ABSTRACT
The binding affinity and kinetics of target engagement are fundamental to establishing structure-activity relationships (SARs) for prospective therapeutic agents. Enhancing these binding parameters for operative targets, while minimizing binding to off-target sites, can translate to improved drug efficacy and a widened therapeutic window. Compound activity is typically assessed through modulation of an observed phenotype in cultured cells. Quantifying the corresponding binding properties under common cellular conditions can provide more meaningful interpretation of the cellular SAR analysis. Consequently, methods for assessing drug binding in living cells have advanced and are now integral to medicinal chemistry workflows. In this review, we survey key technological advancements that support quantitative assessments of target occupancy in cultured cells, emphasizing generalizable methodologies able to deliver analytical precision that heretofore required reductionist biochemical approaches.
Subject(s)
Chemistry, Pharmaceutical/methods , Fluorescent Dyes/chemistry , High-Throughput Screening Assays , Molecular Probe Techniques , Molecular Targeted Therapy/methods , Bioluminescence Resonance Energy Transfer Techniques , Cell Survival/drug effects , Cells, Cultured , Genes, Reporter , Humans , Kinetics , Optical Imaging/methods , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Structure-Activity RelationshipABSTRACT
Cardiovascular disease represents the single largest cause of premature career termination for airline pilots--an entity approximately equal to all other medical causes combined. It is obviously essential to assess risk factors for the development of cardiovascular disease among airline pilots. For that reason, we obtained lipid levels for 14,448 pilot applicants examined during the period from March 1984 through December 1988. Blood lipid levels are well-documented predictors for future cardiovascular diseases. We determined total cholesterol values, high density lipoprotein (HDL) levels, and the cholesterol/HDL ratio for these lipids for our applicant population. We present these data in tabular and graphic form. They suggest a cessation of any increase in blood lipid levels during the fifth decade of life. While the cause is not obvious, there are a number of factors which may play a role in this finding.
Subject(s)
Aerospace Medicine/statistics & numerical data , Cholesterol/blood , Lipoproteins, HDL/blood , Adult , Cardiovascular Diseases/etiology , Humans , Male , Middle Aged , Risk FactorsABSTRACT
In December, 1989, the Department of Transportation (DOT) in conjunction with the Federal Aviation Administration (FAA) mandated an extensive urine drug testing program for selected positions within the airline industry. At the end of 1 year we have tested 7,872 applicants under these rules, with a positive finding rate of 0.17%. We have also tested 32,157 applicants, including those applying for DOT-covered positions, with a positive rate of 2.82%. Considering only the two major drugs of abuse--marijuana and cocaine--we found the positive rate to be an order of magnitude greater than the rate discovered under the DOT program. We present these data together with a discussion of some of the possible reasons for this major disparity. We also present findings for barbiturates and benzodiazepines which are not tested under the DOT program, but which have safety implications related to the aviation industry.
