bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug Resistance in Cancer Chemotherapy
Authors: Wall Amelia M. 
Published: November 2003

Abstract
Systemic therapy with chemotherapeutic agents has greatly improved outcome in many types of cancer over the last 50 years. However, clinical resistance to chemotherapy has prevented certain subtypes of malignancies from responding to currently used systemic therapies. Understanding the unique properties of the tumor cell by which it achieves resistance to cancer chemotherapy will improve our ability to administer rational therapies to patients with cancer. Ultimately, by using strategies to overcome clinical resistance of cancer cells, patients with malignancies that have, to date, been considered refractory to therapy may also achieve excellent responses to chemotherapy.
Antiviral Agents, RNA Viruses (Other than HIV), and Orthopoxviruses
Authors: Tseng Christopher , Laughlin Catherine 
Published: November 2003

AbstractSince our last review on antiviral agents for RNA viruses other than HIV, significant advances have occurred in the field of antiviral chemotherapy. The U.S. Food and Drug Administration (FDA) approved two new drugs (Relenza and Tamiflu) for the treatment of influenza for both adults and children. Pegylated interferon has improved the efficacy of interferon, particularly in combination with ribavirin for the treatment of chronic hepatitis C infections. A monoclonal antibody, Synagis, has been approved for the prevention of serious lower respiratory tract infections in high‐risk pediatric patients. A new drug application (NDA) has also been submitted to the FDA for the treatment of infections caused by rhinoviruses and enteroviruses. This chapter will update the discovery, preclinical evaluation, and clinical data supporting the development of antiviral agents for RNA viruses other than HIV. In addition, as a component of biodefense‐related activities, this chapter will review the historical and current development of antiviral agents for orthopoxviruses.
Organ TransplantDrugs
Authors: Kundu Bijoy 
Published: November 2003

AbstractIn recent years several new immunosuppressive agents for organ transplantation have been introduced for clinical usage. They have greater efficacy and fewer side effects than those of the classical therapies involving corticosteroids, azathioprine, and cyclosporine. The new maintenance immunosuppressive drugs are either immunophilin‐binding drugs or are inhibitors ofde novosynthesis of nucleotides (purines or pyrimidines) that inhibit signal transduction in lymphocytes. The immunophilin‐binding drugs are cyclosporine, tacrolimus, and rapamycin, whereas inhibitors ofde novonucleotide synthesis include mycophenolate mofetil, mizoribine, brequinar, and leflunomide. Gusperimus (deoxyspergualin), which inhibits IL‐1 synthesis, was useful in reversing early and late acute rejection in clinical trials. FTY‐720, another promising drug, prolonged the survival of allografts and synergized with cyclosporin and sirolimus in experimental models. Antibody preparations such as OKT3, as well as the newer recombinant products, which specifically bind to the IL‐2 receptor, basiliximab, and daclizumab, not only reduced acute rejection but were associated with few adverse effects. Antisense oligonucleotides that interfere with the intercellular adhesion molecules involved in rejection gave encouraging results in primate renal allografts. Use of stem cells, donor bone marrow, and xenotransplantation are some of the alternatives that are likely to find application in organ transplantation in the near future.
β‐Lactam Antibiotics
Authors: Andreotti Daniele , Biondi Stefano , Di Modugno Enza 
Published: November 2003

AbstractThis chapter reviews the history of β‐lactams from the discovery of penicillin in 1928 to the more recently studied and the current trends in the field. The most relevant aspects related to the mechanism of action of β‐lactams are covered, and the various mechanisms of resistance to currently available β‐lactams that bacteria have adopted since the introduction of penicillin are described. A classification of β‐lactamases and their relevance in clinics is also provided. Applications of β‐lactams both in the hospital and in the community are reported, with particular attention to their pharmacokinetic properties, related side effects, and their therapeutic indications. The history and discovery of β‐lactams are described and all major classes are covered: penicillins, cephalosporins, oxacephems, carbacephems, penems, monobactams and nocardicins, carbapenems and trinems, classical (e.g., clavulanic acid, sulbactam, tazobactam), and the more recently disclosed β‐lactamase inhibitors. Several aspects related to the most recent developments in β‐lactams are also covered: new molecules active against difficult Gram‐positive strains or endowed with an antibacterial broad spectrum of action; potent orally active β‐lactams; injectable β‐lactams; and β‐lactamase inhibitors. The chapter concludes with a continuing analysis of the industry‐driven trends and the most recent new application of β‐lactams as inhibitors of protein export in bacteria. Finally, a few very interesting Web addresses and a comprehensive reference list are also provided.
Antimycobacterial Agents
Authors: Sensi Piero , Grassi Giuliana Gialdroni 
Published: November 2003

AbstractA few decades ago, the idea that a treatise on chemotherapy, to be published in this millennium, could include a chapter on antimycobacterial agents was probably considered acceptable mainly to illustrate the history of a strong successful fight against some human diseases present in the world since antiquity, such as tuberculosis and leprosy. In fact, starting from the middle of the last century, the introduction of chemotherapy for mycobacterial infections, together with improvements in the hygienic and nutritional conditions, brought about a dramatic decrease in the mortality and morbidity of these illnesses, with a trend toward their elimination. Unfortunately, these successes notwithstanding, mycobacterial infections still require particular attention as a worldwide, challenging health problem. In particular, in the last few years, an unexpected resurgence of tuberculosis has occurred in industrialized countries, probably because of the spread of HIV infection and the increasing and uncontrolled waves of immigration. Moreover, the emergence of multidrug resistant strains ofMycobacterium tuberculosishas made the older therapies largely ineffective. This chapter has been written for the medicinal chemist who wants to be updated on the situation in this area. The present knowledge of the biology of the pathogens, the mycobacteria, has been reviewed, taking into account the recent information on the genome sequence ofM. tuberculosisandM. leprae.It also will review the information on the pathogenesis and epidemiology of the mycobacterial diseases. The antimycobacterial drugs used in therapy have been described in detail, mentioning some aspects of their discovery, but particularly theirin vitroandin vivoactivity, their mechanism of action, their side effects, and the general structure‐activity relationships in the frame of the chemical class to which they belong. Their use in therapy has been considered and evaluated when combined with other antimycobacterial drugs, when the combination is important for an improvement of efficacy and a decrease of probability of resistant strains selection. Some products in the early stage of development, as a starting point for new drugs that are needed, possibly acting on novel targets of the pathogens are also discussed.
Antifungal Agents
Authors: Watkins William J. , Renau Thomas E. 
Published: November 2003

AbstractThe chapter addresses current chemotherapeutic options and trends in the treatment of fungal diseases in humans. The nature of such diseases is discussed, with attendant issues such as relative severity, diagnosis, microbiological methods, and trends in incidence. Emphasis is placed on systemic infections, in which morbidity and mortality are much higher than that in cutaneous diseases. The various drugs with proven clinical utility are then surveyed by chemical class, with a discussion of mode of action, spectrum and emergence of resistance, pharmacokinetic properties, and side effects for each; for the most prominent class of antifungal agents (the azoles), the history of their medicinal evolution is described. Where appropriate, comment is made about new developments in the field with a brief summary of newer agents in clinical development. Also included is a section reviewing chemical series with interesting (and selective) modes of action that have not yet been tested clinically. Finally, the anticipated impact of new technologies on antifungal drug discovery is briefly discussed.
Antimalarial Agents
Authors: Casteel Dee Ann 
Published: November 2003

AbstractMalaria continues to be a major global health problem and seems to be increasing in some parts of the world. By way of an introduction, relevant aspects of the disease, including incidence and resistance, and of the parasite and its biochemistry and genetics are presented. The chemotherapeutic agents now available to prevent and treat malaria are discussed individually. Some of these drugs have been in use for decades or even centuries, such as quinine, chloroquine, and primaquine. Other agents are of more recent origin including mefloquine, halofantrine, atovaquone, and the artemisinins. Chloroquine had been the drug of first resort for many years. It is inexpensive, well‐tolerated, and extremely effective where parasites remain sensitive. But the development of resistance to chloroquine has emphasized the need for new agents and strategies to treat malaria. New information on the genetic basis of chloroquine resistance and on the overall mechanism of action of chloroquine holds promise for advances in therapy. Another important tactic in dealing with infection by resistant parasites is the use of drug combinations. The combination of pyrimethamine and sulfadoxine has been very successful, but resistance is developing. Newer, highly effective combinations include atovaquone with proguanil, lumefantrine with artemether, and chlorproguanil with dapsone. The artemisinin group of compounds has made a powerful positive impact on malaria chemotherapy although their use in monotherapy is not recommended. Details of the mechanism of action of these drugs are becoming clearer. Knowledge about action should assist in addressing issues of possible toxicity. Great progress has been made in sequencing the genome ofPlasmodium falciparum. New molecular targets have been identified as a result and efforts are underway to develop antimalarial agents based on these targets. Researchers around the world are also exploring natural products for yet another lead in antimalarial chemotherapy.“If we take as our standard of importance the greatest harm to the greatest number, then there is no question that malaria is the most important of all infectious diseases1.”“Ah, poor heart! he is so shaked of a burning quotidian tertian, that it is most lamentable to behold [2].”
Anticholinergic Drugs
Authors: Rama Sastry B. V. 
Published: November 2003

AbstractThis chapter contains information on various anticholinergic agents that block the stimulation of muscarinic receptors by acetylcholine. These include solanaceous alkaloids as well as various types of synthetic anticholinergic agents that are used as antispasmodics, antiulcer agents, mydriatics, and cycloplegics. The structure‐activity relationships of various agents, biocomparative methods for pharmacological evaluation, and their users are also discussed.
CNS Stimulants
Authors: Nichols David E. 
Published: November 2003

Abstract
This chapter briefly describes the development, structure‐activity relationships, and mechanism of action for the important psychostimulants such as amphetamines, methylphenidate, and cocaine. Derived from natural products known for centuries, at low doses these drugs lead to increased arousal, improved performance on tasks of vigilance and alertness, and a sense of self‐confidence and well‐being. High doses can produce feelings of elation or euphoria, and result in profound abuse liability. This chapter reviews the current and future use of psychostimulants, as well as other drugs that cause CNS arousal, albeit by different mechanisms.
Sedative‐Hypnotics
Authors: Vida Julius , Yevich Joseph 
Published: November 2003

AbstractThis chapter focuses on sedative‐hypnotic drugs that are sued to alleviate the condition of sleep disturbances. One‐third of our life is spent in sleep; the lack, of which, can cause serious physical, social, and psychological problems. This chapter describes the features of an ideal hypnotic drug and provides a classification of sedative‐hypnotic drugs currently in use. These include the barbiturates, benzodiazepines, halogenated sedative‐hypnotics, heterocyclic sedative‐hypnotics, antihistamines, and other sedative‐hypnotics. Individual members of all of these classes of drugs are discussed in detail. The chapter also describes the physiology of sleep and the sleep cycle, including the nonrapid eye movement and rapid eye movement sleep. A list of neurotransmitters and nonhypnotic drugs that have a direct and indirect action on the sleep cycle are provided. The pharmacology including the evaluation of sedative‐hypnotics are also given. The chapter refers to the discovery of one of the most frequently prescribed hypnotic drugs, Zolpidem. The chapter also examines structure‐activity relationships, recent developments, things to come, and available websites.
Anticonvulsants
Authors: Scott Kenneth R. 
Published: November 2003

AbstractThis chapter reports on the current and prospective anticonvulsant agents: their chemical structures, chemical names, pharmacokinetic parameters, and proposed mechanism(s) of action. Theoretical principles on structure‐activity development are presented as well as a brief explanation of animal testing to predict anticonvulsant activity. A hypothetical anticonvulsant model is presented that, within limits, is useful in elucidating the spatial/structural requirements for anticonvulsant activity against generalized epilepsy.
Antidepressants
Authors: Iversen Leslie , Glennon Richard A. 
Published: November 2003

Abstract

This chapter reviews the 26 antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure‐activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by compounds that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin‐selective reuptake inhibitors, which possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions. Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites
in vivo
. All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of
5‐HT
1A
receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain derived neurotrophic factor). New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, or corticotrophin releasing factor receptors.
Antianxiety Agents
Authors: Currie Kevin S. 
Published: November 2003

AbstractAnxiety is a complex and prevalent cluster of psychiatric disorders consisting of generalized anxiety disorder, panic disorder, social phobia, obsessive‐compulsive disorder, posttraumatic stress disorder, and specific phobias. These conditions are most commonly treated with benzodiazepines, buspirone, and serotonin reuptake inhibitors, all of which fall some way short of the ideal anxiolytic. The clinical applications, side effects, and drug metabolism of these medications are discussed. A multitude of neurotransmitter systems are implicated to a greater or lesser degree in the complex underlying neurobiology and physiology of anxiety, including GABA, serotonin, norepinephrine, glutamate, as well as neuropeptides such as CCK, CRF, and NPY. The increasing understanding of the roles of each neurobiological pathway provides a platform for medicinal chemistry efforts in anxiolytic research. The structure‐activity relationships of current medications and newer, investigational compounds interacting with these systems are discussed, as well as the future prospects for the development of improved anxiolytics.
Investigative Agents for Use in Neurodegenerative Conditions
Authors: Adams James David , Woolf Thomas F. 
Published: November 2003

Abstract
Several strategies are currently being explored for the development of agents to be used in stroke. Agents that inhibit necrotic mechanisms leading to infarction are especially sought. Drugs that enhance DNA repair, inhibit poly(ADP‐ribose) polymerase, enhance cellular energetics, inhibit NAD glycohydrolase, and NAD precursors may provide new ways to treat stroke. NMDA receptor antagonists and NO synthase inhibitors are being actively investigated for use in stroke and other neurodegenerative diseases. This chapter provides an overview of the recent advances in the chemistry of these compounds. A very brief discussion of agents recently developed for use in Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis is presented.
Therapeutic and Diagnostic Agents for Parkinson's Disease
Authors: Neumeyer John L. , Baldessarini Ross J. , Booth Raymond G. 
Published: November 2003

Abstract

This chapter considers the biology and medical chemistry‐based treatment of Parkinson's disease, the second most common of the major neurodegenerative neuropsychiatric disorders. It surveys basic clinical features, neuropathology, and etiological theories based on genetics, maturational and oxidative‐metabolic degenerative processes, and environmental neurotoxins including MPTP. Treatments reviewed include
L
‐dopa as a replacement therapy, direct dopaminergic agonists and their structure‐activity relationships, and agents that potentiate dopamine by preventing the metabolism of dopa or dopamine by peripheral aromatic amino acid decarboxylase, catechol‐
O
‐methyltransferase, or monoamineoxidase. Drugs acting on nondopaminergic systems considered include anticholinergic, adenosine agonist, glutamate antagonist, and serotonin agonist agents. Agents useful for the diagnosis of Parkinson's disease and monitoring progression of the disease include radioactive dopa and dopamine transporter labeling agents for use in brain imaging. Finally, future directions of efforts to improve the treatment of Parkinson's disease are considered, with an emphasis on the continued central importance of medicinal chemistry.
Alzheimer's Disease: Search for Therapeutics
Authors: Rzeszotarski W. Janusz 
Published: November 2003

AbstractOver the next 50 years the incidence of Alzheimer's disease (AD) in the United States is expected to triple from about 420,000 new cases in 1999 to 1.32 million per year. Assuming no successful intervention, the prevalence of AD could be expected to rise over the next 50 years by a factor of about 3.7–8.94 million, with the range of 4.55–15.81 million in the United States alone. With the exception of early‐onset familial AD (FAD) the disease is age correlated and its incidence grows exponentially with age. In part, because of their increased longevity, women represent and will continue to represent the majority (68% in 1997) of the affected population. If one adds the year 2000 U.S. census figures to the population of the European Union (EU‐15) and Japan, the prevalence of AD in “the major pharmaceutical markets” for that year could be estimated as close to 8.7 million. The as yet uncertain etiology of AD precluded the attempts to prevent its onset. Cholesterol, immune response, and oxidation damage appear to precede the deposition of amyloid β‐peptides (Aβ) and formation of senile (neuritic) plaques and intracellular neurofibrillary tangles. This is why the epidemiology andin vitrostudies fail to point to right therapies. The statins, antioxidants, anti‐inflammatory agents, estrogens, or testosterone may belong to preventive measures but may fail as therapeutics. At present, no agent is available to arrest, delay, or reverse the progress of the disease.
Drugs to Treat Eating and Body Weight Disorders
Authors: Carpino Philip A. , Hadcock John R. 
Published: November 2003

AbstractEating and body weight disorders are a group of diseases that are characterized by atypical feeding behaviors and/or unhealthy changes in body weight. Eating disorders such as anorexia nervosa, bulimia nervosa, and binge eating disorder are predominantly psychiatric conditions, caused by unrealistic impressions of ideal body shape or brought on by companion diseases such as depression, anxiety, and obsessive compulsive behavior. Body weight disorders are complex metabolic diseases that can result in significant loss of lean body mass as in cachexia or the deposition of adipose tissue as in obesity. Current management of these diseases involves a combination of pharmacological and nonpharmacological strategies that include drug therapy, nutritional counseling, and cognitive behavioral therapy. Pharmacotherapy, however, is limited by the availability of safe and efficacious drugs. Significant progress has been made in recent years in understanding the etiology of these disorders (especially obesity) and in identifying new molecular targets for future drug discovery. This review describes (1) biochemical and genetic mechanisms of eating and body weight disorders; (2) guidelines for treatment; (3) new and old drugs available for pharmacotherapy, including their mechanisms of action, adverse effects, metabolic fates, and structure‐activity relationships; and (4) promising agents in clinical development.