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Methods, compositions, and kits for treating pain and pruritis

a technology for pruritis and pain, applied in the field of methods, compositions, and kits for treating pain and pruritis, can solve the problems that the administration of local anesthetics also produces unwanted or deletrious effects

Inactive Publication Date: 2010-04-22
THE GENERAL HOSPITAL CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028]The methods, compositions, and kits of the invention allow for a block of pain or itch without altering light touch or motor control. For example, patients receiving an epidural will not have a complete loss of sensory input.

Problems solved by technology

Thus, while the goal of topical or regional anesthesia is to block transmission of signals in nociceptors to prevent pain, administration of local anesthetics also produces unwanted or deletrious effects such as general numbness from block of low threshold pressure and touch receptors, motor deficits from block of motor axons and other complications from block of autonomic fibers.

Method used

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  • Methods, compositions, and kits for treating pain and pruritis
  • Methods, compositions, and kits for treating pain and pruritis
  • Methods, compositions, and kits for treating pain and pruritis

Examples

Experimental program
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Effect test

example 1

[0159]We recorded current through voltage-dependent sodium channels using whole-cell voltage clamp recordings from adult rat DRG neurons. To select for nociceptors, we recorded from small (24±5 μm; n=25) neurons and tested the neurons for the expression of TRPV1 receptors by a short (1-sec) application of 1 μM capsaicin. In 25 / 25 of small neurons tested, capsaicin produced a prolonged (10±3 sec) inward current (FIG. 1A, upper panel), consistent with the neurons being nociceptors. Sodium currents were elicited by depolarizing steps from a holding potential of −70 mV. Bath application of 5 mM QX-314 alone had a minimal effect on sodium current (decrease by 3±0.5% after a 5-minute application, n=25) (FIG. 1A, left; b). Application of capsaicin alone (1 μM for 1-10 minutes) reduced sodium current moderately (31±9% inhibition (n=25). However, when QX-314 was applied together with capsaicin, sodium current was nearly totally abolished (inhibition by 98±0.4%, n=25) (FIG. 1A, left; b). As e...

example 2

[0173]We have also shown that eugenol (C10H12O2), an allyl chain-substituted guaiacol, 2-methoxy-4-(2-propenyl)phenol (active ingredient in oil of clove, and a non-pungent agonist of TRPV1 receptors) promotes entry of QX-314 into dorsal root ganglion neurons by activating TRPV1 channels. FIG. 5 depicts voltage clamp recordings of sodium channel current in small dorsal root ganglion neurons. The data show that eugenol alone has a modest inhibitory effect on sodium current (10-20% inhibition). Co-application of eugenol and QX-314 produces progressive block that can be complete after 7 minutes. Two examples are depicted, which are representative of 10 experiments with similar results. As is demonstrated above, external QX-314 alone has no effect while internal QX-314 blocks sodium channels. Thus, these experiments indicate that eugenol promotes entry of QX-314 into dorsal root ganglion neurons by activating TRPV1 channels.

example 3

[0174]FIG. 6 shows the results of co-application of the TRPA agonist mustard oil (MO) (50 μM) and QX-314 (5 mM). MO alone reduces sodium current by 20-30% and reaches a plateau after approximately 3 minutes. Co-application of MO and QX-314 reduced sodium current dramatically.

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Abstract

The invention features a method for inhibiting one or more voltage-gated ion channels in a cell by contacting the cell with (i) a first compound that activates a channel-forming receptor that is present on nociceptors and / or pruriceptors; and (ii) a second compound that inhibits one or more voltage-gated ion channels when applied to the internal face of the channels but does not substantially inhibit said channels when applied to the external face of the channels, wherein the second compound is capable of entering nociceptors or pruriceptors through the channel-forming receptor when the receptor is activated. The invention also features a quarternary amine derivative or other permanently or transiently charged derivative of a compound that inhibits one or more voltage-gated ion channels when applied to the internal face of the channels but does not substantially inhibit said channels when applied to the external face of the channels.

Description

BACKGROUND OF THE INVENTION[0001]The invention features methods, compositions, and kits for selective inhibition of pain-and itch sensing neurons (nociceptors and pruriceptors) by drug molecules of small molecule 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 receptors that are present in pain- and itch-sensing neurons but to a lesser extent or not at all in other types of neurons or in other types of tissue.[0002]Local anesthetics such as lidocaine and articaine act by inhibiting voltage-dependent sodium channels in neurons. These anesthetics block sodium channels and thereby the excitability of all neurons, not just pain-sensing neurons (nociceptors). Thus, while the goal of topical or regional anesthesia is to block transmission of signals in nociceptors to prevent pain, administra...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/16A61P25/00
CPCA61K31/085A61K31/165A61K9/0014A61K45/06A61K31/167A61K31/14A61P17/04A61K2300/00A61P23/02G01N33/6872C12N2503/02
Inventor BEAN, BRUCE P.WOOLF, CLIFFORD J.
Owner THE GENERAL HOSPITAL CORP
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