Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-03-16
1998-03-31
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 21, 530399, A61K 3800, A61K 3827, A61K 3816, A61K 3828
Patent
active
057338710
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION
This invention relates to pharmaceutical compositions useful for treatment of neuronal damage associated with ischemia, hypoxia or neurodegeneration, and to methods for using the compositions.
BACKGROUND OF THE INVENTION
Neurotrophic factors exhibit a trophic effect on neuronal cells of the brain. The trophic effect has been characterized as enhancing neuronal survival and maintenance of neuronal cell functions associated with differentiated neurons. In vivo studies have shown that a variety of endogenous and exogenous neurotrophic factors exhibit a trophic effect on neuronal cells after ischemic, hypoxic or other disease-induced damage. Examples of specific neurotrophic factors include basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), neurotrophin 4 (NT4) and the insulin-like growth factors I and II (IGF-I, IGF-II).
Some neurotrophic factors, such as bFGF and CNTF, are thought to have broad trophic effects, promoting survival or providing a maintenance function for many different types of neuronal cells. Other neurotrophic factors have a narrower, more specific trophic effect and promote survival of fewer types of cells. For example, in the peripheral nervous system NGF promotes neuronal survival and axonal extension of certain specific neuronal cell types such as sensory and sympathetic neurons (Ebendal, T. et al., Cellular and Molecular Biology of Neuronal Development, Ch. 15, ed. Black, I. B., 1984). However, in the CNS, NGF also supports the survival of cholinergic neurons in the basal forebrain complex (Whittemore et al., Brain Res. Rev., 12:439-464, 1987). BDNF, a basic protein of molecular weight 12,300, supports some sensory neurons that do not respond to NGF (Barde, et al., EMBO J., 1:549-553, 1982 and Hofer and Barde, Nature, 331:261-262, 1988). Neurotrophin 3 (NT3) supports survival of dorsal root ganglion neurons and proprioceptive neurons in the trigeminal mesencephalic nucleus. CNTF, a protein of about molecular weight 23,000, supports ciliary ganglion neurons in the parasympathetic nervous system, sympathetic neurons, dorsal root ganglion neurons in the sensory nervous system and motor neurons in the central nervous system (CNS) (Kandel, E. R., et al., Principles of Neural Science, 3rd Ed., Elsevier Science Publishing Co., Inc., New York, 1991).
Some neurotrophic factors constitute a family of neurotrophic factors characterized by about 50% amino acid homology. One such family is the BDNF/NGF family, which includes BDNF, NGF, NT3 and NT4 (Hohn, A., et al., WO 91/03569).
Fibroblast growth factors (FGFs) are members of a protein family that induce mitogenic, chemotactic and angiogenic activity in a variety of cells of epithelial, mesenchymal, and neuronal origins (Zhu et al., 1990; Moscatelli, et al., U.S. Pat. No. 4,994,559). FGFs are proteins of molecular weight 16,000-25,000 and characterized by their strong binding to heparin (Finklestein, S., et al., Stroke (Suppl. III) III-122-III-124, 1990; Finklestein, S. et al., Rest. Neurol. and Neurosci., 1:387-394, 1990). Both aFGF and bFGF have been reported to have broad specificity of neurotrophic activities. Although the FGFs have similar functional activities, they are discretely different proteins with different properties.
Because of the ability of neurotrophic factors to promote the survival of neurons, they have been suggested to be useful for treating various disorders associated with neuronal cell death. Intracisternal administration of bFGF to rats after middle cerebral artery occlusion was reported to prevent thalamic degeneration (Yamada, K., et al., J. Cerebral Blood Flow and Met., 11:472-478, 1991). Continuous intracerebroventricular infusion of aFGF to a gerbil prevented death of hippocampal CA1 pyramidal cells after 5 minute ischemia (Oomora, Y., et al., Soc. for Neurosci. Abstracts, 16(1):516 Abstr. No. 221.2, 1990) .
Administration of neu
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Alps Brian J.
Brown Christine Mary
Collins Franklin D.
Emmett Caroline J.
Finklestein Seth P.
The General Hospital Corporation
Touzeau P. L.
Tsang Cecilia J.
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