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 Title: |
US5677288:
Use of aminoglycosides to protect against excitotoxic neuron damage
[ Derwent Title ]
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| Country: |
US United States of America
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| Inventor: |
Marangos, Paul J.; Encinitas, CA
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| Assignee: |
Cypros Pharmaceutical Corporation, Carlsbad, CA
other patents from CYPROS PHARMACEUTICAL CORPORATION (691549) (approx. 12)
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| Published / Filed: |
1997-10-14
/ 1994-04-15
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| Application Number: |
US1994000228229
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| IPC Code: |
Advanced:
A61K 31/70;
Core:
more...
IPC-7:
A61K 31/70;
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| ECLA Code: |
A61K31/7036;
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| U.S. Class: |
Current:
514/039;
514/035;
514/036;
514/037;
514/038;
514/040;
Original:
514/039;
514/035;
514/036;
514/037;
514/038;
514/040;
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| Field of Search: |
514/030,36,37,38,39,40,35
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| Priority Number: |
| 1994-04-15 |
US1994000228229 |
| 1992-03-20 |
US1992000855600 |
| 1991-05-15 |
US1991000700765 |
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| Abstract: |
A method is disclosed for reducing excitotoxic damage to neurons, which can occur as a result of stroke, cardiac arrest, or other events or conditions. This method involves administering an aminoglycoside that suppresses the flow of calcium ions into neurons through N-type calcium channels. To be effective for such use, an aminoglycoside must suppress N-channel activity at a potency greater than streptomycin. Aminoglycosides which meet this criterion (which includes neomycin and Gentamicin) can suppress the depolarizing activation of neurons, which in turn controls the release of glutamate, a neurotransmitter that becomes an endogenous toxin under excitotoxic conditions. Numerous aminoglycosides were tested in in vitro screening tests using brain cell membrane fragments to evaluate N-channel blocking potency. Aminoglycosides with the highest N-channel blocking potency were then tested using (1) in vitro tests on hippocampal brain tissue, to evaluate recovery of neuronal activity after a period of oxygen deprivation; (2) in vivo tests to evaluate the control of induced seizures in intact adult mammals; and (3) in vivo tests to evaluate the reduction of brain damage due to surgically-induced ischemia in intact adult mammals. The results showed that (1) aminoglycosides which are more potent than streptomycin in blocking N-channel ion flow are effective in reducing excitotoxic brain damage, without causing undesired side effects, and (2) the effectiveness of all BBB-permeable aminoglycosides tested to date in preventing excitotoxic brain damage is directly correlated with their potency in suppressing N-channel activity. Evaluation of chemical structures also indicates a correlation between the number of primary amino groups on an aminoglycoside, and its potency as an N-channel blocker and neuroprotective agent.
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| Attorney, Agent or Firm: |
Kelly, Patrick D. ;
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| Primary / Asst. Examiners: |
Peselev, Elli;
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| INPADOC Legal Status: |
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| Related Applications: |
| Application Number |
Filed |
Patent |
Pub. Date |
Title |
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| US1992000855600 | 1992-03-20 |
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| US1991000700765 | 1991-05-15 |
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| Parent Case: |
RELATED APPLICATION
This application is a continuation-in-part of U.S. patent application Ser. No. 07/855,600, filed on Mar. 20, 1992, now abandoned which was a continuation-in-part of patent application Ser. No. 07/700,765, filed on May 15, 1991, now abandoned.
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| Family: |
Show 3 known family members
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First Claim:
Show all 15 claims |
I claim:
1. A method of reducing excitotoxic neuron damage in mammals suffering such damage, by means of injecting into a mammalian bloodstream a therapeutically effective quantity of a selected aminoglycoside which reduces neuronal calcium ion uptake through N-type calcium ion channels on neuronal surfaces, wherein the selected aminoglycoside has;
- (a) at least one saccharide ring having at least five atoms:
- (b) more than two primary amine groups; and,
- (c) a potency stronger than streptomycin in reducing calcium ion uptake into neurons through N-type calcium ion channels,
- and wherein the selected aminoglycoside can penetrate mammalian blood-brain barriers and reduce excitotoxic damage to neurons in an adult mammalian brain in a therapeutically effective manner if injected into a mammal suffering such excitotoxic neuron damage and wherein said aminoglycoside is selected from the group consisting of aminoglycoside antibiotics and their pharmaceutically acceptable salts and isomers.
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| Background / Summary: |
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| Drawing Descriptions: |
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| Description: |
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| Forward References: |
Show 8 U.S. patent(s) that reference this one
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| Foreign References: |
None
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| Other Abstract Info: |
CHEMABS 124(19)250954A
CAN127(22)303343W
CHEMABS 127(22)303343W
DERABS C96-069205
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| Other References: |
Chemical Abstracts 115: 41827m (Mikami, 1991).
Caputy, A.J., et al, "The neuromuscular blocking effect of various antibiotics on normal rat skeletal muscle: A quantitative comparison," J. Pharmacol. Exp. Ther. 217: 369-378 (1981).
(10 pages)
Wright, J.M., and Collier, B., "The effects of neomycin upon transmitter release and action," J. Pharmacol. Exp. Ther. 200: 567-587 (1977).
Knaus, H.G., et al, "Neurotoxic aminoglycoside antibiotics are potent inhibitors of 125-I Omega-Conotoxin GVIA binding to guinea pig cerebral cortex membranes," Naunyn Schmiederberg's Arch. Pharmacol. 336: 583-586 (1987).
(4 pages)
Cited by 3 patents
Kasai, H., et al, "Presynaptic Ca-antagonist omega-conotoxin irreversibly blocks N-type ca-channels in chick sensory neurons," Neurosci. Res. 4: 228-235 (1987).
Physician's Desk Reference (1990 edition, p. 1981).
Morel, N. et al, "Factors affecting activity of cerebral microvessels and their sensitivity to calcium antagonists," pp. 283-295 in Krieglstein, J., and Oberpichler, H., Pharmacology of Cerebral Ischemia (Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1990).
Whittingham, S., et al., "In vitro model of ischemia: metabolic and electrical alterations in the hippocampal slice," J. Neuroscience 4: 793-802 (1984).
(10 pages)
Schurr, A. and Rigor, B.M., "Modeling neurodegeneration and neuroprotection in hippocampal slices," pp. 24-43 in Emerging Strategies in Neuroprotection (Marangos and Lal, eds., Birkhauser Publ., Boston, 1992).
Keith, R.A., et al, "Actions of Neomycin on Neuronal L-, N-, and Non-L/Non-N-Type Voltage Sensitive Calcium Channel Blockers," Journal of Molecular Neuroscience 3: 147-154 (1992).
(8 pages)
[ISI abstract]
Perrier, M.L., et al, "Dihydropyridine-[resistant] and omega-Conotoxin-Resistant, Neomycin-Sensitive Calcium Channels Mediate the Depolarization-Induced Increase in Internal Calcium Levels in Cortical Slices from Immature Rat Brain," Journal of Pharmacology and Experimental Therapeutics 261: 324-330 (1992).
(7 pages)
[ISI abstract]
Yamada, K., et al, "Neuropharmacological Characterization of Voltage-Sensitive Calcium Channels: Possible Existence of Neomycin-Sensitive, Conotoxin GVIA- and Dihydropyridines-Resistant Calcium Channels in the Rat Brain," Japanese Journal of Pharmacology 63: 423-432 (1993).
(10 pages)
[ISI abstract]
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