Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-04-15
1997-10-14
Peselev, Elli
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 35, 514 36, 514 37, 514 38, 514 40, A61K 3170
Patent
active
056772882
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.
REFERENCES:
patent: 4446155 (1984-05-01), Osterholm
patent: 4985458 (1991-01-01), Nakayama
patent: 5037846 (1991-08-01), Saccomane et al.
patent: 5122596 (1992-06-01), Phillips et al.
patent: 5227397 (1993-07-01), Saccomano et al.
patent: 5256684 (1993-10-01), Marshall
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).
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).
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).
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). 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).
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).
Cypros Pharmaceutical Corporation
Kelly Patrick D.
Peselev Elli
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