Brain drug targeting: Linker strategies: the engineering of multifunctional drug formulations
Brain drug targeting: Linker strategies: the engineering of multifunctional drug formulations
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DOI：
10.1017/cbo9780511549571.007
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发表时间：
2001
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影响因子：
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通讯作者：
W. Pardridge
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作者：
W. Pardridge
时不时地，这本杂志会为神经药理学的基本书架出版对特殊教科书和专著的评论。没有哪本书比下面评论的两篇课文更能说明这一目标。它们共同引起了当代中枢神经系统(CNS)药物开发的强烈关注。威廉·帕德里奇_S正文介绍了在创造有效的中枢神经系统疗法方面的挑战，这些挑战超出了传统的选择，通常是小于500d的脂溶分子。这本书的副标题是脑部药物开发的未来，这本书透彻地阐述了各种特征的药物可以被输送到预期目标的许多方法。帕德里奇博士是加州大学洛杉矶分校的医学教授，也是血脑屏障方面的杰出权威，他创建了一个特别清晰的总结，其中包括数十年的研究，其中大部分是他自己的。(他1998年关于血脑屏障生理学的文章也是一本经典著作。)在BBrain药物靶向的10个组织清晰、插图丰富的章节中，他详细介绍了许多可用于将各种治疗和诊断试剂注入大脑的工具。引用文献约800篇。该文本提供了一些如何突破血脑屏障的例子，但这些详细的例子并不能掩盖论述的清晰性。帕德里奇博士对血脑屏障背后的关键生理特性以及如何穿越它进行了深入而有说服力的讨论。所描述的潜在载体系统包括阳离子白蛋白和其他内源性蛋白质，如胰岛素和转铁蛋白。使用这种载体蛋白的目的是模仿和利用这些蛋白跨越与药物有关的血脑屏障的能力。综述了其他载体介导的传递蛋白，如羧基导向的蛋白聚乙二醇化，以及用单抗创建可切割和不可切割的载体。连续的章节涉及广泛的给药选择，例如鞘内直接给药、渗透药物和细胞因子药物的血脑屏障破坏、脂质体载体系统，以及利用跨细胞作用的嵌合肽技术(如亲和素-生物素复合体)。该文本还考虑了关于如何将各种放射性药物和神经营养因子(如脑源性神经营养因子)送入大脑用于成像和治疗目的的原则。如导言所述，促进更大、更复杂的分子进入中枢神经系统的目标显然是21世纪神经药理学的挑战。我知道没有比352页的脑部药物靶向更好的起点来理解神经疗法将如何取得进展。另一个关于中枢神经系统药物开发的最好的文本是Franz Hefti的一篇319页的专著，他现在是制药业药物开发的内部人士，以前是神经退行性疾病疗法的领先实验室研究员。多年来，针对中枢神经系统疾病的合理疗法只出现了很少的数量，尽管随着蛋白质组学分析和遗传疾病转基因动物等新技术的发展，这一步伐一直在加快。Hefti博士从行业、政府项目和临床研究的实际要素的角度评估了这一过程和未来的挑战。他的书按等待更好治疗的各种中枢神经系统疾病进行了组织，其中包括抑郁症、焦虑症、精神分裂症、神经退行性疾病(特别是帕金森和阿尔茨海默病)、癫痫、中风、疼痛和中枢神经系统损伤。本文详细介绍了将实验室进展带入临床试验的转化研究过程。在科学家的热情和患者的沮丧中，制药业需要沿着有限的道路前进，以设计和实施急需的药物。赫夫蒂博士概述了药物开发过程，并列举了许多成功和失败的例子。他提供了详细的神经化学背景，解释了今天大多数S神经疗法背后的原理。正文中描述的一个见解是，在中枢神经系统中，药物干预的有效靶点不超过17个，尽管还有许多其他未描述药物效果的例子。这卷不像帕德里奇文本那样复杂，但它包含了丰富的信息，它的信息在当代药物探索和开发的道路上是权威的。每一章都包含重要的参考资料和进一步阅读的建议。提供了所有可用的神经药理学干预类别的全面审查，从他们的历史，干预的生理目标，动物模型，以及实验室方法，如反向药理学和代谢组学开始。针对神经系统疾病的药物靶向治疗背后的乐观情绪，很大程度上是左旋多巴和其他成功的对症治疗帕金森_S病的40年统治。医学博士詹姆斯·帕金森在1817年发表的一篇关于颤抖的瘫痪的专著结束时，提供了一个19世纪的视角，直到最近，这个视角可能也适用于一些神经和精神障碍：
From time to time, this journal will publish reviews of exceptional textbooks and monographs for an Bessential bookshelf^ of neuropharmacology. No books better exemplify this goal than the 2 texts reviewed below. Together, they bring into sharp focus contemporary drug development for the central nervous system (CNS). William Pardridge_s text deals with the challenges in creating effective CNS therapeutics beyond conventional options of, typically, lipidsoluble molecules smaller than 500 d. Subtitled The Future of Brain Drug Development, this volume is a thorough exposition of the many ways that drugs of various characteristics can be delivered to their intended targets. Dr Pardridge, professor of medicine at UCLA and a distinguished authority on the bloodbrain barrier, has created an especially clear summary comprising decades of research, much of it his own. (His 1998 text on blood-brain barrier physiology is also a classic.) In the 10 clearly organized and richly illustrated chapters of BBrain Drug Targeting,^ he has detailed the many tools available for getting a variety of therapeutic and diagnostic agents into the brain. Approximately 800 references are cited. The text provides a number of examples of how the blood-brain barrier has been breached, but these detailed examples do not overshadow the clarity of expositionV this is a text meant to educate by emphasizing concepts and insights from research conducted in animal studies and awaiting human applications. Dr Pardridge provides thorough and cogent discussions of key physiological properties underlying the bloodbrain barrier and how to traverse it. Among potential carrier systems described are cationized albumin and other endogenous proteins such as insulin and transferrin. The goals of using such carrier proteins are to mimic and capitalize on the abilities of these proteins to cross the blood-brain barrier linked to pharmaceuticals. Other vectormediated delivery proteins, such as carboxyl-directed protein pegylation, are reviewed, along with the creation of cleavable and noncleavable carriers with monoclonal antibodies. Successive chapters deal with a wide range of drug delivery options, such as direct intrathecal drug administration, osmoticmedicated and cytokine-medicated blood-brain barrier disruption, liposome carrier systems, and chimeric peptide technology for using transcytosis (such as avidin-biotin complexes). The text also considers principles governing how various radiopharmaceuticals and neurotrophic factors (such as brain-derived neurotrophic factor) might be sent into the brain for imaging and therapeutic purposes. As set out in the introduction, the goal of promoting the entrance into CNS of larger and more complex molecules is clearly the challenge of neuropharmacology in the 21st century. I know of no better starting point for understanding how progress in neurotherapeutics will be made than in the 352 pages of Brain Drug Targeting. Another superlative text on CNS drug development is a 319-page monograph by Franz Hefti, now an insider in pharmaceutical industry drug development and formerly a leading laboratory researcher into the therapeutics of neurodegenerative disorders. Over the years, rational therapeutics for CNS disorders has arrived only in meager quantities, although the pace has been increasing with new technologies such as proteonomic analysis and transgenic animals for genetic disorders. Dr Hefti takes stock of the process and the challenges ahead from the perspective of industry, government programs, and the practical elements of clinical research. His book is organized by the various CNS disorders awaiting better treatment, among them depression, anxiety disorders, schizophrenia, neurodegenerative disorders (especially Parkinson and Alzheimer diseases), epilepsy, stroke, pain, and CNS injury. This text details the process of translational research bringing laboratory advances into clinical trials. Amidst the enthusiasms of scientists and the frustrations of patients, the pharmaceutical industry needs to proceed along circumscribed pathways to design and implement the much-needed drugs. Dr Hefti provides an overview of the drug development process along with many examples of success and failures. He offers detailed neurochemical background for the rationale behind most of today_s neurotherapeutics. One insight described in the text is that there are no more than 17 validated targets of drug interventions in the CNS, although there are many other uncharacterized examples of drug effects. This volume is not written at the same level of complexity as the Pardridge text, but it contains a wealth of information, and its message is authoritative on contemporary pathways for drug exploration and development. Each chapter contains key references and suggestions for further reading. Thorough reviews of all available classes of neuropharmacological interventions are provided, starting with their history, the physiological targets of intervention, animal models, and laboratory methods such as reverse pharmacology and metabolomics. Much of the optimism behind the targeting of drugs for nervous system diseases has been the 4-decade reign of levodopa and other successful symptomatic treatments for Parkinson_s disease. At the end of his 1817 monograph An Essay on the Shaking Palsy, James Parkinson, MD, provided a 19th-century perspective that, until recently, might apply also to a number of neurological and psychiatric disorders: