Methods for the treatment and prevention of diseases of biological conduits

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...

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, derangements of this process can occur, leading to aneurysm formation.

The aorta is the most common location for aneurysm formation, and excessive dilation of the aorta places a person at a higher risk for vessel rupture, hemorrhage, and death.

Strategies to reduce compliance mismatch and associated neointimal hyperplasia are critical for the long-term patency of a blood vessel receiving a graft Synthetic bypass grafts used to divert blood around a site of obstruction, unlike autologous or heterologous material used for anastomotic procedures, are less compliant than non-synthetic bypass grafts.

A compliance mismatch between the rigid synthetic graft material and the compliant artery or vein results in increased stress on the outflow artery or vein.

Poor compliance is a key factor responsible for reduced performance of synthetic vascular grafts.

The mismatch in compliance between the artery or vein and the grafts results in high shear stress and turbulence of the blood flow with local stagnation.