Novel Guidewire Design and Coating for Continuous Delivery of Adenosine During Interventional Procedures.

Background The "no-reflow phenomenon" compromises percutaneous coronary intervention outcomes. There is an unmet need for a device that prevents no-reflow phenomenon. Our goal was to develop a guidewire platform comprising a nondisruptive hydrophilic coating that allows continuous delivery of adenosine throughout a percutaneous coronary intervention. Methods and Results We developed a guidewire with spaced coils to increase surface area for drug loading. Guidewires were plasma treated to attach hydroxyl groups to metal surfaces, and a methoxy-polyethylene glycol-silanol primer layer was covalently linked to hydroxyl groups. Using polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetate, a drug layer containing jet-milled adenosine was hydrogen-bonded to the polyethylene glycol-silanol layer and coated with an outer diffusive barrier layer. Coatings were processed with a freeze/thaw curing method. In vitro release studies were conducted followed by in vivo evaluation in pigs. Coating quality, performance, and stability with sterilization were also evaluated. Antiplatelet properties of the guidewire were also determined. Elution studies with adenosine-containing guidewires showed curvilinear and complete release of adenosine over 60 minutes. Porcine studies demonstrated that upon insertion into a coronary artery, adenosine-releasing guidewires induced immediate and robust increases (2.6-fold) in coronary blood flow velocity, which were sustained for ≈30 minutes without systemic hemodynamic effects or arrhythmias. Adenosine-loaded wires prevented and reversed coronary vasoconstriction induced by acetylcholine. The wires significantly inhibited platelet aggregation by >80% in vitro. Guidewires passed bench testing for lubricity, adherence, integrity, and tracking. Conclusions Our novel drug-releasing guidewire platform represents a unique approach to prevent/treat no-reflow phenomenon during percutaneous coronary intervention.

A novel adenosine precursor 2',3'-cyclic adenosine monophosphate inhibits formation of post-surgical adhesions.

BACKGROUND: Intraperitoneal adenosine reduces abdominal adhesions. However, because of the ultra-short half-life and low solubility of adenosine, optimal efficacy requires multiple dosing. AIM: Here, we compared the ability of potential adenosine prodrugs to inhibit post-surgical abdominal adhesions after a single intraperitoneal dose. METHODS: Abdominal adhesions were induced in mice using an electric toothbrush to damage the cecum. Also, 20 µL of 95 % ethanol was applied to the cecum to cause chemically induced injury. After injury, mice received intraperitoneally either saline (n = 18) or near-solubility limit of adenosine (23 mmol/L; n = 12); 5'-adenosine monophosphate (75 mmol/L; n = 11); 3'-adenosine monophosphate (75 mmol/L; n = 12); 2'-adenosine monophosphate (75 mmol/L; n = 12); 3',5'-cyclic adenosine monophosphate (75 mmol/L; n = 19); or 2',3'-cyclic adenosine monophosphate (75 mmol/L; n = 20). After 2 weeks, adhesion formation was scored by an observer blinded to the treatments. In a second study, intraperitoneal adenosine levels were measured using tandem mass spectrometry for 3 h after instillation of 2',3'-cyclic adenosine monophosphate (75 mmol/L) into the abdomen. RESULTS: The order of efficacy for attenuating adhesion formation was: 2',3'-cyclic adenosine monophosphate > 3',5'-cyclic adenosine monophosphate ≈ adenosine > 5'-adenosine monophosphate ≈ 3'-adenosine monophosphate ≈ 2'-adenosine monophosphate. The groups were compared using a one-factor analysis of variance, and the overall p value for differences between groups was p < 0.000001. Intraperitoneal administration of 2',3'-cAMP yielded pharmacologically relevant levels of adenosine in the abdominal cavity for >3 h. CONCLUSION: Administration of 2',3'-cyclic adenosine monophosphate into the surgical field is a unique, convenient and effective method of preventing post-surgical adhesions by acting as an adenosine prodrug.

Development of a novel adenosine-eluting guidewire (Adenowire) for coronary vasodilation during percutaneous coronary intervention.

AIMS: Microvascular obstruction (MVO) and "no-reflow phenomenon" (NRP) remain barriers to optimal tissue perfusion after percutaneous coronary intervention (PCI). The purpose of this study was to develop, characterise, and test an adenosine-eluting guidewire (Adenowire) for coronary vasodilation. METHODS AND RESULTS: Utilising polyurethane chemistry, we developed a non-toxic pentameric form of adenosine (PA) that can be coated onto guidewires (Adenowire) and that allows continuous elution of adenosine into the distal vascular bed during PCI. We characterised PA with Fourier transform infrared spectroscopy, NMR and MALDI time-of-flight mass spectrometry, established its stability by calorimetry, and confirmed its safety by extensive toxicological testing. Adenowires reliably released adenosine in vitro over 60 minutes. In pigs, insertion of an Adenowire into the left circumflex or left anterior descending coronary artery resulted in immediate and sustained (40 minutes) vasodilation. Electron microscopy demonstrated smooth thin coating of the terminal portion of guidewires and showed lack of fibrin or platelet adhesion to the Adenowire after in vivo use. CONCLUSIONS: Since guidewires are the first devices to cross a culprit lesion, Adenowires would prophylactically medicate vascular beds with adenosine at the target site without the need for additional manipulations by the interventionalist.

Hypertension, tachycardia, and reversible cardiomyopathy temporally associated with milnacipran use.

Elevated catecholamine levels are a well-recognized cause of various types of cardiomyopathy. Causes of catecholamine elevation include tumors, toxins, drugs, emotional stress, and sepsis. Milnacipran is a dual and equipotent inhibitor of norepinephrine and serotonin uptake. It is frequently prescribed as therapy for fibromyalgia, and the drug has a good safety profile. Herein, we report the case of a 42-year-old woman with undefined connective-tissue disease and fibromyalgia who developed a severe and reversible cardiomyopathy while taking recommended doses of milnacipran. The cardiomyopathy was associated with a hyperadrenergic state manifested by tachycardia, hypertension, and elevated plasma catecholamine levels. The discontinuation of milnacipran and the initiation of anti-failure therapy resulted in complete resolution of the cardiomyopathy in 6 months. To our knowledge, this is the first report of milnacipran as a possible cause of catecholamine-induced cardiomyopathy.

Treating acute "no-reflow" with intracoronary adenosine in 4 patients during percutaneous coronary intervention.

Angiographic evidence of impaired tissue perfusion, known as the "no-reflow" phenomenon, is a serious complication of percutaneous coronary intervention-one that is associated with increased mortality rates. Adenosine is an endogenous nucleoside that attenuates many of the mechanisms that are responsible for no-reflow. Herein, we report the cases of 4 patients who developed the no-reflow phenomenon after elective percutaneous coronary intervention to their native coronary arteries and saphenous vein grafts. In all 4 patients, and without adverse effects, small bolus doses of adenosine through the guiding catheter improved epicardial perfusion--measured by either Thrombolysis In Myocardial Infarction (TIMI) flow grade or corrected TIMI frame count-and tissue-level perfusion, graded according to myocardial blush. In view of adenosine's extremely short half-life in blood, the continuous administration of adenosine into the distal vascular bed throughout percutaneous coronary intervention may further improve outcomes by reversing or preventing the no-reflow phenomenon.

Importance of tissue perfusion in ST segment elevation myocardial infarction patients undergoing reperfusion strategies: role of adenosine.

High risk ST segment elevation myocardial infarction (STEMI) patients undergoing reperfusion therapy continue to exhibit significant morbidity and mortality due in part to myocardial reperfusion injury. Importantly, preclinical studies demonstrate that progressive microcirculatory failure (the "no-reflow" phenomenon) contributes significantly to myocardial reperfusion injury. Diagnostic techniques to measure tissue perfusion have validated this concept in humans, and it is now clear that abnormal tissue perfusion occurs frequently in STEMI patients undergoing reperfusion therapy. Moreover, because tissue perfusion correlates poorly with epicardial blood flow (TIMI flow grade), clinical studies show that tissue perfusion is an independent predictor of early and late mortality in STEMI patients and is associated with infarct size, ventricular function, CHF and ventricular arrhythmias. The mechanisms responsible for abnormal tissue perfusion are multifactorial and include both mechanical obstruction and vasoconstrictor humoral factors. Adenosine, an endogenous nucleoside, maintains microcirculatory flow following reperfusion by activating four well-characterized extracellular receptors. Because activation of adenosine receptors attenuates the mechanical and functional mechanisms leading to the "no reflow" phenomenon and activates other cardioprotective pathways as well, it is not surprising that both experimental and clinical studies show striking myocardial salvage with intravenous infusions of adenosine administered in the peri-reperfusion period. For example, a post hoc analysis of the AMISTAD II trial indicates a significant reduction in 1 and 6-month mortality in STEMI patients undergoing reperfusion therapy who are treated with adenosine within 3 hours of symptoms. In conclusion, adenosine's numerous cardioprotective effects, including attenuation of the "no-reflow" phenomenon, support its use in high risk STEMI undergoing reperfusion.

Non-bacterial thrombotic endocarditis in an adult 14 months after cryopreserved aortic allograft valve implantation.

Cryopreserved aortic allograft tissue is used to correct aortic valve disease in adults and to reconstruct the right ventricular outflow tract in children with congenital heart disease. In adults, allograft durability is regarded as comparable to or better than that of manufactured bioprostheses, with failure usually due to slow fibrocalcific degeneration. Normally, allograft semilunar valves have excellent hemodynamics and low rates of infectious endocarditis and thromboembolism. The role of immune-mediated inflammation in post-implant allograft valve performance is slow in onset, and variable. Herein is presented the case of a male adult with rapid deterioration of the aortic valve homograft wall, without loss of the valve leaflets, resulting in severe aortic regurgitation. The pathological findings were consistent with classical marantic (sterile) endocarditis with acute and chronic inflammatory changes associated with advanced atherosclerotic lesions in the allograft aortic wall tissue resulting in thrombosis and subsequent cerebral embolization.

Role of adenosine as adjunctive therapy in acute myocardial infarction.

Although early reperfusion and maintained patency is the mainstay therapy for ST elevation myocardial infarction, experimental studies demonstrate that reperfusion per se induces deleterious effects on viable ischemic cells. Thus "myocardial reperfusion injury" may compromise the full potential of reperfusion therapy and may account for unfavorable outcomes in high-risk patients. Although the mechanisms of reperfusion injury are complex and multifactorial, neutrophil-mediated microvascular injury resulting in a progressive decrease in blood flow ("no-reflow" phenomenon) likely plays an important role. Adenosine is an endogenous nucleoside found in large quantities in myocardial and endothelial cells. It activates four well-characterized receptors producing various physiological effects that attenuate many of the proposed mechanisms of reperfusion injury. The cardio-protective effects of adenosine are supported by its role as a mediator of pre- and post-conditioning. In experimental models, administration of adenosine in the peri-reperfusion period results in a marked reduction in infarct size and improvement in ventricular function. The cardioprotective effects in the canine model have a narrow time window with the drug losing its effect following three hours of ischemia. Several small clinical studies have demonstrated that administration of adenosine with reperfusion therapy reduces infarct size and improves ventricular function. In the larger AMISTAD and AMISTAD II trials a 3-h infusion of adenosine as an adjunct to reperfusion resulted in a striking reduction in infarct size (55-65%). Post hoc analysis of AMISTAD II showed that this was associated with significantly improved early and late mortality in patients treated within 3.17 h of symptoms. An intravenous infusion of adenosine for 3 h should be considered as adjunctive therapy in high risk-patients undergoing reperfusion therapy.

Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial.

AIMS: The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II). METHODS AND RESULTS: Patients presenting with ST-segment elevation anterior AMI were randomized to receive placebo vs. adenosine (50 or 70 microg/kg/min) for 3 h starting within 15 min of reperfusion therapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. > or = or < the median 3.17 h, and by reperfusion modality. In patients receiving reperfusion < 3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P = 0.014), 6-month mortality (7.3 vs. 11.2%, P = 0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P = 0.022). Patients reperfused beyond 3 h did not benefit from adenosine. CONCLUSION: In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.