Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1993-03-22
2001-07-24
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S312000
Reexamination Certificate
active
06265442
ABSTRACT:
BACKGROUND OF THE INVENTION
Although the gene responsible for Huntington's disease (HD) has been localized to chromosome 4 (Gusella et al.,
Nature
306:234-238 (1983)), the pathogenesis of the illness remains obscure. One theory is that an “excitotoxic” process may play a role. This theory was originally based on the observation of similarities between kainic acid striatal excitotoxin lesions and the neuropathologic and neurochemical features of HD (Coyle and Schwarcz,
Nature
263:244-246 (1976); McGeer and McGeer,
Nature
263:512-519 (1976)). Schwarcz et al.,
Science
219:316-318 (1983) found that quinolinic acid striatal excitotoxic lesions are also similar to those of HD. Beal and co-workers found that this compound, and other agonists acting at the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors, could more accurately replicate the neurochemical and histologic features of HD (Beal et al.,
Nature
321:168-171 (1986) and
Synopse
3:38-47 (1989)). The possibility that an excitotoxin acting at NMDA receptors is involved in HD has been strengthened by the finding of Young et al.,
Science
241:981-983 (1988) that NMDA receptors are profoundly depleted in HD. Moreover, this appears to be an early phenomenon in the course of the illness.
Although there have been many researchers investigating HD, little is known about its etiology and possible approaches to lessening or avoiding its effects.
SUMMARY OF THE INVENTION
The present invention relates to a method for treating neurological diseases that are caused by excitatory amino acid induced lesions in the brain. The treatment can be either prophylactic in nature or to alleviate the symptoms of such diseases. The lesions are thought to be caused by an abnormally elevated number of interactions at the excitatory amino acid receptors by these excitatory amino acids or their agonists.
The present invention provides the treatment by administering a substance to the subject individual that increases the brain concentration of a metabolic precursor to an endogenous blocker of the toxic excitatory amino acid interactions at their receptors. The blocker acts either as an antagonist or as an allosteric inhibitor at the excitatory amino acid receptor.
In particular, the endogenous blocker is kynurenic acid. Metabolic precursors to kynurenic acid include kynurine (the immediate metabolic precursor of kynurenic acid) and tryptophan. These precursors can be administered to an individual by direct application into the brain or, preferably, by peripheral loading. Such loading can be accomplished by ingestion or by injection, e.g., intravenously or intraperitoneally. The loading causes the metabolic precursor to cross the blood-brain barrier into the brain where they are metabolically transformed into the endogenous blocker, i.e., kynurenic acid. Alternatively, the metabolic precursors can be stimulated to cross the blood-brain barrier by loading the individual with substances that alter the ratio of protein bound precursor (kynurenine or tryptophan) to free precursor such that more free precursor is available to cross the blood-brain barrier. The substances include neutral amino acids and carbohydrates.
The invention also includes the increase in amount or activity of kynurenine aminotransferase in the brain of the subject individual. This enzyme is responsible for forming kynurenic acid from kynurenine. An increase in its amount or activity will yield increased concentrations of kynurenic acid from the available stores of its metabolic precursors.
REFERENCES:
Gal, E.M., and Shurman, A.D. “Synthesis and Metabolism of L-Kynurenine in Rat Brain,”J. Neurochem., 30:607-613 (1978).
Simon, P., et al., “Inhibition of Excitatory Neurotransmission with Kynurenate Reduces Brain Edema in Neonatal Anoxia,”Neuroscience Letters, 71:361-364, (1986).
Speciale C., et al., “High-Affinity Uptake of L-Kynurenine by a Na+-Independent Transporter of Neutral Amino Acids in Astrocytes,”J. of Neurosci., 9(6):2066-2072, (1989).
Beal M.F., et al., “Systemic Approaches to Modifying Quinolinic Acid Striatal Lesions in Rats,”J. of Neurosci., 8(10):3901-3908, (1988).
During, M.J., et al., “Potential Neurotoxicity of Tryptophan: Striatal Quinolinic Acid Monitored by Microdialysis,”Society for Neuroscience Abstracts, 14(1) (1988) (Abstract No. 290.14).
During, M.J., et al., “Quinolinic Acid Concentrations in Striatal Extracellular Fluid Reach Potentially Neurotoxic Levels Following Systemic L-Tryptophan Loading,”Brain Research, 476:384-387, (1989).
Okuno, E., et al., “&agr;-Ketoglutarate and Pyruvate as Co-Factors of Kynurenine Transaminase in Rat Brain,”Society for Neuroscience Abstracts, 15 (1989) (Abstract 328.9).
Freese, A., “Excitotoxic Models of Huntington's Disease”,Proc. 1988 HST Forum, Harvard Univ-MIT Div of Health Sci and Tech, pp. 53-59 (Oct. 28, 1988).
Beal, M.F., et al., “Replication of the Neurochemical Characteristics of Huntington's Disease by Quinolinic Acid,”Nature321 (6066):168-171 (1986).
During, M.J., et al., “Indolic and Kynurenine Pathway Metabolites of Tryptophan in Rat Bran: Effect of Precursor Availability on In Vivo Release,”Int'l. Study Group for Tryptophan Research, Baltimore, (May 9-12, 1989).
During, M.J. and Freese, A., “Branched-Chain Amino Acids in Amyotrophic Lateral Sclerosis,” (Letter to Editor),The Lancet, II (8612):680 (1988).
During M.J., et al., “Neuroactive Metabolites of L-Tryptophan, Serotonin and Quinolinic Acid, in Striatal Extracellular Fluid,”Federation of European Biochem. Societies Letters, 247(2):438-444 (1989).
Beal, M.F., et al., “Kynurenine Pathway Measurements in Huntington's Disease Striatum: Evidence for Reduced Formation of Kynurenic Acid,”J. of Neurochem., 55(4):1327-1339 (1990).
Swartz, K.J., et al., “Measurement of Kynurenic Acid in Mammalian Brain Extracts and Cerebrospinal Fluid by High-Performance Liquid Chromatography with Fluorometric and Coulometric Electrode Array Detection,”Analytical Biochem., 185:363-376 (1990).
Freese, A., et al., “Regional Brain Quinolinic Acid Levels and Neurochemical Markers of Toxicity: Effects of Acute vs. Chronic Tryptophan Feeding,”Society for Neuroscience Abstracts, 15 (1989) (Abstract No. 306.3).
Moroni, F., et al., “Presence of Kynurenic Acid in the Mammalian Brain,”J. Neurochem., 51(1):177-179, (1988).
Foster A.C., et al., “Kynurenic Acid Blocks Neurotoxicity and Seizures Induced in Rats by the Related Brain Metabolite Quinolinic Acid,”Neuroscience Letters, 48:273-278, (1984).
Andine, P., et al., “The Excitatory Amino Acid Antagonist Kynurenic Acid Administered After Hypoxic-Ischemia in Neonatal Rats Offers Neuroprotection,”Neuroscience Letters, 90:208-212, (1988).
Merck Manual, 14thEd., p. 1362-1363 (1982).*
Medline Abst. 88319420 of Neurosci Lett: 90 :208-12 (1988).*
Chem Abst. 111(10):84105 of WO8807851 (1985).*
Chem Abst. 111(19) : 173999 of EP. 303387(1989).
Beal M. Flint
During Matthew J.
Freese Andrew
Swartz Kenton J.
Hamilton Brook Smith & Reynolds P.C.
The General Hospital Corporation
Weddington Kevin E.
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