WO1998047497A2 - Methodes et compositions afferentes aux fins de la prevention et du traitement de troubles immunologiques, de maladies et d'infections a caractere inflammatoire - Google Patents

Methodes et compositions afferentes aux fins de la prevention et du traitement de troubles immunologiques, de maladies et d'infections a caractere inflammatoire Download PDF

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Publication number
WO1998047497A2
WO1998047497A2 PCT/US1998/008164 US9808164W WO9847497A2 WO 1998047497 A2 WO1998047497 A2 WO 1998047497A2 US 9808164 W US9808164 W US 9808164W WO 9847497 A2 WO9847497 A2 WO 9847497A2
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Prior art keywords
diseases
magnesium gluconate
composition
magnesium
allergic
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PCT/US1998/008164
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English (en)
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WO1998047497A3 (fr
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Thomas E. Fleming
Herbert C. Mansmann, Jr.
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Fleming & Company, Pharmaceuticals
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Priority claimed from US08/844,988 external-priority patent/US5922765A/en
Priority claimed from US08/844,909 external-priority patent/US5939394A/en
Application filed by Fleming & Company, Pharmaceuticals filed Critical Fleming & Company, Pharmaceuticals
Priority to AU71505/98A priority Critical patent/AU7150598A/en
Publication of WO1998047497A2 publication Critical patent/WO1998047497A2/fr
Publication of WO1998047497A3 publication Critical patent/WO1998047497A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to methods and compositions for the prevention and treatment of immunological disorders, inflammatory diseases, septic shock and chronic infections involving lipid peroxide - and cytokine-mediated pathology.
  • the methods and compositions of the invention especially suited for parenteral, enteral or topical administration prevent or inhibit oxidant-induced or cytokine mediated tissue damage, chronic inflammation and other deleterious consequences of reactive species of oxidants.
  • the normal function of the immune system is essential for health, and dysfunction of the immune system leads to myriad diseases.
  • deficiency of immune cell production or defective immune cell function can lead to a wide spectrum of immunodeficiency diseases, and overactivity of various components of the immune system leads to the development of allergic or autoimmune diseases.
  • autoimmune diseases include 1) humoral immunity involving B cells, 2) cell-mediated immunity involving T cells and monocytes, 3) phagocytic cells of the reticuloendothelial system involving macrophages and polymorpho leukocytes, and 4) complement.
  • Defects in antibody production generally result in recurrent bacterial infections.
  • Defects in cellular immunity result in viral, ⁇ ycobacterial and fungal infections, an extreme example being acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • Disorders of phagocyte function are manifested by recurrent skin infections and deficiencies of early and late complement components are associated with autoimmune phenomena.
  • Sepsis is a response to infection caused by any class of microorganism including, but not limited to gram-negative and gram-positive bacteria, fungi, mycobacteria, viruses or protozoans. As sepsis progresses to septic shock, the risk of dying increases substantially. Sepsis results from complex interactions among microbial molecules, leukocytes, humoral factors, the vascular endothelial cytokines, and thromboxanes.
  • allergic diseases involve antigen recognition, humoral and cellular effector mechanisms and inflammatory reactions to environmental antigens, the inflammatory reactions being responsible in causing the deleterious effects.
  • Some examples of allergic diseases are asthma, allergic rhinitis, eczema, atopic dermatitis and allergic contact dermatitis.
  • Autoimmune disease is characterized by production of either antibodies that react with host tissue or immune effector T cells that are autoreactive to endogenous self peptides.
  • Some examples of autoimmune disorders are rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, immune thrombocytopenic purpura, myasthenia gravis, ulcerative colitis, Crohn's disease, scleroderma and psoriasis.
  • the main approach of treating autoimmune diseases consisted of compounds which were designed to suppress the immune system. Verma, X. et. al., 1992, Canadian J. Neurol. Sci. 19: 360-375.
  • Septic shock or endotoxin shock is a pathophysiologic phenomenon resulting from the release of endotoxin from gram-negative organisms.
  • Endotoxins are lipopolysaccharide protein lipid complexes which are released from cell membranes of killed bacteria. The most common are Escherichia coli, Aerobacter aerogenis, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeroginosa, Proteus species, Pseudomonas species, Bacteroides species and Salmonella species.
  • the underlying pathophysiological process of septic or endotoxin shock appears to have an immunological basis involving the release of vasoactive substances and neurohumoral agents, and precipitation of coagulation abnormalities.
  • Treatment of septic shock is directed primarily toward establishing a specific microbial diagnosis and an entry site for the responsible microorganisms.
  • Therapy involves use of antibiotics, glucocorticoids and necessary surgical intervention to drain abscesses or to remove infected foreign bodies. Sheagren, J.N., 1981, N. Engl. J. Med., 305: 456; and Pathophysiology - The Biological Principles of Disease, ed. L.M. Smith and S.O. Thier, W.B. Saunders Company (1985) 164-172.
  • Magnesium is an important element for health and disease.
  • Magnesium deficiency may cause weakness, tremors, seizures, cardiac arrhythmias, hypokalemia, and hypocalcemia.
  • the causes of hypomagnesemia are reduced intake, for example, poor nutrition or intravenous fluids without magnesium; reduced absorption, for example, chronic diarrhea, malabsorption, or bypass/resection of bowel; redistribution, for example, exchange transfusion or acute pancreatitis; and increased excretion, for example, medication, alcoholism, renal tubular disorders, hypercalcemia, hyperthyroidism, aldosteronism, stress or excessive lactation.
  • the present invention relates to methods and compositions for the prevention and treatment of immunological disorders, inflammatory diseases, septic shock and chronic infectious with an effective amount of magnesium gluconate.
  • immunological disorders include allergic and autoimmune diseases.
  • chronic infections include bacterial, viral, mycobacterial, protozoan and fungal infections.
  • the present invention is also directed to a method for the prevention and/or treatment of immunological disorders, inflammatory diseases, septic shock and chronic infections which involves using an effective amount of magnesium gluconate along with conventional therapy.
  • the present invention further relates to methods and compositions containing magnesium gluconate in combination with antioxidants, including, but not limited to, vitamin E, selenium, glutathione, glutathione isopropyl ester, or N- acetylcysteine, for use in the prevention and/or treatment of immunological disorders, inflammatory diseases, septic shock and chronic infections.
  • antioxidants including, but not limited to, vitamin E, selenium, glutathione, glutathione isopropyl ester, or N- acetylcysteine
  • FIG. 1 Effect of magnesium salts on R.-induced loss of BA-endothelial cell glutathione.
  • Figure 4. Effect of magnesium salts on R.-induced loss of endothelial cell proliferation.
  • the invention provides methods and compositions for intervention with magnesium gluconate to inhibit formation of lipid peroxidation products and cytokine-mediated abnormalities to prevent and/or treat immunological disorders, inflammatory diseases and chronic infections.
  • Cytokines refer to soluble proteins secreted by cells of the immune system. They mediate many of the immune and inflammatory reactions and are critical for normal host defense against pathogens. However, excessive production of cytokines may result in severe pathologic tissue injury and disease. The actions of cytokines are pleiotropic (the same protein elicits multiple effects) and redundant (one set of biologic responses may be induced by more than one cytokine) and include the interleukins, (IL-1, IL-5,IL-6 and IL-8) tumor necrosis factor -" and interferon -(.
  • the method of the invention involves administering an effective dose of magnesium gluconate to an individual who is identified as being at enhanced risk of immunological disorders, inflammatory diseases or chronic infections and/or having an immunological disorder, inflammatory disease, septic shock or chronic infection.
  • magnesium salts which inhibit immunological disorders, inflammatory diseases, septic shock or chronic infections may be useful as therapeutic agents, for example, but not limited to magnesium citrate, magnesium carbonate, magnesium chloride, magnesium sulfate or magnesium stearate.
  • the methods of the invention include administering magnesium gluconate along with traditional anti-inflammatory agents, including but not limited to, glucocorticoids, non-steroidal anti-inflammatory drugs, bronchodilators, $- agonists, anticholinergic agents, antihistamines and antibiotics.
  • traditional anti-inflammatory agents including but not limited to, glucocorticoids, non-steroidal anti-inflammatory drugs, bronchodilators, $- agonists, anticholinergic agents, antihistamines and antibiotics.
  • the invention provides a method of preventing and treating immunological disorders, inflammatory diseases, septic shock or chronic infections by further administering antioxidant nutrients including, but not limited to, vitamin E, selenium, glutathione, glutathione isopropyl ester, N-acetylcysteine, or mixtures thereof. While the applicant is under no duty or obligation to explain the mechanism by which the invention works and certainly does not intend in any way for the invention to be limited to any particular mechanism of action, it may be that the ability of magnesium gluconate to prevent and inhibit abnormal production of lipid peroxides and cytokines, contributes to the efficacy or effectiveness for use in the prevention and treatment of immunological disorders, inflammatory diseases, septic shock and chronic infections. These proposed mechanisms of action are in no way meant to limit the scope of the invention and are presented purely for explanatory and/or illustrative purposes.
  • Allergic diseases have been classified into 4 types: 1) Type I - IgE antibodies fixed to mast cells react with antigens, triggering release of histamine and lipid mediators and cytokines, for example in, atopy, anaphylaxis, urticaria and angioedema; 2) Type II - IgG or IgM antibodies react with antigen on target cells and activate complement, causing cell lysis, for example in some drug reactions; 3) Type III - IgG or IgM antibodies form complexes with antigen and complement, generating neutrophil chemotactic factors with resultant local tissue inflammation, for example in serum sickness, arthus reaction and hypersensitivity lung diseases; and 4) Type IV - sensitized T lymphocytes react with antigen, producing inflammation through the action of cytokines
  • Atopic allergy is a type I hypersensitivity reaction to environmental antigens in genetically susceptible individuals who produce IgE antibodies to allergens such as pollens, molds, house dust, animal dander, or foods. Exposure to the offending allergen results in the release of mediators, including histamine, lipid mediators
  • LTB 4 and C 4 Leukotrienes (LT)B 4 and C 4 , prostaglandin (PG)D, and platelet-activating factor) and cytokines (IL-4, IL-5, IL-6, TNF-") in the target organ.
  • IL-4, IL-5, IL-6, TNF- cytokines
  • Asthma is a disease of the airways that is characterized by increased responsiveness of the tracheobronchial tree to a variety of stimuli. Asthma can be triggered by irritants, exercise, cold air, dust or fumes, allergens and viral infections. The response of the airways to antigen inhalation is release by the mast cells of preformed mediators (histamine, heparin, chondroitin sulfate E, tryptase and chymotryptase), cytokines (interleukin (IL)-4, IL-5, IL-6 and tumor neurosis factor (TNF) -”) and lipid mediators LTB 4 , LTC 4 , PGD, and platelet activating factor).
  • mediators histamine, heparin, chondroitin sulfate E, tryptase and chymotryptase
  • cytokines interleukin (IL)-4, IL-5, IL-6 and
  • the early asthmatic response takes place within minutes and is characterized by vasodilation, bronchoconstriction and mucus secretion.
  • the late response is a complex inflammatory process mediated by leukocyte populations recruited to the airways.
  • 5.2 Autoimmune Diseases Autoimmune disease is characterized by production of either antibodies that react with host tissue or immune effector T cells that are autoreactive to endogenous self peptides.
  • lymphocytes produce tissue lesions by release of cytokines or by attracting other destructive inflammatory cell types to the lesion.
  • the inflammatory cell types in turn lead to production of lipid mediators and cytokines with associated inflammatory disease.
  • autoimmune disorders are rheumatoid arthritis, systemic lupus erythematosus (SLE), Graves' disease, immune thrombocytopenic purpura, myasthenia gravis, Addison's disease, hemolytic anemias, neutropenias and lymphopenias.
  • Rheumatoid arthritis is characterized by the presence in serum of autoantibodies and immune complexes that participate in the synovitis and vasculitis by activation of complement and attraction of polymorphonuclear cells.
  • the infiltrating polymorphonuclear cells in turn, release the inflammatory mediators such as histamine, lipid mediators and cytokines.
  • disorders that may represent autoimmune phenomena include the inflammatory bowel diseases, for example, ulcerative colitis and Crohn's disease. Clinically these disorders are characterized by recurrent inflammatory involvement, humoral antibodies to colon cells and bacterial proteins and may exhibit abnormalities of cell-mediated immunity such as diminished responsiveness to various mitogenic stimuli. In addition, inflammatory mediators such as prostaglandin and thromboxane products are further stimuli for the inflammatory response. 5.3 Infectious Diseases
  • Infectious diseases that can be treated or prevented by the methods of the present invention are caused by infectious agents including but not limited to viruses, bacteria, fungi, protozoa and parasites.
  • Viral diseases that can be treated or prevented by the methods of the present invention include, but are not limited to, those caused by hepatitis type A, hepatitis type B, hepatitis type C, influenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpes simplex type II (HSV-II), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, papova virus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type I (HIV-I), and human immunodeficiency virus type II (HIV-II).
  • Bacterial diseases that can be treated or prevented by the methods of the present invention are caused by bacteria including, but not limited to, mycobacteria rickettsia, myco
  • Protozoal diseases that can be treated or prevented by the methods of the present invention are caused by protozoa including, but not limited to, leishmania, kokzidioa, and trypanosoma.
  • Parasitic diseases that can be treated or prevented by the methods of the present invention are caused by parasites including, but not limited to, chlamydia and rickettsia. 5.4 Septic Shock
  • the microbial factors that may trigger clinical features of septic shock include the endotoxins of gram-negative bacteria. These organisms when in the bloodstream have a high propensity to cause the shock syndrome, and many features of this syndrome can be reproduced by administration of fragments of these organisms or purified preparations of the lipopolysaccharide component of their endotoxins.
  • Gram- negative lipopolysaccharides contain three major components: an outer chain of oligosaccharide units antigenically unique to each strain of organism, a central polysaccharide core shared among different gram-negative strains and species and a proximal nonpolar lipid component known as lipid A.
  • Lipid A can directly injure endothelial cells as well as activate macrophages to produce and release interleukin 1 , plasminogen activator, lysosomal enzymes and prostaglandins, thromboxanes, leukotreines and other arachidonic acid metabolites.
  • thromboxane B Elevated levels of thromboxane B, have been documented in the circulation of some patients dying of gram-negative sepsis.
  • thromboxane A may participate in platelet aggregation and localized vasoconstriction in the microvasculature.
  • Pulmonary hypertension is common in experimental models of septic shock and contrasts with the fall in systemic vascular resistance.
  • the use of specific inhibitors of thromboxane synthetase has reduced the pulmonary vascular changes that accompany endotoxin injection into experimental animals. 5.5 Lipid Mediators
  • Prostaglandins, thromboxanes, leukotrienes and other arachidonic acid metabolites are important in the inflammatory and immunologic responses that the body uses to defend itself.
  • HPETE hydroperoxyeicosatetraenoic acids
  • HETE hydroxyeicosatetraenoic acids
  • These oxygenated metabolites are selectively produced by leukocytes, macrophages, neutrophils, eosinophils, or mast cells.
  • these substances are among the important mediators for such disorders as asthma, arthritis, adult respiratory distress syndrome, allergic rhinitis and inflammatory bowel disease. Therefore, therapeutic or preventive intervention using an agent such as magnesium gluconate which inhibits the production of such oxidants, and selectively inhibits formation of proinflammatory metabolites must result in beneficial effects.
  • an agent such as magnesium gluconate which inhibits the production of such oxidants, and selectively inhibits formation of proinflammatory metabolites must result in beneficial effects.
  • TNF- Tumor neurosis factor - x has been implicated in a variety of pathologic states in many different organs of the body.
  • TNF- activates blood cells and causes the adhesion of neutrophils, eosinophils, monocytes/macrophages and T and B lymphocytes.
  • TNF- augments the chemotaxis of inflammatory cells and their penetration into tissues.
  • TNF- has a role in the tissue damage of allergies, autoimmune diseases and inflammatory disorders. For these reasons ways have been sought to regulate the production, secretion, or availability of active forms of TNF-" as a means to control a variety of diseases.
  • a suitable magnesium salt for example, magnesium carbonate
  • citric acid for example, citric acid
  • glucono-delta-lactone a suitable magnesium salt
  • concentrations are utilized: magnesium carbonate in the range of 2 mg per liter to 44g per liter; citric acid in the range of 2.3 mg.
  • Aqueous magnesium gluconate composition of the invention comprise formulations suitable for enteral and parenteral administration. 5.8 Pharmaceutical Preparations and Methods of Administration
  • Magnesium gluconate compositions for use in accordance with the present invention are formulated by mixing magnesium gluconate into an aqueous solution or by mixing a suitable magnesium salt, for example, magnesium carbonate, with glucono-delta-lactone or magnesium carbonate with glucono-delta-lactone and/or citric acid.
  • a suitable magnesium salt for example, magnesium carbonate
  • a therapeutically effective dose refers to that amount of the magnesium compound sufficient to result in the amelioration of symptoms of allergic diseases, autoimmune disease and infectious diseases.
  • a therapeutically effective dose refers to that amount of the antioxidants, including but not limited to, Vitamin E, selenium, glutathione, glutathione isopropyl ester or N- acetylcysteine, sufficient to result in the amelioration of symptoms of allergic diseases, autoimmune disease and infectious diseases.
  • Vitamin E including but not limited to, Vitamin E, selenium, glutathione, glutathione isopropyl ester or N- acetylcysteine
  • Toxicity and therapeutic efficacy of the magnesium compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% in the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Compounds which exhibit large therapeutic indices are preferred.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. 5.9 Formulations
  • Magnesium gluconate compositions for use in accordance with the present invention are formulated by mixing magnesium gluconate into an aqueous solution or by mixing a suitable magnesium salt, for example, magnesium carbonate, with glucono-delta-lactone or magnesium carbonate with glucono-delta-lactone and/or citric acid.
  • Pharmaceutical compositions for use in accordance with the present invention can be formulated by conventional means in aqueous form or by using one or more physiologically acceptable carriers, excipients or buffers.
  • the compounds and their physiologically acceptable salts and solvates can be formulated for administration by insufflation (either through the mouth or the nose) or oral, buccal, parenteral or rectal administration.
  • the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate or talc); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate or talc
  • disintegrants e.g., potato starch or sodium starch glycolate
  • Liquid preparations for oral administration can take the form of, for example, aqueous solutions, syrups or suspensions, or they can be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydrobenzoates, benzoates or sorbic acid).
  • the preparations can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • Preparations for oral administration can be formulated to give controlled release of the active compound.
  • compositions can take the form of tablets, hard and soft gel caps or lozenges formulated in the conventional manner.
  • the compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compositions can, if desired, be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the active ingredient.
  • the pack can for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device can be accompanied by instructions for administration.
  • Patient dosages for enteral or parenteral administration range from 10 to 150 mEq of magnesium gluconate per day, commonly 20-50 mEq per day, and typically from 20 to 30 mEq per day. Stated in terms of milligrams of Mg, usual dosages range from 100 mg per day to 1800 mg per day, preferably from 250 mg per day to 600 mg per day.
  • Dosage amounts of calcium for enteral administration range from 500 to 1500 mg per day.
  • Dosage amounts of antioxidants for enteral administration range from for example for vitamin E: 200 to 1001.U. per day.
  • Dosage amount and interval may be adjusted to provide plasma levels which are sufficient to maintain normal metabolism and immunological response.
  • the antioxidant properties of magnesium gluconate were studied by incubating microsomal membranes prepared from endothelial cells in the presence of 0.25, 0.5, 1.0 and 2.0 mM of magnesium salts including magnesium gluconate, magnesium chloride and magnesium sulfate.
  • Membrane malondialdehyde and site specific OH -mediated deoxyribose oxidation were measured according to methods described by Mak, I.T. & Weglicki, W.B., 1994, Method Enzymol. 234: 620-630; and Mak, I.T. et. al., 1990, Biochem. Pharm. 40: 2169-2175.
  • magnesium sulfate were much lower than those obtained with magnesium gluconate, i.e., magnesium sulfate were approximately 33% as potent as magnesium gluconate (Figs 1-4).
  • the invention is illustrated, by way of protocols for anti-inflammatory therapy used in patients suffering from acute, moderate or severe asthma. These protocols demonstrate the effectiveness of magnesium gluconate in the treatment of various stages asthma. 30 ml Magnesium gluconate (324 mg Mg) (Magonate7 -
  • the magnesium gluconate compositions of the present invention are useful in the treatment of acute, moderate and severe asthma.

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Abstract

Cette invention a trait à des compositions et aux méthodes afférentes aux fins de la prévention et/ou du traitement d'affections allergiques, de maladies auto-immunes, de chocs septiques ou de maladies infectieuses. Il est utilisé, dans le cadre de ces méthodes, du gluconate de magnésium seul ou associé à un ou plusieurs antioxydants ou à un agent anti-inflammatoire. Cette invention concerne également l'inhibition de la production de quantités inopportunes de médiateurs des lipides et de cytokines.
PCT/US1998/008164 1997-04-23 1998-04-23 Methodes et compositions afferentes aux fins de la prevention et du traitement de troubles immunologiques, de maladies et d'infections a caractere inflammatoire WO1998047497A2 (fr)

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US08/844,988 US5922765A (en) 1996-01-18 1997-04-23 Methods and compositions for the prevention and treatment of muscle cramps and improving muscular strength
US08/844,909 US5939394A (en) 1996-01-18 1997-04-23 Methods and compositions for the prevention and treatment of immunological disorders, inflammatory diseases and infections
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001007019A2 (fr) * 1999-07-27 2001-02-01 Zambon Group S.P.A. Utilisation de n-acetyle cysteine pour la preparation de compositions pharmaceutiques topiques destinees au traitement de pathologies allergiques des voies respiratoires
DE10349115A1 (de) * 2003-10-22 2005-06-16 Biosyn Arzneimittel Gmbh Kombinationspräparat zur Behandlung der Sepsis
WO2014022886A1 (fr) * 2012-08-08 2014-02-13 Fischer Karen Jane Procédé, utilisation et composition de complément alimentaire pour au moins traiter un trouble atopique ou non-atopique chez un patient

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3307382A1 (de) * 1983-03-02 1984-09-06 Hans-Peter 8022 Grünwald Walter Arzneimittel, geeignet zur behandlung von entzuendlichen veraenderungen der bronchialschleimhaut
DE3517916A1 (de) * 1985-05-18 1986-11-20 Krüger GmbH & Co KG, 5060 Bergisch Gladbach Vitamin-e-brausetabletten
US5002780A (en) * 1987-07-31 1991-03-26 Caola Kozmetikai Es Haztartasvegyipari Vallalat Magnesium salt of a fatty acid acyl lactylate
FR2688133A1 (fr) * 1992-03-06 1993-09-10 Plantes Tropicales Lab Composition d'hygiene a base d'eau de mer.
CH684630A5 (fr) * 1992-08-21 1994-11-15 Danielle Girardet Composition pharmaceutique à base d'oligo-éléments.
WO1995028937A1 (fr) * 1994-04-20 1995-11-02 Béres Export-Import Rt. Concentre aqueux et son procede de preparation
EP0705542A1 (fr) * 1994-09-21 1996-04-10 Sandoz Nutrition Ltd. Composition diététique destinée à des adolescents
WO1996019182A1 (fr) * 1994-12-21 1996-06-27 Cosmederm Technologies Formulations et procedes pour diminuer l'irritation de la peau
US5552267A (en) * 1992-04-03 1996-09-03 The Trustees Of Columbia University In The City Of New York Solution for prolonged organ preservation
EP0739629A1 (fr) * 1995-04-28 1996-10-30 Ravi Shrivastava Nouvelles associations comprenant du (-)hydroxycitrate et présentant notamment de nouvelles activités thérapeutiques
WO1997025959A2 (fr) * 1996-01-18 1997-07-24 Fleming & Company, Pharmaceuticals Compositions et procedes s'appliquant a la prevention et au traitement de l'atherosclerose et des lesions consecutives a des perfusions au moyen de sels de magnesium
WO1997026894A1 (fr) * 1996-01-25 1997-07-31 Weglicki William B Gluconate de magnesium intraveineux pour le traitement d'etats causes par un stress oxydant imputable a la repartition des radicaux libres
US5681554A (en) * 1995-06-28 1997-10-28 Cosmair, Inc. Composition for treating hair and method for using the same

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3307382A1 (de) * 1983-03-02 1984-09-06 Hans-Peter 8022 Grünwald Walter Arzneimittel, geeignet zur behandlung von entzuendlichen veraenderungen der bronchialschleimhaut
DE3517916A1 (de) * 1985-05-18 1986-11-20 Krüger GmbH & Co KG, 5060 Bergisch Gladbach Vitamin-e-brausetabletten
US5002780A (en) * 1987-07-31 1991-03-26 Caola Kozmetikai Es Haztartasvegyipari Vallalat Magnesium salt of a fatty acid acyl lactylate
FR2688133A1 (fr) * 1992-03-06 1993-09-10 Plantes Tropicales Lab Composition d'hygiene a base d'eau de mer.
US5552267A (en) * 1992-04-03 1996-09-03 The Trustees Of Columbia University In The City Of New York Solution for prolonged organ preservation
CH684630A5 (fr) * 1992-08-21 1994-11-15 Danielle Girardet Composition pharmaceutique à base d'oligo-éléments.
WO1995028937A1 (fr) * 1994-04-20 1995-11-02 Béres Export-Import Rt. Concentre aqueux et son procede de preparation
EP0705542A1 (fr) * 1994-09-21 1996-04-10 Sandoz Nutrition Ltd. Composition diététique destinée à des adolescents
WO1996019182A1 (fr) * 1994-12-21 1996-06-27 Cosmederm Technologies Formulations et procedes pour diminuer l'irritation de la peau
EP0739629A1 (fr) * 1995-04-28 1996-10-30 Ravi Shrivastava Nouvelles associations comprenant du (-)hydroxycitrate et présentant notamment de nouvelles activités thérapeutiques
US5681554A (en) * 1995-06-28 1997-10-28 Cosmair, Inc. Composition for treating hair and method for using the same
WO1997025959A2 (fr) * 1996-01-18 1997-07-24 Fleming & Company, Pharmaceuticals Compositions et procedes s'appliquant a la prevention et au traitement de l'atherosclerose et des lesions consecutives a des perfusions au moyen de sels de magnesium
WO1997026894A1 (fr) * 1996-01-25 1997-07-31 Weglicki William B Gluconate de magnesium intraveineux pour le traitement d'etats causes par un stress oxydant imputable a la repartition des radicaux libres

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BERKOW: "MERCK MANUAL OF DIAGNOSIS AND THERAPY" 1987 , MERCK SHARP & DOHME RESEARCH LABORATORIES , RAHWAY, N.J. XP002080013 14658 see page 65, paragraph 1 - page 67, paragraph 4 *
MANSMANN H C JR: "Manifestation of concurrent intracellular magnesium deficiency in symptomatic allergic patients." SMETANA, R. (ED.). ADVANCES IN MAGNESIUM RESEARCH, 1. MAGNESIUM IN CARDIOLOGY;FIFTH EUROPEAN MAGNESIUM CONGRESS, VIENNA, AUSTRIA, 1995. XIII+617P. JOHN LIBBEY AND CO. LTD.: LONDON, ENGLAND, UK. 0 (0). 1997. 308-312. ISBN: 0-86196-555-8, XP002080011 *
SARMA P.C. ET AL: "Therapeutic uses of magnesium." INDIAN JOURNAL OF PHARMACOLOGY, (1995) 27/1 (7-13). ISSN: 0253-7613 CODEN: INJPD2, XP002080012 India *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001007019A2 (fr) * 1999-07-27 2001-02-01 Zambon Group S.P.A. Utilisation de n-acetyle cysteine pour la preparation de compositions pharmaceutiques topiques destinees au traitement de pathologies allergiques des voies respiratoires
WO2001007019A3 (fr) * 1999-07-27 2001-09-27 Zambon Spa Utilisation de n-acetyle cysteine pour la preparation de compositions pharmaceutiques topiques destinees au traitement de pathologies allergiques des voies respiratoires
DE10349115A1 (de) * 2003-10-22 2005-06-16 Biosyn Arzneimittel Gmbh Kombinationspräparat zur Behandlung der Sepsis
WO2014022886A1 (fr) * 2012-08-08 2014-02-13 Fischer Karen Jane Procédé, utilisation et composition de complément alimentaire pour au moins traiter un trouble atopique ou non-atopique chez un patient
GB2521979A (en) * 2012-08-08 2015-07-08 Karen Jane Fischer A method, use, and dietary supplement composition for at least treating an atopic or non-atopic disorder in a patient
US10543229B2 (en) 2012-08-08 2020-01-28 Karen Jane Fischer Dietary supplement composition as a prophylactic and treatment for skin diseases such as eczema and psoriasis and the like and method of treatment

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