Yin Qinqin, Zhang Yujun, Lv Rong, Gong Deying, Ke Bowen, Yang Jun, Tang Lei, Zhang Wensheng, Zhu Tao
Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China.
Front Pharmacol. 2019 Mar 26;10:243. doi: 10.3389/fphar.2019.00243. eCollection 2019.
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, = 0.004; QXOH-LB vs. LB, = 0.004). The completely recovery time for QXOH-LB (17.5 ± 2.5 h) was significantly longer than levobupivacaine (9.0 ± 1.3 h, = 0.034) and QXOH (9.8 ± 0.9 h, = 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 ( = 0.001). Meanwhile, the time to motor recovery for QXOH-LB was 7.9 ± 2.8 h, significantly longer than 4 h for levobupivacaine ( = 0.003) but similar to 6.0 ± 1.7 h for QXOH ( = 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 ( < 0.01). In the combination, the interaction index of LD 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.
QXOH是一种作用持续时间更长、局部毒性更小的QX314衍生物，是一种处于临床前药物开发阶段的新型局部麻醉剂。先前的研究表明布比卡因可延长QX314的作用效果。因此，我们尝试将QXOH与左旋布比卡因联合使用，以缩短起效时间并延长作用持续时间。在本研究中，我们调查了其在大鼠中的疗效、局部和全身毒性。在皮下浸润麻醉中，在前8小时内，QXOH-左旋布比卡因对皮躯干肌反射的抑制作用大于QXOH和左旋布比卡因（QXOH-左旋布比卡因与QXOH相比，P = 0.004；QXOH-左旋布比卡因与左旋布比卡因相比，P = 0.004）。QXOH-左旋布比卡因的完全恢复时间（17.5±2.5小时）显著长于左旋布比卡因（9.0±1.3小时，P = 0.034）和QXOH（9.8±0.9小时，P = 0.049）。在坐骨神经阻滞中，QXOH-左旋布比卡因起效迅速，明显短于QXOH。在感觉方面，QXOH-左旋布比卡因的恢复时间为17.3±2.6小时，在统计学上长于QXOH的6.0±1.8小时（P = 0.027）和左旋布比卡因的4小时（P = 0.001）。同时，QXOH-左旋布比卡因的运动恢复时间为7.9±2.8小时，显著长于左旋布比卡因的4小时（P = 0.003），但与QXOH的6.0±1.7小时相似（P = 0.061）。在局部毒性方面，QXOH-左旋布比卡因、QXOH、左旋布比卡因和生理盐水在肌肉和坐骨神经的组织学评分上无显著差异（P<0.01）。在联合用药中，LD的相互作用指数为1.39，表明QXOH和左旋布比卡因在全身毒性方面存在拮抗相互作用。在本研究中，我们证明QXOH-左旋布比卡因产生的皮肤麻醉效果比单独使用QXOH或左旋布比卡因产生的效果大2倍，并引发坐骨神经阻滞，其效力分别是左旋布比卡因和QXOH的5倍和3倍。QXOH-左旋布比卡因引起的局部组织炎症较轻，与左旋布比卡因引起的相似。这种固定剂量组合在全身毒性方面导致QXOH和左旋布比卡因之间产生拮抗相互作用。这些结果表明，QXOH-左旋布比卡因可诱导持久的局部麻醉，可能避免临床上重要的局部和全身毒性。
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