Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Nervous system
Reexamination Certificate
2000-10-03
2002-07-23
Witz, Jean C. (Department: 1615)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Nervous system
C514S002600, C514S021800, C514S023000, C530S356000
Reexamination Certificate
active
06423347
ABSTRACT:
The present invention pertains to a method for treating the symptoms of arthritis in mammals and, more particularly, relates to the enteral administration of compositions comprising notochord and/or notochord extracts. The invention preferably uses sturgeon notochord, collagen derived from sturgeon notochord, or mixtures thereof to suppress the clinical manifestations of arthritis. The invention also relates to enteral compositions that contain notochord and its structural components to suppress and/or treat arthritis in mammals.
BACKGROUND OF THE INVENTION
Arthritis, and particularly rheumatoid arthritis (RA), is a painful and often crippling disease that initially results in swollen and inflamed joints, but often progresses to deform or completely destroy joints. This is a result of the body mistakenly attacking its own cartilage. Cartilage is a specialized kind of connective tissue which is found in human adults in three forms: hyaline or glossy cartilage; elastic cartilage; and fibrocartilage. Hyaline cartilage is the type found in the ventral ends of ribs, in joints, and in the walls of the larger respiratory passages. It is the hyaline cartilage that provides a low friction surface to prevent bone from rubbing on bone during motion. As arthritis progresses, cartilage is damaged and bone may also start to erode. This results in severe pain and ultimate destruction of the joint itself.
Arthritis is a group of diseases affecting joints and the component tissues. Several types of arthritis are recognized, and these can be divided into several groups by their clinical course or pathological manifestations. The most common form of arthritis is Osteoarthritis (OA). Osteoarthritis is mainly caused by mechanical damage to the joints, either by repetitive use of particular joints as seen in athletes and physical laborers, or by overloading structural joints as seen in the knee joints of obese individuals.
The second most common form of the disease is RA, which is a chronic multisystem disease of unknown cause. RA is characterized by chronic inflammation of the synovium associated with considerable erosion of both cartilage and bone, particularly in and around the joints. RA is currently understood as an autoimmune disease in which the pathological process appears to start by the presentation of an unknown “rheumatoid” self-antigen by an antigen presenting cell. Studies addressing family history indicate a genetic predisposition wherein a particular amino acid sequence in the third hypervariable region of the HLA-DR molecule is a major genetic element conveying susceptibility to RA. See Lipsky PE, “Rheumatoid Arthritis”
in Harrisons' Principles of Intemal Medicine
, 13th ed. McGraw-Hill, Inc., New York, NY.
The T cell receptor on CD4
+
T cells, which form the target of the antigen, also plays an important role in the inflammatory process. The presentation of the antigen causes the activation of CD4
+
T cells, with the consequent secretion of cytokines such as interleukin-2 (IL-2) and interferon-g (IFN-g). These cytokines induce clonal expansion of the T cells and activation of the cytokine network. These cytokines trigger the production of endothelial adhesion molecules (such as ICAM-1) whose expression in rheumatoid synovium enhances the activation of inflammatory cells in the joints. See Vitali C, Sciuto M, Bombardieri S., “Immunotherapy in Rheumatoid Arthritis: A Review”,
Int J Art Organs
1993:16; 196-200.
The modern therapy for arthritic conditions begins with nonsteroidal anti-inflammatory drugs such as aspirin, anthranilic acid, and ibuprofen; and more aggressive therapies involve disease-modifying antirheumatic drugs, such as D-penicillamine, methotrexate, and sulfasalazine. However, these treatments are often deficient in their efficacy and tolerability, causing a wide range of serious side effects. More severe forms of the disease may even require surgery.
(A) Oral Tolerance
Novel therapies for treating arthritis include immune response modifiers, gene therapy, enzyme inhibitors, monoclonal antibodies and dietary therapy. Dietary therapy for arthritis has received a great deal of publicity over the years. Although scientific basis, at present, for dietary remedies is still in doubt, there are valid reasons for considering whether dietary management can successfully modify disease activity as we better understand its etiology and pathology. “Oral tolerance” is a long recognized method to induce peripheral immune response. It was first described by Wells in 1911 as a state in which systemic anaphylaxis in guinea pigs was prevented by previous feeding of hen's egg proteins. See Wells H, “Studies on the Chemistry of Anaphylaxis III. Experiments with Isolated Proteins, Especially Those of Hen's Eggs”,
J Infect Dis
1911:9:147-151.
Particularly, oral tolerance is thought to be an ideal candidate to consider as a treatment of RA because of the etiology of RA as an autoimmune disease. Orally administered autoantigens have shown activity in several experimental autoimmune models including experimental autoimmune encephalomyelitis, uveitis, myasthenia, diabetes, and collagen- and adjuvant-induced arthritis. See Weiner H L, Friedman A, Miller A, Khoury S J, Al-Sabbagh A, Santos L, Sayegh M, Nussenblatt R B, Trentham D E, Hafler D A. “Oral Tolerance: Immunologic Mechanisms and Treatment of Animal and Human Organ-Specific Autoimmune Diseases by Oral Administration of Autoantigens”,
Annu Rev Immunol
1994; 12:809-837.
The mechanism of how oral tolerance works is, at this time, unclear. The primary mechanisms by which an orally administered antigen induces tolerance are believed to be via the generation of active suppression or clonal anergy.
Collagen-induced arthritis (CIA) in experimental animals is the best known animal model for human RA. See Durie F H, Fava R A, Noelle R J, “Collagen-Induced Arthritis as a Model of Rheumatoid Arthritis” See Clin Immu and Immupath 1994; 73:11-18 and Staines NA, Wooley P H, “Collagen Arthritis—What Can it Teach Us?”
Brit J Rheum
1994;33:798-807. It was first described by Trentham in 1977, see Trentham D E, Townes A S, Kang A H. “Autoimmunity to Type II Collagen: An Experimental Model of Arthritis”,
J Exp Med
1977;146:857-868, and has been demonstrated to resemble human RA sufficiently to now be recognized as an important experimental tool. It is generally induced in susceptible strains of experimental animals (such as mice and rats) by immunization with heterologous type-II collagen (CII) isolated from a heterologous species. See Courtenay J S, Dallman M J, Dayyan A D, Martin A, Mosedale B, “Immunization Against Heterologous Type II Collagen Induced Arthritis in Mice”,
Nature
1980;283-665. In a susceptible strain of mice (DBA/1), immunization with CII initiates a combined humoral and cellular immune response targeted to joint tissues, where the antigen is predominantly located. Differences between the animal model and the human RA include:
(1) the model is an induced state and therefore does not occur spontaneously, as in humans;
(2) the model lacks many extra-articular manifestations of the human RA including subcutaneous nodules and pulmonary fibrosis; and
(3) the induction of the disease is of rapid onset in the model, which is different from humans in that it typically takes years.
Nevertheless, CIA is the best available animal model for human RA.
Intragastric administration of soluble Type II collagen (CII) prior to immunization with CII has been shown to suppress the incidence of CIA in DBA/1 Lac J mice, and WA/KIR rats. See Nagler-Anderson C, Bober L A, Robinson M E, Siskind G W, Thorbecke G J, “Suppression of the Type II Collagen-Induced Arthritis by Intragastric Administration of Soluble Type II Collagen”,
Proc Nati Acad Sci USA
1986;83:7443-7446 and Thompson HSG, Harper N, Devan D, Staines N A, “Suppression of CIA by Oral Administration of Type II Collagen: Changes in Immune and Arthritic Responses Mediated by Active Peripheral Suppression”
Autoimmunity
1993;16:189-199.
Adjuvant-induced arthritis
Aoyagi Seiji
Demichele Stephen J.
Johns Paul W.
Mazer Terrence B.
Abbott Laboratories
Parlet Nickki L.
Witz Jean C.
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