(1952), HoRNING (1956), DoNTENWILL und EDER (1959)]. Wir sahen dabei fast immer basophile Adenome mit z. T. hochgradiger Zellpolymorphie und typischen Crooke-Zellen rpit Vacuolen (Abb. 3a u. b). Die Adenome fiihrten hiiufig zu De- formierungen der Schiidelbasis. Bei diesen Adenomen konnten keine Veriinderun- gen an den endokrinen Driisen oder endokrin gesteuerten Organen nachgewiesen werden, die auf eine Mehrsekretion der vergr6Berten Hypophyse hindeuten. 1. Spezielle Hypophysenadenome Wahrend bei den bisher angefiihrten Adenomen oder Hyperplasien keine be- stimmte Differenzierung nach ihrer Sekretion bzw. Leistung vorgenommen werden konnte, wurden in den letzten Jahren besonders von FURTH (1955, 1957, 1958), FURTH und CLIFTON (1957), CLIFTON (1959) eine Reihe von verschiedenartigen Hypophysenadenomen beschrieben [Obersicht iiber diese Hypophysenade- nome, ihre Ursachen, ihre hormonelle Leistung bzw. Struktur zeigt ein Schema (Tab. 1) aus der Monographie von KwA HoNG GroG (1961)], die als mammatrope, adrenocorticotrope, thyreotrope, somatothyreotrope und amphophile Adenome bezeichnet wurden. Die Differenzierung dieser Adenome bezieht sich z. T. auf ihre spezifische Leistung, z. T. auf ihre typische Zellstruktur. RussFIELD, FRIEDLER Tabelle I. Schematische Einteilung der Hypophysentumoren bei Maus und Ratte Proliferierender Zelltyp anznnehmende Art der Experimentelle Bedingungen tatsiichlich Hormonbildung Hypophysenstimuliernng 1eoretisch erwartet beobachtet tsophiler {J-Z entgranulierter TSH (,thyro- Chirurgische Schilddriisen- Unterbrechung des basophiler trophin" usw. ) entfernung; ,Radiothy- W echselmechanismus {J-Z.

Phytochemicals from medicinal plants are receiving ever greater attention in the scientific literature, in medicine, and in the world economy in general. For example, the global value of plant-derived pharmaceuticals will reach $500 billion in the year 2000 in the OECD countries. In the developing countries, over-the-counter remedies and "ethical phytomedicines," which are standardized toxicologically and clinically defined crude drugs, are seen as a promising low cost alternatives in primary health care. The field also has benefited greatly in recent years from the interaction of the study of traditional ethnobotanical knowledge and the application of modem phytochemical analysis and biological activity studies to medicinal plants. The papers on this topic assembled in the present volume were presented at the annual meeting of the Phytochemical Society of North America, held in Mexico City, August 15-19, 1994. This meeting location was chosen at the time of entry of Mexico into the North American Free Trade Agreement as another way to celebrate the closer ties between Mexico, the United States, and Canada. The meeting site was the historic Calinda Geneve Hotel in Mexico City, a most appropriate site to host a group of phytochemists, since it was the address of Russel Marker. Marker lived at the hotel, and his famous papers on steroidal saponins from Dioscorea composita, which launched the birth control pill, bear the address of the hotel."

The last 15 years have brought an understanding of growth and differentiation at the molecular level, expanding our knowledge of the origin and progression of cancer. Early breakthroughs defining growth control pathways came via studies of oncogenes, mutated signaling molecules that have lost the capacity to tum off their proliferative signal. Oncogenes with diverse growth-promoting activities have been discovered, covering the gamut from cell surface to nuclear signaling. Sequencing of these oncogenes revealed that they were mutated forms of captured cellular genes and displayed tyrosine kinase activity. The epidermal growth factor (EGF) receptor was the first of 40-50 transmembrane tyrosine kinase receptors to be cloned and sequenced. Beyond cell proliferation, activation of EGF receptor by its specific ligands controls important physiological processes, such as cell differentiation, apoptosis, cell migration, and cell shape. Activation of autocrine growth loops, consisting in solid human tumors of upregulated expression of EGFR together with increased production of ligands suggested its crucial role in autonomous tumor growth.

This volume attemptsto provide the formulation scientist with casehistories involving the use of therapeutic proteins and peptides that have been mar- keted or are under clinical testing. In previous volumes of this series,funda- mental theories and principles ofprotein characterization and stability were presented in depth by researchers in their fieldsofexpertise. The way from theory to practice isnot alwaysobvious and straightforward. There isa need for practical examples of how the principles and theories are put into use, specificallyin the development of a pharmaceutical product. It is our hope that this volume will fulfillsuch a need. Itisnot asimple task to choose a panel ofproteinsand peptides from the over 200 agents in human clinical trials. We have tried to collect a wide representation of molecules of different sizes-from 10 amino acids (Leu- prolide) to 1020 amino acids (Muromonab CD3). The examples include agents derived from various sources including monoclonal antibodies (Mur- omonab CD3), recombinant DNA (human and bovine growth hormones), natural source (fibrolase), and chemical synthesis (Leuprolide). Clearly this list is not intended to be encyclopedic. It isthe first time a collection of this sort has been made accessibleto the formulation scientists involved in devel- oping protein and peptide products. Although each chapter in this volume focuses primarily on the charac- terization and stability of a specific molecule, each has unique aspects.

Proteins are still gaining importance in the pharmaceutical world, where they are used to improve our arsenal of therapeutic drugs and vaccines and as diagnostic tools. Proteins are different from "traditional" low-molecular-weight drugs. As a group, they exhibit a number of biopharmaceutical and formulation problems. These problems have drawn considerable interest from both industrial and aca demic environments, forcing pharmaceutical scientists to explore a domain previ ously examined only by peptide and protein chemists. Biopharmaceutical aspects of proteins, e.g., low oral bioavailability, have been extensively investigated. Although all possible conventional routes of ad ministration have been examined for proteins, no real, generally applicable alter native to parenteral administration in order to achieve systemic effects has yet been discovered. Several of these biopharmaceutical options have been discussed in Volume 4 of this series, Biological Barriers to Protein Delivery. Proteins are composed of many amino acids, several of which are notorious for their chemical instability. Rational design of formulations that optimize the native structure and/or bioactivity of a protein is therefore of great importance when long shelf life is required, as it is for pharmaceutical products. This issue has also been examined in two prior volumes of this series: Volume 2: Stability of Protein Pharmaceuticals (Part A) and Volume 5: Stability and Characterization of Protein and Peptide Drugs.

''A wealth of information...these two volumes will be immensely valuable to anyone having to deal with this difficult group of compounds.'' ---Biochemical Systematics and Ecology, from a review of Saponins Used in Traditional and Modern Medicine and Saponins Used in Food and Agriculture

Proceedings of a conference sponsored by the American Association of Pharmaceutical Scientists, the U.S. Food and Drug Administration, and the American Society for Clinical Pharmacology and Therapeutics, held in Arlington, Virginia, April 24-26, 1991

Eine grosse Anzahl heterocyclischer Naturstoffe leitet sich vom Ring- system des Piperidins (1) ab. Als Substituenten einfach oder mehrfach substituierter Piperidinbasen finden sich Methyl-, Carboxyl-, Hydroxyl- und Aminogruppen sowie aliphatische Seitenketten unterschiedlicher Lange. Die Substitution erfolgt bevorzugt an den C-Atomen 2, 3 und 6 sowie am Heteroatom. In zahlreichen Fallen ist der Piperidinring in a- oder ss-Stellung direkt oder uber eine C-Brucke mit einem weiteren Heterocyclus verbunden, z. B. einem Piperidin-, Piperidein-, Pyridin-, Indol-, Chinolizidin- oder Furanrest. Daruber hinaus kann der Piperidin- ring zum 2,6-Dioxopiperidin (Glutarimid) oxydiert oder zum Pipendein dehydriert sein. Wahrend Naturstoffe mit Pyridinstruktur im Tier- und Pflanzenreich weit verbreitet sind und einzelnen von ihnen wie NAD oder Pyridoxal- phosphat als Coenzymen des Primarstoffwechsels besondere Bedeutung zukommt, handelt es sich bei den naturlichen Piperidinverbindungen im allgemeinen um sekundare Pflanzenstoffe (vgl. I8, I9I). Dabei sind einige wie z. B. die Pipecolinsaure (7) sporadisch auf verschiedene Pflanzen- familien verteilt. Andere Piperidinbasen wie die Conium- oder Piper- Alkaloide weisen dagegen eine ausgesprochene Artspezifitat auf. Im Gegensatz zu den meisten Pyridinalkaloiden finden sich die Piperidin- basen oft mit strukturell andersartig gebauten Alkaloiden vom Chino- lizidin- oder Trepantyp vergesellschaftet, was in den meisten Fallen durch eine enge biogenetische Verwandtschaft bedingt sein durfte.

This volume comprises the edited proceedings of the International Taurine Sympo sium held in Osaka, Japan, in June 1995, as a Satellite Symposium of the 15th Biennial of the International Society for Neurochemistry. This Taurine Symposium was the Meeting latest in a series held since 1975 at approximately two-year intervals by an informal group of international researchers. It attracted contributions from 20 countries, ranging from Armenia via Finland and Spain to the United States. Some 121 participants attended. The Symposium was organized and chaired by Junichi Azuma, University of Osaka. Other members of the Organizing Committee in Japan consisted of Kinya Kuriyama and Masao Nakagawa, both from the Kyoto Prefectural University of Medicine, and Akemichi Baba, from Osaka University. The Committee had to contend with the disaster of the Kobe earthquake, which struck on January 21. The epicenter was only around 25 miles from the meeting site, and the quake demolished the home of one Committee member. Despite this unnaturally natural handicap, the participants experienced a superbly organized meeting, one which more than maintained the high social and scientific standards established for this series. In his Welcome Message, Dr. Azuma listed a threefold objective for the Symposium: To provide a forum for the interdisciplinary exchange of information on taurine; to give an opportunity for renewing old friendships and making new friends; and to promote coopera tion among participants from around the world."

Drug products are complex mixtures of drugs and excipients and, as such, their chemical and physical stability kinetics are complex. This book discusses the stability of these dosage forms with preformulation studies through to the studies on the final products. The book is intended for graduate students, researchers and professionals in the field of Pharmaceutics and Pharmaceutical Chemistry.

This volume contains a series of papers originally presented at the symposium on Water Soluble Polymers: Solution Properties and Applications, sponsored by the Division of Colloids and Surface Chemistry of the American Chemical Society. The symposium took place in Las Vegas City, Nevada on 9 to 11th September, 1997 at the 214th American Chemical Society National Meeting. Recognized experts in their - spective fields were invited to speak. There was a strong attendance from academia, g- ernment, and industrial research centers. The purpose of the symposium was to present and discuss recent developments in the solution properties of water soluble polymers and their applications in aqueous systems. Water soluble polymers find applications in a number of fields of which the following may be worth mentioning: cosmetics, detergent, oral care, industrial water treatment, g- thermal, wastewater treatment, water purification and reuse, pulp and paper production, sugar refining, and many more. Moreover, water soluble polymers play vital role in the oil industry, especially in enhanced oil recovery. Water soluble polymers are also used in ag- culture and controlled release pharmaceutical applications. Therefore, a fundamental kno- edge of solution properties of these polymers is essential for most industrial scientists. An understanding of the basic phenomena involved in the application of these polymers, such as adsorption and interaction with different substrates (i. e. , tooth enamel, hair, reverse - mosis membrane, heat exchanger surfaces, etc. ) is of vital importance in developing high performance formulations for achieving optimum efficiency of the system.

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.

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.

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.

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.

The aim and scope of this book is to highlight the sources, isolation, characterization and applications of bioactive compounds from the marine environment and to discuss how marine bioactive compounds represent a major market application in food and other industries. It discusses sustainable marine resources of macroalgal origin and gives examples of bioactive compounds isolated from these and other resources, including marine by-product and fisheries waste streams. In addition, it looks at the importance of correct taxonomic characterization."

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."

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.