Percutaneous coronary intervention (PCI) is the most frequently employed strategy to revascularize atherosclerotic stenosis of native coronary arteries and saphenous vein grafts. Tissue perfusion is frequently impaired following PCI, particularly in patients with ST segment elevation myocardial infarction (STEMI). This results in the ""no-reflow"" phenomenon which is an important predictor of mortality. Adenosine is an endogenous nucleoside that attenuates many of the mechanisms responsible for the ""no-reflow"" phenomenon. Experimental and clinical studies have confirmed adenosine's efficacy in enhancing myocardial salvage and improving microvascular blood flow. Adensoine's full therapeutic potential is compromised due to its ultra short half life requiring large doses to obtain adequate blood levels at the target organ. Since the guidewire is the first PCI device that perturbs the vascular bed, we have developed the concept of elution of adenosine continuously via an adenosine-polymer-coated guidewire. We have developed a number of unique physiologic polymers in which adenosine can be covalently incorporated and placed on a guidewire. We tested out first generation polymers (LDI-glycerol and LDI-adenosine) in a small animal model and verified that it resulted in a substantial increase in blood flow. However in a large animal model the kinetic profile was too rapid for a typical interventional procedure (~45 mins). We have subsequently developed two new polymers, LDI- cysteine and LDI-PEG. Prior to initiating large animal studies in a Phase 2 study it is imperative we optimize the polymer structure, guidewire-coating methodology and kinetic release profile. We therefore propose the following studies with the new polymers to identify an ideal product. First we will develop and characterize the structure of the polymers and permutations thereof and evaluate numerous coating methodologies to optimize release kinetic profile. Second we will evaluate adenosine elution utilizing a temperature controlled recirculating water bath system and measure adenosine release serially with HPLC. Third we will determine if the selected polymer is safe for clinical use by employing NAMSA- based screening tests for cytotoxicity, pyrogenicity, hemolysis, and sensitization. Finally we will evaluate the stability and durability of the polymer with glass transition temperature experiments and by passing coated wires through simulated lesions. If the ""anti-no-reflow"" wire is shown to be effective in improving outcomes after interventional procedures it will represent a major advance in the treatment of patients with coronary artery disease undergoing PCI. This will have important societal benefits due to the large number of interventional procedures performed in the US each year for coronary artery disease.
Public Health Relevance: The improved outcomes that may potentially occur with the device would have important societal benefits due to the large number of interventional procedures performed in the US each year for atherosclerotic disease.
Thesaurus Terms: 1,2,3-Propanetriol;1,2,3-Trihydroxypropane;Acute;Adenosine;Adherence;Adherence (Attribute);Animal Model;Animal Models And Related Studies;Animals;Arteries;Attenuated;Balloon Angioplasty;Bathing;Baths;Blood;Blood Reticuloendothelial System;Blood Vessels;Blood Flow;Body Tissues;Cardiac Artery;Cardiac Infarction;Clinical;Clinical Research;Clinical Study;Complex;Continuous Infusion;Coronary Arteriosclerosis;Coronary Artery Disease;Coronary Artery Disorder;Coronary Atherosclerosis;Coronary Vessels;Coronary Artery;Cysteine;Development;Devices;Disease;Disorder;Dose;Drugs;Electron Microscopy;Exclusion Chromatography;Family Suidae;Gel Chromatography;Gel Filtration;Gel Filtration Chromatography;Gel Permeation Chromatography;Generations;Glass;Glycerin;Glycerol;Hplc;Half-Cystine;Half-Life;Heart Artery;Hemolysis;High Performance Liquid Chromatography;High Pressure Liquid Chromatography;High Speed Liquid Chromatography;Hydrogen Oxide;In Vitro;Infarction;Injury;Intravenous;Kinetics;L-Cysteine;Loinc Axis 4 System;Lesion;Lytotoxicity;Macrogols;Measures;Medical Device;Medication;Method Loinc Axis 6;Methodology;Molecular Weight;Mortality;Mortality Vital Statistics;Myocardial;Myocardial Infarct;Myocardial Infarction;Nuclear Magnetic Resonance;Nucleosides;Organ;Ostamer;Outcome;Pathogenesis;Pathologic Constriction;Pathological Constriction;Patients;Pellethane;Percutaneous Transluminal Angioplasty;Perfusion;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Physiologic;Physiological;Pigs;Polyethylene Glycols;Polyethylene Oxide;Polyethyleneoxide;Polyisocyanates;Polymers;Polyoxyethylenes;Polyurethanes;Prevention;Procedures;Reaction;Receptor Protein;Recurrence;Recurrent;Saphenous Vein;Screening Procedure;Simulate;Site;Stenosis;Sterilization;Structure;Suidae;Swine;System;Temperature;Testing;Therapeutic;Time;Tissues;Toxicity Testing;Toxicity Tests;Transition Temperature;Transluminal Angioplasty;Transluminal Arterial Dilatation;Ventricular Function;Water;Base;Cardiac Infarct;Coronary Attack;Coronary Infarct;Coronary Infarction;Cytotoxicity;Cytotoxicity Test;Developmental;Disease/Disorder;Drug/Agent;Experiment;Experimental Research;Experimental Study;Extracellular;Heart Attack;Heart Infarct;Heart Infarction;Improved;In Vivo;Infarct;Meetings;Model Organism;Monomer;Novel;Percutaneous Coronary Intervention;Phase 2 Study;Phase Ii Study;Polymerization;Porcine;Prophylactic;Receptor;Research Study;Restoration;Screening;Screenings;Success;Suid;Vascular;Vascular Bed
