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Systemic and intrathecal effects of a novel series of phospholipase a2 inhibitors on hyperalgesia and spinal pge2 release

A cell-inhibiting, unsaturated technology, applied in the direction of anti-inflammatory agents, nervous system diseases, active ingredients of ketones, etc., can solve problems such as difficult and difficult to design selective inhibitors

Inactive Publication Date: 2008-10-22
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, designing GIVA- and GVIAPLA2-selective inhibitors that can discriminate between GIVA and GVIAPLA2 in vivo is difficult
Furthermore, selective inhibitors of GVPLA2 are difficult to design

Method used

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  • Systemic and intrathecal effects of a novel series of phospholipase a2 inhibitors on hyperalgesia and spinal pge2 release
  • Systemic and intrathecal effects of a novel series of phospholipase a2 inhibitors on hyperalgesia and spinal pge2 release
  • Systemic and intrathecal effects of a novel series of phospholipase a2 inhibitors on hyperalgesia and spinal pge2 release

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Experimental program
Comparison scheme
Effect test

Embodiment I

Hyperalgesia Animal Model and Measurement Method

animal

[0085] Male Holtzman Sprague-Dawley rats (300-350 g; Harlan Industries) were housed individually and maintained on a 12-hour light / dark cycle with free access to food and water.

Intrathecal Catheter Implantation

[0086] For spinal drug injection, a lumbar catheter was implanted in the rat under isoflurane anesthesia according to a modification of the procedure described by Yaksh (Yakshand Rudy, supra, 1976). A polyethylene catheter (PE-5; Spectranetics, OD 0.014) was inserted into the intrathecal space and advanced through an incision in the atlanto-occipital membrane to the rostral border of the lumbar enlargement. Rats entered the study five days after implantation. In a separate experiment evaluating spinal cord prostaglandin release, rats were prepared with a lumbar loop dialysis catheter with three lumens, as described previously, see (Yaksh, et al., supra, 2001).

[0087] Briefly, the outer two lumens were conn...

Embodiment II

Treatment of carrageenan-induced thermal hyperalgesia following intraperitoneal delivery

[0098] Control. Baseline thermal escape latency was at the level of 10-12 seconds in all groups prior to induction of hyperalgesia. Plantar injections of carrageenan induced inflammation in the injected hindpaw and corresponding thermal hyperalgesia detectable after a duration of 60 min throughout the study. As shown in Figure 5, the heat escape latency in animals treated with IP or IT vehicle was significantly reduced to about 3-5 seconds within 90-120 minutes (see Figures 5 and 6).

[0099] Intraperitoneal delivery. Pretreatment (30 min) with four substances at 3 mg / kg (IP) before carrageenan injection revealed that AX048, but not AX006, AX010 or AX057, lowered the rate of inflamed paw otherwise. Thermal hyperalgesia was observed (Figure 5). Importantly, thermal escape latencies in the healthy paw were not altered in vehicle- or drug-treated animals, eg, the substance functions as an an...

Embodiment III

Treatment of carrageenan-induced thermal hyperalgesia following intrathecal delivery

[0102] Control. In animals receiving intrathecal injections of vehicle, plantar injections of carrageenan resulted in marked unilateral thermal hyperalgesia compared to non-injected paws (FIG. 8).

[0103] Drug Effects Pretreatment with 30 μg / 10 μL of the four substances revealed that AX048, but not AX006, AX010 or AX057, reduced thermal hyperalgesia 15 minutes before carrageenan delivery (see Figure 8). Furthermore, following intrathecal delivery, there was no change in heat escape latency in the healthy paw in either the vehicle or drug-treated groups. Comparison of mean group differences between response latencies in healthy and injured paws also revealed a significant reduction in the AX048-treated group compared to the vehicle-treated group.

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Abstract

Phospholipase A2 (PLA2) forins are expressed in spinal cord whose inhibition induces a potent antihyperalgesia. PLA2 inhibitor compounds are provided that include a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four carbon tether. The compounds block Group IVA calcium dependent PLA2 (cPLA2) and / or Group VIA calcium independent PLA2 (iPLA2) and / or Group V secreted PLA2 (sPLA2).

Description

Systemic and intrathecal effects of a new series of phospholipase A2 inhibitors on hyperalgesia and spinal PGE2 release statement of government support [0001] The present invention is supported in whole or in part by GM20501 and GM064611 of the National Institutes of Health Foundation of the United States (United States National Institutes of HealthNIH Grant). The US Government has certain rights in this invention. Background of the invention [0002] Tissue damage and inflammation lead to a marked facilitation of sensitivity to moderate post-inhibitory stimuli such as the development of hyperalgesia. It has long been considered that this phenomenon is reduced by substances that block the activity of cyclooxygenase (COX) (Vane, Nat. New Biol., 231: 232-235, 1971). Although earlier work suggested that this effect was due to peripheral effects (Ferreira, Nat. New Biol., 240:200-203, 1972), it was later found that inhibition of spinal COX also resulted in a reversal of the fac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/27A61K31/12
CPCC07C237/22C07C235/78A61P25/00A61P25/04A61P29/00A61P43/00C07C233/48C07C229/12
Inventor E·丹尼斯T·亚基K·K·卢卡斯C·斯文松D·A·西克斯G·科科托斯V·康斯坦丁努-科科多
Owner RGT UNIV OF CALIFORNIA
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