Investigation of the pharmacokinetics and metabolism of human proteins has escalated over the last two decades because of the use of recombinant human proteins as therapeutic agents. In addition, the development and improvement of analytical techniques enabling the detection of minute quantities of proteins in biological matrices have aided this process. In assembling this volume, we sought to provide a state-of-the-art as sessment of the pharmacokinetics and metabolism of protein therapeutics through complete reviews of selected examples. A comprehensive review of all protein therapeutics was not attempted; the majority -of the therapeutic protein classes and crucial scientific issues have been addressed, however. Therefore, we are confident that this volume will provide a useful reference for scientists in this field. The volume has been divided into two general parts. The first part (Chapters 1-3) is composed of general reviews of topics of importance in pharmacokinetic/metabolism studies of proteins: goals and analytical meth odologies, effects of binding proteins, and effects of antibody induction, respectively. The second part (Chapters 4-8) consists of specific, detailed reviews by therapeutic protein class: growth factors and hormones, cyto kines, cardiovascular proteins, hematopoietic proteins, and antibodies, respectively. The editors are grateful to the contributors for the patience, personal sacrifice and perseverance required to complete this volume. BoDDE L. FERRAIOLO MARJORIE A. MOHLER CAROL A. GLOFF ix Contents Chapter 1 Goals and Analytical Methodologies for Protein Disposition Studies Bobbe L. Ferraiolo and Marjorie A. Mohler 1. Introduction ................................................. .

production of this volume of the Handbook. If this joint enterprise has succeeded it is thanks to their competence, knowledge and application, for the editor's role is merely that of a coordinator. My thanks are also due to Springer-Verlag, the publishers, who gave me every possible assistance in seeing this volume to completion. Dr. D. Maroske was kind enough to prepare the Subject Index. And lastly I should like to voice my indebtedness to the Management of Sandoz Ltd., Basle, which allowed me to devote a not inconsiderable part of my time to the editing of this volume. I am also very grateful to a number of members of the staff of Sandoz Ltd.: to Mr. J.E. Smith, B. Sc., F.1. L., who translated some chapters and revised the language of others and to Miss Hannelore Straube and Miss Sonja Ebner for their valuable secreterial help.

It was an agreable, though strenuous task to edit a book with so many distin guished contributors, on a subject to which I have given half of my life. In 1959, when Prof. O. EICHLER invited me to edit a book on "Histamine and Anti histaminics", as a supplement to HEFFTER'S Handbuch, I thought the task could be done in three years. Now, five years are gone and only half is fulfilled. Though, so far as the "Histamine" part of the book is concerned, the initial plan has been followed very closely, we had to leave the Anti-histaminics for another volume of unpredictable dimensions. In 1924, eight pages inserted in a Chapter on M utterkorn, by ARTHUR R. CUSHING were considered enough, in vol. II, Part II, pg. 1319-1326, of the Handbuch. Now, 922 pages did not suffice to cover all the aspects of the subject. Especially in the last few years the subject has expanded in so many directions, that the antihistaminic part had to be excluded from the present volume. Possibly, another thousand pages will be necessary to cover what remains of the subject. In planning the book we made great use of the excellent and classical mono graph by W. FELDBERG and E. SCHILF on Histamin, published by Julius Springer, in 1930.

With drug information rapidly migrating to the Web, the chronically poor standards of drug information available to consumers in the developed and the developing world are being further compromised. This book offers insight into the uncharted waters of prescription drug information and promotion on the internet and suggests how it might be transformed into an unprecedented agent for good. It traces the social and political history of prescription drug information and marketing to Western consumers, offers a social and communicative profile of prescription drug Web sites, and evaluates the most widely used sources of prescription drug information, from government organizations and information companies and TV-related sites, to health service provider sites, manufacturers' brand sites, and social media, including YouTube and Wikipedia. The focus throughout is on practical outcomes: How can information for consumer decision making be optimized and how can consumers use it responsibly?

Even high-speed supercomputers cannot easily convert traditional two-dimensional databases from chemical topology into the three-dimensional ones demanded by today's chemists, particularly those working in drug design. This fascinating volume resolves this problem by positing mathematical and topological models which greatly expand the capabilities of chemical graph theory. The authors examine QSAR and molecular similarity studies, the relationship between the sequence of amino acids and the less familiar secondary and tertiary protein structures, and new topological methods.

Self-assembly monolayer (SAM) structures of lipids and macromolecules have been found to play an important role in many industrial and biological phenomena. This book describes two procedures, namely the STM and AFM, that are used to study SAMs at solid surfaces. K.S. Birdi examines the SAMs at both liquid and solid surfaces by using the Langmuir monolayer method. This book is intended for researchers, academics and professionals.

Leading scientists offer detailed profiles of ten protein drugs currently in development. The case histories of these important new compounds are described from the perspective of their formulation, characterization, and stability. This ready reference also features recent data and an abundance of previously unpublished information. The in-depth coverage includes a highly useful compendium of degradation sites occurring in over 70 proteins. An invaluable aid in the rapid identification of potential 'hot spots' in proteins, this accessible compilation allows for inspection of the protein's primary structure and preparation of a hydroflex plot.

Proteomics is an introduction to the exciting new field of proteomics, an interdisciplinary science that includes biology, bioinformatics, and protein chemistry. The purpose of this book is to provide the active researcher with an overview of the types of questions being addressed in proteomics studies and the technologies used to address those questions. Key subjects covered in this book include: * an assessment of the limitations of this approach and outlines new developments in mass spectrometry that will advance future research * high-throughput recombinant DNA cloning methods used to systematically clone all of the open reading frames of an organism into plasmid vectors for large scale protein expression and functional studies such as protein-protein interactions with the two-hybrid system * protein structure * an overview of large-scale experimental attempts to determine the three-dimensional structures of representative sets of proteins * computational approaches to determining the three-dimensional structure of proteins.Proteomics provides a starting point for researchers who would like a theoretical understanding of the new technologies in the field, and obtain a solid grasp of the fundamentals before integrating new tools into their experiments. Written with attention to detail, but without being overwhelmingly technical, Proteomics is a user-friendly guide needed by most biologists today.

The three years since our last conference in San Francisco have again seen a dramatic expansion of the number of antivirals either licensed or in the late stages of clinical trials. d4T is now licensed for HIV infection, famciclovir and the oral pro-drug of acyclovir, valacyclovir, are now licensed for VZV infections in some countries. Moreover. oral ganciclovir, cidofovir, and sorivudine are not far behind. Clinical trials with the second-site reverse transcriptase inhibitors and the protease inhibitors for HlV infection are proceeding rapidly and on a broad scale, and the preliminary results would suggest that several of these classes of drugs will be licensed as well. Despite this optimism, however, there is increasing evidence that antiviral-resistant strains of pathogenic viruses will be a significant problem, perhaps especially with therapy of HIV infection, and there remains a desperate need for improved drugs (with either improved efficacy or decreased toxicity, or both) for CMV and HIV infections. This book is the edited proceedings of the Fourth Triennial Conference on Antiviral Chemotherapy, held in San Francisco, in November 1994. The conference was sponsored by the University of California, San Francisco, and co-sponsored by the International Society for Antiviral Research (ISAR), the Macfarlane Burnet Centre for Medical Research in Melbourne, Australia, and the Australian National Centre for HIV Virology Research. The conference had been organized to present an overview of the field of antiviral chemotherapy.

In the pharmaceutical industry, the incorporation of the disciplines of pharma- kinetics, pharmacodynamics, and drug metabolism (PK/PD/DM) into various drug development processes has been recognized to be extremely important for approp- ate compound selection and optimization. During discovery phases, the identifi- tion of the critical PK/PD/DM issues of new compounds plays an essential role in understanding their pharmacological profiles and structure-activity relationships. Owing to recent progress in analytical chemistry, a large number of compounds can be screened for their PK/PD/DM properties within a relatively short period of time. During development phases as well, the toxicology and clinical study designs and trials of a compound should be based on a thorough understanding of its PK/PD/DM properties. During my time as an industrial scientist, I realized that a reference work designed for practical industrial applications of PK/PD/DM could be a very valuable tool for researchers not only in the pharmacokinetics and drug metabolism departments, but also for other discovery and development groups in pharmaceutical companies. This book is designed specifically for industrial scientists, laboratory assistants, and managers who are involved in PK/PD/DM-related areas. It consists of thirteen chapters, each of which deals with a particular PK/PD/DM issue and its industrial applications. Chapters 3 and 12 in particular address recent topics on higher throughput in vivo exposure screening and the prediction of pharmacokinetics in humans, respectively. Chapter 8 covers essential information on drug metabolism for industrial scientists.

Shunsuke Hirotsu "Coexistence of Phases and the Nature of First-Order Transition in Poly-N-isopropylacrylamide Gels," Masayuki Tokita "Friction between Polymer Networks of Gels and Solvent," Masahiro Irie "Stimuli-Responsive Poly(N-isopropyl- acrylamide), Photo- and Chemicals-Induced Phases Transitions Edward Cussler, Karen Wang, John Burban"Hydrogels as Separation Agents," Stevin Gehrke "Synthesis, Equilibrium Swelling, Kinetics Permeability and Applications of Environmentally Responsive Gels," Pedro Verdugo "Polymer Gel Phase Transition in Condensation- Decondensation of Secretory Products," Etsuo Kokufuta "Novel Applications for Stimulus-Sensitive Polymer Gels in the Preparation of Functional Immobilized Biocatalysts," Teruo Okano "Molecular Design of Temperature-Responsive Polymers as Intelligent Materials," Atsushi Suzuki "Phase Transition in Gels of Sub-Millimeter Size Induced by Interaction with Stimuli," Makoto Suzuki, O. Hirasa "An Approach to Artificial Muscle by Polymer Gels due to Micro-Phase Separation."

This book has its origin in my experience as a teacher of pharmacokinetics in many universities in four different continents. It was not my intention to write a popular book; what distinguishes this one from many others on the same subject is its large use of algebra and calculus. For this I make no apologies; in fact a serious study of pharmacokinetics without the help of mathematics is, in my opinion, impossible. The exact definition of many pharmacokinetic quantities, even the most common, and the correct use of many equations, even the most simple, requires the constant use of mathematical language. On the other hand I have made a considerable effort to use only elementary algebra and elementary calculus, as commonly taught in most introductory university courses. For the few exceptions, when less common mathematical concepts were needed, I have supplied the necessary explanations in four appendices. The first three chapters are a general introduction to the scientific method. Chapters 4 to 12 show different specific methods to deal with pharmacokinetic pr- lems. There is considerable overlap among those chapters; this is intentional and its p- pose is to convince the reader that every problem can be solved in more than one way, including ways that were not mentioned in this book and that intelligent readers can find for their own pleasure. Chapters 13 to 17 show how different parameters of importance in pharmacokinetics can be exactly defined and measured.

Proceedings of the International Symposium on Polymer Therapeutics - Recent Progress in Clinics and Future Prospects, held July 13-14, 2001, in Nara, Japan. The technology of polymer science has developed considerably during the past half-century, and this volume describes some of the aspects of this technology that will have a great impact in the future. Among these advances, for example, are gene delivery to specific disease sites and carrier polymers that respond to a stimulus or particular environment. Cancer targeted drug delivery is another focused area of this volume because of the important nature of EPR-effect of polymer drugs in tumor. Included are discussions of as many examples as possible of polymer drugs that have achieved, or are close to clinical use. The concept of "Polymer drugs" here is limited to primarily injectable and water-soluble agents, although also covered are some drugs in micellar form or liposomes. This book is intended for students and researchers in the field of pharmacology who have particular interests in drug delivery, targeting, and formulation, as well as for clinicians such as oncologists who are interested in the field. People who work at regulatory agencies should also be aware such that drugs with great potential are being developed and will be beneficial to many patients, as well as to health insurance agencies because of improved cost effectiveness.

The three sections of this volume deal with topics of broad interest. The first deals with cetyl alcohol and is a most comprehensive study of this essential ingredient in the cosmetic and pharmaceutical industry, with an explanation of its functionality. The second is a most comprehensive, up-to-date review of acid/base interactions of a variety of materials, including small molecules, proteins and polyelectrolytes. The third section describes the combined radiochemical and electrochemical methods in the evaluation of the properties of solids in contact with solutions.

Introduction and Perspectives This volume is based on the proceedings of the 7th annual symposium on the topic Neuroimmune Circuits, Infectious Diseases and Drugs of Abuse, Bethesda, Maryland, Oc- ber 7-9, 1999. This symposium, as in the past, focused on newer knowledge concerning the relationship between the immune and nervous systems with regards to the effects of drugs of abuse and infections, including AIDS, caused by the immunodeficiency virus. Presentations discussed the brain-immune axis from the viewpoint of drugs of abuse rather than from the subject of the brain or immunity alone. The major aim of this series of conferences has been to clarify the consequences of immunomodulation induced by drugs of abuse in regards to susceptibility and pathogenesis of infectious diseases, both in man and in various animal model systems. The recreational use of drugs of abuse such as morphine, cocaine, and marijuana by large numbers of individuals in this country and around the world has continued to arouse serious concerns about the consequences of use of such drugs, especially on the normal physiological responses of an individual, including immune responses. Much of the recent data accumulated by investigators show that drugs of abuse, especially opioids and cannabinoids, markedly alter immune responses in human populations as well as in experimental animals, both in vivo and in vitro.

Collagen is a fascinating protein not only because of its ubiquitous occurrence in multicellular animals, but also because of its unique chemi cal structure. As the predominant constituent in bone, cartilage, skin, tendon, and tooth, it is not surprising that collagen is of interest to anatomists, biochemists, biomedical engineers, cell biologists, dermatolo gists, dental surgeons, leather chemists, orthopedic surgeons, physiologists, physicians, zoologists, and a host of others. This book was planned to provide an up-to-date comprehensive survey of all aspects of biochemistry of collagen. The recent discovery of genetically distinct collagens with tissue specificity has opened a new era in collagen biochemistry, and Karl Piez discusses this in the opening chapter on primary structure. In the next chapter, Ramachandran and Rama krishnan deal with the molecular structure of collagen, placing special emphasis on the conformational aspects of its polypeptide chains. Follow ing the consideration of primary and secondary structure of collagen, the three-dimensional arrangement of collagen molecules in the fibrils is covered by Miller in Chapter 3. Collagen is generally in the insoluble state in the living organism due to the cross-linking of individual molecules, and Tanzer describes the various aspects of this cross-linkage in Chapter 4. The biosynthesis of collagen is discussed in depth by Prockop and his colleagues."

Volume XXV of the Handbook of Experimental Pharmacology series entitled "Bradykinin, Kallidin, and Kallikrein" was published in 1970. My aim in editing this volume of the series is not to replace, but to update the 1970 edition. During the decade preceding the publication of Vol. XXV, the existence of kinins and kallikreins gained acceptance, the protein components of the system were purified and characterized and the peptides were synthesized. Even after these accomplish ments, interest in the subject has not abated, but has increased substantially. We have learned a great deal about the role that components of the kallikrein-kinin system play in other systems and about the immensely complex and intricate inter actions in blood. Directly or indirectly, kallikrein and kinins affect the coagulation of blood, the activation of complement, and the generation of angiotensin. Kinins release or modulate the actions of other agents, including prostaglandins, histamine, and catecholamines. Inhibitors of kallikrein or kininase II are employed, for example, in extracorporeal circulation or in hypertension. Kallikrein, kinins, and kininases, present in urine, were described first in 1925 and 1954, but have been ignored for decades. These substances are now studied extensively because of their possible role in blood pressure regulation. The evidence that kinins have a metabolic function is also increasing. The abundance of active components of the system in genital organs suggests a role in the fertilization process. The book is organized into chapters which bear upon these issues.

This volume is an important advancement in the application ofpharmacokinetic (PK) and pharmacodynamic (PO) principles to . drug development. The series of topics presented deal with the application of these tools to everyday decisions that a pharmaceutical scientist encounters. The ability to integrate these topics using PK and PO methods has optimized drug development pathways in the clinic. New technologies in the areas of in vitro assays that are more predictive of human absorption and metabolism and advancement in bioanalytical assays are leading the way to minimize drug failures in later, more expensive clinical development programs. of Pharmacokinetics and pharmacodynamics have become an important component understanding the drug action on the body and is becoming increasingly important in drug labeling due to it's potential for predicting drug behavior in populations that may be difficult to study in adequate numbers during drug development. The ability to correlate drug exposure to effect and model it during the drug development value chain provides valuable insight into optimizing the next steps to derive maximum information from each study. These principles and modeling techniques have resulted in an expanded and integrated view of PK and PO and have led to the expectations that we may be able to optimally design clinical trials and eventually lead us to identifying the optimal therapy for the patient, while minimizing cost and speeding up drug development. There is wide utility for the book both as a text and as a reference.

This is the first comprehensive work to review blood platelet biochemistry, physiology, pharmacology, and function. It provides up-to-date information on how platelets function, the biochemical mechanisms that modulate their physiology and function, as well as the pharmacology of platelet inhibitory drugs.

This useful work presents a current overview of key genes involved in the control of apoptosis research together with thoughts on future prospects and clinical applications. While there are several books written on apoptosis, this one deals specifically with its regulation.

Volume 42 of "Progress in Drug Research" contains seven reviews and the various indexes which facilitate its use and establish the con nection with the previous volumes. The articles in this volume deal with organization and management of drug research; luteinizing hor mone regulators; natural products as anticancer agents; flavonoids and their pharmacological activity; serenics in the control of mental disturbances; Transfer Factor and its application and with Transfer Factor in malignancy. In the 34 years that "Progress in Drug Research" has existed, the Edi tor has enjoyed the valuable help and advice of many colleagues. Readers, the authors of the reviews, and last but not least, the review ers have all contributed greatly to the success of this series. Although the comments received so far have generally been favorable, it is nevertheless necessary to analyze and to reassess the current position and the future direction of such a review series. So far, it has been the Editors intention to help disseminate informa tion on the vast domain of drug research, and to provide the reader with a tool with which to keep abreast of the latest developments and trends. The reviews in PDR are useful to the non-specialists, who can obtain an overview of a particular field of drug research in a rela tively short time."

Piper is an economically and ecologically important genus of plant that includes a fascinating array of species for studying natural history, natural products chemistry, community ecology, and evolutionary biology. The diversification of this taxon is unique and of great importance in understanding the evolution of plants. The diversity and ecological relevance of this genus makes it an obvious candidate for ecological and evolutionary studies, but surprisingly, most research on Piper spp. to-date has focused on the more economically important plants P. nigrum (black pepper), P. methysticum (kava), and P. betle (betel leaf). While this book does address the applied techniques of studying Piper, its focus is more on Piper in its natural setting. Piper: A Model Genus for Studies of Phytochemistry, Ecology, and Evolution synthesizes existing data and provides an outline for future investigations of the chemistry, ecology, and evolution of this taxon, while examining its key themes of Piper as a model genus for ecological and evolutionary studies, the important ecological roles of Piper species in lowland wet forests, and the evolution of distinctive Piper attributes. This volume has a place in the libraries of those studying or working in the fields of ecology, evolutionary biology, natural products chemistry, invasive species biology, pharmaceutics, and ethnobotany.

Oxireductases in the Enzymatic Synthesis of Water-Soluble Conducting Polymers, by E. Ochoteco and D. Mecerreyes
*

Transferases in Polymer Chemistry, by J. van der Vlist and K. Loos
*

Hydrolases Part I: Enzyme Mechanism, Selectivity and Control in the Synthesis of Well-Defined Polymers, by M.A.J. Veld and A.R.A. Palmans
*

Hydrolases in Polymer Chemistry: Chemoenzymatic Approaches to Polymeric Materials, by A. Heise and A.R.A. Palmans
*
Hydrolases in Polymer Chemistry: Part III: Synthesis and Limited Surface Hydrolysis of Polyesters and Other Polymers, by G.M. Guebitz
*

Exploiting Biocatalysis in the Synthesis of Supramolecular Polymers, by S. Roy and R. V. Ulijn