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 intratrachealhntranasal) 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). Pigtailed 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 2 4.0% (mean * SD), with peak MHb levels reached at 30 min. The monkeys given the high dose of BNZ (n = 8) demonstrated higher peak MHb levels ( P C 0.05) than the lower dose of BNZ: 14.7 +. 6.5% (mean 2 SD) as the time to peak increased to 45 min. Slight increases in SHb levels (0.024.04 mm I-' rise) measured (P C 0.05) after low and high BNZ doses were 54% and 75% higher than baseline SHb levels after LC. This study indicates that benzocaine applied topically in non-human primates can readily increase MHb concentrations within 30 min to clinically relevant levels required for cyanide prophylaxis, but LC does not. The variability in the peak Hb levels after BNZ is likely to be due to the variability in absorption andor metabolism of the drug. In addition, the slight increase in SHb seen in BNZ groups should prompt investigators to also evaluate this toxic Hb component when evaluating MHb-forming drugs.
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