Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-07-21
1999-12-14
Fay, Zohreh
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514374, 514912, A61K 31445, A61K 3142
Patent
active
060018534
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compositions for the prevention and treatment of cataract formation in the crystalline lens of the eye
2. Discussion of the Background
Aging-related cataract is a gradual opacification of the crystalline lens of the eye, which is presently treated by surgical removal and replacement of the cataractous lens. Cataracts are believed to be a disease of multifactorial origin involving many of the same processes that characterize the process of aging in other tissues. Data accumulated over a period of years from the work of many laboratories indicates that once begun, cataract development probably proceeds via one or more common pathways or processes that culminate in damage to lens fibers. Since cataract is already a slowly progressing disease which occurs predominantly in the elderly, a significant retardation of its rate of development could eliminate the need for many surgical cataract extractions. This reduction would provide tremendous benefits both to individual patients and to the public health system.
Based on research from the inventors and others, several processes have been proposed as crucial factors in cataractogenesis. These processes include oxidation, phase separation phenomena and proteolysis. With the hypothesis that one or more of these processes probably represent "common pathways" involved in lens opacification, the inventors initiated an effort to screen compounds which might inhibit these particular processes for their potential as anti-cataract agents. In keeping with the likelihood that the disease is multifactorial, the inventors tested the agents not only individually but in various combinations as well.
One active area of medical research has been an investigation of the role that free radical scavengers and antioxidants may play in the prevention and treatment of diseases caused by oxidative stress. The focus of many such investigations has been upon biochemical pathways that generate reducing power in cells, for example, glutathione synthesis and cycling. Enzymes that reduce activated oxygen species, such as superoxide dismutase, have also been studied to determine whether they diminish cellular oxidative stress. Compounds for inhibiting lipid oxidation in cell membranes by direct radical scavenging have also been considered to be promising therapeutic interventions. The administration of compounds such as vitamin E, carotenoids, selenium compounds and vitamin C (ascorbate), for their antioxidant effects, is known in the popular culture.
There are many reviews in the literature of in vitro and clinical studies of the medical effect of antioxidants and free radical scavengers (references 1-3, below). Thiol compounds have been of particular scientific interest, because glutathione cycling plays a role in maintaining the redox balance in cells. Selenide compounds having glutathione peroxidase activity, for example, are the subject of U.S. Pat. No. 5,321,138. Thiol derivatives of amino acids have also been studied as antioxidants. In particular, mercaptopropionyl glycine (MPG) has been investigated for it effect in reducing cataract formation (4).
In the present invention, the nitroxide family of radicals is of particular interest. Nitroxides are free radicals that are stable, and which are reducible to their corresponding hydroxylamines. Nitroxides were originally of interest to physical chemists due to their paramagnetic properties, allowing their use as "spin-labels" in electron paramagnetic resonance studies. These compounds have more recently been studied because of their radical scavenging properties; nitroxides mimic the enzymatic activity of superoxide dismutase (5-8). Nilsson et al. disclosed, in WO 88/05044, that nitroxides and their corresponding hydroxylamines are useful in prophylaxis and treatment of ischemic cell damage.
Reddan et al. (9) have investigated the use of the nitroxide TEMPOL to protect lens epithelial cells from hydrogen peroxide damage in vitro. Mitchell et al., in U.S.
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Lorand et al., Inhibition of .beta.-Crystallin Cross-Linking in the Ca.sup.2+ -Treated Lens, Investigative Ophthalmology and Visual Science 28:1218-1222 (1987).
Lucas, V.A. and Zigler, J.S., Transmembrane Glucose Carriers in the Monkey Lens, Investigative Ophthalmology and Visual Science 28:1404-1412 (1987).
Mitchell et al., Inhibition of Oxygen-Dependent Radiation-Induced Damage by the Nitroxide Superoxide Dismutase Mimic, Tempol, Archives of Biochemistry and Biophysics 289:62-70 (1991).
Nilsson et al., Inhibition of Lipid Peroxidation by Spin Labels, Journal of Biological Chemistry 19:11131-11135 (1989).
Nishigari et al., Effect of MPG on Glucocorticoid-Induced Cataract Formation in Developing Chick Embryo, Investigative Ophthalmology and Visual Science, 25:1051-1055 (1984).
Rao et al., Identification and Characterization of the Enzymatic Activity of .zeta.-Crystallin from Guinea Pig Lens, The Journal of Biological Chemistry 267:96-102 (1992).
Reddan et al., The Superoxide Dismutase Mimic TEMPOL Protects Cultured Rabbit Lens Epithelial Cells from Hydrogen Peroxide Insult, Exp. Eye Res. 56:543-554 (1993).
Rice-Evans, C.A. and Diplock, A.T., Current Status of Antioxidant Therapy, Free Radical Biology and Medicine 15:77-96 (1993).
Tumminia et al., The Integrity of Mammalian Lenses in Organ Culture, Exp. Eye Res. 58:367-374 (1994).
Xu et al., Establishment of a Naphthalene Cataract Model in Vitro, Exp. Eye Res. 54:73-81 (1992).
Zigler et al., Effects of Lipid Peroxidation Products on the Rat Lens in Organ Culture: A Possible Mechanism of Cataract Initiation in Retinal Degenerative Disease, Archives of Biochemistry and Biophysics 225:149-156 (1983).
Zigler et al., Rhesus Monkey Lens as an In Vitro Model for Studying Oxidative Stress, Investigative Ophthalmology and Visual Science 30:2195-2199 (1989).
Zigler et al., Prevention of Cataractous Changes in Cultured Rat Lenses by the Hydroxylamine of Tempol (Tempol-H), Investigative Ophthalmology and Visual Science 37:211 (1996).
Krishna C. Murali
Qin Chuan
Russell Paul
Tumminia Santa
Zigler J. Samuel
Fay Zohreh
The United States of America as represented by the Department of
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