Assessing Physostigmine Efficacy by Response Surface Modeling: A Comparison to Pyridostigmine Efficacy

Abstract

The therapeutic efficacy of atropine sulfate/pralidoxime chloride (ATR/2-PAM) treatment therapy and physostigmine (PHY) pretreatment therapy was evaluated in soman-challenged guinea pigs. Response surface analysis (RSM) of treatment efficacy indicated that the optimal ATR/2-PAM dose combination varied as a function of both the soman (GD) challenge level and the PHY pretreatment dose. Efficacy was, therefore, evaluated for varying PHY pretreatment doses in combination with the appropriate optimal ATR/2-PAM treatment (as determined by RSM for each soman challenge dose and PHY dose evaluated). The response surfaces depicting the effects (i.e., probability of survival) of ATR/2-PAM combinations at fixed levels of PHY and GD are presented, and confidence regions and point estimates for optimal ATR/2-PAM treatment combination are included. It was estimated that with optimal therapy a protective ratio (PR) of 6 can be observed. Comparisons were made between the use of PHY/ATR/2-PAM as presented here and the use of PYR/ATR/2-PAM, as discussed by Jones et al.⁽¹⁾ Both studies showed a strong positive (r ≥ 0.98) relationship between dose and the PR. However, the estimated slope parameter for PHY was significantly larger (P < 0.001) than the slope parameter for pyridostigmine (PYR). This difference in slopes may indicate different mechanisms of action for PYR and PHY.

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