WO2000043020A1 - Composition anti-inflammatoire a base d'oeuf et methode de traitement et de prevention de l'inflammation - Google Patents

Composition anti-inflammatoire a base d'oeuf et methode de traitement et de prevention de l'inflammation Download PDF

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Publication number
WO2000043020A1
WO2000043020A1 PCT/US1999/030969 US9930969W WO0043020A1 WO 2000043020 A1 WO2000043020 A1 WO 2000043020A1 US 9930969 W US9930969 W US 9930969W WO 0043020 A1 WO0043020 A1 WO 0043020A1
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Prior art keywords
egg
inflammatory composition
dna
inflammatory
partially purified
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PCT/US1999/030969
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English (en)
Inventor
Lee R. Beck
Orn Adalsteinsson
Michael J. Daley
Sandra Fitzpatrick-Mcelligott
Hellen Chaya Greenblatt
Jeffrey G. Hunchar
Young-Zoon Lee
Subramanian Iyer
Ruye Xing
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Dcv, Inc.
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Priority to CA002355168A priority Critical patent/CA2355168A1/fr
Priority to EP99967649A priority patent/EP1143984A1/fr
Priority to JP2000594474A priority patent/JP2002535279A/ja
Priority to AU23898/00A priority patent/AU2389800A/en
Publication of WO2000043020A1 publication Critical patent/WO2000043020A1/fr

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    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/57—Birds; Materials from birds, e.g. eggs, feathers, egg white, egg yolk or endothelium corneum gigeriae galli
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
    • C07K16/1228—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
    • C07K16/1228—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K16/1232—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia from Escherichia (G)
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
    • C07K16/1228—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K16/1235—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia from Salmonella (G)
    • C—CHEMISTRY; METALLURGY
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    • C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
    • C07K16/1271—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Micrococcaceae (F), e.g. Staphylococcus
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    • C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
    • C07K16/1275—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Streptococcus (G)
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    • C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
    • C07K16/1292—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Actinomyces; from Streptomyces (G)
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
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    • A61K2039/507—Comprising a combination of two or more separate antibodies
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    • C07K2317/23—Immunoglobulins specific features characterized by taxonomic origin from birds

Definitions

  • the invention generally relates to a composition and method for treating and preventing inflammation.
  • the invention specifically relates to an egg anti- inflammatory composition, methods for its production in partially purified form, and methods for its use in the treatment of inflammation, (in particular arthritis), and autoimmune diseases.
  • Inflammation as defined in Dorland's Medical Dictionary, is "a localized protective response, elicited by injury or destruction of tissues, which serves to destroy, dilute or wall off both the injurious agent and the injured tissue.” It is characterized by fenestration of the microvasculature, leakage of the elements of blood into the interstitial spaces, and migration of leukocytes into the inflamed tissue. On a macroscopic level, this is usually accompanied by the familiar clinical signs of erythema, edema, hyperalgesia (tenderness), and pain.
  • the leukocytes phagocytose the complexes of antigen-antibody and complement, and also release the many enzymes contained in their lysosomes. These lysosomal enzymes then cause injury to cartilage and other tissues, and this furthers the degree of inflammation. Cell-mediated immune reactions may also be involved. Prostaglandins, which are key intracellular regulators of cellular function, are also released during this process.
  • the inflammatory response is any response characterized by inflammation as defined above. It is well known, to those skilled in the medical arts, that the inflammatory response causes much of the physical discomfort (i.e., pain and loss of function) that has come to be associated with different diseases and injuries.
  • Rheumatoid arthritis is an autoimmune disease characterized by pain, swelling and stiffness in the joints. Rheumatoid arthritis is a disease which afflicts approximately 3% of Americans, and particularly women. Rheumatoid arthritis is an extremely disabling disease and usually strikes adults between the ages of 30 and 40 years, while the occurrence of clinical illness is greatest among those aged 40 - 60 years. Although drug therapy is somewhat effective, as many as 7% of rheumatoid arthritis sufferers are disabled to some extent as quickly as 5 years after disease onset, and within 10 years, as many as 50% are too disabled to work (Medical Sciences Bulletin, December 1994).
  • Osteoarthritis produces similar symptoms to rheumatoid arthritis.
  • osteoarthritis begins as a degeneration of articular cartilage
  • rheumatoid arthritis begins as inflammation in the synovium
  • each process approaches the other as the disease progresses.
  • cartilage deteriorates and joint congruence is altered
  • a reactive synovitis often develops.
  • rheumatoid arthritis erodes cartilage, secondary osteoarthritis changes in bone and cartilage develop.
  • the involved joints appear the same.
  • Some other forms of arthritis include Ankylosing Seronegative Spondyloarthropathy (ankylosing spondylitis) and reactive arthritis. These conditions are often referred to as the "B-27 associated diseases," and are difficult to differentiate from rheumatoid arthritis. In some cases ankylosing spondylitis, Reiters syndrome or psoriatic arthritis are present coincidingly with Rheumatoid Arthritis in the same patient. In many cases, these patients, are treated with the same disease modifying drugs as those suffering from progressive rheumatoid arthritis.
  • Onset of arthritis generally occurs after the age of 30 in those who are susceptable to such disease.
  • some forms of arthritis may be initiated by different causes, such as slow virus infections. Because there is great overlap, many physicians consider these forms as "generalized rheumatism" and approach management of the diseases in the same way.
  • Some diseases which fall into this category include Chronic Fatigue Syndrome, fibromyalgia (fibrositis) and gout.
  • fibromyalgia fibrositis
  • gout fibromyalgia
  • rheumatoid arthritis is an autoimmune disease, and as such, its etiology is much the same as the etiology of any other autoimmune disease.
  • the body normally recognizes the difference between its own by- products and foreign invaders (i.e. bacteria, viruses, fungi and protozoans, to name a few).
  • an immune cell T or B lymphocyte
  • T or B lymphocyte reacts to a "self-protein" during its development, that cell is deemed defective and usually destroyed or inactivated.
  • a self-reactive immune cell will escape destruction. At a certain later time, that cell can be activated and trigger an immune response.
  • Activation is thought to occur after infection with a common bacteria or virus which contains a polypeptide having a stretch of amino acids which match a stretch on the defective self-protein.
  • bacteria such as Streptococcus, Mycoplasma, and borrelia
  • Streptococcus have been implicated in the initiation of the disease, as well as certain viruses, namely retroviruses.
  • viruses namely retroviruses.
  • autoimmunity often results in such diseases as juvenile diabetes, multiple sclerosis, Graves' disease, Meneri's disease, myasthenia gravis, lupus erythematosus and psoriasis. (Medical Sciences Bulletin, September, 1994).
  • autoimmune diseases of liver bile ducts, and kidneys are: primary biliary cirrhosis, necrotizing glomerulonephritis, "idiopathic" crescentic glomerulonephritis, virus-induced liver and kidney disease, chronic hepatitis, autoimmune and drug-induced hepatatis (Gershwin, Manns, and Mackay 1992). Immune destruction of the islets of Langerhans results in diabetes meillitus (Hagopian and Lernmark 1992) and insulin autoantibodies have been described (Palmer 1987).
  • autoimmunity may play a role in many forms of heart disease includings: postpericardiotomy and postmyocardial infarction syndromes, myocarditis, and idiopahtic dilated cardiomyopathy. Autoimmunity may be responsible for the progression of acute disease of heart muscle to degenerative (Rose, Neumann, Burek, Herskowitz 1992).
  • autoimmune diseases such as polymyositis or inflammatory myopathy (which may include rheumatoid arthritis, polymyalgia rheumatica, myasthenia gravis, myasthenic myopathy, neurogenic atrophy, motor neuron disease, fibromyalgia, fibrositis, muscular dystrophy, endocrine, metabolic, and carcinomatous myopathy).
  • polymyositis or inflammatory myopathy which may include rheumatoid arthritis, polymyalgia rheumatica, myasthenia gravis, myasthenic myopathy, neurogenic atrophy, motor neuron disease, fibromyalgia, fibrositis, muscular dystrophy, endocrine, metabolic, and carcinomatous myopathy.
  • autoimmune origins may be uveitis, Vogt-Koyanagi-Harada syndrome, (Detrick and Hooks 1992), and Sjogren's syndrome, scleroderma, ankylosing spondylititis, dermatomyositis, psoriasis, psoriatic arthritis, Reiter's syndrome (NIH 1994).
  • Alzheimer's disease (Singh et al., 1992), dementia complex (Mastroianni et al., 1991) and autistic children (Singh et al., 1993).
  • Several neurologic diseases such as Sydenham's Chorea, chronic obsessive- compulsive disorders (OCD), attention deficit hyperactivity disorder (ADHD), Tourette's Syndrome (TS) and some cases of schizophrenia may have an auto- immune component and may be associated with anti-neuronal antibodies (Medical Sciences Bulletin, Sept. 1994).
  • OCD chronic obsessive- compulsive disorders
  • ADHD attention deficit hyperactivity disorder
  • TS Tourette's Syndrome
  • schizophrenia may have an auto- immune component and may be associated with anti-neuronal antibodies (Medical Sciences Bulletin, Sept. 1994).
  • Anti-inflammatory drugs are used for the treatment of a wide spectrum of disorders, and the same drugs are often used to treat different diseases. Treatment with anti-inflammatory drugs is not for the disease, but most often for the symptom (i.e., inflammation).
  • the anti-inflammatory, analgesic, and anti-pyretic drugs are a heterogeneous group of compounds, often chemically unrelated, which nevertheless share certain therapeutic actions and side-effects.
  • Corticosteroids represent the most widely- used class of compounds for the treatment of inflammation.
  • Proteolytic enzymes represent another class of compounds that are thought to have anti-inflammatory effects.
  • Hormones that directly or indirectly cause the adrenal cortex to produce and secrete steroids represent another class of anti-inflammatory compounds.
  • the natural and synthetic corticosteroid preparations cause a number of severe side effects, including elevation of blood pressure, salt and water retention, kidney damage and increased potassium and calcium excretion.
  • corticosteroids may mask the signs of infection and enhance dissemination of infectious microorganisms.
  • corticosteroid treatment has been associated with gastric hyperactivity and/or peptic ulcers.
  • Treatment with corticosteroids may also aggravate diabetes mellitus, requiring higher doses of insulin, and may produce psychotic disorders.
  • Hormonal anti-inflammatory agents which indirectly increase the production of endogenous corticosteroids have the same potential for adverse side-effects.
  • NSAJDs non-steroidal anti-inflammatory drugs
  • DMARDs disease-modifying agents
  • methotrexate gold compounds
  • penicillamine sulfasalazine
  • antimalarial drugs antimalarial drugs
  • all of the above drugs have serious side effects, especially when administered in elevated doses.
  • aspirin an NSAID
  • phenylbutazone may produce stomach ulcers and phenacetin may lead to kidney disease.
  • Methotrexate may cause oral ulceration and gastrointestinal (GI) side effects. If a natural food product having anti-inflammatory effects could be obtained, it would provide an easily administratable, readily available, and safe therapeutic composition for the treatment of arthritis, autoimmune diseases and inflammation in general.
  • GI gastrointestinal
  • U.S. Patent No. 4,357,272 discloses the isolation of antibodies from the yolks of eggs derived from hyperimmunized hens. The hyperimmunization was elicited by repetitive injections of immunogens derived from plant viruses, human IgG, tetanus antitoxin, snake antivenins, and Serameba.
  • U.S. Patent No. 4,550,019 discloses the isolation from egg yolks of antibodies raised in the hen by hyperimmunization with immunogens having a molecular or particle weight of at least 30,000. The immunogens used to hyperimmunize the chickens were selected from among plant viruses, human immunoglobulins, tetanus toxin, and snake venoms.
  • U.S. Patent No. 4,748,018 discloses a method of passive immunization of a mammal that comprises parenterally administering purified antibody obtained from the eggs of an avian that has been immunized against the corresponding antigen, and wherein the mammal has acquired immunity to the eggs.
  • U.S. Patent No. 5,772,999 assigned to DCV-Biologics, discloses a method of preventing, countering or reducing chronic gastrointestinal disorders or Non- Steroidal Anti-Inflammatory Drug-induced (NSAID-induced) gastrointestinal damage in a subject by administering hyperimmunized egg and/or milk or fractions thereof to the subject.
  • NSAID-induced Non- Steroidal Anti-Inflammatory Drug-induced
  • the invention is based on the inventors' discovery that there is anti-inflammatory activity in egg and egg products, and particularly in egg products obtained from hyperimmunized avians, which when administered to a subject animal, in particular, mammals, prevents or reduces inflammation in that subject animal.
  • the invention is directed to a partially purified anti-inflammatory composition obtained from the eggs of an avian.
  • the anti-inflammatory composition was partially purified from fractions isolated from both egg yolk and egg white.
  • the invention is also directed to a hyperimmunization process which produces supranormal levels of the anti-inflammatory composition in an avian egg. It is the inventors' belief that the level of the anti-inflammatory composition can be increased in both egg yolk and egg white by the process of hyperimmunization.
  • the invention also encompasses a method of treating inflammation in a subject, and especially mammals, which comprises administering to the subject the partially pure anti-inflammatory composition or a composition comprising the partially pure anti-inflammatory composition. This aspect encompasses administering whole egg itself and/or fractions thereof.
  • the invention is further based on the inventors' discovery that there is activity in egg and egg products, and particularly in egg products obtained from hyperimmunized avians, which when administered to a subject animal, in particular, mammals, treats or prevents arthritis and/or autoimmune diseases in the subject animal.
  • the invention is finally directed to a method wherein the egg product is administered to the subject animal in combination with a drug selected from the group consisting of non-steroidal, anti-inflammatory drugs and disease-modifying, anti-arthritic drugs.
  • Figure 1 is a flow chart of the purification of the less than 3,000 molecular weight anti-inflammatory composition from powdered egg yolk.
  • Figure 2 is a flow chart of the purification of the less than 3,000 molecular weight anti-inflammatory composition from powdered egg white.
  • Figure 3 is our absorbance depiction of the separation of the partially purified anti- inflammatory composition by Sepharose Column.
  • Figure 4 is a chromatogram of the HPLC separation of the partially pruified anti- inflammatory composition from hyperimmune egg yolk.
  • Figure 5 is a graph showing the effect of hyperimmune egg on the incidence of arthritis using the Rat Type II Collagen Model.
  • Figure 6 is a graph showing the effect of the hyperimmune egg, its fractions and the partially purified anti-inflammatory composition on the severity of arthritis in the Rat Type II Colagen Model.
  • the invention generally relates to a composition and method for treatment and prevention of inflammation in general, and particularly arthritis and autoimmune diseases.
  • the composition is preferably a natural food product which comprises hyperimmune egg or egg product.
  • the food product when administered by the method of the invention, not only provides relief from the pain and other symptoms caused by arthritis and autoimmune diseases, but can delay, and even prevent, the onset of such diseases.
  • the preferred antigen mixture injected into the avians to produce the hyperimmune egg product does not contain specific antigens which are known to cause inflammation or autoimmune diseases. Therefore, it is surprising that administration of hyperimmune egg or egg product obtained from avians immunized against a mixed antigen vaccine is effective in reducing the symptoms of and preventing inflammation and autoimmune diseases when administered to a subject.
  • inflammation is used in its art-recognized sense as a localized protective response elicited by injury or destruction of tissues which serves to destroy, dilute or wall off both the injurious agent and the injured tissue, characterized in the inappropriate, uncontrolled form by the classical sequence of pain, heat, redness, swelling, and loss of function, and histo logically involving a complex series of events, including dilation of the arterioles, capillaries, and venules with increased permeability and blood flow, exudation of fluids including plasma proteins, and leukocyte migration into the inflammatory focus.
  • arthritis means any of a variety of disorders marked by inflammation and degeneration of connective tissue structures, especially the joints and related structures. It may be attended by pain, stiffness, or limitation of motion of these parts.
  • Some forms of arthritis include rheumatoid arthritis, osteoarthritis, ankylosing seronegative spondyloarthropathy, reactive arthritis, chronic fatigue syndrome, fibromyalgia (fibrositis) and gout.
  • autoimmune disease is applied the standard medical definition as found in standard medical dictionaries such as Dorland's and Taber's. A description of a variety of autoimmune diseases can be found in the Background section of this document.
  • hyperimmunization means exposure to one or more antigens such that an immune response is elevated and maintained above the natural unexposed state.
  • egg or "egg product” each mean any whole egg (table, hyperimmunized or otherwise) or any product or fraction derived therefrom.
  • table egg or “table egg product” each mean a whole egg, or any product or fraction derived therefrom, obtained from egg-producing animals which are not maintained in a hyperimmune state.
  • anti-inflammatory egg or egg fraction means egg or egg fractions containing the anti-inflammatory composition disclosed herein.
  • anti-inflammatory composition means the composition disclosed herein which counteracts or suppresses the inflammatory process.
  • partially pure egg anti-inflammatory composition means an anti- inflammatory composition at least of the purity described in Example 4 and the exemplary materials and figures.
  • combinatorial derived immunogens refers to a process of generating molecular diversity among immunogens by way of combinatorial synthesis.
  • bioengineered immunogens refers to immunogens which are obtained through the process of gene cloning technologies and genetic manipulation which allow the insertion and translation of proteins which have antigenic properties.
  • genetic vaccine refers to a nucleic acid vaccine which is generally produced by recombinant technologies and which may elicit an immune response.
  • treatment means that the onset of the symptoms (including pain) of the disorder and/or pathogenic origin of the disorder be delayed or completely prevented, or, if present, the symptoms be ameliorated or completely eliminated.
  • the hyperimmune egg product treats arthritis and/or an autoimmune disease not only by suppressing the symptoms of the disorder in humans and other mammals, but also by acting as a prophylactic agent to counteract the presence of the disorder in the recipient.
  • prevention means that the progression of the disease is reduced and/or eliminated, or that the onset of the disease is eliminated.
  • administer means any method of providing a subject with a substance, including orally, intranasally, parenterally (intravenously, intramuscularly, or subcutaneously), rectally, topically or intraocularly.
  • animal means the animal kingdom definition.
  • target animal refers to an animal which functions as the egg or egg product producing animal.
  • subject animal refers to the animal which is administered the egg or egg product produced by the target animal.
  • immunogen means a substance that is able to induce a humoral antibody and/or cell-mediated immune response rather than immunological tolerance.
  • the term signifies the ability to stimulate an immune response as well as react with the products of it, e.g., antibody.
  • the product and method of the invention relate particularly to the use of hyperimmune egg, which is a natural food product, in the treatment and prevention of inflammatory and autoimmune diseases. Being natural, this food product can be used to treat and prevent such diseases without the fear of side effects, except, of course, for allergic reactions in those intolerant to eggs.
  • the invention comprises a hyperimmune egg or egg product which is effective in treating and preventing arthritis and/or an autoimmune disease in a subject animal.
  • the hyperimmune egg is obtained from an egg- producing animal, and more preferably, an avian, which has been hyperimmunized with at least one immunogen.
  • the hyperimmune egg product is one which is preferably administered orally to the subject animal.
  • the hyperimmune egg or egg product can be further separated into more potent fractions which can subsequently be administered to a subject animal in a variety of forms.
  • the invention comprises an anti-inflammatory composition obtained from avian eggs, its partial purification, and the administration of the partially purified composition to a subject for the treatment of inflammation.
  • the invention further comprises the same anti-inflammatory composition partially purified from the egg of an avian that has been hyperimmunized with one or more immunogens, and, in particular, bacterial antigens, or their synthetic equivalent.
  • the anti-inflammatory composition is present in hyperimmune eggs at supranormal levels which provide anti- inflammatory activity in subject animals.
  • the egg anti-inflammatory composition can be partially purified from whole egg, egg yolk or egg white.
  • An example of a preferred partial purification process is as follows: 1. Preparation of a water-soluble fraction from an egg;
  • the anti-inflammatory composition can be partially purified from whole egg, egg yolk or egg white.
  • the composition is purified from egg yolk.
  • the lipid portion is removed from the whole egg or egg yolk by methods well-known to those having skill in the art.
  • defatting can be accomplished with solvents (propane, butane or hexane or with binary solvents), supercritical CO 2 , enzymes and the like, and in the case of liquid egg yolk, defatting can be accomplished by the caprylic acid separation method (CAPS) disclosed by Lee (U.S. Pat. No. 5,367,054).
  • CAPS caprylic acid separation method
  • the resulting water soluble fractions from whole egg, egg yolk or egg white, are subjected to ultrafiltration using ultrafiltration systems equipped with a 3,000 molecular weight cut-off membrane.
  • the ultrafiltration process separates molecules having a molecular weight of more than approximately 3,000 daltons from those having a molecular weight of less than approximately 3000 daltons.
  • the resulting ultra-filtrates contain molecules of less than approximately 3,000 dalton molecular weight are then lyophilized, weighed, and prepared for bioassay testing and further separation.
  • Fractions from the less than 3,000 dalton ultra-filtrate can be separated by, for example, Reverse Phase High Performance Liquid Chromatography to further purify the partially pure anti-inflammatory composition.
  • the egg anti-inflammatory composition in the ultra-filtrate can be further characterized by anion exchange DEAE-Sepharose chromatography.
  • the preferred ultrafiltration is by Amicon RA1000 (3K MWCO) and DEAE ion-exchange chromatography . It is understood, however, that equivalent techniques and materials could be used to isolate the composition, given the information herein, and the knowledge available to the person of ordinary skill in the art.
  • Step 4 The anti-inflammatory activity of the composition can be tested by a standard bioassay which determines anti-inflammatory activity. Some examples include inhibition of leukocyte migration, rat paw edema test, adjuvant-induced arthritis, collagen induced arthritis, and intra-vital microscopy among others. Comparisons of egg anti-inflammatory composition with known anti-inflammatory drugs such as aspirin and indomethacin can also be done. And finally, clinical tests for rheumatoid arthritis, degenerative joint disease and injury induced arthritis can also be used to determine anti-inflammatory activity.
  • the anti-inflammatory action of the partially pure egg anti-inflammatory composition is measured by bio-assays.
  • a preferred bio-assay is the rat type II collagen assay as set forth in Example 6.
  • the leukocyte migration inhibition assay is another useful assay which is generally performed as follows: Samples containing the anti-inflammatory composition are administered to the artificially inflamed adult female rats with 1% carrageenan solution and then the anti-inflammatory effect of the samples at each dosage is determined (using Automated Image Analysis Technique) by the reduction in the number of leukocytes in the pleural exudates of the treated rats as compared to those of control rats.
  • the anti-inflammatory action of the substantially pure anti- inflammatory composition can be tested on edema caused by injecting carrageenan into rat footpads (Winter, C.A., Risley, G.A., Nuss, A.W., "Carrageenan-Induced Edema in the Hind Paw of the Rat as an Assay for Anti- Inflammatory Drugs," Proc. Soc. Exper. Biol. Med. 3:544 (1967)).
  • the 3,000 dalton molecular weight is deduced from the partial isolation and purification of the composition wherein the isolation and purification process uses an ultra-filtration membrane that does not allow the passage of molecular species greater than 3,000 Dalton therethrough.
  • the partially purified anti-inflammatory composition is determined to be non-proteinaceous and non-steroidal because it is small in size and is not degraded by enzymes which degrade proteins. Moreover, the composition is orally active and is not degraded by digestive enzymes.
  • the small stable form of the partially purified anti-inflammatory composition (as differentiated from proteins which are much larger) facilitates its abso ⁇ tion from the digestive tract.
  • the partially purified anti-inflammatory composition is heat-stable.
  • the partially purified egg anti-inflammatory composition can be isolated from whole egg, egg yolk and egg white.
  • the anti-inflammatory composition partially purified from egg yolk shows higher anti-inflammatory activity than anti- inflammatory composition partially purified from egg white.
  • the hyperimmune egg or egg product can be produced by any egg-producing animal. It is preferred that the animal be a member of the class A ves or, in other words, an avian. Within the class Aves, domesticated fowl are preferred, but other members of this class, such as turkeys, ducks, and geese, are a suitable source of hyperimmune egg product.
  • egg-producing animals When such egg-producing animals are brought to a specific state of immunization by means of, for example, periodic booster administrations of immunogens, the animals will produce eggs that, when consumed by a subject, will have beneficial properties, including supranormal levels of the anti-inflammatory composition, which are effective in the treatment and prevention of inflammatory related diseases as well as autoimmune diseases in that subject.
  • the preferred dosage of booster should be equal to or greater than 50% of the dosage necessary to produce primary immunization of the avian.
  • a threshold booster dosage below which the properties are not produced in the avian's egg, even though the avian is in what normally would be called an immune state.
  • the hyperimmune state is preferably produced by any immunogen or combination of immunogens. Hyperimmunization is preferably achieved by multiple exposures to multiple immunogens, multiple exposure to single immunogens, or single exposures to libraries of immunogens. Nearly any immunogen can be used to induce the hyperimmune state, including, but not limited to, bacterial, viral, protozoan, allergan, fungal or cellular substances.
  • immunization may also be accomplished using immunogens which are synthetically derived by combinatorial chemistries.
  • the basic strategy is to assemble multiple combinations of chemical building blocks for producing a population of molecules with diversity.
  • Several methods have recently been developed for solid and solution phase combinatorial synthesis of libraries of oligomers (Fodor, S. et al., Science 251 :767 (1991); Houghton, R. et al., Nature 354:82 (1991)) as well as small organic molecules (Bunin, B. & Ellman, J., J. Am. Chem. Soc. 114:10997 (1992)). Rapid multiple peptide and oligomer synthesis can serve as a source for combinatorial derived immunogens.
  • an alternative strategy would allow the addition of organic building blocks in combinatorial fashion to a backbone molecule for improved immunogenicity.
  • any DNA construct (generally consisting of a promoter region and an antigen encoding sequence) will trigger an immune response.
  • Genetic vaccines consist of antigen-coding vectors, fragments of naked DNA, plasmid DNA, DNA- RNA antigens, DNA-protein conjugates, DNA-liposome conjugates, DNA expression libraries, and viral and bacterial DNA delivered to produce an immune response.
  • Methods of DNA delivery include particle bombardment, direct injection, viral vectors, liposomes and jet injection, among others. When applying these delivery methods, much smaller quantities may be necessary and generally result in more persistent immunogen production.
  • the preferred method for introducing DNA into avians is through intramuscular injection of the DNA into the breast muscle.
  • Methods of DNA delivery include, but are not limited to, particle bombardment, direct injection, liposomes, jet injection (Fynan, E.F. et al., Proc. Natl. Acad. Sci. USA 90:11478-11482 (1993)).
  • the nucleic acids that code for known or unknown immunogens, promoter regions (notably CMV cauliflower mosaic virus) and SV40 bacterial origin can be replicated in bacteria to produce plasmid DNA for use in DNA injections.
  • the preferred method is intramuscular injection to the breast muscle.
  • Vaccine trials are carried out in egg laying avians, preferably chickens. Repeated immunizations are given at one to two week intervals for up to six months.
  • the amounts of DNA used are generally in the order of 50-300 ⁇ g of DNA in saline for direct injection.
  • 4-100 ⁇ g of DNA co-precipitated onto gold beads by the addition of 2.5 M CaCl 2 are preferred. Repeated immunizations can be given intradermally by this method of accelerating DNA coated particles into the live animal.
  • Step 1 Any immunogen or combination of immunogens may be employed as a vaccine.
  • the immunogens can be bacterial, viral, protozoan, fungal, cellular, or any other substances to which the immune system of an egg-producing animal will respond.
  • the critical point in this step is that the immunogen(s) must be capable of inducing immune and hyperimmune states in the egg-producing animal.
  • one preferred vaccine is a mixture of polyvalent bacterial and viral antigens selected from the following antigen families: the enteric bacilli and bacteroides, pneumococci, pseudomonas, salmonella, streptococci, bacilli, staphylococci, neisseria, clostridia, mycobacteria, actinomycetes chlamydiae, and mycoplasma.
  • Viral antigens are preferably selected from the following antigen families: adenoviruses, picornaviruses and herpes viruses, although other viral antigen families will work.
  • S-100 polyvalent vaccine referred to as Series 100
  • the bacteria included in the S-100 vaccine are listed in Table 1 of Example 1. This vaccine has been previously described in US patent Nos. 5,106,618 and 5,215,746, both assigned to Stolle Research and Development Co ⁇ oration.
  • the vaccine can be either a killed or live-attenuated vaccine and can be administered by any method that elicits an immune response. It is preferred that immunization be accomplished by administering the immunogens through intramuscular injection.
  • the preferred muscle for injection in an avian is the breast muscle. Dosage is preferably 0.05-5 milligrams of the immunogenic vaccine.
  • Other methods of administration include intravenous injection, intraperitoneal injection, intradermal, rectal suppository, aerosal, oral, topical or ocular administration. When DNA techniques are used for the hyperimmunization process, much smaller quantities are required, generally 300 micrograms.
  • ELISA enzyme-linked immunosorbent assays
  • tests for the presence of antibodies to the stimulating antigens tests designed to evaluate the ability of immune cells from the host to respond to the antigen.
  • the minimum dosage of antigen necessary to induce an immune response depends on the vaccination procedure used, including the type of adjuvants and formulation of antigen(s) used as well as the type of egg-producing animal used as the host.
  • Step 3 The hyperimmune state is preferably induced and maintained in the target animal by repeated booster administrations of an appropriate dosage at fixed time intervals.
  • the time intervals are preferably 2-8 week intervals over a period of 6- 12 months.
  • Such processes are well known in the art.
  • Several combinations of primary and hyperimmunization are known to those skilled in the art.
  • Step 4. It is necessary to test the eggs for anti-inflammatory activity levels.
  • Step 5 involves the collection and processing of the egg(s) containing the anti-inflammatory composition.
  • the egg can be collected by conventional methods. Processing the egg can be accomplished in a variety of ways described later in this document. The egg can also be further processed to purify the anti-inflammatory composition as described below.
  • the eggs or fractions thereof, including the partially purified anti-inflammatory composition, collected from hyperimmunized animals are processed to produce a hyperimmune egg product, which can subsequently be administered to a subject animal.
  • the egg itself or fractions thereof, including the partially purified anti- inflammatory composition of the present invention are administered to a subject animal by any means that treats or prevents inflammation, including arthritis, and/or autoimmune disease in the subject animal. It is preferred that administration occur by directly feeding the egg or any derivative of the egg to the subject animal. It is important to note that whole egg, egg yolk, and egg white are natural food ingredients which are non-toxic and safe.
  • the egg or any fraction thereof, including the partially purified anti-inflammatory composition is integrated into a nutritional supplement.
  • One preferred method for preparing the egg or any fraction thereof to be inco ⁇ orated into a nutritional supplement involves drying the egg into an egg powder.
  • spray drying is a preferred method. The process of spray drying eggs is well known in the art.
  • Such a dried egg powder can be inco ⁇ orated into drinks in the form of, for example, protein powders, power building drinks, protein supplements and any other nutritional, athlete-associated products.
  • the egg powder can be used in bake mixes, power bars, candies, cookies, etc.
  • Other examples of egg processing include making an omelet, soft or hard-boiling the egg, baking the egg, or, if desired, the egg can be eaten raw or processed as liquid egg.
  • further separation and purification such as in the case of the partially purified anti-inflammatory composition, will allow for other modes of administration such as administering egg product parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intranasally, orally or topically.
  • further separation will provide for the ability to make encapsulated products and pharmaceutical compositions with said egg or fraction thereof.
  • Preparations of the anti-inflammatory composition for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions.
  • nonaqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
  • oral administration is preferably accomplished through solid dosage forms which include capsules, tablets, pills, powders and granules, among others.
  • the anti-inflammatory composition is admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluent.
  • the dosage forms may also comprise buffering agents, pH sensitive polymers, or any other slow-releasing encapsulants which are typically used as encapsulating compositions in the food and drug industry. Tablets and pills can additionally be prepared with an enteric coating.
  • Liquid dosage forms of the anti-inflammatory composition for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, containing inert diluents commonly used in the pharmaceutical art. Besides inert diluents, compositions can also include wetting agents, emulsifying, and suspending , and sweetening agents.
  • the hyperimmune egg or egg product including the partially purified anti- inflammatory composition of the invention is effective in treating and preventing inflammation, and in particular, all forms of arthritis, including, but not limited to, rheumatoid arthritis, osteoarthritis, ankylosing seronegative spondyloarthropathy, reactive arthritis, chronic fatigue syndrome, fibromyalgia (fibrositis) and gout.
  • arthritis including, but not limited to, rheumatoid arthritis, osteoarthritis, ankylosing seronegative spondyloarthropathy, reactive arthritis, chronic fatigue syndrome, fibromyalgia (fibrositis) and gout.
  • the egg product of the invention is equally effective in treating autoimmune diseases, such as rheumatoid arthritis, juvenile diabetes, multiple sclerosis, Graves' disease, Meneri's disease, myasthenia gravis, lupus erythematosus, psoriasis, systemic scleroderma, rheumatic fever and Sjogren syndrome among others.
  • autoimmune diseases such as rheumatoid arthritis, juvenile diabetes, multiple sclerosis, Graves' disease, Meneri's disease, myasthenia gravis, lupus erythematosus, psoriasis, systemic scleroderma, rheumatic fever and Sjogren syndrome among others.
  • the hyperimmune egg product or any active fraction thereof, including the partially purified anti-inflammatory composition is preferably administered to the subject in an amount that is immunologically effective in treating and preventing the particular disorder. Duration and intensity of the treatment will depend upon the particular condition, whether it is present, and, if so, the advancement of the condition in the subject.
  • the hyperimmune egg product or any active fraction thereof, including the partially purified anti-inflammatory composition are also provided in any amount that treats and/or prevents the condition and the symptoms of the condition.
  • hyperimmune eggs or hyperimmune egg products containing the equivalent of less than one to several whole, hyperimmune eggs
  • More potent fractions can be separated and concentrated by methods described herein as well as other known methods in the art.
  • the egg product of the invention as well as the partially purified anti-inflammatory composition were found to be effective in treating rheumatoid arthritis in rats using a collagen-induced arthritis animal model (see Example 2).
  • This animal model is well recognized by those in the art as one which parallels the rheumatoid arthritis effect in humans.
  • the egg product when administered to rats prior to induction of arthritis, delayed, and in some cases, prevented the onset of the arthritic symptoms.
  • the egg product of the invention is effective in not only treating the symptoms of the disease, but also delaying and/or preventing the onset or progression of the disease.
  • the egg product was tested in humans and showed positive effects in treating various forms of arthritis in several humans suffering from such symptoms (see Example 9).
  • the humans who were treated by the egg product demonstrated a clinical reduction in such symptoms as pain in addition to a general reduction in swelling and stiffness.
  • Indicative of an effect on autoimmune disease is the su ⁇ rising reduction of Type II collagen antibodies by the egg product as well as the partially purified anti- inflammatory composition of the invention in this disease model, which was also seen in rats (see Example 3).
  • the egg product of the invention is effective in reducing antibodies involved with other autoimmune diseases such as juvenile diabetes, multiple sclerosis, Graves' disease, Meneri's disease, myasthenia gravis, lupus erythematosus, psoriasis, systemic scleroderma, rheumatic fever and Sjogren syndrome among others.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • DMARDs disease modifying anti-arthritic drugs
  • NSAIDs and DMARDs can cause severe gastrointestinal damage.
  • inflammatory conditions that may be treated by administration of the egg, egg product, and/or the anti-inflammatory composition of the present invention include acute and subacute bursitis, acute non-specific tendinitis, systemic lupus erythematosus, systemic dermatomyositis, acute rheumatic carditis, pemphigus, bullous dermatitis, he ⁇ eteformis, severe erythema, multiform exfoliative dermatitis, cirrhosis, seasonal perennial rhinitis, bronchial asthma, ectopic dermatitis, serum sickness, keratitis, opthalmicus ulceris, diffuse ureitis, chorditis, optic neuritis, sympathetic ophthalmia, symptomatic sarcoidosis, Loeffler's syndrome, berylliosis, hemolytic anemia, mastitis, mastoiditis, contact dermatitis, allergic conjunctivitis, psoriatic arthritis
  • the preferred dose range of hyperimmunized egg or egg product to be given to a subject is between 100 milligrams to 10 grams per kilogram of subject weight.
  • the preferred dose range of the partially purified composition is between 1 microgram and 400 milligrams per kilogram of the anti-inflammatory composition.
  • the dosage of active ingredients may be varied; however it is necessary that the amount of the active ingredient shall be such that a suitable dosage form is obtained. It will be recognized that the selected dosage form depends upon the desired therapeutic effect, on the route of the administration and on the duration of the treatment.
  • Example 1 PREPARATION OF S-100 VACCINE The multivalent vaccine known as "Series 100" or "S-100,” disclosed in U.S. Pat. No. 5,215,746 and containing the bacteria shown in Table 1 (obtained from the American Type Culture Collection), was reconstituted with 15 ml of medium and incubated overnight at 37C. Once good growth was obtained, approximately one- half of the bacterial suspension was used to inoculate one liter of broth which was then incubated at 37C. The remaining suspension was transferred to sterile glycol tubes and stored at -20C for up to six months.
  • the bacteria were harvested by centrifugation.
  • the bacterial pellet was resuspended in sterile physiological saline solution and the bacterial sample was centrifuged three times to wash the cells. After the third wash, the pellet obtained was resuspended in a small amount of double distilled water.
  • the medium- free bacterial suspension was heat-killed by placing the suspension in a glass flask in an 80C water bath overnight. The viability of the broth culture was tested with a small amount of heat-killed bacteria. Broth was inoculated with heat-killed bacteria, incubated at 37C for five days and checked daily for growth, as the bacteria have to be killed for use in the vaccine.
  • the heat-killed bacteria were lyophilized until dry.
  • the dry bacteria were then mixed with sterile saline solution to a concentration of 2.2 x 10 bacterial cells/ml saline (1.0 optical density reading at 660 ran).
  • a killed preparation of pathogens was prepared as described above.
  • the bacteria were mixed with complete Freund's adjuvant, and 5.6 mg of bacterial material were injected into the breast muscle of a chicken.
  • the bacterial preparation was mixed with the incomplete Freund's adjuvant and injected into the chickens at two week intervals for six months.
  • the dried egg yolk as prepared in Example 1 was subjected to liquid solvent extraction with either propane, or butane to separate the lipids from the aqueous yolk fraction containing the anti-inflammatory composition. Briefly, 500 grams of dry egg yolk powder was placed in a column, to which was added 4 liters of liquid propane solvent. The solvent supernatant and extracted lipid were removed. Six additional solvent extractions were performed for a total of six lipid extractions.
  • FIG. 1 shows a flow chart of the purification process.
  • Molecular species below 3,000 daltons from egg yolk contain the anti- inflammatory composition in a low molecular weight, non-aggregated form. From 400 grams of starting material, the yield of anti-inflammatory composition was approximately 12 grams or 3% of the total. Bioassay testing of this 3KDa fraction for anti-inflammatory activity showed high levels of activity (Example 5).
  • Example 2b PREPARATION OF EGG ANTI-INFLAMMATORY ACTIVITY FROM EGG
  • WHITE POWDER Four hundred grams of egg white, isolated from both hyperimmunized egg as described in Example 1 and control table egg, was diluted with four liter of deionized water. The mixture was homogenized and filtered through a 40 ⁇ m filter and ultrafiltered through a 3KDa MW CO ultra-filtration system ( Figure 2). From 400 g of egg white powder, 8.6 g or 2.15 % of anti-inflammatory composition was recovered.
  • Example 3 shows the preparation of the active anti-inflammatory composition from egg white material of both hyperimmune and control table eggs.
  • Example 3 DEAE ION EXCHANGE CHROMATOGRAPHY
  • the egg anti-inflammatory composition was also further characterized by anion exchange DEAE chromatography.
  • 3,000 Dalton ultra-filtration permeates from both delipidated egg yolk and egg white were prepared in the same manner as described in Example 2.
  • a DEAE Sepharose column (2.5 x 40.0 cm) was previously equilibrated at room temperature with 1,000 ml of 20 mM ammonium acetate buffer in sterile double distilled pyrogen free water pH 8.0.
  • 3,000 Dalton permeate of delipidated egg yolk (15 grams) or egg white (18 grams) was dissolved in 200 ml of sterile pyrogen free double distilled water and applied to the DEAE Sepharose colummn (pharmacia Biotech., Fast flow) with a flow rate of 100 ml/h.
  • Figure 3 shows a typical chromatogram of DEAE Sepharose separation of 3Kda permeate from delipidated egg yolk and egg white. Letters indicated the elution profile with buffers. Fractions were collected by every 15 ml elutent and their molecular absorbances at 280 nm and 220 nm were measured. Four fractions were pooled and the water was removed by lyophilization to dryness. Table 2 is the summary of the separation.
  • Figure 4 shows a Max plot chromatography of the separation of 3,000 Dalton permeate from delipidated PL- 100 egg yolk. By using the same analytic condition, 3,000 Dalton permeate prepared from delipidated Table egg yolk was also obtained (chromatography has not shown).
  • Table 3 summaries the result of HPLC analysis of 3,000 Dalton permeates. Peaks that are greater than 0.5% of peak area were collected. The similarities of peaks were compared within +/- 0.5% variability in their retention times. Common peaks mean that they are present in both PL- 100 egg yolk and Table egg yolk while PL- 100 peaks indicates that they are only present in PL- 100 egg. Comparing two fractions, 3,000 Dalton permeate of PI- 100 egg yolk shows 15 more peaks than that of Table egg yolk, suggesting that hyperimmunization on chicken could produce more biological components in its egg.
  • the preferred step is to separate the partially purified, less than approximately 3,000 daltons molecular weight, composition on a preparative HPLC column. Accordingly, a 5.08 X 20 cm column was packed with Zorbax C8 packing material and 4 grams of the less than 3,000 daltons MW ultrafiltrate was purified during each run. Using a mobile phase of 80/20 H 2 0/methanol with 0.05% TFA, at a flow rate of 90 ml per minute, the permeate was separated into the partially purified composition collected and lyophilize. Next the collected peak was re- tested on an analytical C8 column.
  • Collagen induced arthritis in rat is a popular experimental animal model of Rheumatoid arthritis and has been used by several laboratories and research institutions since 1977. Since its initial discovery, the animal model of collagen- induced arthritis has demonstrated many parallels to human rheumatoid arthritis. For example, Stuart and coworkers have demonstrated that several of the clinical signs and historological changes in the joints of arthritic rats resemble those in patients with Rheumatoid Arthritis (Stuart et al 1983).
  • the present example looks at the effect of the egg product and the partially purified anti-inflammatory composition of the invention orally administered to rats prior to and during arthritis induction with collagen II.
  • the suppression of the incidence of arthritis was examined in a dose dependent manner when compared to a control group.
  • Sprague-Dawley female rats-VAF+ (Charles Rivers, Wilmington, MA), weighing 100-125 gm, were randomized to 3 groups (10 animals/group). The experiment was repeated three times so that the final groups included 30 rats/treatment regimen with total of 90 rats for this study.
  • Spray dried hyperimmune egg product (as prepared in Example 1) was diluted for oral gavage. 10% and 0.2% solutions of egg product for oral gavage were made every other day. The second day solution was stored at 4°C until use.
  • Egg Product (3.5ml of the respective solutions) was orally gavaged into rats for 7 days prior to initiation of the type II collagen induced arthritis in rats and for 14 days after induction.
  • the group arthritis index (Al) is a summation of paw scores based on the degree of incidence of arthritis and severity of arthritis as derived from the mean Al.
  • the DCV egg product showed definitive antiarthritic properties in a dose-dependent fashion in the Type II collagen rat model.
  • the compound appeared to be nontoxic at both the low and high doses.
  • the high dose group showed not only a statistically significant decrease in the incidence of arthritis, but also a delay in onset and a decrease in severity of arthritis as compared to the water control.
  • Figure 5 shows that the high dose of egg product, given prior to immunization with Type II collagen, prevented the development of arthritic symptoms in more animals than those not given egg. Also, within eleven days of treatment with the egg product and thereafter for the entire duration of the study, a significant decrease in the incidence of arthritis was observed as compared to group that did not receive any egg.
  • the arthritic index which reflects the degree and severity of arthritis was significantly reduced in animals which received the high dose of hyperimmune egg product as compared to the control group (2.46+.0.55 vs 4.167+_0.51 ; p >0.003, Student t-test).
  • the effect of the low dose of egg product did not differ significantly from the controls.
  • the incidence of arthritis was significantly suppressed in the high-dose group compared to control (30% vs. 70%; p ⁇ 0.03). This decrease in the percent incidence of arthritis seen with the high dose of hyperimmune egg product (Table 4) is as good as has been reported for steroids, NSAIDS (non-steroidal anti-inflammatory drugs) methotrexate, and minocycline.
  • FIG. 6 shows the prevention of arthritis by the high dose of egg product.
  • ANTI-INFLAMMATORY EFFECT OF HYPERIMMUNIZED EGG This example shows the anti-inflammatory effect of hyperimmunized egg (which is prepared as described in Example 1) on carrageenan induced skin edema in dogs on a diet including hyperimmunized egg. These results demonstrate that hyperimmune egg reduces inflammation. The effect on inflammation was comparable to that obtained with the non-steroidal anti-inflammatory drug ibuprofen at 10 mg /kg, ED 50 , dose in this test.
  • Twenty White Eagle Beagles (four groups of five dogs each) were fed a basal diet (350 grams) of commercially available lamb and rice dog food. As illustrated in table 2, two groups of five dogs (groups 1 & 2) received only the basal diet during the conditioning period of approximately 100 days. In addition, dogs from group 2 were treated with the non-steroidal anti-inflammatory drug, ibuprofen, prior to inflammatory challenge with carrageenan. During this same period, the remaining two groups (3&4) were fed the basal diet along with hyperimmune egg (HIE). Group 3 received 3.5 grams of hyperimmune egg, while group 4 received 35 grams of hyperimmune egg added to the diet. At the end of the conditioning diet treatment, the dogs were challenged with an intra-dermal injection of 2% carrageenan and an inflammatory response was elicited.
  • HIE hyperimmune egg
  • the challenge process was as follows. One dog from each group was randomly selected for challenge and testing each day. This procedure was repeated daily for five days until all dogs from all groups were tested. Fifteen minutes prior to the challenge procedure, dogs from group 2 were given 1 Omg kg ibuprofen orally. All dogs were anesthetized by intravenous injection and shaved on the left lateral side (approximately 6 X 8 inches). Two lines of 3 marks were made on the shaved area and numbered 1 - 6. An intra-dermal injection of 0.1 ml saline was given at mark 1 as a negative control. From mark 2 - 6 , a 0.1 ml intra-dermal injection of a 2% solution of carrageenan was given.
  • Injections were administered by the same person for the duration of the study. Intra-dermal injections of this concentration of ca ⁇ ageenan was previously determined to cause a measurable swelling in 100% of the animals which could be reduced by 10 mg/kg ibuprofen. At the completion of the last injection of carrageenan, measurements were made of each swelling using a micrometer and the numbers were recorded. The anesthetized animals were allowed to recover and six hours later the measurements were repeated and recorded. The mean size of the inflammatory response was determined for each group.
  • a nutritional drink supplement was obtained which comprised a high protein, high carbohydrate powder containing 30% of recommended daily allowance of vitamins, and approximately 4.5 grams of hyperimmune powdered egg (approximately equal to 0.4 eggs).
  • the drink supplement was provided by DCV, Inc., Wilmington, DE.
  • Patient #1 was a 29-year-old female, 5 '3" 170 lbs with a previous history of rheumatoid arthritis (juvenile).
  • the patient presented with joint pains, swelling, and tenderness of fingers, wrists, toes, feet, and knees. She complained of functional limitations such as inability to do knee bends or run, and had difficulty with kneeling.
  • Her hematology tests had normal etythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) readings.
  • ESR etythrocyte sedimentation rate
  • CRP C-reactive protein
  • Patient's cholesterol was at 199mg/dl. She was being treated with Minocin 300mg/week, Loestrin Fe 1.5/30 and used multivitamins. The diagnosis was rheumatoid arthritis with uveitis.
  • Scoring of the arthritic symptoms was determined from the patient's own assessment of the symptoms. In particular, the patient was asked to indicate the amount of swelling, pain and/or tenderness of the joints. Based upon this patient assessment, numbers were generated showing the degree of the symptoms. The numbers range from a high of 36 (greatest amount of swelling, pain and tenderness) to a low of 0 (no swelling, pain or tenderness).
  • PATIENT #2 Patient #2 was an 88-year-old female 5'3" 104 lbs. with a previous history of rheumatoid arthritis and chronic sinusitis. She presented with pain in the lower extremities and shoulders. Physical examinations revealed swelling, pain, and tenderness of her fingers and ankles. Functionally she was only able to walk in a limited manner and had difficulty in bending her arms. Her hematology tests indicated elevated ESR (36 mm/hr), CRP (1.64mg/dl) and a total cholesterol at 220 mg/dl.
  • Patient #3 was a 79-year-old male 5' 10" 152 lbs with a history of osteoarthritis and atherosclerotic cardiovascular disease. Symptoms were pain in the lower back, shoulders, knees and feet. Medications included: Nitroderm patch, Digoxin 0.125, aspirin 80mg and Feldene 20mg. Function limitations were: difficulty in moving arms and exhaustion. Hematology results were normal ESR and CRP and cholesterol readings at 217 mg/dl.
  • Scoring of the arthritic symptoms was determined from the patient's own assessment of the symptoms. In particular, the patient was asked to indicate the amount of swelling, pain and/or tenderness of the joints. Based upon this patient assessment, numbers were generated showing the degree of the symptoms. The numbers range from a high of 36 (greatest amount of swelling, pain and tenderness) to a low of 0 (no swelling, pain or tenderness).
  • Sialic acid release with relatively low O-acetyl loss was achieved with 1ml of 2M acetic acid at 80°C for 3 hours in a sealed, crimp-top vial.
  • KDN is added as a pre- hydrolysis internal standard.
  • reaction mixture was cooled and the vial centrifuged to remove any insoluble material. Transfer the supernatant to a micron (0.5 ml), centricon (2 ml), or centriplus (15 ml) 10,000 molecular weight cut-off centrifugation device. The acetic acid in the filtrate was removed by vacuum centrifugation and the sample was redissolved in 0.5 ml of water.
  • the sample was applied to a 1 ml column of Dowex 50 AG 1X8 (hydrogen form) in water to remove cationic contaminants.
  • the flow through and 4-5 ml of water washings were collected in a thin walled centrifuge tube containing 40 ⁇ l of 1 M formic acid.
  • the acidified washings were taken to dryness by vacuum centrifugation to remove the weak acids generated by the column.
  • the sample was redissolved in 0.5 ml of 10 mM sodium formate, pH 5.50 and applied to 1 ml column of Dowes AG 3X4 (formate form) weak anion exchange resin that was buffered in lOmM sodium formate pH 5.50.
  • the column was immediately washed with 5ml of lOmM formic acid. The flow through and washings were discarded.
  • the sialic acids were eluted into a thin walled centrifuge tube with 10ml of 1 M formic acid and the eluate was taken to dryness and then resuspend in water.
  • Sialic acid samples were analyzed by HPAEC/PAD using the Dionex GP40 gradient pump, ED40 electrochemical detector and CarboPac PA-10 guard and analytical columns. Sample injection was made by an AS3500 autosampler. Sialic acids were eluted using lOOmM NaOH (eluent C) and lOOmM NaOH, 1M NaAc (eluent D) by gradient method. The separation gradient for this method was:
  • the above table shows the free and bound sialic acid content in various fractions of egg as analyzed by the Standard Dionex protocol and PAD detection. This procedure performed along with preliminary clean up over Dowex resins, results in quantitative recovery and eliminates other contaminating peaks from that position of the chromatogram.
  • the biological activity of the 3k fraction of the egg yolk in the rat Type II Collagen assay cannot be attributed to the sialic acid content as it is very low ( 2.7mg/dose).

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Abstract

L'invention concerne une composition et une méthode de traitement et de prévention de l'inflammation en général. Ladite composition est un produit de l'oeuf, provenant d'un oiseau ayant été hyperimmunisé à l'aide d'un mélange immunogène. L'invention porte également sur une composition anti-inflammatoire ayant été partiellement purifiée, provenant d'un oeuf immunisé. La composition anti-inflammatoire partiellement purifiée, lorsqu'elle est administrée à un sujet animal, est efficace dans le traitement et la prévention de l'inflammation.
PCT/US1999/030969 1999-01-19 1999-12-28 Composition anti-inflammatoire a base d'oeuf et methode de traitement et de prevention de l'inflammation WO2000043020A1 (fr)

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CA002355168A CA2355168A1 (fr) 1999-01-19 1999-12-28 Composition anti-inflammatoire a base d'oeuf et methode de traitement et de prevention de l'inflammation
EP99967649A EP1143984A1 (fr) 1999-01-19 1999-12-28 Composition anti-inflammatoire a base d'oeuf et methode de traitement et de prevention de l'inflammation
JP2000594474A JP2002535279A (ja) 1999-01-19 1999-12-28 卵抗炎症組成物と炎症の治療および予防方法
AU23898/00A AU2389800A (en) 1999-01-19 1999-12-28 Egg anti-inflammatory composition and method of treating and preventing inflammation

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US09/233,379 1999-01-19

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005523946A (ja) * 2002-04-26 2005-08-11 アボツト・バイオテクノロジー・リミテツド ＴＮＦα抗体および他の薬剤の使用
US7083809B2 (en) 2002-02-11 2006-08-01 Arkion Life Sciences, Llc Purified cytokine inhibitory factor
ITMI20121076A1 (it) * 2012-06-20 2013-12-21 Giellepi S P A Composizione per uso locale nel trattamento del danno tissutale
WO2016114677A1 (fr) * 2014-10-29 2016-07-21 Romvac Company Sa Fabrication et utilisation de protéine pc2 d'œuf hyperimmun
US10450364B2 (en) 2017-02-13 2019-10-22 Arkion Life Sciences, Llc Hyperimmunized egg product for treatment of necrotic enteritis in poultry

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR086437A1 (es) 2011-10-13 2013-12-11 Aixela Juan Cunill Preparado de huevo con propiedades regeneradoras, analgesicas y/o anti-inflamatorias
WO2018043450A1 (fr) * 2016-08-29 2018-03-08 株式会社クレスト Procédé de séparation d'un composant à faible poids moléculaire à partir d'œuf, composition contenant un composant à faible poids moléculaire et dispositif associé

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997035595A1 (fr) * 1996-03-26 1997-10-02 Dcv Biologics L.P. Composition anti-inflammatoire a base d'oeufs, technique d'isolation et usage
WO1998004273A1 (fr) * 1996-07-30 1998-02-05 Dcv Biologics L.P. Procede servant a traiter les lesions gastro-intestinales
WO1999036077A1 (fr) * 1998-01-19 1999-07-22 Dcv, Inc. Composition et methode de traitement et de prevention de l'arthrite et/ou de maladies auto-immunes

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Publication number Priority date Publication date Assignee Title
JPH0499728A (ja) * 1990-08-20 1992-03-31 Nippon Nousan Kogyo Kk 抗炎症作用を有する組成物
DE69530910D1 (de) * 1994-07-15 2003-07-03 Taiyo Kagaku Co Medizinische zusammensetzungen enthaltend ein sialinsäurederivat

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997035595A1 (fr) * 1996-03-26 1997-10-02 Dcv Biologics L.P. Composition anti-inflammatoire a base d'oeufs, technique d'isolation et usage
WO1998004273A1 (fr) * 1996-07-30 1998-02-05 Dcv Biologics L.P. Procede servant a traiter les lesions gastro-intestinales
WO1999036077A1 (fr) * 1998-01-19 1999-07-22 Dcv, Inc. Composition et methode de traitement et de prevention de l'arthrite et/ou de maladies auto-immunes

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7083809B2 (en) 2002-02-11 2006-08-01 Arkion Life Sciences, Llc Purified cytokine inhibitory factor
JP2005523946A (ja) * 2002-04-26 2005-08-11 アボツト・バイオテクノロジー・リミテツド ＴＮＦα抗体および他の薬剤の使用
JP2010248199A (ja) * 2002-04-26 2010-11-04 Abbott Biotechnology Ltd ＴＮＦα抗体および他の薬剤の使用
ITMI20121076A1 (it) * 2012-06-20 2013-12-21 Giellepi S P A Composizione per uso locale nel trattamento del danno tissutale
WO2013190496A3 (fr) * 2012-06-20 2014-02-27 Giellepi S.P.A. Composition et formulation pour le traitement topique d'une inflammation et d'une lésion de tissu
WO2016114677A1 (fr) * 2014-10-29 2016-07-21 Romvac Company Sa Fabrication et utilisation de protéine pc2 d'œuf hyperimmun
US10450364B2 (en) 2017-02-13 2019-10-22 Arkion Life Sciences, Llc Hyperimmunized egg product for treatment of necrotic enteritis in poultry
US11230590B2 (en) 2017-02-13 2022-01-25 Arkion Life Sciences, Llc Hyperimmunized egg product for treatment of necrotic enteritis in poultry

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AU2372400A (en) 2000-08-07
KR100789488B1 (ko) 2007-12-28
EP1143984A1 (fr) 2001-10-17
CA2355168A1 (fr) 2000-07-27
AU1248400A (en) 2000-07-20
KR20010101565A (ko) 2001-11-14
JP2002535279A (ja) 2002-10-22
WO2000043019A2 (fr) 2000-07-27
AU767570B2 (en) 2003-11-13
AU2389800A (en) 2000-08-07
MY135972A (en) 2008-07-31

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