Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-08
2004-04-06
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S912000
Reexamination Certificate
active
06716835
ABSTRACT:
The present invention concerns the use of blocker compounds of calcium channels and/or channels activated by 3′5′ cyclic guanosine monophosphate (cGMP), in the field of treating retinal pathologies, and more particularly retinal diseases resulting from photoreceptor degeneration, in humans or animals, such as retinitis pigmentosa or other pathologies substantially involving the photoreceptors, especially age-related macular degeneration.
BACKGROUND OF THE INVENTION
Retinitis pigmentosa designates a group of these degenerative diseases of the photoreceptors (Berson, 1996) leading to blindness.
Numerous mutations affecting various rod proteins, and potentially the cause of this disease, have been described. Among these mutations can be mentioned those affecting the genes of proteins implicated in the phototransduction cascade, such as rhodopsin, transducin, phosphodiesterase, arrestin, or structural proteins such as peripherin.
The rd (retinal degeneration) mouse has been studied for more than 70 years as a model of retinitis pigmentosa (Farber et al., 1994), inasmuch as the process of retinal degeneration is similar to that observed in the pigmentary retina, the death of the retinal rods being followed by an unexplained loss of the retinal cones. Moreover, the causal mutation was localized in the gene encoding the &bgr; sub-unit of cGMP-phosphodiesterase (PDE) (Bowes et al., 1990), as in certain families affected by the disease (McLaughlin et al., 1993).
PDE is activated during the phototransduction cascade by the &agr; chain of transducin, itself activated by light-stimulated rhodopsin. Activated PDE hydrolyzes cGMP, thus reducing the concentration of cGMP and hence the number of open cGMP-dependent channels, the final consequence being a decrease in the conductance of cations such as Na
+
and Ca
2+
and in turn a reduction of the depolarization current of the photoreceptors into obscurity. In the rd mouse, Farber and Lolley (1974) have shown that an abnormal increase of the cGMP concentration precedes the degeneration of the photoreceptors. The toxicity of cGMP at high concentrations was next established for normal photoreceptors (Lolley and Farber, 1977; Ulshafer et al., 1980).
Several therapeutic approaches intended to prevent photoreceptor loss are at present undergoing investigation in rd mice. It was therefore described that in vivo gene therapy permits retarding a death of photoreceptors for six weeks after sub-retinal injection of a replication-deficient recombinant adenovirus which contains the cDNA encoding murine PDE (Bennett et al., 1996). Photoreceptor transplantation (Gouras et al., 1994, Silverman et al., 1989) was described as permitting preservation of the cone photoreceptors (Mohand-Said et al., 1997). The interpretation of this effect in terms of the paracrine mechanism agrees with the increase of the photoreceptor survival observed in coculture with healthy photoreceptors (Mohand-Said et al., 1998) or after in vivo or in vitro application of trophic factors such as fibroblast or neuronal growth factors (LaVail et al., 1998).
Nevertheless, no treatment for retinal diseases resulting from photoreceptor degeneration is available at present, apart from prescription of vitamin A for retinitis pigmentosa (Berson, 1996).
BRIEF SUMMARY OF THE INVENTION
The present invention particularly concerns providing pharmaceutical compositions that can be used in the field of treating retinal diseases resulting from photoreceptor degeneration in humans or animals.
REFERENCES:
patent: WO 90/06123 (1990-06-01), None
patent: WO 96/00073 (1996-01-01), None
patent: WO 96/03985 (1996-02-01), None
patent: WO 98/50065 (1998-11-01), None
XP-002105534, Deepak Edward et al. “Amelioration of Light-Induced Retinal Degeneration by a Calcium Overload Blocker”, pp. 554-562.
XP-002105535, Deepak Edward et al., “The Amelioration of Light Induced Retinal Degeneration by Flunarizine, a Calcium Channel Blocker”, pp. 1441-20.
XP-002105536, Iman Sahly et al., “Calcium Channel Blockers Inhibit Retinal Degeneration in Retinal-Degeneration-B Mutant of Drosophila”, pp. 435-439.
XP-002105537, Mark Tso, “In Search of Pharmacotherapy For Photoreceptor Degeneration”.
XP-002105538, Carlos Medrano et al., “Oxygen Consumption in the Rat Outer and Inner Retina: Light-and Pharmacologically-Induced Inhibition”, pp. 273-284.
XP-002105539, David Zava et al., “Cyclic GMP Accumulation Causes Degeneration of Photoreceptor Cells: Simulation of an Inherited Disease”, pp. 664-666.
XP-002105540, Jeffrey Stern et al., “Control of the Light-Regulated Current in Rod Photoreceptors by Cyclic GMP, Calcium and L-CIS-Diltiazem”, pp. 1163-1167.
XP-002105541, Basil Pawlyk et al., “Effects of IBMX on the Rod ERG of the Isolated Perfused Cat Eye: Antagonism With Light, Calcium of L-CIS-Diltiazem”, pp. 1093-1097.
Dreyfus Henri
Frasson Maria
Picaud Serge
Sahel Jose
Fay Zohreh
INSERM (Institut National de la Sante et de la Recherche Medical
Young & Thompson
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