Application of Response Surface Methodologies for Determining Optimum Treatment Strategies for Nerve Threat Agents

摘要

The use of atropine and pralidoxime chloride (2-PAM) in combination is the current basis for treatment against nerve threat agent exposure. The objectives of this contract are to optimize pretreatment/treatment strategies and to evaluate biological endpoints (including lethality and behavior) following exposure to several nerve threat agents. Mathematical and statistical procedures utilizing regression techniques allow the estimation of optimum treatment regimens and corresponding confidence regions. The qualitative and quantitative natures of these drug-drug interactions are mathematically derived and statistically evaluated. After these parameters are estimated, predictive interpolation within each experimental region yields optimal treatment levels. Experimental validation of this approach with data sets analyzed in this initial year suggests that therapeutic synergism occurs in the dose-response relationship of ATR/2-PAM at increasing levels of GD and GA and that non-linear models determine combinations of PHY and PYR that effectively predict percent inhibition instead of simply survival. Also, these methodologies have been employed to permit a more efficient use of experimental subjects, ultimately reducing the number of test animals required. This application of response surface methods should provide a significant advantage in developing clinical strategies against nerve threat agents. (AW)