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Method and compsns. for treating inflammatory disease

A technology for inflammatory diseases and inflammatory drugs, which can be used in drug combinations, active ingredients of heterocyclic compounds, anti-inflammatory agents, etc.

Inactive Publication Date: 2003-02-19
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Identification of new pulmonary disease therapeutics is difficult because multiple mediators may contribute to the development of lung disease
As such, it appears impossible to eliminate the influence of a single agent that may have a real effect on all three components of chronic asthma

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 - Binding assay of phosphodiesterase and rolipram

Embodiment 1A

[0029] Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) were assayed for the predominantly present low affinity form. Therefore, using 1mM [ 3 A standard assay for the catalytic activity of PDE4 with cAMP as a substrate enables the evaluation of the activity of test compounds against low-affinity forms of PDE4 (Torphy et al., J.Of Biol.Chem., Vol. 267, No. 3, pp. 1798- 1804, 1992).

[0030] The high-speed centrifugation supernatant of mouse brain was used as protein source and the two [ 3 The isomer of H]-rolipram was prepared with a specific activity of 25.6Ci / mmol. The standard assay conditions were modified from published methods to be the same as the PDE assay conditions except for the final cAMP: 50 mM Tris HCl (pH 7.5), 5 mM MgCl 2 and 1nM [ 3 H]-rolipram (torphy et al., J. Of Biol. Chem., Vol. 267, No. 3, pp. 1798-1804, 1992). The measurement was performed at 30° C. for 1 hour. The reaction was terminated and bound ligand was separated from free lig...

Embodiment 1B

[0032] Determination of phosphodiesterase activity

[0033] Using [ 3 H] cAMP SPA or [ 3 H] cGMP scintillation proximity assay (SPA) enzymatic assay to measure PDE activity. Reactions were performed at room temperature in 96-well plates in 0.1 ml of reaction buffer containing (final concentration): 50 mM Tris-HCl, pH 7.5, 8.3 mM MgCl 2 , 1.7mM EGTA, [ 3 H] cAMP or [ 3 H] cGMP (approximately 2000 dpm / pmol), enzyme and various concentrations of inhibitors. These assays were allowed to run for 1 hour and terminated by adding 50 [mu]l of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and left at room temperature for 20 minutes. Radiolabeled product formation was determined by scintillation spectrometry. With 0.05μM [ 3 H]cAMP was used to measure the activity of PDE3 and PDE7, while 1μM[ 3 H]cAMP was used as substrate to measure PDE4. With 1μM [ 3 H]cGMP was used as substrate to measure the activity of PDE1B, PDE1C, PDE2 and PDE5.

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Abstract

This invention relates to treating an inflammatory disease by administering a phosphodiesterase 4 inhibitor in combination with an inhibitor of prostaglandin synthesis, NSAIDs being exemplary.

Description

field of invention [0001] The present invention relates to compositions and methods for the prevention or treatment of inflammatory diseases by co-administering phosphodiesterase 4 inhibitors with prostaglandin synthesis inhibitors, such as NSAIDs. Background of the invention [0002] Identifying new therapeutic agents for lung disease is difficult because of the variety of mediators that may contribute to the development of lung disease. Thus, it seems impossible to eliminate the influence that a single mediator may have a real effect on all three components of chronic asthma. Another approach to the "mediator pathway" is to modulate the cellular activities that determine the pathophysiology of the disease. [0003] One such method is to increase the content of cAMP (3',5'-cyclic adenosine monophosphate). Cyclic AMP has been shown to be a second messenger that regulates various hormones, neurotransmitters, and biological responses to drugs; [Krebs, 4th International Congr...

Claims

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Application Information

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IPC IPC(8): A61K31/121A61K31/19A61K31/275A61K31/40A61K31/60A61K45/06A61P29/00A61P43/00
CPCA61K31/19A61K31/60A61K45/06A61K31/40A61P29/00A61P43/00A61K2300/00
Inventor 伊丽莎白·T·基廷詹姆斯·M·卡纳吉
Owner SMITHKLINE BECKMAN CORP
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