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Pharmaceutical angiostatic dipeptide compositions and methods of use thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 2 Peptide Repeating Units In Known Peptide ChainPharmaceutical angiostatic dipeptide compositions and methods of use thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060094665, Pharmaceutical angiostatic dipeptide compositions and methods of use thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation-in-part of copending Ser. No. 08/538,701, filed Oct. 3, 1995, incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION [0002] The present invention relates generally to pharmaceutical compositions containing peptides having angiostatic properties and more particularly to pharmaceutical compositions of tryptophan-containing dipeptides and methods of use thereof. [0003] Neovascularization, the genesis of new blood vessels, is triggered early in embryogenesis and also during wound healing, tissue remodeling and probably in the normal course of maintenance of the vascular system. Processes involved in neovascularization include at least endothelial cell and pericyte activation; basal lamina degradation; migration and proliferation of endothelial cells and pericytes; formation of a new capillary vessel lumen; appearance of pericytes around the new vessels; development of a new basal lamina; capillary loop formation; persistence of involution with differentiation of the new vessels; capillary network formation; and, eventually, of the network organization into larger microvessels. [0004] Certain cytokines are known to down-regulate neovascularization, including interleukin-12 (IL-12), transforming growth factor-.beta. (TGF-.beta.), interferon-.alpha. (IFN-.alpha.) and platelet factor 4 (PF-4). However, clinical experience with cytokine therapy has proven problematic due to the toxicity of certain of these compounds. [0005] There are a number of pathologic conditions in which angiogenesis either plays a role in or is involved directly in different sequelae of the disease. These include, for example, neovascularization of tumors in cancer; creation of hemangeomas; neovascularization associated with various liver diseases; angiogenic dysfunction related to an excess of hormone; neovascular sequelae of diabetes; neovascular sequelae to hypertension; neovascularization in post-recovery cerebrovascular accident; neovascularization due to head trauma; neovascularization in chronic liver infection; restenosis following angioplasty; and neovascularization due to heat or cold trauma. [0006] While angiogenesis is undoubtedly required for maintenance of a healthy vascular system, clinical medicine would appreciate the availability of a non-toxic treatment for temporarily down-regulating neovascularization, i.e., inducing a temporary angiostasis. SUMMARY OF THE INVENTION [0007] L-Glu-L-Trp has been known to stimulate the production of immune cells and to normalize their numerical relationship in immune deficiency conditions. (See, e.g., WO 89/06134, WO 92/17191 and WO 93/08815.) However, it has been discovered here that the dipeptide also has angiostatic activity independent of its effect in immune deficiency conditions. The results of studies in vitro showed that low levels of L-Glu-L-Trp dipeptide inhibit neovascularization of chicken chorioallantoic membranes during embryogenesis. In animal studies, L-Glu-L-Trp inhibited neovascularization of Lewis lung tumor when injected intradermally in C57BL/6 mice, and inhibited growth of Sarcoma 180 in Swiss-Webster mice. [0008] Accordingly, this invention provides methods of treating a subject having a pathologic condition involving neovascularization by administering a pharmaceutical preparation comprising an R'-Glu-Trp-R'' dipeptide and a pharmaceutically acceptable carrier to the subject in an amount effective to inhibit neovascularization. [0009] In particular, this invention provides methods of treating subjects having the following pathologic conditions involving neovascularization: hemangiomas; vascularized malignant and benign tumors, including as tumors of the meninges, intracerebral tumors, sarcomas, osteosarcomas, soft tissue tumors such as those of the esophagus and trachea; substance-induced neovascularization of the liver, including that induced secondary to ingestion of drug, alcohol or substances of abuse; angiogenic dysfunction related to an excess of hormone, e.g., estrogen; neovascular sequelae of diabetes, such as central serous chorioretinopathy; neovascular sequelae to hypertension; neovascularization in post-recovery cerebrovascular accident; neovascularization due to head trauma; chronic liver infection (e.g., chronic hepatitis); restenosis following angioplasty; and neovascularization due to heat or cold trauma, such as burn or frostbite. The dipeptide exhibits this activity both in subjects with healthy immune systems, i.e., who are not immune compromised, as well as those subjects who are immune compromised. DETAILED DESCRIPTION OF THE INVENTION [0010] The present invention provides pharmaceutical Glu-Trp preparations comprising an R'-Glu-Trp-R'' dipeptide and a pharmaceutically acceptable carrier. R'-Glu-Trp-R'' dipeptide, as used herein, refers to the dipeptide L-Glu-L-Trp and derivatives or analogues thereof. [0011] As used herein, a derivative of the R'-Glu-Trp-R'' dipeptide includes those in which the dipeptide is derivatized by the covalent attachment of a moiety at R' and/or R''. This includes, for example, pharmaceutically acceptable salts of the dipeptide, amides, imides, esters, anhydrides, ethers, methyl or ethyl-alkyl esters, alkyl, aryl or mixed alkyl/aryl derivatives wherein the formula weight is less than about 5000 Daltons or less than 1000 Daltons, multimeric or cyclic versions of the dipeptide and peptides of fewer than about 20 amino acids or less than about 10 amino acids that include glu-trp within their amino acid sequence. Representative examples include HEW, EWEW, GEW, EWKHG, EWKKHG, EW-NH-NH-GHK-NH.sub.2, Ac-L-Glu-L-Trp-OH, Suc-EW, Cpr-EW, But-EW, RKEWY, RKEW, KEWY, KEW, pEW. [0012] As used herein, analogs of R'-Glu-Trp-R'' dipeptide include those in which L-amino acids are substituted for D-amino acids, such as L-Glu-D-Trp, D-Glu-L-Trp or D-Glu-D-Trp, and analogs of tryptophan such as 5-hydroxy-tryptamine, 5-hydroxy-indol-acetic acid and pyrole analogs in which the nitrogen in the pyrole ring is replaced with carbon. [0013] L-Glu-Trp-L presently is the most preferred R'-Glu-Trp-R'' dipeptide. L-Glu-L-Trp is also referred to herein interchangeably as "EW" and "EW dipeptide", using the single letter convention wherein the first named amino acid is the amino terminus and the last named amino acid is the carboxyl terminus. [0014] As used herein, "neovascularization" refers to the generation of new blood vessels. The process by which new blood vessels are formed may involve processes of endothelial cell and pericyte activation; basal lamina degradation; migration and proliferation (i.e., cell division) of endothelial cells and pericytes; formation of a new capillary vessel lumen; appearance of pericytes around the new vessels; development of a new basal lamina; capillary loop formation; persistence of involution, and differentiation of the new vessels; and, capillary network formation and, eventually, organization into larger microvessels. As referred to herein the process of endothelial cell proliferation, e.g., in a vascular bud, is termed "angiogenesis" and is related to neovascularization as a subprocess. Representative clinical diagnostic manifestations of diseases have been classified and codified (International Classification of Diseases, ICD-9-CM, Washington, D.C. 1989.) Representative laboratory indicia of neovascularization include (but are not limited to) data e.g. collected in angiograms, CAT scans and sonograms, as well as visual examination by endoscopic and/or capillaroscopic procedures. [0015] As used herein the terms "angiostasis," "angiostatic" and "inhibition of neovascularization" mean that the rate or extent of neovascularization in a tissue is decreased from a pre-treatment value to a post-treatment value. Angiostasis may be determined using laboratory or clinical indicia of disease activity, above. Angiostasis may involve inhibiting one or more subprocesses involved in neovascularization, e.g., endothelial or vascular smooth muscle cell proliferation or migration. [0016] As used herein, a "pathologic condition involving neovascularization" refers to a pathologic condition in which neovascularization or the risk of it is a component. This includes, without limitation, pathologies in which neovascularization is the primary pathology, such as hemangiomas; pathologies in which neovascularization is not the primary pathology but contributes to it, such as neovascularization of tumors; and pathologies in which neovascularization is a sequela of the primary disease, such as central serous retinopathy in diabetes. [0017] As used herein, the term "subject" refers to a mammal, including human and non-human primates, domestic animals and livestock, fur bearing animals, and the like, e.g., dogs, cats, rodents, birds, horses, cows, pigs, fish, and the like. Embodiments of the invention encompass therapeutic and prophylactic treatment methods for use in subjects in need thereof. [0018] As used herein the term "immune compromised" refers to a person having a lower than normal number of one or more immune cells, such as NK cells, T4 or T8 T-lymphocytes, B-lymphocytes, or phagocytes, as measured by standard clinical diagnostic indicia. It also includes individuals having diminished function of immune cells as determined by standard functionality testing of such cells, e.g., production of immunoglubulins, chemotaxis, mixed leukocyte reaction or delayed hypersensitivity assay. Immune compromised individuals often present with unusual or unexpected opportunistic infections. [0019] "Polypeptide" is intended to mean a serial array of amino acids of more than 16 and up to many hundreds of amino acids in length, e.g., a protein. [0020] "Abnormal" as used herein refers to laboratory indicia of neovascularization that are outside of the range of values recorded in healthy individuals. [0021] "Normalized" as used herein refers to changes in laboratory or clinical indicia of neovascularization that are, following treatment, returned to within the normal range of values recorded for normal healthy subjects. A subject without a vascular defect and without a known deficiency in any coagulation, fibrinolytic, or vascular system is referred to herein interchangeably as "a normal subject". Continue reading about Pharmaceutical angiostatic dipeptide compositions and methods of use thereof... 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