The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats
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...
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Frontiers Media S.A.
2019-08-01
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00895/full |
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| author | YuJun Zhang YuJun Zhang QinQin Yin QinQin Yin DeYing Gong DeYing Gong Yi Kang Yi Kang Jun Yang Jun Yang Jin Liu Jin Liu WenSheng Zhang WenSheng Zhang |
| author_facet | YuJun Zhang YuJun Zhang QinQin Yin QinQin Yin DeYing Gong DeYing Gong Yi Kang Yi Kang Jun Yang Jun Yang Jin Liu Jin Liu WenSheng Zhang WenSheng Zhang |
| author_sort | YuJun Zhang |
| collection | DOAJ |
| description | 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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| spelling | doaj.art-a3edbaff57bf456da9911709ffeecd792022-12-22T03:49:31ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-08-011010.3389/fphar.2019.00895472626The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in RatsYuJun Zhang0YuJun Zhang1QinQin Yin2QinQin Yin3DeYing Gong4DeYing Gong5Yi Kang6Yi Kang7Jun Yang8Jun Yang9Jin Liu10Jin Liu11WenSheng Zhang12WenSheng Zhang13Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Engineering Laboratory of Transformation Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Engineering Laboratory of Transformation Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Engineering Laboratory of Transformation Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Engineering Laboratory of Transformation Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Engineering Laboratory of Transformation Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Engineering Laboratory of Transformation Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Engineering Laboratory of Transformation Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, ChinaIntroduction: 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.https://www.frontiersin.org/article/10.3389/fphar.2019.00895/fullpreclinical drug developmentpreclinical pharmacokineticslong-acting local anestheticfixed-dose combinationQX-OH |
| spellingShingle | YuJun Zhang YuJun Zhang QinQin Yin QinQin Yin DeYing Gong DeYing Gong Yi Kang Yi Kang Jun Yang Jun Yang Jin Liu Jin Liu WenSheng Zhang WenSheng Zhang The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats Frontiers in Pharmacology preclinical drug development preclinical pharmacokinetics long-acting local anesthetic fixed-dose combination QX-OH |
| title | The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats |
| title_full | The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats |
| title_fullStr | The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats |
| title_full_unstemmed | The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats |
| title_short | The Preclinical Pharmacological Study of a Novel Long-Acting Local Anesthetic, a Fixed-Dose Combination of QX-OH/Levobupivacaine, in Rats |
| title_sort | preclinical pharmacological study of a novel long acting local anesthetic a fixed dose combination of qx oh levobupivacaine in rats |
| topic | preclinical drug development preclinical pharmacokinetics long-acting local anesthetic fixed-dose combination QX-OH |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00895/full |
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