bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the Cellular Sensor That Stimulates the Inflammatory Response to Sterile Cell Death
Authors: Kono Hajime , Karmarkar Dipti , Iwakura Yoichiro , Rock Kenneth L.
Published: March 2010

Cell death provokes a robust inflammatory response. We have previously shown that this response is dependent on IL-1α. In this study, we investigate the cellular mechanism used by a host to sense cell death, produce IL-1α and also the role of IL-1β in this response. In almost all cases examined, the IL-1 that stimulated the death-induced inflammatory response came from the host rather than the cell that was dying. In these situations, host bone marrow-derived cells were the key source of the IL-1α that was required for the inflammatory response. Conditional cellular depletion and reconstitution in CD11b promoter-driven diphtheria toxin receptor transgenic mice revealed that host macrophages played an essential role in the generation of the inflammatory response and were the source of the required IL-1α. In addition, we found a role for IL-1β in the death-induced inflammatory response and that this cytokine was generated by both bone marrow-derived and radioresistant host cells. The one exception to these findings was that when dendritic cells were injected into mice, they provided a portion of the IL-1 that stimulated inflammation, and this was observed whether the dendritic cells were live or necrotic. Together, these findings demonstrate that macrophages play a key role as the primary sentinels that are required to sense and report cell death in ways that initiate the inflammatory response. One key way they accomplish this important task is by producing IL-1α that is needed to initiate the inflammatory response.
Plasmacytoid Dendritic Cells Enhance Mortality during Lethal Influenza Infections by Eliminating Virus-Specific CD8 T Cells
Authors: Langlois Ryan A. , Legge Kevin L.
Published: March 2010

Previous studies have shown that the reduction in CD8 T cell immunity observed during high-dose influenza A virus (IAV) infection is mediated via lymph node (LN) dendritic cells (DCs) that express Fas ligand (FasL) and drive FasL-Fas (DC-T)–induced apoptosis. However, the specific DC subset(s) within the LN and the additional factors required for DC-mediated elimination of IAV-specific CD8 T cells remain unknown. In this paper, we demonstrate that plasmacytoid DCs (pDCs), which downregulate FasL during sublethal, but not lethal, IAV infection, accumulate to greater numbers within the LNs of lethal dose-infected mice. Further our findings show that pDCs from lethal, but not sublethal, dose IAV infections drive elimination of Fas+ CD8 T cells and that this elimination occurs only in the absence of TCR recognition of IAV peptide-MHC class I complexes. Together, these results suggest that pDCs play a heretofore unknown deleterious role during lethal dose IAV infections by limiting the CD8 T cell response.
Redundant and Pathogenic Roles for IL-22 in Mycobacterial, Protozoan, and Helminth Infections
Authors: Wilson Mark S. , Feng Carl G. , Barber Daniel L. , Yarovinsky Felix , Cheever Allen W. , Sher Alan , Grigg Michael , Collins Mary , Fouser Lynette , Wynn Thomas A.
Published: March 2010

IL-22 is a member of the IL-10 cytokine family and signals through a heterodimeric receptor composed of the common IL-10R2 subunit and the IL-22R subunit. IL-10 and IL-22 both activate the STAT3 signaling pathway; however, in contrast to IL-10, relatively little is known about IL-22 in the host response to infection. In this study, using IL-22−/− mice, neutralizing Abs to IL-22, or both, we show that IL-22 is dispensable for the development of immunity to the opportunistic pathogens Toxoplasma gondii and Mycobacterium avium when administered via the i.p. or i.v. route, respectively. IL-22 also played little to no role in aerosol infections with Mycobacterium tuberculosis and in granuloma formation and hepatic fibrosis following chronic percutaneous infections with the helminth parasite Schistosoma mansoni. A marked pathogenic role for IL-22 was, however, identified in toxoplasmosis when infections were established by the natural oral route. Anti–IL-22 Ab-treated mice developed significantly less intestinal pathology than control Ab-treated mice even though both groups displayed similar parasite burdens. The decreased gut pathology was associated with reduced IL-17A, IL-17F, TNF-α, and IFN-γ expression. In contrast to the prior observations of IL-22 protective effects in the gut, these distinct findings with oral T. gondii infection demonstrate that IL-22 also has the potential to contribute to pathogenic inflammation in the intestine. The IL-22 pathway has emerged as a possible target for control of inflammation in certain autoimmune diseases. Our findings suggest that few if any infectious complications would be expected with the suppression of IL-22 signaling.
Impact of Cognitive Impairment on Functional Outcome in Stroke
Authors: Paker Nurdan , Buğdaycı Derya , Tekdöş Demet , Kaya Betül , Dere Çağlayan
Published: March 2010

The aim of this study was to investigate the effect of the cognitive impairment on functional status in patients with subacute stroke. Fifty-two patients with subacute stroke were included in the study. Mini mental state examination (MMSE) test was used for the evaluation of cognitive status. Patients were separated into two groups according to their cognitive functions. Functional follow-up parameters were activities of daily living (ADL), global recovery and ambulation status. All patients were evaluated on admission to rehabilitation unit, at discharge and 6 months after discharge. Forty-four patients were completed the study. Mean age was 66 and 57 years; disease duration on admission was 4,8 and 3,5 months in the cognitively impaired and normal groups, respectively. Significant improvement was found in terms of functional follow-up parameters in both groups at discharge . Functional follow-up parameters did not show statistically significant difference between the groups. But community ambulation rate was higher in cognitively normal group at the sixth month visit. As a result of this study, inpatient rehabilitation was effective both cognitively normal and impaired subacute stroke patients.
Introduction: Drug Discovery in the 21

st

Century
Authors: Gad Shayne Cox
Published: March 2010

The discovery, development, and registration of a pharmaceutical is an immensely expensive operation and represents a unique challenge of high attrition rate of drugs. Early identification of poor or noncompetitive candidates is thus extremely important, forming the basis for screening processes in pharmaceutical discovery and development. This article focuses on a wide variety of approaches to the discovery and identification of potential new drugs.
Cancer Cell Proteomics using Molecular Aptamers
Authors: Tan Weihong , Cao Zehui , Shangguan Dihua , Li Ying , Tang Zhiwen , Mallikratchy Prabodhika , Chen Hui
Published: March 2010

In recent decades, tremendous progress has been made in understanding origination and development of human cancers. Despite our increasing understanding of cancers, finding a cure for cancers remains a great challenge. This article focuses on the use of aptamer probes for molecular diagnosis of cancer.
Strategies and Methods in Monitoring and Targeting Protein–Protein Interactions
Authors: Loregian Arianna , Palù Giorgio
Published: March 2010

Since protein–protein interactions play a role in nearly all events that take place in a cell, information on the function of an unknown protein can be obtained by investigating its interaction with other proteins whose functions are already known. The manipulation of protein–protein interactions that contribute to disease is a potential therapeutic strategy. This article focuses on protein–protein interactions and screening strategies to characterize new inhibitory molecules that act by disrupting biologically relevant protein–protein interactions.
Metal‐Enhanced Fluorescence: Application to High‐Throughput Screening and Drug Discovery
Authors: Aslan Kadir , Gryczynski Ignacy , Malicka Joanna , Lakowicz Joseph R. , Geddes Chris D.
Published: March 2010

Metal‐enhanced fluorescence (MEF) appears to be most suitable to the fluorescence assays used in drug discovery and DNA analysis. The metal–fluorophore effects offer unique perspectives in fluorescence sensing, providing for improved background suppression, increased detection limits, and localized excitation near to silver nanostructures. This article describes the effects of different silver nanostructures on the emission intensity and photostability of fluorophores and the use of MEF in high‐throughput screening and drug discovery.
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

Statistical 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

The 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

Effective 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

Protein 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

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

The 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

Modeling 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

Defining 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

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

Drug 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

Form 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

Metabolism 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

Serious 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

In 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

Productivity 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

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

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

The 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

Irritation 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

The 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

Safety 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

In 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

The 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.
Genomics
Authors: Semizarov Dimitri , Blomme Eric A. G.
Published: March 2010

Genomic technologies have begun to revolutionize drug discovery and development. Identification of genes frequently amplified at the chromosomal level may reveal a target for therapeutic intervention. The article focuses on new genomic technologies including, gene expression microarrays, comparative genomic hybridization, and gene silencing.
Toxicoproteomics: Preclinical Studies
Authors: Merrick B. Alex , Bruno Maribel E.
Published: March 2010

Toxicoproteomics 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

Investigation 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

The 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

The 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

The 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

Cytochrome 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

In 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

Pharmaceutical 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

Tissue 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

The 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

A 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

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 Biological Oncology Drugs
Authors: Reynolds Theresa
Published: March 2010

Biomedical researchers continue to make significant efforts to describe considerations for clinical safety assessment of oncology products. There is a consistent approach to characterization of the preclinical safety profile that requires consideration of a number of factors. Some of these factors include clinical application, drug attributes, and material production.
Preclinical Safety Evaluation of Blood Products
Authors: Lewis Richard M.
Published: March 2010

The 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

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

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

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

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.
Science and Judgment in Establishing a Safe Starting Dose for First‐in‐Human Trials of Biopharmaceuticals
Authors: Visich Jennifer , Ponce Rafael
Published: March 2010

A number of regulatory guidance documents discuss various aspects of the transition from preclinical to clinical study of a novel biopharmaceutical. This article reviews the decision processes surrounding the determination of the initial dose of a novel biopharmaceutical agent to be administered to subjects in clinical trials.
Introduction to Clinical Trials
Authors: Goffin John
Published: March 2010

The ultimate goal of drug development is the creation of new, safe, and effective compounds for treating human disease. Clinical trials comprise the portion of this endeavor involving human subjects. This article focuses on the overall goals and requirements of conducting clinical trials.
Regulatory Requirements for Investigational New Drug
Authors: Rao Venkat
Published: March 2010

Investigational new drug (IND) is a key phase within the drug development life cycle that requires considerable interactions between pharmaceutical companies and the Food and Drug Administration (FDA). Regulatory affairs covering new medical product development are influenced by external factors driven by industry interests and drug legislations. This article examines the investigational new drug application process; the prevailing regulations relating to various aspects of IND investigation; the latest requirements under good tissue practice for highly sophisticated biotechnology‐derived products; various mechanisms, tools, and performance matrix to monitor IND clinical investigations; and emerging biosafety and biosecurity considerations in IND clinical investigations.
Organization and Planning
Authors: Sprague Sheila , Bhandari Mohit
Published: March 2010

Organization and planning play important role in effective management of clinical research study. The study investigators review all protocols and assess the feasibility of the clinical site to conduct the clinical research study. This article discusses different kind of protocols that must be reviewed by the investigators, research coordinators, and other relevant clinical and research associates to ensure that certain conditions are present.
Clinical Trials Data Management
Authors: Santoro Eugenio , Tinazzi Angelo
Published: March 2010

Clinical data management deals with complex medical data. Computer science and various software technologies have revolutionized the way medical information is stored, accessed, and retrieved. This article discusses important issues related to clinical data management aspects, regulatory frameworks, and different kinds of web‐based clinical trials.
Clinical Trials and the Food and Drug Administration
Authors: Mahfouz Tarek M. , Crossgrove Janelle S.
Published: March 2010

The Food and Drug Administration (FDA) protects the health of Americans by enforcing the Federal Food, Drug, and Cosmetic Act and other related public health laws. The role of the FDA in clinical trials is to help protect the rights and welfare of the patients participating in the trial. This article discusses the different steps a new drug goes through before it is marketed and the involvement of the FDA in each step.
Phase IV: Postmarketing Trials
Authors: Wegscheider Karl
Published: March 2010

There is a need and a demand for postmarketing trials of a drug, justifying the introduction of another phase, such as phase IV, for this kind of study. This demand is met more frequently as people become aware of the intricate challenges. This article provides information regarding methodological approaches to phase IV trials.
PhaseIVand Postmarketing Clinical Trials
Authors: Khan Ali Miraj
Published: March 2010

Both postmarketing surveillance programs and clinical phase IV studies are essential to ensure the safety of drugs. These studies disclose beneficial and detrimental effects of drugs, including the existence of causal effects, risk factors, economic consequences, and characterization of drug use in clinical practice. Phase IV clinical trials encompass the detection, assessment, understanding, and prevention of drug‐related problems, with progression of medical services.
Clinical Trials in Interventional Cardiology: Focus on XIENCE V Drug‐Eluting Stent
Authors: Doostzadeh J. , Bezenek S. , Cheong W.‐F. , Sood P. , Schwartz L. , Sudhir K.
Published: March 2010

The development of drug‐eluting stents (DES) represents an exciting area of breakthrough technology in interventional cardiology. Interaction of innovative stent platforms, polymers, and molecular entities, as well as pharmaceutical adjuncts such as dual antiplatelet therapy, present a unique degree of complexity for systematic ongoing evaluation of these devices, their optimal use, and their real safety and performance results. This article describes functionality and applications of DES.
Clinical Trials Involving Oral Diseases
Authors: Pihlstrom Bruce L. , Michalowicz Bryan , Atkinson Jane , Kingman Albert
Published: March 2010

Oral health clinical trials have mainly focused on the diseases of dental caries and periodontal disease, but a limited number have involved other oral diseases and conditions. These include chronic facial pain, particularly associated with the temporomandibular joint, acute pain after extraction of third molars (wisdom teeth), xerostomia (dry mouth), and various oral mucosal diseases. This article focuses on phase III oral health clinical trials in terms of design and analyses, regulatory and management issues, and challenges of conducting trials involving specific oral diseases.
Dermatology Clinical Trials
Authors: Kazanis Maryanne , Van Cott Alicia , Kimball Alexa Boer
Published: March 2010

Dermatology is a wonderful field for conducting clinical trials, as there are many advantages to studying the skin. First, it is an accessible organ that can be easily seen, touched, measured, and sampled. An additional benefit to conducting dermatology clinical trials is that diseases of the skin manifest in both adults and children, so there is a demographic of patients from which to draw a study subject population. This article describes some of the distinctive aspects involved in designing and conducting dermatology clinical trials.
Emergency Clinical Trials
Authors: Borrás‐Blasco Joaquín , Navarro‐Ruiz Andrés , Borrás Consuelo
Published: March 2010

Emergency clinical trials involve the administration of the study drug to healthy human volunteers or to patients under the supervision of a qualified investigator, usually a physician, pursuant to a reviewed protocol. Research in this field continues to grow because this department is often considered as a desirable place to conduct clinical research due to the broad and undifferentiated spectrum of acute conditions encountered. There are some specific aspects when studying emergency medicine that have to be taken into account. One of them is the emphasis on ultrarapid diagnosis and treatment to save the critically ill emergency patient.
Gastroenterology
Authors: Gluud Lise Lotte , Rask‐Madsen Jørgen
Published: March 2010

Clinical gastroenterology deals with diseases of the digestive system, including the esophagus, stomach, intestine, liver, gallbladder, and pancreas. In clinical gastroenterology most trials assess the effects of various drugs, but interventional procedures may also be subject to clinical trials, such as efficacy and safety of endoscopic therapy and primary as well as secondary prevention.
Special Population Studies (Healthy Patient Studies)
Authors: Weilert Doris K.
Published: March 2010

Pharmacokinetic (PK) data in special populations are registration requirements if the target patient population is likely to include special population(s). U.S. and European regulatory guidelines require formal PK studies in geriatric, RI, and HI impairment subjects while PK data in other special populations such as women, ethnic groups, and obese subjects may be obtained by using population analysis approaches. This article focuses on the diversity of physiological effects on NCE PK in people who distinguish themselves from the average adult patient population for which the NCE is being developed.
Musculoskeletal Disorders
Authors: Akai Masami
Published: March 2010

The term musculoskeletal disorders refer to conditions that involve the supporting structures of the body, such as the trunk and the bones and joints of the extremities. Musculoskeletal disorders are the most common cause of severe, long‐lasting pain and physical disability affecting hundreds of millions of people in the world. Treatments in musculoskeletal disorders are classified into “drug therapy,” “therapeutic exercise,” “physical agents,” “orthotics and devices,” “education or care packages,” and “others.”
Paediatrics
Authors: Cusick Anne , Lannin Natasha , Novak Iona
Published: March 2010

This article focuses on issues and practical aspects of the context and conduct of paediatric clinical trials. Investigators should have a breadth of view on issues involved in paediatric trials to enable them to apply technical information to the context of paediatrics. Investigators should also be able to reflect on their own standpoint and responsibility as trial leaders, sponsors or team members who are knowingly putting infants, children or young people at some level of risk in order to answer a question.
Clinical Trials in Dementia
Authors: Raya‐Ampil Encarnita , Cummings Jeffrey L.
Published: March 2010

Dementia is a health problem affecting millions of people worldwide. Its prevalence increases with age and it is almost always a disease of the elderly. It has also been observed that Alzheimer's disease (AD) is the leading cause of dementia. This article reviews MCI and AD trials to derive guidelines on how future trials may be conducted.
Clinical Trials in Urology
Authors: Wignall Geoffrey R. , Wernecke Carol , Nott Linda , Razvi Hassan
Published: March 2010

The wide scope of current urological practice has led to a proliferation of research and clinical trials in this specialty. As a surgical subspecialty devoted to the medical and surgical care of patients with genitourinary disorders, both pharmaceutical and device trials have equally important roles in the advancement of the future care of the urologic patient. This article focuses on the objectives, design, and implementation of clinical trials for conducting urological research.
Brief History of Clinical Trials on Viral Vaccines
Authors: Brooks Megan J. , Sasadeusz Joseph J. , Tannock Gregory A.
Published: March 2010

Most viral vaccines were developed as a consequence of our ability to cultivate viruses in embryonated eggs (from the 1930s) or cell cultures (the 1950s and 1960s). Clinical trials on vaccines are classified as phase I, II, III, or IV, depending on the stage of clinical development of a vaccine. This article focuses on the clinical trials and future trends in the development of different kinds of vaccines.
Randomized Controlled Trials
Authors: Garcea Giuseppe , Berry David P.
Published: March 2010

A randomized controlled trial (RCT) is a study in which subjects are allocated at random to receive one of two possible interventions. RCT provides an unbiased, balanced, and reliable method of determining the efficacy of new drugs or devices. This article focuses on the different methodologies applied in RCTs and their potential flaws.
Biomarkers in Clinical Drug Development: Parallel Analysis of Alzheimer Disease and Multiple Sclerosis
Authors: Betard Christine , Boneschi Filippo Martinelli , Caramelli Paulo
Published: March 2010

Biomarkers are increasingly being used in clinical drug development by research based pharmaceutical and biotechnology companies. Biomarkers can also have a big impact on health care by facilitating the assessment of new drugs that prevent costly chronic progressive disease. This article reviews molecular and neuroimaging biomarkers for multiple sclerosis (MS) and Alzheimer disease (AD).
Review Boards
Authors: Hood Maureen N. , Kaar Jason F. , Ho Vincent B.
Published: March 2010

An institutional review board (IRB) is an independent group or committee consisting of a combination of medical/scientific and nonmedical/nonscientific members that is formally organized to oversee biomedical research involving human subjects at an institution. IRBs or institutional ethics committees (IECs) are an essential part of the clinical trial system. This article presents an overview of the process of the institutional review board (IRB) and institutional ethics committee (IEC) along with resources for researchers who want to be involved in clinical trial research.
Size of Clinical Trials
Authors: Ganju Jitendra
Published: March 2010

The number of subjects required for a clinical trial is obtained from a mechanical application of a formula. Scientific, strategic, operational, and ethical deliberations exert a push and pull on the appropriate number of subjects needed for a trial. This article focuses on the determination of subjects under various values of presumed efficacy and variance and the points to be considered for planning size of trial.
Monitoring
Authors: Stallard Nigel , Todd Susan
Published: March 2010

Monitoring refers to the statistical analysis of data during the course of the trial. Monitoring of data allows the results of an ongoing trial to be regularly assessed and enables termination of the trial as soon as the results are sufficiently convincing that continued recruitment cannot be ethically defended. This article discusses various issues related to the clinical data monitoring and implications regarding monitoring designs.
Explanatory and Pragmatic Clinical Trials
Authors: Herbert Rob
Published: March 2010

Explanatory and pragmatic
attitudes influence many aspects of trial design. Clinical trialists can have explanatory or pragmatic attitudes to clinical trials. Explanatory trialists conceive of clinical trials as being clinical analogs of classic laboratory experiments. In contrast, pragmatic trialists think of clinical trials as a mechanism for informing clinical decisions.
Ethics of Clinical Research in Drug Trials
Authors: Beran Roy G.
Published: March 2010

A drug trial aims to answer a question that has not yet been answered, thereby necessitating the need for a trial. The ethics of clinical drug trials start with the selection of the scientific question to be asked, the capacity to answer that question, and the study design to be adopted for that purpose. It is believed that ethical obligations should include the maintenance of rigorous post‐marketing surveillance concerning the product being trialed, to protect against unexpected serious adverse events (SAEs).