Methods for the treatment and prevention of diseases of biological conduits

a biological conduit and conduit technology, applied in the direction of drug compositions, extracellular fluid disorders, peptide/protein ingredients, etc., can solve the problems of balloon enlargement lumen, hemodialysis graft and fistula flow also compromised, balloon enlargement lumen, etc., to reduce or eliminate compliance mismatch, inhibit compliance mismatch, and inhibit the effect of diameter enlargemen

Inactive Publication Date: 2007-06-21
PROTEON THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0044] One aspect of the present invention includes a method of reducing or eliminating compliance mismatch between a first blood vessel and a second blood vessel joined by an anastomosis by administering to the first or second blood vessel, a composition comprising one or more elastases or collagenases in an amount effective to inhibit compliance mismatch between blood vessels joined by an anastomosis. In one embodiment of the present invention, a method of dilating a biological conduit is presented wherein, a composition is administered comprising one or more elastases or collagenases in an amount effective to dilate the biological conduit.
[0045] An aspect of the present invention involves the blockage of PAR receptors and signal transduction pathway(s) to inhibit the enlargement in the diameter of aneurysmally dilated arteries. The administration of a PAR antagonist may bloc

Problems solved by technology

Although flow can be increased by the relaxation of the smooth muscle cells of a vessel wall, this result is usually temporary and limited in degree.
The balloon enlarges the lumen, often by tearing the wall and disrupting the network of collagen and elastin fibers.
However, the implantation of stents can also cause cellular proliferation and synthesis of extracellular matrix protein, resulting in restenosis.
Flow through the outflow vein of hemodialysis grafts and fistulas is also compromised by a small initial artery and vein diameter.
In addition, nearly all hemodialysis grafts and fistulas eventually fail, usually due to a buildup of intimal hyperplasia in the wall of the outflow vein, leading to a critical stenosis and subsequent thrombosis.
The buildup of this material in the wall of the outflow vein is increased by mismatched compliance properties between the artery and vein, and the synthetic graft and the vein.
Although the dilation of arteries is beneficial in many clinical situations,

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

5.1. Example 1

Obtaining Increased Conduit Dilatation Through Recruitment of Monocytes, Macrophages, and Polymorphonuclear Cells to the Conduit Wall

[0125] Under certain conditions, it is desirable to obtain increases in the lumen diameter of arteries and veins greater than 50%. Methods resulting in appropriate and controlled levels of inflammatory-mediated dilation that yield beneficial outcomes are described here. This example describes how recruitment of activated macrophages to the treated vessel can result in controlled levels of dilation.

[0126] To demonstrate the utility of macrophage recruitment in obtaining increased vessel diameter, surgically exposed common carotid arteries (CCA) of a minimum of 4 rabbits are exposed to either: a) pancreatic elastase type I alone (20 U / mL), b) a series of Monocyte Chemoattractant Protein-1 (MCP-1) concentrations ranging from 0.1 to 1000 pg / ml plus bacterial LPS at 10 ug / kg or less i.v. (Escherichia coli, Sigma Chemical Co., St.Louis, Mo.) ...

example 2

5.2. Example 2

Induction of Beneficial Inflammatory Responses in Pancreatic Elastase Type I Treated Conduits Via PAR Receptor Activation by Trypsin or Plasmin

[0128] Under certain conditions, it is desirable to obtain increases in the lumen diameter of arteries and veins greater than 50%. Methods resulting in appropriate and controlled levels of inflammatory-mediated dilation that yield beneficial outcomes are described here. This example describes how activation of the PAR receptor pathway can result in controlled levels of dilation of treated arteries and veins.

[0129] This example demonstrates that activators of the PAR receptor must be delivered under carefully controlled conditions and levels to exert the desired effect. In this case, the common carotid artery was surgically exposed in rabbits and treated with either a) 0.9 mg / mL porcine pancreatic elastase type I (Elastin Products Co., Owervville, MO) b) 0.9 mg / mL porcine pancreatic elastase type I+0.9 mg / mL chymotrypsin c) 0.9...

example 3

5.3. EXAMPLE 3

Procedure For Identifying Conditions For Induction of Beneficial Inflammatory Responses in Pancreatic Elastase Type I Treated Conduits Via PAR Receutor Activation

[0131] To identify appropriate conditions that result in synergistic interactions of pancreatic elastase type I with trypsin or plasmin, mouse abdominal aortas are surgically exposed and surgical clamps are placed on the segment to be treated, to stop the flow of blood through the segment. The clamped segment is then treated with either a) 20 U / mL porcine type I elastase b) 2U / mL porcine type I elastase +trypsin or plasmin at concentrations ranging from InM to 1 uM trypsin (bovine pancreatic, Sigma Chemical Company, St. Louis, MO) or from 0.2 to 5 Units / mL plasmin (Sigma Chemical Company, St.Louis, MO) or c) Saline for 30 minutes, with a minimum of four animals per treatment. Measurements are made before, during, and immediately after treatment using a digital camera. Incisions are closed and the animals were...

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Abstract

Methods are described for dilating biological conduits by removing elastin and remodeling collagens in the wall of the conduit. Methods include the use of agents that increase the release of endogenous elastase and collagenase in the wall of the conduit, either by cells that are normally present in the wall of the conduit or by inflammatory cells that are attracted to the conduit, thereby providing additional conduit dilation. Methods also include the use of agents that increase conduit wall permeability and expose elastin and collagen fibers. Methods also include removing components of the extracellular matrix of arteries and veins leading to an inhibition of intimal hyperplasia in the wall of the vessels by decreasing biomechanical stimuli directed toward the cells in the wall of the vessel. Methods further include the use of agent that degrade micro fibers, in addition to elastin, in order to decrease the resynthesis of elastin. Methods also include the use of agent that stabilize the diameter of aneurysmal arteries by blocking cell surface receptors in the wall of the aneurysmal artery that are important in the recruitment of inflammatory cells.

Description

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 60 / 449,086, filed Feb. 20, 2003, which is incorporated by reference herein in its entirety.1. FIELD OF THE INVENTION [0002] The present invention relates to methods for treating or preventing disease in biological conduits. The present invention further relates to methods for delivering therapeutic and prophylactic agents to biological conduits. In certain embodiments, the methods described herein relate to achieving dilation of blood vessels by directly or indirectly degrading elastin and / or remodeling the collagen matrix blood vessel walls. In other embodiments, the methods described herein relate to reducing abnormal dilation of blood vessels by reducing inflammation in the vessel wall. 2. BACKGROUND OF THE INVENTION [0003] 2.1. Blood Vessel Structure [0004] A blood vessel is composed of three distinct layers. From inside to outside, these layers include the intima, the media a...

Claims

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Application Information

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IPC IPC(8): A61K38/48A61M31/00A61BA61B17/00A61F2/958A61K38/17A61K39/395
CPCA61K38/4826A61K38/4833A61K38/484A61K38/486A61K38/488A61K2300/00A61K38/195A61K38/4886A61P43/00A61P7/00A61P9/00A61P9/08A61P9/10
Inventor FRANANO, NICHOLAS F.ROMANO, CHARLES P.
Owner PROTEON THERAPEUTICS INC
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