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

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.

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 ) in ND7/23 cells.

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.

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