Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2001-10-02
2003-01-14
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
Reexamination Certificate
active
06506801
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed, in part, to novel methods of treating complicated anosmia in a mammal, to methods of enhancing the rate of olfactory nerve recovery in a mammal, and to methods of enhancing nerve regeneration in a mammal.
BACKGROUND OF THE INVENTION
Injuries to the central nervous system (CNS), such as, for example, stroke, chronic nasal sinus disease, allergic rhinitis, neurodegenerative disease, head trauma, viral or bacterial infection, and surgery, can result in olfactory dysfunction, which affects nearly three million Americans. A complete loss of smell is referred to as “anosmia” whereas a decrease in smell sensitivity is referred to as “hyposmia.” Unfortunately, there is little that can be done to cure or treat the condition effectively. Further, recovery from head trauma can take many months or even years and is often incomplete even after apparent physical recovery.
The ability of the olfactory system to replace degenerating olfactory neurons caused by age or injury has been examined. Morphological studies have demonstrated degeneration of mature olfactory neurons in the olfactory epithelium after axotomy, followed by an increase in the proliferation of basal cells. Cancalon et al.,
J. Cell Biol.,
1980, 84, 779-794; Graziadei et al.,
J. Cell Biol.,
1973, 59, 525-30; Graziadei and Monti Graziadei, The olfactory system: a model for the study of neurogenesis and axon regeneration in mammals. In: C. W. Cotman (Ed.), Neuronal Plasticity, New York, Raven Press, 1978, pp. 131-153; Oley et al,
J. Comp. Physiol. Psychol,
1975, 88, 477-495; and Simmons et al.,
J. Neurophysiol.,
1981, 45, 529-549. With time, the basal cells differentiate into olfactory neurons that can connect to the olfactory bulb and restore function. Costanzo,
Brain. Res.,
1985, 361, 258-266 and Yee et al.,
Physiol. Behav.,
1995, 58, 959-968. Few studies, however, have examined possible ways to improve recovery after denervation. The time for some recovery of behavioral function varies with species; in hamsters, for example, recovery occurs in approximately 20 days. Anatomical recovery is reported to take about 30 days in most species studied. Cummings et al.,
J. Comp. Neurol.,
2000, 421, 362-373; Monti Graziadei et al.,
J. Neurocytol.,
1979, 8, 197-213; Graziadei and Monti Grazaiadei, The olfactory system: a model for the study of neurogenesis and axon regeneration in mammals. In: C. W. Cotman (Ed.), Neuronal Plasticity, New York, Raven Press, 1978, pp.131-153. Within the central nervous system, it is thought that minimal regeneration occurs, except for a population of stem cells within the subventricular zone that proliferate and are thought to contribute to cell repopulation in the olfactory bulb. Gheusi et al.,
Proc. Natl. Acad. Sci. USA,
2000, 97, 1823-1828.
Vitamin A has been used to treat uncomplicated anosmia but was found not to be useful in treating anosmia associated with skull injuries and fractures with sheering of olfactory nerves, i.e., complicated anosmia. Duncan et al.,
Archives of Otolaryngology,
1962, 75, 116-124. Recent evidence has demonstrated that retinoic acid (RA), a metabolite of vitamin A, plays an important role in the development and morphogenesis of the fetal olfactory system. Anchan et al.,
J. Comp. Neurol.,
1997, 379, 171-184; LaMantia et al.,
Neuron,
1993, 10, 1035-1048; and Simmons et al.,
J. Neurophysiol.,
1981, 45, 529-549. There is also evidence that RA plays a role in the growth of the adult olfactory system. Gustafson et al.,
Dev. Brain Res.,
1999, 114, 121-126; Whitesides et al.,
J. Comp. Neurol.,
1998, 394, 445-461; Zhang,
Biochem. Biophys. Res. Commun.,
1999, 256, 346-351; and Corcoran et al.,
Nat. Neurosci.,
1999, 2, 307-308. Vitamin A has been postulated to have an effect on mRNA expression levels of olfactory marker protein (Aderoju et al.,
Amer. Chem. Soc. Abstracts,
2000, Abstract 193) and gene expression in neurons in vivo (Asson-Barres et al.,
Amer. Chem. Soc. Abstracts,
2000, Abstract 195). In addition, retinoic acid has been postulated to play a role in olfactory epithelium via retinoic acid binding proteins (Ahmad et al.,
Amer. Chem. Soc. Abstracts,
2000, Abstract 194). Thus, methods of treating complicated anosmia in mammals, enhancing the rate of olfactory nerve recovery in mammals, and enhancing nerve regeneration in mammals is greatly needed.
SUMMARY OF THE INVENTION
The present invention is directed to, inter alia, methods of treating complicated anosmia in a mammal comprising administering an effective amount of a retinoid compound to the mammal.
The present invention is also directed to methods of enhancing the rate of olfactory nerve recovery in a mammal after injury comprising administering an effective amount of a retinoid compound to the mammal.
The present invention is also directed to methods of enhancing nerve regeneration in a mammal comprising administering an effective amount of a retinoid compound to the mammal.
REFERENCES:
Roydhouse, N., New Zealand Medical Journal, 101(849), 465 (Jul. 13, 1988).*
Aderoju, A.O. et al., “Vitamin A in olfactory mucosa and its effect on gene expression in neurons in vivo”,Amer Chem Soc. Abstracts, 2000, Abstract 195.
Ahmad, O. et al., “Expression of cellular retinoic acid binding proteins in mature rat olfactory epithelium”,Amer. Chem Soc Abstracts, 2000, Abstract 194.
Anchan, R.M, et al., “Disruption of local retinoid-mediated gene expression accompanies abnormal development in the mammalian olfactory pathway”,J. Comp. Neurol., 1997, 379, 171-184.
Butler,et al., “. . . bulbectomized rats with new olfactory- . . . connections are anosmic” Neurosci. Lett., 1984, 48, 247-254.
Cancalon, P. et al., “Study of regeneration in the garfish olfactory nerve”,J. Cell Biol., 1980, 84, 779-794.
Chiang, M.Y. et al., “An essential role for retinoid receptors RAR&bgr; and RXRy in long term potentiation and depression”,Neuron, 1999, 21, 1353-1361.
Corcoran, J. et al., “Nerve growth factor acts via retinoic acid synthesis to stimulate neurite outgrowth”,Nat Neurosci., 1999, 2, 307-308.
Costanzo, R.M. “Neural regeneration and functional reconnection following olfactory nerve transection in hamster”,Brain. Res., 1985, 361, 258-266.
Cummings, D.M. et al., “Pattern of olfactory bulb innervation returns after recovery from reversible peripheral deafferentation”J. Comp. Neurol., 2000, 421, 362-373.
Duncan, R.B. et al., “Treatment of uncomplicated anosmia by vitamin A”,Archives of Otolaryngology, 1962, 75, 116-124.
Gheusi, G. et al., “Importance of newly generated neurons in the adult olfactory bulb for odor discrmination”,Proc. Natl. Acad. Sci. USA, 2000, 97, 1823-1828.
Graziadei, P.P.C. et al., “Neuronal regeneration in frog olfacotry system”,J. Cell Biol., 1973, 59, 525-30.
Graziadei & Graziadei, “The olfactory system: a model for the study of neurogenesis and axon regeneration in mammals”. In C.W. Cotman (ed), Neuronal Plasticity, New York, Raven Press, 1978, pp 131-153.
Graziadei, G.A.M. et al., “Neuroegenesis and neuron regeneration in the olfactory system of mammals. II. Degeneration and reconstitution of the olfactory sensory neurons after axotomy”,Jrl. of Neurocytology., 1979, 8, 197-213.
Gustafson, A-L et al., “CRBP1 and CRABP I localisation during olfactory nerve development”,Dev. Brain Res., 1999, 114, 121-126.
Harding, J.W. et al., “Denervation of the primary olfactory pathway in mice. V. Long-term effect of intranasal ZnSO4 irrigation on behavior, biochemistry and morphology”,Brain Res., 1978, 140, 271-285.
Hoag, W.G. et al., Biology of a laboratory mouse, E.L. Green(Ed.), Dover Publications Inc, New York, 2000, 39-43.
LaMantia, A.S. et al., “Retinoic acid induction and regional differentiation prefigure olfactory pathway formation in the mammalian forebrain”,Neuron, 1993, 10, 1035-1048.
Oley, N. et al., “Recovery of structure and function following transection of the primary olfactory nerves in pigeons”,J. Comp. Physiol. Psychol., 1975, 88, 477-495.
Remington's Pharmaceutical Sciences(Mack Pub. Co., Easton, PA, 1980).
Setzer, A.K.
Rawson Nancy E.
Yee Karen K.
Monell Chemical Senses Center
Spivack Phyllis G.
Woodcock & Washburn LLP
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