Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-28
2002-09-03
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S912000, C514S913000
Reexamination Certificate
active
06444676
ABSTRACT:
BACKGROUND OF THE INVENTION
Apoptosis has been established as an important mechanism associated with neuronal cell loss in ocular conditions such as ischemia-reperfusion injury, glaucomatous neuropathy, retinal vessel occlusion and ocular neurodegenerative diseases including retinopathies and optic nerve neuropathies. Under normal conditions, apoptosis is a physiological cell death process of eliminating unwanted cells (programmed cell death) without the involvement of inflammation or necrosis. During apoptosis, cells exhibit a condensation of the cytoplasm, internucleosomal fragmentation of DNA, condensation of chromatin and nucleus (pyknosis), alteration of cell membrane morphology (blebbing), and disruption of cytoskeleton (cell shape changes). Such cellular events lead to the subsequent collapse of the cell into discrete vesicles with intact membranes (apoptotic bodies) and its eventual phagocytosis by neighboring phagocytic cells (Buja et al.,
Apoptosis and necrosis: basic types and mechanisms of cell death., Arch Pathol Lab Med,
volume 117, pages 1208-1214 (1993); Bright & Khar,
Apoptosis: programmed cell death in health and disease., Biosci Report,
volume 14, pages 67-81 (1994)).
In addition to mediating naturally-occurring programmed cell death, apoptosis in neuronal tissues can also be induced by neurotransmitters (such as amino acid excitotoxicity), cytokines, toxins, ischemia, mechanical trauma or trophic factor withdrawal (Raff et al.,
Programmed cell death and the control of cell survival: lessons from the nervous system. Science,
volume 262, pages 695-700 (1993); and Thompson.
Apoptosis in the pathogensis and treatment of disease., Science,
volume 267, pages 1456-1462, (1995)).
Apoptosis has been shown to play a role in the death of retinal ganglion cells (“RGC”) during experimental glaucoma. For example, in monkey eyes with experimental ocular hypertension, there are at least ten times more apoptotic RGC than in fellow control eyes (Van Buskirk & Cioffi,
Glaucomatous optic neuropathy., Am J Ophthalmol,
volume 113, pages 447-452 (1992); and Quigley et al.,
Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis., Invest Ophthalmol Vis Sci,
volume 36, pages 774-786 (1995)). Elevated intraocular pressure (“IOP”) in rats was shown to induce apoptosis of RGC (Büichi,
Cell death in the rat retina after a pressure
-
induced ischemia
-
reperfusion insult: an electron microscopic study. I. Ganglion cell layer and inner nuclear layer., Exp Eye Res,
volume 55, pages 605-613 (1992); and Garcia-Valenzuela et al.,
Programmed cell death of retinal ganglion cells during experimental glaucoma., Exp Eye Res,
volume 61, pages 33-44 (1995)). Additionally, optic nerve transection (an experimental procedure designed to mimic certain aspects of glaucomatous retinopathy) in monkeys, rabbits and rats was shown to induce apoptosis in RGCs (Villegas-Perez et al.,
Rapid and protracted phases of retinal ganglion cell loss follows axotomy in the optic nerve of adult rat. J Neurobiol,
volume 24, pages 23-36 (1993); Berkelaar et al.,
Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats., J Neurosci,
volume 14, pages 4368-4374, (1994); Garcia-Valenzuela et al.,
Apoptosis in adult retinal ganglion cells after axotomy., J Neurobiol,
volume 25, pages 431-438 (1994); and Quigley et al.,
Invest Ophthalmol Vis Sci,
volume 36, pages 774-786 (1995)). RGC apoptosis also occurs in accelerated retinal ischemic diseases. The retina of an individual suffering from anterior ischemic optic neuropathy was shown to have increased the number of apoptotic RGC (Levin & Louhab,
Apoptosis of retinal ganglion cells in anterior ischemic optic neuropathy., Arch Ophthalmol,
volume 114, pages 488-491 (1996)). Taken together, these studies strongly suggest that apoptosis is the, or at least a major, mechanism of RGC death during glaucomatous neuropathy.
Poly (ADP-ribose) polymerase (PARP; also known as “poly(ADP-ribose) synthetase”) is an enzyme with a molecular mass of 113 kDa (De Murcia et al.,
Poly
(
ADP
-
ribose
)
polymerase: molecular biological aspects., BioEssays,
volume 13, pages 455-462 (1991)). Though it binds to chromatin under physiological conditions, it has a higher affinity for DNA strand breaks. It uses the oxidized form of nicotinamide adenine dinucleotide (“NAD
+
”) as a substrate to synthesize ADP-ribose polymer and transfers the polymer onto other proteins (“poly ADP-ribosylation”). Many proteins can be modified by PARP, such as DNA ligases, DNA and RNA polymerases, endonucleases, histones, topoisomerases and PARP itself. Poly ADP-ribosylation of these proteins affects their activities; some are activated, yet most are inactivated (Cosi et al.,
Poly
(
ADP
-
ribose
)
polymerase
(
PARP
)
revisited. A new role for an old enzyme: PARP involvement in neurodegeneration and PARP inhibitors as possible neuroprotective agents., Ann NY Acad Sci,
volume 825, pages 366-379 (1997)). PARP can be activated by activation of caspases and by DNA damage. It is hypothesized to be a suicidal mediator when massive DNA damage occurs in a cell. Even though its exact mechanism of action is unknown, some speculate that change in enzymatic activities of proteins modified by poly ADP-ribosylation leads to impairment in cell function and apoptosis; others suggest that PARP serves in a futile “ADP-ribose polymerization and hydrolysis” cycle, which leads to energy depletion and apoptosis (Berger,
Cellular response to DNA damage: the role of poly
(
ADP
-
ribose
),
Radioation Res,
volume 101, pages 4-15 (1985)).
PARP inhibitors, such as benzamide, 3-aminobenzamide, 3-aminophtalhydrazide and 1,5-dihydroxyisoquinoline have been shown to prevent neuronal apoptosis induced by various injuries including amino acid excitotoxicity (Wallis, et al.,
Neuroprotection against nitric oxide injury with inhibitors of ADP
-
ribosylation., Neuropharm Neurotoxicol,
volume 5, pages 245-248 (1993); Cosi et al.,
Poly
(
ADP
-
ribose
)
polymerase: early involvement in glutamate
-
induced neurotoxicity in cultured cerebellar granule cells., J Neurosci Res,
volume 39, pages 38-46 (1994); and Cosi et al.,
Poly
(
ADP
-
ribose
)
polymerase
(
PARP
)
revisited. A new role for an old enzyme: PARP involvement in neurodegeneration and PARP inhibitors as possible neuroprotective agents., Ann NY Acad Sci,
volume 825, pages 366-379 (1997)). 3-Aminobenzamide (at 3 mM or higher concentrations, administered via intracameral infusion) also has been shown to reduce ischemia/reperfusion damage and DNA fragmentation in rat retina (Lam,
The effect of
3-
aminobenzamide, an inhibitor of poly
-
ADP
-
ribose polymerase, on ischemia/reperfusion damage in rat retinal, Res Commun Mol Pathol Pharmacol,
volume 95, pages 241-252 (1997)).
U.S. Pat. No. 5,756,510 (Griffin et al.) discloses benzamide analogs that inhibit PARP DNA repair enzymes, and potentially useful in potentiating the effects of cytotoxic drugs or radiotherapy in cancer therapy.
U.S. Pat. No. Re. 36,397 (Zhang et al.) discloses PARP inhibitors and their potential use in the prevention of neurotoxicity mediated through N-methyl-D-aspartate (NDMA) receptors, and in the treatment of vascular stroke and neuronal diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease.
Nowhere in the art, however, has it been disclosed or suggested to use of these compounds to prevent, treat or ameliorate glaucomatous retinopathy and optic neuropathy.
SUMMARY OF THE INVENTION
The present invention is directed to compositions and methods of preventing, treating or ameliorating retinopathies and optic nerve diseases and disorders related to glaucoma. In particular, the present invention is directed to compositions containing compounds that inhibit the activation of PARP or PARP activity and methods of using these compositions to prevent, treat or ameliorate diseases and disorders of the retina and optic nerve related to glaucoma.
While not intending to be bound by theory, the inve
Clark Abbot F.
Pang Iok-Hou
Fay Zohreh
Yeager Sally S.
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