bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anticoagulants, Antithrombotics, and Hemostatics
Authors: Bisacchi Gregory S. 
Published: November 2003

AbstractMaintenance of proper blood flow is a complex and highly regulated physiological process, with multiple complementary and opposing mechanisms of control. Imbalances in these mechanisms can lead to a variety of pathological consequences, such as hemorrhage or obstructive clot (thrombus) formation in veins or arteries, leading to stroke, pulmonary embolism, heart attack, and other serious conditions. One of the overriding challenges with current or future drug strategies for antithrombotic, thrombolytic (clot dissolving), and hemostatic therapy is the precise correction of the pathologic imbalance without overcompensating and thus creating safety issues. Unfractionated heparin is widely used as an anticoagulant, but is being replaced in many of its applications by currently available alternative parenteral agents such as the low molecular weight heparins and the direct thrombin inhibitors. These efficacious alternative agents offer advantages in terms of more predictable pharmacokinetics and improved safety, thereby reducing or eliminating the need for patient monitoring and reducing or eliminating the risk of heparin‐induced thrombocytopenia. Orally bioavailable direct thrombin and/or Factor Xa inhibitors now under development seem poised to become available over the next several years and will represent viable alternatives to both the parenteral anticoagulants and to warfarin, the only currently available oral anticoagulant. These agents promise the convenience of an oral drug without the need of intensive patient monitoring, as warfarin requires. Other therapeutic targets under current investigation for anticoagulation include Factor VIIa and Factor IXa. Antiplatelet agents such as aspirin, clopidogrel, and the parenteral GPIIb/IIIa antagonists are valuable and widely used drugs. New antiplatelet agents that act by already validated mechanisms (e.g., P2Y12receptor antagonism) or that act by mechanisms not targeted by current agents will also likely emerge in the not too distant future. Newer clot‐selective fibrinolytics have advantages over older agents such as streptokinase. Fibrinolytic agents still in development may offer further improvements in terms of safety and longer plasma half‐life.
Inhibition of Sickle Hemoglobin Polymerization as a Basis for Therapeutic Approaches to Sickle‐Cell Anemia
Authors: Noguchi Constance Tom , Schechter Alan N. , Haley John D. , Abraham Donald J. 
Published: November 2003

AbstractThis chapter reviews current understanding of the molecular and cellular basis of the pathophysiology of sickle‐cell anemia, with emphasis on the biophysics of the intracellular polymerization of sickle hemogobin. Factors that modify the severity of the disease manifestations, primarily by altering polymerization tendency, are discussed. This framework is used to present an overview of the major rational approaches to the therapy of sickle‐cell anemia based on inhibiting polymerization with agents that affect either the hemoglobin molecule or the sickle erythrocyte. Discussion of agents that may decrease vascular entrapment of sickle erythrocytes is also presented. Detailed review of the most important current approaches to therapy—pharmacologically elevating fetal hemoglobin—focuses primarily on hydroxyurea, the only drug currently FDA approved for treating sickle‐cell anemia. A brief discussion of other approaches, including stem cell transplantation and gene therapy, concludes the chapter.
Iron Chelators and Therapeutic Uses
Authors: Bergeron Raymond J. , McManis James S. , Weimar William R. , Wiegand Jan , Eiler‐McManis Eileen 
Published: November 2003

AbstractIron is an essential cofactor in a variety of biological redox reactions; life without this metal is virtually unknown. Because of its exceptionally poor solubility in the biosphere, bacteria produce relatively low molecular weight, virtually iron(III)‐specific, ligands, siderophores, for the purpose of acquiring this transition metal. On the other hand, higher eukaryotes generate proteins to acquire and store iron. In humans, the process of iron absorption and processing is very tightly controlled. However, the lack of an efficient means of elimination can, under certain conditions, result in iron overload, which can elicit oxidative tissue damage through the Fenton reaction. Accordingly, chelating agents have been tested over the last several decades for the purpose of rendering excess iron excretable. The currently accepted therapy for global iron overload, as occurs after repeated blood transfusions, is a siderophore, desferrioxamine B (DFO), which is administered subcutaneously as its mesylate salt (Desferal). Two synthetic agents, diethylenetriamine pentaacetic acid (DTPA) and 1,2‐dimethyl‐3‐hydroxypyridin‐4‐one (Ferriprox, deferiprone, L1), have been used for the treatment of iron overload as well. Unfortunately, all three of these ligands have drawbacks. The kinetics and lack of oral bioavailability of DFO require that this compound be administered subcutaneously 12 h/day, up to 6 days/week, a regimen with which many patients find it difficult to comply. The lack of chelating specificity of DTPA restricts its use to those who cannot tolerate therapy with DFO; questions remain unanswered regarding the efficacy and toxicity profile of L1. The ongoing efforts to find a worthy successor to DFO include the use of a synthetic agent,N,N′‐bis(2‐hydroxybenzyl)ethylenediamine‐N,N′‐diacetic acid (HBED), which, although it would require subcutaneous administration, is significantly more efficient than DFO. Another avenue is using siderophores (e.g., desferrithiocin, parabactin) as platforms from which to design either orally or parenterally active iron chelators. Because of the necessity of striking a balance between efficacy (i.e., sufficient iron chelation) and toxicity (i.e., excessive iron removal), drug development in the arena of iron chelation therapy presents unique challenges. However, the application of sensible drug design principles predicated on our understanding of iron metabolism, modern synthetic techniques, and the use of appropriate animal models should bring about improved therapeutic agents for the treatment of both global and focal iron overload in the years to come.
Thyroid Hormones and Thyromimetics
Authors: Ryono Denis E. , Grover Gary J. , Mellstrom Karin 
Published: November 2003

Abstract
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

AbstractSteroids 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

AbstractSubstances 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

AbstractThe 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

AbstractWe 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

AbstractOver 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

Abstract

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

AbstractDerivatives 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

AbstractThis 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

AbstractOver 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

AbstractSynthetic 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

AbstractThe 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

AbstractVarious 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

AbstractThis 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

AbstractThe 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.