Compositions and methods for the treatment of disorders of the central and peripheral nervous systems

a central and peripheral nervous system and composition technology, applied in the direction of drug compositions, biocide, heterocyclic compound active ingredients, etc., can solve the problems of producing other, undesired effects, etc., to reduce the neurodegenerative effects of acute ethanol ingestion, reduce the activity of chloride-dependent cotransport systems, and relieve pain.

Inactive Publication Date: 2006-02-16
NEUROTHERAPEUTICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030] Yet another aspect of the present invention involves treatment of neurotoxicity attributable to a variety of chemical and biological agents, as well as some infectious agents. Compositions and methods of the present invention are especially effective in reducing the neurodegenerative effects of acute ethanol ingestion. Additionally, compositions of the present invention may be administered prophylactically to protect cortical tissue from the effects of neurotoxicity attributable, for example, to acute ethanol ingestion. Treatment compositions of the present invention for treating, or for prophylactic administration to protect from neurotoxicity, comprise ion-dependent cotransporter antagonists, preferably cation-chloride cotransporter antagonists. According to a preferred embodiment, agents and methods of the present invention for protecting from neurotoxicity preferentially act on the Na+, K+, 2Cl− chloride-dependent cotransport system of glial cells and have reduced activity on the chloride-dependent cotransport systems of other cells types, such as neurons and renal cells.
[0031] Another aspect of the present invention relates to methods and agents for relieving pain, or the perception of pain, by effecting or modulating propagation of action potentials or conduction of impulses in certain nerve fibers, particularly unmyelinated fibers, in the peripheral nervous system. More specifically, changes in extracellular ionic concentrations and ionic gradients in cells in the peripheral nervous system, affected by ion-dependent cotransporters, diminishes the perception or sensation of pain. Agents of the present invention for tr...

Problems solved by technology

Although such loop diuretics produce the desired modulation of the extracellular anionic chloride concentrations and ionic g...

Method used

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  • Compositions and methods for the treatment of disorders of the central and peripheral nervous systems
  • Compositions and methods for the treatment of disorders of the central and peripheral nervous systems
  • Compositions and methods for the treatment of disorders of the central and peripheral nervous systems

Examples

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example 1

The Effects of Furosemide on Epileptiform Discharges in Hippocampal Slices

[0059] During these studies, spontaneous epileptiform activity was elicited by a variety of treatments. Sprague-Dawley rats (males and females; 25-35 days old) were decapitated, the top of the skull was rapidly removed, and the brain chilled with ice-cold oxygenated slicing medium. The slicing medium was a sucrose-based artificial cerebrospinal fluid (sACSF) consisting of 220 mM sucrose, 3 mM KCI, 1.25 mM NaH2PO4, 2 mM MgSO4, 26 mM NaHCO3, 2 mM CaCl2, and 10 mM dextrose (295-305 mOsm). A hemisphere of brain containing hippocampus was blocked and glued (cyanoacrylic adhesive) to the stage of a Vibroslicer (Frederick Haer, Brunsick, Me.). Horizontal or transverse slices 400 μm thick were cut in 4° C., oxygenated (95% O2; 5% CO2) slicing medium. The slices were immediately transferred to a holding chamber where they remained submerged in oxygenated bathing medium (ACSF) consisting of 124 mM NaCl, 3 mM KCl, 1.25 ...

example 2

The Effects of Furosemide on Epileptiform Discharges in Hippocampal Slices Perfused with High-K+ (10 mM) Bathing Medium

[0065] Rat hippocampal slices, prepared as described above, were perfused with a high-K+ solution until extended periods of spontaneous interictal-like bursting were recorded simultaneously in CA3 (top traces) and CA1 (lower traces) pyramidal cell regions (FIGS. 2A and 2B). After 15 minutes of perfusion with furosemide-containing medium (2.5 mM furosemide), the burst discharges increased in magnitude (FIGS. 2C and 2D). However, after 45 minutes of furosemide perfusion, the bursts were blocked in a reversible manner (FIGS. 2E, 2F, 2G and 2H). During this entire sequence of furosemide perfusion, the synaptic response to a single test pulse delivered to the Schaffer colalterals was either unchanged or enhanced (data not shown). It is possible that the initial increase in discharge amplitude reflected a furosemide-induced decrease in inhibition (Misgeld et al., Science...

example 3

The Effects of Furosemide on Epileptiform Activity Induced by i.v. Injection of Kainic Acid in Anesthetized Rats

[0067] This example illustrates an in vitro model in which epileptiform activity was induced by i.v. injection of kainic acid (KA) into anesthetized rats (Lothman et al., Neurology 31:806, 1981). The results are illustrated in FIGS. 3A-3H. Sprague-Dawley rats (4 animals; weights 250-270 g) were anesthetized with urethane (1.25 g / kg i.p.) and anesthesia maintained by additional urethane injections (0.25 g / kg i.p.) as needed. Body temperature was monitored using a rectal temperature probe and maintained at 35-37° C. with a heating pad; heart rate (EKG) was continuously monitored. The jugular vein was cannulated on one side for intravenous drug administration. Rats were placed in a Kopf stereotaxic device (with the top of the skull level), and a bipolar stainless-steel microelectrode insulated to 0.5 mm of the tip was inserted to a depth of 0.5-1.2 mm from the cortical surfa...

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Abstract

The present invention relates to methods and compositions for treating selected conditions of the central and peripheral nervous systems employing non-synaptic mechanisms. More specifically, one aspect of the present invention relates to methods and materials for treating seizure and seizure disorders, epilepsy, status epilepticus, migraine, spreading depression, intracranial hypertension; for treating the pathophysiological effects of head trauma, stroke, ischemia and hypoxia; for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol; and for treating neuropsychiatric disorders and central nervous system edema by administering agents that modulate ionic concentrations and/or ionic gradients in the brain, particularly ion-dependent or cation-chloride cotransporter antagonists. Electrolyte cotransport antagonists and combinations of such compositions with other agents for treating various conditions are disclosed.

Description

REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 056,528, filed Jan. 23, 2002, which claims priority under 35 U.S.C. § 19(e) to U.S. Patent Application No. 60 / 263,830, filed Jan. 23, 2001, and is a continuation-in-part of U.S. patent application Ser. No. 09 / 470,637, filed Dec. 22, 1999, now U.S. Pat. No. 6,495,601, which claims priority under 35 U.S.C. §119(e) to U.S. Patent Application 60 / 113,620, filed Dec. 23, 1998.TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to methods and compositions for treating selected conditions of the central and peripheral nervous systems employing non-synaptic mechanisms. More specifically, one aspect of the present invention relates to methods and compositions for treating seizures and seizure disorders, epilepsy, status epilepticus, migraine headache, cortical spreading depression, intracranial hypertension, neuropsychiatric disorders, central nervous system ede...

Claims

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Application Information

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IPC IPC(8): A61K31/513A61K31/00A61K31/192A61K31/196A61K31/341A61K31/549A61K31/635A61K45/06
CPCA61K31/00A61K31/192A61K31/196A61K31/341A61K31/513A61K31/549A61K31/635A61K45/06A61K2300/00A61P25/00
Inventor HOCHMAN, DARYL W.
Owner NEUROTHERAPEUTICS PHARMA
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