WO2000076536A1 - Use of adenosine to minimize reperfusion injury - Google Patents

Abstract

Compositions and methods for minimizing reperfusion injury are disclosed during treatment of myocardial infarction with thrombolytic agents or percutaneous transluminal angioplasty. The methods involve co-administering adenosine with a thrombolytic agent or before, during and/or after treatment with percutaneous, transluminal angioplasty. The compositions include adenosine and a thrombolytic agent, in a ratio of concentrations such that the adenosine can be delivered at a rate of between 40 and 60 νg/kg/min, and the thrombolytic can be co-administered at an effective rate for treating myocardial infarction.

Description

USE OF ADENOSINE TO MINIMIZE REPERFUSION INJURY

Field of the Invention

This application is generally in the area of minimization of reperfusion injury during treatment of myocardial infarction with thrombolytic agents or percutaneous transluminal angioplasty.

Background of the Invention

Heart attacks are primarily caused by blockages in the heart, which are caused by plaque buildup and blood clots in coronary vessels.

Approximately 1.5 million Americans suffer a heart attack each year. Both the short and long term survival in these patients is dependent on the amount of heart muscle damage.

Heart attack patients are commonly treated with percutaneous transluminal angioplasty and/or thrombolytic agents. Percutaneous transluminal angioplasty involves inserting an inflatable balloon catheter into the occluded vessel, and expanding the balloon, thereby expanding the vessel. In the majority of cases, the expanded vessel remains unoccluded. In a significant minority of cases, however, the vessel closes up again, a process known as restenosis. Restenosis has been associated with an inflammatory reaction, which may be mediated by various anti-inflammatory agents.

Thrombolytic (clot dissolving) agents such as streptokinase, urokinase, tissue plasminogen activator and the like, dissolve blood clots in the heart. They are typically effective at minimizing damage to the heart and are routinely prescribed to patients suffering from a myocardial infarction. The introduction of thrombolytic drugs and balloon angioplasty has resulted in reperfusion as a logical treatment for patients with an acute heart attack. However, the introduction of oxygen and white blood cells into the heart muscle when the clot dissolves is associated with additional damage to the small blood vessels downstream from the main arteries. This damage is known as reperfusion injury, and results in an increase in the amount of heart muscle damaged.

Accordingly, it would be advantageous in treatments of myocardial infarctions to reperfuse the heart tissue which has been shut off from the blood supply, and minimize the resulting damage caused by the reperfusion. Administration of drugs that minimize reperfusion injury result in a substantial saving of heart muscle and improvement of the pumping function of the heart relative to the use of thrombolytic agents and percutaneous transluminal angioplasty alone.

Adenosine is an endogenous arteriolar vasodilator which has been proposed for use in minimizing reperfusion injury because it is known to have certain cardioprotective properties. For example, it is known that the administration of adenosine after reperfusion limits vascular injury after prolonged ischemia. Babbitt et al., Circulation, 80:1388 (1989); Olaffson et al., Circulation, 76:1135 (1987); Forman et al., Circulation, 81JV-69 (1990); Pitarys et al., Circulation, 83:237 (1991).

Adenosine has a very short plasma half-life, of the order of 10-20 seconds (see, Fredholm and Sollevi, J. Physiol., 313:351-62 (1981)), and thus the concentration of injected adenosine is rapidly reduced to normal serum levels. Because of the transitory presence of the injected adenosine, it must be administered continuously to maintain plasma levels.

United States Patent No. 5,731,296 to Sollevi discloses minimizing reperfusion injury by administering adenosine with a thrombolytic agent. The adenosine is administered intravenously or via intracoronary administration at a dosage range of between 10 and 100 μg/kg/min.

Adenosine is generally known to cause hypotensive effects in at least a significant minority of patients at dosages as low as 70 μg/kg/min, with an increasing number of patients suffering from the hypotensive effects as the dosage is increased. These effects include anxiety, increased heart rate, a feeling of pressure on the chest, and a general feeling of extreme discomfort. These negative effects mitigate against using adenosine to treat heart attack victims, at least at doses at which it would be expected to cause a significant hypotensive effect.

U.S. Patent No. 5,206,222 to Forman discloses minimizing reperfusion injury by administering adenosine and lidocaine, where the dosage range of adenosine is less than about 300 μg/kg/min, preferably between 0.03 and 30 μg/kg/min. When administered at a rate of 300 μg/kg/min, adenosine causes hypotensive effects in most patients. The preferred range is disclosed as not causing hypotensive effects. When administered at a rage of between 0.03 and 30 μg/kg/min, Forman teaches that no hypotensive effects are observed.

Adenosine is generally believed to be effective for certain indications at dosage rates at which it functions as a selective coronary vasodilator. Adenosine administration typically follows a dosage response to curve, in which the coronary vasodilating effect of adenosine is rather insignificant at dosage rates less than 35 μg/kg/min (Wilson et al., Circulation, 82: 1595- 1606, 1990) or up to 40μg/kg/min (Edlund et al, Clinical Physiology 15: 623-636, 1995). The minimum effective dose for the coronary vasodilating effect of adenosine by intravenous administration is approximately 50 μg/kg/min (Edlund et al., Clinical Physiology 15: 623-636, 1995). It would be advantageous to provide compositions and methods useful for minimizing reperfusion injury which do not suffer from the limitations of significant hypotensive effects or marginal efficacy. The present invention provides such compositions and methods.

Summary of the Invention Compositions and methods for minimizing reperfusion injury in a patient are disclosed. Reperfusion injury is minimized by administering adenosine to human patients by continuous intravenous infusion at a dosage rate of between 40 and 60 μg/kg/min, preferably between 45 and 55 μg/kg/min, and most preferably, about 50 μg/kg/min.

Detailed Description of the Invention

Adenosine's effect is readily controlled because it is active at relatively small doses and because of its short plasma half-life (10-20 seconds). In addition, its activity quickly ceases when adenosine administration is terminated.

Adenosine, in the amounts used in accordance with the invention, is essentially non-toxic. It is rapidly taken up by the body to form ATP, and upon degradation its metabolites are present at or below levels normally resulting from physical exercise. When administered in the dosage rates described herein, adenosine minimizes reperfusion injury without causing significant hypotensive effects. Adenosine also is useful in inhibiting clot formation during percutaneous transluminal coronary angioplasty (PTCA) and coronary thrombolysis (CTL).

Dosage Rate of Adenosine Administration

Reperfusion injury is minimized by administering adenosine to human patients by continuous intravenous infusion at a dosage rate of between 40 and 60 μg/kg/min, preferably between 45 and 55 μg/kg/min, and most preferably, about 50 μg/kg/min. The infusion can be given before, during and/or after administration of a thrombolytic agent and/or percutaneous, transluminal angioplasty. Preferably, the coadministration of the adenosine and the thrombolytic is relatively near in time, for example, within about 30 minutes of each other, when they are not administered simultaneously.

The effective dosage rate for adenosine was selected based on several factors. Sollevi teaches that adenosine is effective at dosage rates between 10 and 100 μg/kg/min. However, at dosage rates between 10 and 30 μg/kg/min, adenosine does not significantly function as a selective coronary vasodilator. At dosage rates between 70 and 100 μg/kg/min, adenosine is associated with hypotensive effects, at least for a significant minority of patients. At dosage rates between 50 and 60 μg/kg/min, adenosine increased coronary flow with no effect on mean arterial pressure (Edlund et al., Clinical Physiology 15: 623-636, 1995).

A study was undertaken to evaluate the effects of adenosine at minimizing reperfusion injury. When adenosine was co-administered with a thrombolytic at a dose of 70 μg/kg/min, the adenosine was able to reduce reperfusion injury by a factor of about 66 percent relative to when thrombolytic agents alone were used. However, 28 percent of the patients were observed to suffer from adverse hypotensive effects.

The co-administration of adenosine and thrombolytics at a dosage rate for adenosine of 40-60 μg/kg/min is efficacious, without causing the hypotensive side effects. Phase II clinical studies are currently underway where adenosine is being administered in this dosage range. Also, the administration of adenosine during percutaneous transluminal angioplasty at a dosage rate for adenosine of 40-60 μg/kg/min is efficacious, without causing hypotensive side effects. The selection of the range of adenosine administration was also selected based on knowledge of the concentration of adenosine required to cause a significant amount of receptor activation. Adenosine has a relatively short half life, and is rapidly removed from the blood stream. At low concentrations, an insignificant number of adenosine receptors will be activated, and any effect due to adenosine administration will be minimal. Accordingly, it is necessary to achieve useful plasma concentrations of adenosine to activate a significant number of adenosine receptors. Applicant determined that at a dosage rate of between 40 and 60 μg/kg/min, adenosine is able to activate a significant number of adenosine receptors to cause an effective reperfusion injury reducing effect. Below 30 μg/kg/min, adenosine is not believed to have this effect.

Methods of Administration Adenosine may be administered to human patients by continuous intravenous infusion in any pharmaceutically acceptable form suitable for use in continuous, intravenous infusion. A preferred form is an aqueous solution of adenosine, and more preferably adenosine in isotonic saline. The concentration of adenosine in the solution is not narrowly critical, although concentrations of at least about 5 mM (or about 1.5 milligrams per milliliter of solution) are desired to avoid the need for excessive infusion rates to achieve desired serum levels.

When used for continuous infusion, the unit dosage form typically has a volume of at least 250 millihters, and preferably in the range of 250 to 500 millihters, to provide an adequate supply of adenosine. Consequently, the unit dosage form generally will contain from about 0.4 to about 3 grams of adenosine.

The adenosine solution should be sterile and free from fungi and bacteria. Such solutions have been found to be stable at room temperature for at least two years.

Such solutions are prepared by mixing adenosine with the aqueous carrier, e.g. water or an isotonic solution, and other desired ingredients, to achieve a solution having the desired concentration, and thereafter sterilizing the solution.

Continuous infusion can be performed using any technique known to the art. Because adenosine has such a short plasma half-life and it is active at relatively low concentrations, it is desired that the method be one which minimizes or avoids fluctuations of serum adenosine levels. Accordingly, use of high precision injection pumps is preferred.

Percutaneous Transluminal Angioplasty Coronary artery disease in human beings is often treated by inserting a special catheter, equipped with an inflatable balloon, into a coronary artery which has an angiographically demonstrable stenosis. The procedure, known as percutaneous transluminal coronary angioplasty (PTCA), is executed as follows: under radiological control, the balloon of the catheter is placed in the stenosed part of the vessel. The balloon is inflated several times, each time with increasing pressures, and for a duration of approximately one minute. The catheter is then withdrawn from coronary circulation and the flow through the treated vessel is checked by means of coronary angiography.

The widening of the diseased part of the coronary vessel can cause cracks in the intimal cell layer of the vessel. This trauma leads to activation of biochemical processes leading to local production of substances able to constrict the vessel, as well as activating platelets, which are circulating in the blood, in such a way that they are more easily deposited on the site of the previous stenosis. Platelet deposition is the first step in the coagulation process, which ultimately can lead to the formation of a blood clot. These factors may ultimately lead to a re-occlusion of the vessel. Restenosis generally occurs within 6 months of treatment in 25% or more of the cases, and 5-10% or more occur in the first few days after treatment. In order to lessen or prevent the negative effects of PTCA described above, vasodilating substances such as nitroglycerine, sodium nitroprusside and the like, as well as platelet inhibiting substances and substances preventing blood coagulation such as acetylsalicylic acid, dipyridamol, heparin, coumarin and warfarin have been administered to the patient before and after the procedure.

These substances have actions that are either too potent to be safe in conjunction with the PTCA procedure, since bleeding complications from the catheter puncture sites may occur, or too weak or unpredictable to be fully effective.

Adenosine may be used effectively in conjunction with PTCA because it possesses a unique combination of beneficial properties which all work to antagonize the complicating reactions described above. It has a potent vasodilatory effect on the coronary circulation which enables good blood flow through the treated vessel, which in turn prevents platelet deposition on the traumatized vessel site.

Adenosine antagonizes the action of locally produced vaso-constrictor substances. Adenosine also has an inhibiting effect on platelet aggregation, which further inhibits the chances of clot formation in the treated vessel. These effects are further enhanced by the ability of adenosine to inhibit presynaptic neural mechanisms regulating the release of catecholamines from nerve endings of the sympathetic nervous system which, as is well known, have consequences that all work for clot formation.

The ability of adenosine to bind to adenosine A₂ receptor subtypes is also of use in minimizing reperfusion injury caused by percutaneous transluminal angioplasty. Agonism of the A₂ receptor subtype is associated with anti-inflammatory effects. Accordingly, adenosine, administered at the dosage rates described herein, is effective at binding the A₂ receptor subtypes in an amount sufficient to minimize inflammation, and accordingly, minimize reperfusion injury, without causing a significant amount of hypotensive side effects.

Adenosine is preferably administered into a peripheral vein such as the femoral vein, subclavian vein or brachial vein. Preferably, administration is begun shortly, e.g., a few minutes, before PTCA and continued for the duration of the PTCA and for several hours, e.g., 24 hours after PTCA. The adenosine treatment may be given to patients undergoing the PTCA treatment under current medication with other anti-anginal drugs, such as adrenergic blocking drugs, calcium antagonists, diuretics, digitalis glycosides, angiotension converting enzyme inhibitors, antihyperlipidemic drugs, nitrate compounds including nitroglycerin or other vasodilatory compounds.

Coronary Thrombolysis

Acute myocardial infarction is typically treated by introducing thrombolytic substances into the bloodstream to dissolve the clot(s) in the coronary circulation, which in most cases are the cause of the diseased state. This procedure is known as coronary thrombolysis (CTL). Suitable thrombolytic agents, including streptokinase, urokinase and tissue plasminogen activator, are administered intraveneously or via intracoronary administration. When administered via intracoronary administration, the dosage can be more toward the lower end of the 40-60 μg/kg/min scale, since it activates the adenosine receptors in the heart without its blood plasma concentration having been significantly diminished by travel from the site of the intraveous line to the heart. The same vascular and platelet reactions which occur with PTCA also occur in CTL once the thrombolysis has been achieved. All of the advantages noted above for use of adenosine in PTCA are also applicable to the CTL procedures now in use.

In the CTL context, however, it may be advantageous to administer the adenosine concomitantly with the thrombolytic agent, either separately or pre-mixed with adenosine in a fixed solution. Administration of the adenosine may be initiated before or after administration of the thrombolytic agent.

In both CTL and PTCA, adenosine is administered intravenously at a dosage rate of 40-60, preferably 45-55, and most preferably, about 50 μg/kg/min.

Although the minimization of reperfusion injury is independent of the type of thrombolytic agent used, a useful dosage of tissue plasminogen activator, a specific thrombolytic agent, is as follows.

The recommended dose is 100 mg administered as 60 mg (34.8 million IU) in the first hour (of which 6 to 10 mg is administered as a bolus), 20 mg (11.6 million IU) over the second hour, and 20 mg (11.6 million IU) over the third hour. For smaller patients (less than 65 kg), a dose of 1.25 mg/kg, administered over three hours, as described above, may be administered. The thrombolytic agent can be co-administered with anticoagulants such as heparin, aspirin and/or dipyridamole.

This invention has been described in terms of specific embodiments set forth in detail herein, but it is to be understood that these are by way of illustration and the invention is not necessarily limited thereto. Modifications and variations will be apparent from the disclosure and may be resorted to without departing from the spirit of the invention as those of skill in the art will readily understand. Accordingly, such variations and modifications are considered to be within the purview and scope of the invention and the following claims.

Claims

I claim:

1. A method of reducing reperfusion injury in a patient comprising continuously administering adenosine into the blood stream of the patient at a rate of administration of between 40 and 60 μg of adenosine per kilogram body weight per minute, in conjunction with treatment with a thrombolytic agent or percutaneous, transluminal angioplasty.

2. The method of claim 1 in which adenosine is administered to an anesthetized patient undergoing surgery.

3. The method of claim 1, wherein the dosage rate of adenosine is between 45 and 55μg of adenosine per kilogram body weight per minute.

4. The method of claim 1 , wherein the dosage rate of adenosine is approximately 50 μg of adenosine per kilogram body weight per minute.

5. The method of claim 1, wherein the thrombolytic agent is streptokinase or tissue plasminogen activator.

6. A composition comprising adenosine and a thrombolytic agent, wherein the composition includes sufficient adenosine and thrombolytic agent such that, when the adenosine is administered at a rate of between 40 and 60 μg of adenosine per kilogram body weight per minute, the thrombolytic agent is co-administered at an effective rate to treat a myocardial infarction.

7. The composition of claim 6, wherein the composition includes sufficient adenosine for a three hour infusion of adenosine at a dosage rate of between 40 and 60 μg/kg/min, and sufficient thrombolytic agent for a three hour infusion at a dosage rate of 0.3-0.5 mg/kg/hr can be administered.