Assessing pyridostigmine efficacy by response surface modeling

Abstract

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.