bluuebunny/crossref_metadata_2025 huggingface dataset:
Theories and Practices of Organizational Development
Authors: Austin John R. , Bartunek Jean M.
Published: November 2003

We review research on and the practice of Organization Development. Organization development has been an active area for research during the past decade, and current research benefits from well‐developed theoretical frameworks of organization change. Organization Development has also been a fertile ground for the development of change practice methodologies during this time. To organize this chapter, we distinguish between change process and implementation theories. Change process theories, which typically guide research on change, are sorted using Van de Ven and Poole's (1995) typology of teleologic, life‐cycle, dialectic, and evolutionary motors for change. Likewise, we categorize implementation theories, which typically guide the practice of change, by their underlying motors of participation, self‐reflection, action research, and narrative/rhetorical intervention. We identify some contemporary organization development interventions in terms of their implementation motors and indicate ways implementation and change process motors may complement each other. Despite their common interest in change, and complementary theoretical motors, we find that change process research and implementation research occupy relatively separate intellectual spheres. This divide is hindering further theory development regarding change. We outline some possible causes of the divide and propose strategies to bridge it.
Changes in Workers, Work, and Organizations
Authors: Cascio Wayne F.
Published: November 2003

Demographic changes and increasing cultural diversity in the workforce, globalization, the rapid advance of technological improvements, and the Internet are three broad changes that have combined to alter dramatically the characteristics, beliefs, and attitudes of workers over the past several decades. In addition, seamless webs of communications media enable virtual teams and various forms of telework arrangements to function effectively. Work anytime, anyplace is now a reality, as work and organizations have become global, with an emphasis on speed. This has led progressive organizations to develop new strategies for attracting and retaining talent. The chapter reviews a number of such strategies, and concludes that to be beneficiaries, rather than victims of such changes, organizations need to reexamine their human resource management systems—recruitment, staffing, performance management, training and development, compensation and reward systems—to ensure that they are attracting the kind of talent and encouraging the kinds of behavior that are consistent with their overall strategy. Likewise, individuals need to reexamine their assumptions and skill sets in order to retain their marketability. This implies commitment to lifelong learning and skill development, viewing diversity as an opportunity, and maintaining networks of contacts to tap for job leads as the need arises.
Stress in Organizations
Authors: Sonnentag Sabine , Frese Michael
Published: November 2003

This chapter summarizes research on stress in organizations. We give an introduction into the concepts of stress, stressors, and stress reactions. We present theories on organizational stress and review evidence from empirical research. Particularly, we focus on observational and longitudinal studies that show that stressors at work have a detrimental effect on health and well‐being. We discuss resources such as control at work, social support, coping styles, and self‐esteem as potential moderators in the stress process. We describe findings from laboratory and field studies on stress and its effect on performance. We address the question whether stress is related to other organizational variables, including organizational commitment, absenteeism, and turnover. We review research findings on stress interventions and discuss stressor reduction, increase of resource, strain reduction, and life‐style change as major stress intervention approaches. We suggest directions for future research for increasing knowledge about stress in organizations.
Career Dynamics
Authors: Greenhaus Jeffrey H.
Published: November 2003

The chapter examines recent theory and research on careers. After discussing the changing landscape of work and careers, the author reviews research on career success, stages of career development, and career decision making, examining gender issues where appropriate. He concludes the chapter with suggestions for future research that are consistent with the realities of the current work environment and the nature of contemporary careers.
Organizational Culture and Climate
Authors: Ostroff Cheri , Kinicki Angelo J. , Tamkins Melinda M.
Published: November 2003

Our focus is on organizational culture and climate and the role that these constructs play in understanding individual as well as collective attitudes, behavior, and performance. We begin with the assumption that both constructs rest upon the notion of shared meanings or a shared understanding of aspects of the organizational context. Climate is defined as a perceptually based description of the what the organization is like in terms of practices, policies, procedures, and routines while culture helps define the underlying reasons and mechanisms for why these things occur in an organization based on fundamental ideologies, assumptions, values, and artifacts. The first half of the chapter provides a comprehensive review of the culture and climate literatures. The second half is framed around a multilevel model that integrates culture and climate through the linking mechanism of organizational structure, practices, and policies. This discussion elucidates a set of mechanisms that foster the emergence of organizational culture and climate and highlights the impact of weak emergent processes on individual and organizational outcomes. We then discuss the topic of culture and climate change and conclude by reviewing directions for future research.
Diversity in Organizations
Authors: Alderfer Clayton P. , Sims Adrienne D.
Published: November 2003

During the last two decades, industrial and organizational psychology has devoted an increasing proportion of its efforts to understanding the effects of increasing organization and identity group diversity. As the discipline has broadened its scope to address these complex phenomena, investigators have employed a variety of theories and methods for research and practice. While some have favored the search for reproducible empirical generalizations, others have moved in the direction of formulating systematic theoretical positions to define, explain, predict, and control the phenomena of interest. This chapter examines the contributions and limitations of inductive empiricism, individual collectivism theory, social identity theory, relational demography, and embedded intergroup relations theory for understanding and changing diversity in organizations. The present authors identify areas of agreement and of divergence among the several perspectives and, on a comparative basis, indicate the ways in which embedded intergroup relations theory addresses problematic issues unresolved by the other points of view.
Recent Trends in Quantitative Structure‐Activity Relationships
Authors: Tropsha A.
Published: November 2003

The field of quantitative structure‐activity relationships (QSARs) as an integral part of computer‐aided drug design and discovery is experiencing one of the most exciting periods in its history. The most important recent developments in the field concur with a substantial increase in the size of experimental data sets available for the analysis and an increased application of QSAR models as virtual screening tools to discover biologically active molecules in chemical databases and/or virtual chemical libraries. Modern QSAR approaches are characterized by the use of multiple descriptors of chemical structure combined with the application of both linear and nonlinear optimization approaches, and a strong emphasis on rigorous model validation, to afford robust and predictive QSAR models. This chapter reviews recent and developing trends in QSAR and offers practical guidelines for the development of reliable QSAR models.
Drug‐Target Binding Forces: Advances in Force Field Approaches
Authors: Kollman Peter A. , Case David A.
Published: November 2003

This article discusses the basic physical chemical principles that determine the strength of non‐covalent interactions between ligands and receptors. We consider the basic thermodynamic principles involved in association and consider how molecular mechanics force fields can be helpful in understanding such phenomena. Three examples are discussed in some detail: biotin‐avidin, trimethoprim‐dihydrofolate reductase, and intercalator‐DNA interactions.
Combinatorial Library Design, Molecular Similarity, and Diversity Applications
Authors: Mason Jonathan S. , Pickett Stephen D.
Published: November 2003

This chapter discusses molecular similarity and diversity concepts and methods and their main applications to combinatorial library design, the selection of compound subsets, and ligand‐based “virtual screening.” Relevant medicinal chemistry applications discussed include the design of “diverse,” “representative,” and “thematic/focused/biased” libraries and subsets. The latter application is of particular relevance, in that there is a recent trend to approach drug discovery by a “target class” or “gene family” approach, such as 7‐TM G‐protein‐coupled receptors.
Virtual Screening
Authors: Muegge Ingo , Enyedy Istvan
Published: November 2003

Virtual screening can be considered as anin silicoanalog to high throughput screening. Its goal is the drastic reduction of compound libraries to a manageable size for synthesis and biological testing. Virtual screening applications are not standardized and packaged in single software products. They rather consist of cascades of diverse filter programs that address different characteristics of putative lead chemical matter. Fast counting schemes for profiling physicochemical properties and machine learning approaches address druglike properties of small molecules related to pharmacology and toxicology. Focused libraries for target classes can be designed, for example, for combinatorial synthesis. Pharmacophores derived from known ligands of a given target can be used in virtual pharmacophore screening. Finally, structure‐based virtual screening employs docking and scoring approaches to find the binding mode of putative protein‐ligand complexes and estimate their binding affinities.
Docking and Scoring Functions/Virtual Screening
Authors: Sotriffer Christoph , Klebe Gerhard , Stahl Martin , Böhm Hans‐Joachim
Published: November 2003

Docking is a computational procedure to investigate the binding between potential ligands and a macromolecular target whose 3D structure is known. Accordingly, it plays an essential role in structure‐based drug design. Any automated docking program relies on a search algorithm to explore potential binding modes, and a scoring method that translates computationally determined protein–ligand interactions into approximate estimates of binding affinity. Accurate scoring is essential for both the determination of the correct binding geometry and the ranking of different ligands with respect to their putative affinity. This chapter provides an overview of the general strategies currently used to address the tasks of searching and scoring for the purpose of docking. In addition, the process of virtual screening is discussed as the major application of fast docking methods. In virtual screening, the goal is to detect active molecules in compound libraries to increase the hit rate in subsequent biological assays. Recent applications have demonstrated that this goal can be successfully met. Virtual screening by docking is thus a valuable tool in the modern drug discovery process, complementary to high‐throughput screening and combinatorial chemistry technologies.
Bioinformatics: Its Role in Drug Discovery
Authors: Parry‐Smith David J.
Published: November 2003

Bioinformatics is the science of understanding the organization of information in biological systems and exploiting that understanding in solving biological problems. Such problems typically involve assessment of the function of a gene by comparing its similarity with that of previously characterized genes or gene products. In the context of drug discovery, bioinformatics is used both as a means of enabling identification of novel drug targets and also of organizing data in drug discovery information systems. An understanding of the relationships between data, information, and knowledge in these research processes is crucial to appreciating the impact bioinformatics can make in drug discovery. Aspects of some of the bioinformatics necessary to gain an insight into the use of genomics are presented, along with discussions of transcript expression profiling, functional genomics, and structural genomics as sources of data for bioinformatics.
NMRand Drug Discovery
Authors: Craik David J. , Clark Richard J.
Published: November 2003

In this chapter we give an overview of the two major approaches used in NMR and drug discovery: structure‐based design and NMR‐based screening. Combined with the more traditional uses of NMR in medicinal chemistry, they demonstrate the versatility of NMR as a tool for drug discovery. Structure‐based design is considered in two parts, ligand‐based design and receptor‐based design. In the former, NMR provides information on structure elucidation of drug leads, conformational analysis, charge state, tautomeric equilibria, and molecular dynamics and assists in the development of pharmacophore models. In receptor‐based design NMR allows the structures of macromolecular drug targets to be determined and their interactions with ligands to be elucidated. NMR‐based screening is a newer application of NMR technology in drug discovery but it is showing great promise as a tool for lead generation and optimization. Screening approaches based on chemical‐shift perturbation, magnetization transfer, diffusion, relaxation, NOEs, and spin labels are described. The utility of NMR has been enhanced over the last decade by developments in both instruments and methodology. On the instrumental side, increases in magnetic field strengths and the development of cryoprobes have increased sensitivity. Linkages of NMR to liquid chromatography and/or mass spectrometry have increased versatility. On the methods front there have been a range of new approaches discovered that will enhance the study of larger molecular complexes. Advances in protein expression and labeling have played a major role in stimulating the development of new NMR pulse sequences to extract information from such complexes.
Mass Spectrometry and Drug Discovery
Authors: van Breemen Richard B.
Published: November 2003

Combinatorial chemistry and high‐throughput screening have become the primary tools of the medicinal chemist in an effort to accelerate the pace of drug discovery. The goal of this new paradigm is to produce in a short time large numbers of synthetic organic compounds representing a great diversity of chemical structures through a process called combinatorial chemistry, and then quickly screen themin vitroagainst pharmacologically significant targets such as enzymes or receptors. As a result, lead compounds might emerge from such combinatorial chemistry drug discovery programs in a few weeks instead of several years. Although a variety of spectroscopic and chromatographic techniques are being used to support drug discovery in various capacities, only high performance liquid chromotography (HPLC) combined with mass spectrometry (LC‐MS and LC‐MS‐MS) is compatible with virtually all drug‐like molecules. In addition to providing a universal means to characterize and distinguish drugs and drug candidates based on both molecular weight and structural features, mass spectrometry provides high throughput. With the development of routine LC‐MS interfaces and ionization techniques such as electrospray and atmospheric pressure chemical ionization, mass spectrometry has also become an ideal HPLC detector for the analysis of combinatorial libraries. Furthermore, a variety of mass spectrometry–based screening assays have been developed to address the need to screen complex mixtures of combinatorial compounds as well as to screen natural product extracts as a means of expanding the molecular diversity of drug leads. The use of mass spectrometry in support of combinatorial library synthesis and purification is addressed in this chapter, as well as screening applications such as frontal affinity chromatography–mass spectrometry, gel permeation chromatography–LC–MS, Fourier transform ion cyclotron resonance (FTICR) electrospray mass spectrometry of receptor–ligand complexes, affinity chromatography–mass spectrometry, and pulsed ultrafiltration mass spectrometry.
Electron Cryomicroscopy of Biological Macromolecules
Authors: Henderson Richard , Baker Timothy S.
Published: November 2003

Electron lenses are greatly superior to X‐ray lenses and can be used to produce a magnified image of an object as easily as a diffraction pattern. This then allows the electron microscope to be switched back and forth instantly between imaging and diffraction modes so that the image of a single molecule at any magnification can be obtained as conveniently as the electron diffraction pattern of a thin crystal. This chapter presents a comprehensive survey of the electron microscopy of biological molecules.
Peptidomimetics for Drug Design
Authors: Estiarte M. Angels , Rich Daniel H.
Published: November 2003

The past and present role of peptidomimetics to drug discovery and protein design is summarized. The historical evolution of this area of research and the current state‐of‐the‐art research strategies are described. A detailed description of each of the peptidomimetics types that have appeared in the literature so far is discussed. Some examples are used to illustrate the drug design process that proceeds from the native peptide to a completely non‐peptide peptidomimetic structure. Special attention is given to important pharmaceutical targets such as the cysteine, metallo, serineor aspartic proteases, integrins, G‐protein–coupled receptors, etc. The principles currently used are highlighted in the discussions of some of the most successful examples. It is obvious that major progress in this area is primarily derived of recent advances in all aspects of science. Molecular modeling, X‐ray crystallography, and high field NMR have greatly contributed to this endeavor. Peptidomimetic inhibitors were traditionally developed by modifying peptide bonds, by mimicking the transition states for enzyme‐catalyzed reactions, or by constraining the conformational mobility of a peptide‐derived chain; the latter was used to overcome some of the pharmacokinetic barriers encountered in using peptides as drugs. Lately, these difficulties have been partially solved with rational drug design ofde novocompounds. Several methods have been successfully applied, with noteworthy examples currently in clinical trials, and many others are expected in the near future. It would be wrong, however, to imply that this process is a universal panacea. New ideas are urgently needed to produce clinical candidates faster and to solve some of the undesired pharmacokinetic issues.
Approaches to the Rational Design of Enzyme Inhibitors
Authors: McLeish Michael J. , Kenyon George L.
Published: November 2003

Selective inhibitors of enzyme‐catalyzed reactions are widely used in both biochemical and medical science. The inhibitor may be used to block either a single enzyme or a metabolic pathway. The utility of an enzyme inhibitor as a mechanistic probe or a therapeutic agent will depend, in part, on the potency of the inhibitor and its specificity toward its target enzyme. These properties will, in turn, depend on the number and type of interactions the inhibitor makes with the enzyme and the overall mode of inhibition. Here we provide a concise overview of the forces involved in inhibitor binding, and a brief summary of the treatment of enzyme kinetic data. Enzyme inhibitors have been divided into two groups, reversible and irreversible, based on whether the inhibitor binds covalently to its target enzyme. Within these groups inhibitors have been classified on the basis of kinetics, structure, and mechanism. Examples are provided in all cases and, where possible, these are of inhibitors possessing therapeutic interest. The criteria for inclusion in each class of inhibitor are described, as well as the kinetic implications, with particular reference to the specificity of the inhibition. Treatment of the examples includes discussion of the design aspects and, if appropriate, a historical perspective that demonstrates the development of a rational approach to inhibitor design.
Chirality and Biological Activity
Authors: Draffan Alistair G. , Evans Graham R. , Henshilwood James A.
Published: November 2003

Throughout the past two decades, the relationship between chirality and biological activity has become an area of vital importance to medicinal chemists in both the design and synthesis of novel small molecules. In this chapter, the definition of chirality and its biological implications are covered. The synthetic, chromatographic, and crystallization approaches to single isomer compounds are discussed with reference to the differing biological activities exhibited by stereoisomers.
Structural Concepts in the Prediction of the Toxicity of Therapeutical Agents
Authors: Rosenkranz Herbert S.
Published: November 2003

Currently available substructure‐based structure‐activity relationship (SAR) methodologies, if expertly used, can be employed to predict the toxicological potential of therapeutic agents. Moreover, with robust SAR models of toxicological phenomena, it is feasible to understand the basis of these toxicities and to ascertain their relevance to possible human health risks. At present, SAR approaches to the evaluation of toxicity must be used in conjunction with human expert knowledge. The currently available technology can be used to design molecules of reduced toxicity which retain their therapeutic effectiveness.
Natural Products as Leads for New Pharmaceuticals
Authors: Buss A. D. , Cox B. , Waigh R. D.
Published: November 2003

A review of the use of natural products as starting points in the search for new pharmaceuticals, covering the broad areas of “Drugs affecting the centeral nervous system, ” “Neuromuscular blocking drugs,” “Anticancer drugs,” “Marine sources,” “Antibiotics,” “Cardiovascular drugs,” “Antiasthma drugs,” and “Antiparasitic drugs.” The review covers more than 100 years of development, from “old” drugs, such as morphine and quinine, to very recent discoveries, such as conotoxin and galantamine, and includes a discussion of the attributes of natural products as leads in the drug discovery process. Between 1990 and 2000, a total of 41 drugs derived from natural products were launched on the market by major pharmaceutical companies. In the chosen examples, the process of drug development is traced from the discovery of the activity of the natural compound, through chemical modification and biological evaluation, to either success or failure as a clinical product, highlighting the very different pathways to innovation that occur in each product.
High‐Throughput Screening for Lead Discovery
Authors: Houston John G. , Banks Martyn N.
Published: November 2003

High‐throughput screening is now an integral part of the early drug discovery process. This high capacity technology addresses the need to screen large numbers of biological targets against large numbers of compounds to find starting points for medicinal chemistry programs. Over the last decade, technological innovation, integrated automation, and novel biological reagents have been combined to create high‐throughput screening systems. This technology connects disease targets of interest with large arrays of test compounds to enable the discovery of potential new drug candidates. The process of bioassay design, screen construction, hit identification, and compound profiling is the basic backbone of the lead discovery process. It is underpinned by a set of large scale, novel technologies that provide a seamless, highly efficient discovery process.
Application of Recombinant
DNA
Technology in Medicinal Chemistry and Drug Discovery
Authors: Basu Soumitra , Oyelere Adegboyega K.
Published: November 2003

Drug discovery is usually a long and arduous process. However, pharmaceutical industries are making a significant progress in simplifying certain aspects of drug discovery process, especially in the area of target discovery, validation, and lead‐compounds discovery. Advances in recombinant DNA technology are intimately connected with the explosion of newly identified pharmaceutically important targets, and an understanding of how these targets function to regulate biological processes of interest. This is providing new and exciting opportunities for therapeutic intervention in diseases including those diseases that were thought to be untreatable a few years back. In this chapter we describe how each stage of drug discovery, from target identification to lead generation and even clinical trials, have benefited from the tools of recombinant DNA technology.
Therapeutic Agents Acting on RNA Targets
Authors: Rife Jason P.
Published: November 2003

There are many therapeutics that target RNA, such as streptomycin, gentamicin, tetracycline; some of them have been around for years. All of them bind to ribosomal RNA and alter normal ribosome function. The modern strategies of drug discovery and design pertain nearly exclusively to protein targets. However, the field of drug discovery for RNA targets is maturing rapidly, largely because of the exciting ribosome/drug complexes that have recently been solved. Potential RNA drug targets abound for bacteria, viral, and cellular systems. Nevertheless, questions remain as to whether or not compounds can be found that simultaneously satisfy RNA binding and pharmacological properties, such as absorption and membrane permeation. The range of interactions observed, from Coulombic to hydrophobic, and the predicted “drug‐like” qualities of several ribosome binding antibiotics suggest that the discovery of drugs that target RNA can be a general phenomenon.
Allosteric Proteins and Drug Discovery
Authors: Bell J. Ellis , Burnett James C. , Bell Jessica K. , Galatin Peter S. , Abraham Donald J.
Published: November 2003

The existence of allosteric phenomena in the control of proteins allows for exquisite control of many of the cell's normal processes. Allosteric interactions involve the binding of an “allosteric” ligand to a site other than the functional (active) site of the protein, with a concomitant alteration in activity. Two major theoretical models have been presented to explain allosteric interactions, that of Monod, Wyman, and Changeux and that of Koshland, Nemethy, Filmer, Dalziel, and Engel. Although there are essential differences between the two models, both require that allosteric ligands interact with one or more forms of the protein to trigger a modulating effect. In only a few cases is much structural detail known about more than one conformational state of any given allosteric protein, or how the binding of small molecule effectors to an allosteric site triggers protein modulation. In this review the essential features of allosteric enzymes and allosteric models are examined in a context that leads to consideration of how drugs may be designed such that they either mimic or block normal allosteric effects. Several existing “allosteric” drugs, and a number of potential targets for the rationale design of future allosteric drugs, are discussed.
Receptor Targets in Drug Discovery and Development
Authors: Williams Michael , Mehlin Christopher , Triggle David J.
Published: November 2003

Drug discovery has entered a new century with an unheralded wealth of sophisticated technologies and information generation platforms, including the draft map of the human genome, which theoretically will allow the more rapid development of medicines with improved selectivity and safety profiles. To use the bewildering exponential flow of data related to the molecular targets involved in the cause(s) of various diseases and the increasingly sophisticated computer‐based technologies that define the requirements for chemical diversity and diversity space requires an understanding of basic receptor/enzyme theory. The latter, based on the Law of Mass Action, defines the concepts of agonism, antagonism, and more recently, allosteric modulation. The application of receptor/enzyme theory to the practical aspects of lead compound identification and optimization is based on defining structure‐activity relationships (SARs) for a variety of physiological and pharmacological parameters and involves the evaluation of new chemical entities in
in vitro
and
in vivo
assays that measure efficacy, selectivity, side effect liability and absorption, distribution, metabolism and excretion, and toxicology. Understanding how knowledge of drug targets has evolved; the challenges to validating new targets, especially those evolving from the genome; and assays beyond high‐throughput screening that provide objective SAR information, as well as designing compounds to interact with these targets that have “druggable” characteristics, are the keys to successful, and by definition, financially viable, drug discovery.
Nicotinic Acetylcholine Receptors
Authors: Colquhoun David , Shelley Chris , Hatton Chris , Unwin Nigel , Sivilotti Lucia
Published: November 2003

Nicotinic receptors are cation‐permeable ion channels activated by the neurotransmitter acetylcholine. The muscle‐type receptor mediates all fast synaptic excitation on voluntary muscle. We review both the structure and the function of muscle/
Torpedo
receptor, and the function of several mutants. Recent developments both in knowledge of structure and in analysis of single‐channel records are beginning to throw light on the role of single amino acid residues in the molecular events (the binding of an agonist and the gating of the channel) that lead to channel opening. In the nervous system, nicotinic channels mediate the majority of fast excitation only in autonomic ganglia, but are also present at presynaptic locations. Issues of receptor classification and subunit composition are particularly relevant for neuronal channels because of the numerous subunit combinations possible and because relatively few selective competitive antagonists are available, a situation that may improve with the characterization of alpha‐conotoxins. Inherited mutations in nicotinic channels give rise to rare congenital forms of human disease (myasthenia for muscle and epilepsy for neuronal receptors).
Analog Design
Authors: Cannon Joseph G.
Published: November 2003

The chapter addresses the design of nonprotein, nonpeptide drug analogs. Strategies and applications of classical and nonclassical bioisosteres, rigid and semirigid analogs; homologation of alkyl chains; changes in ring size and ring‐position isomers; substitution of aromatic for aliphatic rings; alteration of stereochemistry; design of fragments of lead molecules; and variation of interatomic distances are discussed. Numerous examples from the literature of each type of molecular modification are presented, together with summaries of pharmacological consequences of the modifications. Advantages and disadvantages of each category are cited.
Large‐Scale Synthesis
Authors: Gupton Frank , Grozinger Karl
Published: November 2003

The capability to fulfill drug substance requirements in support of the various elements of pharmaceutical development is an essential component of the overall drug development process. The preparation of bulk materials for toxicology, formulation development, and clinical supplies can represent a significant challenge, depending on such factors as the molecular complexity of the drug candidate, the quantities of materials required, and the state of development of the synthetic process. As a drug candidate proceeds through the various stages of drug development and into commercial launch, the challenge of process development is to ensure the uninterrupted supply of drug substance without compromising the ability to ultimately supply a commercially viable chemical process. This chapter serves to provide a general overview of the issues and requirements associated with the development and scale‐up of chemical processes for bulk active drug substances. An account of the nevirapine process development efforts at Boehringer Ingelheim is also provided as an example of the evolution of a chemical process from the initial efforts in medicinal chemistry through to commercial‐scale operations.
Metabolic Considerations in Prodrug Design
Authors: Balant Luc P.
Published: November 2003

This review concentrates on prodrugs designed by pharmaceutical chemists to overcome biopharmaceutical or pharmacokinetic (essentially metabolic) problems encountered with active principles. The investigations presented in this review illustrate the types of problems pharmaceutical chemists have tried to solve and the metabolic, kinetic, or biopharmaceutical rationale behind these attempts. Although very little published information is available on pharmacokinetic methods useful in the study of prodrugs and on the regulatory requirements needed for prodrug development, the authors have tried to develop some general ideas that might be useful in this regard.
Drug Discovery: The Role of Toxicology
Authors: Moe James B. , McKim James M.
Published: November 2003

This chapter describes the principles of toxicology in the context of rational application of toxicology and related disciplines in the discovery of new therapeutic agents. Fundamental types of mechanisms involved in the genesis of adverse effects produced by pharmaceutical agents on host organs, tissues, and cells are described. Various emerging technologies are presented as tools for use in the drug candidate selection and optimization processes to predict adverse effects and improve probability of discovery and development of new therapeutic agents.
Drug Absorption, Distribution, and Elimination
Authors: Benet Leslie Z. , Perotti Beatrice Y. T. , Hardy Larry
Published: November 2003

The chapter provides basic quantitative explanations of practical pharmacokinetic concepts that are key to understanding how drugs enter and depart from the body. The parameters that are discussed include hepatic and renal clearance, bioavailability, extraction ratio, half‐life, and volume of distribution. Relationships between these parameters are defined, and their utility for the design of dosing regimens to provide effective and nontoxic therapy is shown with some examples. The application of pharmacokinetics plays an essential role in the various preclinical and clinical phases of drug development, as well as in other areas such as environmental toxicology.
The FDA and Regulatory Issues
Authors: Rzeszotarski W. Janusz
Published: November 2003

A brief outline of information that is available on the Web pertinent to the FDA and regulatory issues. The process of new drug approval and its continuous modification reflects both the progress of science and the globalization of the world's economy. The reader is encouraged to follow the changes by constant monitoring of the FDA and the industry sites dedicated to these issues. The history of drug regulation in the United States, the evolving structure of the FDA, the steps to be taken in the process of obtaining the approval to market the new molecular entity, and the post‐approval requirements are briefly described.
Intellectual Property in Drug Discovery and Biotechnology
Authors: Kaba Richard A. , Maloney Timothy P. , Krueger James P. , Kratz Rudy , Tabin Julius
Published: November 2003

Intellectual property is the branch of law that protects and, indeed, encourages the creation of certain products of the human mind or intellect. This chapter is intended to provide a basic understanding and appreciation of intellectual property law, especially as it relates to patents, trademarks, and trade secrets, in the United States and, to a lesser extent, in the remainder of the world. Issues and concerns particularly related to the drug discovery and development process are emphasized. By making effective use of the legal protection afforded by the intellectual property laws in the United States and elsewhere, the drug developer can protect its investment, enhance the value of the technology being developed, and earn a profit sufficient to allow and encourage further research into improving existing drugs and therapies as well as developing new drugs and therapies. By better understanding these intellectual property laws, the drug developer, together with experienced intellectual property counsel, can develop an effective intellectual property strategy. In this way, new and emerging technologies as well as new drug discoveries can be identified, managed, and protected as an integral part of an organization's research and development activities to create a strong intellectual property portfolio.
Myocardial Infarction Agents
Authors: Billman George E. , Altschuld Ruth A.
Published: November 2003

A myocardial infarction begins with the occlusion of a coronary artery, usually resulting from the rupture of an atherosclerotic plaque. Pharmacologic treatment begins with conventional pain relief and under appropriate circumstances thrombolytic agents are administered. Anticoagulants are used in conjunction with thrombolytic agents to assist thrombolysis and prevent reocclusion of the affected vessel. Lethal arrhythmias such as ventricular fibrillation are a major cause of death following myocardial infarction. β‐Adrenoceptor antagonists are used to reduce the incidence of this sudden cardiac death. Angiotensin converting enzyme inhibitors are used to reduce post‐infarction ventricular remodeling, which is a leading cause of congestive heart failure.

Current therapy has significantly reduced in hospital mortality but acute myocardial infarction remains the leading cause of death in the United States. Congestive heart failure secondary to myocardial infarction is becoming an epidemic. Additional therapeutic agents and/or strategies are needed to reduce death and disability following myocardial infarction.
Endogenous Vasoactive Peptides
Authors: Webb Randy L. , Ksander Gary M.
Published: November 2003

The control of vasomotor tone regulates the overall cardiovascular system and its responses to physiological and pathophysiological stress. It provides differential blood flow to regional vascular beds under normal physiologic conditions, at times of normal stress, such as exercise, and during conditions of pathological stress, such as congestive heart failure. Although the vascular system regulates many of its functions at the site of the blood vessel itself, other factors that may control vascular tone include the autonomic nervous system, circulating hormones functioning in an endocrine role, and reflex metabolic control. Many newly discovered peptides were found to be widespread in autonomic and sensory neurons innervating the vasculature, and they possess potent vasoactive effects on many blood vessels. Vasoactive peptides have been shown to play an important role in many pathological situations, for example, asthma, arthritis, vascular headaches, hypertension, and other cardiovascular diseases. In this chapter, we will outline the evidence for the different actions of various vasoactive peptides, their interaction with other systems, the possible role they have in diseases, and the present and future therapeutic use of vasoactive peptide agonists and antagonists.
Hematopoietic Agents
Authors: Harrington Maureen
Published: November 2003

Hematopoesis is a life‐long process that involves the continuous formation and turnover of blood cells. Maintaining adequate blood cell production, as well as being able to meet increased demand, is in part under the control of a group of hormone‐like glycoproteins that includes the hematopoietic growth factors and the interleukins. More specifically, the production of hematopoietic stem cell self‐renewal (giving rise to identical daughter cells) and production of the specific progenitor cells that are increasingly restricted in their developmental pathway are under the control of the hematopoietic growth factors and the interleukins. In the chapter, four cytokines approved by the Food and Drug Administration for use in humans are described; this is followed by a limited discussion of one cytokine, stem cell factor, that currently has orphan drug status and a brief description of two cytokines currently undergoing clinical evaluation. The field of cytokine research is always expanding as new interleukins are identified each year. As our understanding of the cell and molecular biology of cytokine action on hematopoiesis increases, the clinical use of these agents will become more refined.
Anticoagulants, Antithrombotics, and Hemostatics
Authors: Bisacchi Gregory S.
Published: November 2003

Maintenance of proper blood flow is a complex and highly regulated physiological process, with multiple complementary and opposing mechanisms of control. Imbalances in these mechanisms can lead to a variety of pathological consequences, such as hemorrhage or obstructive clot (thrombus) formation in veins or arteries, leading to stroke, pulmonary embolism, heart attack, and other serious conditions. One of the overriding challenges with current or future drug strategies for antithrombotic, thrombolytic (clot dissolving), and hemostatic therapy is the precise correction of the pathologic imbalance without overcompensating and thus creating safety issues. Unfractionated heparin is widely used as an anticoagulant, but is being replaced in many of its applications by currently available alternative parenteral agents such as the low molecular weight heparins and the direct thrombin inhibitors. These efficacious alternative agents offer advantages in terms of more predictable pharmacokinetics and improved safety, thereby reducing or eliminating the need for patient monitoring and reducing or eliminating the risk of heparin‐induced thrombocytopenia. Orally bioavailable direct thrombin and/or Factor Xa inhibitors now under development seem poised to become available over the next several years and will represent viable alternatives to both the parenteral anticoagulants and to warfarin, the only currently available oral anticoagulant. These agents promise the convenience of an oral drug without the need of intensive patient monitoring, as warfarin requires. Other therapeutic targets under current investigation for anticoagulation include Factor VIIa and Factor IXa. Antiplatelet agents such as aspirin, clopidogrel, and the parenteral GPIIb/IIIa antagonists are valuable and widely used drugs. New antiplatelet agents that act by already validated mechanisms (e.g., P2Y12receptor antagonism) or that act by mechanisms not targeted by current agents will also likely emerge in the not too distant future. Newer clot‐selective fibrinolytics have advantages over older agents such as streptokinase. Fibrinolytic agents still in development may offer further improvements in terms of safety and longer plasma half‐life.
Inhibition of Sickle Hemoglobin Polymerization as a Basis for Therapeutic Approaches to Sickle‐Cell Anemia
Authors: Noguchi Constance Tom , Schechter Alan N. , Haley John D. , Abraham Donald J.
Published: November 2003

This chapter reviews current understanding of the molecular and cellular basis of the pathophysiology of sickle‐cell anemia, with emphasis on the biophysics of the intracellular polymerization of sickle hemogobin. Factors that modify the severity of the disease manifestations, primarily by altering polymerization tendency, are discussed. This framework is used to present an overview of the major rational approaches to the therapy of sickle‐cell anemia based on inhibiting polymerization with agents that affect either the hemoglobin molecule or the sickle erythrocyte. Discussion of agents that may decrease vascular entrapment of sickle erythrocytes is also presented. Detailed review of the most important current approaches to therapy—pharmacologically elevating fetal hemoglobin—focuses primarily on hydroxyurea, the only drug currently FDA approved for treating sickle‐cell anemia. A brief discussion of other approaches, including stem cell transplantation and gene therapy, concludes the chapter.
Iron Chelators and Therapeutic Uses
Authors: Bergeron Raymond J. , McManis James S. , Weimar William R. , Wiegand Jan , Eiler‐McManis Eileen
Published: November 2003

Iron is an essential cofactor in a variety of biological redox reactions; life without this metal is virtually unknown. Because of its exceptionally poor solubility in the biosphere, bacteria produce relatively low molecular weight, virtually iron(III)‐specific, ligands, siderophores, for the purpose of acquiring this transition metal. On the other hand, higher eukaryotes generate proteins to acquire and store iron. In humans, the process of iron absorption and processing is very tightly controlled. However, the lack of an efficient means of elimination can, under certain conditions, result in iron overload, which can elicit oxidative tissue damage through the Fenton reaction. Accordingly, chelating agents have been tested over the last several decades for the purpose of rendering excess iron excretable. The currently accepted therapy for global iron overload, as occurs after repeated blood transfusions, is a siderophore, desferrioxamine B (DFO), which is administered subcutaneously as its mesylate salt (Desferal). Two synthetic agents, diethylenetriamine pentaacetic acid (DTPA) and 1,2‐dimethyl‐3‐hydroxypyridin‐4‐one (Ferriprox, deferiprone, L1), have been used for the treatment of iron overload as well. Unfortunately, all three of these ligands have drawbacks. The kinetics and lack of oral bioavailability of DFO require that this compound be administered subcutaneously 12 h/day, up to 6 days/week, a regimen with which many patients find it difficult to comply. The lack of chelating specificity of DTPA restricts its use to those who cannot tolerate therapy with DFO; questions remain unanswered regarding the efficacy and toxicity profile of L1. The ongoing efforts to find a worthy successor to DFO include the use of a synthetic agent,N,N′‐bis(2‐hydroxybenzyl)ethylenediamine‐N,N′‐diacetic acid (HBED), which, although it would require subcutaneous administration, is significantly more efficient than DFO. Another avenue is using siderophores (e.g., desferrithiocin, parabactin) as platforms from which to design either orally or parenterally active iron chelators. Because of the necessity of striking a balance between efficacy (i.e., sufficient iron chelation) and toxicity (i.e., excessive iron removal), drug development in the arena of iron chelation therapy presents unique challenges. However, the application of sensible drug design principles predicated on our understanding of iron metabolism, modern synthetic techniques, and the use of appropriate animal models should bring about improved therapeutic agents for the treatment of both global and focal iron overload in the years to come.