Published Online
on September 17, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

Safety of Binodenoson, a Selective Adenosine A2A Receptor Agonist Vasodilator Pharmacologic Stress Agent, in Healthy Subjects with Mild, Intermittent Asthma

John J. Murray^1,9; John M. Weiler²; Lawrence B. Schwartz³; William W. Busse⁴; Rohit K. Katial⁵; Richard F. Lockey⁶; E. R. McFadden, Jr.⁷; Glenn C. Pixton⁸ and Richard J. Barrett⁸

¹ Vanderbilt University Medical Center, Nashville, TN;
² Iowa Clinical Research Corporation, Iowa City, IA;
³ Virginia Commonwealth University, Richmond, VA;
⁴ University of Wisconsin Medical School, Madison, WI;
⁵ National Jewish Medical and Research Center, Denver, CO;
⁶ University of South Florida, Tampa, FL;
⁷ MetroHealth Medical Center, Cleveland, OH;
⁸ King Pharmaceuticals Research and Development, Inc., Cary, NC

^* Corresponding author; email: jmurray{at}mmc.edu

Background—The pharmacologic stress (PS) agents adenosine and dipyridamole are contraindicated in asthma patients because of the risk of adenosine receptor-mediated bronchospasm. Binodenoson, a selective adenosine A_2A receptor agonist, produces maximal coronary hyperemia during PS testing, yet has a low affinity for the adenosine A₁, A_2B, and A₃ receptors likely responsible for bronchospasm. This study was conducted to assess the safety of binodenoson in 87 healthy young adult volunteers with documented mild, intermittent asthma.

Methods and Results—This study consisted of a dose-escalating, single-blind phase and a placebo-controlled, double-blind phase conducted in healthy, young adults with documented mild, intermittent, asthma. In the single-blind phase, 3 sequential cohorts of 8 subjects received intravenous binodenoson (0.5, 1.0, and 1.5 µg/kg). In the double-blind phase, commenced after medical review of results from the single-blind phase, subjects were randomized 2:1 to either binodenoson 1.5 µg/kg (n=41) or placebo (n=22). The primary endpoint was clinically significant bronchoconstriction, defined as a decrease in forced expiratory volume in 1 second (FEV1) of 20% from the pre-injection measure. Secondary safety endpoints were changes from pre-injection measure in FEV1, forced vital capacity (FVC), and forced expiratory flow during the middle 50% of the FVC (FEF_25%-75%); vital signs; pulse oximetry; and adverse events. Binodenoson caused no clinically significant bronchoconstriction or alterations in pulmonary function parameters, and transiently increased heart rate and systolic blood pressure. The most common treatment-emergent adverse events were tachycardia, dizziness, and flushing.

Conclusions—Binodenoson was safe, well tolerated, and caused no clinically significant bronchoconstriction or pulmonary responses in a small population of healthy subjects with mild, intermittent asthma.

Key Words: asthma • binodenoson • bronchoconstriction • pharmacologic stress