bluuebunny/crossref_metadata_2025 huggingface dataset:
Excretion Systems
Authors: Maeda Kazuya , Sugiyama Yuichi
Published: October 2012

In previous chapters, the expression and function of metabolic enzymes and drug transporters have been overviewed as important factors dominating ADME (the absorption, disposition, metabolism, and excretion) of drugs. As common features, each metabolic enzyme and transporter consists of a wide variety of isoforms, and the substrate specificity of each isoform is very broad, thereby providing an evolutionary ability to protect the body against numerous kinds of xenobiotics. Thus, a single compound can often be recognized by multiple metabolic enzymes and transporters as a substrate because it partly overlaps with different isoforms of enzymes and transporters. These molecules are appropriately located at several tissues in the body and increase efficiency in the detoxification of xenobiotics. For example, in the liver, efficient detoxification can be achieved by the sequential processing of compounds, such as in the cellular uptake from the blood circulation to hepatocytes via influx transporters, phase I and II metabolism, and biliary excretion via efflux transporters.

In this chapter, we present an overview of how combinations of enzymes and transporters work concertedly as a detoxification “system”. Moreover, when evaluating the efficiency of detoxification quantitatively, because these molecules have different roles and do not function in parallel in this system, clearance of xenobiotics in each tissue cannot be expressed simply as the sum or product of an intrinsic clearance of each isoform of metabolic enzymes and transporters. Therefore, we will also discuss theoretical considerations and experimental methods to evaluate the influence of the function of each molecule on the overall efficiency of a detoxification system from the viewpoint of pharmacokinetics.
Pharmacokinetics and Toxicokinetics in Drug Discovery and Development
Authors: Varma Manthena V. S. , Radi Zaher A. , Rotter Charles J. , Litchfield John , El‐Kattan Ayman F.
Published: October 2012

Lack of efficacy and safety are considered to be the major contributing factors for drug failure in the clinic. Drug molecules with favorable pharmacokinetic profile are more borne to be both efficacious and safe. Therefore, inclusive preclinical pharmacokinetic assessment is a key to ensure compounds success in the clinic. This will be critical in weeding out weak clinical candidates early on. In addition, it is equally important to identify the probable causes of poor ADME exhibited by some compounds as this information is useful to medicinal chemists for improving upon backbones that exhibit un favorable pharmacokinetic profile.

Toxicity study is the foundation of an IND (Investigational new drug application) and therefore, the final selection of a compound can be performed only after proper toxicological evaluation in animal models. Toxicokinetics forms an integral part of toxicity study and is used to assess the exposure of candidates in toxicity models and correlate the drug levels in blood and various tissues with the toxicological findings. In this book chapter, an overview of the principles of drug pharmacokinetics and toxicokinetics is presented with introduction to the concepts of toxicogenomics and metabolites in safety testing.
Pharmacokinetic Data Analysis and Modeling ofADMEProcesses
Authors: Zhang Steven
Published: October 2012

The PK of unchanged drug and the pseudo‐PK parameters of total radioactivity (TRA) must be estimated in human ADME studies. With multiple PK samples collected in plasma and excreta, the PK parameters that represent the extent of a drug in or clearance from the circulation system are readily determined using a noncompartment approach that can be executed quickly in routine and traditional PK data analysis without assumption on disposition of drug in the body. Mechanism‐ or compartment‐based PK models contain specific expression to characterize, in a quantitative manner, processes on the causal path from absorption, distribution, and metabolism to elimination. Data analysis using modeling will provide information on not only the extent of a drug in the body but also the rate of a drug transferring through different parts of the body. Pooling PK data from a human ADME together with the data from the other studies of the same molecule can help scientists build a more robust population PK model, which can be used in interpreting or predicting the underlying physiological or pathological processes that drugs act on and for optimizing therapy with drugs that have a complex disposition.
Pharmacodynamics
Authors: Rao Indranil , Vinay HK , Mandlekar Sandhya
Published: October 2012

Pharmacodynamics is the science which deals with the physiological effects of drug on the body. A drug after reaching the blood circulation is transported to its target which may be a receptor or an enzyme which the drug agonizes or inhibits. This causes a response which can be measured and are known as biomarkers. Mathematical methods are then used to describe their temporal profile and further, to predict the effect at different doses, or help in design of further studies. This chapter deals with basic aspects of pharmacodynamics such as targets; types of actions; biomarkers; and a variety of mathematical models and methods.
Translational Drug Discovery Research: Integration of Medicinal Chemistry, Computational Modeling, Pharmacology,ADME, and Toxicology
Authors: Vangala Subrahmanyam , Pinjari Jakir , Patole Prashant , Ravindran Selvan , Gangal Rajeev , Wangikar Pralhad , Basu Sudipta , Ahmed Tausif , Rastogi Himanshu
Published: October 2012

Discovering a new drug is a complex but sequential process from discovery to preclinical development, followed with clinical drug development. It has been estimated that ∼ 87% of the phase III failures are accounted for either due to lack of efficacy (66%) or due to safety issues (21%). Majority of these failures are for compounds targeted for novel mechanisms of actions with unmet medical need, in particular, oncology and neurodegenerative disorders. Some of the reasons for these failures can be attributed to lack of appropriate preclinical animal models, biomarkers/surrogate markers, and effective pharmacokinetic (PK)–pharmacodynamic (PD) evaluation during early drug discovery. Translational research that integrates computer‐aided drug design (CADD), PK, PD, drug metabolism (DM), and drug transport along with biomarkers and humanized animal models are instrumental in making informed decisions from early drug discovery through clinical development. The ability to correlate drug effect through modeling and simulations starts from early drug discovery and preclinical evaluation, including use of novel biomarkers. Such models validate the PK and PD relationships and provide a basis for their applications and guide the Phase I through Phase III clinical trials more effectively, minimizing the late stage failures. Thus, PK–PD evaluation has become an integral part of drug discovery and provides valuable insights to aid in optimizing the next steps for drug development. This chapter is focused on translational drug discovery research with particular emphasis on selective utilization of CADD; absorption, distribution, metabolism, and excretion; toxicology; PK; and PD evaluations, which identify potential liabilities early so as to minimize late‐stage failures during drug development. This chapter also provides a brief overview on means and measures that can be adopted to integrate early drug discovery research along with efficacy and safety biomarkers for meaningful transition to drug development.
ADMEof Natural Toxins
Authors: González‐Pérez Vanessa , Kroll David J.
Published: October 2012

A common myth among the general public is that any substance derived from nature is inherently safe. To the contrary, some of the most potent and specifically‐targeted toxins have been identified and isolated from plants, mushrooms, and microorganisms. With regard to this volume, many of these toxins are of particular relevance in the pharmacokinetic study of xenobiotics, particularly their metabolism. This chapter highlights a select group of primarily small molecule toxins or protoxins of historical (i.e., aflatoxins) or contemporary (i.e., mycotoxins from “toxic mold”) relevance. Marine peptide toxins are intentionally omitted to maintain focus but are an additional class of highly‐selective acute and potentially lethal toxins from nature.
Methods for Determination of Enzyme Kinetics and Metabolic Rates
Authors: Subramanian Murali , Tracy Timothy S.
Published: October 2012

Determination of the enzyme kinetics and clearance mechanisms of new chemical entities is critical in assessing their viability as new drug therapies. The first step in this process is choosing the appropriatein vitrosystem for these analyses. While liver microsomes are the most widely used system, they may not be the most appropriate if conjugative enzymes play a key role in the clearance pathways, where human hepatocytes may be more useful. Finally, expressed enzyme systems can provide some advantages in determining specific enzyme involvement. Overcoming the challenges of poorly metabolized compounds further complicates selection of the rightin vitrosystem. Once the appropriate biological test system has been identified enzyme kinetic parameters, includingVmaxandKm, can be determined. Optimally, determination of enzyme kinetic parameters is accomplished by measuring production of metabolite(s), but in cases where authentic standards of metabolites are not available, substrate depletion experiments may provide reasonable estimates. However, occasionally, atypical kinetics (non‐hyperbolic) may also be observed and appropriate kinetic models must be applied to assure thatin vitro–in vivocorrelations utilize the appropriateVmaxandKmvalues. In either case, typical or atypical kinetics, thein vitrokinetic parameters are subsequently scaled to predictin vivometabolic clearance, a critical step in making dose projections of the new chemical entity.
Utility of Molecular‐BasedIn VitroAssays in Metabolic Liability of Drug Candidates
Authors: Lee Ji Young , Moeller Timothy A. , Shipman Rob , Kaushansky Alexis , Sahi Jasminder
Published: October 2012

Molecular‐based assays provide valuable information on the metabolic and toxicological liabilities of drug candidates afterin vitroandin vivotreatments. Pharmacogenetic and pharmacogenomic evaluations related to drug transport, metabolism, and safety have improved our understanding of the functional variability of genes involved in drug disposition. DNA and protein microarrays have helped to explain the effects of some genetic polymorphisms on drug disposition and idiosyncratic toxicities in subsets of populations. Nucleic‐acid‐based microarrays use DNA or mRNA fragments that hybridize specifically with complementary sequences and provide quantitative data on the effects of drug treatment on individual genes. Arrays can be customized to specifically understand ADME‐related changes in a limited number of genes or utilized to evaluate thousands of genes in order to form a more holistic picture of gene/protein changes after drug treatment as compared to parallel controls. Protein microarray technology is often used to complement the gene arrays and to study protein–ligand interactions. Microarrays are also used to study toxicogenomics, and the data are integrated to get an overall picture of the absorption, distribution, metabolism, excretion, and toxicology (ADMET) profile of a drug candidate. Thus, genomic and proteomic investigations coupled with computational analyses provide more predictive extrapolations of the ADMET profile of drug candidates.
In Vitro
Liver Systems to Study Induction/Inhibition: Prediction of
In Vivo
Metabolism and Drug–Drug Interactions
Authors: Komura Hiroshi , Iwaki Masahiro
Published: October 2012

This chapter was the review focused on the evaluation systems for metabolic stability, CYP inhibition and induction not only in the selection process of development candidates including lead optimizations in drug discovery but also to support a design of clinical studies in drug development. In the former process, the advanced
in vitro
systems have been developed, associating with an inevitable paradigm shift from the throughput to the quality. The similar trend has been gradually transmitted to the prediction of clearance and DDI. The predictions appeared to be in the movement from the basic models to the more mechanistic models including PBPK.
Precision‐Cut Tissue Slices: A SuitableIn VitroSystem for the Study of the Induction of Drug‐Metabolizing Enzyme Systems
Authors: Ioannides Costas , Lake Brian G.
Published: October 2012

Most xenobiotic‐metabolising enzyme systems, and in particular the cytochromes P450, may be markedly up‐regulated following exposure to inducing agents. A rise in activity of these enzyme systems may lead to drug interactions with adverse or even fatal outcomes. Furthermore, modulation of these enzyme systems may bring about a profound change in an individual's susceptibility to a chemical toxin. The use of precision‐cut tissue slices as anin vitrosystem allows the rapid and facile investigation of the potential of a chemical to induce cytochrome P450 and other xenobiotic‐metabolising enzymes in different animal species, as well as in humans. Various tissues (e.g. liver, lung, intestine) can be used, and the effect of chemicals investigated in a concentration‐dependent manner, and employing a number of endpoints.
Integrated Approaches to Blood–Brain Barrier
Authors: Rong Haojing , Feng Bo , Di Li
Published: October 2012

In vivo, in vitroandin silicomethodologies are discussed to address the challenges of CNS drug discovery and development. The most important parameter that governsin vivopharmacology is the free drug concentration at the site of action in the brain. Four different approaches can be used to estimate free drug concentration in human brain. Lessons learned on prediction successes are highlighted using thirty‐two Pfizer clinical drug candidates with human CSF and/or receptor occupancy data.
Why Do We Need
In Vivo
Models in Drug Metabolism?
Authors: Beaumont Kevin
Published: October 2012

Despite the significant improvements in the use of
in silico
and
in vitro
models in drug metabolism, preclinical animal experiments are still required to fully understand drug disposition. Most drug discovery and development programs target human disease and so such
in vivo
experiments must be translatable to human. This is a problem since animals express different drug metabolizing enzymes and drug transporters and have different blood flow values to those in human. Consequently, pharmacokinetics and disposition can be very different between animals and humans. In general, passive processes (such as oral absorption, distribution of unbound drug and passive renal elimination scale well from animals to human. Scaling of active processes (such as metabolism and drug transport) can be prone to significant species differences, and require significant care in extrapolation to human. Due to gut physiology and species differences in metabolism, preclinical food effects and drug‐drug interaction studies are not recommended.
Utility of Genetically Modified Animal Models for Drug Metabolism and Drug Transporters
Authors: Bessire Andrew , Youdim Kuresh , Hurst Susan , Lee Caroline A.
Published: October 2012

Genetically modified animals (GEMA) providein vivotools to understand the role of enzymes, transcriptional factors, and transporters in drug disposition and drug toxicities. Several phase I and II enzymes, transcriptional factors, and the clinically relevant drug transporters have been reviewed in this chapter by highlighting how the animal models have elucidated or validated their role in drug disposition, endogenous substrate regulation, or drug toxicities. The utility of animal models in research and drug development providesin vivotools to gain a better understanding of the role of drug‐metabolizing enzymes, transcriptional factors, and transporters in the absorption, disposition, metabolism, and drug‐related toxicities.
General Principles of Mass Spectrometry:GC‐MS,LC‐MS, andLC‐MS/MS
Authors: Thomas Brian F. , Daw Richard C. , Grabenauer Megan
Published: October 2012

A variety of mass spectrometry techniques aid in both targeted and nontargeted analyses. This chapter introduces some of the most prevalent instrumentation for example, quadrupole, ion trap, and, time‐of‐flight mass spectrometers, as well as hybrid instrument configurations. Beyond the instrumentation itself, successful analytical techniques rely on a number of experimental design considerations including suitable ionization mechanisms, chromatographic approaches, and appropriate derivatization reactions. The most robust techniques applied toward structural elucidation, metabolite identification, or biomarker discovery involve high resolution accurate mass data, enabling isotope pattern analysis and mass defect filtering, as well an array of other data acquisition and processing techniques that capitalize on the enhanced mass accuracy. These advanced techniques are becoming more routine because of increases in computational power and advances in software tools to aid in data processing and interpretation.
A Perspective on the Evolving Field of Ambient Ionization Mass Spectrometry
Authors: Bereman Michael S.
Published: October 2012

Ambient ionization mass spectrometry is a rapidly expanding field with applications ranging from biology, pharmaceuticals, polymers, environmental analysis to national security. These techniques perform ionization at atmospheric pressure with minimal sample preparation. The rate of introduction of these techniques has increased significantly over the last decade. In this chapter, methods are explained with schematics, and limitations of each method are discussed where applicable. Finally, several applications of these techniques are given using examples from the recent literature reports.
The Role of Biomarkers in Drug Discovery and Development: Enabling PK/PD
Authors: Szekely‐Klepser Gabriella , Kindt Erick
Published: October 2012

The goal of drug discovery and development is to find the right drug and to administer it at the right dose with the right frequency to the right patient. Biomarkers can be an invaluable tool to enable meeting this goal by confirming the efficacy and safety of drug candidates, providing an understanding of their mechanism of action, and determining the efficacious dose and dosing regimen by establishing the correlation between the pharmacokinetics (PK) and pharmacodynamics (PD) of the drugs. This chapter provides a definition of biomarkers and illustrates their roles and applications in pharmaceutical drug development.
Idiosyncratic Drug Reactions and the Potential Role of Metabolism
Authors: Uetrecht Jack P.
Published: October 2012

There is a large amount of circumstantial evidence that supports the hypothesis that most idiosyncratic drug reactions (IDRs) are caused by reactive metabolites rather than the parent drug. When the total daily dose is included in the calculation, there is a rough correlation between the amount of covalent binding and the risk that a drug will be associated with a significant incidence of IDRs, especially those affecting the liver. However, there are drugs that form a large amount of reactive metabolites and rarely cause IDRs, and there are drugs such as ximelagatran that do not appear to form reactive metabolites and yet had to be withdrawn from the market because of an unacceptable risk of IDRs.

There are a wide variety of proteins that are targets of covalent binding, and clearly, not all covalent binding is associated with the same risk of causing an IDR. It is likely that most IDRs are immune mediated, although this is not without controversy, especially with respect to idiosyncratic liver toxicity. There are several hypotheses that address the issue of how drugs initiate an immune response, but in the absence of valid animal models, they are very difficult to rigorously test. These hypotheses include the hapten hypothesis, the danger hypothesis, the p‐I (pharmacological interaction) hypothesis, epigenetic effects leading to activation of the immune system, direct activation of antigen‐presenting cells, and some of the newer biological agents simply appear to alter the balance in the immune system and do not involve reactive metabolites. It is likely that the mechanism by which different drugs induce an immune response is different, at least in detail. There are also hypotheses that do not involve the immune system such as mitochondrial toxicity and the inflammagen hypothesis.

In the absence of valid animal models, it is important to use the clinical characteristics of IDRs to evaluate the hypotheses. A very important characteristic is the usual delay between starting a drug and the onset of the IDR. Another important characteristic is that different drugs can cause different types of IDRs in different people and even the same drug can cause different types of IDRs in different people. This is most easily explained by an immune mechanism in which this variability is due to variability in T‐cell‐receptor specificity, which is different even in identical twins. However, until we have a much better understanding of the detailed mechanisms of IDRs, it will be difficult to predict which drug candidates are likely to cause a relatively high incidence of IDRs and which patients are at high risk of such adverse reactions.
Single‐Step Deposition of Au‐ and Pt‐Nanoparticle‐Functionalized Tungsten Oxide Nanoneedles Synthesized Via Aerosol‐Assisted CVD, and Used for Fabrication of Selective Gas Microsensor Arrays
Authors: Vallejos Stella , Umek Polona , Stoycheva Toni , Annanouch Fatima , Llobet Eduard , Correig Xavier , De Marco Patrizia , Bittencourt Carla , Blackman Chris
Published: October 2012

Tungsten oxide nanostructures functionalized with gold or platinum NPs are synthesized and integrated, using a single‐step method via aerosol‐assisted chemical vapour deposition, onto micro‐electromechanical system (MEMS)‐based gas‐sensor platforms. This co‐deposition method is demonstrated to be an effective route to incorporate metal nanoparticles (NP) or combinations of metal NPs into nanostructured materials, resulting in an attractive way of tuning functionality in metal oxides (MOX). The results show variations in electronic and sensing properties of tungsten oxide according to the metal NPs introduced, which are used to discriminate effectively analytes (C2H5OH, H2, and CO) that are present in proton‐exchange fuel cells. Improved sensing characteristics, in particular to H2, are observed at 250 °C with Pt‐functionalized tungsten oxide films, whereas non‐functionalized tungsten oxide films show responses to low concentrations of CO at low temperatures. Differences in the sensing characteristics of these films are attributed to the different reactivities of metal NPs (Au and Pt), and to the degree of electronic interaction at the MOX/metal NP interface. The method presented in this work has advantages over other methods of integrating nanomaterials and devices, of having fewer processing steps, relatively low processing temperature, and no requirement for substrate pre‐treatment.
Size‐Controlled Synthesis of Cu2‐xE (E = S, Se) Nanocrystals with Strong Tunable Near‐Infrared Localized Surface Plasmon Resonance and High Conductivity in Thin Films
Authors: Liu Xin , Wang Xianliang , Zhou Bin , Law Wing‐Cheung , Cartwright Alexander N. , Swihart Mark T.
Published: October 2012

A facile method for preparing highly self‐doped Cu2‐xE (E = S, Se) nanocrystals (NCs) with controlled size in the range of 2.8–13.5 nm and 7.2–16.5 nm, for Cu2‐xS and Cu2‐xSe, respectively, is demonstrated. Strong near‐infrared localized surface plasmon resonance absorption is observed in the NCs, indicating that the as‐prepared particles are heavily p‐doped. The NIR plasmonic absorption is tuned by varying the amount of oleic acid used in synthesis. This effect is attributed to a reduction in the number of free carriers through surface interaction of the deprotonated carboxyl functional group of oleic acid with the NCs. This approach provides a new pathway to control both the size and the cationic deficiency of Cu2‐xSe and Cu2‐xS NCs. The high electrical conductivity exhibited by these NPs in metal‐semiconductor‐metal thin film devices shows promise for applications in printable field‐effect transistors and microelectronic devices.
A Novel Method to Precisely Assemble Loose Nanofiber Structures for Regenerative Medicine Applications
Authors: Beachley Vince , Katsanevakis Eleni , Zhang Ning , Wen Xuejun
Published: October 2012

Polymer nanofibers are favorable for tissue engineering scaffolds because of their high surface‐to‐volume ratio and biomimicry of the extracellular matrix. Random and uniaxially oriented polymer nanofibers are easily fabricated by conventional electrospinning techniques; however, control over fiber organization within nanofiber structures is limited when they are collected directly from an electrospinning jet. The regenerative medicine applications of electrospun scaffolds could be expanded by developing assembly methods that allow better control of fiber organization. Here, a novel technique is presented that utilizes parallel automated tracks to orient and collect nanofibers from an electrospinning jet. The stabilized fibers are then subsequently assembled into desirable structures. It is difficult to assemble complex structures directly from an electrospinning jet because of high electrical charge and velocities, so this technology adds an intermediate step where nanofibers are immobilized on automated tracks. The result is a continuous steady‐state delivery of static stabilized nanofibers that provides a unique and promising platform for automated post processing into useful nanofiber structures. This technique also allows for an indefinite amount of time, as determined by design parameters, for fibers to dry or cool before they contact other nanofibers in the collection site, thus eliminating potential for fiber‐to‐fiber adhesions even with slow evaporating solvents or high‐temperature melts. To demonstrate potential in regenerative medicine applications, several nanofiber structures were fabricated, including: 2D structures with well‐controlled fiber density; 3D loosely assembled aligned nanofiber structures with good cell penetration properties; and, complex layer‐by‐layer 3D aligned fiber structures assembled by integration with post‐processing techniques.
Extension of the Stöber Method to Construct Mesoporous SiO2 and TiO2 Shells for Uniform Multifunctional Core–Shell Structures
Authors: Li Wei , Zhao Dongyuan
Published: October 2012

Core–shell nanoparticles (CSNs) have attracted considerable attention because of their promising applications in a wide range of fields. Recently, substantial efforts have been focused on the development of facile and versatile methods for preparing CSNs with mesoporous SiO2 or TiO2 shells because of their fascinating properties, such as high surface area, large pore channels and high pore volume. This Research News reviews the recent progress in facile, versatile and reproducible approaches which are simply extended from the well‐known Stöber method to construct mesoporous SiO2 and TiO2 shells for uniform multifunctional core–shell nanostructures. Several strategies, including the surfactant‐templating process, the long‐chain organosilane‐assisted approach, the phase transfer assisted surfactant‐templating process, and the kinetics‐controlled coating approach, are discussed. In addition, new trends in this field for the creation of multifunctional CSNs and novel nanostructures are highlighted.
Feeding and Resting Postures of Wild Northern Muriquis (Brachyteles hypoxanthus)
Authors: IURCK MARIA F. , NOWAK MATTHEW G. , COSTA LENY C.M. , MENDES SÉRGIO L. , FORD SUSAN M. , STRIER KAREN B.
Published: October 2012

Increased body size in Brachyteles has been regarded as an important evolutionary adaptation that allowed a greater reliance on leaves compared to other more frugivorous Atelidae, but its association with muriqui positional behavior and substrate use is still unknown. Here, we present original data on the feeding and resting postures of the northern muriqui (Brachyteles hypoxanthus) and evaluate predictions about the relationships between body size, postural behavior, and substrate use derived from previously published data for other atelids (e.g. Alouatta, Ateles, and Lagothrix). The study was undertaken from August 2002 to July 2003 on a large group of well‐habituated muriquis inhabiting the Reserva Particular do Patrimônio Natural – Felíciano Miguel Abdala in Minas Gerais, Brazil. Consistent with our predictions, we found that B. hypoxanthus was highly suspensory during postural feeding (60.9%) and commonly used tail–hind limb suspension/horizontal tripod (38.0%) or tail–forelimb/hind limb suspension (21.4%). However, although tail‐suspensory postures permitted the muriquis to use the terminal canopy and small‐sized substrates, these areas were also accessed via tail‐assisted above‐branch postural behaviors involving multiple substrates. Unexpectedly, tail‐suspensory postures were found to be frequently associated with large substrates, tree trunks, and the understory. We suggest that Brachyteles’ ability to access food resources from all areas of a feeding tree and from tree crowns at different canopy levels may account for their ability to efficiently exploit food resources in seasonal disturbed forest fragments of the Brazilian Atlantic Forest today. Am. J. Primatol. 75:74‐87, 2013. © 2012 Wiley Periodicals, Inc.
Reducing the Ecological Impact of Field Research
Authors: BEZANSON MICHELLE , STOWE ROCHELLE , WATTS SEAN M.
Published: October 2012

Researchers and students at biological field stations, especially in remote areas, are subject to leaving “footprints,” as we conduct research, work, and live in sensitive ecosystems. These footprints include travel, personal trash and waste, and field equipment (e.g. flagging, tree markers, plot markers, trail markers, monitoring devices, etc.). In this commentary, we argue that the field of primatology's commitment to minimum impact research should be more explicitly and visibly integrated into our ethical protocols with regard to field research and instruction in sensitive environments. We review current ethical codes and potential solutions to reducing our “researcher footprints” while conducting fieldwork. UsingCostaRica as an example, we address how sustainable fieldwork differs among varying cultural contexts and argue that researchers should be made responsible and accountable for how our presence, research, and teaching might impact the environment. We conclude by recommending a set of guidelines to be added to ethical protocols regarding research design, station policies, and the conduct of research and teaching in the field. Am. J. Primatol. 75:1‐9, 2013. © 2012 Wiley Periodicals, Inc.
Synthesis and Selective Human Monoamine Oxidase B Inhibition of Heterocyclic Hybrids Based on Hydrazine and Thiazole Scaffolds
Authors: Carradori Simone , D'Ascenzio Melissa , De Monte Celeste , Secci Daniela , Yáñez Matilde
Published: October 2012

A new scaffold of hydrazothiazoles has been designed as monoamine oxidase (MAO) inhibitors combining the hydrazine moiety of iproniazid and the thiazole nucleus of glitazones, a class of peroxisome proliferator‐activated receptor (PPAR)γ agonists recently co‐crystallized with human MAO‐B. The resulting derivatives were synthesized and assayed to evaluate their in vitro activity against both the A and B isoforms of hMAO. All compounds were shown to be selective hMAO‐B inhibitors with IC50 values in the low micromolar/high nanomolar range. Such results suggest that the hydrazothiazole scaffold could be considered as an interesting pharmacophore for the future design of new lead compounds as coadjuvants for the treatment of neurodegenerative diseases.
Bibliometric perspectives on medical innovation using the medical subject Headings of PubMed
Authors: Leydesdorff Loet , Rotolo Daniele , Rafols Ismael
Published: October 2012

Multiple perspectives on the nonlinear processes of medical innovations can be distinguished and combined using the Medical Subject Headings (MeSH) of the MEDLINE database. Focusing on three main branches—“diseases,” “drugs and chemicals,” and “techniques and equipment”—we use base maps and overlay techniques to investigate the translations and interactions and thus to gain a bibliometric perspective on the dynamics of medical innovations. To this end, we first analyze the MEDLINE database, the MeSH index tree, and the various options for a static mapping from different perspectives and at different levels of aggregation. Following a specific innovation (RNA interference) over time, the notion of a trajectory which leaves a signature in the database is elaborated. Can the detailed index terms describing the dynamics of research be used to predict the diffusion dynamics of research results? Possibilities are specified for further integration between the MEDLINE database on one hand, and the Science Citation Index and Scopus (containing citation information) on the other.
Brain estrogen signaling effects acute modulation of acoustic communication behaviors: A working hypothesis
Authors: Remage‐Healey Luke
Published: October 2012

Although estrogens are widely considered circulating “sex steroid hormones” typically associated with female reproduction, recent evidence suggests that estrogens can act as local modulators of brain circuits in both males and females. The functional implications of this newly characterized estrogen signaling system have begun to emerge. This essay summarizes evidence in support of the hypothesis that the rapid production of estrogens in brain circuits can drive acute changes in both the production and perception of acoustic communication behaviors. These studies have revealed two fundamental neurobiological concepts: (1) estrogens can be locally produced in brain circuits, independent of levels in nearby circuits and in the circulation and (2) estrogens can have very rapid effects within these brain circuits to modulate social vocalizations, acoustic processing, and sensorimotor integration. This vertebrate‐wide span of research, including vocalizing fishes, amphibians, and birds, emphasizes the importance of comparative model systems in understanding principles of neurobiology.
DETECTING CHANGES IN NON‐SIMULATED EVENTS USING PARTIAL INTERVAL RECORDING AND MOMENTARY TIME SAMPLING: EVALUATING FALSE POSITIVES, FALSE NEGATIVES, AND TRENDING
Authors: Schmidt Megan G. , Rapp John T. , Novotny Marissa A. , Lood Elizabeth A.
Published: October 2012

Several studies have evaluated false positives and false negatives produced with partial interval recording (PIR) and momentary time sampling (MTS) using simulated data. However, no study to date has evaluated false positives and negatives using a large sample of non‐simulated behaviors. In addition, few studies have evaluated whether interval methods of data collection alter trends that are evident in continuous records. We conducted three experiments to evaluate the extent to which various interval sizes of MTS and PIR produced false negatives (Experiment 1), false positives (Experiment 2), and trends that were inconsistent with the continuous records (Experiment 3). Collectively, the results show the following: (i) 10‐s PIR and 10‐s MTS produced few false negatives and few false positives (i.e., both were sensitive) to changes in duration events; (ii) 10‐s PIR produced very few false negatives, but an unexpected high percentage of false positives for frequency events; and (iii) each interval size of PIR and MTS produced a high percentage of changes in trending for duration events and frequency events. We briefly discuss the potential limitations and clinical implications of these findings. Copyright © 2012 John Wiley & Sons, Ltd.
Quantification and validation of HPLC‐UV and LC‐MS assays for therapeutic drug monitoring of ertapenem in human plasma
Authors: Pickering Matthew , Brown Stacy
Published: October 2012

Rapid and simple HPLC‐UV and LC‐MS methods were developed and validated for the quantification of ertapenem (Invanz™) in human plasma. Ertapenem is a unique drug in that current dosing recommendations call for a 1 g dose for normal renal function patients, despite body weight. These assays, which involve a protein precipitation followed by liquid–liquid extraction, allow for fast therapeutic drug monitoring of ertapenem in patients, which is especially useful in special populations. Both methods were sufficient to baseline resolve meropenem (internal standard) and ertapenem, and were validated over 3 days using a six‐point calibration curve (0.5–50 µg/mL). Validation was collected using four different points on the calibrations curve yielding acceptable precision (<15% inter‐day and intra‐day; <20% for lower limit of quantitation, LLOQ) as well as accuracy (<15% inter‐day and intra‐day; <20% for LLOQ). The lower limit of detection (LOD) was determined to be 0.1 and 0.05 µg/mL for the HPLC‐UV and LC‐MS methods, respectively. The developed HPLC‐UV and LC‐MS methods for ertapenem quantification are fast, accurate and reproducible over the calibration range and can be used to determine ertapenem plasma concentrations for monitoring clinical efficacy. Copyright © 2012 John Wiley & Sons, Ltd.
Oriented immobilized anti‐hIgG via Fc fragment‐imprinted PHEMA cryogel for IgG purification
Authors: Bereli Nilay , Ertürk Gizem , Tümer M.Aşkın , Say Rıdvan , Denizli Adil
Published: October 2012

Antibodies are used in many applications, especially as diagnostic and therapeutic agents. Among the various techniques used for the purification of antibodies, immunoaffinity chromatography is by far the most common. For this purpose, oriented immobilization of antibodies is an important step for the efficiency of purification step. In this study, Fc fragment‐imprinted poly(hydroxyethyl methacrylate) cryogel (MIP) was prepared for the oriented immobilization of anti‐hIgG for IgG purification from human plasma. Non‐imprinted poly(hydroxyethyl methacrylate) cryogel (NIP) was also prepared for random immobilization of anti‐hIgG to compare the adsorption capacities of oriented (MIP/anti‐hIgG) and random (NIP/anti‐hIgG) cryogel columns. The amount of immobilized anti‐hIgG was 19.8 mg/g for the NIP column and 23.7 mg/g for the MIP column. Although the amount of immobilized anti‐hIgG was almost the same for the NIP and MIP columns, IgG adsorption capacity was found to be three times higher than the NIP/anti‐hIgG column (29.7 mg/g) for the MIP/anti‐hIgG column (86.9 mg/g). Higher IgG adsorption capacity was observed from human plasma (up to 106.4 mg/g) with the MIP/anti‐hIgG cryogel column. Adsorbed IgG was eluted using 1.0 m NaCl with a purity of 96.7%. The results obtained here are very encouraging and showed the usability of MIP/anti‐hIgG cryogel prepared via imprinting of Fc fragments as an alternative to conventional immunoaffinity techniques for IgG purification. Copyright © 2012 John Wiley & Sons, Ltd.
Synthesis and Structural Characterisation of Selective Non‐Carbohydrate‐Based Inhibitors of Bacterial Sialidases
Authors: Brear Paul , Telford Judith , Taylor Garry L. , Westwood Nicholas J.
Published: October 2012

The major human pathogen Streptococcus pneumoniae plays a key role in several disease states including septicaemia, meningitis and community‐acquired pneumonia. Although vaccines against S. pneumoniae are available as prophylactics, there remains a need to identify and characterise novel chemical entities that can treat the diseases caused by this pathogen. S. pneumoniae expresses three sialidases, enzymes that cleave sialic acid from carbohydrate‐based surface molecules. Two of these enzymes, NanA and NanB, have been implicated in the pathogenesis of S. pneumoniae and are considered to be validated drug targets. Here we report our studies on the synthesis and structural characterisation of novel NanB‐selective inhibitors that are inspired by the β‐amino‐sulfonic acid family of buffers.
When the Leader Gets Loose: In Vivo Biosynthesis of a Leaderless Prenisin Is Stimulated by a trans‐Acting Leader Peptide
Authors: Khusainov Rustem , Kuipers Oscar P.
Published: October 2012

The nisin leader is believed to be crucial for nisin biosynthesis. Here, by using a construct completely lacking the leader peptide, we show that an up to fivefold‐dehydrated leaderless prenisin can be obtained, as judged by MALDI‐TOF MS, and that some of these species are biologically active, thus suggesting that at least three lanthionine rings are present. Notably, by expressing the leader peptide in trans together with the leaderless prenisin, we were able to increase the dehydration/cyclization efficiency of both NisB and NisC, but still with limited efficiency until the fifth dehydratable residue (Thr13) was processed, thereby enabling three rings to form. This, for the first time, demonstrates that 1) the leader is not absolutely necessary for the dehydration reaction of class I lantibiotics to occur in vivo; 2) the leader acts in trans in vivo; 3) the leader increases the efficiency of modification. Based on previous work and our current study, a model for the interactions of NisB and NisC with prenisin is proposed, in which the leader induces a more active conformation and/or productive complex formation of the biosynthetic machinery, and, when covalently bound, is involved in increasing the efficiency of dehydration to the C‐terminal end of the prenisin substrate molecule.
Residue 75 of Interleukin‐8 is Crucial for its Interactions with Glycosaminoglycans
Authors: Nordsieck Karoline , Pichert Annelie , Samsonov Sergey A. , Thomas Lars , Berger Christian , Pisabarro M. Teresa , Huster Daniel , Beck‐Sickinger Annette G.
Published: October 2012

The interactions between regulatory proteins such as interleukin‐8 (IL‐8) and glycosaminoglycans are of great interest both for the general understanding of regulatory processes in biology and for the development of implant coatings and innovative materials that suppress undesired immune responses and improve wound healing. In previous work, a number of residues of IL‐8 that interact strongly with several glycosaminoglycans (GAGs) have been identified. In particular, the negatively charged Glu75 was reported to be involved in interactions with charged GAGs. To improve understanding of the role of this residue, we generated a selectively 15N‐labeled E75K variant of IL‐8(1–77) by expressed protein ligation. NMR and fluorescence spectroscopy in combination with molecular modeling were applied to evaluate the particular role of residue 75 in interactions with GAGs. Remarkably, more residues in the variant responded to GAG binding than in the wild‐type. For the first time, we identified amino acids 34 to 36 as additional residues in the loop region of IL‐8(1–77) that participate in the interactions with GAGs. These findings indicate that the N terminus of the E75K variant is more important as a second binding site for GAGs than that of the wild‐type IL‐8(1–77).
Stress Response in Microbiology. Edited by José M. Requena.
Authors: Shaw Lindsey N.
Published: October 2012

Horizon Press, Hethersett, 2012, X+436 pp., hardcover, £ 180.00.—ISBN 978‐1‐908230‐04‐1
Deprotonation‐Induced Aromaticity Enhancement and New Conjugated Networks in meso‐Hexakis(pentafluorophenyl)[26]hexaphyrin
Authors: Cha Won‐Young , Lim Jong Min , Yoon Min‐Chul , Sung Young Mo , Lee Byung Sun , Katsumata Sho , Suzuki Masaaki , Mori Hirotaka , Ikawa Yoshiya , Furuta Hiroyuki , Osuka Atsuhiro , Kim Dongho
Published: October 2012

meso‐Hexakis(pentafluorophenyl)‐substituted neutral hexaphyrin with a 26π‐electronic circuit can be regarded as a real homolog of porphyrin with an 18π‐electronic circuit with respect to a quite flat molecular structure and strong aromaticity. We have investigated additional aromaticity enhancement of meso‐hexakis(pentafluorophenyl)[26]hexaphyrin(1.1.1.1.1.1) by deprotonation of the inner NH groups in the macrocyclic molecular cavity to try to induce further structural planarization. Deprotonated mono‐ and dianions of [26]hexaphyrin display sharp B‐like bands, remarkably strong fluorescence, and long‐lived singlet and triplet excited‐states, which indicate enhanced aromaticity. Structural, spectroscopic, and computational studies have revealed that deprotonation induces structural deformations, which lead to a change in the main conjugated π‐electronic circuit and cause enhanced aromaticity.
Heteroleptic FeII Complexes of 2,2′‐Biimidazole and Its Alkylated Derivatives: Spin‐Crossover and Photomagnetic Behavior
Authors: Phan Hoa V. , Chakraborty Pradip , Chen Meimei , Calm Yitzi M. , Kovnir Kirill , Keniley Lawrence K. , Hoyt Jordan M. , Knowles Elisabeth S. , Besnard Céline , Meisel Mark W. , Hauser Andreas , Achim Catalina , Shatruk Michael
Published: October 2012

Three iron(II) complexes, [Fe(TPMA)(BIM)](ClO4)2⋅0.5H2O (1), [Fe(TPMA)(XBIM)](ClO4)2 (2), and [Fe(TPMA)(XBBIM)](ClO4)2 ⋅0.75CH3OH (3), were prepared by reactions of FeII perchlorate and the corresponding ligands (TPMA=tris(2‐pyridylmethyl)amine, BIM=2,2′‐biimidazole, XBIM=1,1′‐(α,α′‐o‐xylyl)‐2,2′‐biimidazole, XBBIM=1,1′‐(α,α′‐o‐xylyl)‐2,2′‐bibenzimidazole). The compounds were investigated by a combination of X‐ray crystallography, magnetic and photomagnetic measurements, and Mössbauer and optical absorption spectroscopy. Complex 1 exhibits a gradual spin crossover (SCO) with T1/2=190 K, whereas 2 exhibits an abrupt SCO with approximately 7 K thermal hysteresis (T1/2=196 K on cooling and 203 K on heating). Complex 3 is in the high‐spin state in the 2–300 K range. The difference in the magnetic behavior was traced to differences between the inter‐ and intramolecular interactions in 1 and 2. The crystal packing of 2 features a hierarchy of intermolecular interactions that result in increased cooperativity and abruptness of the spin transition. In 3, steric repulsion between H atoms of one of the pyridyl substituents of TPMA and one of the benzene rings of XBBIM results in a strong distortion of the FeII coordination environment, which stabilizes the high‐spin state of the complex. Both 1 and 2 exhibit a photoinduced low‐spin to high‐spin transition (LIESST effect) at 5 K. The difference in the character of intermolecular interactions of 1 and 2 also manifests in the kinetics of the decay of the photoinduced high‐spin state. For 1, the decay rate constant follows the single‐exponential law, whereas for 2 it is a stretched exponential, reflecting the hierarchical nature of intermolecular contacts. The structural parameters of the photoinduced high‐spin state at 50 K are similar to those determined for the high‐spin state at 295 K. This study shows that N‐alkylation of BIM has a negligible effect on the ligand field strength. Therefore, the combination of TPMA and BIM offers a promising ligand platform for the design of functionalized SCO complexes.