Method and compositions for treatment or prevention of inflammatory conditions

a technology of inflammatory conditions and compositions, applied in drug compositions, biocides, metabolic disorders, etc., can solve problems such as significant detrimental effects in patients, and achieve the effects of inhibiting nf-b-dependent inflammatory response, inhibiting monocyte adhesion and chemotaxis, and inhibiting tnf-

Inactive Publication Date: 2010-09-02
UNIVERSITY OF ROCHESTER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0011]The data presented herein shows for the first time that the vincamine derivative vinpocetine acts in vitro and in vivo to inhibit NF-κB-dependent inflammatory response by targeting IKK. Vinpocetine inhibits TNFα-induced NF-κB activation and the subsequent induction of pro-inflammatory mediators in a variety of cell types. Vinpocetine also inhibits monocyte adhesion and chemotaxis. Moreover, vinpocetine potently inhibited TNFα- or LPS-induced inflammatory response in the lungs of mouse. The IKK-targeted activity of vinpocetine was also shown to be independent of its well-known inhibitory effect on Phosphodiesterase 1 (PDE1) activity and Ca2+ / Na+ regulation. The present invention identifies vinpocetine and other vincamine derivatives as novel anti-inflammatory agents that act via disruption of the IKK pathway, which affords a novel therapeutic strategy for the treatment of various NF-κB-dependent inflammatory diseases or conditions. Based on these results, it is expected that vincamine and other vincamine derivatives that can induce IKK inhibition will similarly be useful.

Problems solved by technology

However, while steroids indeed exhibit a potent anti-inflammatory effect, the extensive usage of steroids also results in significant detrimental effects in patients.

Method used

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  • Method and compositions for treatment or prevention of inflammatory conditions
  • Method and compositions for treatment or prevention of inflammatory conditions
  • Method and compositions for treatment or prevention of inflammatory conditions

Examples

Experimental program
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example 1

Vinpocetine Inhibits NF-κB Activation in a Variety of Cell Types

[0086]Because NF-κB plays a critical role in regulating inflammatory response, whether vinpocetine acts as an anti-inflammatory agent by inhibiting NF-κB was investigated. The effect of vinpocetine on NF-κB-dependent promoter activity was first evaluated by using luciferase reporter plasmids in a variety of cell types. As shown in FIG. 1A, vinpocetine potently inhibited TNFα-induced NF-κB-dependent promoter activity in vascular smooth muscle cells (VSMCs) in a dose-dependent manner. Similar results were also observed in human umbilical vein endothelial cells (HUVECs, FIG. 1B), human lung epithelial A549 cells (FIG. 1C), and macrophage cell line (RAW264.7) (FIG. 1D). Similarly to TNFα, IL-1- and LPS-induced NF-κB-dependent promoter activity was also inhibited by vinpocetine. It should be noted that no significant cytotoxic effects on cell morphology and viability were observed at the tested doses.

[0087]This experiment wa...

example 2

Vinpocetine Inhibits TNFα-Induced Pro-Inflammatory Mediators in a Variety of Cell Types

[0088]Next it was determined whether vinpocetine also inhibits TNFα-induced up-regulation of NF-κB-dependent pro-inflammatory mediators including cytokines, chemokines and adhesion molecules at the mRNA level. As shown in FIG. 3A, vinpocetine potently inhibited TNFα-induced expression of TNFα, IL-1β, IL-8, monocot chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) in VSMCs, as assessed by real-time RT-PCR analysis. Similarly, vinpocetine was also found to inhibit TNFα-induced expression of TNFα, IL-1β, IL-8, MCP-1, VCAM-1, and intercellular adhesion molecule 1 (ICAM-1) in HUVECs (FIG. 3B), expression of TNFα, IL-1β, and IL-8 in A549 cells (FIG. 3C), and expression of TNFα, IL-1β, and macrophage-inflammatory protein 2 (MIP-2) in RAW264.7 (FIG. 3D).

[0089]This experiment was repeated with A549 cells using substantially the same procedures, except with varying doses of a comm...

example 3

Vinpocetine Inhibits Monocyte Adhesion of EC and Chemotactic Activity of VSMC

[0090]To further evaluate the physiological consequences of the inhibitory effect of vinpocetine on induction of pro-inflammatory mediators, monocyte adhesion and chemotactic activities in ECs and VSMCs were measured, respectively. These cells types are known to be dependent on adhesion molecules (such as ICAM-1 and VCAM-1) and chemokines (such as MCP-1) (Kunsch et al., “Oxidative Stress as a Regulator of Gene Expression in the Vasculature,”Circ Res 85:753-66 (1999), which is hereby incorporated by reference in its entirety). As shown in FIG. 5A-B, monocyte adhesion to HUVECs was markedly inhibited by vinpocetine, as assessed by adhesion assay. Moreover, vinpocetine also inhibited monocyte chemotaxis to VSMCs induced by TNFα in a dose-dependent manner (FIG. 5C), as measured by transwell migration with Boyden chamber.

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Abstract

Pharmaceutical compositions and methods for treating or preventing an inflammatory condition in a patient are disclosed. The pharmaceutical compositions and methods include the use of vincamine or a vincamine derivative, either alone or in combination with one or more additional therapeutic agents, including a steroid (preferably a corticosteroid), an angiotensin II receptor (type 1) antagonist, an angiotensin-converting enzyme (ACE) inhibitor, and a non-steroidal anti-inflammatory drug.

Description

[0001]This application claims the priority benefit of U.S. Provisional Patent Application Ser. No. 60 / 973,998, filed Sep. 20, 2007, which is hereby incorporated by reference in its entirety.STATEMENT OF GOVERNMENT SUPPORT[0002]The present invention was made with government support under grants P01 HL077789 and RO1 DC005843, both awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention relates to the use of vincamine derivatives for treating or preventing an inflammatory condition, and pharmaceutical compositions useful for practicing these therapeutic or preventative treatments.BACKGROUND OF THE INVENTION[0004]Inflammation is a hallmark of a variety of important human diseases, such as atherosclerosis (Libby et al., “Inflammation and Atherosclerosis,”Circulation 105:1135-43 (2002); Libby, “Inflammation in Atherosclerosis,”Nature 420:868-74 (2002)), lung inflammatory disease (Tetley, “Inflammato...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/14A61P29/00A61P9/10A61P17/06A61P19/02A61P3/10A61K31/573A61K31/4375
CPCA61K31/4375A61K31/573A61K45/06A61K2300/00A61P3/10A61P9/10A61P11/00A61P17/06A61P19/02A61P29/00A61K9/0046
Inventor YAN, CHENLI, JIAN-DONGBERK, BRADFORDJEON, KYE-IMXU, XIANGBIN
Owner UNIVERSITY OF ROCHESTER
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