Adenosine A2A receptor agonist (regadenoson) in human lung transplantation

Abstract

BACKGROUND: Currently, there are no clinically approved treatments for ischemia-reperfusion injury after lung transplantation. Pre-clinical animal models have demonstrated a promising efficacy of adenosine 2A receptor (A 2A R) agonists as a treatment option for reducing ischemia-reperfusion injury. The purpose of this human study, is to conduct a Phase I clinical trial for evaluating the safety of continuous infusion of an A 2A R agonist in lung transplant recipients. METHODS: An adaptive, two-stage continual reassessment trial was designed to evaluate the safety of regadenoson (A 2A R agonist) in the setting of lung transplantation. Continuous infusion of regadenoson was administered to lung transplant recipients that was started at the time of skin incision. Adverse events and dose-limiting toxicities, as predetermined by a study team and assessed by a clinical team and an independent safety monitor, were the primary end-points for safety in this trial. RESULTS: Between January 2018 and March 2019, 14 recipients were enrolled in the trial. Of these, 10 received the maximum infused dose of 1.44 mg/kg/min for 12 hours. No dose-limiting toxicities were observed. The steady-state plasma regadenoson levels sampled before the reperfusion of the first lung were 0.98 § 0.46 ng/ml. There were no mortalities within 30 days. CONCLUSIONS: Regadenoson, an A 2A R agonist, can be safely infused in the setting of lung transplantation with no dose-limiting toxicities or drug-related mortality. Although not powered for the evaluation of secondary end-points, the results of this trial and the outcome of pre-clinical studies warrant further investigation with a Phase II randomized controlled trial.

Lymphocytic Airway Inflammation in Lung Allografts

“…The use of azithromycin as prophylaxis for CLAD or as a rescue from BOS has been implemented by several institutions, as detailed previously with varying degrees of success (85-87, 90, 92). Also, an adenosine A2A receptor antagonist is under investigation to reduce invariant NKT cell mediated inflammation in PGD (173). Other strategies to dampen airway inflammation, such as regulatory T cell adoptive therapy and/or pretransplant allograft modification during ex vivo lung perfusion, have shown preclinical promise as adjuncts to traditional immune suppression (174).…”

Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation

“…Selective adenosine A 2a receptor stimulation has been identified as a potential cytoprotective strategy to mitigate IRI in various settings, due to its well-documented anti-inflammatory effects [ 22 ]. Recently, Lau et al have published data on the effects of regadenoson, an adenosine A2a receptor agonist, in the setting of clinical lung transplantation [ 33 ]. In this pilot study of 14 lung transplantation recipients, the authors concluded that regadenoson can be safely infused in the setting of human lung transplantation with no dose-limiting toxicities or drug-related mortality.…”

The Role of Purinergic Signaling in Heart Transplantation

“…For example, the partial adenosine A1 receptor agonist neladenoson bialanate has been commonly used in chronic heart failure treatment ( 154 , 155 ). Adenosine A2A receptor agonist CGS21680 reduces the inflammatory response of lung transplantation ( 156 , 157 ) and liver transplantation ( 47 ). It can as well significantly reduce the infarct area of isolated perfused mouse hearts ( 48 ).…”