Valuation is a hot topic among life sciences professionals. There is no clear understanding on how to use the different valuation approaches and how to determine input parameters. Some do not value at all, arguing that it is not possible to get realistic and objective numbers out of it. Some claim it to be an art. In the following chapters we will provide the user with a concise val- tion manual, providing transparency and practical insight for all dealing with valuation in life sciences: project and portfolio managers, licensing executives, business developers, technology transfer managers, entrep- neurs, investors, and analysts. The purpose of the book is to explain how to apply discounted cash flow and real options valuation to life sciences p- jects, i.e. to license contracts, patents, and firms. We explain the fun- mentals and the pitfalls with case studies so that the reader is capable of performing the valuations on his own and repeat the theory in the exercises and case studies. The book is structured in five parts: In the first part, the introduction, we discuss the role of the players in the life sciences industry and their p- ticular interests. We describe why valuation is important to them, where they need it, and the current problems to it. The second part deals with the input parameters required for valuation in life sciences, i.e. success rates, costs, peak sales, and timelines.

Mitochondrial medicine deals with diseases that are related to mitochondrial dysfunction due to a number of causes from free radical damage to genetic mutation. This book is based on extensive data gathered over 30 years of clinical and experimental research. In it, internationally recognized authors share their experience in various fields of their expertise and guide readers through the disease process, from basic biochemical mechanisms to diagnosis to therapeutic aspects.

Liver disease is a widespread and increasing problem throughout the world, however little is published on how different types and degrees of liver dysfunction affect the body's ability to handle medicines."Drugs and the Liver" is designed to assist practitioners in making pragmatic choices for their patients. It aims to: enable the practitioner to assess liver function using biochemical markers, other tests, signs, symptoms and disease knowledge; identify which pharmacokinetic and pharmacodynamic parameters of a drug are likely to be affected by different types of liver disease; and consider the impact of a drug's side effects on a patient with liver disease.This practical guide covers background information on liver function, the principles of drug use in liver disease and includes a section of worked examples of commonly asked questions. It will be invaluable to clinical pharmacists and anyone making medicine choices in patients with liver impairment.

Polycyclic hydrocarbons are of interest in many fields of science: theoretical chemistry, physical chemistry, organic chemistry, dyestuff chemistry and biology. With regard to the latter, I am indebted to Dr. Regina Schoental of the Medical Research Council for the review in this present work of carcinogenesis by polycyclic hydrocarbons. This book is designed to present the facts in a simple and clear order and to derive empirical rules from them, but it does not present a com prehensive theory about polycyclic hydrocarbons. An attempt is made instead to extend classical symbolism into modern structural chemistry. Thus extensive use is made of Robinson's aromatic sextet, which is applied in an uncompromising and strict way. This quasi-classical attempt is encouraged further by such completely unexpected dis coveries as those of Dewar benzene and of the electronic asymmetry of formally symmetric hydrocarbons. How difficult it is to break away from any established way of thinking has been admirably expressed by Kekule ("Organische Chemie," 1861, Part 1, page 4, translated from the German): "All our ideas are based, to an extent much greater than we ordinarily believe, on those of our predecessors. Our accumulated experience, the notions of which our training has accustomed us to, of whatever kind they have been, influence the course of our thoughts far more than we are willing to admit; only too frequently the following of our regularly used, well trodden way of thinking leads us to overlook the simplest of correlations."

Polycyclic hydrocarbons are of interest in many fields of science: theoretical chemistry, physical chemistry, organic chemistry, dyestuff chemistry and biology. With regards to the latter, I am indebted to Dr. Regina Schoental of the Medical Research Council for the review in this present work of carcinogenesis by polycyclic hydrocarbons. This book is designed to present the facts in a simple and clear order and to derive empirical rules from them, but it does not present a com prehensive theory about polycyclic hydrocarbons. An attempt is made instead to extend classical symbolism into modern structural chemistry. Thus extensive use is made of Robinson's aromatic sextet, which is applied in an uncompromising and strict way. This quasi-classical attempt is encouraged further by such completely unexpected dis coveries as those of Dewar benzene and of the electronic asymmetry of formally symmetric hydrocarbons. How difficult it is to break away from any established way of thinking has been admirably expressed by Kekule ("Organische Chemie," 1861, Part 1, page 4, translated from German): "All our ideas are based, to an extent much greater than we ordinarily believe, on those of our predecessors. Our accumulated experience, the notions of which our training has accustomed us to, of whatever kind they have been, influence the course of our thoughts far more than we are willing to admit; only too frequently the following of our regularly used, well trodden way of thinking leads to us overlook the simplest of correlations."

This classic work by Poucher, first published in 1923, was last produced in three volumes titled, respectively The Raw Materials of Perfumery (seventh edition, 1974), The Production, Manufacture and Application of Perfumes (eighth edition, 1974) and Modern Cosmetics (eighth edition, 1974). Its popularity is well demonstrated by there having been three reprints of these editions in 1976, 1979 and 1984, res pecti vel y . The history of events can be traced by reference to the prefaces to earlier editions and those interested should study these with care since they give a fascinating insight into developments in the subject fields covered by Poucher's Perfumes, Cosmetics and Soaps over the years. It is not proposed to provide a resume here. In this Volume I, the current edition attempts to provide data about raw materials in a more formalized way than before, so that not only the history of some compounds can be checked, but also so that useful reference information can be obtained. It is particularly relevant to do this, since it is not always easy to be certain of nomenclature. Moreover, as we move towards 'ingredient labelling' (a trend not welcomed by some), a high level of uniformity will be needed. Whether this will come from adoption of CTFA terminology, use of CAS numbers or some other system is not clear. Where possible, such data have been included so that readers may identify materials more readily. Where given, CAS numbers are located in the top right-hand corner of each entry.

The field of DNA vaccines has undergone explosive growth in the last few years. As usual, some historical precursors of this approach can be d- cerned in the scientific literature of the last decades. However, the present state of affairs appears to date from observations made discreetly in 1988 by Wolff, Malone, Felgner, and colleagues, which were described in a 1989 patent and published in 1990. Quite surprisingly, they showed that genes carried by pure plasmid DNA and injected in a saline solution, hence the epithet "naked DNA," could be taken up and expressed by skeletal muscle cells with a low but reproducible frequency. Such a simple methodology was sure to spawn many applications. In a separate and important line of experimentation, Tang, De Vit, and Johnston announced in 1992 that it was indeed possible to obtain humoral immune responses against proteins encoded by DNA delivered to the skin by a biolistic device, which has colloquially become known as the "gene gun. " The year 1993 saw the publication of further improvements in the me- ods of naked DNA delivery and, above all, the first demonstrations by several groups of the induction of humoral and cytotoxic immune responses to viral antigens expressed from injected plasmid DNA. In some cases, protection against challenge with the pathogen was obtained. The latter result was - questionably the touchstone of a method of vaccination worthy of the name.

Advances in understanding the molecular mechanisms of disease together with the advent of recombinant DNA and other technologies have opened opportunities for a vast array of novel therapeutic biopharmaceuticals and diagnostic agents. However, even natural biomolecules present a myriad of problems that limit their potential as pharmaceutical agents. Rapid degra- tion and elimination, immunological reactions, and toxicity are often asso- ated with new biopharmaceuticals, much as with conventional agents. Targeted delivery systems have the potential to increase the efficacy of existing diagnostic and therapeutic agents and also create an opportunity for the use of new pharmaceuticals, substances that themselves can be harmful to normal tissues. Both passive and active targeting have been exploited. Most active targ- ing strategies have focused on antibody conjugates since preparation of highly specific monoclonal antibodies is well established. However, a new wave of c- jugates exploiting other ligands is underway. Access to the target tissue remains an obstacle and is an area where passive targeting can be useful. In Drug Targeting: Strategies, Principles, and Applications we have tried to compile a state-of-the-art volume on current targeting approaches. The first section focuses on certain key strategies applied to date, and how to build the antibody- ligand constructs. This is followed by a section on theoretical considerations for t- geting, focusing on approaches relevant to solid tumors. The last section deals with some experimental and clinical applications of targeted drug delivery systems.

Reasoning in terms of molecular recognition may be traced back to Emil Fischer, who practiced the art of chemistry at Humboldt University in Prussian Berlin a century ago. Today, it is clearly recognized that molecular recognition impacts and determines all life processes. It has become a key research field in both chemistry and biology and the emerging interface of what now is being called "chemical biology". The technological advances derived from this knowledge are particularly important, diverse, and directly evident in the pharmaceutical industry. Under the auspices of the Ernst Schering Research Foundation, a workshop held in Berlin in February 1998 addressed novel basic developments of potential relevance to drug research efforts. A balance of timely research topics in molecular recognition is presented in the lectures delivered by a multidisciplinary international panel of renowned scholars and documented in this volume.

This volume summarizes current research on the influence of plant polyphenols on human health, promoting collaboration between chemists and biologists to improve our understanding of their biological significance, and expanding the possibilities for their use.

This Adis Pocket Reference presents an up-to-date, succinct, and practical approach to drug therapy for type 2 diabetes.

Seven review articles and original papers provide a representative overview of the research work done in hydrogen bond research at Austrian universities. The topics covered by the contributions are: state-of-the-art of understanding hydrogen bonding in biopolymers; recent NMR techniques for studying hydrogen bonding in aqueous solutions; intramolecular hydrogen bonding and proton transfer in a class of Mannich bases derived from substituted phenols and naphthols; competition between intramolecular hydrogen bonds in ortho-disubstituted phenols; molecular dynamic simulations on proton transfer in 5,8-dihydroxynaphthoquinone and in the formic acid dimer; accurate calculations of the intermolecular interactions in cyanoacetylen dimers; correlation between OH...O bond distances and OH stretching frequencies as derived from structural and spectroscopic data of minerals.

In the past few years, antisense methodology has moved from in vitro studies to in vivo studies and first human trials. While the basic concept of antisense technology is simple, the methodological problems associated with its use are numerous and complex. Antisense- based methods have proven to be a field of research where careful attention to experimental protocols and appropriate controls is necessary. The Manual of Antisense Methodology emphasizes the application of antisense oligonucleotides, and is a guide for the identification of antisense and non-antisense effects in different experimental settings. The work is organized into three sections: antisense application in vitro, antisense application in vivo (animal models) and finally, clinical antisense studies. Where at all possible, the methods are described in sufficient detail to allow reproduction of a given experiment. The Manual of Antisense Methodology will be of interest to researchers in immunology, cancer research, pharmacology and internal medicine; and physicians conducting clinical studies in these fields.

The lung and its contiguous structures are commonly involved in several of the rheumatic diseases (Table 1), either by direct manifestation of disease or as a secondary effect from infection or complications of therapy. In this chapter, we detail the various pulmonary manifestations of the major rheu- matological conditions. The common symptoms of pulmonary diseases and how frequently they are implicated in rheumatic disorders are review- ed. In addition, radiology and physiology of the lung, diagnostic proce- dures and therapeutic options are discussed. Table l. Respiratory associations of the rheumatic disorders Disease Airways Parenchyma Vessels WalVmuscles Lung Pleura Pulmonary Chest pleurisy hypertension Rheumatoid bronchiectasis, pneumonia, arthritis obliterative fibrosing effusion bronchiolitis alveolitis, empyema nodules Systemic pneumonia pleurisy hypertension lupus fibrosing effusion shrinking lungs erythematosus alveolitis, with high atelectasis diaphragm Systemic bronchiectasis fibrosing hypertension "encased chest" sclerosis alveolitis, aspiration pneumonia Sjogren's bronchitis fibrosing alveolitis syndrome lymphoma Dermatomyositis aspiration myopathy polymyositis pneumonia, fibrosing alveolitis Ankylosing upper lobe cos- spondylitis fibrosis vertebral fixation joint Behget's haemorrhage aneurysm syndrome Relapsing upper airway polychondritis narrowing Pulmonary vasculitides nodules The Respiratory System in Rheumatic Diseases 25 1. 2. Respiratory Symptoms The most common respiratory symptoms in patients with rheumatic disease and pulmonary involvement are non-specific and include cough, breathlessness and chest pain and can be the result of involvement of air- ways, lung parenchyma, pleura, chest wall or pulmonary vessels. 1. 3. Tissue Involvement 1. 3. 1.

Combinatorial chemistry and molecular diversity approaches to scientific inquiry and novel product R&D have exploded in the 1990s! For example, in the preparation of drug candidates, the automated, permutational, and combinatorial use of chemical building blocks now allows the generation and screening of unprecedented numbers of compounds. Drug discovery - better, faster, cheaper? Indeed, more compounds have been made and screened in the 1990s than in the last hundred years of pharmaceutical research. This first volume covers: (i) combinatorial chemistry, (ii) combinatorial biology and evolution, and (iii) informatics and related topics. Within each section chapters are prepared by experts in the field, including, for example, in Section I: Coverage of mixture pools vs. parallel individual compound synthesis, solution vs. solid-phase synthesis, analytical tools, and automation. Section II highlights selection strategies and library-based evolution, phage display, peptide and nucleic acid libraries. Section III covers databases and library design, high through-put screening, coding strategies vs. deconvolutions, intellectual property issues, deals and collaborations, and successes to date.

Advances in molecular biology and recombinant DNA technology have accelerated progress in many fields of life science research, including gene therapy. A large number of genetic engineering approaches and methods are readily available for gene cloning and therapeutic vector construction. Significant progress is being made in genomic, DNA sequencing, gene expression, gene delivery and cloning. Thus gene therapy has already shown that it holds great promise for the treatment of many diseases and disorders. In general it involves the delivery of recombinant genes or transgenes into somatic cells to replace proteins with a genetic defect or to transfer with the pathological process of an illness. The viral and non-viral delivery systems may hold the potential for future non-invasive, cost-effective oral therapy of genetically-based disorders. Recent years have seen considerable progress in the discovery and early clinical development of a variety of gene therapeutic products. The availability, validation, and implementation of gene therapeutic products has also enabled success in testing and evaluation. New challenges will need to be overcome to ensure that products will also be successful in later clinical development and ultimately for marketing authorisation. These new challenges will include improvements in delivery systems, better control of in-vivo targeting, increased level transduction and duration of expression of the gene, and manufacturing process efficiencies that enable reduction in production costs. Perhaps profound understanding of regulated gene design may result in innovative bioproducts exhibiting safety and efficacy profiles that are significantly superior to those achieved by the use of naturally occurring genes. This procedure may contribute considerably to fulfilling standards set by regulatory authorities. This book provides an overview of the current advances in the field of gene therapy and the methods that are being successfully applied in the manufacture of gene therapeutic products, and hopefully will stimulate further progress and advancement in this field to meet the ever-increasing demands.

Bioinformatics brings computational methods to the analysis and processing of genomic data. Bioinformatics: Databases and Systems focuses on the issues of system building and data curation that dominate the day-to-day concerns of bioinformatics practitioners. Included are chapters by many of today's leading bioinformatics practitioners, describing most of the current paradigms of system building and curation, including both their strengths and weaknesses. Biological topics covered include sequence databases, metabolic pathways, phenotypes, variety collections, gene expression atlases and neuroinformatics. Species range from bacteria to mammals to plants. Software systems and technologies covered include OPM, CORBA, SRS, KLEISLI, ACEDB, Web-based integration and laboratory workflow. Bioinformatics: Databases and Systems provides a valuable introduction for newcomers to the field, and a useful reference for veterans.

If the antibody industry is to achieve its full potential in the next decade, the individual technical potentials must be exploited, the limitations must be addressed, and lessons learned must be applied both to current purification methods and to the new technologies that continue to emerge. This book presents an overview of the current advances applied in the manufacture of monoclonal antibody including: -concepts in development of manufacturing strategies, -importance of antibody fragments, -application of chromatography method development, -quality control, -effect of expression on antibody properties, -virus removal and safety, -pharmacokinetics, -regulatory aspects.

This new book is derived from its parent volume Pharmacy Practice and is a succinct, focused guide to pharmaceutical preparations and calculations. Covering everything from calculations to routes of administration dosage forms, it provides pharmacy students with everything they need to know about the maths and methodologies essential to good exam preparation and the safe, effective practice of pharmacy. Each chapter begins with Study Points and ends with Key Points to reinforce learning. Appendices include medical abbreviations, Latin terms and abbreviations, systems of weights and measurements and presentation skills. Some chapters also carry self-assessment questions for more complex areas of pharmaceutical practice.

Inspite of considerable progress in prevention, diagnosis, and treatment, pulmonary embolism has remained a threat to the patient and a challenge for the physician both in conservative, as well as in operative disciplines. Pulmonary embolism is according to pathology observations still the most frequently overlooked clinical diagnosis. In 1-5 per 100 autopsies, clinically unexpected pulmonary emboli are found. In addition, the sequelae of recurrent pulmonary emboli, the syndrome of pulmonary hypertension with or without right heart failure, continues to present a therapeutic dilemma - and no progress is in sight. In intensive care medicine pulmonary embolism, either acute, massive, and/or recur- rent, continues to be both a therapeutic as well as a preventive challenge mobilizing pharmacotherapeutic, catheter-interventional, and operative resources. Diagnostic, therapeutic, and preventive strategies are currently in use. Their basis, however, seems surprisingly thin, as far as our knowledge on the natural course of this chameleon-like illness with and without fibrinolytic, anticoagulative, catheter or opera- tive treatment is concerned. A large European multicenter register has been initiated by Professors Kasper and Geibel with the help of Boehringer Ingelheim Pharmaceutics, in order to better describe the natural course of pulmonary embolism under current treat- ment modalities. Furthermore, recently the clinical significance of the valve patent foramen ovale as a source of paradoxical emboli is beginning to be better understood. Many concepts therefore require revision.

The development of new technology means that compromised patients previously confined to hospital may now be treated at home. Those patients receiving intravenous feeding, cytotoxic drugs and new insulin therapy, are fully trained by the health-care professionals (doctors, pharmacists and nurses) to encourage self-reliance and understanding which are vital to success. There are hazards in treating these patients in the home environment, e.g. microbiological risks which are currently being evaluated, failure of equipment, and social problems as patients adjust to a new life in the community. Neverthless, the balance of benefits favour restoration of the patient to a self-reliant positive life at home. The delivery of this important new dimension in therapy was described at a symposium held in the University of York by innovators in the field. Discussion enabled the core of knowledge and experience developed by multi-disciplinary teams to be shared. The problems of supplying parenteral nutrition and medication for the compromised patient in the home and the family situation were aired and solutions presented. The special care for hospital out-patients receiving cytotoxic drug therapy and safe procedures for staff handling these agents was presented and together with responses to questions indicated the direction for UK hospital pharmacists to follow. More information is needed and it is hoped that this account of these proceedings will stimulate interest in these aspects of health care.

Volume 4 of the Encyclopedia of the Alkaloids covers the literature to the end of 1981 and includes those compounds which have been discovered since Volume 3 was published in 1977. There is also a small number of entries giving recently determined structure or addi tional information regarding alkaloids given in the preceding three volumes. It is a great pleasure to thank the staff of the John Rylands Science Library of the Univer sity of Manchester for kindly providing me with access to the literature on this subject. Woodhouses, JOHN S. GLASBY Manchester, England May, 1982 Contents A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 0 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 P . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 0 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Q . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 R . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31O G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 U . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358 I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 J . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 W . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 X . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 M . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 Z . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370 Formula Index. . . . . . . . . . . . . . . . . . . . 371 A ACETYLALLOYOHIMBINE (Alkaloid NRB6) C23H2SN203 M. p. Indefinite I I OAc The root bark of Rauwolfia nitida yields this yohimbine-type alkaloid which has been ob tained as an off-white amorphous powder having no definite melting point. The base is lae 2 vorotatory with a specific rotation of [aJ5 -89 Degrees (c 0. 01, CHCI ) and gives an ultraviolet 3 spectrum in MeOH with absorption maxima at 225,284 and 290 nm. The structure has been established from chemical and spectroscopic analysis. M. A. Amer, W. E. Court, Phytochem. , 20,2569 (1981) 14-ACETYLBROWNINE ___ :(OMe M. p.

Volume 3 of the Encyclopedia of the Alkaloids covers the literature to the end of October 1976 and includes a large number of these compounds which have been discovered since the first two volumes were published in 1975. There are some entries where recent work has resulted in new structures being put forward or where additional details regarding compounds have been provided. Additional references to compounds given in the first two volumes are marked with an asterisk. The opportunity has also been taken to provide a formula index covering all three volumes. It is a great pleasure to thank Academician Professor S. Yu. Yunusov of the Institute of Chemistry at the University of Tashkent, Uzbekistan, for pointing out a number of errors in the two previous volumes and for kindly providing me with invaluable detailed information of the alkaloids which have been isolated and studied by Soviet chemists over many years.