formed or secretory granule associated mediators and nonpreformed or newly synthesized mediators. The pre-formed mediators include biogenic amines, most notably histamine. The pre-formed mediators also comprise granule macromolecules such as proteoglycans, most notably heparin and chondroitin sulfate E; chemotactic factors such as eosinophil and neutrophil chemotactic factors of anaphylaxis; and enzymes such as proteases, tryptase, chymase, cathepsin G-like enzyme, elastase, carboxypeptidase A and acid hydrolases. The nonpreformed mediators include products of arachidonic acid, prostaglandin D
2
, leukotrienes C
4
and B
4
and platelet activating factor. Another class of mediators, the cytokines, are produced by mast cells upon IgE-mediated activation, or by other cells, including recruited T
H
2 lymphocytes. The cytokines are predominantly responsible for the late phase reaction which begins two to four hours after elicitation of many immediate hypersensitivity reactions. One cytokine, tumor necrosis factor alpha, may exist in the mast cells as preformed stores, or may represent a newly synthesized product released over a period of hours.
Mediators released from human mast cells are central to the pathophysiology of allergy, asthma and anaphylaxis. In particular, mast cells and their release of histamine and other mediators play an important role in the symptomatology of asthma and other human diseases. During the early phase of human lung hypersensitivity reactions upon exposure to antigen (i.e., pollens, cats, etc.), mast cells release and are the major source of histamine, and newly synthesized lipid products of arachidonic acid metabolism: prostaglandin D
2
and leukotriene C
4
. These mediators produce immediate breathlessness, which subsides in one hour but returns within 2-4 hours (the “late phase” response). Attesting to their primal role in hypersensitivity responses, human lung mast cells (HLMC) are characterized by mRNA generation, protein synthesis and release of so-called T
H
2 cytokines within these first few hours of activation. These cytokines including IL-5, and IL-13 are believed to be central to the evolution of chronic allergic/asthmatic states. In the lung, only mast cells are a source of histamine. Thus, histamine release is a distinct marker of mast cell activation and behavior. For a review of the role of mast cells in inflammatory responses in the lung, see Schulman,
Critical Reviews in Immunology,
13(1):35-70 (1993), the entire disclosure of which is incorporated herein by reference.
Clinically, asthma is recognized by airway hyperactivity and reversible airways obstruction. Pathological derangements at the tissue level include constriction of airway smooth muscle, increased vascular permeability resulting in edema of airways, outpouring of mucus from goblet cells and mucus glands, parasympathetic nervous system activation, denudation of airway epithelial lining cells, and influx of inflammatory cells. Underlying these tissue effects are direct effects of potent mediators secreted following physical, inflammatory, or immunological activation and degranulation. The early phase of the asthmatic reaction is mediated by histamine and other mast cell mediators that induce rapid effects on target organs, particularly smooth muscle. The pathophysiologic sequence of asthma may be initiated by mast cell activation in response to allergen binding to IgE. Evidence exists to link exercise-induced asthma and so-called “aspirin-sensitive” asthma to HLMC degranulation.
Pharmacologic Modulation of Mast Cell Function
A limited number of pharmacologic agents have been tested for effect on HLMC activation-secretion. The beta-adrenergic agonist pharmacologic agents, as typified by fenoterol, are the most potent global inhibitors of HLMC. Though widely touted as “mast cell stabilizers,” disodium cromoglycate and nedocromil sodium poorly inhibit purified HLMC histamine release. While certain corticosteroids have been found to suppress IgE-mediated generation of late-phase cytokine mRNA and protein (e.g., IL-5), release of early phase mediators (e.g., histamine and LTC
4
) are unaffected by corticosteroids. HLMC release has been shown to be inhibited by the immunosuppressant agents FK-506, cyclosporin A and auranofin. Arachidonate pathway inhibitors are of considerable importance, they may leave the release of other allergic mediators (e.g., histamine, proteases) unaffected. Such arachidonate pathway inhibitors include inhibitors of 5-lipoxygenase and inhibitors of cyclooxygenase.
Adenosine and Adenosine Triphosphate
ATP is found in every cell of the human body; it plays a major role in cellular metabolism and energetics. ATP is released into the extracellular fluid under physiologic and pathophysiologic conditions. For example, ATP is released from ischemic cells, activated platelets, apoptotic and necrotic cells, nerve terminals as a co-transmitter, and muscle fibers during exercise. Inhalation of aerosolized ATP has been shown to trigger bronchoconstriction in h
Pelleg Amir
Schulman Edward S.
Drinker Biddle & Reath LLP
Duska Scientific Co.
Fay Zohreh
Kwon Brian-Yong
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