George Poste - Böcker

This volume focuses on recent developments in our understanding of selected adhesion processes that may offer new approaches to developing therapeutics for a variety ofdiseases. The volume first introduces the molecules involved in key adhesive processes, then describes the biological consequences of several adhe- sive interactions, and closes with a description of the initial therapeutic ap- proaches to antagonizing. adhesion. These papers were originally presented at the SmithKline Beecham Pharmaceuticals Seventh U. S. Research Symposium held in Philadelphia in October of 1992. ofacell to asurface. In its simplestsense, cellularadhesion is the adherence The cells of interest in the context of this volume are bacterial and mammalian, with an emphasis on leukocytes; surfaces can be other cells and tissues (such as bone), matrix proteins, or inanimate objects such as in-dwelling medical devices and catheters. Interaction between adhesion molecules usually results in a spe- cific biological response. Adhesion is a form ofcellularcommunication, and represents the way a cell senses its environment through contact.Like hormones and cytokines, the sol- uble mediators used by cells for communication, adhesion molecules are defined molecular entities that recognize specific receptor structures on the surface to which they adhere. Recent activity has focused on defining the structure of the individual molecules responsible for many types ofcellularadhesion. New adhe- sion proteins are being cloned with the help of specific antibodies and precise functional assays.

The NATO Advanced Studies Institute series "Targeting of Drugs" was originated in 1981. It is now a major international forum, held every two years in Cape Sounion, Greece, in which the present and the future of this important area of research in drug delivery is discussed in great depth. Previous ASIs of the series dealt with drug carriers of natural and synthetic origin, their interaction with the biological milieu, ways by which the latter influences such interaction, strategies by which milieu interference curtailing the function of drug carriers is circumvented and, more recently, with the application of drug carriers for the delivery of peptides and proteins. The present book contains the of the 7th NATO ASI "Targeting of Drugs: Advances in System Constructs", proceedings held in Cape Sounion during 24 June -5 July 1993. As the title implies, the book deals with a variety of approaches to carrier design or modification that contribute to optimal carrier function. to Mrs Concha Perring for her assistance with the We express our appreciation organization of the ASI. We thank Dr. G. Deliconstantinos who, as chairperson of the Local Committee, contributed to the success of the Institute. The ASI was held under the sponsorship of NATO Scientific Affairs Division and co-sponsored and generously financed by SmithKline Beecham Pharmaceuticals (King of Prussia). Financial assistance was also provided by Liposome Technology Inc. (Menlo Park), Vestar Inc. (San Dimas) and Zeneka (Macclesfield).

The heat-shock proteins in E. coli are transiently overexpressed af- ter shift to a higher growth temperature. The genes that encode the HSPs are preceded by promoters transcribed in vitro by a form of RNA poly- 32 32 merase holoenzyme containing a 32-kd a subunit (Ea ). The a subunit is encoded by the rpoH (htpR) gene, previously identified as a positive 32 effector of the heat-shock response. Our evidence suggests that Ea is the enzyme that transcribes heat-shock genes at all temperatures. The level 32 of a may be regulated at several points: Accumulation of rpoH mRNA 32 is affected by temperature shift, a synthesis is regulated posttranscrip- 32 tionally, and a is an unstable molecule with a tl/2 of 5 min. Many mu- tations in the HSPs are shown to have defects in proteolysis. References Baker. T. A. , Grossman. A. D . . and Gross. C. A. , 1984, A gene regulating the heat shock response in Escherichia coli also affects proteolysis. Proc. Natl. A cad. Sci. US. A. 81:6779-6783. Bardwell, J. C. A . . and Craig, E. A . . 1984. Major heat shock gene of Drosophila and the Escherichia coli heat-inducible dnaK gene are homologous, Proc. Natl. Acad. Sci. US. A. 81:848-852. Bukhari. A. I. .and Zipser. D . . 1973, Mutants of Escherichia coli with a defect in the degradation of nonsense fragments, Nature New Bioi. 243:238-241. Charette. M. F. , Henderson, G. W. , and Markovitz, A.

It is less than 80 years since John Newport Langley first proposed the role of "receptive substances" as the site of drug action from his obser­ vations on the effects of nicotine and curare at the myoneural junction. The many advances in our understanding of receptor biology that have occurred during the intervening period mirror the extraordinary growth of knowledge in the biological sciences and in cell and molecular biology in particular. Receptor biology, in common with many other topics in contemporary biology, is on the threshold of a transition from being a descriptive, phenomenological discipline to one in which underlying mechanisms and regulatory principles can be defined with increasing pre­ cision. This change, together with the evolution of powerful analytical techniques and timely convergence of ideas from a number of previously separate fields of inquiry, is generating an increasingly unified theoretical and experimental framework for the study of receptor function. These themes, and the mood of anticipation that a real understanding of receptor function in health and disease is emerging, are reflected in in this volume, which summarizes the proceedings of the Sec­ the papers ond Smith Kline & French Research Symposium on New Horizons in Therapeutics held in Philadelphia in 1984.

This volume focuses on recent developments in our understanding of selected adhesion processes that may offer new approaches to developing therapeutics for a variety ofdiseases. The volume first introduces the molecules involved in key adhesive processes, then describes the biological consequences of several adhe- sive interactions, and closes with a description of the initial therapeutic ap- proaches to antagonizing. adhesion. These papers were originally presented at the SmithKline Beecham Pharmaceuticals Seventh U. S. Research Symposium held in Philadelphia in October of 1992. ofacell to asurface. In its simplestsense, cellularadhesion is the adherence The cells of interest in the context of this volume are bacterial and mammalian, with an emphasis on leukocytes; surfaces can be other cells and tissues (such as bone), matrix proteins, or inanimate objects such as in-dwelling medical devices and catheters. Interaction between adhesion molecules usually results in a spe- cific biological response. Adhesion is a form ofcellularcommunication, and represents the way a cell senses its environment through contact.Like hormones and cytokines, the sol- uble mediators used by cells for communication, adhesion molecules are defined molecular entities that recognize specific receptor structures on the surface to which they adhere. Recent activity has focused on defining the structure of the individual molecules responsible for many types ofcellularadhesion. New adhe- sion proteins are being cloned with the help of specific antibodies and precise functional assays.

'nle NATO Advanced studies Institute series "Targeting of Drugs" was originated in 1981. It is now a major international forum, held every two years in cape Sounion, Greece, in which the present and the future of this important area of research in drug delivery is discussed in great depth. Five previous ASIs of the series dealt with drug carriers of natural and synthetic origin, their interaction with the biological milieu, with ways by which the latter influences such interaction and strategies by which milieu interference curtailing the ftmction of drug carriers is circumvented or relieved. 'nle present book contains the proceedings of the 6th NATO ASI "Targeting of Drugs: 'nle nias who, as chairperson of the Local Corrmittee, contriruted to the success of the Institute. 'nle ASI was held under the sponsorship of NATO Scientific Affairs Division and co-sponsored and generously financed by SmithKline Beecham Phannaceuticals (King of Prussia). Financial assistance was also provided by Syntex Laboratories Inc. (Palo Alto), Syntex Research (Palo Alto) and pfizer Central Research (Sandwich).

It is widely accepted that vaccination still renains the best answer to ITDst infectious diseases. Recently, vaccine developnent has been greatly facilitated by advances in ITDlecular and cell biology which have laid the foundations of a new generation of vaccines. '!hese are exemplified by submit vaccines produced through gene cloning and synthetic peptides mimicking snall regions of proteins on the outer coat of viruses and capable of eliciting virus neutralizing antibodies. However, submit and peptide vaccines are only weakly or non-inmmogenic in the absence of immunological adjuvants. The latter are a diverse array of agents that augment specific cell-mediated immune responses to the antigens and the formation of protective antibodies. '!his book contains the proceedings of the 3rd NATO Advanced Studies Institute (ASI) "New-Generation vaccines: '!he Role of Basic Irrmmology" held at Cape Sounion Beach, Greece, during 24 June-5 July, 1992.It deals with recent developnents in the understanding of inmmity at the ITDlecular and cellular levels and the application of such knowledge in the search for novel inmmological adjuvants and the fonnulation of new-generation vaccines for experimental and clinical use. We express our appreciation to Professor K. Dalsgaard and H. Snippe for their cooperation in planning the ASI and to Mrs. Concha Perring for her excellent production of the manu- scripts. '!he ASI was held tmder the sponsorship of NATO Scientific Affairs Division and generously co-sponsored by SrnithKline Beecham Pharmaceuticals (Fhiladelp,. ia). Financial assistance was also provided by Pasteur Merieux (Marcy L'Etoile), British Biotechnology Ltd.

The success of vaccination in controlling infectious diseases is well documented. However, low profitability, expense and liability have hindered research and development of vaccines. Recently, increasing realization (enhanced by the AIDS pandemic) of the need to overcome such difficulties has led to steps being taken by national authorities, non-profit and commercial organizations to resolve them. This has been facilitated by developments in recombinant DNA techniques, the advent of monoclonal anti­ bodies and progress in the understanding of the immunological structure of proteins which have laid the foundation of a new generation of vaccines. Such vaccines are defined at the molecular level, can elicit immune responses controlling infectious organisms and are therefore potentially free of the problems encountered in conventional ones. Unfortunately, subunit and synthetic peptide vaccines are often only weakly or non­ inmunogenic. However, developments in both antigen production and immuno­ potentiation of weak antigens have opened new avenues with exciting prospects for vaccine design.

Targeting of drugs via carrier systems to sites in the body in need of pharmacologic intervention is a rapidly growing area of research in the treatment or prevention of disease. It has evolved from the need to preferentially deliver drugs, enzymes, vitamins, hormones, antigens, etc. to target cells and organs so as to avoid toxicity, waste of drugs through premature secretion or inactivation and at the same time render treatment more convenient and cost-effective. A wide assortment of naturally occ­ urring or semi-synthetic drug carriers (e. g. antibodies, glycoproteins, lectins, peptide hormones, cells and liposomes), their inter action with relevant receptors and mediation of optimal pharmacological action were discussed in the two previous NATO Advanced Studies Institutes (ASI) of this series, "Targeting of Drugs" and "Receptor-Mediated Targeting of Drugs", the proceedings of wh ich were published by Plenum in 1982 and 1984 respectively. This book contains the proceedings of the 3rd NATO ASI "Targeting of Drugs with Synthetic Systems" held as be fore at Cape Sounion, Greece during 24 June-5 July 1985. It deals mostly with man-made carriers such as a variety of polymers, matrices, liposomes and other colloidal micro­ particles. The twenty chapters discuss the interaction of such carriers with the biological milieu, approaches to bypass the reticuloendothelial system (or, when needed, take advantage of its interception of carriers to optimally deliver drugs to phagocytes) and ways to improve delivery to specific cells, often with the help of carrier-linked ligands.

The characterization of the cellular and molecular mechanisms that mediate inflammation provides a foundation that supports future studies that will de­ fine mechanisms more intimately. It encourages substantial optimism about the opportunities to understand the inflammatory process and to use that information to develop novel therapeutic approaches. Recent progress has defined the cells that mediate the inflammatory response, many of the inter­ cellular transmitters, the receptors, signal transduction processes and regula­ tory mechanisms. Thus, we now have the opportunity to understand inflammation in pharmacologic terms and to attack the key molecular targets to develop new therapeutics. Among the cells involved in the inflammatory response are the lympho­ cytes, neutrophils and endothelial cells. Maintenance of homeostasis, re­ sponse to proinflammatory stimuli and pathophysiologic responses are products of complex interactions between these and other elements of the immune systems. Each of these cells displays a variety of receptors to define the stimuli to which they respond. The receptors displayed that the signal transduction processes and cellular responses are regulated genetically and epigenetic ally . The critical role of membranes and particularly the phospho­ lipid components of the membranes is emphasized by recent studies.

A major vehicle for the transition of carrier-mediated drug delivery from a theoretical/experimental status to one with practical uses has been the NATO Advanced Studies Institute series "Targeting of Drugs". Three previous ASls of the series[1-3], also held in Cape Sounion, dealt with carriers of natural and synthetic origin, their preparation and drug incorporation as well as a wide range of applications. This book contains the proceedings of the 4th NATO ASI "Targeting of Drugs: Anatomical and Physiological Considerations" held in Cape Sounion, Greece during 20 June - 1 July 1987. Historically, carrier systems have been chosen on the basis of selective affinity for target sites. For instance, monoclonal antibodies bind selectively to antigens on the surface of cells and the same applies to ligands such as certain glycoproteins which bind to cell receptors. Colloidal carriers on the other hand, are "passively" targeted to the reticuloendothelial system. However, effective drug delivery depends not only on demonstration of affinity of the carrier system for its target but also, and perhaps crucially, on the way(s) by which the carrier-drug entity interacts with the interposed biological milieu. The book deals in depth with a number of biological milieus as travelled space for carriers en route to their destination, difficulties arising from unfavorable milieu-carrier interactions and ways to circumvent such difficulties. It also identifies, when possible, situations where proposed uses would or would not be realistic and provides perspectives for future goals.

The NATO Advanced Studies Institute series "Targeting of Drugs" was originated in 1981. It is now a major international forum, held every two years in Cape Sounion, Greece, in which the present and the future of this important area of research in drug carriers is discussed in great depth. Four previous ASls of the series dealt with drug carriers of natural and synthetic origin, their interaction with the biological milieu and with ways by which the latter influences such interaction. The present book contains the proceedings of the 5th NATO ASI "Targeting of Drugs: Optimization Strategies" held in Cape Sounion during 24 June-5 July, 1989. A logical sequel to the last one, the ASI deals with strategies by which milieu inter- ference curtailing the function of drug carriers is circumvented or removed. We express our appreciation to Drs. R. Langer and E. Tomlinson for their valuable advice throughout the planning of the ASI and to Dr. G. Deliconstantinos who, as Chairman of the Local Committee contributed so effectively to its success.The ASI was held under the sponsorship of NATO Scientific Affairs Division and co-sponsored and generously financed by Smith Kline French Laboratories (now SmithKline Beecham), Philadelphia, USA. Financial assistance was also provided by CIBA Geigy (Horsham), Schering (West Berlin), Farmitalia Carlo Erba (Milan), Liposome Technology Inc. (Menlo Park), Pfizer (Sandwich), Dior (Paris), Syntex Research (Palo Alto), ICI Pharmaceuticals (Mereside), Boehringer (Mannheim) , Wyeth (Taplow), Merck Sharp Dohme (Rahway), Sandoz A.G. (Basle) and Lilly Research Centre Ltd.

Vaccination, chiefly responsible for the eradication of smallpox and the control of poliomyelitis and German measles in man and of foot-and­ mouth, Marek's and Newcastle disease in domestic animals, remains the best answer to infectious diseases. Early vaccines were live wild type organ­ isms but these have been largely replaced by attenuated or killed organisms or by purified components (subunits) thereof. More recently, developments in recombinant DNA techniques, the advent of monoclonal antibodies and progress in our understanding of the immunological structure of proteins, have laid the foundations for a new generation of vaccines. For instance, subuni t vaccines have been produced through gene cloning and a number of peptides mimicking small regions of proteins on the outer coat of viruses and capable of eliciting virus neutralizing antibodies, have been synthes­ ized. Such vaccines are defined at the molecular level, can elicit immune responses controlling specific infectious organisms and are, thus, potent­ ially free of the problems inherent in conventional ones. However, because subunit and peptide vaccines are only weakly or non-immunogenic, they re­ quire the presence of immunological adjuvants. These are a diverse array of agents that promote specific humoural and/or cell-mediated immunity responses to antigens. This book contains the proceedings of the 1st NATO Advanced Studies Institute "Immunological Adjuvants and Vaccines" held in Cape Sounion Beach, Greece during 24 June-5 July, 1988.

Dopamine, in addition to its importance as a precursor of norepinephrine, is now known to be an important neurotransmitter in regulating functional activities in a number of major organ systems, including the central ner­ vous system. the cardiovascular system, the kidney, and the gut. Recent advances in our understanding of the functional role of dopamine, its mechanism of action and the pharmacology of dopaminergic agents have occurred on a broad front. The last few years have witnessed significant progress in the identification and classification of central and peripheral dopamine receptors and the factors that affect their responsiveness to inhibitory and stimulatory ligands. These advances have been paralleled by new insights into the contribution of alterations in dopaminergic reg­ ulation in causing disease and the utility of dopamine agonists and an­ tagonists as therapeutic modalities. This volume, the first in a series of publications arising from the annual Smith Kline and French Research Symposium on New Horizons in Therapeutics, provides a comprehensive survey of current research on peripheral dopamine receptors and the physiologic and therapeutic con­ sequences of stimulating pre-and postsynaptic dopamine receptors. Research in dopamine pharmacology mirrors the remarkable ad­ vances that are occurring in the field of pharmacology at large as a con­ sequence of the involvement of an ever-larger number of scientific dis­ ciplines in the study of drug action.