Abstract
Background: lidocaine is one of the most commonly used local anesthetics for the treatment of pain and arrhythmia. However, it could cause systemic toxicities when plasma concentration is raised. To reduce lidocaine’s toxicity, we designed a hydroxyl derivative of lidocaine (lido-OH), and its local anesthesia effects and systemic toxicity in vivo were quantitively investigated.Method: the effectiveness for lido-OH was studied using mouse tail nerve block, rat dorsal subcutaneous infiltration, and rat sciatic nerve block models. The systemic toxicities for lido-OH were evaluated with altered state of consciousness (ASC), arrhythmia, and death in mice. Lidocaine and saline were used as positive and negative control, respectively. The dose-effect relationships were analyzed.Results: the half effective-concentration for lido-OH were 2.1 mg/ml with 95% confident interval (CI95) 1.6–3.1 (lidocaine: 3.1 mg/ml with CI95 2.6–4.3) in tail nerve block, 8.2 mg/ml with CI95 8.0–9.4 (lidocaine: 6.9 mg/ml, CI95 6.8–7.1) in sciatic nerve block, and 5.9 mg/ml with CI95 5.8–6.0 (lidocaine: 3.1 mg/ml, CI95 2.4–4.0) in dorsal subcutaneous anesthesia, respectively. The magnitude and duration of lido-OH were similar with lidocaine. The half effective doses (ED50) of lido-OH for ACS was 45.4 mg/kg with CI95 41.6–48.3 (lidocaine: 3.1 mg/kg, CI95 1.9–2.9), for arrhythmia was 16.0 mg/kg with CI95 15.4–16.8 (lidocaine: 3.0 mg/kg, CI95 2.7–3.3), and for death was 99.4 mg/kg with CI95 75.7–124.1 (lidocaine: 23.1 mg/kg, CI95 22.8–23.4). The therapeutic index for lido-OH and lidocaine were 35.5 and 5.6, respectively.Conclusion: compared with lidocaine, lido-OH produced local anesthesia at similar potency and efficacy, but with significantly reduced systemic toxicities.
Highlights
Local anesthetics (LAs) are very critical in pain management
LAs carry the risk of systemic toxicities, known as local anesthetic systemic toxicity (LAST), which frequently interferes with the central nervous system and the cardiovascular system, resulting in altering consciousness state, cardiovascular depression, arrhythmia, seizure, and asystole in extreme cases (Wadlund, 2017)
Central nervous system toxicity (Cheung et al, 2011): Mice received a single injection of lido-OH or lidocaine through the tail vein using 0.3 ml insulin syringe and 30G hypodermic needle, the mice were removed to a transparent plastic box and observed for behaviors of altered state of consciousness (ASC) such as convulsion, ataxia, sedation, or loss of righting reflex
Summary
Local anesthetics (LAs) are very critical in pain management. LAs inhibit the conduction of afferent nerve impulses of nociceptive stimuli, producing reliable analgesia while avoiding the common side effects of other analgesics such as gastro-intestinal bleeding, coagulation disorder, liver or kidney function impairment, addiction, tolerance, etc., (Ma et al, 2017; Morrison et al, 2021). LAs carry the risk of systemic toxicities, known as local anesthetic systemic toxicity (LAST), which frequently interferes with the central nervous system and the cardiovascular system, resulting in altering consciousness state, cardiovascular depression, arrhythmia, seizure, and asystole in extreme cases (Wadlund, 2017). Due to LAs’ non-selective inhibition of ion channels, electrical activity in the neurons and myocardium are disturbed. Both lipo-solubility and interaction with ion channels are important for LAST. Lido-OH preserves the characteristic molecular structures of lidocaine, including the lipid aromatic group, the hydro amine group, and the amide linkage. It may inherit the basic chemo-physical properties from lidocaine. The research hypothesis: 1) the potency and efficacy of analgesia for lido-OH were similar with lidocaine in mouse tail nerve block, rat dorsal subcutaneous infiltration, and rat sciatic nerve block models; 2) the doses for lido-OH to elicit central nerve toxicity, cardiac toxicity, and death were higher than lidocaine; and 3) less lido-OH, compared with lidocaine, is distributed into the brain and heart after intravenous injection
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