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Methods, compositions, and kits for treating pain and pruritis

A technology of composition and compound, applied in the field of treatment of pain and itching, composition and kit, capable of solving problems such as autonomic fiber block

Inactive Publication Date: 2009-12-23
PRESIDENT & FELLOWS OF HARVARD COLLEGE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, while the goal of local or regional anesthesia is to block signaling in nociceptors to prevent pain, the administration of local anesthetics can also have unwanted or deleterious effects, such as caused by low threshold pressure and tactile receptor sensitivity. Generalized numbness due to block of motor axons, motor deficits due to block of motor axons, and other complications due to 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
Comparison scheme
Effect test

Embodiment 1

[0213] We recorded currents through voltage-dependent sodium channels in adult rat DRG neurons using whole-cell voltage clamp recordings. To select nociceptors, we recorded from small (24±5 μm; n=25) neurons and tested the expression of TRPV1 receptors in these neurons by short (1 sec) application of 1 μM capsaicin. In 25 / 25 small neurons tested, capsaicin produced prolonged (10±3 sec) inward currents ( figure 1 A, upper panel), consistent with neurons acting as nociceptors. Sodium currents were elicited by a depolarization step holding the potential at -70 mV. Soaking alone (Bath) applied 5mM QX-314 had the least effect on sodium current (after 5 minutes of application, it decreased by 3±0.5%, n=25) ( figure 1 A, left column; b). Capsaicin alone (1 [mu]m, 1-10 min) resulted in a modest reduction in sodium current (31±9% inhibition (n=25)). However, when QX-314 was administered together with capsaicin, the sodium current was almost completely abolished (98±0.4% inhibition,...

Embodiment 2

[0232] We also show that eugenol (C 10 h 12 o 2 ), an allyl chain-substituted guaiacol, 2-methoxy-4-(2-propenyl)phenol (the active ingredient in clove oil, a non-stimulatory agonist of the TRPV1 receptor ), promotes the entry of QX-314 into dorsal root ganglion neurons by activating TRPV1 channels. Figure 5 Voltage-clamp recordings of sodium channel currents in small dorsal root ganglion neurons are shown. The data demonstrate that eugenol alone has a modest inhibitory effect on sodium current (10-20% inhibition). Coadministration of eugenol and QX-314 produced a progressive blockade that was complete after 7 minutes. Two examples are shown, which are representative of 10 trials with similar results. As shown above, external QX-314 alone had no effect, whereas internal QX-314 blocked sodium channels. Thus, these experiments suggest that eugenol promotes QX-314 entry into DRG neurons by activating TRPV1 channels.

Embodiment 3

[0234] Figure 6 Results are shown for co-administration of the TRPA agonist mustard oil (MO) (50 μΜ) and QX-314 (5 mM). MO alone reduced the sodium current by 20-30%, which plateaued after about 3 minutes. Co-administration of MO and QX-314 significantly reduced sodium currents.

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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 present invention is characterized by the selective inhibition of pain- and itching (itch) sensory neurons (sensing neurons (nociceptors and pruriceptors)) by small molecular weight drug molecules, and at the same time inhibits non-pain (non- Methods, compositions and kits for minimizing the effects of pain) on sensory neurons or other cell types. According to the methods of the invention, small, hydrophilic drug molecules enter by passing through receptors present on pain- and itch-sensing neurons but less or not present in other types of neurons or other types of tissue. into the intracellular compartment of pain-sensory neurons. [0002] Local anesthetics such as lidocaine and articaine work by inhibiting voltage-dependent sodium channels in neurons. These anesthetics block sodium channels and thereby block the excitability of all neurons, not just pain-sensing neurons (nociceptors). Thus, while the goal of local or regional anesthe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/085A61K31/165A61K31/167A61P29/00
CPCA61K31/167A61K31/245A61K31/445A61K45/00
Inventor B·P·比恩C·J·伍尔夫
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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