The discovery of mammalian nitric oxide (NO-) synthesis from I-ar- ginine has led to profound increases in our understanding of basic physiological and pathophysiological processes. This understanding has been achieved by major advances in several areas. Three major ni- tric oxide synthase (NOS) isoforms have been identified at the protein and gene level and their specific tissue localization has been linked to processes subject to regulation by NO-. The molecular basis for the di- verse effects of NO- on cell function has been shown to derive from its chemical reactivity with oxygen-containing species and both heme and non-heme iron-dependent enzymes. The potential regulation of heme- dependent enzymes such as cytochromes P450, guanylate cyclase, cy- clooxygenase, and mitochondrial cytochrome oxidase continues to emerge as a key area in NO- research. In addition, it has become clear that the expression of NOS isoforms and NO- release from cells is subject to regulation by sexual steroids and that, in tum, NO- has the potential to regulate steroid biosynthesis via inhibition of cytochromes P450 involved in steroidogenesis. These recent observations on interactions between the NO-/NOS and cytochrome P450/sexual steroid pathways have important implica- tions for understanding fundamental mechanisms involved in endocri- nological processes. They are also likely to lead to novel insights and novel therapeutic approaches for the management of pathophysiologi- cal conditions associated with alterations in sexual steroid hormones.

Protein folding remains one of the most exclusive problems of modern biochemistry. Structure analysis has given access to the wealth of the molecular architecture of pro teins. As architecture needs static calculations, protein structure is always related to thermodynamic factors that govern folding and stability of a particular folded protein over the non-organized polypeptide chain. During the past decades a huge amount of thermodynamic data related to protein folding and stability has been accumulated. The data are certainly of importance in dechiffring the protein folding problem. At the same time, the data can guide the con struction of modified and newly synthesized proteins with properties optimized for particular application. The intention of this book is a generation of a data collection which makes the vast amount of present data accessible for multidisciplinary research where chemistry, phy sics, biology, and medicine are involved and also pharmaceutical and food research and technology. It took several years to compile all the data and the author wishes to thank everyone who provided data, ideas or even unpublished results. The author is, in particular, indebted to Prof. Wadso (Lund, Sweden) and IUPAC's Steering Committee on Bio physical Chemistry. Furthermore, support by the Deutsche Forschungsgemeinschafi (INK 16 AI-I) is acknowledged."

Saponins are complex molecules made up of sugars linked to a triterpenoid or a steroid or a steroidal alkaloid. These natural products are attracting much attention in recent years because of the host of biological activities they exhibit. The diversity of structural features, the challenges of isolation because of their occurrence as complex mixtures, the pharmacological and biological activities still to be discovered, and the prospect of commercialization - these all are driving the study of saponins. Triterpenoid saponins are dominating constituents of this class and occur widely throughout the plant kingdom including some human foods e. g. beans, spinach, tomatoes, and potatoes, and animal feed e. g. alfalfa and clover. Saponins were initially a rather neglected. area of research primarily because of great difficulties in their isolation and characterization. With the advent of more sophisticated methods of isolation and structure elucidation through the last two decades, there has been increased interest in these natural products. Besides structure determination, research activities are now moving forward to clarify structure-activity relationships. Our previous reviews on triterpenoid saponins (l, 2) covered literature from 1979 to mid-1989. The literature on triterpenoid saponins up to 1988 has also been covered by two reviews by HILLER et at. (3, 4). This review incorporates newer trends in isolation and structure determination of triterpenoid saponins, new triterpenoid saponins isolated and biological properties of these products reported during the period late 1989-mid 1996. 2."

Phytochemists are aware that their focus of interest is receiving attention from a wider segment of society and from a greater diversity of disciplines within the scientific community than ever before. Nonetheless, they were bemused to learn three years ago that "until recently scientists didn't even know phytochemi cals existed" (Newsweek, April 24, 1994). Changing public perception of the positive contributions of phytochemicals to human well-being has foundations in scientific advances. With popular reports emphasizing the important implica tions of phytochemicals in the daily lives of people, there is a pressing need for those working in this area to explain their diverse scientific activities to the public. Chemicals from plant foods are linked through epidemiological and ex perimental studies with reduced incidence of chronic degenerative diseases. Phytomedicines, standardized according to particular constituents, are making increasing contributions to health care. Naturally occurring constituents of plants are recognized as fundamental to the appeal, quality, and marketability of food products. In light of such developments, perceptions by phytochemists of their own discipline and its applications are expanding. Until recently, food phyto chemistry largely implied food toxicants. Food plants were familiar, but seldom the source of novel economically important compounds. Increasingly sophisti cated methods of analysis, however, have opened new opportunities for under standing the nature and functions offood constituents, and for manipulating them to improve the quality, acceptability, and value of food products.

Micro-TAS '98 is the third of a series of symposia initiated by MBSA (University of Twente) in 1994, on the subject of miniaturizing, and integrating within a monolithic structure, the chemical, biochemical and biological procedures commonly used for analysis and synthesis. The primary tool used to develop micro-total analysis systems (mu- TAS) has been micro-photolithographic patterning and micromachining. These powerful tools of Micro System Technology (MST or MEMS) have been applied in highly imaginative ways to develop microchip chemical arrays, fully integrated pump and fluid manifolds, and electrokinetically driven micro-channel systems to be used for genetic analysis, clinical diagnostics and environmental monitoring, and to integrate reactions as diverse as the polymerase chain reaction (PCR) and the large volume, partial oxidation of ammonia. This text illustrates the rapid expansion of the field, the extensive industrial involvement, the increasing number of participating researchers, the expanding range of concepts and applications that utilize MST and microfluidic devices, and new MST-compatible plastic micro-machining to meet the needs of the life science community. This volume contains the proceedings of the Third International Symposium on Micro-Total Analysis Systems, mu-TAS '98, held on October 13-16 in Banff, Alberta, Canada. State-of-the-art invited and contributed papers presented by the world's leading mu- TAS research groups provide a highly informative picture of the growth since 1994 and of the promising future of this exciting and rapidly growing field.

The volumes of this classic series, now referred to simply as "Zechmeister" after its founder, L. Zechmeister, have appeared under the Springer Imprint ever since the series' inauguration in 1938. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in his field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists, and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline.

The Leguminosae is an economically important family in the Dicotyledonae with many cultivated species, e. g. , beans and peas. The family also contains many well-known medicinal plants. It is composed of 17,000 or more species that constitute nearly one twelfth of the world's flowering plants (1). Traditionally the family has been divided into three subfamilies, Caesalpinioideae, Mimosoideae and Papilionoi- deae, which are sometimes recognized as separate families Caesalpinia- ceae, Mimosaceae and Papilionaceae. The International Code of Botanical Nomenclature permits alternative nomenclatures, the family names being replaced by Fabaceae, Fabales and Faboideae, and this usage will be common (2). Licorice (liquorice, kanzoh in Japanese, gancao in Chinese) is the name applied to the roots and stolons of some Glycyrrhiza species (Fabaceae) and has been used by human beings for at least 4000 years. The earliest written reference to the use of licorice is contained in the Codex Hammurabi dating from 2100 B. C. , and the subsequent history in the West has been described in the earlier reviews (3-6). In the Far East, references to the effectiveness of licorice are contained in the "Shen Nong Ben Cao Jing", the first Chinese dispensatory whose original anonymous volumes probably appeared by the end of the third century (7, 8).

The volumes of this classic series, now referred to simply as "Zechmeister" after its founder, L. Zechmeister, have appeared under the Springer Imprint ever since the series' inauguration in 1938. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in his field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists, and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline.

In order to make further progress in elucidating the mechanism of NOS catalysis it will be essential to throw light on the interaction between the enzyme and its substrate. An understanding of the catalytic site will also assist the development of therapeutically important NOS inhibitors. In particular. it will be useful to uncover any differences that exist between the substrate binding sites of the three NOS isozymes which might be exploited for the development of isoform selective NOS inhibitors. A comparison of NOS to other Arg-binding proteins has shown no significant sequence homology (159). Moreover, the lack of a 3D structure and absence of significant sequence homology between the NOS oxygenase domain and known cytochromes P450 has made it difficult to identify residues and construct a model of the distal heme pocket responsible for substrate binding. However, a number of groups are currently working towards crystallisation of the separate NOS reductase and oxygenase domains of the three isoforms for X-ray diffraction studies; the first X-ray structure is likely to be forthcoming within a matter of months. * The results of these studies are expected to resolve many of the uncertainties surrounding the structure of the NOS catalytic site. Preliminary X-ray diffraction analysis of CPR from rat liver has already been reported by MASTERS et al. (524) and the future emergence of a detailed structure for this protein should throw light on the structure and function of the NOS reductase domain.

It was in 1979 when GROVE et al. isolated from pollen of rape (Brassica nap us) a highly active plant growth promoter, named it brassinolide and elucidated its structure as (22R,23R,24S)-2

The volumes of this classic series, now referred to simply as "Zechmeister" after its founder, L. Zechmeister, have appeared under the Springer Imprint ever since the series' inauguration in 1938. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in his field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists, and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline.

The Sixth International Conference on Miniaturized Chemical and Biochemical Analysis Systems, known as IlTAS2002, will be fully dedicated to the latest scientific and technological developments in the field of miniaturized devices and systems for realizing not only chemical and biochemical analysis but also synthesis. The first IlTAS meeting was held in Enschede in 1994 with approximately 160 participants, bringing together the scientists with background in analytical and biochemistry with those with Micro Electro Mechanical Systems (MEMS) in one workshop. We are grateful to Piet Bergveld and Albert van den Berg of MESA Research Institute of the University of Twente for their great efforts to arrange this exciting first meeting. The policy of the meeting was succeeded by late Prof. Dr. Michael Widmer in the second meeting, IlTAS'96 held in Basel with 275 participants. The first two meetings were held as informal workshops. From the third workshop, IlTAS'98 (420 participants) held in Banff, the workshop had become a worldwide conference. Participants continued to increase in IlTAS2000 (about 500 participants) held in Enschede and IlTAS2001 (about 700 participants) held in Monterey. The number of submitted papers also dramatically increased in this period from 130 in 1998, 230 in 2000 to nearly 400 in 2001. From 2001, IlTAS became an annual symposium. The steering committee meeting held in Monterey, confirmed the policy of former IlTAS that quality rather than quantity would be the key-point and that the parallel-session format throughout the 3.

Understanding General Chemistry details the fundamentals of general chemistry through a wide range of topics, relating the structure of atoms and molecules to the properties of matter. Written in an easy-to-understand format with helpful pedagogy to fuel learning, the book features main objectives at the beginning of each chapter, get smart sections, and check your reading section at the end of each chapter. The text is filled with examples and practices that illustrate the concepts at hand. In addition, a summary, and extensive MCQs, exercises and problems with the corresponding answers and explanations are readily available. Additional features include: Alerts students to common mistakes and explains in simple ways and clear applications how to avoid these mistakes. Offers answers and comments alongside sample problems enabling students to self-evaluate their skill level. Includes powerful methods, easy steps, simple and accurate interpretations, and engaging applications to help students understand complex principles. Provides a bridge to more complex topics such as solid-state chemistry, organometallic chemistry, chemistry of main group elements, inorganic chemistry, and physical chemistry. This introductory textbook is ideal for chemistry courses for non-science majors as well as health sciences and preparatory engineering students.

"The greater our knowledge increases, the more our ignorance unfolds. " U. S. President John F. Kennedy, speech, Rice University, September 12, 1962 My primary purpose for writing this book was much more than to provide another information source on Chemistry, Manufacturing & Controls (CMC) that would rapidly become out of date. My primary purpose was to provide insight and practical suggestions into a common sense business approach to manage the CMC regulatory compliance requirements for biopharmaceuticals. Such a common sense business approach would need (1) to be applicable for all types of biopharmaceutical products both present and future, (2) to address the needs of a biopharmaceutical manufacturer from the beginning to the end of the clinical development stages and including post market approval, and (3) to be adaptable to the constantly changing CMC regulatory compliance requirements and guidance. Trying to accomplish this task was a humbling experience for this author In Chapter 1, the CMC regulatory process is explained, the breadth of products included under the umbrella ofbiopharmaceuticals are identified, and the track record for the pharmaceutical and biopharmaceutical industry in meeting CMC regulatory compliance is discussed. In Chapter 2, while there are many CMC commonalities between biopharmaceuticals and chemically-synthesized pharmaceuticals, the significant differences in the way the regulatory agencies handle them are examined and the reasons for why such differences are necessary is discussed. Also, the importance of CMC FDA is stressed."

During the past decade there have been many changes in the perfumery industry which are not so much due to the discovery and application of new raw materials, but rather to the astronomic increase in the cost of labour required to produce them. This is reflected more particularly in the flower industry, where the cost of collecting the blossoms delivered to the factories has gone up year after year, so much so that most flowers with the possible exception of Mimosa, have reached a cost price which has compelled the perfumer to either reduce his purchases of absolutes and concretes, or alternatively to substitute them from a cheaper source, or even to discontinue their use. This development raises an important and almost insoluble problem for the perfumer, who is faced with the necessity of trying to keep unchanged the bouquet of his fragrances, and moreover, to ensure no loss of strength and diffusiveness. Of course, this problem applies more especially to the adjustment of formulae for established perfumes, because in every new creation the present high cost of raw materials receives imperative con sideration before the formula is approved."

Much of chemistry, molecular biology, and drug design, are centered around the relationships between chemical structure and measured properties of compounds and polymers, such as viscosity, acidity, solubility, toxicity, enzyme binding, and membrane penetration. For any set of compounds, these relationships are by necessity complicated, particularly when the properties are of biological nature. To investigate and utilize such complicated relationships, henceforth abbreviated SAR for structure-activity relationships, and QSAR for quantitative SAR, we need a description of the variation in chemical structure of relevant compounds and biological targets, good measures of the biological properties, and, of course, an ability to synthesize compounds of interest. In addition, we need reasonable ways to construct and express the relationships, i. e. , mathematical or other models, as well as ways to select the compounds to be investigated so that the resulting QSAR indeed is informative and useful for the stated purposes. In the present context, these purposes typically are the conceptual understanding of the SAR, and the ability to propose new compounds with improved property profiles. Here we discuss the two latter parts of the SARlQSAR problem, i. e. , reasonable ways to model the relationships, and how to select compounds to make the models as "good" as possible. The second is often called the problem of statistical experimental design, which in the present context we call statistical molecular design, SMD. 1.

In this volume we have included some contributions among the plenary lectures, oral presentations and posters that have been presented at the 1st Joint Greek-Italian Meeting on "The Chemistry of Biological systems and Molecular Chemical Engineering" organized at Loutraki, Club Poseidon, Greece 1990. We hope similar meetings will follow every two years alternating between the two countries in order to strengthen the scientific ties among the scientists working in this field. The inter- disciplary aspect of the meeting has been evident by the wide presence of scientists in bioinorganic, bio-organic, biological fields and molecular engineers who will get together and exchange ideas and experiences. We take this opportunity to thank the Greek Chemical Society, the Italian Chemical Society, the "Gruppo Interdivisionale di Chimica dei Sistemi e dei Processi Biologici", Consiglio Nazionale delle Ricerche, Nuclear Research Center "Demokritos" and the Greek Ministry for Research and Technology. ENRICO RIZZARELLI THEOPHILE THEOPHANIDES CONTRIBUTORS Numbers in parentheses indicate the pages on which the author's contributions begin Mojgan Aghazode Tabrizi, Department of Pharmaceutical Science, via Scandiana 21, University of Ferrara, 44100 Ferrara, ITALY (119) Maria Albano, Department of Chemistry, University of Calabria, Arcavacata di Rende, 87030 Cosenza ITALY (23) Rossano Amadelli, Photochemical Center of C. N. R. , Department of Chemistry, University of Ferrara, via L. Borsari 46, 44100 Ferrara, ITALY (103) Amalia Anagnostopoulou-Konsta, Department of Physics, National Technical University, 57 73 Athens, GREECE (45) Jane D.

INHALT: The Concept of the BBB: an Historical Perspective Anatomy of the BBB Pathophysiology of BBB * Brain oedema Breakdown of the BBB BBB Dysfunction after SAH * Clinical Monitoring Neuroradiological Evaluations of BBB Dysfunction after SAH * Computerised Tomography and Magnetic Resonance * SPECT and PET Experimental Data * Literature Review of BBB Dysfunction after Experimental SAH * Qualitative Assessments * Quantitative Assessments * Time Course of BBB Dysfunction after SAH * Additional Pathophysiological Changes after SAH - Cerebral Vasospasm - CSF Eicosanoids - Cerebral Metabolism - Behavioural and Neurological Deficits - Intracranial Pressure - Blood Pressure, Blood Gases, Plasma pH, Plasma Glucose, Body Temperature Strategies for Pharmacological Interventions * Hydroxyl Radical Scavenger AVS * Glutamate Antagonist Felbamate * Calpain Inhibitor II Challenges and Future Directions * Advances in Cerebrovascular Pathophysiology Elucidation * Gene Therapy

HMG-CoA reductase inhibitors (statins) are established drugs for the treatment of hypercholesterolemia. Furthermore, they induce regression of vascular atherosclerosis as well as reduction of cardiovascular-related morbidity and death in patients with and without coronary artery disease. This book deals with statins which have substantially altered the approach to therapy of atherosclerosis and its sequelae. Emphasis is placed on the scientific background to the discoveries and the development of the therapy, including an overview of the current state of knowledge of the drugs. Clinical data are reviewed extensively. This book not only provides the reader with valuable information but also stimulates further research into the pathogenesis of atherosclerosis and the mechanisms behind the action of effective statins. It sets the stage for creative thinking among scientists of many disciplines for the accomplishment of our ultimate goals in treating atherosclerosis and its sequelae. This topical volume...

Scientists from many disciplines require making observations which are dependent upon the behavior of compounds in solution. This ranges from areas in geography, such as oceanography, to areas in chemistry, such as chromatography, to areas in biology, such as pharmacology. Historically, information would be obtained by observing a response for a given set of conditions and then the conditions would be changed and a new response obtained. In this approach there would be little effort made to actually understand how a compound was behaving in solution but rather just the response was noted. Understanding the behavior of compounds in solution is critical to understanding their behavior in biological systems. This has become increasingly important during the last twenty years as an understanding of the biochemistry related to human illness has become better understood. The development of the pharmaceutical industry and the need to rapidly screen large numbers of compounds has made scientists in the area of drug development aware that the pharmacological activity of compounds can be predicted by knowing their solution physical chemical properties. This is not to say that a specific drug-active site interaction can be predicted but rather a prediction can be made whether or not a compound will be absorbed, transported, or distributed within a physiological system in such a way that an interaction can occur.

Literally thousands of papers have been published on nitric oxide over the past ten years. But there is no single monograph available that has previously attempted to summarize the important features of the roles of nitric oxide in inflammation. The voluminous literature regarding the incredible range of chemical and biological effects of nitric oxide and reactive nitrogen oxide species, RNOS, may present a tangle of confusing information to the researcher. This volume brings together experts from nitric oxide and inflammation research and presents a concise up-to-date overview as well as future aspects of this rapidly growing field.

Sequence-specific DNA binding ligands, amongst which triple helix forming oligonucleotides are the most efficient as yet, represent promising tools in a number of fields. One of their most promising applications is as antiviral tools: they can specifically target a viral gene, even if it is integrated into the host genome, and be used to specifically inactivate the viral gene or even destroy the cells harboring this gene. However, from science fiction to science there remains a gap; and we are at the moment on the threshold of this fascinating field. Triple Helix Forming Oligonucleotides considers the different aspects of the design and improvement, current or future, of these molecules and their structural analysis, as well as their applications, with special emphasis on the attempts to obtain biological effects of these potentially important tools. What emerges is that the current state of the research is encouraging, and that these molecules are already useful in some biotechnology applications.

Interest in chemical entities capable of blocking or modifying cell metabolism ultimately goes back to the discovery of the structure of DNA in the 1950s. Understanding of the biochemical processes involved in cell metabolism rapidly led to the idea that compounds could be designed which might interfere with these processes, and thus could be used in the treatment of the diseases caused by viral infection. Since then, several classes of drugs have been discovered which depend for their effect on modification of the proper functioning of nucleic acids and, with the introduction of acyclovir for the treatment of Herpes infections, nucleoside analogues have become the cornerstone of antiviral chemotherapy. The success of the early nucleoside agents, the toxicity and metabolic instability of many nucleoside analogues, and the effects of viral pathogens on public health are driving the design, synthesis and evaluation of new nucleoside analogues, with much attention turning to nucleosides containing non natural' sugar analogues. This book focuses on the development of these agents, and draws together all the available material in an easily consulted form, which at the same time guides the reader into the research literature on the subject. Written primarily for the medicinal chemist, coverage includes both synthetic strategies and outline guidance on the main trends in biological activity. Particular attention is drawn to the comparison of synthetic routes to compounds with their natural analogues. Finally, the important antiviral activities of the compounds are treated, including anti-retrovirus, anti-hepadnavirus and anti-herpes virus properties. Written mainly for medicinal chemists in the pharmaceutical industry and synthetic organic chemists in academe, this book will also be attractive to researchers in institutions focusing on cellular metabolism. Advanced students of organic chemistry will find the clear discussion of the synthetic strategies adopted in the development of these compounds a useful introduction to this exciting and challenging area.