PURPOSE: Beta-agonists are accepted as first-line treatment for patients with asthma or COPD, but are known to have cardiovascular side-effects. MN-221 is a highly selective beta2 adrenoceptor agonist which may limit beta 1-mediated side effects. This study was conducted to assess the cardiovascular impact of MN-221 intravenously administered in addition to albuterol.
METHODS: Telemetered naïve dogs were initially treated with nebulized albuterol or the beta2-adrenergic receptor agonist, MN-221, via intravenous infusion. Following the individual albuterol or MN-221 treatments, the dogs were crossed over and received albuterol combined with MN-221.
RESULTS: Treating with albuterol in combination with different dose levels of MN-221 had a similar effect of increased heart rate (HR) as that observed after treatment with the individual components. However, there was no additive nor synergistic effect of the combined treatment on HR. In fact, there were no statistical differences between: albuterol (5 ug/kg) and MN-221 (3.0 ug/kg) or albuterol (5 ug/kg) + MN-221 (0.3 or 3.0 ug/kg); or MN-221 (30 ug/kg) and albuterol (5 ug/kg) + MN-221 (30 ug/kg). Upon combination of albuterol (10 ug/kg) + MN-221, the two lower MN-221 doses actually attenuated the albuterol-induced increase in HR and there was no substantial HR increase in the combination at the highest dose of MN-221. Additionally, there was no significant effect of treatment with albuterol + MN-221 on the QTc interval and only a small decrease in MAP at the highest dose of MN-221.
CONCLUSION: While both albuterol and Mn-221 induced an increase in HR independently, adverse effects on heart rate were not observed upon combination in dogs. Other cardiovascular parameters (OTc and MAP) were not adversely affected in the albuterol + MN-221 combination. These findings are consistent with some other data implicating MN-221 as a partial agonist at beta 1-adrenergic receptors.
CLINICAL IMPLICATIONS: MN 221 adjunctive to standard care may provide benefit in asthma and COPD exacerbations without adding cardiovascular risk.
DISCLOSURE: Alan Dunton, Shareholder Matsuda, Yuichi Iwaki, and Feldman are shareholders of MediciNova, Inc.; Employee Matsuda, Yuichi Iwaki, and Feldman are employees of MediciNova, Inc. Dunton is the head of Danerius, LLC.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. MN-221 is a new beta adrenoreceptor agonist under development by MediciNova, Inc.