EADB: an estrogenic activity database for assessing potential endocrine activity.

Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body's endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; http://www.fda.gov/ScienceResearch/BioinformaticsTools/EstrogenicActivityDatabaseEADB/default.htm) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of chemicals. As a case study, a classification model was developed using EADB for predicting ER binding of chemicals.

'Impedance matching' of data sets in biomarker research.

The goal of biomarker research in drug development is to identify better ways of monitoring the effects of drugs on biological systems. Biomarker data are used to support decision making at various stages in the drug development process, and are also used to provide information on how drug use might be optimized in different patient populations. The evaluation and qualification of new safety biomarkers includes a rigorous analysis of the ability of a given biomarker to report specific pathological events at the cellular, tissue or systemic level. This evaluation often relies on the mapping of a continuous data set (eg, biomarker levels) onto discrete phenotypic descriptors (eg, pathology scores). The approach has been applied successfully to discover new and improved biomarkers of tissue injury, but may involve uncertainty when used to evaluate the ability of a biomarker to detect early events or events occurring near the threshold of drug action. Alternative approaches based on study endpoints that provide continuous descriptions of a disease state or drug action, coupled with measurements of changes in biological function, may provide a better 'impedance match' between input and output data in biomarker research, and improve the early assessment and prediction of drug safety issues.

Reassessing the validity of surrogate markers of drug efficacy in the treatment of coronary artery disease.

Surrogate markers of disease progression and drug efficacy have become an essential part of cardiovascular drug development. Some surrogate markers, such as LDL-cholesterol (LDL-C), have been studied extensively and are widely accepted as valid indicators of cardiovascular risk and as a basis for regulatory approval. Other markers, such as carotid intima-media thickness (IMT), can provide insights into coronary atherosclerosis, but their utility as surrogate endpoints remains uncertain. The ENHANCE clinical trial, which demonstrated robust, beneficial changes in LDL-C and other biochemical surrogate markers, but no reduction in carotid IMT, has highlighted the need to understand the use and contextual limitations of surrogate markers in guiding cardiovascular drug development and medical decision-making.

What happens when cardiac Na channels lose their function? 1--numerical studies of the vulnerable period in tissue expressing mutant channels.

OBJECTIVE: The vulnerable period (VP) defines an interval during which premature impulses can trigger reentrant arrhythmias leading to ventricular fibrillation and sudden death. The mechanistic basis of the success or failure of impulse propagation during the VP remains unclear. Recent clinical reports of gene mutations, drugs and cardiac disease link a variety of often lethal conditions with loss of cardiac Na channel function (NaLOF) and reentrant proarrhythmia. We hypothesized that during the VP, the Na conductance at the stimulus site is graded and that NaLOF would favor reentry specifically by flattening this gradient, which would destabilize antegrade front formation. METHODS: Using numerical studies of propagation in a one-dimensional cable of ventricular cells, we identified the boundaries of the VP using paired (s1-s2) stimulation. We explored VP alterations associated with different NaLOF scenarios including reduced channel density, accelerated rate of inactivation, and prolonged recovery from inactivation. RESULTS: Following the passage of a wave over the s2 site, a gradient in the restoration of Na channel conductance was demonstrated to exist during the VP. The VP boundaries coincided with different thresholds for stable retrograde and antegrade impulse propagation. Reducing channel density, accelerating inactivation and slowing the recovery from inactivation flattened the restoration gradient and extended the VP. VP extension was directly proportional to the time constant of Na channel recovery. CONCLUSIONS: Mutations that accelerate inactivation, slow recovery from inactivation, or reduce Na channel density flatten the restoration gradient within the VP which prolongs the VP and increases the probability that a premature impulse will initiate reentry. These studies define a new mechanism that links alterations in Na channel function with conditions that enable premature excitation to generate proarrhythmia and sudden death.