Comparison of hydroxylamine, 4-dimethylaminophenol and nitrite protection against cyanide poisoning in mice

Intraperitoneal doses of 4-dimethylaminophenol hydrochloride (DMAP), hydroxylamine hydrochloride (H₂NOH) and sodium nitrite (NaNO₂) were found where each converted a maximum of about 37% of the total circulating hemoglobin in mice to methemoglobin. Those doses in mmol/kg were: 0.29 for DMAP, 1.1 for H₂NOH, and 1.1 for NaNO₂. For DMAP and H₂NOH the peak was sharp and at about 7 min after injection whereas for NaNO₂ the peak was much broader and at about 40 min. The i.p. LD₅₀'s in mmol/kg were: 0.48 for DMAP, 1.8 for H₂NOH and 2.3 for NaNO₂. When mice pretreated with each of the methemoglobin-generating agents were challenged with sodium cyanide, the ratios of the LD₅₀'s in protected mice to those in control mice (protection index, PI) were 1.5 for H₂NOH, 2.0 for DMAP and 3.1 for NaNO₂. When sodium thiosulfate was also given in combination with each of the three methemoglobin-generating agents, the protective effect was at least additive. The PI against sodium sulfide was also significantly greater in mice pretreated with NaNO₂ than in mice given H₂NOH. Methemoglobins generated from human and mouse hemoglobins by either NaNO₂ or by H₂NOH had identical binding affinities (dissociation constants) for cyanide. When human red cells containing methemoglobin generated by exposure to either NaNO₂ or H₂NOH were injected into the peritoneal cavity of mice and then followed by cyanide challenges, there was no difference in the PI for the two kinds of methemoglobin. Not only was the PI the same in each case with human cells, but it was also identical with that in mice given NaNO₂ systemically to generate the same total amount of methemoglobin. The difference in PI between NaNO₂ and H₂NOH (or DMAP) in mice appears to be related to the high rate of methemoglobin reductase activity in mouse RBC. It appears likely that cyanmethemoglobin is a substrate for mouse methemoglobin reductase activity, and that NaNO₂ is an inhibitor of mouse methemoglobin reductase. No differences in cyanide antagonism between NaNO₂ and H₂NOH would be anticipated in humans because of the slow rates of methemoglobin reduction in human red cells.     

DMAP注射液对犬氢氰酸吸入中毒的急救效果及其评价

测定了犬氢氰酸(HCN)吸入中毒的毒性。中毒条件:HCN浓度1103.80±48.32γ/L,暴露时间4.55±2.04min,观察时间24h。LD_50、sLD_50及LD_99分别为844.31、172.39及959.18γ/kg。 对室温下保存一年的两种DMAP注射液进行了抗氰效果观察。HCN浓度1068.64±42.04γ/L,吸入1min后,一次肌注10％DMAP注射液(3.25mg/kg)。注入后继续中毒,动物最终接受毒剂量3449.18±116.33γ/kg(≈4.08×LD_50)。11只犬全部活存。效果非常显著,P<0.01。 4.11×LD_50HCN吸入中毒,待动物呼吸停止,一次静注10％DMAP注射液,剂量同上,获得了同样的急救效果(6只犬活存5只,第6只犬因药液未及时输入而不计)。 中毒症状和体征随血氰浓度升高而加重,吸入至死时,全血氰浓度为110±26.6γ/100ml。 DMAP注射液能迅速将组织中与细胞色素氧化酶结合的氰转移至血液中。用药后第二阶段(中毒后10～20min)及第三阶段(终止中毒后30min)的血氰含量比第一阶段(中毒后2～4min)分别提高4.6和8.3倍。