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  Pharmaceutical compositions comprising an adenosine receptor agonist or antagonistUSPTO Application #: 20060084626Title: Pharmaceutical compositions comprising an adenosine receptor agonist or antagonist Abstract: Adenosine receptor agonists, particularly an agonist which binds to the A3 adenosine receptor, are used for induction of production or secretion of G-CSF within the body, prevention or treatment of toxic side effects of a drug or prevention or treatment of leukopenia, particularly drug-induced leukopenias; and inhibition of abnormal cell growth and proliferation. (end of abstract)
Agent: Browdy And Neimark, P.l.l.c. 624 Ninth Street, Nw - Washington, DC, US Inventor: Pina Fishman USPTO Applicaton #: 20060084626 - Class: 514046000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Purines (including Hydrogenated) (e.g., Adenine, Guanine, Etc.), Adenosine Or Derivative The Patent Description & Claims data below is from USPTO Patent Application 20060084626. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention is generally in the field of cancer and concerns a cancer therapy or a therapy intended to counter the side effect of cancer treatment. BACKGROUND OF THE INVENTION [0002] Myelotoxicity is a prevailing, severe, complication of chemotherapy and is one of the factors that limit the administrable dose of the chemotherapeutic drug. It causes more life threatening patient morbidity and actual mortality than any other chemotherapeutic side effect and may result in an increased number of hospital stay days. In addition, drug induced myelosuppression limits the administration of larger, potentially more effective doses of chemotherapy to patients with malignancies. Several approaches to resolve this adverse event have included the use of lithium, prostaglandin E, interferon, lactoferrin and the growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-colony stimulating factor (G-CSF). To date, use of growth factors such as G-CSF is a standard therapy for cancer patients with neutropenia. It stimulates the proliferation and differentiation of hematopoietic progenitors and also controls the functional activities of neutrophils and macrophages. However, the G-CSF treatment is costly and as it is a recombinant protein, it has accompanying side effects. [0003] Adenosine, an endogenous purine nucleoside, is ubiquitous in mammalian cell types. Adenosine present in the plasma and other extracellular fluids mediates many of its physiological effects via cell surface receptors and is an important regulatory protein. It is released into the extracellular environment from metabolically active or stressed cells. It is known to act through its binding to specific G-protein associated A1, A2 and A3 membranal receptors (Linden, 1991; Stiles, 1990). The interaction of adenosine with its receptors initiates signal transduction pathways, mainly the adenylate cyclase effector system, which utilizes cAMP as a second messenger. While A1 and A3 receptors, which are coupled with Gi proteins, inhibit adenylate cyclase and lead to a decrease in the level of intracellular cAMP, the A2 receptor, which is coupled to Gs proteins, activates adenylate cyclase, thereby increasing cAMP levels (Stolfi et al, 1983). [0004] Since specific surface receptors for adenosine are found in nearly all cells, almost all organ systems of the body are regulated to some extent by its local release. This includes regulation of the electrophysiological properties of the heart, sedation and suppression of neurotransmitter's release and regulation of rennin release and vascular tone in the kidney (Belardinelli et al, 1989; Collis, 1989; Clarke and Coupe, 1989; Dubey et al, 1997). Adenosine exerts various effects on the immune system including anti-inflammatory activity through the inhibition of cytokine release, inhibition of platelet aggregation, induction of erythropoietin production and modulation of the lymphocyte function (Soderback et al, 1991; Gilbertsen, 1987; Bouma et al, 1994). Further, adenosine was found to play a role in the modulation of some central nervous system (CNS) functions, in wound healing, in diuresis and in controlling pain. It was also demonstrated that adenosine is capable of inducing proliferation in a wide range of normal cell types (Rozengurt, 1982; Gonzales et al, 1990; Sandberg and Fredholm, 1981; Pastan et al, 1975). This modulation of cell growth is likely mediated through the adenylate cyclase effector system described above. [0005] In a recent study it was found that adenosine acts as a chemoprotective agent, which activity is likely related to its capability to stimulate bone marrow cell proliferation. Further, it was found that adenosine exerted an inhibitory effect on the proliferation of tumor cells, apparently through G0/G1 cell cycle arrest and reduction of the telomeric signal (Djaldetti et al, 1996; Fishman et al, 1998). The dual effect has turned adenosine into an attractive concept for cancer treatment. SUMMARY OF THE INVENTION [0006] In accordance with the present invention it was found that adenosine A3 receptor agonists (A3RAg) have a dual effect in that they inhibit proliferation of malignant cells on the one hand, and counter toxic side effects of chemotherapeutic drugs on the other hand. Specifically, the A3RAg compounds inhibit proliferation and growth of tumor cells, synergize with an anti-tumor cytotoxic drug in reducing the tumor load, induce proliferation and differentiation of bone marrow cells and white blood cells and counter toxic side effects of other drugs, particularly chemotherapeutic drugs. Furthermore, it was discovered in accordance with the invention that the A3RAg exerts these activities by a variety of forms of administration including parenteral administration and particularly oral administration. It was further found in accordance with the invention that some of the A3RAg activity may be mimicked by other agonists and antagonists of the adenosine A1 or A2 receptors: the adenosine A1 receptor agonists (AlRAg) shares with the A3RAg its ability to induce G-CSF secretion; adenosine A2 receptor agonist (A2RAg) shares with the A3RAg its ability to inhibit proliferation of malignant cells; and the adenosine A2 receptor antagonist (A2RAn) shares with the A3RAg its ability to counter toxic side effects of drugs, e.g., treat or prevent leukopenia. [0007] The invention relates in its broadest sense, to the use of an active ingredient to yield one of the following therapeutic/biological effects: inducing production or secretion of G-CSF within the body; prevention or treatment of toxic side effects of a drug or prevention or treatment of leukopenia, particularly drug-induced leukopenia; and inhibition of abnormal cell growth and proliferation. The active ingredient may be an A3RAg or an agonist or antagonist of the adenosine receptor system that can yield one of these therapeutic effects, achieved by the use of the A3RAg. [0008] Several embodiments are provided by the invention. The first embodiment, to be referred to herein as the "G-CSF-inducing embodiment" involves the use of an active ingredient, which may be an A3RAg or an A1RAg to yield secretion of the G-CSF within the body of a treated subject. G-CSF is known to stimulate proliferation and differentiation of hematopoietic progenitors and controls the functional activities of neutrophils and macrophages. Thus, a G-CSF-inducing agent, such as those mentioned above, may have a high therapeutic value, for example, in countering (i.e., preventing, reducing or ameliorating) myelotoxicity. [0009] Provided in accordance with this embodiment is a method for inducing G-CSF secretion within the body of a subject, comprising administering to the subject an effective amount of an active ingredient selected from the group consisting of A3RAg, an A1RAg and a combination of an A3RAg and an A1RAg. In accordance with this embodiment there is further provided a method for the therapeutic treatment, comprising administering to a subject in need an effective amount of said active ingredient for achieving a therapeutic effect, the therapeutic effect comprises induction of G-CSF production or secretion. Still further provided by this embodiment is use of said active ingredient for the manufacture of a pharmaceutical composition for inducing G-CSF secretion. Also provided by this embodiment is a pharmaceutical composition for inducing production or secretion of G-CSF within the body, comprising a pharmaceutically acceptable carried an effective amount of said active ingredient. [0010] In accordance with another embodiment of the invention, to be referred to herein at times as the "Leukopenia-prevention embodiment" or more specifically as the "neutropenia-prevention embodiment", an active ingredient which may be an A3RAg, or an A2RAn, is used for the prevention or treatment of leukopenia, which may result from myelotoxicity. [0011] In accordance with this embodiment there is provided a method for inducing proliferation or differentiation of bone marrow or white blood cells in a subject, comprising administering to the subject an effective amount of an active ingredient selected from the group consisting of an A3RAg, an adenosine A2RAn and a combination of an A3RAg or an A2RAn. Also provided by this embodiment is a method for prevention or treatment of leukopenia, comprising administering to a subject in need an effective amount of said active ingredient. Further provided in accordance with this embodiment is use of said active ingredient for the manufacture of a pharmaceutical composition for inducing proliferation or differentiation of bone marrow or white blood cells. Still further provided in accordance with this embodiment is use of said active ingredient for the manufacture of a pharmaceutical composition for the prevention or treatment of leukopenia. The pharmaceutical composition can particularly be used for prevention or treatment of leukopenia. [0012] In accordance with a related embodiment, to be referred to herein as the "toxicity-preventing embodiment" the abovementioned active ingredient (namely one of the A3RAg, or A2RAn, as well as a combination thereof, is used to counter toxic side effects of drugs, such as chemotherapeutic drugs or nemoleptic drugs. [0013] In accordance with this latter embodiment there is thus provided a method for prevention or treatment of toxic side effects of a drug, comprising administering to a subject in need an effective amount of an active ingredient selected from the group consisting of an A3RAg, an A2RAn and a combination of an A3RAg and an A2RAn. Also provided in accordance with this embodiment is use of said active ingredient for the manufacture of a pharmaceutical composition for the prevention or treatment of drug-induced toxicity. Still further provided by this embodiment is pharmaceutical composition for prevention or treatment of toxic side effects of a drug, comprising an effective amount of said active ingredient and a pharmaceutically acceptable carrier. [0014] For the purpose of countering drug-induced leukopenia or drug-induced toxic side effects in general, it is at times desirable to formulate a drug that has such toxic side effects together with said active ingredient for combined administration of the two. The invention thus also provides a pharmaceutical composition comprising, in combination a drug that can cause toxic side effect in a subject treated thereby and said active ingredient; as well as use of said active ingredient for the manufacture of such a pharmaceutical composition. Said active ingredients included in said composition being an amount effective for prevention or treatment of the toxic side effects. [0015] In accordance with yet another embodiment of the invention, to be referred to herein as the "proliferation-inhibiting embodiment", an active ingredient, which may be an A3RAg, an A2RAg, or a combination of the two, is used for selectively inhibiting abnormal cell growth, e.g., tumor cell growth. [0016] In accordance with this embodiment there is provided a method for inhibiting abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of an active ingredient selected from the group consisting of an A3RAg, an A2RAg and a combination of an A3RAg and an A2RAg. Also provided in accordance with this embodiment is use of said active ingredient for the manufacture of a pharmaceutical composition for inhibiting abnormal cell growth. Still further provided by this embodiment is a pharmaceutical composition for inhibiting abnormal cell growth, comprising said active ingredient, and a pharmaceutically acceptable carrier. [0017] In one embodiment of the invention the administration of the active ingredient is intended to achieve dual therapeutic effect: inhibition of abnormal cell growth and reduction of toxic side effects of a drug causing such effects. [0018] The preferred active ingredient in accordance with the invention is an A3RAg. The preferred route of administration of the active ingredient, in accordance with the invention is the oral administration route. However, this preference does not exclude other active ingredients neither other administration routes of the active ingredients. [0019] The dosage of the active ingredient, particularly where the active ingredient is an A3RAg, is preferably less than 100 .mu.g/kg body weight, typically less than 50 .mu.g and desirably within the range of 1-10 .mu.g/kg body weight. BRIEF DESCRIPTION OF THE FIGURES [0020] In order to understand the invention and to see how it may be carried out in practice, a preferred embodiment will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: Continue reading... Full patent description for Pharmaceutical compositions comprising an adenosine receptor agonist or antagonist Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Pharmaceutical compositions comprising an adenosine receptor agonist or antagonist patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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