USE OF ATP IN CONTROLLED REGIONAL REPERFUSION AS TREATMENT DURING ACUTE MYOCARDIAL INFARCTION

Inventor: Dr. Jenchen Yang

Field of the Invention

[00001] The invention relates generally to the area of treatment and/or reduction of infarct size attendant to myocardial infarction reperfusion. The beneficial effect of the invention is achieved through the use of pharmaceutical compositions that contain ATP- MgCI ₂ to reduce infarct size at the site of reperfusion during myocardial infarction.

Background of the Invention

[00002] ST-elevation myocardial infarction (STEMI) continues to be a significant public health problem in industrialized countries and is becoming an increasingly significant problem in developing countries. It has been established that early coronary reperfusion during acute myocardial infarction salvages jeopardized myocardium and reduce infarct size. ¹ ' ² ' ³ One method for establishing reperfusion, thrombolytic therapy, has been shown to improve survival in recent clinical trials. ⁴ ' ⁵ ' ⁶ However, thrombolytic therapy is limited by its perceived or definite contraindications, intracranial bleeding, inability to establish Thrombosis In Myocardial Infarction (TIMI-3) flow in many patients, and high rates of recurrent ischemia and re-occlusion. Percutaneous coronary intervention (PCI) has been used in an effort to overcome the limitations of thrombolytic therapy. Certainly a preference for PCI has emerged in recent years. ⁷ One of the articles by Keeley and Grines, for example, was a meta-analysis of 23 randomized trials

suggesting superiority of catheter-based reperfusion over fibrinolytic therapy for the treatment of ST-elevation myocardial infarction (STEMI). ⁸

[00003] It is clearly demonstrated that the etiology of acute myocardial infarction is caused by occlusive thrombus in the majority of cases. The myocardium supplied by the vessel distal to the occlusion becomes ischemic. In the ischemic state there is a gradation of cardiac muscle injury and a sequence of functional loss. ⁹ In animal studies on coronary occlusion, an immediate cellular leak of K ⁺ occurs and the rate of relaxation declines. Within one to two minutes, there is a complete loss of contraction followed by the onset of contracture in seven to ten minutes in isolated preparations. The major problem of this initial period, if the occlusion zone is not too great, is electrical dysfunction. The next 1 to 6 hours is the period of variable reversible injury. Depending on the degree of collateral circulation, this period can even be extended up to 24 hours; which may be the reason for survival benefit of thrombolytic therapy up to 24 hours after the onset of symptoms in the ISIS-II study. ⁵

[00004] Myocardial ischemia results in rapid depletion of adenosine 5'- triphosphate (ATP), the universal high energy compound which is required for various metabolic processes. Although mechanical function ceases when ATP concentration remains high (~50%), the initial decline in cardiac function and loss of ATP appears related.

[00005] Studies from a number of laboratories have shown that infusion of ATP- MgCI ₂ proved beneficial for the survival of animals after hemorrhagic shock, ^{10 11} ' ¹² ' ¹³ severe burns, ¹⁴ sepsis-peritonitis, ¹⁵ post-ischemic hepatic failure, ¹⁰ ' ¹⁶ and endotoxin shock. ¹⁷ ' ¹⁸ Moreover, ATP-MgCI ₂ has been shown to accelerate the recovery of renal

function after acute renal failure in rats ¹⁹ as well as mini-pigs. ²⁰ In addition, it has been shown that kidneys that were subjected to episodes of warm ischemia could be salvaged by addition Of ATP-MgCI ₂ to the perfusate. ²¹ ATP-MgCI ₂ has also been effective in hastening renal recovery from a toxic injury. ¹⁰ Kraven et al ²² have shown that infused ATP-MgCI ₂ decreased tissue lactate production, and they suggested that this was due to a direct intracellular effect of administered ATP. Moreover, these investigators ²³ also showed that the treatment of animals in shock with ATP-MgCI ₂ returned the altered member permeability toward normal. Machiedo et al ²⁴ reported that exogenously administered ATP-MgCI ₂ can reverse the inhibition of ornithine metabolism and the change in tissue lactate level during hemorrhagic shock. Since both of these are intracellular ATP-dependent reactions, this led them to conclude that ATP-MgCI ₂ administration after hemorrhagic shock either replenishes intracellular ATP levels or returns the altered cell membrane permeability toward normal or both. In addition, ATP- MgCI ₂ is being used in Japan for the treatment of acute renal failure. ²⁵ ATP-MgCI ₂ is also given to hepatectomy, sepsis-peritonitis, and acute hepatic failure patients. [00006] Myocardial protection during surgically induced ischemia is provided by infusion of cardioplegic solutions which are designed to decrease energy requirements that will minimize cellular injury. Whether the degree of cellular injury is reversible or not is multifactorial, and recent evidence suggests that conditions of reperfusion are a major determinant of reversibility. A number of investigators have consequently tried to alter the reperfusion conditions so as to provide an environment which would allow the cellular reparative process to proceed as efficiently and rapidly as possible, while additional injury is avoided. Those reperfusion conditions involved providing an initial

reperfusate administered under carefully controlled conditions which is low in calcium, high in osmolarity, and contains such additives as calcium channel blockers, oxygen free radicals scavengers and glucose. Under certain conditions of reperfusion, functional recovery has improved. Fedelesova et al ²⁶ demonstrated that ATP injected into isolated nonperfused hypothermic dog hearts improved nucleotide and phosphocreatine levels. Furthermore, analysis of the intra-and extra-cellular distribution of nucleotides using ¹⁴ C- and ³² P- labeled ATP demonstrated that a portion of the ATP entered the cell. Ziegelhoffer et al ²⁷ showed that a small amount of exogenously administered ATP but not ADP or AMP increased the ATP and total adenine nucleotide content of hypoxic myocardium. In a global ischemic model in the intact dog heart, McDonagh et al ²⁸ demonstrated improved myocardial recovery following normothermic ischemia with infusion of low dose ATP-MgCI ₂ . Kopf et al ²⁹ ' ³⁰ also demonstrated that infusion of ATP- MgCI ₂ can improve myocardial performance following prolonged ischemia.

[00007] Whether the ATP-MgCI ₂ molecule can cross the plasma membrane and entered the cell remains controversial. It has been assumed that because of its highly polar nature with three negative charges, ATP cannot cross the plasma membrane. When ATP is complex with MgCI ₂ , it has one instead of three negative charges. In addition, the cell membrane is known to be permeable to macromolecules following ischemia. ³¹ Buchthal et al ³² demonstrated that externally added ATP induced contraction in isolated muscle fibers and suggested that ATP had permeated the cell membranes. In another study by Williams et al ³³ the addition of ATP to cultured myocardial cells

caused an increase in ATP content and this effect was not due to breakdown products of ATP since neither adenosine nor AMP produced this effect.

Summary of the Invention

[00008] The purpose of the present invention is to provide controlled regional reperfusion using ATP-MgCI ₂ after percutaneous coronary revascularization for acute myocardial infarction in order to reduce infarct size, improve left ventricular systolic function, and improve survival.

[00009] The present invention includes a method of treating myocardial infarct through controlled regional reperfusion. This regional reperfusion is preferably preformed at or near the site of any percutaneous intervention procedure related to treatment, such as the site of balloon angioplasty and the insertion of a stent. Typically, the regional reperfusion is carried out by direct arterial infusion to an open artery, and preferably within a short time (typically right after the percutaneous revascularization procedure related to treatment).

[00010] In general terms, the present invention includes a method for controlled regional reperfusion using ATP-MgCI ₂ after percutaneous coronary revascularization for acute myocardial infarction, the method comprising the step of administering an effective amount Of ATP-MgCI ₂ to the infarct-related vessel. The method of the present invention involves administering an effective amount Of ATP-MgCI ₂ to an artery of said body of at a dosage sufficient to reduce ischemia. It is preferred that the dosage of the ATP-MgCI ₂ is at least 0.03 mg/kg/min.

[00011] The method for controlled regional reperfusion using ATP-MgCb after percutaneous coronary revascularization for acute myocardial infarction, also may include steps of: (a) performing cardiac catheterization and coronary angiogram; (b) identifying the infarct-related vessel; (c) performing a left ventriculogram and calculating the left ventricular ejection fraction; and (d) performing a percutaneous coronary intervention; and after percutaneous revascularization of the infarct related vessel, infusing ATP-MgCI ₂ intracoronary via balloon catheter at a rate of at least 0.03 mg/kg/min.

[00012] The method of the present invention may be used to reduce the effects of ischemia to other organs, such as the brain, liver or kidneys.

Detailed Description of the Preferred Embodiment

[00013] In accordance with the foregoing summary, the following presents a preferred embodiment of the present invention which is presently considered to be the best mode thereof. Example Protocol

[00014] Patients presented with acute myocardial infarction clinically may be taken to the catheterization laboratory. Cardiac catheterization and coronary angiogram then may be performed in the standard fashion. The infarct related vessel may thereby be identified clinically and angiographically. A left ventriculogram is then to be performed and the left ventricular ejection fraction will be calculated by the area-length method from the right anterior oblique projection of the left ventriculogram before percutaneous coronary intervention. After successful percutaneous revascularization of the infarct

related vessel, the guide wire will then be withdrawn from the balloon catheter and infusion Of ATP-MgCI ₂ at a rate of 0.03 mg/kg/min is then performed for about 30 minutes via the central lumen of the balloon catheter. Heart rate, blood pressure, pulmonary capillary wedge pressure, and cardiac output then may be monitored pre- and post- infusion of ATP- MgCI ₂ . It is preferred that the ATP- MgCI ₂ is 99% pure. [00015] Follow up left ventricular function study by echocardiogram may then be performed within one week or prior to hospital discharge and at six months. Long-term follow up for MACE (recurrent angina, Ml, and death) may be carried out thereafter at an appropriate cardiology clinic.

[00016] The administration of ATP- MgCI ₂ in accordance with the present invention typically and preferably will be done in accordance with percutaneous intervention at the affected site, such as the placement of a stent or application of balloon angioplasty to the affected area. The ATP- MgCI ₂ is directly infused into an artery, such as the infarct related coronary artery, which best prevents its breakdown and allows it to be effective at the affected site. It may be directly infused in solution preferably for approximately 10 to 30 minutes after percutaneous intervention, and may be done using the same balloon catheter.

[00017] Preferably, the ATP- MgCI ₂ will be in the form of a buffered solution at physiologic pH, such through use of a phosphate buffer in saline. Safety of Administering ATP- MqCI?

[00018] ATP-MgCI ₂ has been used for intravenous infusion into human subjects under various conditions in Japan and Europe. ATP has also been used as an intravenous bolus up to a maximum of 60 mg for treatment of supraventricular

tachycardia. ³⁴ In the United States, the safety and hemodynamic response of ATP- MgCl ₂ in man has been demonstrated by Chaudry et al. ³⁵ Also, ATP- MgCI ₂ has been infused into the left coronary artery in patients with coronary artery disease with reduction of myocardial oxygen consumption in the absence of changes in the measured determinants of myocardial oxygen demand. This finding suggests a possible oxygen sparing effect of ATP. ^{36 37}

[00019] Accordingly, direct regional reperfusion using ATP- MgCI ₂ is likewise a safe method of treatment for acute myocardial infarction, as well as for treating other conditions where ischemia may occur.

Discussion

[00020] The state of the art paper by Kloner and Rezkalla ³⁸ summarized elegantly the past and current approach of cardiac protection during acute intervention or surgery. The concept of glucose-insulin-potassium infusion provides substrates to increase glycolytic ATP (adenosine triphosphate) synthesis during reperfusion is a reasonable idea ³⁹ , but more direct approach is to provide the universal energy source directly by infusion of ATP-MgCI ₂ during acute intervention, as is done in accordance with the present invention. ATP-MgCI ₂ treatment after experimental acute myocardial ischemia protects the heart from the adverse effects of ischemia. ⁴⁰ ATP-loaded liposomes effectively protected the ischemic heart muscle in rabbits with an experimental myocardial infarction as evidenced by a significantly decreased fraction of the irreversibly damaged heart within the total area at risk. ⁴¹

References

The following references are hereby incorporated herein by reference:

1. Reimer KA, Lowe JE ₁ Rasmussen MM, Jennings RB. The wave front phenomenon of ischemic cell death. 1. Myocardial infarct size versus duration of coronary occlusion in dogs. Circulation 1977;56:786-94.

2. Theroux P, Ross J ₁ Franklin D ₁ Kemper WS Sasayama S. Coronary artery reperfusion. Ill Early and late effects on regional myocardial function and dimensions in conscious dogs. Am J Cardiol 1976;38:599-606.

3. Stack RS ₁ Phillips HR ₁ Grierson DS et al. Functional improvement of jeopardized myocardium following intracoronary streptokinase infusion in acute myocardial infarction. J Clin Invest 1983;72:84-95.

4. Gruppo ltaliano per Io Studio della Streptochinasi nelNnfarto Miocardio (GISSI): Long-term effects of intravenous thrombolysis in acute myocardial infarction: Final report of the GISSI study. Lancet 1987;2:871-4.

5. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;1 :349-60.

6. Fibrinolytic Therapy Trials' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet. 1994;343:311-322.

7. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med. 1993;32:673-679.

8. Keeley EC, Boura JA, Grines CL. Comparison of primary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials. Lancet. 2003;361 :13-20.

9. Langer GA, Weiss JN, Schelbert HR. Cardiac ischemia. Part I - Metabolic and physiologic response. West J Med 1987 June; 146:713-723.

10- Chaudry IH, Clemens MG, Baue AE. Alterations in cell function with ischemia and shock and their correction. Arch Surg 1981 ;116:1309-1317. 11. DiStazio J, Maley WB, Thompson H, Sembrat S, Stremple J. Effect of ATP-

MgCI ₂ -glucose administration during hemorrhagic shock on cardiac metabolism function and survival. Adv Shock Res 1980;3:153-166. 12. KOC EA, Diakoumis KN, Karl RC. Effect of ATP- MgCI ₂ On plasma glucose, insulin and glucagon levels in rats subjected to hemorrhagic shock. Surg. Forum

1980;31 :8-10. 13. Kraven T, Rush BF, Ghosh A, Adams-Griffin M. Improved survival and metabolic changes in a rat shock model produced by ATP-MgCI _2. Curr. Surg. 1979;36:435-

437. 14.Zaki MS, Burke JL, Trelstad RL. Protective effect of adenosine-triphosphate administration in burns. Arch. Surg. 1978; 113:605-610.

15.Chaudry IH ₁ Clemens MG, Ohkawa M, Schleck S, Baue AE. Restoration of hepatocellular function and blood flow following ischemia with ATP-MgCI ₂ . Adv.

Shock Res. 1982;8: 177-186. 16. Hirasawa H, Ohkawa M, Odaka M, Sato H. Improved survival, RES function and

ICG clearance tests with ATP-MgCI ₂ following hepatic ischemia. Surg. Forum

1979;30: 158-160.

17. Filkins JP ₁ Buchanan BJ. Protection against endotoxin shock and impaired glucose homeostasis with ATP. Circ. Shock 1977;4:253-258.

18. Fulton RL. Prevention of endotoxin death with nicotinamide and adenosine triphosphate. Surg. Forum 1974;25:17-19.

19. Siegel NJ, Glazier WB, Chaudry IH, Gaudio KM, Lytton B, Baue AE, Kashgarian M. Enhanced recovery from acute renal failure by post-ischemic infusion of adenine nucleotides and magnesium chloride in rats. Kidney Int. 1980; 17:338- 349.

20. Lytton B, Glazier WB, Chaudry IH, Baue AE. The use of adenosine triphosphate with magnesium chloride in the treatment of post-ischemic renal injury. Trans Am Assoc Genitourin Surg. 1978;70:145-8.

21. Lytton B, Vaisbort VR, Glazier WB, Chaudry IH, Baue AE. Improved renal function using ATP-MgCI ₂ in preservation of canine kidneys subjected to warm ischemia. Transplantation 1981 ;31 :187-189.

22. Kraven T, Rush B, Slotman GJ, Adams-Griffin M. Permeability of the shock cell to ATP-MgCI ₂ . Surg. Forum 1979;30:7-9.

23. Kraven T, Rush B, Ghuman SS, Dikdan GS. Reversal of altered permeability of the shock cell to ATP-MgCI ₂ . Surg. Forum 1980;31 :3-5. 24. Machiedo GW, Ghuman S, Rush BF, Kraven T, Dikdan GS. The effect of ATP-

MgCI ₂ infusion on hepatic cell permeability and metabolism following hemorrhagic shock. Surgery 1981 ;90:328-335. 25.0daka M, Hirasawa H, Tabata Y, Kobayashi H, Sato H. A new treatment of acute renal failure with direct hemo-perfusion enhancement of reticuloendothelial system and ATP-MgCI ₂ . Satellite Symp. Acute Renal Failure, TeI Aviv, Israel,

June 1981 , p.125. 26. Fedelesova M, Ziegelhoffer A, Krause E, Wollenberger A. Effect of exogenous adenosine triphosphate on the metabolic state of the excised hypothermic dog heart. Circ. Res. 1969;24:617-27. 27. Ziegelhoffer M, Fedelesova A, Kostolansky S. Specific ATP action on the metabolism of isolated heart: Influence of pH, divalent cation concentration and stability of complexes. Acta Biol. Med. Ger. 1972;28:893. 28. McDonagh PF, Laks H, Chaudry IH ₁ Baue AE. Improved myocardial recovery from ischemia. Arch. Surg. 1984; 119:1379-84. 29. Kropf GS, Chaudry IH, Condos SG, Baue AE. Improved myocardial performance after prolonged ischemia with ATP-MgCI ₂ cardioplegia. Surg. Forum

1986;37:234. 30. Kropf GS, Chaudry IH, Condos SG, Baue AE. Reperfusion with ATP-MgCI ₂ following prolonged ischemia improve myocardial performance. J Surg Res

1987;43:114-117.

31. Higgins TJ, Bailey PJ. The effect of cyanide and iodoacetate intoxication and ischemia on enzyme release from the perfused rat heart. Biochim Biophys Acta.

1983;762:67-75. 32. Buchthal F, Deutsch A, Knappic G. Further investigation on the effect of adenosine triphosphate and related phosphorous compounds on isolated striated muscle fibers. Acta Physiol. Scand. 1946;11 :325. 33. Williams D, Ribell D, Rovetto MJ. ATP induced increase in ATP content of cultured myocardial cells. Fed. Proc. 1979;38:1389. 34.Viskin S, Fish R, Glick A, Glikson M, Eldar M, Belhassen B. The adenosine triphosphate test: A bedside diagnostic tool for identifying the mechanism of supraventricular tachycardia in patients with palpitation. J Am Coll Cardiol

2001 ;38:173-7. 35.Chaudry IH, Keefer JR, Barash P, Clemens MG, Kropf GS, Baue AE. ATP-

MgCb infusion in man: increased cardiac output without adverse systemic hemodynamic effects. Surg Forum 1984;35:14-16. 36.Wohlgelernter D, Jaffe C, Cleman M ₁ Young L, Clemens M, Chaudry IH. Effects of ATP- MgCI ₂ On coronary blood flow and myocardial oxygen consumption.

Circulation 1985;72:lll-315. 37.Nanto S, Kitakaze M, Takano Y, Hori M, Nagata S. lntracoronary administration of adenosine triphosphate increases myocardial adenosine levels and coronary blood flow in man. Jpn Circ J. 1997 Oct;61 (10):836-42. 38. Kloner RA, Rezkalla SH. Cardiac Protection During Acute Myocardial Infarction:

Where Do We Stand in 2004? J Am Coll Cardiol 2004;44:276-86.

39.0pie LH, Sack MN. Metabolic plasticity and the promotion of cardiac protection in ischemia and ischemic preconditioning. J MoI Cell Cardiol 2002;34:1077- 1089.

40. Katircioglu SF, Ulus AT, Saritas Z. ATP-MgCI ₂ treatment after experimental acute myocardial ischemia and reperfusion. Panminerva Med. 2000 Mar;42(1):11-5.

41.Verma DD, HartnerWC, Levchenko TS, Bernstein EA, Torchilin VP. ATP-loaded liposomes effectively protect the myocardium in rabbits with an acute experimental myocardial infarction. Pharmaceutical Research 2005;22:2115- 2120.

Other embodiments and configurations may be devised without departing from the spirit of the inventions and the scope of the appended claims.