Topical anesthetic‐induced methemoglobinemia and sulfhemoglobinemia in macaques: A comparison of benzocaine and lidocaine

Abstract

Benzocaine (BNZ) and lidocaine (LC) are commonly used topical (spray) anesthetics approved for use in humans. Benzocaine has structural similarities to methemoglobin (MHb)-forming drugs that are current candidates for cyanide prophylaxis, while LC has been reported to increase MHb in man. In this study, we compared MHb and sulfhemoglobin (SHb) production in three groups of Macaques (Chinese rhesus and Indian rhesus (Macaca mulatta) and pig-tailed macaques (Macaca nemestrina)) after exposure to BNZ and LC. Formation of SHb, unlike MHb, is not thought to be reversible and therefore is considered to be of greater toxic significance. Both MHb and SHb levels were measured periodically on a CO-Oximeter. All rhesus macaques (n = 8) were administered an intratracheal/intranasal) dose of 56 mg (low dose) or 280 mg (high dose) of BNZ or 40 mg of LC in a randomized cross-over design (all animals received all three treatments). Pig-tailed macaques (n = 6) were given an intranasal dose of 56 mg of BNZ and 40 mg of LC. As no differences in the peak MHb or time to peak (mean +/- SD) were observed among the three macaque subspecies, the data were pooled. Lidocaine did not cause MHb or SHb formation above baseline in any monkey. In contrast, all monkeys (n = 14) had a significant elevation in peak MHb formation after 56 mg of BNZ, which ranged from 4.0% to 19.4% with an average of 8.6 +/- 4.0% (mean +/- SD), with peak MHb levels reached at 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Physico-chemical characterization of benzocaine-β-cyclodextrin inclusion complexes

“…BZC has a chemical resemblance to the ethyl ether p-amine-propyophenone (PAPP), which induces hemoglobin oxidation [6]. The literature reports increased Met-hemoglobin (Met-Hb) levels induced by BZC in different species [6][7][8][9][10][11].…”

Two cases of methemoglobinemia following zopiclone ingestion

“…Our patients ingested 750 mg and 1100 to 1500 mg. Zopiclone may overwhelm the body's reducing capacity when taken in large overdose. Oxidizer-induced methemoglobinemia has been demonstrated to be dose-related in monkey and man (5,8,9). However, based on studies in phenotypically similar sheep (10), there may be great individual variability.…”

Toxicity in rhesus monkeys following administration of the 8-aminoquinoline 8-[(4-amino-l-methylbutyl)amino]-5-(l-hexyloxy)-6-methoxy-4-methylquinoline (WR242511)

“…WR242511 produced little or no elevation of MHb levels in rhesus monkeys, a species previously shown to respond to a variety of other MHb formers [10,13,[19][20][21]. Furthermore, toxicity was observed in the WR242511-exposed rhesus monkeys, ranging from hemoglobinuria (at both 3.5 and 7.0 mg/kg) and myoglobinuria (at 7.0 mg/kg) to liver, lung, and kidney damage, with death resulting in the most severely affected animals.…”

“…The rhesus monkey was also the model of choice in an extensive US Army post-WWII-era evaluation of novel antimalarials, including numerous 4-and 8-aminoquinolines (not including WR242511, which had not yet been synthesized) [17,18]. The rhesus monkey has also shown consistent MHb elevation following exposure to benzocaine as well as the 8-aminoquinoline pamaquine [17,19]. Finally, in a related recent preliminary experiment conducted in this laboratory, 5 of the rhesus monkeys reported currently demonstrated consistent MHb formation following the administration of the prototypical MHb former NaNO 2 [20,21].…”