Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-10-09
2002-05-07
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S912000
Reexamination Certificate
active
06384081
ABSTRACT:
BACKGROUND OF THE INVENTION
The instant invention broadly relates to inhibition of the formation of substances which promote the advancement of diseases that can cause blindness, More specifically, the invention inhibits the formation of species of metalloproteinase which are formed as a product of diseases of the eye. Still more specifically, in a preferred embodiment, the invention provides for the administration of an effective amount of a tetracycline analog, its salts, conjugates or derivatives for inhibiting the formation of metalloproteinase species including collagenase, elastase, and most particularly, geletanase in various parts of the eye, more particularly, the retina and/or vitreous of a patient inflicted with an advancing eye disease, most particularly, at least one of any form of retinitis characterized by the formation of metalloproteinase and its species. In an alternate preferred embodiment, the invention provides for the administration of an effective amount of a tetracycline analog, its salts, conjugates or derivatives, in synergistic combination with at least one other therapeutic substance, its salts, conjugates or derivatives, for inhibiting the formation of metalloproteinase species including collagenase, elastase, and most particularly, geletanase in various parts of the eye, more particularly, the retina and/or vitreous of a patient inflicted with an advancing eye disease, most particularly, at least one of any form of retinitis characterized by the formation of metalloproteinase and its species.
Mammalian extracellular matrix (ECM) turnover is thought to be initiated by the secretion of several proteinases, which cause partial degradation of specific matrix components. Thereafter, the disrupted matrix components are taken up and degraded further within lysosomal vesicles. Interstitial collagenase, gelatinase or type IV collagenase, and stromelysin or proteoglycanase are members of a family of matrix metalloproteinases with sufficient diversity in substrate specificities to achieve this initial disruption. These metalloproteinases are active at neutral pH and are known to be secreted by a variety of different cell types.
Interstitial collagenase (MMP-1), also called type I-II-III collagenase is an endopeptidase capable of cleaving each of the &agr;-chains of the collagen triple helix at a Gly-Ile or Gly-Leu site located about one-fourth the distance from the carboxy-terminus. This produces thermally unstable soluble fragments about one-fourth and three-fourths the original size, which in turn are susceptible to degradation by gelatinases. Hasty et al., J. Biol. Chem. 262, 10048-10052 (1987) report by immunologically distinct interstitial collagenases from fibroblasts and neutrophils. The latter has a higher catalytic rate toward Type I collagen, while the former is more active toward Type III collagen. Goldberg et al., J. Biol. Chem. 261, 6600-6605 (1986) report that there are two forms of interstitial collagenase produced by human skin fibroblasts-one, an unmodified procollagenase, Mr≈52 kDa, and the other, a glycosidated form, Mr≈57 kDa. None of these interstitial collagenases appear capable of degrading Type IV or V collagen.
Ocular tissues have been shown to secrete interstitial collagenase, and the secretion has been shown to be controlled by various extracellular factors. Johnson-Wint Proc. Natl. Acad. Sci. USA 77, 5331-5335 (1980) demonstrated that cornea stromal cell collagenase production is regulated by simulators and inhibitors secreted by corneal epithelial cells. In an earlier report Johnson-Muller et al., Pro. Natl. Acad. Sci. USA 75, 4417-4421 (1978) described other soluble chemical and biological agents capable of stimulating macrophages to secrete collagenase. These include: neutral proteases, prostaglandins, bacterial endotoxins, colchicine, phorbol myristic acid, and cytochalasin B. Others (Beaman et al., Exp. Eye Res. 22, 209-218 (1976)) have described regulation of collagenase activity in corneal tissue by cyclic-AMP.
Gelatinase (MMP-2) or Type IV collagenase is a neutral metalloproteinase capable of hydrolyzing basement membrane type IV collagen into the characteristic ¼ amino-terminal ¾ carboxyl-terminal fragments. The protein is secreted by a variety of cells, for example fibroblasts and tumor cells, as a 70 kDa Type IV procollagenase. This latent proenzyme is converted to a 62 kDa Type IV collagenolytically active enzyme by the autocatylitic removal of an 80 residue peptide fragment from the amino terminus (Stetler-Stevenson et al., J. Biol. Chem. 264, 1353-1356 (1989). In addition to Type IV collagenolytic activity, gelatinase has been reported to have activity toward gelatin (degraded Type I, II and III collagen), Type V and Type VII collagen, fibronectin, and Lenin. (See for example Murphy et al., J. Biol. Chem. 199, 807-811 (1981)). This enzyme is known to be inhibited by EDTA and 1,10-phenanthroline, and to require Zn and/or Ca for its activity. Hibbs et al., J. Biol. Chem. 260, 2493-2500 (1985) has demonstrated the enzyme to be rapidly secreted from neutrophils stimulated with phorbol myristate acetate (TPA).
Stromelysin (MMP-3) is a neutral metalloendopeptidase secreted by various cell types. This enzyme has been reported to have a 55% homology with interstitial collagenase. Chin et al., J. Biol. Chem. 260, 12367-12376 (1985) demonstrated that rabbit synovial fibroblasts induced by agents such as TPA, Cytochalasin B, and poly-(2-hydroxyethyl methacrylate) secrete prostromelysin, Mr=51 kDa. This metal (Zn, Ca) dependent proteinase was activated by trypsin and 4-aminophenolmercuric acetate (AMPA) to a Mr≈41 kDa form with activity toward casein, cartilage proteoglycans, &agr;-(1)-proteinase inhibitor, immunoglobulin G2a, fibronectin, laminin, and Type IV collagen. In addition to be inhibited by metal chelators such as EDTA and 1,10-phenanthroline, the enzyme is normally secreted from endothelial cells complexed with tissue inhibitor of metalloproteinases (TIMP), Herron et al., J. Biol. Chem. 261, 2810-2813 (1986). The complete sequence of human skin fibroblast stromelysin has been determined by Wilhelm, et al., Proc. Natl. Acad. Sci. USA 84, 6725-6729 (1987). These authors demonstrated great homology between human stromelysin and rat transin, an oncogene transformation-induced protein. The induction of transin transcription by various oncogenes and epidermal growth factor (EGF) was described by Matrisian et al., Mol. Cell. Biol. 6, (1986). Other transforming factors shown to induce stromelysin in human fibroblasts include tumorgenic agents such as u.v. light, mitomycin-c, and interleukin-1 (IL-1). Whitham, et al., J. Biol. Chem. 240, 913-916 (1986).
The members of the foregoing family of matrix metalloproteinases share many structural and functional similarities, including inhibition by an endogenous inhibitor, tissue inhibitor of metalloproteinases (TIMP). TIMP from human amniotic fluid and cultured fetal lung fibroblasts has been sequenced, and was reported to be immunologically identical to a variety of forms of the protein found in other tissues or body fluids, these inhibitors range in size from Mr≈20-28 kDa. It appears that a variety of cells coordinate synthesis of MMP-1, MMP-2 and MMA-3 with their specific inhibitor TIMP in vivo (Herron et al., J. Biol. Chem. 261, 2814-2818 (1986)).
A variety of agents arc known to stimulate secretion of both MMPs and TIMP from various cells; however, few are known to do so differentially. One exception, reported by Duncan et al., Biochemical Pharmacology 32, 3853-3858 (1983) is Razoxane, which inhibited collagenase production and stimulated TIMP production.
The existence of these metalloproteinases and their inhibitor in ocular tissue, other than cornea and sclera, has not been demonstrated. Furthermore, the relationship of these secreted proteins to ocular disease, especially glaucoma and retinal disease, has not been ascertained.
Broadly, the instant invention is applicable to any eye disease characterized by the presence of metalloproteinase an
Fay Zohreh
Feldman P.C. Stephen E.
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