The development of more effective treatments for neuropsychiatric disorders requires scientific progress on a broad front. Animal models have a vital role to play in advancing the field. When deployed in conjunction with detailed study of these diseases in man they bring the power to make controlled experimental interventions which allow the functional consequences of genetic variations and polymorphisms to be understood in terms of their cellular, systems and behavioural effects. Further, they provide a means by which complex cognitive and behavioural phenomena may be dissected and understood. Finally, they provide a bridge to understanding the effects of drugs on the functioning of the central nervous system, thereby improving our understanding of the actions of those drugs in man.

As an addition to the European postgraduate training system for young neurosurgeons, we began to publish in 1974 this series of Advances and Technical Standards in Neurosurgery which was later sponsored by the European Association of Neurosurgical Societies. This series was first discussed in 1972 at a combined meeting of the Italian and German Neurosurgical Societies in Taormina, the founding fathers of the series being Jean Brihaye, Bernard Pertuiset, Fritz Loew and Hugo Krayenbuhl. Thus were established the principles of European co operation which have been born from the European spirit, flourished in the European Association, and have been associated throughout with this senes. The fact that the English language is now the international medium for communication at European scientific conferences is a great asset in terms of mutual understanding. Therefore we have decided to publish all contri butions in English, regardless of the native language of the authors. All contributions are submitted to the entire editorial board before publication of any volume for scrutiny and suggestions for revision. Our series is not intended to compete with the publications of original scientific papers in other neurosurgical journals. Our intention is, rather, to present fields of neurosurgery and related areas in which important recent advances have been made. The contributions are written by specialists in the given fields and constitute the first part of each volume.

Covers four pillars of safety statistics: cross-disciplinary scientific engagement, effective and efficient operational process, visual analytics, and intelligent data architecture Links safety monitoring to benefit risk evaluation Presents an emerging topic that links to ICH E19 and TransCelerate safety efforts

Global simultaneous development is becoming more necessary as the cost of developing medical products continues to grow. The strategy of using multiregional clinical trials (MRCTs) has become the preferred method for developing new medicines. Implementing the same protocol to include subjects from many geographical regions around the world, MRCTs can speed up the patient enrolment, thus resulting in quicker drug development and obtaining faster approval of the drug globally. After the publication of the editors' first volume on this topic, there have been new developments on MRCTs. The International Council for Harmonisation (ICH) issued ICH E17, a guideline document on MRCTs, in November 2017, laying out principles on MRCTs. Beyond E17, new methodologies have been developed as well. Simultaneous Global New Drug Development: Multi-Regional Clinical Trials after ICH E17 collects chapters providing interpretations of principles in ICH E17 and new ideas of implementing MRCTs. Authors are from different regions, and from academia and industry. In addition, in contrast to the first book, new perspectives are brought to MRCT from regulatory agencies. This book will be of particular interest to biostatisticians working in late stage clinical development of medical products. It will also be especially helpful for statisticians in regulatory agencies, and medical research institutes. This book is comprehensive across the MRCT topic spectrum, including Issues regarding ICH E17 Implementation MRCT Design and Analysis Methodologies Perspectives from authorities in regulatory agencies, as well as statisticians practicing in the medical product industry Many examples of real-life applications based on actual MRCTs.

During the past decade, remarkable progress has been made in the development of newer drugs to prevent and treat thromboembolic disorders, such as oral direct anti-Xa and anti-IIa antagonists, as well as oral antiplatelet ADP antagonists with rapid onset and offset. In addition, there has been concentrated effort aimed at identifying novel uses of traditional antithrombotic drugs, such as aspirin, heparin, and oral anticoagulants, as well as combinations of agents, such as more than one antiplatelet, antiplatelet with anticoagulant, antiplatelet with or without thrombolytic. Anticoagulants, Antiplatelets, and Thrombolytics, Second Edition provides updates on various strategies in thrombosis, experimental models, and clinical and recent advances in the discovery and development of novel antithrombotics. As a volume in the highly successful Methods in Molecular Biology(TM) series, this collection provides the kind of detailed description and implementation advice that is crucial for getting optimal results. Easy to use and up to date, Anticoagulants, Antiplatelets, and Thrombolytics, Second Edition is an ideal guide for researchers aiming for the future of this vital field, focusing on the prevention of thromboembolic disorders and the protection of the vascular endothelium.

Lung cancer has seen a paradigm shift in disease treatment over the past few years, with major changes in the therapeutic drugs now available as well as in the overall management approach. For targeted and immunotherapeutic approaches, understanding the biology of acquired resistance is a key strategy that has yielded productive advances in the subsequent treatment. Future advances also include incorporating biomarker data obtained from solid and liquid biopsies, as well as combination of immunotherapy with radiotherapy and in special populations such patients with CNS involvement.

The growing knowledge on tumor-immune response interactions and on the tumor microenvironment did not translate so far into better control of cancer by anti-tumor vaccination. The percentage of patients who benefited from vaccination strategies is still too small to justify their general use. It is the aim of this book to present an alternative to the conventional approach of developing injected tumor vaccines to activate anti-tumor immunity, which will fight cancer. It is argued that in situ tumor ablation (destruction) that involves tumor antigen release; cross presentation and the release of danger associated molecular patterns (DAMPs) can make the tumor its own cellular vaccine. Tumor ablation methods using chemicals, radiation, photodynamic therapy, cryoablation, high-temperature, radiofrequency, high intensity focused ultrasound, and electric-based ablation have been developed for focal tumors. In this book experts will deal with two main topics: I. What are the principles of the various ablation modalities, and II. How each method affects the tumor cells and their microenvironment, and how these effects are responsible for the induction of specific anti-tumor immunity. The aims of this book are thus: 1. Familiarize the readers with various methods of in situ tumor ablation. 2. Review the literature and stimulate comparisons on the efficacy of different ablation methods for the treatment of tumors of different histotypes. 3. Review the literature on the effects of various ablation methods on systemic and local anti tumor immunity and on other manifestations of the interactions of tumors with their microenvironment. 4. Stimulate comparative studies on the immunostimulatory effects of different ablation modalities.

This detailed book explores protocols for a wide array of preclinical pharmacology and toxicology evaluations to be applied to chemical drugs and their development through in vitro, involving tissues and cell lines, and in vivo models, using animals as experimental systems, utilized to conduct pharmacological research. Written for the Springer Protocols Handbooks series, the methodologies included in this collection have been standardized by the authors through extensive use in the lab so that they are ready to be applied in the labs of readers around the world. Authoritative and practical, Bioassays in Experimental and Preclinical Pharmacology aims to assist undergraduate and postgraduate students, research scholars, scientists, and other academicians performing research in the vital field of drug discovery.

Antibody-drug conjugates (ADCs) stand at the verge of a transformation. Scores of clinical programs have yielded only a few regulatory approvals, but a wave of technological innovation now empowers us to overcome past technical challenges. This volume focuses on the next generation of ADCs and the innovations that will enable them. The book inspires the future by integrating the field's history with novel strategies and cutting-edge technologies. While the book primarily addresses ADCs for solid tumors, the last chapter explores the emerging interest in using ADCs to treat other diseases. The therapeutic rationale of ADCs is strong: to direct small molecules to the desired site of action (and away from normal tissues) by conjugation to antibodies or other targeting moieties. However, the combination of small and large molecules imposes deep complexity to lead optimization, pharmacokinetics, toxicology, analytics and manufacturing. The field has made significant advances in all of these areas by improving target selection, ADC design, manufacturing methods and clinical strategies. These innovations will inspire and educate scientists who are designing next-generation ADCs with the potential to transform the lives of patients.

This book is based on contributions presented at the 1st World Congress on Gallium-68 and Peptide Receptor Radionuclide Therapy, which examined recent developments in theranostics - the emerging field of molecular targeting of vectors that can be used for both diagnosis and therapy, when modified accordingly. The focus of this book is on the rapidly developing research into and clinical applications of gallium-68 and other generator-produced PET radionuclides in the personalized diagnosis and treatment of neuroendocrine tumors and other diseases. In addition, new PET radiopharmaceuticals are considered, and the latest ideas and concepts, presented. Theranostics embodies both molecular and personalized medicine. It is at the cutting edge of medicine, and the contents of this volume will be of interest to chemists, physicians, and investigators dealing with generators, PET radiochemistry, molecular imaging, and radionuclide therapy.

Microbial infection is increasingly seen as a problem as we begin to run out of antibiotics. Understanding how microbes cause disease is essential. In recent years it has begun to emerge that bacteria, fungi, protozoa and viruses can use their cell stress proteins to cause infection. This volume brings together the world's leading experts in the study of the microbial and human cell stress proteins that are involved in enabling microorganisms to infect humans and cause serious disease.

Coherent treatment of a variety of approaches to multiple comparisons Broad coverage of topics, with contributions by internationally leading experts Detailed treatment of applications in medicine and life sciences Suitable for researchers, lecturers / students, and practitioners

This book is devoted to the problems of oxidation chemical reactions and addresses bimodal reaction sequences. Chemical reactions of oxidation, occurring under certain conditions and in multicomponent systems are complex processes. The process of the oxidation essentially changes in the presence and contact of the solid substances with reactants. The role of solid substances and the appearance of this phenomenon in oxidation reaction are discussed. The reader will understand the "driving forces" of this phenomenon and apply it in practice. Written for chemists, physicists, biologists and engineers working in the domain of oxidation reactions. Key Selling Features: Covers the historical background, modern state of the art, and perspectives in investigations of the coupling between heterogeneous and homogeneous reactions Discusses the feasible pathways of the coupling of heterogeneous and homogeneous reactions in oxidation in man-made and natural chemical systems Addresses the abundance, peculiarities and mechanisms of the bimodal reaction sequences in oxidation with dioxygen in recent decades Discusses the existence of the bimodal reaction sequences in chemical systems investigations in atmospheric chemistry and heterogeneous photocatalysis Presented in a simple concise style, accessible for both specialists and non-specialists

A highly practical guide to public health intervention development. This book has been developed to assist anyone involved with effective health promotion project design. It cuts through the complex theories and technical frameworks to provide a 6 step formula for creating effective and sustainable interventions. Key features Adopts a pragmatic approach that addresses barriers and challenges to project delivery Utilises the Six Steps in Quality Intervention Development framework - a unique model designed specifically to improve intervention planning Combines the theory and concepts behind intervention development with practical methods of delivery on the ground Includes detailed case studies that provide examples of how the six steps can be used for successful intervention design As the health needs of an increasingly globalised world continue to evolve and shift, effective planning and intervention work will only become more important. Written by leading researchers and experts who draw on a wealth of experience in the field, this book will be essential reading for any student, practitioner or policy maker requiring an understanding of practical intervention design.

We have surpassed the omics era and are truly in the Age of Molecular Therapeutics. The fast-paced development of SARS-CoV-2 vaccines, such as the mRNA vaccines encoding the viral spike protein, demonstrated the need for and capability of molecular therapy and nanotechnology-based solutions for drug delivery. In record speed, the SARS-CoV-2 viral RNA genome was sequenced and shared with the scientific community, allowing the rapid design of molecular therapeutics. The mRNA vaccines exploit the host cell endoplasmic reticulum to produce viral spike proteins for antigen presentation and recognition by the innate and adaptive immune system. Lipid nanoparticles enable the delivery of the fragile, degradation-sensitive nucleic acid payloads. Molecular-based therapeutics and nanotechnology solutions continue to drive the scientific and medical response to the COVID-19 pandemic as new mRNA, DNA, and protein-based vaccines are developed and approved and the emergency use approved vaccines are rapidly manufactured and distributed throughout the globe. The need for molecular therapies and drug delivery solutions is clear, and as these therapies progress and become more specialized there will be important advancements in organelle targeting. For example, using organelle targeting to direct lipid nanoparticles with mRNA payloads to the endoplasmic reticulum would increase the efficacy of mRNA vaccines, reducing the required dose and therefore the biomanufacturing demand. Likewise, improving the delivery of DNA therapeutics to the nucleus would improve efficacy. Organelles and molecules have always been drug targets, but until recently we have not had the tools or capability to design and develop such highly specific therapeutics. Organelle targeting has far-reaching implications. For example, mitochondria are central to both energy production and intrinsic apoptosis. Effectively targeting and manipulating mitochondria has therapeutic applications for diseases such as myopathies, cancer, neurodegeneration, progerias, diabetes, and the natural aging process. The SARS-CoV-2 vaccines that exploit the endoplasmic reticulum (for mRNA vaccines) and the nucleic translational process (DNA vaccines) attest to the need for organelle and molecular therapeutics. This book covers the status, demand, and future of organelle- and molecularly targeted therapeutics that are critical to the advancement of modern medicine. Organelle and molecular targeting is the drug design and drug delivery approach of today and the future; understanding this approach is essential for students, scientists, and clinicians contributing to modern medicine.

The conceptual process of drug discovery is one that is often the result of an identified need in a defined disease area. This need represents a mandate from the marketing department of a phar- maceutical company or a breakthrough at the research level that has agreed applicability in response to a valid therapeutic demand. Although the intelligent design and development of new thera- peutic entities, as evidenced by Sir James Black's H -receptor an- 2 tagonist cimetidine (Tagamet), is intellectually satisfying, many novel drugs arise from serendipity, from the chance observation of the research scientist or the clinician, that a compound has unex- pected actions of use for the treatment of human disease states. Drugs that have been identified by this route include the antipsy- chotic chlorpromazine and the putative anxiolytic buspirone. The events surrounding the process of drug discovery and de- velopment are the theme of the present volume, which attempts to present, in a logical and lucid manner, the complexity of a process that is often naively assumed to represent nothing more than the identification of a new compound and its rapid introduction into humans, free of such complications as efficacy, selectivity, safety, bioavailability, toxicity, and need.

Genetically-engineered mouse models for cancer research have become invaluable tools for studying cancer biology and evaluating novel therapeutic approaches. This volume focuses on state-of-the-art methods for generating, analyzing and validating such models for studying aspects of human cancer biology. Additionally, these models are emerging as important pre-clinical systems in which to test cancer prevention and therapeutic strategies in order to select compounds for testing in clinical trials.

The concepts of estimands, analyses (estimators), and sensitivity are interrelated. Therefore, great need exists for an integrated approach to these topics. This book acts as a practical guide to developing and implementing statistical analysis plans by explaining fundamental concepts using accessible language, providing technical details, real-world examples, and SAS and R code to implement analyses. The updated ICH guideline raises new analytic and cross-functional challenges for statisticians. Gaps between different communities have come to surface, such as between causal inference and clinical trialists, as well as among clinicians, statisticians, and regulators when it comes to communicating decision-making objectives, assumptions, and interpretations of evidence. This book lays out a path toward bridging some of these gaps. It offers ? A common language and unifying framework along with the technical details and practical guidance to help statisticians meet the challenges ? A thorough treatment of intercurrent events (ICEs), i.e., postrandomization events that confound interpretation of outcomes and five strategies for ICEs in ICH E9 (R1) ? Details on how estimands, integrated into a principled study development process, lay a foundation for coherent specification of trial design, conduct, and analysis needed to overcome the issues caused by ICEs: ? A perspective on the role of the intention-to-treat principle ? Examples and case studies from various areas ? Example code in SAS and R ? A connection with causal inference ? Implications and methods for analysis of longitudinal trials with missing data Together, the authors have offered the readers their ample expertise in clinical trial design and analysis, from an industrial and academic perspective.

For more than a century, bioactive heterocycles have formed one of the largest areas of research in organic chemistry. They are important from a biological and industrial point of view as well as to the understanding of life processes and efforts to improve the quality of life. Heterogeneous Catalysis: A Versatile Tool for the Synthesis of Bioactive Heterocycles highlights the recent methodologies used in the synthesis of such bioactive systems and focuses on the role of heterogeneous catalysis in the design and synthesis of various biologically active heterocyclic compounds of pharmacological interest. Topics include: Synthetic protocols for the construction of heterocyclic systems employing silica-bound catalysts Recent advances in heterogeneous copper-catalyzed reactions for the synthesis of bioactive heterocycles Features of silica-based heterogeneous catalysts, such as abundance, ease of use, and stability Ultrasound as an effective tool for accelerating reactions Organic transformations catalyzed by nano-ZnO as a valuable heterogeneous catalyst Heterogeneous catalysts employed in the synthesis of coumarins Heterocyclizations in the presence of silver salts Home-made organometallic silica sources, known as silatranes Reflecting the focused studies currently conducted in these areas, the book also examines anticancer, antifungal, antibacterial, anti-HIV, anti-inflammatory, antioxidant, and many more biological activities of heterocyclic compounds. It is essential reading for postgraduate and research scholars in the fields of biochemistry, chemical biology, medicinal chemistry and pharmaceutical chemistry.

The Springer Handbook of Enzymes provides concise data on some 5,000 enzymes sufficiently well characterized and here is the second, updated edition. Their application in analytical, synthetic and biotechnology processes as well as in food industry, and for medicinal treatments is added. Data sheets are arranged in their EC-Number sequence. The new edition reflects considerable progress in enzymology: the total material has more than doubled, and the complete 2nd edition consists of 39 volumes plus Synonym Index. Starting in 2009, all newly classified enzymes are treated in Supplement Volumes."

This book provides a compilation of the most up-to-date literature on the topic of immediate early genes (IEGs). It reviews and details experiments and theories that challenge the reader to expand their view on how IEG research is currently being used to advance our understanding of static and active brain circuits. In addition, the book explores roles of IEGs in clinical neuropathology.

Phylogenetic presentation of medicinal plants and a chemotaxonomical rationale of antiviral, antibacterial, and antifungal action. Discusses chemical structure-activity relationship, pharmacokinetics, and oral bioavailability of antimicrobial principles Introduces the molecular mechanism of natural products on viruses, bacteria, and fungi. Contains a selection of botanical plates and useful bibliographic references A useful research tool for postgraduates, academics, and the pharmaceutical, herbal, or nutrition industries.

Phylogenetic presentation of medicinal plants and a chemotaxonomical rationale of antiviral, antibacterial, and antifungal action. Discusses chemical structure-activity relationship, pharmacokinetics, and oral bioavailability of antimicrobial principles Introduces the molecular mechanism of natural products on viruses, bacteria, and fungi. Contains a selection of botanical plates and useful bibliographic references A useful research tool for postgraduates, academics, and the pharmaceutical, herbal, or nutrition industries.

Methodologies for Biosimilar Product Development covers the practical and challenging issues that are commonly encountered during the development, review, and approval of a proposed biosimilar product. These practical and challenging issues include, but are not limited to the mix-up use of interval hypotheses testing (i.e., the use of TOST) and confidence interval approach, a risk/benefit assessment for non-inferiority/similarity margin, PK/PD bridging studies with multiple references, the detection of possible reference product change over time, design and analysis of biosimilar switching studies, the assessment of sensitivity index for assessment of extrapolation across indications without collecting data from those indications not under study, and the feasibility and validation of non-medical switch post-approval. Key Features: Reviews withdrawn draft guidance on analytical similarity assessment. Evaluates various methods for analytical similarity evaluation based on FDA's current guidelines. Provides a general approach for the use of n-of-1 trial design for assessment of interchangeability. Discusses the feasibility and validity of the non-medical switch studies. Provides innovative thinking for detection of possible reference product change over time. This book embraces innovative thinking of design and analysis for biosimilar studies, which are required for review and approval of biosimilar regulatory submissions.

The overall themes of this book are recent advances in mechanisms of pain and the application of those in clinics. Specific attention is paid to developing countries where practice of pain management seriously lags behind current scientific understanding. Both the local traditions for curing pain and the substances used are presented in this book.