Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-18
2003-01-21
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S912000
Reexamination Certificate
active
06509355
ABSTRACT:
This invention is directed to the use of glutamate antagonists to treat disorders of the outer retina.
BACKGROUND OF THE INVENTION
The pathogenesis of retinal degenerative diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) is multifaceted and can be triggered by environmental factors in those who are genetically predisposed. One such environmental factor, light exposure, has been identified as a contributing factor to the progression of retinal degenerative disorders such as ARMD (
Sur Ophthal,
1988, 32. 252-269). Photo-oxidative stress leading to light damage to retinal cells has been shown to be a useful model for studying retinal degenerative diseases for the following reasons: damage is primarily to the photoreceptors and retinal pigment epithelium of the outer retina (
Invest Ophthal
&
Vis Sci,
1966, 5, 450-472;
Sur Ophthal,
1988, 32, 375-413,
Invest Ophthal
&
Vis Sci,
1996, 37, 1236-1249); they share a common mechanism of cell death, apoptosis (
Trans AM Ophthal Soc,
1996, 94, 411-430,
Res Commun Mol Paihol Pharmacol,
1996, 92, 177-189); light has been implicated as an environmental risk factor for progression of ARMD and RP (
Arch Ophthal,
1992, 110, 99-104;
Invest Ophihal
&
Vis Sci,
1996, 37, 775-782); and therapeutic interventions which inhibit photo-oxidative injury have also been shown to be effective in animal models of heredodegenerative retinal disease (
Proc Nat Acad Sci,
1992, 89, 11249-11253;
Nature,
25 1990, 347, 83-86).
A number of different classes of compounds have been reported to minimize retinal photic injury in various animal models: antioxidants, such as, ascorbate (
Invest Ophthal
&
Vis Sci,
1985, 26, 1589-1598), dimethylthiourea (
Invest Ophthal
&
Vis Sci,
30 1992, 33, 450-472;
Arch Ophthal,
1990, 108, 1751-1752), &agr;-tocopherol (
Nippon Ganka Gakkai Zasshi,
1994, 98, 948-954), and &bgr;-carotene (
Cur Eye Res,
1995, 15, 219-232); calcium antagonists, such as, flunarizine, (
Exp Eye Res,
1993, 56, 71-78,
Arch Ophthal,
1992, 109, 554-622); growth factors, such as, basic-fibroblast growth factor, brain derived nerve factor, ciliary neurotrophic factor, and interleukin-1-&bgr; (
Proc Nat Acad Sci,
1992, 89, 11249-11253); glucocorticoids, such as, methylprednisolone (
Graefes Arch Clin Exp Ophihal,
1993, 231, 729-736), dexamethasone (
Exp Eye Res,
1992, 54, 583-594); and iron chelators, such as, desferrioxamine (
Cur Eye Res,
1991, 2, 133-144).
To date, excitatory amino acid antagonists have not been evaluated in models of outer retinal degeneration as several studies have demonstrated that principally inner retinal cells are sensitive to excitatory amino acid toxicity, while exposure to excitatory to amino acids has no effect on outer retina photoreceptors and retinal pigment epithelial (RPE) cells (
Exp Brain Res,
1995, 106, 93-105: Vis Neurosci, 1992, 8, 567-573). However, when tested in a model of mechanical stress induced ischemia reperfusion, inner retina function and RPE function were moderately protected by dextromethorphan treatment but no significant protective effect was measured for outer retina function (
Arch Ophihal,
1993, 111, 384-388). Similarly, MK-801 was found to be minimally effective at 60 days in preventing the spread of laser induced thermal burns to the retina, but did not significantly prevent photoreceptor loss when evaluated at 3 and 20 days post laser exposure (
Invest Ophthal
&
Vis Sci,
1997, 38, 1380-1389).
A series of N-methyl-D-aspartate (NMDA) antagonists including eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, 840S, and related structural analogs are effective neuroprotectants that are believed to modulate excitatory amino acid toxicity by interacting at the polyamine binding site of the NMDA receptor (
Journal of Pharmacology and Experimental Therapeutic,
1990, 253, 475-482,
British Journal of Pharmacology,
1995, 114, 1359-64,
Bioorganic
&
Medicinal Chemistry Letters,
1993, 13, 91-94,
Journal of Medicinal Chemistry,
1995, 38, 313845,
Journal of Medicinal Chemistry,
1998, 41, 1172-1184,
Journal of Medicinal Chemistry,
1991, 34, 3085-3090, WO 97/09309 Synthélabo, WO 97/09310 Synthélabo). More specifically ifenprodil, eliprodil, and CP-101,606 have recently been shown to preferentially block to the NR1A/NR2B subtype of the polyamine binding site of the NMDA receptor (
Neuroscience Letters,
1997, 223, 133-136,
Journal of Pharmacology and Experimental Therapeutic,
1996, 279, 515-523). The selective interaction of the compounds with the polyamine site of the NMDA receptor subunit is believed to be responsible at least in part for both the neuroprotective activity and the relatively favorable side effects profile of this class of compounds when compared to NMDA antagonists that act at other sites on the NMDA receptor, such as MK-801 and PCP.
In addition to having activity as NMDA antagonists, certain compounds, such as, eliprodil and ifenprodil, have calcium antagonist activity at both the calcium, N, P, and L channels. (
European Journal of Pharmacology,
1996, 299, 103-1 12,
European Journal of Pharmacology,
1994, 257, 297-301). Other calcium antagonists, such as, flunarizine, have also been shown to be protective in light induced damage models (
Exp Eye Res,
1993, 56, 71-78;
Arch Ophthal,
109, 1991, 554-62).
REFERENCES:
patent: 4690931 (1987-09-01), Wick et al.
patent: 5547963 (1996-08-01), Poindron et al.
patent: 5604244 (1997-02-01), DeSantis, Jr. et al.
patent: 5710165 (1998-01-01), Kapin et al.
patent: 97/09309 (1997-03-01), None
patent: 97/09310 (1997-03-01), None
Young, Richard W., “Solar radiation and age-related macular degneration,”Sur. Ophthal., vol. 32(4):252-269, Jan.-Feb., 1988.
Bressler, et al., “Age-related macular degeneration,”Sur Ophthal, vol. 32(6):375-413, May-Jun. 1988.
Curcio, et al., “Photoreceptor loss in age-related macular degeneration,”Invest Ophthal&Vis Sci, vol. 37(7):1236-1249, Jun. 1996.
Tso, et al., “Apoptosis in human retinal degenerations,”Trans AM Ophthal Soc, vol. 94, 411-431, 1996.
Marshall, et al., “Histopathology of ruby and argon laser lesions in monkey and human retina,”British Journal of Ophthalmology, vol. 59:610-613, 1975.
Taylor, et al., “Long-term effects of visible light on the eye,”Arch Ophthal, vol. 110:99-104, Jan. 1992.
Naash, et al., “Induced acceleration of photoreceptor degeneration in transgenic mice expressing mutant rhodopsin,”Invest Ophthal&Vis Sci., 1996, vol. 37(5):775-782, Apr. 1996.
Cruickshanks, et al., “Sunlight and age-related macular degeneration. The Beaver Dam eye study,”Archives of Ophthalmology, vol. 111:514-518, 1993.
Faktorovich, et al., “Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast . . . ,”Nature, vol. 347:83-86, Sep. 6, 1990.
Li, et al., “Amelioration of photo injury in rat retina by ascorbic acid: A histopathologic study,”Invest Ophthal&Vis Sci, vol. 26:1589-1598, Nov., 1985.
Organisciak, et al., “Protection by dimethylthiourea against retinal light damage in rats,”Invest Ophthal&Vis Sci, vol. 33(5):1599-1609, Apr. 1992.
Lam, et al., “Amelioration of retinal photoic injury in albino rats by dimethylthiourea,”Arch Ophthal. vol. 108, 1751-1757, 1990.
Kozaki, et al., “Light-induced retinal damage in pigmented rabbit—2. Effect of alpha-tocopherol,”Nippon Ganka Gakkai Zasshi, vol. 98(10):948-954, Oct. 1994.
Rapp, et al., “Evaluation of retinal susceptibility to light damage in pigmented rats supplemented with beta-Carotene,”Cur Eye Res, vol. 15, 219-223, 1995.
Li, et al., “Amelioration of retinal photic injury by a combination of flunarizine and dimethylthiourea,”Exp Eye Res, vol. 56:71-78, 1993.
Edward, et al., “Amelioration of light-induced retinal degeneration by a calcium overload blocker,”Arch Ophthal, vol. 109:554-562, Apr. 1991.
LaVail, et al., “Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light,”Proc Nat Acad Sci, vol. 89:11249-11253, Dec. 1992.
Lam, et al., “Methylprednisolone therapy in laser injury of the retina,”Graefes Ar
Barnes George E.
Chandler Michael L.
Collier, Jr. Robert J.
Hellberg Mark R.
Kapin Michael A.
Alcon Laboratories Inc.
Fay Zohreh
Yeager Sally S.
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