Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Reissue Patent
2001-10-09
2004-01-13
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Reissue Patent
active
RE038386
ABSTRACT:
BACKGROUND OF THE INVENTION
This is an application for the Reissue of U.S. Pat. No.
6
,
063
,
775
, published May
16
,
2000
.
The instant invention broadly relates to retardation of the biochemical formation of materials incidental to HIV and/or AIDS, which promotethe advancement of HIV to AIDS; which promote the advancement of AIDS and other opportunistic diseases to which a patient could inevitably succumb. Specifically, the invention retards the biochemical formation of species of metalloproteinase which are formed as a product of conditions such HIV and/or AIDS. Still more specifically, the invention provides for the administration of an effective amount of a drug which retards the biochemical formation of metalloproteinase species including coliagenase and gelatinase, incidental to the conditions of HIV and/or AIDS. Still even more specifically, the invention provides for the administration of an effective amount of a chemically modified tetracycline (CMT) analog which retards the biochemical formation of metalloproteinase species including gelatinase, collagenase and elastase, incidental to the conditions of HIV and/or AIDS.
Tetracyclines are useful as broad spectrum antibiotics because they have the ability to retard protein synthesis in a wide variety of bacteria. As disclosed in the above-identified pending patent applications, it has also been discovered that tetracyclines, antibiotic tetracyclines and non-antibiotic tetracyclines, have the ability to retard collagen-destructive enzymes, such as collagenase, responsible for the break-down of connective tissue in a number of diseases, such as periodontal disease, corneal ulcers and rheumatoid arthritis.
The use of tetracycline antibiotics, while effective, may lead to undesirable side effects. For example, the long term administration of antibiotic tetracyclines may reduce or eliminate healthy flora, such as intestinal flora, and may lead to the production of antibiotic resistant organisms or the overgrowth of yeast and fungi.
Tetracycline may be a chemically modified tetracycline (CMT) or any tetracycline administered to a mammal in a dose that is effectively non-antimicrobial in the mammal. Preferably, the tetracycline is chemically modified so as to reduce its antimicrobial properties. Methods for reducing the antimicrobial properties of a tetracycline are disclosed in “The Chemistry of the Tetracyclines”, Chapter 6, Mitscher, (1978), at page 211. As pointed out by Mitscher, modification a positions 1, 2, 3, 4, 10 and 12a lead to loss of bioactivity. The use of such modified tetracyclines is preferred in the present invention, since they can be used to higher levels than antimicrobial tetracyclines with fewer side effects.
The tetracycline molecule is amenable to substantial modification without losing its antibiotic properties. Examples of modifications that may and may not be made to the basic tetracycline structure have been reviewed by Mitscher in the Chemistry of Tetracyclines, Chapter 6. According to Mitscher, the substituents at positions 5-9 of the tetracycline ring, may be modified without complete loss of antibiotic properties. Changes to the basic ring system or replacement of the substituents at positions 1-4 and 10-12, however, generally lead to synthetic tetracyclines having substantially less or effectively no antibacterial activity. For example, 4-dedimethylaminotetracycline is commonly considered to be a non-antibacterial tetracycline.
U.S. Pat. No. 5,532,227 to Golub, et al teaches a method for treating mammals suffering from excessive extracellular protein glycosylation which is associated with diabetes, scleroderma and progeria by administering to the mammal a tetracycline which effectively inhibits excessive protein glycosylation.
Inhibition of metalloproteinase activity with various species of non-antimicrobial tetracycline, is well known in the prior art:
U.S. Pat. No. 5,321,017 to Golub, et al teaches a method for treating mammals suffering from rheumatoid arthritis and other tissue-destructive (chronic inflammatory or other) conditions associated with excess metalloproteinase activity which comprises: administering to the mammal an amount of a tetracycline that is effectively anti-metalloproteinase, but that is not effectively antimicrobial, and an amount of non-steroidal anti-inflammatory agent which, when combined with the effectively anti-metalloproteinase amount of tetracycline, results in a significant reduction of tissue destruction and/or bone loss.
U.S. Pat. No. 5,045,538 to Schneider, et al teaches a method for treating mammals suffering from skeletal muscle wasting and/or intracellular protein degradation of skeletal muscle systems by administering to the mammal an amount of tetracycline which results in a significant reduction of the muscle wasting and protein degradation. In addition, there is also disclosed a method of increasing the protein content of skeletal muscle systems of mammals by administration of tetracyclines. The tetracyclines useful in the above methods are both antimicrobial and non-antimicrobial. In a preferred embodiment, the method of treatment utilizes a non-antimicrobial tetracycline such as dedimethylaminotetracycline.
U.S. Pat. No. 5,324,634 to Zucker teaches diagnostic agents and methods for detecting the presence of metastatic activity in biological samples such as plasma. The agent and method preferably immunologically detect matrix metalloproteinases in complexed form with endogenous inhibitors of MMP's A kit for detecting the metalloproteinases is also disclosed.
U.S. Pat. No. 5,260,059 to Acott, et al relates to a method of treating ocular disease by modulating cellular secretion of a family of matrix metalloproteinases and their inhibitor. Specifically, differential stimulation of secretion of interstitial collagenase, gelatinase or type IV collaginase, stromelysin or proteoglycanase, and their tissue glycoprotein inhibitor is employed to treat open-angle glaucoma, retinal degeneration and detachment, ocular neovascularization and diabetic retinopathy.
U.S. Pat. No. 5,595,885 to Stetler-Stevenson, et al teaches an isolated protein of 21,600 Da which binds to both latent and activated type IV collagenase with high affinity at 1:1 molar stoichiometry, thereby abolishing enzyme activity. The protein is purified by affinity chromatography on solid phase metalloproteinase, or solid phase metalloproteinase substrates which bind the enzyme-inhibitor complex. The complete primary structure of this protein (initially called CSC-21K), as determined by sequencing overlapping peptides spanning the entire protein, reveals homology with a protein called TIMP, Tissue Inhibitor of Metalloproteinases. In addition, a cDNA for this novel inhibitor, now designated TIMP-2, was cloned from a melanoma cell and its sequence was compared with that of human TIMP-1. Northern blots of melanoma cell mRNA showed two distinct transcripts of 0.9 kb and 3.5 kb which are down-regulated by transforming growth factor-beta, and are unchanged by phorbol ester treatment. The inhibitor of the present invention may be used for treatment of pathologic conditions resulting from inappropriate degradation of extracellular matrix molecules by matrix metalloproteinases, such as metastatic neoplasia, myocardial infarction, and arthritis. Therapeutic treatments using this inhibitor may include formulations for inhalation and inclusion complexes adapted for buccal or sublingual administration, or administration of a recombinant DNA molecule which expresses a DNA segment that encodes the matrix metalloproteinase inhibitor of this invention.
U.S. Pat. No. 5,308,839 to Golub, et al teaches a method for treating mammals suffering from rheumatoid arthritis, other tissue-destructive conditions, and chronic inflammatory or other conditions associated with excess metalloproteinase activity which comprises: administering to the mammal an amount of a tetracycline that is effectively anti-metalloproteinase, but that is not effectively antimicrobial, and an amount of a non-steroidal anti-inflammatory
Criares Theodore J.
Feldman Stephen E.
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