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COX-2 selective carprofen for treating pain and inflammation in dogs

A COX-2, selective technology for use in anti-inflammatory agents, organic actives, non-central analgesics, etc. to address low levels of potency and reduced potency of inhibition

Inactive Publication Date: 2000-05-31
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It was found that the S-enantiomers of all three NSAIDs inhibited the two isozymes with equal potency; however, the potency of the inhibition of the two isozymes by their R-enantiomers was significantly and correspondingly reduce
In other words, all three R-enantiomers showed equal potency in the inhibition of COX-1 and COX-2, but in all cases at significantly lower potency levels than the corresponding S-enantiomer many

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] Comparative evaluation of carprofen and other nonsteroidal anti-inflammatory drugs on the inhibition rate of cyclooxygenase-1 and -2 in dogs

[0149] Scheme design for the evaluation of dog COX-1 activity

[0150] Test drug compounds were dissolved and diluted with 0.1 ml of DMSO / 9.9 ml of Hanger's Balanced Salt Solution (HBSS) the day before testing and stored overnight at 4°C. On the day of the experiment, blood was drawn from the donor dog and citrated, centrifuged at 190 x g for 25 minutes at room temperature, and the obtained platelet-rich plasma was transferred to a new tube for further experiments. The platelets were washed by centrifugation at 1500 xg for 10 minutes at room temperature. The platelets were washed with platelet buffer containing Hanger's buffer (Ca free) and 0.2% bovine serum albumin (BSA) and 20 mM HEPES. Platelet samples were then adjusted to 1.5 × 10 7 After that, 50 μl of calcium ionophore (A23187) and calcium chloride solution were added t...

Embodiment 2

[0155] Determination of COX-1 and COX-2 Activity Inhibition Rates of Carprofen Using Dog Whole Blood in Vitro

[0156] The purpose of this experiment is to determine the inhibitory ability of carprofen to COX-1 and COX-2 activity in dog whole blood by in vitro method. Three dogs were administered orally (PO) the drug in capsule form at a dose of 10 mg / kg racemic 6-chloro-α-methyl-carbazole-2-acetic acid (carprofen), followed by 2 mg / kg Carprofen was administered to three other dogs in the same manner, and three dogs were not administered. Blood samples were collected from all dogs at zero hour before experimental dosing and 1, 3, and 6 hours thereafter. Prepare test tubes to contain 2 μl of (A) calcium ionophore A23187 to a final concentration of 50 μM, which stimulates thromboxane B2 (TXB 2 ) for COX-1 activity assay; or (B) lipopolysaccharide (LPS) to a final concentration of 10 μg / ml, which stimulates prostaglandin E 2 (PGE 2 ) production was used to measure COX-2 activ...

Embodiment 3

[0162]Determination of COX-2 Activity Inhibition Rate of Carprofen Using Dog Whole Blood in Vitro

[0163] This experiment was carried out according to the procedure of the above-mentioned Example 2, but changed according to the following detailed description.

[0164] Tablets were administered orally (PO) to three dogs at hour zero at a dose of 2 mg / kg racemic 6-chloro-α-methyl-carbazole-2-acetic acid (carprofen), followed by 4 mg / kg Carprofen was administered to three other dogs in the same manner at hour zero, and three dogs were not administered. Zero hour blood samples were collected from all dogs prior to experimental dosing and 2 and 4 hours thereafter. Tubes were prepared to contain 2 μl of lipopolysaccharide (LPS) to a final concentration of 10 μg / ml. Test tubes of the non-administered group were used as a control group. 500 μl of blood samples were added to each of the above test tubes, after which they were incubated overnight at 37° C. After incubation, 10 μl of...

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PUM

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Abstract

Treating or preventing inflammatory processes and diseases in dogs associated with the activity of inducible cyclo-oxygenase-2 (COX-2), while at the same time reducing or eliminating undesirable side effects associated with simultaneous inhibition of the activity of constitutive cyclo-oxygenase-1 (COX-1) by selectively inhibiting COX-2 activity with reference to COX-1 activity, wherein the selectivity ratio or COX-2 : COX-1 activity inhibition is at least 3:1 based on ex vivo inhibition levels measured in whole blood; the inhibitor is a member selected from the group of anti-inflammatory compounds consisting essentially of salicylic acid derivatives, p-aminophenol derivatives, indole and indene acetic acids, heteroaryl acetic acids, arylpropionic acids, anthranilic acids, enolic acids, and alkanones; the inhibitor in particular is comprised of (+)(S)-enantiomer of 6-chloro-alpha-methyl-9H-carbazole-2-acetic acid.

Description

field of invention [0001] The present invention relates to the treatment of pain and inflammation in dogs with anti-inflammatory agents, which are non-steroidal anti-inflammatory drugs (NSAIDs), and in particular these agents have efficacy in reducing the occurrence of gastrointestinal side effects which are prevalent in dogs and A problem with potentially serious harm. Background of the invention [0002] As is well known to those of ordinary skill in the art, such as veterinarians, canines, ie, dogs, especially older dogs, are highly susceptible to chronic inflammation, such as joint degenerative disease. Because of the large number of dogs that are kept as pets, or are exploited for purposes such as guard dogs or guide dogs, there has been an ongoing effort to find an agent that would stop or stop the development of these inflammatory conditions in dogs, or at least slow down the process. Symptoms such as pain and edema. Recently, the anti-infla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/403A61K31/40A61P29/00A61P43/00C07D209/88
CPCA61K31/40A61P29/00A61P43/00
Inventor 克里斯汀·M·伦迪安东尼·P·里基茨
Owner PFIZER INC
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