The quaternary lidocaine derivative QX-314 in combination with bupivacaine for long-lasting nerve block: Efficacy, toxicity, and the optimal formulation in rats

Yin, Qinqin; Li, Jun; Zheng, Qingshan; Yang, Xunzhe; Lv, Rong; Ma, Longxiang; Liu, Jin; Zhu, Tao; Zhang, Wensheng

doi:10.1371/journal.pone.0174421

Cited by 12 publications

(12 citation statements)

References 31 publications

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“…Compared with neoSTX-Bup, QXOH-LB may have some advantages in term of systemic toxicity. As demonstrated in a pharmacodynamic study using rat sciatic nerve block models focusing on the efficacy and toxicity of multiple formulations of QX314 plus bupivacaine combination, the optimal formulation was 0.9% (25 mM) QX314 with 0.5% (15 mM) bupivacaine, which established approximately 10 h of non-selective sciatic nerve block with moderate local tissue inflammations (Yin et al, 2017). Unfortunately, combinations with QX314 ≥ 25 mM induce severe tissue inflammations.…”

Section: Discussionmentioning

confidence: 99%

“…Neurobehavioral measurements were summarized as previously described (Sagie and Kohane, 2010; Yin et al, 2017). In hot plate test for nociceptive block assessment, a rat was vertically hold in order to make the paw of the injected side placed on a heated metal plate (the temperature of the plate was 56°C, RB-200 Hot Plate, Chengdu Techman Software Co., Ltd.,).…”

Section: Methodsmentioning

confidence: 99%

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A Fixed-Dose Combination, QXOH/Levobupivacaine, Produces Long-Acting Local Anesthesia in Rats Without Additional Toxicity

Yin

Zhang

et al. 2019

Front. Pharmacol.

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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 LD 50 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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A Fixed-Dose Combination, QXOH/Levobupivacaine, Produces Long-Acting Local Anesthesia in Rats Without Additional Toxicity

Yin

Zhang

et al. 2019

Front. Pharmacol.

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“…Anionic liposomes produced a longer duration of the nerve blockage when compared with the cationic and neutral liposomes. Interestingly, QX-314 was attached to the surface of anionic liposomes by electrostatic interactions (Yin et al, 2017). Similar to the results with QX-OH, the T max of Levo-Bupi with in combination with QX-314 was extended to 4 h in the sciatic nerve block ( Supplementary Figure 1A ).…”

Section: Discussionmentioning

confidence: 99%

The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats

et al. 2019

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Introduction: Previous studies demonstrated that 35 mM QX-OH/10 mM Levobupivacaine (LL-1), a fixed-dose combination, produced a long-acting effect in rat local anesthesia models. All preclinical pharmacodynamic results indicated that LL-1 had potential for postsurgical pain treatment. The objective of this study was to investigate the pharmacokinetics of LL-1. Then, the possible mechanism of the extended duration by the combination was examined. Methods and Results: All experiments were examined and approved by the Committee of Animal Care of the West China Hospital Sichuan University (Ethical approval number, 2015014A). The compound action potentials were recorded to verify the pharmacodynamic result in ex vivo. In frog sciatic nerve, LL-1 produced an effective inhibition with rapid onset time. The concentration-time profiles of LL-1 were determined in plasma and local tissues after sciatic nerve block. The maximum concentration of QX-OH and levobupivacaine were 727.22 ± 43.38 µg/g and 256.02 ± 28.52 µg/g in muscle, 634.26 ± 36.04 µg/g and 429.63 ± 48.64 µg/g in sciatic nerve, and 711.71 ± 25.14 ng/ml and 114.40 ± 10.19 ng/ml in plasma, respectively. The absorption of QX-OH into circulation was very rapid at 0.71 ± 0.06 h, which was faster than that of levobupivacaine (4.11 ± 0.39 h, p = 0.003). The half-time of QX-OH in plasma and local tissues had no significant difference (p = 0.329), with the values of 2.64 h, 3.20 h, and 3.79 h in plasma, muscle, and sciatic nerve, respectively. The elimination profile of levobupivacaine differed from that of QX-OH, which was slower eliminated from plasma (4.89 ± 1.77 h, p = 0.036) than from muscle (1.38 ± 0.60 h) or sciatic nerve (1.28 ± 0.74 h). When levobupivacaine was used alone, the Tmax in plasma was 1.07 ± 0.16 h. Interestingly, the Tmax of levobupivacaine in the plasma was increased by four times in combination with QX-OH (4.11 ± 0.39 h). Levobupivacaine promotes cellular QX-OH uptake. Conclusion: The preclinical pharmacokinetic study of LL-1 in the rat plasma, muscle, and sciatic nerve was accomplished. Then, the possible mechanism of the prolonged duration was that QX-OH delayed the absorption of levobupivacaine from the injection site into circulation, and levobupivacaine accelerated QX-OH to accumulate into cells.

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“…Future studies should investigate the role of TRPV1 and other vanilloid receptor agonists on QX-314 anesthesia. Furthermore, the LA effects of QX-314, like other conventional LAs, is known to be enhanced by adjuncts, including chemical permeation enhancers, dexmedetomidine, and site 1 sodium channel blockers 17,31–33. It remains to be seen whether coadministration of such adjuncts with QX-314 would improve topical corneal anesthesia.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Duration Topical Corneal Anesthesia With the Cationic Lidocaine Derivative QX-314

Woodruff

Santamaria

Mehta

et al. 2019

Trans. Vis. Sci. Tech.

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PurposeTopical corneal local anesthetics are short acting and may impair corneal healing. In this study we compared corneal anesthesia and toxicity of topically applied N-ethyl lidocaine (QX-314) versus the conventional local anesthetic, proparacaine (PPC).MethodsVarious concentrations of QX-314 and 15 mM (0.5%) PPC were topically applied to rat corneas. Corneal anesthesia was assessed with a Cochet-Bonnet esthesiometer at predetermined time points. PC12 cells were exposed to the same solutions to assess cytotoxicity. Repeated topical corneal administration in rats was then used to assess for histologic evidence of toxicity. Finally, we created uniform corneal epithelial defects in rats and assessed the effect of repeated administration of these compounds on the defect healing rate.ResultsQX-314 (15 mM) and PPC (15 mM) caused similar total duration (114 ± 17 and 87 ± 16 minutes, respectively; P = 0.06) of anesthesia. The depth of anesthesia was similar between these low-dose groups at 15 minutes after application (1.8 ± 0.3- and 2.0 ± 0.8-cm filament lengths). QX-314 (100 mM) provided more prolonged corneal anesthesia (174 ± 13 minutes; P < 0.0001), with improved depth at 15 minutes (0.7 ± 0.3-cm filament length; P = 0.007). All tested concentrations of QX-314 demonstrated similar or less toxicity than 0.5% PPC.ConclusionsTopical administration of QX-314 is effective for corneal anesthesia and demonstrates no histologic signs of local toxicity in a rodent model. In higher concentrations, QX-314 provides more than twofold the duration of anesthetic effect than does 0.5% PPC.Translational RelevanceOur study reveals a clinically relevant compound providing prolonged duration topical corneal anesthesia.

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The quaternary lidocaine derivative QX-314 in combination with bupivacaine for long-lasting nerve block: Efficacy, toxicity, and the optimal formulation in rats

Cited by 12 publications

References 31 publications

A Fixed-Dose Combination, QXOH/Levobupivacaine, Produces Long-Acting Local Anesthesia in Rats Without Additional Toxicity

A Fixed-Dose Combination, QXOH/Levobupivacaine, Produces Long-Acting Local Anesthesia in Rats Without Additional Toxicity

The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats

Prolonged Duration Topical Corneal Anesthesia With the Cationic Lidocaine Derivative QX-314

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