bluuebunny/crossref_metadata_2025 huggingface dataset:
Thyroid Hormones and Thyromimetics
Authors: Ryono Denis E. , Grover Gary J. , Mellstrom Karin
Published: November 2003

Thyroid hormones and thyromimetics bind their cognate receptors in the nucleus to regulate the expression of diverse genes throughout the body. Consequently, such agents represent significant promise for the development of new therapies—particularly in the area of metabolic diseases, such as obesity and hyperlipidemia. Unfortunately, the potential for this class of drugs has historically been limited because of concerns for mechanism‐related side effects, particularly those that are cardiovascular in nature. This chapter discusses the molecular mechanism and physiology of thyroid hormone action and the therapeutic potential and structure‐activity relationships of thyroid hormones and thyromimetics. Improved assays using purified thyroid hormone receptors, greater knowledge of receptor‐ligand interactions, and importantly, new advances in understanding the molecular biology of nuclear hormone receptors may now point the way to developing new thyromimetic drugs with selective, and consequently safer, profiles of biological activity.
Fundamentals of Steroid Chemistry and Biochemistry
Authors: Brueggemeier Robert W. , Li Pui‐kai
Published: November 2003

Steroids are a unique class of chemical compounds found throughout the animal and plant kingdom. This class includes sterols such as cholesterol and ergosterol, bile acids, and steroid hormones. Chemical research on steroids began with isolation and structure determination, and major research efforts focused on total synthesis and on the development of numerous reactions for modifying the steroid scaffold. Methods in microbial transformations of steroids were developed to produce large quantities of steroid starting materials at reduced costs. Research in steroid biochemistry first began with studies on the biosynthesis and metabolism of steroids, followed soon thereafter by investigations on the biochemical mechanism of action of steroids. Over the past several decades, steroid biochemistry and molecular biology have focused on steroidogenic enzymes, nuclear steroid receptors, and gene expression. The discovery of the anti‐inflammatory effects of cortisone in the treatment of rheumatoid arthritis and the report of the contraceptive effects of estrogen and progestin preparations illustrated for the first time that steroids could be considered as medicinal agents. As a result, extensive research on the medicinal chemistry, pharmacology, and clinical studies of steroid agonists and antagonists has evolved and continues to provide new insights and new medicinal agents for therapies in many different diseases and chemoprevention strategies.
Female Sex Hormones, Contraceptives, And Fertility Drugs
Authors: Ruenitz Peter C.
Published: November 2003

Substances that interact with estrogen or progesterone receptors have clinical applications in hormone replacement therapy, birth control, prevention and treatment of hormone‐dependent cancer, and in stimulation of fertility. This chapter describes the specific drugs in each of these categories, and their counterparts now in clinical trials or in use experimentally, with respect to mechanism of pharmacologic action, noteworthy routes of biotransformation, structure–activity relationships, and current and future prospects for therapeutic uses. The history of discovery and current understanding of the molecular endocrinologic basis of selective estrogen receptor modulators are covered, as are mechanistic, structural, and clinical aspects of drugs that interfere with estrogen biosynthesis (aromatase inhibitors). Structural and pharmacologic aspects of environmental/dietary estrogens and progestins are also included.
Male Sex Hormones, Analogs, and Antagonists
Authors: Brueggemeier Robert W.
Published: November 2003

The steroid testosterone is the major circulating sex hormone of the male and serves as the prototype for the androgens, the anabolic agents, and androgen antagonists. The endogenous androgens are biosynthesized from cholesterol in various tissues in the body; the majority of the circulating androgens are made in the testes under the stimulation of the gonadotropinluteinizing hormone(LH). The reduction of testosterone to dihydrotestosterone is necessary for the androgenic actions of testosterone in many androgen target tissues such as the prostate; the oxidation of testosterone by the enzyme aromatase produces estrogens. The androgenic actions of testosterone and dihydrotestosterone are due to their binding to the androgen receptor, followed by nuclear localization, dimerization of the receptor complex, and binding to a specific DNA sequence. This binding of the homodimer to the androgen response element leads to gene expression, stimulation or repression of the synthesis of new mRNA, and subsequent protein biosynthesis. The synthetic androgens and anabolics were prepared to impart oral activity to the androgen molecule, to separate the androgenic effects of testosterone from its anabolic effects, and to improve upon its biological activities. Novel nonsteroidal androgens, termed selective androgen receptor modulators, were developed to impart agonist activity in selective tissues. Drug preparations are used for the treatment of various androgen‐deficient diseases, for the therapy of diseases characterized by muscle wasting and protein catabolism, for postoperative adjuvant therapy, and for the treatment of certain hormone‐dependent cancers. The two major categories of androgen antagonists are the antiandrogens, which block interactions of androgens with the androgen receptor, and the inhibitors of androgen biosynthesis and metabolism. Such compounds have therapeutic potential in the treatment of acne, virilization in women, hyperplasia and neoplasia of the prostate, and baldness and male contraception.
Anti‐Inflammatory Steroids
Authors: Avery Mitchell A. , Woolfrey John R.
Published: November 2003

We know today that structural changes in steroids can bring about potency alterations in animal pharmacology through a number of mechanisms. The processes that are affected include pharmacokinetic parameters such as drug absorption and drug distribution, as well as drug metabolism to more or less active metabolites. There is now a large body of literature dealing with these phenomena that makes predictive thinking possible in these areas. Other mechanisms that are involved in the effect of structural changes on pharmacological activity in steroids include the effect of steroid structure on receptor affinity and the manner in which changes in the steroid agonist affect intrinsic activity through alterations in gene expression. These and other concepts relating to anti‐inflammatory steroids are discussed in this chapter.
Peptide and Protein Hormones, Peptide Neurotransmitters, and Therapeutic Agents
Authors: Hruby Victor J. , de Chavez Catherine Gehrig , Kavarana Malcolm
Published: November 2003

Over 50% of all current drugs and perhaps an even higher percentage of drug targets have as their major target receptors/acceptors for which the native ligand/recognition motif is a peptide. Furthermore, most targets for drugs are proteins or conjugated proteins. Peptide hormones and neurotransmitters constitute a very large number of these ligands and almost all of them are important in a wide variety of diseases. Thus robust methods for the design, synthesis, and biological evaluation of peptides, proteins, peptide analogs, and peptidomimetics are needed. In this chapter we briefly discuss the major synthetic, structural, conformational, and topographical considerations that go into peptide design of peptide analogs, derivatives, and mimetics that can serve as drug candidates. We then provide a selected discussion on the design of four different examples of peptide hormone and neurotransmitter ligands, and conclude with a brief discussion of future perspectives in this critically important area of current and future drug research.
Inhibitors of Gastric Acid Secretion
Authors: Roberts Sonia , McDonald Iain M.
Published: November 2003

The discovery of potent and selective inhibitors of gastric acid secretion now negates the need for surgical intervention in the treatment of many hypersecretory disorders. The side effects associated with cholinergic antagonists has led to their being superseded by the use of selective histamine
H
2
‐receptor antagonists (cimetidine, ranitidine, famotidine) and the more potent irreversible proton‐pump inhibitors (omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole). Current therapeutic regimes for the treatment of ulcer disease recommend concurrent proton‐pump administration while eradicating
Helicobacter pylori
, a bacterial infection that is strongly associated with ulcer formation. Because achlorhydria increases the likelihood of gastrointestinal infection, current research within this area is now targeting the design of reversible proton‐pump inhibitors and CCK
2
/gastrin‐receptor antagonists. These newer therapeutic approaches, however, are unlikely to produce the rapid and potent inhibition of acid secretion realized by the irreverisble PPIs, which in addition have few side effects and a proven track record of success. Key drug developments in the treatment of acid hypersecretion, from the anticholinergic agents to the highly potent and effective proton‐pump inhibitors currently in use, are covered in this chapter.
Retinoids
Authors: Leid Mark
Published: November 2003

Derivatives of vitamin A, collectively known as retinoids, play key roles in development, cellular differentiation, vision, and reproduction. Retinoids are now well established as valuable therapeutic agents in the treatment of a variety of skin and proliferative disorders. This chapter covers the biosynthesis and metabolism of naturally occurring retinoids, the role of these retinoids in the visual cycle, and the clinical usefulness and adverse effects of retinoids and synthetic derivatives in the treatment of disease.
Radiopaques
Authors: Peng C. T.
Published: November 2003

This review discusses radiopaques from research and development to application. Radiopaques attenuate X‐rays and may be either high atomic‐numbered materials or iodinated organic compounds. The latter may appear sometimes in liposomes or particulates. The theoretical and historical aspects, classification by structures, methods of synthesis, structure‐activity relationship, physical, chemical, and pharmacological properties, and related reactions, essential to the understanding of safety, tolerability, and efficacy of radiopaques in medical use, are included in the discussion.
Molecular Biology of Cancer
Authors: Martinez Jesse D. , Parker Michele Taylor , Fultz Kimberly E. , Ignatenko Natalia A. , Gerner Eugene W.
Published: November 2003

Over the past 50 years, our understanding of cancer has grown dramatically. Conceptual models that explain the tumor development process have been formulated. The biological characteristics that account for the behavior of tumor cells in experimental systems andin vivoand the genetic alterations that account for these changes have been catalogued in detail. Additionally, new preventative strategies and therapeutic agents using this wealth of information are now being formulated. In this chapter, we present a brief overview of our current understanding of cancer as a disease as well as give specific examples of some of the approaches being adopted to combat it.
Synthetic DNA‐Targeted Chemotherapeutic Agents and Related Tumor‐Activated Prodrugs
Authors: Denny William A.
Published: November 2003

Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents remain important DNA alkylators. Methotrexate, and more recent lipophilic analogs, together with older drugs such as 5‐fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. Cytosine arabinoside and more recent compounds like gemcitabine, fludarabine, cladribine, and pentostatin inhibit DNA polymerase action during DNA synthsis. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs targeted at DNA. The increasing power of organic chemistry increasingly allows the synthesis of close analogs of cytotoxic, but complex, natural products as potential drugs; recent examples are synthetic analogs of the duocarmycins and the epothilones. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor‐activated prodrugs of DNA‐active agents. Using hypoxia, gene therapy, or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive non‐tumor cell populations.
Antitumor Natural Products
Authors: Mitscher Lester A. , Dutta Apurba
Published: November 2003

The literature associated with major naturally occurring antitumor agents and related substances is reviewed and illustrated. Covered are dactinomycin, bleomycin, mitomycin, plicamycin, anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin, and valrubicin), camptothecins (topotecan and irinotecan), idopodophyllotoxins (etoposide and teniposide), taxus diterpenes (docetaxel and paclitaxel), and vinca dimeric alkaloids (vinblastine, vincristine, and vinorelbine).
Radiosensitizers and Radioprotective Agents
Authors: Bump Edward A. , Hoffman Stephen J. , Foye William O.
Published: November 2003

Various approaches have been developed for diminishing the effects of radiation on normal tissues or enhancing tumor cell killing by ionizing radiation. An important potential use for these agents is to modify the outcome of radiation therapy. Potential radioprotectors or radiosensitizers are organized in this review according to mechanism of action. Most of the agents studied are believed to act by reacting with DNA radicals that are produced within milliseconds of exposure to ionizing radiation. According to this mechanism, protectors restore a single electron to electron‐deficient radicals, preventing degradation of the structure of DNA, whereas sensitizers, such as molecular oxygen or nitroimidazoles, form adducts with these radicals, resulting in damage fixation. WR2721 (Ethyol) is the best‐characterized chemical radioprotector. Preferential activation of WR2721 in certain normal tissues by removal of a phosphate group provides a rationale for selective protection of these tissues. Cytokines and biological modifiers represent an important emerging class of radioprotectors that may be particularly useful in modifying bone marrow injury. Nitroimidazoles have been the most widely studied chemical radiosensitizers. Although clinical results with nitroimidazoles have not been impressive, the potential for this approach has not been fully explored, given that the doses that can be administered have been limited by drug toxicity and supplemental strategies, such as concurrent depletion of endogenous protectors, have not been explored in the clinic. Modifiers of tumor oxygenation represent an important class of radiosensitizers that are currently generating considerable clinical interest. RSR13, a modifier of the oxygen affinity of hemoglobin, is highlighted as an example of the process of drug development for this type of agent.
Synthetic Antiangiogenic Agents
Authors: Blaschuk Orest W. , Symonds J. Matthew
Published: November 2003

This chapter focuses on synthetic antagonists of matrix metalloproteinases, receptor tyrosine kinases, integrins, and microtubules. These proteins are believed to be critical regulators of angiogenesis, the process by which new vasculature arises from preexisting blood vessels.
Future Strategies in Immunotherapy
Authors: Lake Douglas F. , Dionne Sara O.
Published: November 2003

The following chapter discusses cutting edge, current, and future immunotherapeutic strategies. The first section reviews basic molecular and cellular components of the immune system. The second section emphasizes FDA‐approved humanized and chimeric antibodies for the treatment of cancer and rheumatoid arthritis including herceptin, rituxan, mylotarg, campath, remicade, and Enbrel, because these types of genetically engineered molecules represent the future of molecular medicine treatments. The function and significance of antibody targets are defined where possible. A brief description of clinical trial results and adverse drug reactions is provided for each humanized or chimeric antibody. Formulations of each antibody are also discussed where appropriate. Next, cutting edge strategies using dendritic cells pulsed with tumor associated peptides, tumor cell lysates, apoptotic tumor cells, tumor RNA, and tumor‐derived exosomes are also addressed. Transduction of DC with adenovirus and pox virus vectors is discussed along with ongoing clinical trials and exciting pre‐clinical developments of promising strategies. The chapter concludes with a summary of what must occur in the immunotherapy field for success in the near future.
Drug Resistance in Cancer Chemotherapy
Authors: Wall Amelia M.
Published: November 2003

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

Since 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

In 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

This 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

A 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

The 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

Malaria 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

This 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

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

This 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

This 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

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

Anxiety 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.
Antipsychotic Agents
Authors: Altar C. Anthony , Martin Arnold R. , Thurkauf Andrew
Published: November 2003

This chapter surveys the clinical applications of antipsychotic agents, their therapeutic indications and adverse effects, and the use of animal models. The chapter discusses structure‐activity relationships as well as pharmacokinetics, biotransformation, drug interactions, and strategies for drug discovery.
Investigative Agents for Use in Neurodegenerative Conditions
Authors: Adams James David , Woolf Thomas F.
Published: November 2003

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

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

Over 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

Eating 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.
Antiprotozoal Agents
Authors: Fries David S. , Fairlamb Alan H.
Published: November 2003

The chapter provides coverage of all drugs currently used for the treatment of human African trypanosomiasis (African sleeping sickness), American trypanosomiases (Chagas' disease), and leishmaniasis. Collectively, this group of diseases is caused by flagellated protozoan of the order Kinetoplastida. The drugs currently used to treat these diseases include melarsoprol, suramin, pentamidine, organic antimonials, and several nitroheterocyclic agents. The agents have all been in use for 25–75 years. They have a high degree of toxicity and the first four in the preceding list must be given by parenteral injection over a 2‐ to 6‐week time period. Tolerance has developed to most of the drugs in at least some geographical areas. Eflornithine is the only agent approved in the last 50 years for the treatment of African trypanosomiasis, although it is expensive, requires prolonged systemic dosage, and is effective only against
T. brucei gambiense
. Megazol, trybazine, DB289, and CGP 40215A have all yielded encouraging results in
in vivo
preclinical studies against African trypanosomiasis. All four of these agents have entered or are scheduled to enter clinical trials. Nifurtimox and benznidazole are the only agents approved to treat Chagas' disease. The agents are toxic, rarely produce long‐term cures, and resistance to them has developed. The third‐generation triazole antifungal agents posaconazole and UR‐9825 have given encouraging preclinical results against Chagas' disease. Meltefosine has been found to be orally active and to produce 98% cure rates of visceral leishmaniasis. New classes of experimental antitrypanosomal agents include the bisphosphonates, which disrupt lipid metabolism, and cysteine protease inhibitors. Agents from both of these mechanistic classes are being advanced as potential antitrypanosomal agents. Kinetoplastid biochemistry offers numerous opportunities for the development of chemotherapeutic agents having a high degree of selective toxicity. Trypanothione, the
N
1
,
N
8
‐bis(glutathionyl)spermidine metabolite that replaces glutathione in redox protection reactions in kinetoplastids, is one hopeful target for drug design. A second possible target is the kinetoplastid organelle named the glycosome. African trypanosomes and perhaps other kinetoplastids are highly dependent on glycolysis for energy production. Enclosing the enzymes for glycolysis in glycosomes increases the efficiency of glycolysis compared to its rate in mammalian cells. Any potent inhibitor of an enzyme contained in the glycosome, or of any of the biochemical processes associated with glycosomal function, might be an effective drug against these parasites.
Structure‐Based Drug Design
Authors: Hardy Larry W. , Abraham Donald J. , Safo Martin K.
Published: November 2003

Structure‐based drug design is achievable by exploiting the three‐dimensional information intrinsic in structural models of proteins that are involved in human disease. Many other tools (biochemistry, cellular and whole‐animal biology, organic synthesis, pharmaceutics, and computational analysis) must by tightly integrated to fulfill the promise of the structure‐based approach, and the use of this approach does not automatically guarantee success. However, the successes that have been achieved make it clear that structure‐based methods provide an efficient, effective, and elegant approach to medicinal chemistry. Examples are described in this chapter of the use of structure‐based methods in designing compounds that have entered human clinical trials and, in many cases, were launched as products. Some of the lessons that have been learned about best practices in the application of structure‐based methods are summarized.
Phenotypic abnormalities: Terminology and classification
Authors: Merks Johannes H.M. , van Karnebeek Clara D.M. , Caron Hubert N. , Hennekam Raoul C.M.
Published: November 2003

Clinical morphology has proved essential for the successful delineation of hundreds of syndromes and as a powerful instrument for detecting (candidate) genes (Gorlin et al. [2001]; Syndromes of the Head and Neck; Oxford: Oxford University Press. 1 p]. The major approach to reach this has been careful clinical evaluations of patients, focused on congenital anomalies. A similar careful physical examination performed in patients, who have been treated for childhood cancer, may allow detection of concurrent patterns of anomalies and provide clues for causative genes. In the past, several studies were performed describing the prevalence of anomalies in patients with cancer. However, in most studies, it was not possible to indicate the biologic relevance of the recorded anomalies, or to judge their relative importance. Are the detected anomalies common variants, and should they thus be regarded as normal, or are they minor anomalies or true abnormalities, indicating a possible developmental cause? Classification of items in the categories of common variants (disturbances of phenogenesis with a prevalence >4%), minor anomalies (disturbances of phenogenesis with a prevalence ≤4%), and malformations (disturbances of embryogenesis) should allow weighing the importance of the scored items in the population under study, and should facilitate assessment of developmental disturbances (if any) in a study group. The lack of published consensus in the literature led us to produce a classification list with a twofold goal. First, we wanted to enhance uniformity in the scoring and classification of apparently abnormal physical findings by a nomenclature for errors of morphogenesis detectable on surface examination, and secondly a uniform classification system. This should allow investigators to evaluate systematically the presence of patterns in phenotypic anomalies, in the general population, and in patients with various disorders, suspected to be a developmental anomaly. Also, normal values may be obtained this way. Second, the list will allow a determination of the importance of the collected symptoms in a study population. We tested the feasibility of the application of the classification list in a study population: the list was piloted in a group of patients who have had cancer as a child, to detect patterns of anomalies related to specific types of tumors. © 2003 Wiley‐Liss, Inc.
Coloboma and other ophthalmologic anomalies in Kabuki syndrome: Distinction from charge association
Authors: Ming Jeffrey E. , Russell Karen L. , Bason Lynn , McDonald‐McGinn Donna M. , Zackai Elaine H.
Published: November 2003

Kabuki (Niikawa–Kuroki) syndrome is associated with growth retardation, developmental delay, congenital heart disease, cleft palate, and characteristic facial features. Although the external appearance of the eyes has been well‐described, the type and frequency of structural and functional eye anomalies has not been emphasized. We report three children with Kabuki syndrome who also had a retinal coloboma. A diagnosis of CHARGE association was initially suggested in two of the patients before the typical facial features of Kabuki syndrome emerged. A detailed review of reported cases of Kabuki syndrome shows that a variety of eye anomalies are associated with Kabuki syndrome. The incidence of coloboma is greatly increased in Kabuki syndrome. Thus, ophthalmologic abnormalities are frequently associated with Kabuki syndrome, and an ophthalmologic evaluation should be performed for each patient. Phenotypic overlap, including congenital heart, ear, and renal defects, can lead to the diagnosis of CHARGE association, especially since the typical facial features of Kabuki syndrome may not be apparent in early infancy. Thus, Kabuki syndrome should be considered in patients with coloboma if other features consistent with this condition are present, and follow‐up evaluations are indicated for establishing the proper diagnosis. © 2003 Wiley‐Liss, Inc.