bluuebunny/crossref_metadata_2025 huggingface dataset:
Toxicologic Pathology
Authors: Tchounwou Paul B. , Centeno José A.
Published: March 2010

The science of toxicologic pathology has been critical for the understanding of adverse effects of physical, chemical, and biologic agents on biologic systems. Toxicologic pathology has emerged as a scientific discipline that integrates toxicology and pathology. This article discusses important aspects of toxicologic pathology at the molecular and cellular levels and also presents an overview of radiation‐induced toxicologic pathology.
Preclinical Development of Protein Pharmaceuticals: An overview
Authors: Das Dipankar , Suresh Mavanur R.
Published: March 2010

Biogeneric protein pharmaceuticals are a new category of therapeutics. Almost all of the current approved biopharmaceuticals are therapeutic proteins and vaccines. This article presents an overview of various aspects of preclinical development of protein pharmaceuticals, including influence of carbohydrate in protein drugs and immunogenicity issues.
Auditing and Inspecting Preclinical Research and Compliance with Good Laboratory Practice (
GLP
)
Authors: Dent N.J.
Published: March 2010

The Good Laboratory Practice (GLP) guidelines have progressed through various transitional phases to become guidelines in some countries and regulatory/statutory instruments in others. The objective of the GLPs is to ensure that a standard approach is undertaken, covering traceability and accountability of medical research and drug development process. This article discusses various aspects of auditing and inspecting preclinical research compliance with GLP.
Biotransformations in Drug Metabolism
Authors: King Roberta S.
Published: March 2010

Metabolism can affect the spectrum of consequences of drug action including both the desired therapeutic effects and undesired effects. During the clinical studies and post‐marketing stages, metabolism data can be used to promote safe use of a drug, including dosing adjustments or warnings about drug‐drug interactions. This article discusses various stages of biotransformations in drug metabolism including functional group biotransformation and major P450 reactions.
Pharmacogenetics and Pharmacogenomics
Authors: Yengi Lilian G.
Published: March 2010

The fields of pharmacogenetics, genomics, and drug transporters have profoundly impacted drug metabolism research by providing plausible mechanisms for interindividual variability in drug response and metabolism‐related toxicity. Pharmacogenetics is a branch of study that analyzes the effects of genetic differences between individuals. This article discusses various issues related to pharmacogenetics, including gene regulation and its potential impact on the efficacy and safety of new drug candidates.
Introduction to Drug Transporters
Authors: Leung Louis , Oganesian Aram
Published: March 2010

The role of transporter proteins in drug and endogenous substance disposition has increasingly gained recognition over the last decade. Inhibition or induction of different drug transporters in different tissues can lead to clinical drug‐drug interactions that may result in adverse effects or lack of efficacy. The article offers insights into the role of drug transporters in drug development, drug absorption, metabolism, and toxicity.
Automated Drug Screening forADMETProperties
Authors: Reichman Melvin , Gill Helen
Published: March 2010

The survival and growth of the pharmaceutical industry relies on favorable, early clinical trial outcomes. Poor outcomes are commonly due to poor absorption, distribution, metabolism, excretion, and toxicology of drugs. The article offers insights into various technologies forin vitroandin vivostudies related to drug development.
Approaches to Performing Metabolite Elucidation: One Key to Success in Drug Discovery and Development
Authors: Nassar Ala F.
Published: March 2010

Absorption, distribution, metabolism, excretion, and toxicology (ADMET) studies are widely used in drug discovery and development. Drug discovery efforts have been aimed at identifying and addressing drug metabolism issues at the earliest possible stage. Metabolite identification is crucial to the drug discovery and development process. The article discusses approaches to performing metabolite elucidation at various drug development stages.
An Introduction to Metabolic Reaction Phenotyping
Authors: Davis Carl D. , Rodrigues A. David
Published: March 2010

Optimizing the metabolic stability of a new chemotype in drug discovery can improve oral bioavailability and help to identify a drug candidate that will achieve efficacious exposure in the target patient population. The role of drug‐metabolizing enzymes (DMEs) and metabolic clearance in the overall determination of a drug's oral bioavailability and pharmacokinetics (PK) is fully incorporated into the process of discovery and development of improved therapeutic agents. This article describes experimental and kinetic methods used to identify the role of enzymes in the overall metabolic clearance of a drug and illustrates some concerns related to the contribution and interindividual variation of some notable enzymes.
Clinical Drug–Drug Interactions
Authors: Deshmukh Sujal V.
Published: March 2010

Pharmacokinetic interactions that lead to adverse reaction are extremely detrimental to the patients and constitute as a major concern to the health care providers. There are several different approaches that the medical practitioners can use to avoid drug‐drug interactions (DDIs). This article focuses on the pharmacokinetic‐based DDIs.
Pharmaceutical Excipients in Drug–Drug Interaction
Authors: Chen Chuan , Sadeque Abu J.M.
Published: March 2010

During the development of a given drug formulation, the interactions between the drug and excipients need to be carefully studied to ensure that the drug is stable in the formulation. Enzyme‐based drug interaction involving excipients appears to occur predominantly in preclinical studies. The article discusses drug‐drug interaction potential of pharmaceutical excipients, with a focus on solubilizing excipients.
Mechanisms of Reproductive Toxicity
Authors: Keating Aileen F. , Hoyer Patricia B.
Published: March 2010

Reproductive toxicology involves detecting and understanding potentially detrimental environmental influences on reproductive success in females and males. Environmental exposure to xenobiotics that have the potential to impact human reproduction has increased. This article outlines how xenobiotics can impact reproductive function in females and males.
Role of Bioactivation Reactions in Chemically Induced Nephrotoxicity
Authors: Lash Lawrence H.
Published: March 2010

Kidneys express a diverse array of enzymes that can catalyze the bioactivation of many drugs and xenobiotics. The kidneys are particularly susceptible to chemically induced toxicity because of their basic physiology and biochemistry. The article discusses the role of bioactive reactions in chemically induced nephrotoxicity.
Drug Metabolism in Regulatory Guidances, Clinical Trials, and Product Labeling
Authors: Milton Mark N.
Published: March 2010

Drug metabolism is playing an ever‐increasing role in the drug development process. Drug metabolism scientists can face several challenges when attempting to locate guidances or guidelines that mention drug metabolism. The article discusses the role of drug metabolism in clinical trials and the contribution of drug metabolism to the product label.
Demonstration of Comparability of a Licensed Product after a Manufacturing Change
Authors: Lewis Richard M.
Published: March 2010

The demonstration of comparability of a licensed product after a manufacturing change has been addressed by several published regulatory guidance documents, such as the FDA guidance, the EMEA guideline, and the ICH guidance. The comparability exercise may include a combination of analytical testing, biological assays, assessment of pharmacokinetics and/or pharmacodynamics and toxicity in animals, and clinical testing. This article focuses on the regulatory guidelines and general principles and practices for determining comparability of a licensed product after a manufacturing change.
Enzyme Replacement Therapies
Authors: Andrews Laura , O'Callaghan Michael
Published: March 2010

Enzyme replacement therapy (ERT) is a therapeutic approach where the specific enzyme that is absent or inactive in affected individuals is replaced with a functional enzyme molecule. Significant advances in enzyme replacement therapy that has opened up a new era of hope for lysosmal storage disease (LSD) sufferers. This article addresses the issues facing development of enzyme replacement treatments for lysosmal storage diseases (LSDs).
Toxicology of Oligonucleotide Therapeutics and Understanding the Relevance of the Toxicities
Authors: Levin Arthur A. , Henry Scott P.
Published: March 2010

There are four categories of oligonucleotide therapeutics. These include the following: single‐stranded oligonucleotides that work through RNAse H or steric effects; double‐stranded RNAs that work through the dicer pathway; immunostimulatory oligonucleotides that work by stimulating innate immunity, and aptamers that work by binding to proteins and modifying their function. This article describes the existing practices for assessing the toxicity of oligonucleotide therapeutics and the rationale for these practices.
Preclinical Safety Evaluation of Monoclonal Antibodies
Authors: Treacy George , Martin Pauline
Published: March 2010

Monoclonal antibodies are populations of identical, monospecific antibodies with defined specificity and affinity for a target antigen. The design of preclinical safety evaluation of monoclonal antibodies is based on the class of monoclonal, the target epitope, and the clinical indication. This article focuses on preclinical safety evaluation of monoclonal antibodies.
Immunomodulatory Biopharmaceuticals and Risk of Neoplasia
Authors: Bugelski Peter J. , Sachs Clifford , Cornacoff Joel , Martin Pauline , Treacy George
Published: March 2010

A number of immunomodulatory biopharmaceuticals (IMBPs), such as peptides, recombinant proteins, and monoclonal antibodies, have been approved or are currently in development to treat chronic inflamatory diseases. IMBPs by virtue of their intended pharmacologic activity may act as atypical tumor promoters and thus pose a hazard for developing certain tumor types, especially lymphomas and skin cancer. This article focuses on focus on well‐characterized, high‐purity protein biopharmaceuticals derived from conventional recombinant expression systems that modulate immune function.
Practical Considerations in the Design of Preclinical Safety Assessments for Biopharmaceuticals
Authors: Demady Damon R.
Published: March 2010

The primary goals of preclinical safety evaluation articulated in ICH S6 are to identify an initial safe dose and subsequent dose escalation schemes in humans. It also involves the identification of potential target organs for toxicity and for the study of whether such toxicity is reversible, and to identify safety parameters for clinical monitoring. These goals are generally accepted across all product classes.
Predicting Human Adverse Drug Reactions from Nonclinical Safety Studies
Authors: Valentin Jean‐Pierre , Keisu Marianne , Hammond Tim G.
Published: March 2010

An adverse drug reaction (ADR) is an adverse event where a causal relationship between the adverse event (AE) and the medicinal product is at least a reasonable possibility. Lack of safety remains the major cause of attrition during clinical development, accounting for approximately 35–40 percent of all drug discontinuation. This article focuses on the nature, frequency, and consequences of ADRs in two different clinical situations.
History of Clinical Trial Development and the Pharmaceutical Industry
Authors: Peppercorn Jeffrey , Roberts Thomas G. , Hammond Tim G.
Published: March 2010

The history of clinical trials and the pharmaceutical industry is closely tied to the history of bioethics, which shape the regulation of clinical research and pharmaceutical development.

The history of clinical trials begins with the recognition of disease as a discrete condition that is similar enough from patient to patient to allow the rational application of the experimental method to determine which therapies work and which do not. This article presents an overview of some of the key developments and ongoing issues that should serve as an introduction to the rich history of clinical trials and the rise of the pharmaceutical industry.
Phase
I
Clinical Trials
Authors: Norfleet Elizabeth , Cox Gad Shayne
Published: March 2010

Phase I trials are the earliest stage clinical trials of a new drug or device typically performed with just a few persons to determine the safety and pharmacokinetics of a new drug. The main objectives of phase I trials are to assess tolerability, monitoring the side effects in relation to increase of the doses, and confirm the maximum tolerated dose. This article discusses design characteristics of different kind of Phase I trials.
Phase
II
Clinical Trials
Authors: Tan Say‐Beng , Machin David
Published: March 2010

Phase II trials are conducted to evaluate the drug's activity for patients with a particular disease or condition and to determine the level of short‐term side effects and possible risks associated with the use of the drug. The drug is further evaluated in randomized phase III trials where it is compared with the current standard treatment in a larger number of patients when preliminary evidence of effectiveness is found in these phase II trials. Phase II trials are single‐armed studies that investigate the antidisease activity of the new therapeutic regimen.
Oncology
Authors: Zwitter Matjaz
Published: March 2010

Various issues associated with the design and conduct of clinical research in oncology are discussed. It is estimated that only between 3 and 10% of cancer patients participate in clinical trials, with even lower representation of elderly patients and minorities. There is a critical need for infrastructure to support trials, especially additional support staff and research nurses. Other obstacles to clinical research include legal restrictions, as seen in the European Union Clinical Trials Directive or in the Declaration of Helsinki.
Clinical Trials on Cognitive Drugs
Authors: Farina Elisabetta , Baglio Francesca
Published: March 2010

Cognitive disabilities, especially memory disturbances and cognitive deficits, posttraumatic brain injury (TBI), and poststroke are important targets for clinical pharmacological trials due to their important epidemiological and social impact. Brain changes leading to cognitive decline and dementia, and their relation to disability, are key topics requiring investigation at the population level. It is expected that pharmacological approaches will become increasingly integrated with behavioral, genetic, and neuroimaging methods to investigate disease processes and the normal and preclinical individual differences that underlie successful— or unsuccessful—aging.
Cross‐Over Designs
Authors: Porcher Raphaël , Chevret Sylvie
Published: March 2010

Cross‐over designs refer to clinical trials where patients sequentially receive several of the compared treatments. The cross‐over design provides disease condition of subjects at the beginning of each treatment period and intuitively appeals to compare treatments. This article reviews the main issues concerning the use and analysis of cross‐over designs.
Ethical Issues in Clinical Research
Authors: Tremellen Kelton , Belford David
Published: March 2010

Medical research has the potential to create huge benefits to society and enhance the professional reputation of the researchers responsible for the discoveries. However, a researcher must never knowingly compromise the welfare of a research participant, irrespective of how important the research outcomes are to society in general. This article aims to educate clinical researchers in the common pitfalls of human experimentation and ways to avoid these ethical problems in pharmaceutical trials.
Imaging as a Localized Biomarker: Opportunities and Challenges
Authors: Moody Jonathan B. , Murphy Philip S. , Ficaro Edward P.
Published: March 2010

In recent years, the concept of imaging biomarkers is increasingly being utilized in drug development and for producing images of physiological and physicochemical processes in a living subject. Continuous research and development for more than 30 years has produced a steady stream of new imaging technologies as well as incremental improvements that address the limitations of existing technologies. This article focuses on understanding the opportunities for using imaging biomarkers as tools in drug development while recognizing the current challenges and how efforts to overcome these challenges are evolving.
Qualification of Safety Biomarkers for Application to Early Drug Development
Authors: Mattes William B. , Sistare Frank D.
Published: March 2010

Biomarkers are judged on the basis of whether they have been subjected to a process of validation. There are a number of preclinical and clinical studies and resources available to qualify a biomarker as a characterization biomarker appropriate for regulatory decision making. This article focuses on the qualification of safety biomarkers for application to early drug development.
Development of Serum Calcium and Phosphorus as Clinical Biomarkers for Drug‐Induced Systemic Mineralization: Case Study with aMEKInhibitor
Authors: Brown Alan P.
Published: March 2010

The nonclinical safety of PD0325901 was evaluated in Sprague‐Dawley rats given single oral or intravenous (IV) doses, in beagle dogs given oral and IV escalating doses, and in cynomolgus monkeys given escalating oral doses to assess acute toxicity and assist in dose selection for subsequent studies. A significant toxicity was observed that involved mineralization of vasculature and various soft tissues. This article focuses on the development of serum calcium and phosphorus as clinical biomarkers for drug‐induced systemic mineralization.
Opportunities and Pitfalls Associated with Early Utilization of Biomarkers: Case Study in Anticoagulant Development
Authors: Criswell Kay A.
Published: March 2010

All pharmaceutical companies are focusing on ways, such as improving target validation, selecting candidates with a greater chance of success, and identifying those compounds that will fail earlier in their development, to reduce the cost of discovering and developing new drugs. Therefore, developing a strategy for development of safety and efficacy biomarkers is key to early prediction of compound success or failure. This article focuses on opportunities and pitfalls associated with early utilization of biomarkers in drug development process.
Funding Biomarker Research and Development through the Small Business Innovative Research Program
Authors: Varani James
Published: March 2010

Obtaining funds through the Small Business Innovative Research (SBIR) program is every bit as challenging as being successful through the traditional mechanisms. One can increase the chances of being successful by understanding the process and by carefully studying past successes as well as past failures. This article discusses some of the key features of the SBIR program and things that may increase the likelihood of success in funding a biomarker‐development project through the SBIR program.
Novel and Traditional Nonclinical Biomarker Utilization in the Estimation of Pharmaceutical Therapeutic Indices
Authors: Car Bruce D. , Gemzik Brian , Foster William R.
Published: March 2010

Accurate determination of therapeutic indices from nonclinical studies across multiple species provides an invaluable tool for advancing compounds with reduced potential for harm and reduced likelihood of attrition for safety concerns. The robustness of those estimates over time is also central to the ability to conduct proof‐of‐concept studies in humans in phases IIa and IIb. This article focuses on novel and traditional nonclinical biomarker utilization in the estimation of pharmaceutical therapeutic indices.
Optimizing the Use of Biomarkers for Drug Development: A Clinician's Perspective
Authors: Gimona Alberto
Published: March 2010

The need for the pharmaceutical industry to increase its productivity and, in particular, the need to concentrate the available limited resources to the most promising drug candidates lead to the current emphasis on development and use of biomarkers. Biomarkers predict the efficacy of a compound at the early stage of development, increasing the efficiency of the development process. This article provides clinician's perspective on optimizing the use of biomarkers for drug development.
Strategies for the Cytosolic Delivery of Macromolecules: An Overview
Authors: Asokan Aravind , Cheung Roland , Cho Moo J.
Published: March 2010

The advent of molecular biology and genetics has identified numerous biotechnology‐derived macromolecular drugs as potential targets for development. The delivery of small molecules requires compromise between aqueous solubility and membrane partition properties while that of proteins and genes requires protection from enzymatic degradation and denaturation. This article focuses on strategies to promote the cytosolic delivery of macromolecular therapeutics.
Pharmaceutical Bioassay
Authors: Li Jun , Zhao Ming , Peng Shiqi
Published: March 2010

This article focuses on various types of biopharmaceutical bioassays, such as toxicity bioassay, antiviral assay, anticancer assay, hepatoxicity assay, hepatoprotective assay, anti‐inflammatory assay, thrombus‐related assay, immunomodulating assay, estrogen assay, antimalarial assay, and blood pressure‐related assay. The elucidation of the mechanisms of special enzymes provides the bases for highly specific and sensitive bioassays focused on the target enzymes and cells. Lux‐Fluoro assay is developed on specific lesions for cells induced by DNA damaging chemicals may lead to cell death or induce an error‐prone repair pathway leading to mutagenesis and cancer induction.
Genetic Markers and Genotyping Analyses for Genetic Disease Studies
Authors: Kwitek Anne E. , Olivier Michael
Published: March 2010

Major research efforts have resulted in a sequence of information for many genomes, providing a tremendous resource for biomedical researchers to examine gene sequences, their regulation, and their role in health and disease. The discovery of the microsatellite as a highly polymorphic genetic marker, and its ability to generate genotypes in a high‐throughput manner, revolutionized genetic analyses of disease and greatly facilitated the mapping and sequencing of not only the human genome. This article focuses on different genotyping approaches commonly used in genetic laboratories.
Pharmacokinetics
Authors: Shibata Nobuhito , Ito Yukako , Takada Kanji
Published: March 2010

Recombinant DNA technology has produced many proteins and peptides drugs in large scale, and they are becoming increasingly important as therapeutic agents. The successful development of recombinant proteins depends on the proper characterization of their pharmacokinetics and an understanding of the relationship between drug exposure or dose and the pharmacological response. This article describes the pharmacokinetics of clinically important peptide/protein drugs, such as insulin, erythropoietin (EPO), granulocyte‐colony stimulating factor (G‐CSF), interferon, growth hormone, leuprolide, desmopressin, and antibodies in relation to their administration routes and formulations.
Pharmacokinetics Of Nucleic‐Acid‐Based Therapeutics
Authors: Schmitz John C. , Pandyra Aleksandra , Koropatnick James , Berg Randal W.
Published: March 2010

Nucleic‐acid‐based therapies consist of various forms of gene and antisense therapeutics. Gene and antisense therapeutics have unique applications based on local delivery, which limits the distribution of the therapeutic in the body and precludes considerations of their pharmacokinetics (PK). This article presents chemical structures of antisense oligonucleotides (ASOs) being developed as therapeutics and the published animal and human PK data regarding ASOs of two chemistries, exemplified by Genasense and OGX‐011.
Growth Factors and Cytokines
Authors: Mann Mandeep K. , Cairns Brian E.
Published: March 2010

Neurotrophic factors, such as nerve growth factor (NGF) and cytokines, are involved in nociceptive and neuropathic pain conditions, such as diabetic peripheral neuropathies. It is also observed that intramuscular injection of human NGF at a concentration equivalent to that which resulted in mechanical sensitization in humans caused a significant decrease in the mechanical threshold of rat masseter muscle afferent fibers. This article focuses on NGF and tumor necrosis factor alpha and their role in the mechanisms of neuropathic and nociceptive pain.
Protein Engineering with Noncoded Amino Acids: Applications to Hirudin
Authors: De Filippis Vincenzo
Published: March 2010

The incorporation of noncoded amino acids into proteins has emerged as a novel and promising approach in protein science. Several different strategies are being pursued to incorporate noncoded amino acids, including peptide synthesis native chemical ligation, enzyme‐catalyzed semisynthesis, biosynthetic incorporation
via
auxotrophic bacterial strain expression, and nonsense suppression methodologies in cell‐free or whole‐cell expression systems. This article discusses the use of noncoded amino acids in structure‐activity relationship (SAR) studies of hirudin binding to thrombin, as well as the incorporation of noncoded analogs of tryptophan and tyrosine as spectroscopic probes for studying the hirudin‐thrombin interaction.
Manufacturing Specialties
Authors: Carl Stephen M. , Lindley David J. , Knipp Gregory T. , Morris Kenneth R. , Oliver Erin , Becker Gerald W. , Arnold Robert D.
Published: March 2010

Recent advances in molecular and cellular biological techniques and the potential clinical benefits of biotechnology drug products have led to a substantial increase in their development by biotechnology and traditional pharmaceutical companies. As the clinical importance and commercial potential for biological products grows, new challenges are arising based on the many technological limitations related to the development and marketing of these complex agents. This article focuses on some of the fundamental issues associated with successful biopharmaceutical drug product development and aims to provide an understanding of the subtleties associated with their characterization, processing, and manufacturing.
Oil‐in‐Water Nanosized Emulsions: Medical Applications
Authors: Tamilvanan Shunmugaperumal
Published: March 2010

Oil‐in‐water (o/w) nanosized emulsions have been used for enhancing lipophilic drug absorption and clinical efficacy of lipophilic drugs. Due to their subcellular and submicrometer size, emulsions allow for efficient delivery of therapeutic agents to target sites in the body. This chapter focuses on the classification, preparation, and medical applications of o/w nanosized emulsions.
Quality Process Improvement
Authors: Wang Jyh‐hone
Published: March 2010

Quality process improvement follows the steps of process diagnosis, process stabilization, process improvement, and process performance improvement. Various tools and methods can be applied to each step for an efficient quality process. This article discusses the steps of quality process improvement and the tools and methods that can be used in each step of the process.
Chemical Imaging and Chemometrics: Useful Tools for Process Analytical Technology
Authors: Roggo Yves , Ulmschneider Michel
Published: March 2010

Chemical imaging or vibrational hyperspectral imaging is a form of imaging in which chemical information from spectroscopy is combined with spatial information. Hyperspectral images can be collected with a single‐point detector, however array detectors measure all pixels simultaneously, reduce recording time, provide uniform background, and improve the signal‐to‐noise ratio. This article defines chemical imaging and describes image formation and instrumentation in chemical imaging.
Analytical Method Validation and Quality Assurance
Authors: Taverniers Isabel , Van Bockstaele Erik , De Loose Marc
Published: March 2010

Due to fast development of analytical methodologies, great importance is nowadays attached to the quality and reliability of the measurement data. This is influenced by a higher demand for regulatory compliance and under more exigent European and international standards such as the International Organization of Standardization/International Electrotechnical Commission 17025 norm for laboratory accreditation. This article focuses on method validation, traceability, measurement uncertainty (MU) of results, standardization, internal quality control (IQC), external quality control (EQC), and the role of method validation within quality assurance (QA).
Modeling transdermal permeation. Part 2. Predicting the dermatopharmacokinetics of percutaneous solute
Authors: Lian Guoping , Chen Longjian , Pudney Paul D. A. , Mélot Mickaël , Han Lujia
Published: March 2010

The prediction of percutaneous absorption and bioavailability in vivo, using the recently reported “bricks‐and‐mortar” model is discussed. Two sets of in vivo data have been simulated: the tape‐striping data of 4‐cyanophenol and Raman spectrometry data of transretinol. The predicted transdermal permeation using theoretically derived properties agreed well with the experimental data. The prediction shows that about 2/3 of the 4‐cynophenol in the SC partitioned into the corneocytes, indicating diffusion of moderately hydrophobic solutes across the corneocytes is also important. Only for highly hydrophobic solute like transretinol, diffusion across the corneocytes is negligibly small. The study demonstrates that with the mechanism‐based computer model, many dermatopharmacokinetic parameters can be derived, providing much insight into how vehicle formulation and topical administration affects the absorption and distribution of solute in the SC, as well as its bioavailability in epidermis/dermis. © 2010 American Institute of Chemical Engineers AIChE J, 2010
Serum immunoglobulin free light chain measurements and heavy chain isotype usage provide insight into disease biology in patients with POEMS syndrome
Authors: Stankowski‐Drengler Trista , Gertz Morie A. , Katzmann Jerry A , Lacy Martha Q. , Kumar Shaji , Leung Nelson , Hayman Suzanne R. , Buadi Francis , Kyle Robert A. , Rajkumar S. Vincent , Dispenzieri Angela
Published: March 2010

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome is a rare paraneoplastic syndrome in which nearly all patients have a monoclonal lambda restricted plasma cell disorder. We investigated whether patients with POEMS have abnormal serum immunoglobulin free light chain (FLC) ratios. Fifty patients with newly diagnosed POEMS syndrome were assessed. Cystatin C levels were measured to discern whether subclinical renal insufficiency could account for FLC elevations in the presence of a normal FLC ratio. Forty‐five patients (90%) had elevated lambda FLC; however, only nine (18%) had abnormal FLC ratios. The rise in serum FLC of POEMS patients appeared to be multifactorial—both a function of subclinical renal insufficiency and polyclonal activation of medullary and extramedullary plasma cells. Those patients expressing a clonal IgA were more likely to have clonal plasmacytosis observed on iliac crest biopsy than those with IgG. In summary, serum immunoglobulin profiles are unique in POEMS syndrome as compared with other plasma cell disorders. Am. J. Hematol. 2010. © 2010 Wiley‐Liss, Inc.
Novel Conjugates of Aspirin with Phenolic Acid as Anti‐inflammatory Agents Having Significantly Reduced Gastrointestinal Toxicity
Authors: Jiang Shan , Ding Ning , Zhang Wei , Zhang Yichun , Geng Meiyu , Li Yingxia
Published: March 2010

A series of novel conjugates of aspirin with natural phenolic acid antioxidants connected through a diol linker were designed and synthesized as potential bifunctional agents combining antioxidant and anti‐inflammatory activity for reducing gastrointestinal toxicity. In general, the conjugates were found to be efficient antioxidants and many of them demonstrated much more potent anti‐inflammatory activity than aspirin. Among them, 5a and 5b which bear the best anti‐inflammatory activity exhibited significantly reduced ulcerogenic potency and toxicity compared to aspirin. However, it is evident that the anti‐inflammatory activity of these dual‐acting molecules in vivo, was not simply consistent with their antioxidant ability in vitro.
Synthesis and in‐vitro Cytotoxic Evaluation of Novel Pyridazin‐4‐one Derivatives
Authors: Mojahidi Souad , Rakib El Mostapha , Sekkak Hanan , Abouricha Said , Benchat Nouredine , Mousse Hassan Ait , Zyad Abdelmajid
Published: March 2010

A new series of N‐aryl‐4‐oxo‐1,4‐dihydro‐pyridazine‐3‐carboxylic acids has been synthesized by condensation of aryldiazonium with 4‐hydroxy‐6‐methyl‐2‐pyrone. Some of these compounds exhibited in‐vitro cytotoxic activity with moderate to excellent growth inhibition against the murine P815 mastocytoma cell line. Compound 5b showed an important cytotoxic activity against cell line P815 (IC50 = 0.40 μg/mL).
Regulation of CCN2/Connective tissue growth factor expression in the nucleus pulposus of the intervertebral disc: Role of Smad and activator protein 1 signaling
Authors: Tran Cassie M. , Markova Dessislava , Smith Harvey E. , Susarla Bala , Ponnappan Ravi Kumar , Anderson D. Greg , Symes Aviva , Shapiro Irving M. , Risbud Makarand V.
Published: March 2010

Objective

To investigate transforming growth factor β (TGFβ) regulation of connective tissue growth factor (CTGF) expression in cells of the nucleus pulposus of rats, mice, and humans.

Methods

Real‐time reverse transcription–polymerase chain reaction and Western blot analyses were used to measure CTGF expression in the nucleus pulposus. Transfections were used to measure the effects of Smads 2, 3, and 7 and activator protein 1 (AP‐1) on TGFβ‐mediated CTGF promoter activity.

Results

CTGF expression was lower in neonatal rat discs than in skeletally mature rat discs. An increase in CTGF expression and promoter activity was observed in rat nucleus pulposus cells after TGFβ treatment. Deletion analysis indicated that promoter constructs lacking Smad and AP‐1 motifs were unresponsive to treatment. Analysis showed that full‐length Smad3 and the Smad3 MH‐2 domain alone increased CTGF activity. Further evidence of Smad3 and AP‐1 involvement was seen when DN‐Smad3, SiRNA‐Smad3, Smad7, and DN‐AP‐1 suppressed TGFβ‐mediated activation of the CTGF promoter. When either Smad3 or AP‐1 sites were mutated, CTGF promoter induction by TGFβ was suppressed. We also observed a decrease in the expression of CTGF in discs from Smad3‐null mice as compared with those from wild‐type mice. Analysis of human nucleus pulposus samples indicated a trend toward increasing CTGF and TGFβ expression in the degenerated state.

Conclusion

TGFβ, through Smad3 and AP‐1, serves as a positive regulator of CTGF expression in the nucleus pulposus. We propose that CTGF is a part of the limited reparative response of the degenerated disc.
A randomized, double‐blind, controlled study of ultrasound‐guided corticosteroid injection into the joint of patients with inflammatory arthritis
Authors: Cunnington Joanna , Marshall Nicola , Hide Geoff , Bracewell Claire , Isaacs John , Platt Philip , Kane David
Published: March 2010

Objective

Most corticosteroid injections into the joint are guided by the clinical examination (CE), but up to 70% are inaccurately placed, which may contribute to an inadequate response. The aim of this study was to investigate whether ultrasound (US) guidance improves the accuracy and clinical outcome of joint injections as compared with CE guidance in patients with inflammatory arthritis.

Methods

A total of 184 patients with inflammatory arthritis and an inflamed joint (shoulder, elbow, wrist, knee, or ankle) were randomized to receive either US‐guided or CE‐guided corticosteroid injections. Visual analog scales (VAS) for assessment of function, pain, and stiffness of the target joint, a modified Health Assessment Questionnaire, and the EuroQol 5‐domain questionnaire were obtained at baseline and at 2 weeks and 6 weeks postinjection. The erythrocyte sedimentation rate and C‐reactive protein level were measured at baseline and 2 weeks. Contrast injected with the steroid was used to assess the accuracy of the joint injection.

Results

One‐third of CE‐guided injections were inaccurate. US‐guided injections performed by a trainee rheumatologist were more accurate than the CE‐guided injections performed by more senior rheumatologists (83% versus 66%; P = 0.010). There was no significant difference in clinical outcome between the group receiving US‐guided injections and the group receiving CE‐guided injections. Accurate injections led to greater improvement in joint function, as determined by VAS scores, at 6 weeks, as compared with inaccurate injections (30.6 mm versus 21.2 mm; P = 0.030). Clinicians who used US guidance reliably assessed the accuracy of joint injection (P < 0.001), whereas those who used CE guidance did not (P = 0.29).

Conclusion

US guidance significantly improves the accuracy of joint injection, allowing a trainee to rapidly achieve higher accuracy than more experienced rheumatologists. US guidance did not improve the short‐term outcome of joint injection.
Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus‐prone mice
Authors: Deng Guo‐Min , Liu Lena , Bahjat Frances Rena , Pine Polly R. , Tsokos George C.
Published: March 2010

Objective

Spleen tyrosine kinase (Syk) is involved in membrane‐mediated signaling in various cells, including immune cells. It is overexpressed in T cells from patients with systemic lupus erythematosus (SLE), and its inhibition has been shown to improve T cell function as well as to improve disease manifestations in (NZB × NZW)F1 lupus‐prone mice and in patients with rheumatoid arthritis. While clinical trials examining Syk inhibition in patients with SLE are being considered, the aim of our experiments was to determine whether the therapeutic effects of Syk inhibition extend to other strains of lupus‐prone mice and whether they result in improvement in skin disease and modification of established disease.

Methods

Female MRL/lpr or BAK/BAX mice were studied. Starting either at age 4 weeks (before disease) or at age 16 weeks (after established disease) and continuing for up to 16 weeks, mice were fed chow containing the Syk inhibitor R788 or control chow.

Results

We found that inhibition of Syk in MRL/lpr and BAK/BAX mice prevented the development of skin disease and significantly reduced established skin disease. Similarly, Syk inhibition reduced the size of the spleen and lymph nodes, suppressed the development of renal disease, and suppressed established renal disease. Discontinuation of treatment resulted in extended suppression of skin disease for at least 8 weeks and suppression of renal disease for 4 weeks.

Conclusion

Syk inhibition suppresses the development of lupus skin and kidney disease in lupus‐prone mice, suppresses established disease in lupus‐prone mice, and may represent a valuable treatment for patients with SLE.
Highly localized energy transfer induced by the interaction between a large vortex and four small vortices
Authors: Luo Zhexian , Ping Fan
Published: March 2010

The scale interaction is simulated using a two‐dimensional barotropic model with an initial condition of a large‐scale vortex accompanied with four small‐scale vortices. We show that both direct and inverse energy cascades occur simultaneously and that the spatial distribution of energy transfer flux across a moderate length scale is characterized by a highly localized configuration, which contains several closed systems with a spatial scale of 50–100 km embedded in two wave trains. This would imply that the temporal change of enstrophy at closed centers is more complex than that at noncenters. The increase of complexity is further correlated with amplification of the enstrophy difference, which is the value of enstrophy at t = 24 h minus that at the initial time. Copyright © 2010 Royal Meteorological Society
Analysis of work trips made by taxi in canadian cities
Authors: Kattan Lina , de Barros Alexandre , Wirasinghe S. C.
Published: March 2010

This paper presents two regression models for work trips made by taxi for the year 1996 and the year 2001, respectively for 25 Canadian cities. These regression models indicates the primary factors that influence work commuting by taxi. Two major factors are identified: the total number of work trips made by public transit and the total number of low‐income households. The 2001 regression model indicates an increase of the value of the transit commuter's coefficient from its 1996 figure. These results highlight the important role that taxis play in: (i) decreasing the demand for parking especially in urban cores and (ii) serving the transportation disadvantaged population especially in outlying areas poorly served by public transport. Copyright © 2010 John Wiley & Sons, Ltd.
Access mode choice behaviors of water transportation: a case of Bangkok
Authors: Park Dongjoo , Lee Seungjae , Kim Chansung , Choi Changho , Lee Chungwon
Published: March 2010

This research attempted to analyze the impacts of the enhancement of access modes to the main water transportation mode in Bangkok, Thailand. In order to achieve this purpose, access mode choice behaviors are modeled using the probability distribution function (PDF) model, the multinomial logit (MNL) model, and the nested logit (NL) model. The study also attempted to analyze the catchment areas for different access modes and the factors affecting them. Factors affecting the extent of the catchment area such as main haul distance were evaluated. Based on survey results, service attributes such as access cost, in‐vehicle travel time, and out‐of‐vehicle travel time (OVTT) were found to have a significant impact on access mode choice behavior. Socioeconomic factors such as age, gender, income, and occupation were found to affect access mode choice behavior as well. Apart from these factors, trip departure time, egress mode used, and main haul distance were also found to affect access mode choice behavior. It was evaluated that the NL model is most suitable to model access mode choice behavior. A selected NL model was applied in order to predict the impacts of adopting different policies. It was found that reducing in‐vehicle travel time, waiting time and/or cost of the bus ride gave most significant impact on the enhancement of access modes. As results of this study, various methods have been suggested to enhance the access/egress service of the water transportation. Copyright © 2010 John Wiley & Sons, Ltd.
Interaction of angiotensin receptor type 1 blockers with ATP‐binding cassette transporters
Authors: Weiss J. , Sauer A. , Divac N. , Herzog M. , Schwedhelm E. , Böger R. H. , Haefeli W. E. , Benndorf R. A.
Published: March 2010

ATP‐binding cassette (ABC)‐transporters, such as P‐glycoprotein (P‐gp/ABCB1), multidrug resistance‐associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC‐transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan‐cilexetil, irbesartan, losartan, olmesartan, olmesartan‐medoxomil, eprosartan) on ABC‐transporter activityin vitro. P‐gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ™ Kit. Induction of P‐gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P‐gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P‐gp currently known (IC50=0.38±0.2 µMfor murine P‐gp) and it also inhibited human BCRP (IC50=16.9±8.1 µM) and human MRP2 (IC50=25.4±0.6 µM). Moreover, the prodrug candesartan‐cilexetil, but not candesartan itself, significantly inhibited P‐gp and BCRP activity. None of the compounds tested induced mRNA transcription of P‐gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC‐transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P‐gp and possibly also by BCRP or MRP2. Copyright © 2010 John Wiley & Sons, Ltd.
Organophosphorus compound detection on a cell chip with yeast coexpressing hydrolase and eGFP
Authors: Fukuda Takeshi , Tsuchiya Keiji , Makishima Hirokazu , Tsuchiyama Kouta , Mulchandani Ashok , Kuroda Kouichi , Ueda Mitsuyoshi , Suye Shin‐ichiro
Published: March 2010

Organophosphorus compounds (OPs) such as pesticides, fungicides, and herbicides are highly toxic but are nevertheless extensively used worldwide. To detect OPs, we constructed a yeast strain that co‐displays organophosphorus hydrolase (OPH) and enhanced green fluorescent protein (EGFP) on the cell surface using a Flo1p anchor system. OP degradation releases protons and causes a change in pH. This pH change results in structural deformation of EGFP, which triggers quenching of its fluorescence, thereby making this cell useful for visual detection of OPs. Fluorescence microscopy confirmed the high‐intensity fluorescence displayed by EGFP on the cell surface. The yeast strain possessed sufficient OPH hydrolytic activities for degrading OPs, as measured by incubation with 1 mM paraoxon for 24 h at 30°C. In addition, with 20 mM paraoxon at 30°C, fluorescence quenching of EGFP on the single yeast cell was observed within 40 s in a microchamber chip. These observations suggest that engineered yeast cells are suitable for simultaneous degradation and visual detection of OPs.
Iridium‐Catalyzed Asymmetric Hydrogenation of Imines
Authors: Baeza Alejandro , Pfaltz Andreas
Published: March 2010

We have evaluated a wide range of iridium complexes derived from chiral oxazoline‐based N,P ligands for the asymmetric hydrogenation of imines and identified three efficient catalysts. These catalysts are readily synthesized by straightforward convenient routes and are air and moisture stable. In the reduction of acetophenone N‐arylimines and related acyclic substrates, excellent enantioselectivities (up to 96 % ee) were obtained by using 0.1–0.5 mol % of catalyst at −20 °C and 5–50 bar hydrogen pressure.
A stereodynamic tripodal ligand with three different coordinating arms: Synthesis and zinc(II), copper(I) complexation study
Authors: Liang Jian , Canary James W.
Published: March 2010

A tetradentate tripodal ligand containing a chiral center and three different coordinating arms was designed and synthesized. Its complexation properties with ZnII and CuI were studied by NMR and optical spectroscopy. NMR experiments demonstrated the formation of two diastereomers, indicating the stabilization of the central tertiary amine configuration by metal coordination. The inversion of pyramidalization of the central tertiary amine of the ligand was found to be highly dependent upon metal ion, solvent, and temperature. Dynamic NMR measurements were used to estimate the energy of activation required for nitrogen atom inversion. Finally, absorption and circular dichroism measurements confirmed the expectation that metal complexes of the ligand gave rise to circular dichroism but that such spectra were not characterized by exciton‐coupling, in contrast to previously described ligands containing two identical arms with strong chromophores. Chirality 2011. © 2010 Wiley‐Liss, Inc.