QX-OH/Levobupivacaine: A Structurally Novel, Potent Local Anesthetic Produces Fast-Onset and Long-Lasting Regional Anesthesia in Rats

Abstract

Purpose

Local anesthetics (LAs) are an important alternative for postoperative analgesia; however, the short duration of LAs limits their use. Thus, we previously developed LL-1, a mixture of QX-OH and levobupivacaine (LB) that produces regional anesthesia for more than 10 h in rats. The aim of this study is to investigate the long-acting mechanism of LL-1 in vivo and in vitro.

Methods

Regional anesthetic effects and local toxicity of the LL-1, QX-OH and LB treatment groups were investigated in a sciatic nerve block rat model. Whole-cell patch-clamping recordings were used to measure the inhibition Na_v currents (I_Na) in ND7/23 cells.

Results

The onset of LL-1 (35mM QX-OH+10mM LB) and 10 mM LB was 10 min, which was much faster than 35 mM QX-OH (27 [18, 60] min, t[12] = −4.535, p = 0.001). The duration of LL-1 (35mM QX-OH+10 mM LB) was significantly longer than 35 mM QX-OH or 10 mM LB alone (F[3, 35] = 191.336, p < 0.0001). No differences in local tissue toxicity were found between LL-1 and LB. In patch-clamping recordings, 5 mM QX-OH produced ~20% inhibition of I_Na currents. LB at 40 μM inhibited I_Na by 65.51%±3.63%, while QX-OH 2 mM+LB 40 μM inhibited I_Na by 77.37%±3.36% (t[14] = 2.358, p = 0.025), and QX-OH 5 mM+LB 40 μM inhibited I_Na by 83.88%±1.57% (t[13] = 4.191, p = 0.0003). Furthermore, I_Na inhibition by QX-OH+LB was more persistent than that of LB alone during washout.

Conclusion

LL-1 can produce an additive and stable inhibition of Nag_v currents, which can contribute to the long-lasting regional anesthetic action.

Keywords:

• long-lasting local anesthetics
• QX-OH
• levobupivacaine
• voltage-gated sodium channel
• Na_v

Acknowledgments

The authors thank Li Li, Fei Chen, and Chunjuan Bao from the Institute of Clinical Pathology, West China Hospital of Sichuan University, for processing histological staining.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (grants No. 81571353, J.L. and No. 81771486, C.Z.); and the Science & Technology Department of Sichuan Province (2019YJ0029, C.Z.).