Local Anesthetic Activity and Acute Toxicity of (±) −2-(N-Ethylpropylamino) −2′,6′-butyroxylidide, a New Long-Acting Agent

Adams, H. Jack; Kronberg, George H.; Takman, Bertil H.

doi:10.1002/jps.2600611133

Cited by 39 publications

(13 citation statements)

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“…Although these are essentially preliminary studies in small animals, the rank order of the relative potencies and duration of action of lidocaine, etidocaine, and bupivacaine in our experiments are in good agreement with their clinical profiles of action [Adams et al, 1972;Covino, 1971;Henn and Brattsand, 19661, and our results suggest that RWJ 20085 may be more potent and long-acting than the local anesthetics to which it has been compared. While there are known differences in the clinical onset of their local anesthetic effects, our results did not detect any differences between their onset in animals.…”

Section: Discussionsupporting

confidence: 88%

“…They and others [Truant, 1958;Covino, 19711 reported that the duration of 2% lidocaine was 1.5 to 2 hr in rats; and while we could not evaluate the effects of a similar concentration in mice due to the appearance of CNS symptoms, we found that 1% lidocaine inhibited grip for 15 minutes. However, etidocaine [Adams et al, 19721 and bupivacaine [Adams et al, 1972;Covino, 19711 were less potent but longer-acting in rats than we observed in mice. The duration of action of etidocaine or bupivacaine was 2 hr or more in rats.…”

Section: Discussioncontrasting

confidence: 80%

“…However, relatively higher concentrations of either bupivacaine, etidocaine, or lidocaine would be required to achieve a duration of action comparable to that of RWJ 20085. The evaluation of compounds by the intradermal route is predictive [Covino, 19711 of clinical local anesthetic activity since duration of action by this route in humans [Grambling et al, 1964;Swerdlow and Jones, 19701 and guinea pigs [Adams et al, 1972;Covino, 19711 was similar.…”

Section: Discussionmentioning

confidence: 97%

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

Dubinsky¹,

Shriver²,

Sanfilippo³

et al. 1990

Drug Development Research

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(2.5 x 1 OP3M) and lidocaine (5.0 x I Op3M) 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 x 1 O-4M). When their intramuscular therapeutic ratios (TR = lethal dose LD,,/l ocal anesthetic ED, , ) 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 LD, , 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.

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 80%

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

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

Dubinsky¹,

Shriver²,

Sanfilippo³

et al. 1990

Drug Development Research

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show abstract

“…Studies of the relative CNS toxicity of various local anesthetics have been carried out previously in mice (deJong and Bonin, 1980), rats (Adams et al, 1972), monkeys (Munsen et al, 1970, 1975, sheep (Morishima et al, 1981), and dogs (Eicholzer and Feldman, 1976). CNS effects include initial excitation, leading to convulsive activity, followed by depression and respiratory arrest.…”

Section: Discussionmentioning

confidence: 98%

Toxicological Assessment of Lidocaine in the Pregnant Rat

et al. 1985

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Teratogenic and toxicological effects of lidocaine administered during pregnancy were evaluated in the Sprague Dawley rat. High doses of lidocaine administered during specific periods of gestation were shown to produce no apparent adverse toxicological or teratogenic effects. Histological, enzymological, and physical features of the fetuses, utilizing conventional toxicological parameters, were all found to be normal following maternal administration of lidocaine. Analysis of these data suggests that the administration of lidocaine during pregnancy had no detectable adverse effects on the fetus.

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“…Racemic RS(±) bupivacaine is the most widely used local anesthetic because of its longer effectiveness than lidocaine [4,5] and selective action on different neuronal fibers. However, RS(±) bupivacaine is 6-to 10-fold more cardiotoxic than lidocaine [6][7][8], and dextro R(+) bupivacaine is associated with greater negative chronotropism and more cardiac arrhythmias than the levo S(−) isomer [9][10][11]. This cardiotoxic consequence has been explored in pediatric patients for several decades with controversial results.…”

Section: Introductionmentioning

confidence: 99%

Influence of age on bupivacaine cardiac arrhythmogenic effects

Kiuchi¹,

Zapata‐Sudo²,

Trachez³

et al. 2017

Cardiovasc Disord Med

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The cardiotoxic effects of bupivacaine, a widely used local anesthetic, may be age-dependent because neonates and children tolerate a higher plasma concentration of bupivacaine after intravenous administration than adults. No studies have compared the toxicity profiles of the bupivacaine isomers in human neonates and children, but differences in the lethal dose have been observed between adult and younger rats. Here, we determined the age dependency of cardiac toxicity induced by racemic RS(±) bupivacaine and its levo S(−) isomer in hearts obtained from 2-and 16-week-old male Wistar rats (n=30 each) using a Langendorff ex vivo assay. We found that both RS(±) and S(−) bupivacaine significantly reduced heart rate and prolonged the PR interval and QRS complex duration. The effects of both compounds were significantly greater in older rats, and RS(±) bupivacaine had a greater effect than S(−) bupivacaine. Furthermore, RS(±) bupivacaine induced significantly more severe arrhythmias in 16-week-old than in 2-week-old rats. By contrast, the same concentration of S(−) bupivacaine was associated with mild arrhythmias in both age groups. Thus, although RS(±) bupivacaine induced greater cardiotoxicity than S(−) bupivacaine, the effects of both compounds were age related, with hearts from older animals showing more signs of toxicity.

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Local Anesthetic Activity and Acute Toxicity of (±) −2-(N-Ethylpropylamino) −2′,6′-butyroxylidide, a New Long-Acting Agent

Cited by 39 publications

References 1 publication

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

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

Toxicological Assessment of Lidocaine in the Pregnant Rat

Influence of age on bupivacaine cardiac arrhythmogenic effects

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