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

We recently showed that the quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia with a slow onset in animal models in vivo. As quaternary agents do not rapidly penetrate biological membranes or the blood-brain barrier, QX-314 may represent a local anesthetic with decreased systemic toxicity compared with conventional tertiary aminoamines. To test this hypothesis, we conducted an in vivo animal study in mice to compare QX-314 with lidocaine in terms of its relative central nervous system (CNS) and cardiac toxicity. With approval from the institutional Animal Care Committee, we used the up-and-down method to determine the relative potencies (ED(50)) of lidocaine and QX-314 for CNS and cardiac toxicity in adult CD-1 mice (weight, 20 to 35 g). The animals were administered either intravenous lidocaine or QX-314 (dose range, 7.5 to 30 mg center dot kg(-1)) and were observed for signs of CNS toxicity (convulsions, ataxia, loss of righting reflex, and/or death). We also observed animals for electrocardiographic evidence of toxic effects on cardiac automaticity, conductivity, and rhythmicity. The ED(50) of lidocaine for CNS toxicity as determined by the up-and-down method was 19.5 mg center dot kg(-1) (95% confidence interval [CI], 17.7 to 21.3 mg center dot kg(-1); n = 6) compared with 10.7 mg center dot kg(-1) for QX-314 (95% CI, 9.1 to 12.3 mg center dot kg(-1); n = 6) (potency ratio, 1.8). Similarly, the ED(50) of lidocaine for electrocardiographic evidence of cardiac toxicity was significantly higher than that of QX-314 (ED(50) of lidocaine, 21.2 mg center dot kg(-1); 95% CI, 19.0 to 23.4 mg center dot kg(-1); n = 6 vs ED(50) of QX-314, 10.6 mg center dot kg(-1); 95% CI, 8.4 to 12.8 mg center dot kg(-1); n = 6) (potency ratio, 2.0). In this in vivo animal study, the relative potencies of QX-314 for systemic CNS and cardiac toxicity were significantly higher than those of lidocaine. These data do not support the hypothesis that QX-314 is a safer local anesthetic compared with lidocaine in terms of systemic toxicity. Whereas our results do not exclude the possibility that QX-314 may represent a clinically useful agent to produce long-lasting local anesthesia and nociceptive blockade after a single shot in humans, its systemic toxicity relative to conventional tertiary aminoamide local anesthetics and the underlying mechanisms warrant further study.