Acute myocardial infarction is the leading cause of death in most industrialized nations. The estimated annual incidence in the US is 865,000 events, with ST-segment elevation myocardial infarction (STEMI, severe AMI) comprising an estimated 500,000 events per year. Fibrinolytic therapy is widely utilized to restore coronary blood flow due to its widespread availability to the broad cross-section of patients. The current regimen, including tissue plasminogen activator, aspirin, clopidogrel and heparin, still induces inadequate coronary reperfusion in 30-40% of patients and early thrombotic reocclusion in 5-10% patients. Moreover, successful recanalization causes detrimental reperfusion injury that accounts for up to 50% of the final size of a myocardial infarct. Net clinical adverse outcomes remain 10-12% at 30 days after treatment and 16-17% STEMI patients die during 1-year follow-up. Moreover, both morbidity and mortality are dramatically increased in patients experiencing peri-procedure bleeding. Importantly, most of the recurrent MI and major bleeding events occur in the first hours and days after treatment. Consequently, the search for more efficacious and safer acute antithrombotic agents with effective attenuation of reperfusion injury remains the "holy grail'of drug development. APT102 is an optimized human apyrase with two amino acid substitution that has significantly higher activity than the wild-type apyrases. This enzyme inhibits platelet activation and limits vascular inflammation by enzymatically hydrolyzing extracellular ADP and ATP. Adenosine is further generated by CD73 which prevents tissue damage during hypoxia and in the setting of cardiac reperfusion injury. In addition, APT102 prevents platelet desensitization and maintains homeostasis. With the Phase I award, we demonstrated that in the r-tPA induced fibrinolysis model in dogs, treatment of APT102 completely prevented re-occlusion, maintained normal blood flow, and profoundly reduced infarct size of hearts by 80% compared with clopidogrel. Meanwhile, APT102 did not prolong bleeding time, as did clopidogrel. The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel. The long-term goal is to develop APT102 as a highly effective antithrombotic and anti-inflammatory therapy with minimal bleeding risk that will profoundly improve efficacy and safety of acute treatment for AMI and other thrombotic patients.
The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel.
|Lin, Gen-Min; Liu, Kiang; Colangelo, Laura A et al. (2016) Low-Density Lipoprotein Cholesterol Concentrations and Association of High-Sensitivity C-Reactive Protein Concentrations With Incident Coronary Heart Disease in the Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol 183:46-52|
|Criqui, Michael H; Aboyans, Victor; Allison, Matthew A et al. (2016) Peripheral Artery Disease and Aortic Disease. Glob Heart 11:313-326|
|Ho, Jennifer E; Enserro, Danielle; Brouwers, Frank P et al. (2016) Predicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes. Circ Heart Fail 9:|
|Del Gobbo, Liana C; Imamura, Fumiaki; Aslibekyan, Stella et al. (2016) Ï‰-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies. JAMA Intern Med 176:1155-66|
|Ahmed, Haitham M; Miller, Michael; Nasir, Khurram et al. (2016) Primary Low Level of High-Density Lipoprotein Cholesterol and Risks of Coronary Heart Disease, Cardiovascular Disease, and Death: Results From the Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol 183:875-83|
|Yu, Bing; Pulit, Sara L; Hwang, Shih-Jen et al. (2016) Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. Circ Cardiovasc Genet 9:64-70|
|O'Neal, Wesley T; Qureshi, Waqas T; Nazarian, Saman et al. (2016) Electrocardiographic Time to Intrinsicoid Deflection and Heart Failure: The Multi-Ethnic Study of Atherosclerosis. Clin Cardiol 39:531-6|
|Kaufman, Joel D; Spalt, Elizabeth W; Curl, Cynthia L et al. (2016) Advances in Understanding Air Pollution and CVD. Glob Heart 11:343-352|
|Wong, Nathan D; Zhao, Yanglu; Patel, Rohini et al. (2016) Cardiovascular Risk Factor Targets and Cardiovascular Disease Event Risk in Diabetes: A Pooling Project of the Atherosclerosis Risk in Communities Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study. Diabetes Care 39:668-76|
|Bittencourt, Marcio Sommer; Blankstein, Ron; Mao, Songshou et al. (2016) Left ventricular area on non-contrast cardiac computed tomography as a predictor of incident heart failure - The Multi-Ethnic Study of Atherosclerosis. J Cardiovasc Comput Tomogr 10:500-506|
Showing the most recent 10 out of 594 publications