Milestones in Drug Therapy – serie

Growth factor receptors have long been known to drive malignant transformation and cancer progression. The epidermal growth factor receptor (EGFR, ErbB, HER) system is likely the best described membrane receptor tyrosine kinase family in malignant tumors. With implementation of the growth-inhibitory anti-HER-2 antibody trastuzumab (Herceptin) for the treatment of HER-2-positive advanced metastatic breast cancer, a new era has dawned in the therapy of this malignant disease. Unfortunately, trastuzumab-sensitive cancers invariably develop resistance to the antibody after some time. Recent clinical studies have revealed that these refractory tumors are still responsive to inhibition of the HER receptor family using dual HER-1/-2 inhibitors such as lapatinib (Tykerb/Tyverb). Moreover, a multiplicity of novel, improved irreversibly acting small molecular HER tyrosine kinase inhibitors are in the pipeline of many drug developing companies and are being evaluated in the clinical setting.

In this monograph about gene therapy of autoimmune and inflammatory d- orders we have gathered international experts and leaders from different fields to review the state of the art advances on topics ranging from disease entities to vectors and engineered cells. The different approaches described in each chapter take into consideration the biomedical knowledge of these diseases and address the complexities of delivering long-term genetic interventions. Gene therapy also serves as a testing ground for new therapeutic entities and helps provide proof of principle for their potential therapeutic role in animal models of disease. Scaling up from mice to men still remains an important h- dle not only from the quantitative point of view, but also for currently unknown and unexpected secondary effects of the vector or the transgene. Some of these approaches have already been tested in the clinic, but much more needs to be done to understand the human conditions treated and the n- ural history of their pathology. We are indebted to the secretarial assistance of Ms. Lin Wells (Bone and Joint Research Unit, London, UK) and the help of Hans Detlef Klüber for his help in getting this book published. We hope this book will be of interest to c- nicians and scientists and inspiring to students of the subject who will use their own ingenuity and knowledge to further forward this discipline into clinical use.

Both metabotropic and ionotropic glutamate receptors present attractive “druggable” targets in treating disorders of the central nervous system. There has been a dramatic shift in the focus of glutamate-based therapies away from neurologic disorders such as stroke and traumatic brain injury to the treatment of psychiatric disorders. This “Milestones in Drug Therapy” volume offers a unique, contemporary overview of preclinical and clinical evidence that modulating glutamatergic tone is an effective means of treating psychiatric disorders ranging from depression and anxiety to schizophrenia and drug abuse. The ability to treat diseases such as depression and schizophrenia through multiple, glutamate-based mechanisms offers a unique therapeutic opportunity, as described in this book.

Malaria has defeated previous efforts at eradication and remains a massive global public health problem despite being readily preventable and treatable. It is a devastating disease that also extracts huge economic costs from the poorest countries in endemic regions.  Starting with an overview of the disease and its current political, financial and technical context, this Milestones in Drug Therapy volume describes the history, chemistry, mechanisms of action and resistance, preclinical and clinical use, pharmacokinetics and safety and tolerability of the current range of antimalarial drugs. There is particular emphasis on artemisinins and related peroxides, as these drugs have now become the frontline treatment for malaria. Next generation antimalarials, molecular markers for detecting resistance, the importance of diagnostics and disease prevention are also covered in detail.

Granulocyte colony-stimulating factor (G-CSF or GCSF) is a secreted glycoprotein that stimulates the proliferation and differentiation of granulocyte precursor cells, and induces mobilization of peripheral blood progenitor cells from the bone marrow. Development of recombinant human G-CSF has had a profound impact on the treatment of many diseases, including severe chronic neutropenia and cancer, and has enabled peripheral stem cell transplantation to supplant bone marrow transplantation in the autologous setting. This Milestones in Drug Therapy volume describes the experience of the last 20 years of treatment with recombinant human G-CSF, including the basic science, the use of recombinant human G-CSF in both the oncology and nononcology settings, and the safety and economics of its use. Many of the authors were the original investigators of recombinant human G-CSF and other authors are key researchers who provide their outlook for the next 20 years for use of and research with recombinant human G-CSF.

In this monograph about gene therapy of autoimmune and inflammatory d- orders we have gathered international experts and leaders from different fields to review the state of the art advances on topics ranging from disease entities to vectors and engineered cells. The different approaches described in each chapter take into consideration the biomedical knowledge of these diseases and address the complexities of delivering long-term genetic interventions. Gene therapy also serves as a testing ground for new therapeutic entities and helps provide proof of principle for their potential therapeutic role in animal models of disease. Scaling up from mice to men still remains an important h- dle not only from the quantitative point of view, but also for currently unknown and unexpected secondary effects of the vector or the transgene. Some of these approaches have already been tested in the clinic, but much more needs to be done to understand the human conditions treated and the n- ural history of their pathology. We are indebted to the secretarial assistance of Ms. Lin Wells (Bone and Joint Research Unit, London, UK) and the help of Hans Detlef Klüber for his help in getting this book published. We hope this book will be of interest to c- nicians and scientists and inspiring to students of the subject who will use their own ingenuity and knowledge to further forward this discipline into clinical use.

Growth factor receptors have long been known to drive malignant transformation and cancer progression. The epidermal growth factor receptor (EGFR, ErbB, HER) system is likely the best described membrane receptor tyrosine kinase family in malignant tumors. With implementation of the growth-inhibitory anti-HER-2 antibody trastuzumab (Herceptin) for the treatment of HER-2-positive advanced metastatic breast cancer, a new era has dawned in the therapy of this malignant disease. Unfortunately, trastuzumab-sensitive cancers invariably develop resistance to the antibody after some time. Recent clinical studies have revealed that these refractory tumors are still responsive to inhibition of the HER receptor family using dual HER-1/-2 inhibitors such as lapatinib (Tykerb/Tyverb). Moreover, a multiplicity of novel, improved irreversibly acting small molecular HER tyrosine kinase inhibitors are in the pipeline of many drug developing companies and are being evaluated in the clinical setting.

Tamoxifen is a pioneering medicine for the treatment and prevention of breast cancer. It is the first drug targeted therapy in cancer to be successful. Tamoxifen targets the tumor estrogen receptor. The therapy is known to have saved the lives of millions of women over the past 40 years.This monograph, written by V. Craig Jordan - known as the “father of tamoxifen” - and his Tamoxifen Team at the Georgetown University Washington DC, illustrates the journey of this milestone in medicine. It includes a personal interview with V. Craig Jordan about his four decades of discovery in breast cancer research and treatment. V. Craig Jordan was there for the birth of tamoxifen as he is credited for reinventing a “failed morning after contraceptive” to become the “gold standard” for the treatment of breast cancer. He contributed to every aspect of tamoxifen application in therapeutics and all aspects of tamoxifen’s pharmacology. He discovered the selective estrogen receptor modulators (SERMs) and explored the new biology of estrogen-induced apoptosis.

This book provides a detailed overview of B-cell directed therapies in patients with rheumatic and systemic autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, ANCA-associated vasculitis and cryoglobulinemia. Organ-specific autoimmune diseases are discussed with respect to the use of B-cell directed therapies in neurological autoimmune diseases and autoimmune cytopenias. Situations in which B-cell targeted therapy may be indicated are identified, thereby offering comprehensive support for therapeutic decisions on the basis of the latest published evidence. The book also offers a valuable reference tool for rheumatologists, internists, nephrologists, immunologists, and all specialists involved in the multidisciplinary care of patients with rheumatic and systemic autoimmune diseases.

Chronic obstructive pulmonary disease (COPD) is a multi-component condition that results in increasingly limited airflow, usually associated with an abnormal inflammatory response of the lung. It constitutes a major public health burden worldwide, while only very few effective therapies are available.This book provides a comprehensive overview of the development of Onbrez Breezhaler, a newly approved once-daily inhaled β2 agonist for the treatment of COPD. It reviews the current pharmacotherapy for COPD and discusses topics such as the chemical design and the pre-clinical pharmacology of the molecule, the early clinical development, the INHANCE study (which provides a successful example of the use of an adaptive design in the confirmatory setting) and the Phase III clinical efficacy study, as well as the history and performance of the Breezhaler device. Finally, a list of emerging targets is included that could well offer future treatment options for COPD.

Influenza continues to be an ongoing problem despite the existence of vaccines and drugs. Disease outbreaks can occur relatively quickly as witnessed with the recent emergence of the influenza virus A/H1N1 pandemic. The development of new anti-influenza drugs is thus a major challenge. This volume describes all aspects of the virus structure and function relevant to infection. The focus is on drug discovery of inhibitors to the enzyme sialidase, which plays a key role in the infectious lifecycle of the virus. Following an overview of the influenza virus, the haemagglutinin, the interactions with the cell receptors and the enzymology of virus sialidase, recent results in drug design are presented. These include a full coverage of the design, synthesis and evaluation of carbohydrate as well as non-carbohydrate influenza virus sialidase inhibitors. Further reviews of the clinical experience with influenza virus sialidase inhibitors and of the development of resistance to these inhibitor drugs complement the topic.

Tamoxifen is a pioneering medicine for the treatment and prevention of breast cancer. It is the first drug targeted therapy in cancer to be successful. Tamoxifen targets the tumor estrogen receptor. The therapy is known to have saved the lives of millions of women over the past 40 years.This monograph, written by V. Craig Jordan - known as the “father of tamoxifen” - and his Tamoxifen Team at the Georgetown University Washington DC, illustrates the journey of this milestone in medicine. It includes a personal interview with V. Craig Jordan about his four decades of discovery in breast cancer research and treatment. V. Craig Jordan was there for the birth of tamoxifen as he is credited for reinventing a “failed morning after contraceptive” to become the “gold standard” for the treatment of breast cancer. He contributed to every aspect of tamoxifen application in therapeutics and all aspects of tamoxifen’s pharmacology. He discovered the selective estrogen receptor modulators (SERMs) and explored the new biology of estrogen-induced apoptosis.

Granulocyte colony-stimulating factor (G-CSF or GCSF) is a secreted glycoprotein that stimulates the proliferation and differentiation of granulocyte precursor cells, and induces mobilization of peripheral blood progenitor cells from the bone marrow. Development of recombinant human G-CSF has had a profound impact on the treatment of many diseases, including severe chronic neutropenia and cancer, and has enabled peripheral stem cell transplantation to supplant bone marrow transplantation in the autologous setting. This Milestones in Drug Therapy volume describes the experience of the last 20 years of treatment with recombinant human G-CSF, including the basic science, the use of recombinant human G-CSF in both the oncology and nononcology settings, and the safety and economics of its use. Many of the authors were the original investigators of recombinant human G-CSF and other authors are key researchers who provide their outlook for the next 20 years for use of and research with recombinant human G-CSF.

Malaria has defeated previous efforts at eradication and remains a massive global public health problem despite being readily preventable and treatable. It is a devastating disease that also extracts huge economic costs from the poorest countries in endemic regions.  Starting with an overview of the disease and its current political, financial and technical context, this Milestones in Drug Therapy volume describes the history, chemistry, mechanisms of action and resistance, preclinical and clinical use, pharmacokinetics and safety and tolerability of the current range of antimalarial drugs. There is particular emphasis on artemisinins and related peroxides, as these drugs have now become the frontline treatment for malaria. Next generation antimalarials, molecular markers for detecting resistance, the importance of diagnostics and disease prevention are also covered in detail.

This volume describes the pathogenesis and pathophysiology of several pulmonary diseases as well as their treatment. It also discusses the underlying genetic and molecular biological basis, which opens the way for new treatments for these conditions.It focuses on the treatment of cystic fibrosis including CFTR (cystic fibrosis transmembrane-conductance regulator) modulator therapies, drug therapies that augment airway surface liquid as well as anti-inflammatory and anti-infective therapies. Further topics include long-term, low-dose macrolide therapy for diffuse panbronchiolitis; novel agents for previously untreatable idiopathic pulmonary fibrosis; possible new treatments for pulmonary alveolar proteinosis (PAP); and multiple novel therapeutic targets for treating lymphangiomyomatosis. Research into these conditions has led to major advances in our understanding of the underlying genetic and molecular basis of this disease, and to dramatic improvements in survival and quality of life for affected individuals.

Angiotensin converting enzyme inhibitors (ACEI) represent the first class of antihypertensive agents that was designed and developed on the basis of a well-defined physiopathological axis of arterial hypertension, a vascular dis­ order that is now becoming one of the major causes of morbidity/mortality, not only in developed societies but also in the highly populated developing coun­ tries [1]. CAPTOPRIL, the prototype of the "PRIL" family, which now comprises more than 40 molecule-species, was quite hazardous and the clinical develop­ ment almost failed when serious side-effects were reported in an alarmist fash­ ion in reputable scientific journals, such as the New England Journal of Medicine and Lancet. Squibb & Sons came very close to withdrawing CAPTOPRIL from clinical investigation [2]. However, after re-examination of the data obtained from different categories of patients and appropriate dose-adjustments, the clinical use of CAPTOPRIL turned out to be revolutionary. The prototype, as well as other members of the "PRIL" family became the starting point for numerous basic and clinical research programs, focusing on the interactions of ACEI with the kinin, endothelin, and nitric oxide systems, and the contribution of the receptors for AT I, AT 2, bradykinin Bland B , ETA and ET B to the pharmacological actions 2 of the respective peptides. This research activity led to the development of new pharmacological agents, such as the angiotensin receptor antagonists and, more recently, the neutral endopeptidase inhibitors. In the near future, bradykinin receptor antagonists also will be available to modulate ACEI phar­ macological actions.

Since the introduction of ciprofloxacin in 1987, fluoroquinolones have expanded far beyond their early role in the treatment of urinary tract infections. Clinical applications beyond genitourinary tract infections include upper and lower respiratory infections, gastrointestinal infections, gynecologic infec- tions, sexually transmitted diseases, and some skin and soft tissue infections. Their ease of administration, favorable pharmacokinetic properties, excellent tolerability, and efficacy give them enormous potential for use and misuse alike. Quinolones have few common adverse effects, most notably nausea, headache and dizziness. Less frequent but more serious adverse events include prolongation of the corrected QT interval, phototoxicity, liver enzyme abnor- malities, arthropathy, and cartilage and tendon abnormalities. While possess- ing many of the favorable properties of intravenous agents, most fluoro- quinolones offer the convenience of oral administration, thus contributing to decreased health-care costs through increased outpatient therapy and short- ened hospital stays.With the recent introduction of agents such as gatifloxacin and moxifloxacin, the traditional Gram-negative coverage of fluoroquinolones has been expanded to include Gram-positive organisms, most importantly Streptococcus pneumoniae.

There are only very few chemical classes of antibiotics in medical use, and these have originated over a span of more than 60 years of research. Almost half a century ago, the first member of the macrolides, erythromycin, was introduced as a treatment option for bacterial infections. Erythromycin is a very complex fermentation product obtained from the soil bacterium Saccharopolyspora ery­ thraea (originally named Streptomyces erythreus). The success of erythromycin, based on its efficacy and tolerability, stimulated researchers throughout the world to undertake intense efforts to understand the biology and chemistry of macrolides and to use this experience to improve the properties of this compound class. The second generation of macrolides, based on chemical modifications of erythromy­ cin, is currently being in broad use, especially for treatment of respiratory tract infections. We presently foresee the introduction of a new generation of macro­ lides, i. e. the ketolides, which have the potential to overcome rising resistance problems. This monograph is intended to give the interested reader an overview on "macrolide experience", covering important areas from basic research to clinical use. Starting from a historic overview, the essential basic parameters - efficacy, pharmacokinetics, pharmacodynamics, and pharmacology - are highlighted in order to introduce the reader to the rationale for clinical use of macrolides. The following group of chapters cover the complex chemistry of the macro­ lactone structures, giving historic background, basic structure-activity relation­ ships of various derivatization strategies, and perspectives for future discovery of new semisynthetic macrolide antibiotics.

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...

Important clinical issues as the outcome of long term treatment with antidepressants, the time of onset of the antidepressant response and the limitations of the antidepressants currently available are covered in this monograph. Leading researchers in the area of clinical and experimental psychopharmacology critically assess the progress in their specialist fields. The mechanisms of action of antidepressants are considered, followed by clinical research into the role of the hypothalamic-pituitary-adrenal axis and the immune system in the biology of depression and in response to treatment. The final chapter deals with the important chemical entities now undergoing development as antidepressants. The purpose of this monograph is not only to inform but also to stimulate research into the biology of depression and the mechanisms behind the action of effective antidepressants. This monograph is of interest to psychiatrists, psychologists, pharmacologists, neuroscientists and endocrinologists.

Recombinant protein drugs are intimately associated with the impressive success story of the Biotech Industry during the past thirty years, some of them belonging to the most successful pharmaceutical products. More than thirty different proteins are available for a variety of clinical applications, over 300 proteins are presently being evaluated in clinical trials. In this new volume of the MDT series, historical, technical and clinical aspects of recombinant protein drug discovery and development are presented, covering past, present and future highlights. Leading scientists and co-founders of early Biotech companies describe technical breakthroughs and the fascinating story of pioneering discoveries, as well as the long way of translating them into products and business. Therefore, this book represents an exciting documentation of the beginning of a new era in the pharmaceutical industry. In addition, scientists from basic research, clinic and industry actively involved in new developments discuss...

Following 50 years of glucocorticoid use in a clinical setting, an international body of expert scientists and physicians presents the most expansive survey of glucocorticoid pharmacology to date. This work traces the history of glucocorticoid biology from the seminal description of glucocorticoid insufficiency by Thomas Addison in the mid-19th century, up to current advances in elucidating the molecular basis of glucocorticoid action. Important discoveries are presented, as well as milestones in drug development, a survey of current clinical practice, and prospects for novel glucocorticoid-based therapeutics. Scientists and clinicians will appreciate the scope of this work, which is of special interest to workers in the fields of endocrinology, inflammation and autoimmune disease.

Expanding from the classic use of immunosuppressants in transplantation and rejection, this current overview highlights their new roles in clinical medicine. Immunosuppressants are at the forefront of new treatment modalities. Individual chapters focus on their use not only in prevention or treatment of transplant rejection, but also on their use in immune-complex and autoimmune diseases, including rheumatoid arthritis; on combination therapies to achieve synergy in immunosuppression; on new drugs, low molecular weight chemicals, the use of antibodies and gene therapy; on immunological tolerance to prevent or inhibit transplant rejection; and how data derived from transplant studies can be applied to other avenues of immunosuppression. Clinicians and researchers will appreciate the scope of the work and the presentation of new approaches in the rapidly developing field of immunosuppression.

The introduction of chlorpromazine in 1953, and haloperidol in 1958, into clinical practice dramatically altered the therapy of schizophrenic patients. Although representing by no means a cure for this severe psychiatric ill­ ness, it allowed, for the first time, to adequately control the severe hallu­ cinations and delusional beliefs which prevent these patients from leading a more or less independent life. Indeed these antipsychotics (and the many congeners that were to follow) significantly reduced the number ofchronic schizophrenic inpatients in psychiatric clinics all over the world. However soon after their introduction it became clear that, like all other available drugs, antipsychotics were by no means miracle drugs. In fact, two major problems appeared. First, the antipsychotics had very little effect on the so-called negative or defect symptoms, like social isolation, apathy and anhedonia, and secondly virtually all antipsychotics produced a number of side-effects, of which the neurological (often called extra­ pyramidal) side-effects were the most troublesome. Especially the tardive dyskinesia, which occurred in about 15 to 20% of the patients after pro­ longed treatment, represented a major problem in the treatment of schizo­ phrenic patients.

Although surprising, it seems fitting that a drug developed at the dawn of the era of rational drug design and therapeutics, methotrexate, should remain in common use for the therapy of so many different kinds of illnesses. Moreover, methotrexate has completely revolutionized the way in which medicine is practiced in a number of speciality areas. First developed to treat malignancies, methotrexate is now commonly used to treat gynecological problems, inflammatory arthritis, skin disease and probably other ailments as well. This work is designed to give a broad overview of the history of methotrexate's development, its prior use and its current therapeutic uses. As discussed in Chapter I, aminopterin and methotrexate were designed to inhibit mammalian folate metabolism but the concept of folic acid antag­ onism was soon applied to the development of antibacterial and anti­ parasitic agents. Trimethoprim and sulfa drugs were among the first antibiotics developed and they also remain quite useful today for the treat­ ment of a variety of infections.

For over thirty years the benzodiazepines monopolised not only the anxiolytic market but also clinical and animal research in anxiety. Indeed many animal tests developed since the 1960s have been optimised for the benzodiazepines and some programmes have even screened candidates as potential anxiolytics on their benzodiazepine-like side-effects rather than their anxiolytic activity. With the realisation of the drawbacks of the benzodiazepines, namely their potential for tolerance and dependency, there has been a renewed interest in alternative anxiolytics both from existing drugs such as the tricyclic and monoamine oxidase antidepressants and from newer agents such as buspirone. In addition anxiety is no longer considered to be a unique entity but rather an umbrella term for a series of specific anxiety disorders such as panic disorder without or with agoraphobia, generalised anxiety disorder (GAD), specific phobias, social phobias and post-traumatic stress disorder (PTSD). These new clinical categories have opened another dimension in the therapy of anxiety requiring the optimisation of treatments for different syndromes. This book is a critical review of today's anxiolytics and those that may become the anxiolytics of tomorrow. What is clear is that currently there are few clinically satisfactory alternatives to the benzodiazepines for the treatment of acute anxiety. For chronic anxiety, it is generally agreed that benzodi­ azepines are not the treatment of first choice. The tricyclic and monoamine oxidase antidepressants, the serotonin reuptake inhibitors and buspirone offer better solutions for chronic anxiety but they are still far from being ideal.

The drugs named calcium channel blockers (CCBs) were initially termed cal­ cium antagonists (see Chapter 1). They are also designated as calcium entry blockers (CEBs), calcium blockers, calcium channel antagonists, calcium channel inhibitors (and in French anticalciques). As this is reported in several chapters of this book, their main effect is a blockade of calcium entry into cells through voltage operated calcium channels (VOCCs). Chemically related drugs, such as Bay K 8644, exert the opposite effect by increasing the proba­ bility of calcium channel opening. One of the subcommittees of the Nomenclature Committee (NC-IUPAR) of the International Union of Pharmacology has been devoted to the classification of calcium channels and the site of action of drugs modifying channel function. The members of this Committee are noted for their significant contribution to the field (Tab. 1). A report has been published in 1992 in Pharmacological Reviews [3]. A list of criteria was approved for the identification of distinct drug binding 2 sites on Ca + channels. It included: (a) the demonstration of a stereoselective binding site supported by drug interaction studies (competition with other drugs, non-competitive interactions with other sites, reversal of inhibitory effects by channel activators); (b) demonstration of the electrophysiologieal effects of the drug and selectivity of action compared to other sites; (c) deter­ mination of the affinity for the type and subtype of ion channel. These criteria have identified different classes of Ca antagonists (see Chapter 2).

During the past decade research into the pharmacology of cognition, particularly regarding learning and memory, has supported the concept that many potential neural targets exist for the development of cognitive-enhancing drugs. Whereas the main impetus for this research has been the ever growing population of individuals with dementing disorders such as Alzheimer`s disease, attention is also being focused on issues relating to cognitive impairment associated with "normal" aging. This book is useful as a source of information for making informed decisions regarding the relative utility and attributes of the various neural targets that have been studied to date.