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Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors.
This e-book will review special features of the cerebral circulation and how they contribute to the physiology of the brain. It describes structural and functional properties of the cerebral circulation that are unique to the brain, an organ with high metabolic demands and the need for tight water and ion homeostasis. Autoregulation is pronounced in the brain, with myogenic, metabolic and neurogenic mechanisms contributing to maintain relatively constant blood flow during both increases and decreases in pressure. In addition, unlike peripheral organs where the majority of vascular resistance resides in small arteries and arterioles, large extracranial and intracranial arteries contribute significantly to vascular resistance in the brain. The prominent role of large arteries in cerebrovascular resistance helps maintain blood flow and protect downstream vessels during changes in perfusion pressure. The cerebral endothelium is also unique in that its barrier properties are in some way more like epithelium than endothelium in the periphery. The cerebral endothelium, known as the blood-brain barrier, has specialized tight junctions that do not allow ions to pass freely and has very low hydraulic conductivity and transcellular transport. This special configuration modifies Starling's forces in the brain microcirculation such that ions retained in the vascular lumen oppose water movement due to hydrostatic pressure. Tight water regulation is necessary in the brain because it has limited capacity for expansion within the skull. Increased intracranial pressure due to vasogenic edema can cause severe neurologic complications and death.
This text/reference uses 574 figures and illustrations to help explain the relationships between blood and the cerebrospinal fluid (CSF) and central nervous system (CNS). The authors focus on the interaction of these fluids and the relative importance of the transport mechanisms of hormones from blood to nervous tissue. Carrier-mediated transport of many neuroactive peptides is discussed. Special aspects of the blood-brain barrier are covered in detail. An entire chapter is devoted to the comparative physiology of the CSF and the brain barriers. Physiologists in all fields will have an interest in the updated theories covered in this book.
This book highlights advances and prospects of a highly versatile and dynamic research field: Therapeutic ultrasound. Leading experts in the field describe a wide range of topics related to the development of therapeutic ultrasound (i.e., high intensity focused ultrasound, microbubble-assisted ultrasound drug delivery, low intensity pulsed ultrasound, ultrasound-sensitive nanocarriers), ranging from the biophysical concepts (i.e., tissue ablation, drug and gene delivery, neuromodulation) to therapeutic applications (i.e., chemotherapy, sonodynamic therapy, sonothrombolysis, immunotherapy, lithotripsy, vaccination). This book is an indispensable source of information for students, researchers and clinicians dealing with non-invasive image-guided ultrasound-based therapeutic interventions in the fields of oncology, neurology, cardiology and nephrology.
The endothelial cells of the cerebral vasculature constitute, together with perivascular elements (astrocytes, pcricytes, basement membrane), the blood-brain barrier (BBB), which strictly limits and specifically controls the exchanges between the blood and the cerebral extracellular spacc.The existence of such a physical, enzymatic, and active barrier isolating the central nervous system has broad physiological, biological, pharmacological, and patho logical consequences, most of which are not yet fully elucidated. The Cerebral Vascular Biology conference (CVB '95) was organized and held at the "Carre des Sciences" in Paris on July I 0-12, 1995. Like the CVB '92 conference held in Duluth, Minnesota, three years ago, the objectives were to provide a forum for presentation of the most recent progresses and to stimulate discussions in the ticld of the biology, physiology. and pathology of the blood-brain barrier. The Paris conference gathered more than !50 participants. including investigators in basic neuroscience, physicians. and stu dents, who actively contributed to the scientific program by their oral or poster presentations. This volume contains a collection of short articles that summarize most of the new data that were presented at the conference. Six thematic parts focus on physiological transports. drug delivery, multidrug resistance P-glycoprotein, signal transduction at the BBB. interactions between the immune system and the cerebral endothelial cells, and the blood-brain barrier-related pathologies in the central nervous system. In addition, two introductory articles present new insights in the rapidly evolving topics of cerebral angiogenesis and gene transfer to the brain.
This book presents a comprehensive collection of current knowledge and leading research about the blood-brain barrier. The chapters are organized in four main parts providing basic information and novel insights about the physiology of the blood-brain barrier, the challenges related to finding and developing drugs crossing the blood-brain barrier, experimental methods to study the blood-brain barrier and the role of the blood-brain barrier in disease mechanisms and its consequences for drug development. In the first part the readers will discover the structure, function and developmental aspects of the blood-brain barrier and gain novel insights into the complexity and functionality of the neurovascular unit and energy metabolism of brain endothelial cells. Chapters of the second part focus on translational challenges from the bench to the bedside in CNS drug development, shed light on the importance to understand the brain distribution of drugs related to their efficacy, elaborate on general pharmacokinetic considerations for CNS drugs and introduce current and novel drug delivery strategies to overcome the blood-brain barrier. The experimental part of the book covers mathematical and in vitro models as well as animal and human methods in blood-brain barrier research. Specific emphasis is set on the description of the methods, the role of species differences for data interpretation, novel human models based on stem cells with the potential for personalized medicine and technical considerations and tips helpful for readers interested in working with these models. In the fourth part particular attentions is given to the blood-brain barrier, its changes and participation during disease progression. Chapters summarize alterations of the blood-brain barrier that are present in common disorders such as Alzheimer’s disease, multiple sclerosis, stroke, traumatic brain injury, epilepsy and brain tumors. Present therapies will be discussed and the consequences for novel treatment approaches that need to bypass the blood-brain-barrier will be explored. In addition, experts discuss the question in how far changes at the blood-brain barrier are causally linked to disease progressions and consequently could serve as therapeutic targets. This collection is designed to appeal to a wide readership from students through basic and applied scientist to pharmacologists, medical doctors and stakeholders from the pharmaceutical industry and regulatory affairs. Due its comprehensive content the book has the potential to become a standard work in the field of blood-brain barrier research.
This book is devoted to exploring the complexities of the blood-brain barrier. The book begins by reviewing the historical experiments that led to the concept of a barrier protecting the brain from variations in the blood. Transport kinetics and carrier-mediated processes are described, and the mechanism by which molecules can cross the barrier is discussed. Ways in which the barrier can be disrupted and opened are covered as well. Subsequent chapters in the book describe the transport of glucose and amino acids into the central nervous systems, cover recent findings by which peptides and proteins are able to gain entry or are excluded from the brain, and analyze models that can be used for investigating how the blood-brain barrier can be disordered in neurological disease processes.
Understanding the structure and function of the blood-brain barrier (BBB) and recogniz ing its clinical relevance require a concert of scientific disciplines applied from a view point of integrative physiology rather than from only molecular or analytical approaches. It is this broad scope that is emphasized in this book. In my opinion, four original contributions define the field as it exists today. The first, a monograph by Broman,1 entitled The Permeability of the Cerebrospinal Vessels in Normal and Pathological Conditions, was the model for many subsequent clinical and 3 experimental studies on BBB pathology. Second, experiments by Davson, summarized in his book entitled Physiology of the Ocular and Cerebrospinal Fluids, indicated that passive entry of nonelectrolytes into brain from blood is governed largely by their lipid 4 solubility. This research supported the original suggestion by Gesell and Hertzman that cerebral membranes have the semipermeability properties of cell membranes. The modem era of the barrier was introduced with the 1965 paper by Crone,2 entitled "Facilitated transfer of glucose from blood to brain tissue. " This paper identified stereospecific, facilitated transport of glucose as part of a system of regulatory barrier properties at a time when only a barrier to passive diffusion had been contemplated. Finally, the 1967 paper by Reese and Kamovsky, 11 entitled "Fine structural localization of a blood-brain barrier to exogenous peroxidase," sited the barrier at the continuous layer of cerebrovascular endothelial cells, which are connected by tight junctions.
Focused on central nervous system (CNS) drug discovery efforts, this book educates drug researchers about the blood-brain barrier (BBB) so they can affect important improvements in one of the most significant – and most challenging – areas of drug discovery. • Written by world experts to provide practical solutions to increase brain penetration or minimize CNS side-effects • Reviews state-of-the-art in silico, in vitro, and in vivo tools to assess brain penetration and advanced CNS drug delivery strategies • Covers BBB physiology, medicinal chemistry design principles, free drug hypothesis for the BBB, and transport mechanisms including passive diffusion, uptake/efflux transporters, and receptor-mediated processes • Highlights the advances in modelling BBB pharmacokinetics and dynamics relationships (PK/PD) and physiologically-based pharmacokinetics (PBPK) • Discusses case studies of successful CNS and non-CNS drugs, lessons learned and paths to the market