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Vascular disease therapies

a technology for vascular disease and therapies, applied in the field of vascular disease therapies, can solve the problems of endothelial dysfunction, devastating vascular complications of diabetes, and affect every major organ, and achieve the effect of reducing vascular calcification

Inactive Publication Date: 2006-12-14
FIBROGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0032] The present invention provides a method for reducing vascular dysfunction or improving vascular function in a subject, the method comprising administering to the subject an effective amount of an anti-CTGF agent, thereby reducing vascular dysfunction or improving vascular function in the subject.
[0035] In certain embodiments, the method may in particular be for reducing endothelium dysfunction; treating or reducing arterial stiffness, especially arterial stiffness selected from the group consisting of axial, radial and circumferential arterial stiffness; reducing vascular permeability; reducing extravasation; reducing intima-media thickening; or reducing common carotid artery intima-media thickening. In particular, the method may be for reducing edema or tissue edema. The method may similarly be for reducing damage to or dysfunction of blood vessels; or reducing vascular calcification.

Problems solved by technology

Vascular complications of diabetes are devastating, and can affect every major organ.
Hyperglycemia and AGEs can cause changes (e.g., damage) to the normal structure and function of the endothelium and can lead to endothelial dysfunction.
In addition, hyperglycemia and AGEs have been associated with various vascular complications, including damage to the body's microvasculature and macrovasculature.
Patients with diabetes are at critical risk for congestive heart failure.
Further, diabetes increases the likelihood of severe carotid atherosclerosis.
It contributes to lower-extremity ulceration, impaired wound healing, and decreased ability to fight infection.
The reasons for this include delayed or prevented delivery of oxygen (ischemia), nutrients, and antibiotics to the infected area and impaired immune response.
However, such therapies are not universally successful, and often are ineffective at reversing the vascular complications and pathology (e.g., damage) associated with diabetes or improving the function of affected vessels, organs, and tissues.

Method used

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Examples

Experimental program
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Effect test

example 1

Anti-CTGF Therapy Improves Hemodynamic Parameters and Cardiac Function

[0108] The methods of the invention were used to demonstrate broad-spectrum efficacy in an animal model for certain aspects of vascular complications associated with diabetes as follows. Diabetes mellitus was induced in Sprague Dawley rats by a single i.v. dose of streptozotocin (STZ) (65 mg / kg). STZ-induced diabetes in rats leads to increased vascular permeability (Lawson et al. (2005) Regul Pept 124:221-224) and decreased cardiac function (Machackova et al. (2004) Mol Cell Biochem 261:271-278). Experimental rats received an intravenous injection of 0.1M citrate-buffered streptozotocin (pH 4.1) at a dosage of 65 mg / kg (65 mg / ml) on day zero. Successful induction of diabetes in animals treated with STZ was confirmed on day 2 by an elevation in fasted blood glucose levels (>250 mg / dl).

[0109] Diabetic animals were divided into treatment groups (Vehicle, 3 mg / kg, 5 mg / kg, or 10 mg / kg anti-CTGF antibody, CLN-1). Tre...

example 2

Anti-CTGF Therapy Reduces Arterial Stiffness

[0115] The effect of anti-CTGF therapy on arterial stiffness (a measure of vascular function, and in particular macrovascular function) was measured using the animal model of diabetes described above in Example 1. Various measurements of arterial stiffness were obtained, including passive and active pressure-volume data from the carotid artery. For these measurements, the distal portion of the left carotid artery was cannulated with PE-50 tubing connected to a three-way stopcock. A modified Krebs buffer solution was infused into the carotid artery via the cannula. The proximal end of the carotid artery was occluded using a vascular occluder. To measure force developed during infusion of the buffer solution, a pressure transducer was connected to the three-way stopcock. The PE-tubing end was also connected to an isometric force transducer to measure the isometric axial force during pressurization. A digital image analysis system was used t...

example 3

Anti-CTGF Therapy Reduces Vascular Permeability

[0136] The effect of anti-CTGF therapy on vascular permeability (a measure of vascular function, in particular microvascular function) was measured using the animal model of diabetes described above in Example 1. At various times after the induction of diabetes, rats were tested for increased vascular permeability (VP) as follows. Unanesthetized rats were given intravenous injections of Evans Blue (EB) dye (20 mg / kg). Twenty minutes later, animals were sacrificed by anesthetic overdose and their hearts removed. Skin sections from the trunk, posterior to the shoulder, were removed and weighed. In this assay, increased vascular permeability is characterized by extravasation of dye into the skin. The skin was immersed in formamide (4 ml / g wet weight) at 24° C. for 24 hours. The absorbance of EB dye extracted in formamide was then measured by spectrophotometry at 620 nm using a plate reader. In this assay, the concentration of EB dye is pr...

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Abstract

The present invention relates to methods and agents for treating impaired vascular and cardiac function. Methods and agents for treating various physiological and pathological features associated with vascular dysfunction and cardiac dysfunction are also provided.

Description

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 678,495, filed on 05 May 2005, U.S. Provisional Application Ser. No. 60 / 690,957, filed on 15 Jun. 2005, and U.S. Provisional Application Ser. No. 60 / 734,433, filed on 07 Nov. 2005, each of which is incorporated by reference herein it its entirety.FIELD OF THE INVENTION [0002] The present invention relates to methods and agents for treating impaired vascular and cardiac function. Methods and agents for treating various physiological and pathological features associated with vascular dysfunction and cardiac dysfunction are also provided. BACKGROUND OF THE INVENTION [0003] Vascular complications of diabetes are devastating, and can affect every major organ. Patients with diabetes have an increased incidence of atherosclerosis, and of cardiovascular, peripheral vascular, and cerebrovascular disease. Vascular complications and disease account for most of the mortality and morbidity of diabetic individu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17
CPCC07K16/22A61K2039/505A61P43/00A61P7/10A61P9/00A61P9/04A61P9/10A61P3/10
Inventor PAROBOK, INGRID LANGSETMOJACOB, CHRISTOPHER T.LIU, DAVID Y.
Owner FIBROGEN INC
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