Permanently charged sodium and calcium channel blockers as Anti- inflammatory agents

a sodium and calcium channel blocker, permanent charge technology, applied in the direction of antibacterial agents, antinoxious agents, immunological disorders, etc., can solve the problems of affecting the excitability of all neurons, causing deleterious effects, and provoking the effect of local anesthetics

Inactive Publication Date: 2012-07-05
PRESIDENT & FELLOWS OF HARVARD COLLEGE +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]In a first aspect, the invention features a method for treating neurogenic inflammation in a patient, such as a human, by administering a therapeutically effective amount of a compound that is capable of entering a nociceptor through a channel-forming receptor present in the nociceptor when the receptor is activated and inhibiting a voltage-gated ion channel present in the nociceptor, wherein the compound does not substantially inhibit said channel when applied to the extracellular face of the channel and when the receptor is not activated. In certain embodiments, the compound is an inhibitor of voltage-gated sodium channels. Exemplary inhibitors of this class are QX-314, N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine and pancuronium. In other embodiments, the compound is a quarternary amine derivative or other charged derivative of a compound selected from riluzole, mexilitine, phenyloin, carbamazepine, proca

Problems solved by technology

However, these anesthetics block sodium or calcium channels and thereby the excitability of all neurons, not just pain-sensing neurons.
Thus, administration of local anesthetics produces unwanted or deleterious effects such as general numbness from block of low thresho

Method used

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  • Permanently charged sodium and calcium channel blockers as Anti- inflammatory agents
  • Permanently charged sodium and calcium channel blockers as Anti- inflammatory agents
  • Permanently charged sodium and calcium channel blockers as Anti- inflammatory agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Treatment of Neurogenic Inflammation with Intravenous Injection of QX-314

[0181]FIG. 1 is a graph showing the effect of intravenous QX-314 (0.4 mg / kg) on the edema elicited by injection of complete Freund's adjuvant (CFA) in the rat hindpaw determined by measuring the total volume of the hindpaw by plethysmography. The degree of swelling produced by injection of CFA is reduced by administration of QX-314 reflecting reduction in neurogenic edema resulting from the blockade of nociceptors by QX314. QX-314 by itself has no effect different from administration of saline.

example 2

Entry of N-Methyl-Verapamil into Dorsal Root Ganglion Neurons Through Capsaicin-Activated TRPV1 Channels

[0182]N-methyl-verapamil, a charged derivative of the known calcium channel blocker verapamil and structurally related to D-890, can be loaded into dorsal root ganglion neurons through activation of TRPV1 channels by capsaicin. The internally-loaded N-methyl-verapamil then produces long-lasting inhibition of the voltage-dependent calcium channels in the neurons. Entry of the drug into the cell, and its blocking action, depends on applying the drug in the presence of capsaicin to activate the TRPV1 channels present in the neuronal membrane.

[0183]As shown in FIG. 2, the inhibition of voltage-dependent calcium channel current in a DRG neuron by N-methyl-verapamil applied in the presence of capsaicin to open TRPV1 channels. The traces show currents through voltage-activated calcium channels in a dissociated rat dorsal root ganglion neuron, recorded in whole-cell mode. Current was carr...

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Abstract

The invention provides compounds, compositions, methods, and kits for the treatment of neurogenic inflammation.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit of U.S. Provisional Application No. 61 / 224,512, filed Jul. 10, 2009, which is hereby incorporated by reference.FIELD OF THE INVENTION[0002]The invention provides compounds, methods and kits for the treatment of neurogenic inflammation.BACKGROUND OF THE INVENTION[0003]The invention features methods and kits for the treatment of neurogenic inflammation by targeting nociceptors with drugs of low molecular weight, while minimizing effects on non-pain-sensing neurons or other types of cells. According to the method of the invention, small, hydrophilic drug molecules gain access to the intracellular compartment of pain-sensing neurons via entry through receptor / channels that are present in pain-sensing neurons but to a lesser extent or not at all in other types of neurons or in other types of tissue. Neurogenic inflammation is a mode of inflammation mediated by the efferent (motor) functions of sensory neurons, i...

Claims

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Application Information

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IPC IPC(8): A61K31/277C07C237/14C07C255/33A61P25/00A61P29/00A61P11/06A61P11/10A61P19/02A61P17/00A61P1/00A61P13/02A61P25/06A61P17/06A61P11/02A61K31/16
CPCA61K31/00A61K31/165A61K31/167A61K31/277A61K45/06C07D235/14C07D295/192A61K2300/00A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P11/10A61P11/14A61P13/00A61P13/02A61P13/10A61P17/00A61P17/04A61P17/06A61P17/10A61P19/02A61P25/00A61P25/02A61P25/06A61P27/02A61P27/14A61P29/00A61P31/04A61P37/08A61P39/02A61P43/00
Inventor WOOLF, CLIFFORD J.BEAN, BRUCE P.
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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