Jones D E, Carter W H, Carchman R A
Fundam Appl Toxicol. 1985 Dec;5(6 Pt 2):S242-51. doi: 10.1016/0272-0590(85)90134-4.
The therapeutic efficacy of atropine sulfate/pralidoxime chloride (ATR/2-PAM) treatment (im) therapy, and pyridostigmine bromide (PYR) pretreatment (oral) therapy were evaluated in soman-challenged guinea pigs. ATR/2-PAM efficacy was assessed as protective ratio (PR = treated soman LD50/control soman LD50); PYR efficacy was assessed both as PR and by response surface modeling (RSM) techniques. The optimal ATR/2-PAM treatment gave a PR of 3.78. PYR pretreatment (1 hr) produced a dose(log)-dependent (r = 0.96) inhibition of whole blood AChE and afforded significant (p less than 0.05) increases in PR (with doses greater than 0.12 mg/kg PYR) against soman when followed by 64 mg/kg ATR/100 mg/kg 2-PAM treatment. These PRs, however, were poorly correlated (r = 0.45) with the corresponding level of PYR-induced AChE inhibition. In contrast, RSM analysis of efficacy indicated that the optimal ATR/2-PAM dose combination varied as a function of both the soman-challenge level and the PYR pretreatment dose. Efficacy was therefore evaluated for varying PYR pretreatment doses in combination with the appropriate optimal ATR/2-PAM treatment (as determined by RSM for each soman challenge dose and PYR dose evaluated). When assessed in this manner, PYR efficacy (PYR) was found to be highly correlated (r = 0.97) with PYR-induced AChE inhibition. Since percentage of AChE inhibition was directly correlated with PYR dose (log), these results indicate that PYR pretreatment efficacy is a highly correlated, dose-dependent phenomenon, providing ATR/2-PAM treatment is optimized.
在经梭曼攻击的豚鼠中评估了硫酸阿托品/氯解磷定（ATR/2-PAM）治疗（肌内注射）疗法以及溴吡斯的明（PYR）预处理（口服）疗法的疗效。ATR/2-PAM的疗效通过保护率来评估（PR = 经治疗的梭曼半数致死量/对照梭曼半数致死量）；PYR的疗效通过保护率以及响应面建模（RSM）技术来评估。最佳的ATR/2-PAM治疗的保护率为3.78。PYR预处理（1小时）对全血乙酰胆碱酯酶产生剂量（对数）依赖性抑制（r = 0.96），并且在随后给予64 mg/kg ATR/100 mg/kg 2-PAM治疗时，对于梭曼产生显著（p < 0.05）的保护率增加（当PYR剂量大于0.12 mg/kg时）。然而，这些保护率与相应的PYR诱导的乙酰胆碱酯酶抑制水平相关性较差（r = 0.45）。相比之下，疗效的RSM分析表明，最佳的ATR/2-PAM剂量组合随梭曼攻击水平和PYR预处理剂量而变化。因此，针对不同的PYR预处理剂量与适当的最佳ATR/2-PAM治疗（由针对每个评估的梭曼攻击剂量和PYR剂量的RSM确定）相结合来评估疗效。当以这种方式评估时，发现PYR疗效（PYR）与PYR诱导的乙酰胆碱酯酶抑制高度相关（r = 0.97）。由于乙酰胆碱酯酶抑制百分比与PYR剂量（对数）直接相关，这些结果表明，在优化ATR/2-PAM治疗的情况下，PYR预处理疗效是一种高度相关的剂量依赖性现象。
