QXOH, a QX314 derivative with longer duration and lesser local toxicity, is a novel
local anesthetic in preclinical drug development. Previous studies demonstrated that
bupivacaine can prolong the effects of QX314. So, we attempted to combine
QXOH with
levobupivacaine to shorten the onset time and lengthen the duration. In this study, we investigated the efficacy, local and systemic toxicity in rats. In subcutaneous
infiltration anesthesia, the inhibition of cutaneous trunci muscle reflex for
QXOH-LB was greater than
QXOH and
levobupivacaine in the first 8 h (
QXOH-LB vs.
QXOH, P = 0.004;
QXOH-LB vs. LB, P = 0.004). The completely recovery time for
QXOH-LB (17.5 ± 2.5 h) was significantly longer than
levobupivacaine (9.0 ± 1.3 h, P = 0.034) and
QXOH (9.8 ± 0.9 h, P = 0.049). In sciatic nerve block,
QXOH-LB produced a rapid onset time, which was obviously shorter than
QXOH. For sensory, the time to recovery for
QXOH-LB was 17.3 ± 2.6 h, which was statistically longer than 6.0 ± 1.8 h for
QXOH (P = 0.027), and 4 h for
levobupivacaine (P = 0.001). Meanwhile, the time to motor recovery for
QXOH-LB was 7.9 ± 2.8 h, significantly longer than 4 h for
levobupivacaine (P = 0.003) but similar to 6.0 ± 1.7 h for
QXOH (P = 0.061). In local toxicity, there was no significant difference of histological score regarding muscle and sciatic nerve in
QXOH-LB,
QXOH,
levobupivacaine and saline (P < 0.01). In the combination, the interaction index of LD50 was 1.39, indicating antagonistic interaction between
QXOH and
levobupivacaine in terms of systemic toxicity. In this study, we demonstrated that
QXOH-LB produced cutaneous
anesthesia which was 2-fold greater than that produced by
QXOH or LB alone, and elicited sciatic nerve block with a potency that was 5- and 3-fold that of LB and
QXOH, respectively. Local tissue
inflammation by
QXOH-LB was mild, similar to that induced by LB. This fixed-dose combination led to an antagonistic interaction between
QXOH and LB in terms of systemic toxicity. These results suggested that
QXOH-LB induced a long-lasting
local anesthesia, likely, avoiding clinically important local and systemic toxicities.