Pharmacological profile of RWJ 20085: A new,potent, long-acting local anesthetic

RWJ 20085 is a potent, long-acting local anesthetic that has been studied in vivo and in vitro relative to several clinically active agents. In mice, RWJ 20085 ED₅₀ = 0.0078% (0.0053–0.011%)] was more potent by perineural infiltration than bupivacaine ED₅₀ = 0.035% (0.026–0.046%)], etidocaine ED₅₀ = 0.025% (0.016–0.035%)], or lidocaine ED₅₀ = 0.18% (0.13–0.26%)]. The onset of action of each compound was 5 minutes, and the duration was 90 minutes for RWJ 20085 and 30 minutes for bupivacaine or etidocaine while lidocaine was active for only 15 minutes. In the rabbit corneal assay, RWJ 20085 ED₅₀ = 0.012% (0.0049–0.023%)] was more potent than bupivacaine ED₅₀ = 1.4% (0.47–3.05%)]. The lowest topical local anesthetic ED₅₀ of each agent was observed within 5 or 15 minutes after administration, and RWJ 20085 was active for 300 minutes, whereas bupivacaine and etidocaine were active for 90 or 45 minutes, respectively. In the guinea pig intradermal assay RWJ 20085 ED50 = 0.017% (0.0094–0.028%)], bupivacaine ED₅₀ = 0.016% (0.0078–0.028%)], and etidocaine ED₅₀ = 0.02% (0.0093–0.042%)] were equipotent while lidocaine ED₅₀ = 0.072% (0.040–0.12%)] was less potent. The onset of action of each compound was 5 minutes. The duration of action of RWJ 20085 and etidocaine was 60 minutes, whereas bupivacaine and lidocaine were active for 45 and 15 minutes, respectively. In the frog isolated-sciatic nerve preparation, similar concentrations of RWJ 20085 (2.5 × 10^?3M) and lidocaine (5.0 × 10^?3M) produced a 50% reduction of the amplitude of the pretreatment action potential; however, bupivacaine and etidocaine were each effective at a lower concentration (5.0 × 10^?4M). When their intramuscular therapeutic ratios (TR = lethal dose LD₅₀/local anesthetic ED₅₀) were calculated in mice, the therapeutic ratio of RWJ 20085 (82) was less than that of etidocaine (103) but was larger than that of either lidocaine (36) or bupivacaine (29). Calculation of the therapeutic ratios by using the intravenous LD₅₀ values suggests that lidocaine would have the smallest margin of safety if inadvertently administered by the intravenous route. The therapeutic ratios of the other agents were larger than that of lidocaine; however, there was little difference among them. RWJ 20085 has a low potential for dermal irritation as shown in rabbits and has no liability for contact sensitization as shown in guinea pigs. RWJ 20085 may have clinical utility as an injectable and/or topical local anesthetic.