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La major part de fàrmacs dissenyats per tractar malalties del sistema nerviós central no són efectius perquè no poden creuar la barrera hematoencefàlica (BHE). Una de les estratègies més prometedores per superar aquest obstacle és l'ús de llançadores peptídiques. Tanmateix, l'eficiència i selectivitat d'aquests encara s'ha de millorar. Els objectius principals de la tesi eren, per una banda, trobar noves llançadores resistents a proteases i, per l'altra, augmentar el transport d'anticossos monoclonals a través de la BHE. Tenint en compte que l'apamina és un pèptid del verí de l'abella que creua la BHE, vam iniciar l'estudi demostrant que els residus implicats en la toxicitat no eren necessaris pel transport. Aleshores vam generar anàlegs simplificats i MiniAp-4 va mostrar el millor compromís entre estabilitat en sèrum, permeabilitat i immunogenicitat. Aquest pèptid va incrementar el transport de la GFP, quantum dots i nanopartícules d'or en un model cel·lular humà de BHE. A més, va augmentar en 7,6 vegades la concentració de cianina-5.5 en el cervell de ratolins. Pel que fa el transport d'anticossos, vam posar a punt diversos mètodes per conjugar els pèptids llançadora a diferents parts de la immunoglobulina, incloent els extrems Nterminals, les cadenes glicosídiques, les lisines i les cisteïnes. Cap conjugació va disminuir l'afinitat dels anticossos pels seus epítops exceptuant la del N-terminal. Vam escollir la modificació de les cisteïnes utilitzant química tiol-maleimida i també la de les lisines mitjançant cicloaddició alquí-azida catalitzada per coure (Cu15C) per generar conjugats emprant diverses llançadores. Alguns d'aquests van mostrar un transport significativament més elevat que l'anticòs sol en el model cel·lular humà de BHE, en especial una mini-apamina i el RVG29 enllaçats mitjançant Cu15C. La major eficiència de les llançadores amb aquesta unió és atribuïble a la major accessibilitat per interaccionar amb els seus receptors. Per concloure, en aquesta tesi hem generat anàlegs d'apamina resistents a protaeses, més reduïts, menys tòxics i menys immunogènics. A més, MiniAp-4 és capaç de transportar diversos compostos a través de la BHE in vitro i in vivo. També hem demostrat que el transport d'anticossos es pot augmentar mitjançant diferents llançadores peptídiques, incloent les mini-apamines.
In an era wherein nanotechnology has sparked a huge research interest, brain drug delivery is not an exception. Aiming at fighting several central nervous system (CNS) conditions, tailored nanoparticles open new avenues to address several challenges in the fields of drug delivery and brain targeting. This book gathers contributions from experts in different, complementary fields, having in common their interest in developing new strategies for brain delivery based on nanotechnologies. The book encompasses general aspects pertaining to fundamental development, including tripartite in silico–in vitro–in vivo approaches. It also covers a diversity of nanomedicines applied in treatment and/or diagnosis and monitoring of CNS disorders. Aspects concerning their translation from the bench to clinical practice are also seamlessly discussed. This book will inspire readers to discover possible approaches to holistically delivering drugs into the brain. Edited by Carla Vitorino, Andreia Jorge and Alberto Pais, this book will appeal to anyone involved in nanomedicine, pharmaceutics, neurological and cancer therapies, drug delivery research and computational and regulatory sciences.
Written for students interested in learning about multiple sclerosis, this book describes how this frequently disabling disease affects patients, exploring its effects on minds, bodies, and daily lives. Written by a professor of medicine who is also personally affected by the disease, Multiple Sclerosis offers an overview of every aspect of the condition. It begins by introducing the central nervous system and describing how multiple sclerosis affects the brain and spinal cord. The author then reviews early understanding of MS, how it was first recognized as a disease, and the discoveries that have helped explain its causes. Moving to contemporary understanding of multiple sclerosis, the book explores the epidemiology of MS in the United States and around the world, describes MS symptoms, and reviews today's treatments and research directions. Perhaps most important, it presents the experiences of persons living with multiple sclerosis, concluding with a discussion of factors affecting these individuals in their homes, families, and communities.
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.
Bee or wasp venom therapy is the therapeutic application of honeybee venom or wasp venom to the treatment of various diseases. Venoms from either honeybees or wasps are known to possess a wide variety of pharmaceutical properties. Recent studies using these venoms have demonstrated diverse mechanisms on a range of conditions. However, identification of a single constituent out of the venom, the possible mechanisms, and a justification of the route of application and formulation are essential in the future. Understanding the signalling pathways associated with the compound-mediated in vivo dynamics and further communication between cells at the molecular level will facilitate the development of new therapeutics.
This book presents an updated discussion of the chemical composition and biological properties of the main bee products. Specific attention is focused on the beneficial biological activities of bee products in human health. Honey, royal jelly, propolis, bee pollen and bee venom are used as nutriment and in traditional medicine. Their composition is rather variable and depends on the floral source and external factors, such as seasonal, environmental conditions and processing. Bee products are rich in several essential nutrients and non essential nutrients, as sugars, minerals, proteins, free amino acids, vitamins, enzymes and polyphenols, that seem to be closely related to their biological functions. The effects of these products in nutrition, aging and age-related diseases, cancer, neurodegenerative diseases and pathogen infections are discussed.
Vols. for 1942- include proceedings of the American Physiological Society.
Basic Sciences in Ophthalmology aims to link clinical ophthalmology directly to its basic science roots. This first volume describes the physics and chemistry required for a sound understanding of modern ophthalmology. The book opens with an extensive discussion of the interaction of light with matter and the way in which light is used in ophthalmic examinations and treatments. After describing traditional methods of imaging, particular emphasis is placed on modern instrumentation such as OCT. The interaction between light and tissues in different types of laser treatment is also addressed. The chemistry section focuses on compounds particularly relevant to the eye, such as oxygen and water. The origin and consequences of oxidative stress are reviewed, and the physical behavior of chemical compounds in the eye is explained. Understanding is facilitated through the use of many examples taken from the field of ophthalmology. The text is complemented by about 450 figures.