bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methods for the Design and Analysis of Replicate‐Experiment Studies to Establish Assay Reproducibility and the Equivalence of Two Potency Assays
Authors: Eastwood Brian J. , Chesterfield Amy K. , Wolff Mary C. , Felder Christian C. 
Published: March 2010

AbstractStatistical parameters estimated in validation studies to establish the reliability of single‐concentration assays, such as the Signal Window and Z'‐Factor, are well established. These statistics do not ensure that potency estimates from concentration–response assays will be sufficiently reliable for structure–activity relationship use. The minimum significant ratio (MSR) was proposed as a statistical parameter to estimate the precision of potency estimates from concentration–response assays. This article focuses on the statistical models describing the data generated from biochemical concentration–response assays and the statistical properties of the outcomes.
GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders
Authors: Madsen Ulf , Bräuner‐Osborne Hans , Greenwood Jeremy R. , Johansen Tommy N. , Krogsgaard‐Larsen Povl , Liljefors Tommy , Nielsen Mogens , Frølund Bente 
Published: March 2010

AbstractThe complex functions of the mammalian central nervous system (CNS) are primarily determined by (S)‐glutamic acid (Glu) and 4‐aminobutyric acid (GABA), which hyperpolarizes neurons via multiple receptor subtypes. Glu can act as a neurotoxin and cause injury to neurons in neurological disorders, including reversal of Glu transporters. This article discusses functionality of GABA and glutamate receptor ligands, including their therapeutic potentials in CNS disorders.
Strategies in the Design of Antiviral Drugs
Authors: De Clercq Erik , Herdewijn Piet 
Published: March 2010

AbstractEffective vaccines have led to the eradication of important viral pathogens such as smallpox, polio, measles, mumps, and rubella. The strategies for interfering with the key events in the viral replicative cycle have the potential to target virtually all important human viral pathogens. This article focuses on approaches targeted at specific processes in viral infection, including virus adsorption, virus‐cell fusion, viral DNA or RNA synthesis, and viral enzymes.
Protein Kinase Inhibitors in Drug Discovery
Authors: Parang Keykavous , Sun Gongqin 
Published: March 2010

AbstractProtein kinases (PKs) have essential roles in cell‐signaling pathways by interacting with extracellular ligands such as growth factors and hormones and transmitting signals across the cell membrane to the cytoplasm and the nucleus. It is important to understand the mechanistic features of the particular target kinase when designing protein kinase inhibitors (PKIs). This chapter focuses on inhibitors directed against critical molecular targets that are approved or are in clinical trials.
RNA
‐Based Therapies
Authors: Pascolo Steve 
Published: March 2010

Abstract
Most diseases with unmet medical needs can be addressed by one or several therapies based on RNA. Cancer‐related diseases, for example, may be treated by one or a combination of RNA therapies. Similarly, the spread of infectious diseases such as AIDS or malaria may be prevented or treated with RNA‐based therapeutics. This article discusses potential therapeutic features of RNA, including aptamers, specific control of tumor growth or virus infections, adjuvant formulations, and a protein‐encoding feature used for gene therapy and vaccination.
Novel Imaging Agents for MolecularMRImaging of Cancer
Authors: Artemov Dmitri , Bhujwalla Zaver M. 
Published: March 2010

AbstractThe response of solid tumors to therapy is traditionally measured by changes in tumor volume over the course of treatment. Because of its high spatial resolution and contrast in soft tissues, magnetic resonance imaging (MRI) provides an informative noninvasive approach to measuring tumor volumes.
Modeling and Informatics in Drug Design
Authors: Bharatam Prasad V. , Khanna Smriti , Francis Sandrea M. 
Published: March 2010

AbstractModeling and informatics have become indispensable components of rational drug design. Modeling in drug design has two facets: modeling on the basis of knowledge of the drugs/leads/ligands and modeling based on the structure of macromolecules. This article focuses on various molecular modeling methods, including computational chemistry, computational biology, computational medicinal chemistry, and pharmacoinformatics.
Computer Techniques: Identifying Similarities Between Small Molecules
Authors: Meek Peter , Moyna Guillermo , Zauhar Randy 
Published: March 2010

AbstractDefining similarity between molecules is a complex task. There is a vast expanse ofin silicotechniques that “detect” similarity between small molecules.In silicosearch techniques prove most useful when the similarity measurement (scoring index) reliably returns molecules with the same desired characteristics as the query. This article focuses on current computational methodologies available for the comparison of structurally similar compounds.
Chemical and Physical Characterizations of Potential New Chemical Entity
Authors: Adeniji Adegoke , Adejare Adeboye 
Published: March 2010

Abstract
Elucidation of the chemical and physical properties of a potential new chemical entity (NCE) is critical to drug discovery efforts as part of “pharmaceutical profiling.” Knowledge of these properties could give insight into how the compound acts or binds to the target receptor to elicit desired or undesired effects and also help with formulation studies. This article focuses on most common chemical and physical characterization methods for a novel potential NCE.
Permeability Assessment
Authors: Ganta Srinivas , Sharma Puneet , Garg Sanjay 
Published: March 2010

AbstractDrug permeability is considered an important parameter in drug discovery and lead optimization. It is essential to have reliable methods of predicting thein vivopermeability by thoughtful use ofin vitropermeability models. This article focuses on careful review and selection of appropriate methods for permeation study of a new molecule.
Salt and Cocrystal Form Selection
Authors: Newman Ann W. , Childs Scott L. , Cowans Brett A. 
Published: March 2010

AbstractForm selection is critical to the successful development of an active pharmaceutical ingredient (API). Form selection improves properties, such as solubility and ultimately bioavailability, and increase the potential viability of a candidate. This article discusses solid form screening and the selection process for pharmaceutical compounds with the main focus on salts and cocrystals.
In VitroMetabolism in Preclinical Drug Development
Authors: Pelkonen Olavi , Tolonen Ari , Turpeinen Miia , Uusitalo Jouko 
Published: March 2010

AbstractMetabolism is a major determinant governing both pharmacokinetics and clinical response of the majority of drugs and a great deal of effort is now directed at assessing key metabolic parameters in the early stages of drug development. Severalin vitromethods are now available for determination of metabolic features, yielding data that predictin vivobehavior of the studied drug molecules. This article focuses onin vitrometabolism in preclinical drug development.
In VitroEvaluation of Metabolic Drug–Drug Interactions: Scientific Concepts and Practical Considerations
Authors: Li Albert P. 
Published: March 2010

AbstractSerious drug–drug interactions have led to the necessity of a drug manufacturer to withdraw or limit the use of marketed drugs. Screening for drug–drug interaction in early phases of drug development allows the avoidance of the development of drug candidates with high potential for adverse drug interactions. This article focuses on the scientific principles, technologies, and experimental approaches for the preclinical evaluation of drug–drug interactions.
Interrelationship between Pharmacokinetics and Metabolism
Authors: Paxton James W. 
Published: March 2010

AbstractIn drug development, approximately 40% of all new chemical entities (NCEs) fail to become clinically successful drugs due to undesirable pharmacokinetic properties. A knowledge of the capacity for the metabolism of an NCE and an understanding of the human metabolism pathways and the enzymes involved have now become key components in the selection of compounds for clinical development. This article examines the relationship between metabolism and the resulting pharmacokinetic profile of a drug, and reviews the major factors that may have an impact on a drug's metabolism and may have a detrimental effect on its pharmacokinetics and clinical use.
Preclinical Drug Development Planning
Authors: Bhogal Nirmala , Combes Robert , Balls Michael 
Published: March 2010

AbstractProductivity in drug development has been disappointing over the last decade, due to lack of efficacy and/or unexpected adverse reactions. This high attrition rate can be dramatically reduced by improving the preclinical testing process, by taking account of multidisciplinary approaches and by improving the design of preclinical projects to facilitate the collection and interpretation of relevant information from such studies, and its extrapolation to the clinical setting. This article provides an overview of the early drug discovery and development processes, includingin vitroandin silicomethods.
In Vitro
Mammalian Cell Mutation Assays
Authors: Bigger C. Anita H. , Moore Martha M. , Heflich Robert H. 
Published: March 2010

Abstract

The
in vitro
mammalian cell mutation assays used for preclinical safety testing detect forward mutations at various target genes. The most frequently used
in vitro
cell mutation assay in drug development is the Mouse Lymphoma Assay (MLA). This article discusses various aspects of regulatory guidance for the use of
in vitro
mammalian cell mutation assays and their role in genetic toxicity evaluation of pharmaceuticals.
In Vitro
Mammalian Cytogenetic Tests
Authors: Preston R. Julian 
Published: March 2010

Abstract

In vitro
cytogenic tests are undertaken in any cancer risk assessment process for exposures to environmental chemicals. Hazard identification is the first step in the cancer risk assessment process. A hazard is considered to be represented by genetic alterations assessed as gene mutations or chromosomal alterations. This article focuses on the numerical and structural induction of chromosomal alterations.
In vivoGenotoxicity Assays
Authors: Hartmann Andreas , Dobo Krista L. , Martus Hans‐Jörg 
Published: March 2010

AbstractThe assessment of a genotoxic potential of a drug candidate is typically determined through a series of tests conductedin vitroandin vivo. Genotoxicity assays provide a means to identify potential genotoxic carcinogens relatively early in the drug development process. This article provides an overview of the standardin vivocytogenetic assays that are commonly used as part of the genotoxicity test intended for hazard identification.
Irritation and Local Tissue Tolerance Studies in Pharmacetical Safety Assessment
Authors: Gad Shayne Cox 
Published: March 2010

AbstractIrritation and local tissue tolerance studies assess the short‐term hazard of pharmaceutical agents in the immediate region of their application or installation. Local tolerance effects are generally limited to irritation but may also include hematocompatability and pyrogenicity. This article discusses various factors affecting irritation responses and test outcome, including phototoxicity and parenteral irritation.
Toxicokinetics: An Integral Component of Preclinical Toxicity Studies
Authors: Singh Sonu Sundd 
Published: March 2010

AbstractThe establishment of preclinical safety data for an investigational new drug is a global regulatory requirement. Toxicokinetics has emerged as an area that is little different from pharmacokinetics. This article presents an overview of the use of toxicokinetics in various toxicity studies and discusses factors that affect the measurement and interpretation of toxicokinetic data.
Current Practices in Safety Pharmacology
Authors: Bass Alan S. , Siegl Peter K. S. , Gintant Gary A. , Murphy Dennis J. , Porsolt Roger D. 
Published: March 2010

AbstractSafety pharmacology is branch of study that attempts to understand the human risk posed by exposure to the promising new drug. The field of safety pharmacology allows for the study of new and marketed therapeutic agents aimed at identifying their pharmacodynamic properties. This article offers an overview of existing practices in safety pharmacology, including ionic current assays and repolarization (APD) assays.
Safety Assessment of Biotechnology‐derived Therapeutics
Authors: Cosenza Mary Ellen 
Published: March 2010

AbstractIn recent years, the biotechnology field has grown and is now a large part of pharmaceutical therapeutics development. The assessment of safety in the preclinical development of biologically‐derived therapeutics differs from that of traditional small molecules. This article focuses on the standard approaches to safety assessment and toxicity evaluation of biologically‐derived therapeutics and current issues in the field.
The Pharmacogenomics of Personalized Medicine
Authors: Reid Ronald E. 
Published: March 2010

AbstractThe preclinical development of genetic data for application in the pharmacogenomics of disease therapy and management has become more complex than the earlier studies had suggested. The pharmacokinetic parameters determine the eventual distribution of the drug in the body including the concentration of the drug at the site of pharmacodynamic action. This article discusses various aspects of pharmacogenomics of personalized medicine, including molecular profiling technologies.
Toxicoproteomics: Preclinical Studies
Authors: Merrick B. Alex , Bruno Maribel E. 
Published: March 2010

AbstractToxicoproteomics is the application of global protein measurement technologies to toxicology research. The wide application of proteomics has generated great interest and enthusiasm in many established scientific disciplines in basic biology and medicine, including the field of toxicology. The article discusses various aspects of toxicoproteomics in the preclinical development of drugs, including mechanistic toxicology and preclinical models of idiosyncratic toxicity.
Factors Affecting Metabolism
Authors: King Roberta S. 
Published: March 2010

AbstractInvestigation of the differences in metabolism among species, age groups, genders, polymorphic enzymes, and presence of modulators is applicable to both drug development and drug therapy. In the process of drug development, knowledge of these differences in metabolism helps to correlate pharmacokinetic (PK), toxicology, and structure‐effect studies from animal models to humans. The article discusses various physiological factors affecting drug metabolism.
Structural Modifications of Drug Candidates: How Useful Are They in Improving Metabolic Stability of New Drugs? PartI: Enhancing Metabolic Stability
Authors: Nassar Ala F. 
Published: March 2010

AbstractThe drug discovery process in the pharmaceutical industry has undergone a sea change in the last decade due to advances in molecular biology. The design of drugs with optimal potency, pharmacokinetic properties, and less toxicity is challenging given the opposing requirements for absorption and metabolism. This article discusses structural modification of drug candidates.
Structural Modifications of Drug Candidates: How Useful Are They in ImprovingPKParameters of New Drugs? PartII: Drug Design Strategies
Authors: Nassar Ala F. 
Published: March 2010

AbstractThe prodrug approach has been widely used in drug design. Prodrugs most commonly use either oxidative or reductive activation. Considering the risks and costs of new drug development, it is critical to eliminate high‐risk compounds as early as possible. The article discusses various factors related to structural modification and drug design strategies.
Enzyme Inhibition
Authors: Hollenberg Paul F. 
Published: March 2010

AbstractThe inhibition of the metabolism of one drug by another drug taken concurrently by the patient has now been shown to be a very important cause of adverse drug reactions (ADRs). The potential for drugs to interact with one another by competing for metabolism by the same drug‐metabolizing enzyme continues to be a significant health concern. The article discusses approaches for the prediction of possible drug‐drug interactions resulting from inhibition of the drug‐metabolizing enzymes.
Evaluating and Predicting Human CytochromeP450 Enzyme Induction
Authors: Sinz Michael , Kim Sean , Ferguson Stephen , LeCluyse Edward 
Published: March 2010

AbstractCytochrome P450 (CYP) isoforms are the predominate enzymes involved in the biotransformation and elimination of xenobiotics. The use of nuclear hormone receptor and hepatocyte‐based cellular assays has allowed the medical fraternity to predict and understand enzyme induction to a much greater degree than in the past. The article focuses on CYP enzyme induction, including methods to evaluate, predict, and quantitate drug interactions due to enzyme induction.
Nuclear Receptor‐Mediated Gene Regulation in Drug Metabolism
Authors: Wang Hongbing , xie wen 
Published: March 2010

AbstractIn the past decade, significant progress has been made in the understanding of the comprehensive role of nuclear receptors (NRs) in the regulation of drug‐metabolizing enzymes (DMEs) and drug transporter system. It has become clear that pregnane X receptor (PXR) and constitutive androstane receptor (CAR) can function as master xenosensors to regulate the expression of majority of the DMEs and transporters. This article focuses on recent advances in the understanding of the regulation of DMEs by nuclear receptors.
Chemical Mechanisms in Toxicology
Authors: Grillo Mark P. 
Published: March 2010

AbstractPharmaceutical scientists working in drug metabolism and toxicology today consider reactive metabolites of drugs or drug candidates an important potential toxicological issue. There is a critical demand for increased research on the mechanisms of immune‐mediated toxicities at the molecular level. This article deals with the mechanisms involved in the biotransformation of drugs to chemically reactive metabolites, current experimental techniques used to identify reactive metabolites, and the potential consequences of reactive metabolite formation.
Tissue Cross‐Reactivity Studies for Monoclonal Antibodies: Predictive Value and Use for Selection of Relevant Animal Species for Toxicity Testing
Authors: Hall William C. , Price‐Schiavi Shari A. , Wicks Joan , Rojko Jennifer L. 
Published: March 2010

AbstractTissue cross‐reactivity studies provide a rational in vitro assay to determine the range and intensity of distribution of potential epitopes reactive with a monoclonal antibody test article prior to its administration to humans. The predictive value of the assay lies in incorporating the characteristics of the monoclonal antibody (isotype, subtype, and other molecular modifications) with the biological activity of the molecule itself, and the potential in vivo distribution of it. This article outlines important considerations in the conduct of the tissue cross‐reactivity study and provides best practices guidelines for interpreting the information gained from this assay relative to human safety.
Reproductive Toxicity Testing for Biopharmaceuticals
Authors: Martin Pauline L. 
Published: March 2010

AbstractThe reproductive toxicity testing strategies have been developed for the evaluation of the reproductive and developmental toxicity of chemicals and medical products following the thalidomide tragedy of 1957 to 1961. The testing strategies need to be justified on a case‐by‐case basis. No single testing strategy can be applicable to all types of molecules. This article focuses on reproductive toxicity testing strategies applied in support of the approved biopharmaceuticals and their relevance to the evaluations of human safety.
Preclinical Evaluation of Cancer Hazard and Risk of Biopharmaceuticals
Authors: Cavagnaro Joy A. 
Published: March 2010

AbstractA variety of preclinical approaches have been used for assessing carcinogenic potential of pharmaceuticals. The need for carcinogenicity assessment of a biopharmaceutical is based on an intended duration of, cause for concern, indication, patient population including the nature of the disease and its effect on life span and overall patient health, route and exposure, and extent of systemic exposure. This article focuses on need and various preclinical approaches for preclinical carcinogenicity assessment of biopharmaceuticals.
Assessment of Autoimmunity and Hypersensitivity
Authors: Descotes Jacques , Vial Thierry 
Published: March 2010

Abstract
Biopharmaceuticals, either via their (immuno)‐pharmacological mechanism of action, or their chemical structure (foreign proteins), have the potential for inducing autoimmunity and/or hypersensitivity reactions in treated human subjects. Therefore autoimmunity and hypersensitivity are critical issues to be considered during the preclinical as well as the clinical safety evaluation of all biopharmaceuticals. This article focuses on regulatory guidance and assays for predicting hypersensitivity and autoimmunity of biopharmaceuticals.
Preclinical Safety Evaluation of Blood Products
Authors: Lewis Richard M. 
Published: March 2010

AbstractThe focus of clinical safety evaluation of blood products has shifted to toxicological evaluations. This has come with the development of recombinant materials or biochemically modified molecules to address specific disease states. This article focuses on preclinical programs that offer suggestions for the development of plans for various groups of products regulated in the Office of Blood and Blood Products, the CBER, and the FDA.
Considerations in Design of Preclinical Safety Evaluation Programs to Support Human Cell‐Based Therapies
Authors: Cavagnaro Joy A. 
Published: March 2010

Abstract
This article focuses on various preclinical development considerations for designing preclinical safety evaluation programs to support human‐based cell therapies. The success of cell‐based therapy will depend on optimal selection, manufacture, and survival of the implanted cells. Cellular products need to be in compliance with CFR part 312 regardless of whether the finished product is shipped across state lines.
Preclinical Safety Evaluation of Biopharmaceuticals: Combination Products (Biologic/Device)
Authors: Babbitt Bruce , Sall Barry 
Published: March 2010

Abstract
Combination products include a wide variety of products that merge medical devices, pharmaceuticals, and/or biologics. The preclinical testing program for a biologic‐device combination product should adequately address safety issues associated with device components and those that involve the biologic. This article discusses the key issues that should be considered when preparing a preclinical development plan for a combination product.
Preclinical Safety Study Design Templates and Estimated Costs
Authors: Wolfe Gary W. 
Published: March 2010

Abstract
Preclinical studies are designed to identify target organs and biomarkers and to set starting dose levels, recommend dose–escalation schemes and target organs of toxicity. It is important to design the study to answer specific questions concerning design of the preclinical study test article while maximizing the use of the animals. A well‐designed preclinical program that addresses questions of toxicity conducted internally or at a well‐qualified CRO is necessary for a satisfactory preclinical safety evaluation program to support successful clinical development.
Survey of Preclinical Toxicology Programs for Approved Biopharmaceuticals
Authors: O'connor Anita Marie 
Published: March 2010

Abstract
A survey of US marketed biopharmaceuticals approved over the past 20 years is presented. It is a simply a profile of the species and types of toxicology studies done for each drug for marketing approval. Most common types of biopharmaceuticals are monoclonal antibodies, fusion or conjugate proteins, growth factors, replacement enzymes, peptides, and cellular therapies.