bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiac Drugs: Antianginal, Vasodilators, and Antiarrhythmics
Authors: Joshi Gajanan S. , Burnett James C. , Abraham Donald J. 
Published: November 2003

AbstractThe development of novel drugs to replace and/or supplement existing therapeutics for treating various cardiac disorders continues to generate significant and growing interest and has evolved hand‐in‐hand with clinical research that has facilitated a better understanding of the underlying causes of cardiac disease. However, even with these new advances and treatments, heart disease remains the number one killer of men and women in the United States—it is estimated that approximately 40% of Americans (∼60 million between the ages of 40–70) have some form of this disease. Since the later half of the 20th century, finding safe and effective means for treating increasing incidences of heart disease worldwide has been at the forefront of the medical community's consciousness. This concern has sparked the discovery and development of a wide range of cardiac drugs, which continue to account for a large portion of sales in the pharmaceutical industry. A constant flow of new cardiovascular drugs, with greater potency and improved safety profiles, will continue to provide physicians with the means for treating cardiovascular diseases in the future. Importantly, the first draft of the human genome is a turning point in the search for new medications that will address the causes, versus the symptoms, of many human ailments—including cardiovascular diseases. This chapter is designed to serve as a general reference and reviews past treatments, significant new developments, and future trends in the development of antianginal, vasodilating, and antiarrhythmic therapeutics.
Diuretic and Uricosuric Agents
Authors: Fink Cynthia A. , McKenna Jeffrey M. , Werner Lincoln H. 
Published: November 2003

AbstractHerein is presented the development and therapeutic use of diuretic agents, a topic that constitutes one of the most significant advances in medicine made during the twentieth century. Diuretics are among the most frequently prescribed therapeutic agents for the treatment of edema, hypertension, and congestive heart failure and they act primarily by inhibiting the reabsorption of sodium ions from the renal tubules in the kidney. Recent advances in renal and ion‐transport research have led to a more precise understanding of the cellular mechanisms of actions of the various classes of diuretic agents. This understanding has aided the design of newer and more effective agents. Today diuretics are grouped as loop, potassium‐sparing, thiazide, or osmotic diuretics and include compounds that have combined diuretic and uricosuric properties. Uricosuric agents increase the excretion of uric acid, a principal product of purine metabolism; and because hyperuricemia is an adverse effect sometimes observed with diuretic treatment, arising from decreased extracellular volume and increased urate reabsorption, this combined property is advantageous. However, given that diuretics themselv are convenient, inexpensive, and generally are well tolerated, they will probably continue to play a role in the treatment of hypertension.
Antihyperlipidemic Agents
Authors: Sierra Michael L. 
Published: November 2003

AbstractCoronary heart disease (CHD) is the leading cause of morbidity and mortality in developed nations and atherosclerotic cardiovascular disease accounts for approximately half of all deaths attributed to CHD. Dyslipidemia, including hypercholesterolemia, hypertriglyceridemia, and hypoalphalipoproteinemia, is a major risk factor for CHD. Clinical studies have demonstrated the link between elevated serum cholesterol and coronary disease. Randomized controlled studies investigating the benefit of therapies that lower serum levels of low density lipoprotein cholesterol have demonstrated improvements in coronary morbidity and mortality in patients with or without diagnosed CHD. Furthermore, data are accumulating based on the VA‐HIT trial and several other ongoing trials with fibrates that the treatment of high serum triglycerides and low concentrations of high density lipoprotein cholesterol can also lead to improvements in coronary morbidity and mortality. This review discusses the development of the HMG‐CoA reductase inhibitors and how they have, thanks to their excellent efficacy and good safety profile, revolutionized the clinical management of hypercholesterolemia. Other treatments such as fibrates, bile acid sequestrants, cholesterol absorption inhibitors, and nicotinic acid derivatives as well as new emerging treatments are also discussed.
Oxygen Delivery by Allosteric Effectors of Hemoglobin, Blood Substitutes, and Plasma Expanders
Authors: Campanini Barbara , Bruno Stefano , Raboni Samanta , Mozzarelli Andrea 
Published: November 2003

Abstract
The blood is a complex body fluid containing a large variety of cells and molecules serving vital functions. In particular, hemoglobin, contained in the red cells, loads, carries, and delivers oxygen and carbon dioxide in the circulation. In the last 30 years intense efforts have been made (1) to develop allosteric effectors of hemoglobin that affect oxygen affinity to treat diseases such as sickle‐cell anemia, ischemia, hypoxia, and to improve the efficiency of radio‐ and chemotherapy; (2) to obtain blood substitutes based either on organic molecules that solubilize oxygen or on genetically and/or chemically modified hemoglobins; and (3) to formulate solutions that maintain the blood volume and oncotic pressure in surgery and hemorrhagic events. In spite of the pharmacological relevance of these molecules, only plasma expanders are already available on the U.S. market. This is an indication of the difficulties in mimicking the multifaceted roles of hemoglobin.
Chemokine and Cytokine Modulators
Authors: Fuentes Maria Elena , Mirzadegan Tara , Wilhelm Robert S. 
Published: November 2003

AbstractThe ability to respond to exogenous stimuli is a key characteristic in the survival of multicellular organisms. Both chemokines and cytokines participate in this process with different mechanisms. Chemokines are mostly involved in chemoattraction of different cell types to inflamed tissues. Cytokines, on the other hand, regulate gene expression in a wide variety of cell types. Both types of molecules are mostly inducible, although some participate in homeostatic processes. Chemokines exert their action through the activation of seven‐transmembrane spanning receptors also called G‐protein‐coupled receptors. Cytokine receptors are usually formed of two or more single‐spanning membrane subunits and phosphorylation is crucial in the signaling cascade. Because of the nature of the receptors, significant information is available regarding attempts to block chemokine receptors with small molecule antagonists. The situation is quite different for cytokine receptors, in which most of the antagonists described so far are either receptor antibodies or soluble receptors. In this chapter we summarize data available for both families.
COX‐2 Inhibitors and Leukotriene Modulators
Authors: Bell Randy L. , Harris Richard R. , Stewart Andrew O. 
Published: November 2003

AbstractAgents that modulate the effects of eicosanoids have proved to be important therapeutics. In the early 1990s a number of agents that modulate the actions or synthesis of leukotrienes were optimized and tested in asthma. This major effort provided for the approval of two CYSLT1 antagonists, montelukast and zafirlukast; and one 5‐lipoxygenase inhibitor, zileuton, which proved effective in the treatment of asthma. More recently, the breakthrough discovery of a second cyclooxygenase isozyme, COX‐2, provided the impetus for the discovery of selective COX‐2 agents. These agents, which include celecoxib, rofecoxib, and valdecoxib, have been shown to have significant anti‐inflammatory and analgesic effects while being gastric sparing, in contrast to nonselective cyclooxygenase inhibitors commonly referred to as NSAIDs. The gastric‐sparing properties of these agents and others currently in development should open new therapeutic modalities. One of the most exciting of these is in the prevention and treatment of cancer.
Agents Acting on Prostanoid Receptors
Authors: Jenkins David W. , Humphrey Patrick P.A. , Coleman Robert A. 
Published: November 2003

Abstract

The prostaglandins and thromboxanes comprise a family of C
20
fatty acids, known as the prostanoids. They are primarily synthesized from arachidonic acid and exert a multitude of physiological and pathophysiological actions through the activation of membrane‐bound receptors. The current scheme of prostanoid receptor classification proposes receptors for each of the naturally occurring prostanoids and was originally based on comparisons of prostanoid receptor agonist and antagonist potencies in functional preparations. This scheme has been confirmed and expanded by the use of molecular techniques, which have led to the cloning of the known prostanoid receptors and also the discovery of a number of prostanoid receptor subtypes and isoforms. Many compounds with varying potencies and selectivities at the known prostanoid receptors have been synthesized, although few have proved highly valuable in the clinic. The use of prostanoids in clinical practice has been largely limited to those occurring naturally, where they are used predominantly as abortifacients and in the induction of labor. Several synthetic analogs have also been used for these and other purposes, including the treatment of gastric ulcers and glaucoma. Hopefully, the next few years will lead to the further discovery of new prostanoid receptor ligands that will become successful medicines.
Vitamins
Authors: Block John H. 
Published: November 2003

AbstractVitamins are essential components of the diet that are required in small amounts. Biochemical processes cannot operate without them. Vitamins have a variety of functions and some have dual roles. Vitamin A (retinol) is both a regulator of cell division and a structural component of the visual pigment rhodopsin. Vitamin D (cholecalciferol) is a hormonal regulator of calcium transport and cell division. Vitamin K is a coenzyme for carboxylation of glutamic acid. Vitamin E (α‐tocopherol) is a lipid‐soluble antioxidant. Thiamine (vitamin B1) is a coenzyme for decarboxylation of α‐keto acids and transketolase reactions in carbohydrate metabolism. Riboflavin (vitamin B2) is the active portion of the coenzymes FMN and FAD. Niacin and niacinamide are the active portions of the coenzymes NAD and NADP. The pyridoxine group (vitamin B6), as pyridoxal phosphate (PLP), is the coenzyme for amino acid metabolism, including transaminations and decarboxylations. Pantothenic acid is a structural component of coenzyme A. Biotin is a coenzyme for four carboxylation reactions. Folic acid, as tetrahydrofolate, is a coenzyme for one‐carbon metabolism. Vitamin B12(cobalamin), with folic acid, is required for regeneration of methionine and, singly, is the coenzyme required for the rearrangement of methylmalonyl CoA. Ascorbic acid is a general free‐radical scavenger and required for at least eight biochemical reactions requiring oxidations.
Lifestyle and Over‐the‐Counter Drugs
Authors: Abu‐Izza Khawla , Li Vincent , Parr Graham 
Published: November 2003

AbstractThis chapter attempts to show how lifestyle drugs and over‐the counter (OTC) drugs relate to each other and the challenges that they face. It also traces the history of OTC drugs and regulations, shows how the OTC Review process works, and shows how the United States, Europe, and Japan classify OTC drugs. It briefly explains the three major criteria for Rx‐to‐OTC switch—safety, labeling, and effectiveness. The chapter also provides an overview and a generalized definition of lifestyle drugs. Four examples of lifestyle drugs are provided: hair growth drugs, smoking cessation drugs, sexual disorder drugs, and sunscreens. The selected examples cover both prescription only and OTC lifestyle drugs. The chapter ends with a look into the future for OTC and lifestyle drugs.
Microarrays and Gene Expression Profiling Applied to Drug Research
Authors: Windle Brad , Guiseppi‐Elie Anthony 
Published: November 2003

AbstractDNA microarray technology combines the recent advances in genome sequence availability with high‐speed robotics. Arrays of gene sequences representing entire genomes, including the human genome, have been produced, allowing the analysis of expression for all genes in a genome in a single experiment. Global gene expression profiles of cells are being explored in a broad range of biomedical applications, from identifying cell lineages to predicting response to therapy in patients. The basic principles of microarray fabrication and analysis are presented in this chapter. Current applications of gene expression profiling to drug development, including target identification, and mechanism of action are reviewed. Finally, the potential for new applications of this technology in drug discovery and development is discussed.
SNPs: Single Nucleotide Polymorphisms and Pharmacogenomics—Individually Designed Drug Therapy
Authors: Puckett Brian J. , Terra Steven G. , Walker Joe 
Published: November 2003

AbstractPharmacogenomics is a rapidly expanding field aimed at understanding interpatient variability in drug response through the exploration and investigation of the human genome. It is an incontrovertible fact that large interpatient variability exists in response to medications. Variation in response has existed as long as medications have been used for the prevention and treatment of disease. In many ways, the field of pharmacogenomics began serendipitously in the 1950s after seminal observations describing variability in response to medications. Examples included peripheral neuropathy from isoniazid among slow acetylator, prolonged apnea from succinylcholine caused by pseudocholinesterase deficiency, and severe hypotension from debrisoquine among cytochrome P450 (CYP) 2D6 poor metabolizers. For the next 40 years, pharmacogenetic studies focused almost exclusively on the etiologies of altered variability in pharmacokinetic responses to medications. As we entered the 1990s, pharmacogenomic studies began to include studies that examined pharmacodynamic variability in drug response. Now instead of examining only differences in drug metabolizing enzymes, scientists began to focus on genes that encode drug transporters, drug targets, and ion channels. The ultimate goal of pharmacogenomics is to be able to accurately predict, based on an individual's genomic information, which medications will provide the greatest benefit with the least harm, thus transforming medicine into an era of personalized therapeutics. This chapter provides a review of pharmacogenomics and how single nucleotide polymorphisms may impact pharmacotherapy and drug discovery. The chapter further explores the abundant recent literature as well as provides insight into some of the issues, limitations, and ethical considerations of pharmacogenomics.
Plasmid DNA–Mediated Gene Therapy
Authors: Banerjee Rajkumar , Huang Leaf 
Published: November 2003

AbstractNon‐viral gene delivery has earned a special position in gene therapy because of its less immunogenic and less toxic effect than the viral counter part. One of the methods is direct injection of naked DNA to the organs of interest. Plasmid DNA (pDNA) that carry recombinant genes of interest are used for introducing genes to cells and organs. Various physical methods, e.g., gene gun and electroporation, increase the efficiency of the naked DNA incorporation. Lipid‐based vectors have the advantage of protecting the DNA against degradation by endogenous DNAasein vivoand can be targeted to specific cellular site in some special cases. A variety of lipid‐based systems have been designed, mostly containing cationic lipids of different structures. Second‐generation vectors containing polymers are more stable and more targetable than the first‐generation vectors. Although significant progress has been made, non‐viral vectors are still limited by their efficiency and some cytotoxicity inherited in the bacterial pDNA. Understanding mechanisms and means to overcome the cellular barriers for the DNA delivery will undoubtly promote further development of pDNA mediated gene delivery.
Selective Toxicity
Authors: Block John H. 
Published: November 2003

Abstract
Most drugs can be considered toxic in that they replace the natural ligand for a receptor. A goal in drug design is to develop a molecule that is selective for a particular receptor located on a specific target organ or tissue. The molecule also will show selectivity for the target organism whether it is a mammal, bacterium, fungus, virus, parasite, or insect. Therefore, an ideal biologically active molecule will produce a specific pharmacological response without causing adverse reactions. There are at least four ways to improve a drug's selectivity. These methodologies are based on the biochemistry of the disease or the biochemistry of the drug's receptor, unequal distribution of the drug, differences in the target cell's structure, and the drug's stereochemical properties. Pharmacological classes differs in their ability to show selectivity. Cancer chemotherapeutic agents generally show poor selectivity, whereas phosphodiesterase inhibitors can be selective for a specific enzyme isoform. Most bacterial antibiotics show excellent selective toxicity for bacteria with minimal serious adverse reactions experienced by the patient. In contrast, antiviral and antifungal drugs can produce untoward reactions in patients. To improve patient acceptance, an important goal is to design the drug such that it be transported to the desired receptor and “ignore” other sites. This chapter reviews methods used to improve drug selectivity.
Antiviral Agents, DNA
Authors: Middleton Tim , Rockway Todd 
Published: November 2003

AbstractThe seven families of DNA viruses that cause disease in humans show tremendous variety in the relationships that they have with their hosts. This variety is reflected both in the disease states that they cause and the approaches used to develop antiviral drugs to treat them. The most successful antiviral tools have been nucleoside analogs, particularly those targeting the polymerases of herpesviruses and hepatitis virus B. The list of nucleoside analog drugs continues to expand as compounds are developed with greater potency or range, better bioavailability, or improved side effect profiles. Other viral targets have started to receive more attention, including helicases, proteases, and enzymes required for virion assembly. These targets should gain in importance as resistance to currently available drugs becomes more prevalent. In addition, expanding the list of viable viral targets is particularly important with regard to members of the parvovirus, papillomavirus, and polyomavirus families, which do not encode a viral polymerase. Some effective antiviral treatments have not targeted the virus but rather the immune response to the viral infection. An optimal immune response is critical to elimination of some classes of viruses, and exploiting this aspect of the host‐virus interaction provides another approach to antiviral drug development.
Rationale of Design of Anti‐HIVDrugs
Authors: Mehanna Ahmed S. 
Published: November 2003

AbstractThe acquired immunodeficiency syndrome disease, abbreviated AIDS, is caused by the retrovirus, human immunodeficiency virus subtype1 (HIV‐1). Infection with the virus leads to severe suppression of the immune system and potential exposure to the so‐called opportunistic infections such as pneumonia, which could be fatal. Most of the currently available anti‐AIDS medications are inhibitors for the reverse transcriptase and protease enzymes. The growing resistance to the currently available drugs requires developing new agents that act by different mechanisms beyond transcriptase and protease inhibition. Treatment of AIDS and development of anti‐HIV agents to stop the virus replication requires acquaintance with various steps of the virus life cycle and the mechanism of how it reproduces itself. The present chapter describes the molecular aspects of the AIDS virus including its structure, molecular biology, and life cycle. Approaches to design anti‐HIV drugs are presented with update on the status of anti‐HIV therapeutic agents in the light of the continuous growing viral mutation.
Anthelmintics
Authors: Griffith Robert K. 
Published: November 2003

Abstract
This chapter discusses the agents currently available for the treatment of helmintic infections in humans. Current therapy for helmintic infections is dominated by praziquantel, benzimidazoles, and ivermectin. Praziquantel is the drug of choice for trematode infections including all types of schistosomiasis and various flukes. Ivermectin is the drug of choice for onchocerciasis and most other forms of filariasis, often used in combination with albendazole. Benzimidazoles are drugs of choice for most infections caused by nematodes. Unfortunately, no significant new classes of anthelmintic drugs have been introduced in nearly 20 years.
Adrenergics and Adrenergic‐Blocking Agents
Authors: Griffith Robert K. 
Published: November 2003

Abstract

This chapter reviews the drugs currently available in the United States that exert their therapeutic effects through actions on α‐ and β‐adrenoceptors and biosynthesis, release, and processing of the neurotransmitter norepinephrine. Included in the review are drugs acting as selective and nonselective agonists and antagonists at both α‐ and β‐adrenoceptors, as well as drugs that interfere with norepinephrine biosynthesis and release. Therapeutic categories include antihypertensives, bronchodilators, antiglaucoma agents, vasopressors, and nasal decongestants. Structure‐activity relationships are reviewed as are the structure and function of various adrenoceptors. Briefly covered is the metabolism of representative drugs in each structural class as well as recent developments in approaches to new drugs in the areas of selective α
1A
‐antagonists for treatment of prostatic hypertrophy and selective β
3
‐agonists for treatment of obesity and diabetes.
Cholinergics
Authors: Cannon Joseph G. 
Published: November 2003

AbstractThe transmission of impulses throughout the cholinergic nervous system is mediated by acetylcholine, and compounds that produce their pharmacologic effects by mimicking or substituting for acetylcholine are called cholinergics or parasympathomimetics. Compounds that inhibit or inactivate the body's normal hydrolysis of acetylcholine by acetylcholinesterase in nervous tissue and/or by butyrylcholinesterase (pseudocholinesterase, cholinesterase) in the plasma are called anticholinesterases. The gross observable pharmacological effects of both types of compounds are quite similar. More recently, compounds have been found that enhance the release of acetylcholine from cholinergic nerve terminals, thus (like the anticholinesterases) producing cholinergic effects by an indirect mechanism. These concepts are discussed in this chapter.