| Abstract: |
The conventional bottom-to-up approach of R&D is usually from aims to design, to experimental findings, to fitting empirical curves, formula, or model, to statistical analysis, to drawing conclusion/hypothesis. The alternative nonconventional, top-to-down approach is the mathematical system analysis to derive the unified general pharmacodynamics theory/equation/algorithm (PD) based on mass-action law (MAL) for automated computer simulation. Thus, the approach allows using small number of dose-data-points to fit the unified MAL-PD theory/algorithm, for the efficient, cost-effective automated computer simulation to achieve quantitative/digital/indexed conclusions. The MAL-PD indicates: (I) The median-effect eq. (MEE)"dose-effect dynamics" defines PD-parameters: Dm (median-effect-dose) for potency, and mvalue for the dynamic-order signifying the shape of dose-effect curve (DEC), where m=1, >1 and <1 indicate hyperbolic, sigmoidal and flat sigmoidal, respectively, and (II)Computer simulation of combination index eq. (CIE) with Fa-CI plot, allow the quantification of Synergism (CI<1), Additive effect (CI=1) and Antagonism (CI>1) at different effect levels. The advantages of MAL-PD approach are: (A)In animal studies or clinical trials rarely tolerated over 3 (or more) "dose-data points" with acceptable dose-rage and dose density; (B)MAL theory/algorithm allows the samegeneral MAL-principle to bridge between the basic in vitro/animal studies and the clinical trials; (C)The MEE with its plot (MEP), linearizes DECs into straight lines, and thereby MEP leads to the "Two Dose-Data-Points Minimum Theory", where the 3rd point is dose zero, and the 4th dose-point is Dm, which is the universal reference-point and dynamic-order common-link; (D)Since all terms of the MEE and CIE of the MAL-PD equations are "dimensionless ratio", therefore, MAL-PD/CI is generally valid/applicable in R&D, regardless of nature of the effectors (e.g., drugs, biologicals, radiation, UV, pH) or units (e.g., ug, nM, IU, Rad, Gy, ug/ml, mg/kg. mg/M2 ), or mechanisms of action (competitive, noncompetitive, uncompetitive, sequential, ordered, ping-pong, or random); and regardless of in vitro, in animals, or in clinical trials. In conclusion, the MAL-PD/CI theory serves as the general largest-common-denominator forsimplifying the complexity and diversity of biological systems, forbiomedical R&D, and for drug evaluations, with automated simulations. Specific examples for real data analysis/simulation in vitro, and in animals will be illustrated for single drugs, and their combinations, for anticancer and antiviral studies. © FASEB. |
