Simulating the influence of plasma protein on measured receptor affinity in biochemical assays reveals the utility of Schild analysis for estimating compound affinity for plasma proteins.

BACKGROUND AND PURPOSE: Plasma protein binding (PPB) influences the free fraction of drug available to bind to its target and is therefore an important consideration in drug discovery. While traditional methods for assessing PPB (e.g. rapid equilibrium dialysis) are suitable for comparing compounds with relatively weak PPB, they are not able to accurately discriminate between highly bound compounds (typically >99.5%). The aim of the present work was to use mathematical modelling to explore the potential utility of receptor binding and cellular functional assays to estimate the affinity of compounds for plasma proteins. Plasma proteins are routinely added to in vitro assays, so a secondary goal was to investigate the effect of plasma proteins on observed ligand-receptor interactions. EXPERIMENTAL APPROACH: Using the principle of conservation of mass and the law of mass action, a cubic equation was derived describing the ligand-receptor complex [LR] in the presence of plasma protein at equilibrium. KEY RESULTS: The model demonstrates the profound influence of PPB on in vitro assays and identifies the utility of Schild analysis, which is usually applied to determine receptor-antagonist affinities, for calculating affinity at plasma proteins (termed KP ). We have also extended this analysis to functional effects using operational modelling and demonstrate that these approaches can also be applied to cell-based assay systems. CONCLUSIONS AND IMPLICATIONS: These mathematical models can potentially be used in conjunction with experimental data to estimate drug-plasma protein affinities in the earliest phases of drug discovery programmes.

Projecting future drug expenditures--1992.

The effects of inflation, generic competition, and the introduction of new drug entities on future drug expenditures are discussed. The impact of inflation can be predicted by analyzing trends in historical data and determining factors that may affect drug use. Useful sources include U.S. Bureau of Labor Statistics Producer Price Index figures for pharmaceuticals, commercially available data on drug product pricing, and market basket indices compiled by the Health Care Financing Administration (HCFA) and the American Hospital Association. HCFA predicts that quarterly increases in pharmaceutical prices in 1992-93 will range from 6.4% to 8.1%. Pharmaceutical industry analysts predict overall annual inflation rates for pharmaceuticals in 1991-92 ranging from 8% to 10%. To evaluate generic competition, information on the expiration of patents and market exclusivity can be used. Decreases of 30-70% in the list price of a drug product can be expected after the introduction of a generic product, and the price usually stabilizes at approximately 50% of the list price of the innovator product at the time the first generic product was marketed. Predicting when new drug entities will be introduced is difficult; analysts say the usual time from filing of a new drug application to FDA approval is two years. The FDA says approval usually follows within a few weeks after an advisory panel's recommendation for approval, and marketing can be expected within a few months after final FDA approval. Assumptions about future drug expenditures should take into account historical and predicted rates of inflation, the status of generic competition for existing products, and the prospects for introduction of new drug entities.(ABSTRACT TRUNCATED AT 250 WORDS)

Using evaluation techniques to select health education programs.

Health educators often are faced with the job of selecting a new program to meet particular objectives. When one or more options is available, the selection process may involve the application of rather sophisticated evaluation skills whether or not the health educator is aware of the fact. By consciously applying evaluation techniques, health educators can increase the likelihood that a new program will meet their needs. The article provides guidelines for choosing an effective program by posing questions that normally are raised at the end of a program during the summative evaluation but are equally relevant at its beginning during the program selection stage. Seeking the answers to these questions before a program is implemented can contribute much toward ensuring the desired outcomes will be achieved.