Evaluation of the cardiotoxicity and resuscitation of rats of a newly developed mixture of a QX-314 analog and levobupivacaine
Journal of Pain Research, March 2017
Qi Wang, Qinqin Yin, Jun Yang, Bowen Ke, Linghui Yang, Jin Liu, Wensheng Zhang
This study was designed to evaluate the cardiotoxicity of a QX-314 analog (QX-OH) and a mixture of QX-OH and levobupivacaine (LL-1) and to compare the ability to resuscitate rats after asystole induced by levobupivacaine (Levo-BUP), QX-314, QX-OH, and LL-1. First, we used the "up-and-down" method to determine median dose resulting in appearance of cardiotoxicity (CD50C) and asystole (CD50A) of Levo-BUP, QX-314, QX-OH, and LL-1 in rats. Safety index (SI; ratio of CD50C compared with 2-fold median effective dose needed to produce sensory blockade) of the 4 drugs was calculated. Isobolograms were used for drug interaction analysis. Second, rats received 1.2-fold CD50A in the 4 groups. When asystole occurred, standard cardiopulmonary resuscitation was started and continued for 30 min or until return of spontaneous circulation (ROSC) with native rate-pressure product ≥30% baseline for 5 min. Ranking of CD50C was Levo-BUP < QX-314 ≈ QX-OH. Ranking of CD50A was Levo-BUP < QX-314 < QX-OH. However, the SI of Levo-BUP was significantly higher than that of QX-314 (10.60 vs. 1.20) or QX-OH (10.60 vs. 1.44). The SI of LL-1 was similar to that of Levo-BUP. Nonsynergistic interaction was observed for cardiac effects between QX-OH and Levo-BUP. ROSC was attained initially by 8 of 8 rats in the Levo-BUP group, 3 of 8 in the QX-314 group, 6 of 8 in the QX-OH group, and 8 of 8 in the LL-1 group. Sustained recovery was achieved in the Levo-BUP group but not in the other groups. Levo-BUP and LL-1 are safer than QX-314 or QX-OH. Cardiac effects between QX-OH and Levo-BUP were nonsynergistic. Initial successful resuscitation could be achieved in the QX-OH- and LL-1-induced asystole, but advanced life support might be needed.
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