A comparison of the systemic toxicity of lidocaine versus its quaternary derivative QX-314 in mice

Cheung, Helen; Lee, Sang Mook; MacLeod, Bernard A.; Ries, Craig R.; Schwarz, Stephan

doi:10.1007/s12630-011-9479-5

Cited by 33 publications

(35 citation statements)

References 31 publications

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“…4 However, it has been observed that intrathecally administered QX-314 caused irritation and death in mice, 6 whereas systemic administration caused central nervous system and cardiac toxicity. 7 In addition, irreversible nerve blockade is seen in animals administered with high concentrations of QX-314. 4 Because irreversible nerve dysfunction can be associated with severe local tissue toxicity, 1 we sought to determine whether QLD administration caused tissue injury.…”

Section: Conclusion: Coadministration Of Site 1 Sodium-channel Blockmentioning

confidence: 99%

“…Compared with amino-amide local anesthetics, QLDs have a similar intracellular site of action 12 but are considered less permeable across the cell membrane. 7,13 Tetrodotoxin (TTX) and saxitoxin (STX) are naturally occurring neurotoxins that bind to site 1 on the extracellular part of the sodium channel 14 and effectively block peripheral nerve conduction. 15,16 Synergism has also been previously observed between site 1 blockers and tricyclic antidepressants.…”

Section: Conclusion: Coadministration Of Site 1 Sodium-channel Blockmentioning

confidence: 99%

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Duration and Local Toxicity of Sciatic Nerve Blockade With Coinjected Site 1 Sodium-Channel Blockers and Quaternary Lidocaine Derivatives

Shankarappa

Sagie

Tsui

et al. 2012

Regional Anesthesia and Pain Medicine

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Background and Objectives Quaternary lidocaine derivatives (QLDs) have recently received much attention because of their potential application in prolonged or sensory-selective local anesthesia. However, associated tissue toxicity is an impeding factor that makes QLDs unfavorable for clinical use. Based on the proposed intracellular site of action, we hypothesized that nerve blocks obtained from lower concentrations of QLDs would be enhanced by the co-application of extracellularly acting site-1 sodium channel blocker, resulting in prolonged block duration but with minimal tissue toxicity. Methods QLDs (QX-314 and QX-222), site 1 sodium channel blockers (tetrodotoxin, 30 μM or saxitoxin, 12.5 μM), or both were injected in the vicinity of the sciatic nerve. Thermal nociceptive block was assessed using a modified hot plate test; motor block by a weight-bearing test. Tissue from the site of injection was harvested for histological assessment. Results Co-application of 25 mM QX-314 and 100 mM QX-222 with site 1 sodium channel blockers produced an 8- to 10- fold increase in the duration of nerve blocks (P<0.05), compared to QLDs or site 1 blockers alone. QLDs elicited severe myotoxicity; this was not exacerbated by co-injection of the site-1 sodium channel blockers. Conclusion Co-administration of site 1 sodium channel blockers and QLDs greatly prolongs the duration of peripheral nerve block without enhancing local tissue injury, but minimal myotoxicity still persists. It is not clear that the risks of QLDs are outweighed by the benefits in providing prolonged nerve blockade.

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Section: Conclusion: Coadministration Of Site 1 Sodium-channel Blockmentioning

confidence: 99%

Section: Conclusion: Coadministration Of Site 1 Sodium-channel Blockmentioning

confidence: 99%

Duration and Local Toxicity of Sciatic Nerve Blockade With Coinjected Site 1 Sodium-Channel Blockers and Quaternary Lidocaine Derivatives

Shankarappa

Sagie

Tsui

et al. 2012

Regional Anesthesia and Pain Medicine

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“…31 Previous research has shown an ED50 for central nervous system and cardiac toxicity in mice of approximately 19.5 mg/kg and 21.2 mg/kg. 32 The cardiac side effects of lidocaine, contributed by the blockage of voltage-gated sodium channels, appear at plasma levels higher than 10 μg/ml in humans. 33 Considering the high ED50 for lidocaine in mice and extensive animal research in lidocaine toxicity with similar dosage, we did not measure plasma levels of lidocaine, and we have strong indications we stayed under critical plasma levels of lidocaine.…”

Section: Discussionmentioning

confidence: 99%

Lidocaine increases the anti‐inflammatory cytokine IL‐10 following mechanical ventilation in healthy mice

Wal

Vaneker

Steegers

et al. 2014

Acta Anaesthesiol Scand

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Background: Mechanical ventilation (MV) induces an inflammatory response that may result in (acute) lung injury. Lidocaine, an amide local anesthetic, has anti-inflammatory properties in vitro and in vivo, possibly due to an attenuation of pro-inflammatory cytokines, intracellular adhesion molecule-1 (ICAM-1), and reduction of neutrophils influx. We hypothesized an attenuation of MV-induced inflammatory response with intravenously administered lidocaine. Methods: Lidocaine (Lido) (2, 4, and 8 mg/kg/h) was intravenously administered during 4 h of MV with a tidal volume of 8 ml/ kg, positive end expiratory pressure 1,5 cmH2O and FiO2 0.4. We used one ventilated control (CON) group receiving vehicle. After MV, mice were euthanized, and lungs and blood were immediately harvested, and cytokine levels and ICAM-1 levels were measured in plasma and lung homogenates. Pulmonary neutrophils influx was determined in LEDER-stained slices of lungs. Anesthetic need was determined by painful hind paw stimulation. Results: Lidocaine-treated animals (Lido 2, 4 and 8 mg/kg/h) showed higher interleukin (IL)-10 plasma levels compared to control animals. Lidocaine treatment with 8 mg/kg/h (Lido 8) resulted in higher IL-10 in lung homogenates. No differences were observed in pro-inflammatory cytokines, ICAM-1, and pulmonary influx between the different ventilated groups. Conclusions: Intravenously administered lidocaine increases levels of plasma IL-10 with infusion from 2, 4, and 8 mg/kg/h and pulmonary levels of IL-10 with 8 mg/kg/h in a murine mechanical ventilation model. Intravenously administered lidocaine appears to reduce anesthetic need in mice.

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“…In addition, for its high water solubility, cardiac toxicity of QX-314 might also be weak because toxicity of local anesthetics on heart positively correlates with their hydrophobicity [19]. However, a recent study indicated that CNS and cardiac toxicities of QX-314 were similar or even more serious than that of lidocaine [20].…”

Section: Introductionmentioning

confidence: 99%

The Quaternary Lidocaine Derivative QX-314 Produces Long-Lasting Intravenous Regional Anesthesia in Rats

et al. 2014

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BackgroundThe lidocaine derivative, QX-314, produces long-lasting regional anesthesia in various animal models. We designed this study to examine whether QX-314 could produce long-lasting intravenous regional anesthesia (IVRA) in a rat model.MethodsIVRA was performed on tail of rats. EC50 (median effective concentration) of QX-314 in IVRA was determined by up-and-down method. IVRA on tail of rats was evaluated by tail-flick and tail-clamping tests. For comparison between QX-314 and lidocaine, 60 Sprague-Dawley rats were randomly divided into 6 groups (n = 10/group), respectively receiving 0.5 ml of 0.5% lidocaine, 0.25% QX-314, 0.5% QX-314, 1.0% QX-314, 2.0% QX-314 and normal saline. To explore the role of TRPV1 channel in IVRA of QX-314, 20 rats were randomly divided into 2 groups (n = 10/group), respectively receiving 0.5 ml of 1% QX-314 and 1% QX-314+75 µg/ml capsazepine. Toxicities of QX-314 on central nervous system and cardiac system were measured in rats according to Racine's convulsive scale and by electrocardiogram, respectively.ResultsQX-314 could produce long-lasting IVRA in a concentration-dependent manner. EC50 of QX-314 in rat tail IVRA was 0.15±0.02%. At concentration of 0.5%, IVRA duration of QX-314 (2.5±0.7 hour) was significantly longer than that of 0.5% lidocaine (0.3±0.2 hour, P<0.001). TRPV1 channel antagonist (capsazepine) could significantly reduce the effect of QX-314. For evaluation of toxicities, QX-314 at doses of 5 or 10 mg/kg did not induce any serious complications. However, QX-314 at dose of 20 mg/kg (1% QX-314 0.5 ml for a rat weighing 250 g) induced death in 6/10 rats.ConclusionsQX-314 could produce long-lasting IVRA in a concentration-dependent manner. This long-lasting IVRA was mediated by activation of TRPV1 channels. Evaluation of toxic complications of QX-314 confirmed that low but relevant doses of QX-314 did not result in any measurable toxicity.

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A comparison of the systemic toxicity of lidocaine versus its quaternary derivative QX-314 in mice

Cited by 33 publications

References 31 publications

Duration and Local Toxicity of Sciatic Nerve Blockade With Coinjected Site 1 Sodium-Channel Blockers and Quaternary Lidocaine Derivatives

Duration and Local Toxicity of Sciatic Nerve Blockade With Coinjected Site 1 Sodium-Channel Blockers and Quaternary Lidocaine Derivatives

Lidocaine increases the anti‐inflammatory cytokine IL‐10 following mechanical ventilation in healthy mice

The Quaternary Lidocaine Derivative QX-314 Produces Long-Lasting Intravenous Regional Anesthesia in Rats

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