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Transplants

a technology of grafts and organs, applied in the field of transplants, can solve the problems of poor outcomes, early graft occlusion rate of 20%, no therapy has proven clinically successful, and injury,

Inactive Publication Date: 2010-05-13
HIBERNATION THERAPEUTICS A KF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036]A major difference between a composition of the invention (such as a composition which includes (i) a potassium channel opener or agonist and / or an adenosine receptor agonist; and (ii) an antiarrhythmic agent) compared with adenosine alone is that the relaxation profile is not dependent on an intact endothelium (as it is with adenosine). The effect of the invention on denuded vasculature rings is as if the endothelium had not been removed. One clinical significance of this surprising result is improved storage of a subject's harvested conduit arteries or veins for prepared for bypass surgery (or other vascular surgery) which are known to suffer varying degrees of endothelial damage. During dissection, storage or anastomoses, the luminal endothelial layer, the outer adventitial layer and the medial smooth muscle layer are vulnerable to damage and spasm (uncontrolled contraction). The invention protects the vessel wall including the endothelium and relaxes vascular smooth muscle and thereby reducing vascular spasms during vessel dissection, storage or anastomoses. It can also provide better protection against short-term and long-term restenosis. The mechanism of action as to how greater relaxation occurs in the presence of a composition according to the invention, such as adenosine and lidocaine, over the summed effects of adenosine alone and lidocaine alone has not been fully determined.

Problems solved by technology

Carrel knew that damage to the vascular endothelium, the largest organ of the body, led to injury, thrombus and poor outcomes.
Thus, an ongoing problem is the early graft occlusion rate of 20% in the first year.
However, no therapy has proven to be clinically successful as evidenced by the high 20% patency failure in the first year.
For example, one troubling and continuing problem with harvested and transplanted grafts for CABG and vascular surgery is vasospasm.
In the past 10 years, vasospasm has become particularly challenging with a resurgence of use of the radial artery graft after it was abandoned in the mid-1970s because of a high incidence of vasospasm and a 35% failure rate at 2 years.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of Adenosine, Lidocaine and Adenosine Plus Lidocaine on Rat Aorta Muscle Tension and Relaxation

[0166]This example illustrates the different effect on intact isolated vasculature rings of an adenosine-lidocaine solution according to the invention, which did not lead to relaxation by over 5% until 200 uM. Adenosine and AL (adenosine and lidocaine) show similar effects, and about 30% greater falls in relaxation than lidocaine alone at 400 and 500 uM concentrations when bathed in 10 mM glucose in Krebs-Henseleit at pH 7.4 37° C. under aerobic conditions (95% O2 & 5% CO2). A major difference between AL and adenosine alone is that the AL-induced relaxation profile is not dependent on an intact endothelium. The effect of AL in the denuded rings is as if the endothelium is not removed.

[0167]Animal Preparation: Male Sprague Dawley rats (300-350 g) were fed ad libitum and housed in a 12-hour light / dark cycle. On the day of the experiment rats were anaesthetized using CO2 anaesthesia wh...

example 1a

Effect of Increasing the Concentrations of Adenosine (10, 50, 100, 200, 300, 400 and 500 uM) on the Tension of Intact and Denuded Rat Aortic Rings Precontracted with Noradrenalin (FIG. 1).

[0194]The effect of increasing the concentrations of adenosine on the tension of intact and denuded rat aortic rings precontracted with norepinephrine are shown in FIG. 1a and Table 1. In intact rat aortic rings, the mean tension in the precontracted state was 3.68±0.11 g (n=6). Expressed as a percent of baseline (3.68 g), the tension values were 99, 96, 89, 76, 61, 48 and 39% for 10, 50, 100, 200, 300, 400 and 500 uM adenosine respectively (Table 1). Muscle tension did not begin to decrease by over 5% relative to the precontracted state until 100 uM adenosine with a relaxation of 10%. At 200, 300, 400 and 500 uM adenosine concentrations, the percent tension decrease was 24, 39, 52 and 61% respectively relative to the baseline norepinephrine precontracted state (Table 2). In denuded aortic rings, t...

example 1b

Effect of Increasing the Concentrations of Lidocaine on the Tension of Intact and Denuded Rat Aortic Rings Precontracted with Noradrenalin (FIG. 2)

[0202]The effect of increasing the concentrations of lidocaine on the tension of intact and denuded rat aortic rings precontracted with norepinephrine are shown in FIG. 2 and Table 1. The mean tension for intact rings in the precontracted state 3.58±0.07 g (n=6) (Table 1). Expressed as a percent of baseline, tension values were 100, 96, 96, 91, 84, 76 and 72% for 10, 50, 100, 200, 300, 400 and 500 uM lidocaine respectively (Table 1). Muscle tension did not begin to decrease by over 5% relative to the precontracted state until 200 uM lidocaine with a relaxation of 9% and at 300, 400 and 500 uM lidocaine concentrations, the percent tension decrease was 16, 24 and 28% respectively relative to baseline. This tension relaxation profile for lidocaine in intact rings was similar to adenosine alone in denuded rings (ie for adenosine denuded rings...

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Abstract

The present invention relates to a method of reducing injury to cells, a tissue or organ to be explanted from a body and upon implantation into a body by administering a composition to the cell, tissue or organ, including: (i) a potassium channel opener or agonist and / or an adenosine receptor agonist; and (ii) an antiarrhythmic agent. The invention also provides a composition for reducing injury to vasculature ex vivo including: (i) a potassium channel opener or agonist and / or an adenosine receptor agonist; and (ii) an antiarrhythmic agent.

Description

FIELD OF THE INVENTION[0001]This invention relates to a method of protecting cells, a tissue or organ of a body, particularly during surgery. It has particular but not exclusive application in the context of coronary artery bypass graft surgery in protecting a blood vessel during harvesting, testing and storage as well as implantation of the graft and its patency.BACKGROUND OF THE INVENTION[0002]Pioneering work in the surgical technique of anastomosis of arteries and veins was made in the early 1900s by the French surgeon Alexis Carrel (1873-1944). From Carrel's careful methods of protecting the vessels during harvest and storage and delicate anastomosis operations he laid the groundwork for the development of vascular surgery and transplantation. In 1912, Carrel wrote: “In operations on blood-vessels certain general rules must be followed. These rules have been adopted with the view of eliminating the complications which are especially liable to occur after vascular sutures, namely...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/08A61K33/06A01N1/02A61K31/70
CPCA01N1/02A01N1/0226A61K31/167A61K31/53A61K45/06A61P41/00A61K2300/00
Inventor DOBSON, GEOFFREY PHILLIP
Owner HIBERNATION THERAPEUTICS A KF
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