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Use of inhibitors of soluble epoxide hydrolase to synergize activity of cox and 5-lox inhibitors

a technology of soluble epoxide hydrolase and inhibitor, which is applied in the direction of biocide, elcosanoid active ingredients, drug compositions, etc., can solve the problems of apoptosis or cell death, and achieve the effect of increasing the

Inactive Publication Date: 2010-11-11
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a composition that includes a first enzyme inhibitor that targets soluble epoxide hydrolase (sEH) and a second enzyme inhibitor that targets cyclo-oxygenase (COX)-1, COX-2, or 5-lipoxygenase (LOX). When administered to a subject, this combination of enzyme inhibitors increases the effect of the first enzyme inhibitor over its effect in the absence of the second enzyme inhibitor. The first enzyme inhibitor can be selected from a group of urea, carbamate, or amide pharmacophore, while the second enzyme inhibitor can be selected from a group of aspirin, acetaminophen, diclofenac potassium, or magnesium salicylate. The composition can also include a cis-epoxyeicosantrienoic acid or an epoxide of docosahexaenoic acid or eicosapentaenoic acid. The second enzyme inhibitor can be selected from a group of aspirin, acetaminophen, diclofenac potassium, or naproxen sodium. The patent also provides methods for increasing the effect of the first enzyme inhibitor by administering the second enzyme inhibitor and a third enzyme inhibitor that targets sEH or LOX.

Problems solved by technology

Activated PKR stalls translation by phosphorylation of the translation initiation factors eIF2α, and activated 2′,5′-AS causes mRNA degradation by 2′,5′-oligonucleotide-activated ribonuclease L. These responses are intrinsically sequence-nonspecific to the inducing dsRNA; they also frequently result in apoptosis, or cell death.

Method used

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  • Use of inhibitors of soluble epoxide hydrolase to synergize activity of cox and 5-lox inhibitors
  • Use of inhibitors of soluble epoxide hydrolase to synergize activity of cox and 5-lox inhibitors
  • Use of inhibitors of soluble epoxide hydrolase to synergize activity of cox and 5-lox inhibitors

Examples

Experimental program
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example 1

[0132]This Example sets forth the materials and methods used in the studies whose results are set forth in FIGS. 2a and 2b.

Animal Experiments

[0133]Male, 7- to 8-week-old C57BL / 6 mice (Charles River, Wilmington, Mass.) weighing between 22 and 28 g were used in the inflammation experiments. The mice were acclimated for 5 days prior to experimentation. They were housed in groups of four per cage, in a controlled environment in American Association for Laboratory Animal Care-accredited facilities and were fed mouse chow ad libitum.

[0134]The mice were administered lipopolysaccharide (“LPS”) to induce inflammatory responses. Saline was used as a carrier for the LPS. The sEH inhibitor used in the studies was 12-(3-adamantane-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE). Because AUDA-nBE takes some time to reach physiologically effective levels in the body, mice to which AUDA-BE was to be administered were given the AUDA-BE prior to exposure to LPS.

[0135]The mice were divided into gr...

example 2

[0145]This Example discusses the results of the studies conducted using the materials and methods discussed in the previous Example.

[0146]FIGS. 2A and 2B show the levels of 8,9 EET and 8,9 DHET, respectively, in mice injected with sterile saline alone or with sterile saline and lipopolysaccharide (“LPS”). As described in Example 1, groups of mice were treated with the COX-1 and -2 inhibitor indomethacin, or with AUDA butyl ester (AUBA-BE), or with both indomethacin and AUDA-BE.

[0147]Referring to FIG. 2A, as shown on the far left of the Figure, mice that were not treated with either AUDA-BE or indomethacin showed no detectable levels of 8,9 EET. The results for the three groups of mice represented in the rest of the figure show two bars, one black and one gray. The black bar in each group represents the concentration of 8,9 EET seen in mice that received the treatment (AUDA-BE, indomethacin, or both, as stated on the axis), but which were not also exposed to the inflammatory agent LP...

example 3

[0149]This Example sets forth materials and methods for tail flick and hind paw withdrawal studies showing response to pain stimuli.

[0150]Briefly, mice are kept under 12:12 h light: dark cycle and water and food is supplied ad libitum. Mice are trained for three days to the experimental chambers in 30 min sessions each time. The next day baseline readings are taken. Vehicle control (oleic oil) is then injected sc in the next day and measurements are taken. Two days later, animals are injected through the sc route with test compounds dissolved in the oil vehicle and their responses are recorded after 90 minutes.

[0151]Tail flick and hind paw withdrawal latency tests are conducted according to D'Amour and Smith, J Pharmacol Exp Ther 72:74-9 (1941), and Woolfe and McDonald, J Pharmacol Exp Ther, 80:300-7 (1944). In tail flick assays, mice are placed in restrainers and left undisturbed for 30 minutes. Readings are then taken by placing the posterior end of the tail onto a tail flick appa...

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Abstract

The invention relates to methods, compositions, and uses of those compositions for making medicaments, for potentiating the beneficial effects of inhibitors of COX-1, COX-2, and 5-LOX, and reducing adverse effects, by also administering inhibitors of soluble epoxide hydrolase (“sEH”), with or without also administering one or more cis-epoxyeicosantrienoic acids. The invention further relates to the use of inhibitors of sEH as analgesics and to methods and compositions of epoxides of eicosapentaenoic acid and docosahexaenoic acid, optionally with an inhibitor of sEH, to reduce pain or inflammation or both.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. application Ser. No. 11 / 330,033, filed Jan. 10, 2006, which claims priority from U.S. Provisional Application No. 60 / 643,028, filed Jan. 10, 2005, the contents of each are hereby incorporated by reference.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with government support under grant nos. R37 ES02710 and P01 ES04699, awarded by the National Institute of Environmental Health Sciences of the National Institutes of Health. The government has certain rights in the invention.REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK[0003]NOT APPLICABLEBACKGROUND OF THE INVENTION[0004]Arachidonic acid is released from membrane phospholipids by the enzyme phospholipase A2. This highly unsaturated fatty acid is metabolized through one of three pathways: the cyclooxygenases (“CO...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/415A61K31/405A61K31/351A61K31/336A61K31/27A61K31/16A61K31/17A61P29/02
CPCA61K31/12A61K31/132A61K45/06A61K31/635A61K31/616A61K31/612A61K31/606A61K31/603A61K31/60A61K31/557A61K31/5415A61K31/167A61K31/17A61K31/192A61K31/196A61K31/20A61K31/201A61K31/202A61K31/22A61K31/336A61K31/341A61K31/365A61K31/40A61K31/403A61K31/405A61K31/407A61K31/415A61K31/42A61K31/444A61K2300/00A61P25/04A61P29/00A61P29/02A61P43/00
Inventor HAMMOCK, BRUCE D.SCHMELZER, KARAINCEOGLU, AHMET BORA
Owner RGT UNIV OF CALIFORNIA
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