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Methods of using beta glucan as a radioprotective agentRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, PolysaccharideMethods of using beta glucan as a radioprotective agent description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050245480, Methods of using beta glucan as a radioprotective agent. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation of International Application No. PCT/US03/25237, which designated the United States and was filed on Aug. 13, 2003, published in English, which claims the benefit of U.S. Provisional Application No. 60/403,424, filed on Aug. 13, 2002. The entire teachings of the above applications are incorporated herein by reference. BACKGROUND OF THE INVENTION [0003] Beta(.beta.)-glucan is a complex carbohydrate, generally derived from several sources, including yeast, bacteria, fungi and cereal grains. Each type of .beta.-glucan has a unique structure in which glucose is linked together in different ways, resulting in different physical and chemical properties. For example, .beta.(1,3) glucan derived from bacterial and algae is linear, making it useful as a food thickener. The frequency of side chains, known as the degree of substitution or branching frequency, regulated secondary structure and solubility. Beta glucan derived from Yeast is branched with .beta.(1,3) and .beta.(1,6) linkages, enhancing its ability to bind to and stimulate macrophages. .beta.(1,3/1,6) glucan purified from baker's yeast (Saccharomyces cerevisiae) is a potent anti-infective beta-glucan immunomodulator. [0004] The cell wall of S. cerevisiae is mainly composed of .beta.-glucans, which are responsible for its shape and mechanical strength. While best known for its use as a food grade organism, yeast is also used as a source of zymosan, a crude insoluble extract used to stimulate a non-specific immune response. Yeast-derived beta (1,3) glucans stimulate the immune system, in part, by activating the innate anti-fungal immune mechanisms to fight a variety of targets. Baker's yeast .beta.(1,3/1,6) glucan is a polysaccharide composed entirely of .beta.(1,3)-linked sugar (glucose) molecules forming the polysaccharide backbone with periodic .beta.(1,3) branches linked via .beta.(1,6) linkages). It is more formally known as poly-(1,6)-.beta.-D-glucopyranosy- l-(1,3)-.beta.-D-glucopyranose. Glucans are structurally and functionally different depending on the source and isolation methods. [0005] Beta glucans possess a diverse range of activities. The ability of .beta.-glucan to increase nonspecific immunity and resistance to infection is similar to that of endotoxin. Early studies on the effects of .beta.(1,3) glucan on the immune system focused on mice. Subsequent studies demonstrated that .beta.(1,3) glucan has strong immunostimulating activity in a wide variety of other species, including earthworms, shrimp, fish, chicken, rats, rabbits, guinea pigs, sheep, pigs cattle and humans. Based on these studies, .beta.(1,3) glucan represents a type of immunostimulant that is active across the evolutionary spectrum, likely representing an evolutionarily innate immune response directed against fungal pathogens. However, despite extensive investigation, no consensus has been achieved on the source, size, and form of .beta.(1,3) glucan ideal for use as an immunostimulant. [0006] Radiation and chemotherapeutic drugs can suppress the production of blood cells and platelets in the bone marrow, an adverse side-effect known as myelosuppression. Exposure to radiation can cause a rapid depletion of immune (hematopoietic) cells and platelets derived from the bone marrow (BM) that are necessary for controlling life threatening infections and bleeding episodes. [0007] Radioprotectants allow for more effective antitumor treatments by minimizing the side effects of radiotherapy or chemotherapy. Advances in radioprotection also enable military forces to operate, when required, in nuclear or radioactive combat environments while minimizing both long-term and short-term risks of the consequences of exposure to ionizing radiation. Radioprotectants can also be useful for protecting or treating astronauts who are exposed to space radiation. Finally, readily available and easily administered radioprotectants could be of crucial importance in minimizing the damage from terrorist actions or industrial nuclear accidents. [0008] The use of .beta.(1,3/1,6) glucans as hematopoietic agents has been tentatively explored in several references. For example, U.S. Pat. No. 5,532,223 by Jamas et al. demonstrates the use of parenteral neutral soluble glucan to stimulate hematopoietic and immunological effects without stimulating the production of undesired cytokines. Patchen and colleagues demonstrated that parenterally administered soluble and particulate beta-glucans can enhance hematopoietic recovery and the ability to resist infection in mice exposed to radiation when administered either before or after exposure to radiation. See M. L. Patchen et al., "Glucan: mechanisms involved in its `radioprotective` effect", J Leukoc. Biol., 42, 95(1987). Beta glucan has also been used as a topical antioxidant to protect the skin from damage caused by ultraviolet radiation. See J. A. Greene, "Composition for protecting skin from damaging effects of ultraviolet light", U.S. Pat. No. 6,235,272. However, these laboratory studies have not provided a convenient formulation of .beta.-glucan. The majority of these applications utilize soluble material that requires administration by injection, a costly and painful route that can result in poor patient compliance. However, many drugs are not amenable to oral formulation due to properties that limit oral bioavailability. Therefore, a need exists for formulations that can lead to greater patient compliance and maintain bioavailability. Additionally, there remains a need for a formulation of .beta.-glucan, particularly an oral formulation, which can be readily stored and administered to humans to prevent or treat myelosuppression and serve as an effective radioprotectant. SUMMARY OF THE INVENTION [0009] The present invention relates to the use of particulate, bioavailable, .beta.(1,3/1,6) glucan as a radioprotectant. The .beta.(1,3/1,6) glucan can be readily administered orally and is bioavailable to the site of action (e.g., bone marrow). Disclosed herein is a method of treating and preventing injury from ionizing radiation and/or chemotherapy by administering a prophylactically or therapeutically effective amount of particulate, bioavailable .beta.(1,3/1,6) glucan. In a certain embodiments, the .beta.(1,3/1,6) glucan comprises whole glucan particles, microparticulate .beta.-glucan particles or a combination of whole glucan particles and microparticulate .beta.-glucan particles. Whole glucan particles typically have a diameter of 1 micron or greater and microparticulate .beta.-glucan particles a diameter of 1 micron or less. The whole glucan particles, microparticulate .beta.-glucan particles or a combination of whole glucan particles and microparticulate .beta.-glucan particles may be administered orally and/or parenterally, with oral administration of whole glucan particles being preferred. Ranges of about 0-100 mg/kg of body weight of body weight of .beta.-glucan administered daily constitute a therapeutically effective dose. [0010] The present invention also discloses a method of treating and preventing radiation and/or chemotherapy related afflictions, such as myelosuppression and decreased macrophage activity by administering a prophylactically or therapeutically effective amount of .beta.(1,3/1,6) glucan. The radiation and/or chemotherapy related afflictions may be caused either by ionizing radiation, chemotherapy, or other adverse conditions. Oral administration of a daily therapeutically effective dose of about 0-100 mg/kg of body weight of whole glucan particles is particularly preferred. The glucan can be co-administered with other agents for enhancing stem cell activation. [0011] The invention also relates to methods of treating or preventing the reduction of macrophage activity created by radiation or chemotherapy by administering a prophylactically or therapeutically effective amount of particulate, bioavailable .beta.(1,3/1,6) glucan. In another embodiment, the invention relates to the use of a particulate bioavailable .beta.(1,3/1,6) glucan for the manufacture of a medicament for oral use in treating myelosuppression following radiation, wherein the orally administered glucan enhances hematopoietic stem progenitor cells by fuictioning with the complement system by providing a second signal for CR3 activation. [0012] Also described herein are methods of enhancing glucan-mediated hematopoietic progenitor stem cell recovery after exposure to radiation via the complement system, comprising administering to an individual a therapeutically effective orally bioavailable amount of whole glucan particles, wherein the glucan enhances regeneration of hematopoietic progenitor stem cells. The .beta.(1,3/1,6) glucan functions with complement activation after injury to promote stem cell attachment to the injury site via stem cell CR3 binding to iC3b stem cells that are attached via iC3b by providing the "second signal" for CR3 activation. This ligation of glucan to the lectin domain of CR3 is more efficient than the natural lectin site signal mediated by damaged tissue heparin sulphate. In certain embodiments of the methods of the invention, the orally administered glucan is transported to the bone marrow and degraded. At the bone marrow, the the degraded oral glucan activates stem cells via the complement system by binding to iC3b deposited on injured stem cell and activating CR3. That is, the method of the invention pertains to a method of enhancing glucan-mediated hematopoietic progenitor stem cell recovery after exposure to radiation via the complement system, comprising administering to an individual a therapeutically effective orally bioavailable amount of whole glucan particles, wherein the glucan via the complement system enhances regeneration of hematopoietic progenitor stem cells. The orally administered glucan is taken up by macrophages, transported to the bone marrow, degraded and the released fragments primes the CR3 of stem cell thereby activating the stems cell to differentiate and proliferate. The .beta.(1,3/1,6) glucan in via the complement system promotes stem cell proliferation and differentiation by binding to iC3b deposited on injured stem cells and activating CR3. BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIG. 1 graphically depicts a time course of white blood cell counts for wild type and CR3 deficient mice post a sublethal irradiation exposure. [0014] FIG. 2 graphically depicts histograph overlays showing net C3 staining after subtraction of background non-specific staining and compare marrow from treated versus untreated mice. Cyclophosphamide or sub-lethal radiation injury to bone marrow results in complement activaton with deposition of C3 on viable bone marrow cells. Normal or C3-deficient (C3-/-) mice were treated with either cyclophosphamide (200 mg/kg, left panel) or 3.0 Gy of total body gamma radiation (right panel) and then isolated marrow cells from treated versus untreated mice were analyzed for the presence of bound C3 by staining with goat anti-mouse C3-FITC and flow cytometry. Any staining of marrow cells from C3-/- mice with the anti-C3-FITC reagent was assumed to be non-specific and was subtracted from the total staining obtained with marrow cells from comparable treated or untreated wild-type (C3+/+) mice. With cyclophophamide, staining for C3 was observed on days 3 and 4 after treatment (day 4 shown). With irradiated mice, C3 staining was observed only at 24 (shown) and was not observed 3 days after radiation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0015] The present invention relates to methods of using an oral, bioavailable .beta.(1,3/1,6) glucan as a pharmaceutical agent for the treatment and prevention of radiation and/or chemotherapy related injuries and/or afflictions, such as myelosuppression and decreased macrophage activity. Moreover, the present invention relates to methods of using .beta.(1,3/1,6) glucan in whole glucan particle form and/or microparticulate .beta.-glucan particle form as an agent, such as a pharmaceutical or dietary, for the treatment and prevention of radiation and/or chemotherapy related afflictions. Additionally, the present invention relates to the use of .beta.(1,3/1,6) glucan in whole glucan particle form, microparticulate .beta.-glucan particle form or any combination thereof as a radioprotectant. [0016] Whole glucan particle (WGP) is a purified, yeast cell wall preparation. The whole glucan particles are produced by removing the mannan protein outer layer and exposing the .beta.-glucan while retaining glucan's in vivo morphology. In certain embodiments, the whole glucan particles have a particle size of 1 micron or greater. Microparticulate glucan particles are defined herein to be portions of whole glucan particles that result from finely grinding yeast cell wall .beta.(1,3/1,6) glucan down to a particle size of about 1 micron or less. The preparation and use of these compounds for the prevention and treatment of myelosuppression is described below. [0017] Various forms of particulate and soluble .beta.-glucans have been prepared. One example is microparticulate glucan particles, which can be formed by finely grinding yeast cell wall .beta.(1,3/1,6) glucan down to a particle size of about 1 micron or less. Beta glucan in this form has been applied to use as a nutritional supplement and skin restorer, such as disclosed in U.S. Pat. No. 5,702,719, by Donzis. Other useful particulate glucan useful in the methods described herein, are WGP.TM. Beta Glucan and BetaRight.TM. obtained from Biopolymer Engineering, Inc., Eaton, Minn. [0018] Microparticulate .beta.-glucan particles have also been shown to enhance the host's immune system. See U.S. Patent Nos. 5,223,491 and 5,576,015, the teachings of which are incorporated herein by reference in their entirety. Another form is neutral soluble .beta.-glucans, which are prepared through a series of acid, alkaline and neutral treatment steps to yield a conformationally pure neutral soluble glucan preparation. The neutral soluble glucan preparation enhances a host's immune system but does not induce the production of IL-1 and TNF and thus do not cause inflammation. See U.S. Pat. 5,783,569, the teachings of which are incorporated herein by reference in its entirety. [0019] Another form of .beta.-glucan is an insoluble particle known as whole glucan particles (WGP). Whole glucan particles are the remnants of the yeast cell wall prepared by separating growing yeast from its growth medium and subjecting the intact cell walls of the yeast to alkali, thus removing unwanted proteins and nucleic acid material. In certain embodiments, what remains is a spherical beta-glucan particle with the outer mannan protein removed. Whole glucan particles may be obtained from any glucan-containing fungal cell wall source, but the preferred source is a strain of S. cerevisiae. These insoluble particles have been shown to enhance host resistance to a wide range of infections, increase antibody production (adjuvant activity), increase leukocyte mobilization, and enhance wound healing. Methods of producing WGP are known in the art and are disclosed in U.S. Patent Nos. 4,810,646, 4,492,540, 5,037,972, 5,082,936, 5,250,436, and 5,506,124, the contents of which are incorporated herein by reference in their entirety. WGP can be further broken down into various components, each with differing affinities for binding to subsets of receptors found on innate immune cells. These various conformational forms are, in increasing order of complexity, random coil, single helix, triple helix, and triple helical multimer. WGP has shown a variety of biological activities, including use as a vaccine adjuvant (U.S. Pat. No. 5,741,495), an anti-infective agent (Pedroso M., "Application of beta-1,3-glucan to prevent shipping fever in imported heifers," Arch. Med. Res. 25(2), 181 (1994)), and an antitumor agent (Borchers, A. T., et al., Proc. Soc. Exp. Biol. Med., 221(4), 281 (1999)). Each conformational form possesses different activities as is demonstrated by the different specificities observed for glucan receptors. [0020] The .beta.-glucans for use in the methods described herein are oral bioavailable formulations. Continue reading about Methods of using beta glucan as a radioprotective agent... 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