TITLE

Predicting Low Dose Effects for Chemicals in High Through-Put Studies

AUTHOR(S)
Stanek, Edward J.; Calabrese, Edward J.
PUB. DATE
July 2010
SOURCE
Dose-Response;2010, Vol. 8 Issue 3, p301
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
High through-put studies commonly use automated systems with 96-well plates in which multiple chemicals are tested at multiple doses using log-2 dose increments after a suitable incubation period. There are typically multiple (ranging from five to eleven) doses on each chemical, and occasionally plate replications of the dose-response studies. The target endpoint for such studies is typically the LC50, but for some chemicals, there may be multiple doses below a benchmark dose where there is no apparent adverse response relative to control response. We show how an estimation approach can lead to clearly interpretable results about response in the low dose region using data from a high throughput study of 2189 chemicals on yeast. Accurate estimates can be obtained of response for study chemicals by using best linear unbiased predictors (BLUPs) in a mixed model, and summarized via plots with expected response (assuming no low-dose effect) with confidence intervals for response below the benchmark dose for each chemical, providing an informative summary of response at low doses. We conclude that this approach can provide valuable insights that would be missed if the observational data were only considered through the lens of statistical methods appropriate for experimental studies.
ACCESSION #
59192582

 

Related Articles

  • No regional difference in cisatracurium dose–response and time-course-of-action between patients in China and Bosnia. Dahaba, A. A.; Suljevic, I.; Bornemann, H.; Wu, X.-M.; Metzler, H. // BJA: The British Journal of Anaesthesia;Mar2011, Vol. 106 Issue 3, p331 

    Background Variability in drug response could result from a variety of genetic and environmental factors that are often hard to define or quantify. A number of studies demonstrated regional geographic variations in potency of neuromuscular blocking agents (NMBAs). The aim of our study was to...

  • Computational Chemistry as an Integral Component of Lead Generation. Roche, Olivier; Guba, Wolfgang // Mini Reviews in Medicinal Chemistry;Jul2005, Vol. 5 Issue 7, p677 

    From library shaping to ADME-Tox prediction via virtual screening, computational chemistry is an integral component of Lead Generation. It provides a series of tools that help focusing on compounds with a balanced pharmacodynamic and ADME-Tox profile together with a high potential to optimize...

  • Building a Tiered Approach to In Vitro Predictive Toxicity Screening: A Focus on Assays with In Vivo Relevance. McKim Jr., James M. // Combinatorial Chemistry & High Throughput Screening;Feb2010, Vol. 13 Issue 2, p188 

    One of the greatest challenges facing the pharmaceutical industry today is the failure of promising new drug candidates due to unanticipated adverse effects discovered during preclinical animal safety studies and clinical trials. Late stage attrition increases the time required to bring a new...

  • Comparative Analysis of Machine Learning Methods in Ligand-Based Virtual Screening of Large Compound Libraries. Xiao H. Ma; Jia Jia; Feng Zhu; Ying Xue; Ze R. Li; Yu Z. Chen // Combinatorial Chemistry & High Throughput Screening;May2009, Vol. 12 Issue 4, p344 

    Machine learning methods have been explored as ligand-based virtual screening tools for facilitating drug lead discovery. These methods predict compounds of specific pharmacodynamic, pharmacokinetic or toxicological properties based on their structure-derived structural and physicochemical...

  • What's wrong with drug screening today. Nolan, Garry P. // Nature Chemical Biology;Apr2007, Vol. 3 Issue 4, p187 

    The author focuses on the fundamental revamping of how drug screening is conducted and how drugs are analyzed during preclinical and early clinical development. An overview of the standard assay systems for drug screening as a source of discouragement and dead ends during development and...

  • Modeling Success in PK/PD Testing. Kamath, Lakshmi // Drug Discovery & Development;Feb2006, Vol. 9 Issue 2, p26 

    The article features the development of drugs and the cost it takes to be approved by the experts in the U.S. It takes millions of dollars just to introduce a single product in the market while on the other hand only a number of candidate drugs have passed in the screening. Less than 10 percent...

  • High-throughput Evaluation of Lipophilicity and Acidity by New Gradient HPLC Methods. Markuszewski, Michal Jan; Wiczling, Pawel; Kaliszan, Roman // Combinatorial Chemistry & High Throughput Screening;Jun2004, Vol. 7 Issue 4, p281 

    There is a need for fast testing of drug candidates for properties of pharmacokinetics and pharmacodynamics importance, in particular lipophilicity and acidity. These two parameters can conveniently be estimated by gradient reversed-phase HPLC. Appropriate conventional organic solvent gradient...

  • In vitro microscale systems for systematic drug toxicity study. Jong Sung // Bioprocess & Biosystems Engineering;Jan2010, Vol. 33 Issue 1, p5 

    Abstract  After administration, drugs go through a complex, dynamic process of absorption, distribution, metabolism and excretion. The resulting time-dependent concentration, termed pharmacokinetics (PK), is critical to the pharmacological response from patients. An in vitro...

  • 5--Aminosalicylic Acid Enemas in Refractory Distal Ulcerative Colitis: Long--Term Results. Guarino, Julius; Chatzinoff, Martin; Berk, Theodore; Friedman, Lawrence S. // American Journal of Gastroenterology;Aug1987, Vol. 82 Issue 8, p732 

    In this trial, we examined the role of 4-g 5-aminosalicylic acid (5-ASA) enema in the long-term management of patients with previously refractory distal ulcerative colitis. Of 20 such patients treated with nightly 5-ASA enemas, 16 improved symptomatically, with 15 achieving clinical remission...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics