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Screening method and therapy with agonists of DDAH I

An agonist and pharmaceutical technology, which can be used in the screening of DDAH I agonists and the field of therapy with DDAH I agonists, which can solve problems such as harm to liver function and low hepatic blood flow.

Inactive Publication Date: 2012-07-11
UCL BUSINESS PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Existing therapies to lower portal pressure to reduce the risk of variceal bleeding are limited to approximately 40% efficacy due in part to the resistance of agents such as beta-blockers
Moreover, it has been suggested that this agent reduces liver perfusion, which may further compromise liver function, since hepatic blood flow is already low in cirrhosis despite systemic vasodilation

Method used

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  • Screening method and therapy with agonists of DDAH I
  • Screening method and therapy with agonists of DDAH I
  • Screening method and therapy with agonists of DDAH I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Example 1: Infliximab Treatment Increases DDAH1 Levels and Decreases Portal Pressure

[0104] Three groups of rats were used in these experiments: BDL rats treated with vehicle, BDL rats treated with the anti-TNF monoclonal antibody infliximab, and mock-treated rats.

[0105] Such as figure 1 As shown, bile duct ligation was found to significantly reduce eNOS activity, but treatment of BDL rats with infliximab restored eNOS activity to levels similar to those observed in mock animals.

[0106] Such as figure 2 As shown, bile duct ligation also resulted in significantly higher ADMA concentrations in liver tissue compared to mock animals. However, treatment with infliximab significantly reduced ADMA levels.

[0107] Such as image 3 As shown, bile duct ligation significantly reduced the expression of DDAH-1 isoforms in the liver. After treatment with infliximab, the expression level of DDAH-1 was restored to the level of mock animals.

[0108] Such as Figure 4 ...

Embodiment 2

[0114] Example 2: The farnesoid receptor agonist INT-747 increases DDAH1 levels and decreases gating Venous pressure

[0115] Farnesoid receptor (FXR) is a bile acid responsive nuclear receptor previously shown to be hepatoprotective against bile duct ligation (BDL) injury in rats. FXR agonists have a variety of target genes including DDAH1. This study tested the hypothesis that an FXR agonist (INT-747) would restore DDAH-1 levels thereby restoring eNOS activity and reducing portal pressure.

[0116] Four weeks after BDL or mock surgery in Sprague-Dawley rats (n=14), BDL rats were gavaged with 5 mg / kg of the FXR agonist INT-747 (6-ethylchenodeoxy) in vehicle (corn oil) Cholic acid, Intercept Pharmaceuticals Inc.) for 5 days or gavage vehicle only.

[0117] Rats were evaluated for direct portal pressure after 5 days of treatment and sacrificed, and plasma and liver tissue were collected for analysis. eNOS activity was radiometrically determined by the conversion of label...

Embodiment 3

[0123] It has been demonstrated that injection of naked plasmid DNA with a promoter effective in mammalian cells results in efficient hepatic transduction of the gene of interest in rodents (Maruyama et al. J Gene Med 2002, 4:333-41). This approach, termed 'hydrodynamic gene therapy', was used to determine the effect of DDAH-1 transduction on portal pressure in BDL rats.

[0124] Plasmids containing human DDAH-1 cDNA were injected into BDL rodents or mock rodents generated as above via a branch of the jugular vein. A control plasmid containing GFP was used as a control for intervention in BDL animals. Animals underwent direct portal pressure measurements 48 hours post-intervention, and plasma and tissue were collected for analysis of hepatic DDAH-1 mRNA (rtPCR) and protein expression (Western blot), as well as routine histology and biochemistry.

[0125] All animals treated tolerated hydrodynamic injections well and were provided ad libitum access to food and water. 48 hours...

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Abstract

The present invention derives from the finding that decreased levels of DDAH I are associated with increased portal pressure and that by increasing DDAH I levels in vivo, portal pressure may be reduced. Accordingly, the invention provides methods for reducing portal blood pressure comprising administering to a subject in need thereof an agonist of DDAH I.

Description

field of invention [0001] The present invention arises from the unexpected discovery that decreased DDAH I levels are associated with increased portal pressure and that portal pressure can be reduced by increasing DDAH I levels in vivo. The present invention takes advantage of this discovery to identify and provide DDAH I agonists useful for lowering portal pressure, eg, for treating portal hypertension. Background of the invention [0002] NIH statistics for the period 1976-80 show that cirrhosis caused more than 26,000 deaths in the United States. When this figure is extrapolated to include the current increasing burden of viral and alcoholic liver disease in the West and in the underdeveloped world, this figure exceeds the millions of cases worldwide each year. This number is likely to continue to increase with the identification of new entities of non-alcoholic fatty liver disease (associated with diabetes and metabolic syndrome) that are increasingly recognized as chro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/575A61K39/395A61P1/16
CPCC07K2317/24C07K16/241A61K31/00A61K31/575C07K2316/96A61K2039/505C07K2317/76A61P1/16A61P7/00
Inventor 拉杰什瓦尔·P·慕克吉拉吉夫·加兰高塔姆·梅塔
Owner UCL BUSINESS PLC