bluuebunny/crossref_metadata_2025 huggingface dataset:
Mass Spectrometry and Drug Discovery
Authors: van Breemen Richard B. , Newsome Andrew G. , Dahl Jeffrey H.
Published: September 2010

In the twenty‐first century, medicinal chemists are producing large numbers of organic compounds through a process called combinatorial chemistry and then testing them against pharmacological targets such as enzymes or receptors using high‐throughput screening. As a result, lead compounds can emerge from drug discovery programs in a few weeks instead of several years. Although a variety of spectroscopic and chromatographic techniques are used to support drug discovery, only HPLC or UHPLC combined with mass spectrometry (LC‐MS) are compatible with virtually all drug‐like molecules. In addition to providing a universal means to characterize drug molecules based on molecular mass and structural features, mass spectrometry provides high throughput. With the development of routine LC‐MS interfaces and ionization techniques such as electrospray and atmospheric pressure chemical ionization, mass spectrometry has also become an ideal HPLC detector for the analysis of combinatorial libraries. Furthermore, a variety of mass spectrometry‐based screening assays have been developed to screen complex mixtures of compounds including natural product extracts as a means of expanding the molecular diversity of drug leads. The use of mass spectrometry in support of combinatorial library synthesis and purification is addressed as well as screening applications such as frontal affinity chromatography‐mass spectrometry, gel permeation chromatography‐LC‐MS, affinity chromatography‐mass spectrometry, and pulsed ultrafiltration mass spectrometry. Since drug development issues such as metabolic stability and the formation of reactive metabolites are now being considered during the drug discovery process, some applications of mass spectrometry to early drug development are addressed.
Membrane Transport Proteins and Drug Transport
Authors: Swaan Peter W.
Published: September 2010

To exert their intended therapeutic goal, drugs need to cross epithelial barriers to reach their site of action. Transport proteins have critical physiological roles in nutrient absorption and transport of endogenous compounds. These systems can serve as useful pharmacological targets and may be used as a mechanism to increase drug absorption. However, we have little understanding of these proteins at the molecular level because of the absence of high resolution crystal structures. Numerous efforts have been made to characterize the P‐glycoprotein efflux pump, the peptide transporter PepT1, and the apical sodium‐dependent transporter, which are important not only for their native transporter function but also as drug targets to increase absorption and bioactivity.In vitroand computational approaches have been applied to gain some insight into these transporters with some success. This represents an opportunity for optimizing molecules as substrates for the solute transporters and providing a further screening system for drug discovery. Clearly the future growth in knowledge of transporter function will be led by integratedin vitroandin silicoapproaches.
Drug Transport and Membrane Transport Proteins
Authors: Swaan Peter W.
Published: September 2010

In order to exert their intended therapeutic goal, drugs need to cross epithelial barriers to reach their site of action. Transport proteins have critical physiological roles in nutrient absorption and transport of endogenous compounds. These systems can serve as useful pharmacological targets and may be utilized as a mechanism to increase drug absorption. However, there is little understanding of these proteins at the molecular level due to their resistance to crystallization. Numerous efforts have been made to characterize the P‐glycoprotein efflux pump, the peptide transporter (PepT1), and the apical sodium dependent transporter (ASBT), which are important not only for their native transporter function but also as drug targets to increase absorption and bioactivity.In vitroand computational approaches have been applied to gain some insight into these transporters and their substrate specificities. This represents an opportunity for optimizing molecules as substrates for solute transporters and providing a further screening system for drug discovery. This chapter will demonstrates that future growth in knowledge of transporter function will be lead by integratedin vitroandin silicoapproaches.
Allosteric Proteins and Drug Discovery
Authors: Bell J. Ellis , Bell Jessica K.
Published: September 2010

The existence of allosteric phenomena in the control of proteins allows for exquisite control of many of the cell's normal processes. Allosteric interactions involve the binding of an “allosteric” ligand to a site other than the functional (active) site of the protein, with a concomitant alteration in activity. Two major theoretical models have been presented to explain allosteric interactions, that of Monod, Wyman, and Changeux and that of Koshland, Nemethy, Filmer, Dalziel, and Engel. Although there are essential differences between the two models, both require that allosteric ligands interact with one or more forms of the protein to trigger a modulating effect. In only a few cases, much structural detail is known about more than one conformational state of any given allosteric protein, or how the binding of small‐molecule effectors to an allosteric site triggers protein modulation. Our current understanding of how conformational signals may be transmitted between proteins is assessed, particularly in the light of recent discussion of intrinsically disordered regions of proteins. Methods for identifying potential ligands that may elicit allosteric effects is also discussed. In this chapter, the essential features of allosteric enzymes and allosteric models are examined in a context that leads to consideration of how drugs may be designed such that they either mimic or block normal allosteric effects. Several existing “allosteric” drugs, and a number of potential targets for the rationale design of future allosteric drugs, are discussed.
Large‐Scale Synthesis
Authors: Gupton Frank
Published: September 2010

The capability to fulfill drug substance requirements to support the various elements of pharmaceutical development is an essential component of the overall drug development process. The preparation of bulk materials for toxicology, formulation development, and clinical supplies can represent a significant challenge, depending on such factors as the molecular complexity of the drug candidate, the quantities of materials required, and the state of development of the synthetic process. As a drug candidate proceeds through the various stages of drug development and into commercial launch, the challenge of process development is to ensure the uninterrupted supply of drug substance without compromising the ability to ultimately supply a commercially viable chemical process. This chapter provides a general overview of the issues and requirements associated with the development and scale‐up of chemical processes for bulk active drug substances. An account of the nevirapine process development efforts at Boehringer Ingelheim is also provided as an example of the evolution of a chemical process from the initial efforts in medicinal chemistry to commercial‐scale operations.
Physicochemical Characterization and Oral Dosage Form Selection Based on the Biopharmaceutics Classification System
Authors: Amidon Gregory E. , He Xiaorong , Hageman Michael J.
Published: September 2010

Identifying an active lead molecule, selecting a viable drug candidate and developing a marketable product are profoundly influenced by molecular properties and dosage form design. This chapter discusses the importance of a molecule's physicochemical properties and the link with oral dosage form design strategies. The Biopharmaceutics Classification Scheme (BCS) is used to identify oral dosage form options that have the best chance of overcoming drug delivery problems. Physicochemical characterization not only can guide the selection of formulation strategies but also, if incorporated into the lead selection process, can influence analog selection and lead optimization. The end result of considering physicochemical properties is to reduce the risk of failure by facilitating the identification of appropriate dosage form design options and, at the same time, allow discovery chemists to maximize chances of identifying commercially viable leads.
SyntheticDNA‐Targeted Chemotherapeutic Agents And Related Tumor‐Activated Prodrugs
Authors: Denny William A.
Published: September 2010

Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. The original antimetabolites such as cytosine arabinoside and 5‐fluorouracil have been augmented by more recent compounds such as gemcitabine, fludarabine, cladribine, and pentostatin, which inhibit DNA polymerase action during DNA synthesis. A new development is the related compounds deazacytidine and decitabine, which inhibit reactivate silenced genes by inhibition of cytosine methylation. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents are direct DNA‐modifying agents that still play an important role in clinical treatment. 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. 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 whose therapeutic effects are due to enzyme‐mediated DNA modification. 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 nontumor cell populations.
Medicinal Chemistry Approaches for Multitarget Drugs
Authors: Morphy Richard , Rankovic Zoran
Published: September 2010

It has become increasingly well recognized that modulating multiple biological targets in parallel can be beneficial for treating diseases with complex etiologies such as cancer, asthma, and psychiatric diseases. Both screening and knowledge‐based strategies have been used for generating ligands with a specific multitarget profile (designed multiple ligands or DMLs). DML projects are often challenging for medicinal chemists, with the need to appropriately balance affinity for two or more targets while obtaining physicochemical and pharmacokinetic properties that are consistent with the administration of an oral drug. The physicochemical properties of DMLs are influenced to a large extent by the proteomic superfamily to which the targets belong and the lead generation strategy that is pursued. Since DML projects are resource hungry, an early assessment of the feasibility of any given DML project is essential.
Protein–Protein Interactions as Drug Discovery Targets
Authors: Dömling Alexander
Published: September 2010

Protein–protein interactions (PPIs) recently have been recognized as a major class of drug targets. Many of the successful “classical” biotechnology protein drugs are agonists or antagonists of PPIs and there are established pathways for their development. However, small molecular weight compounds as antagonists of PPIs still pose a major problem to discovery due to the inherent physicochemical properties of their targets. Recently, several small molecular weight antagonists of PPIs advanced into clinical trials and thus comprise a proof‐of‐concept to this young area in medicinal chemistry. This chapter summarizes the area of small molecular weight antagonists of PPIs with a focus on recent success stories. After a short introduction into the structural biology of PPIs, recognized important PPI targets, discovery pathways of their inhibitors are discussed. The PPI p53‐Mdm2 with potential applications in cancer is used as a case study to demonstrate to diversity of approaches leading to many different lead structures. In contrast, the discovery of IL‐2/IL‐2 rec. antagonists is discussed to highlight adaptive high affinity binding to hotspot regions.
QM
and
QM
/
MM
Approaches to Evaluating Binding Affinities
Authors: Shaw Katherine E. , Woods Christopher J. , Mulholland Adrian J.
Published: September 2010

Binding free energy predictions have the potential to play pivotal roles in the drug discovery process, ranging from aiding selection of hit molecules from large databases of compounds to optimizing lead structures. Calculation of relative binding free energies from molecular simulations (e.g., molecular dynamics or Monte Carlo simulations), though computationally intensive, have proved their worth in a number of pharmaceutical applications. Despite this, it is now clear that, in many cases, the methods typically used in such simulations to model molecular interactions have significant limitations. For example, in protein–ligand systems in which charge transfer or polarization are important, or where a metal ion is present in the binding site, conventional molecular mechanics (MM) methods may not represent binding accurately. Methods based on quantum mechanics (QM), for all or part of the system, are potentially more accurate. This chapter reviews recent advances in the growing field of calculating or predicting binding free energies using a quantum mechanical (i.e., quantum chemical, electronic structure) treatment of all or part of the system, for example, a QM description of the ligand alone (or with part of the binding site), coupled to a MM treatment of the protein (QM/MM calculations) or a QM description of the entire protein–ligand complex.
Pharmacophores
Authors: Martin Yvonne C.
Published: September 2010

A pharmacophore is a hypothesis of the 3D shape and electrostatic features that a molecule must possess in order to have a particular biological activity. The hypothesis may derive either from the 3D structure of a macromolecule–ligand complex or from the structure–activity relationships of ligands. The contribution briefly describes how the pharmacophores are generated. Tables, each with more than 30 examples, summarize the results of the application of ligand‐based and structure‐based methods to the identification of novel biologically active compounds during 2006–2008.
Protein Flexibility in
In Silico
Screening
Authors: Gohlke Holger , Kopitz Hannes
Published: September 2010

We summarize computational approaches in structure‐based ligand design (SBLD) and
in silico
screening that address issues of protein flexibility and mobility. In particular, we consider how protein plasticity can be incorporated into docking strategies. As a first requirement, one needs to detect what can move and how. Moving protein parts can be identified from experimental information as well as established computational techniques such as molecular dynamics (MD) simulations, graph theoretical and geometry‐based approaches, or harmonic analysis‐based methods. Second, this knowledge needs to be transformed into a docking algorithm. A multitude of approaches considering protein mobility has been introduced recently, with motions modeled either implicitly or explicitly. In the latter case, one can further distinguish between modeling of side‐chain‐only motions and motions including backbone changes. In all cases, accuracy needs to be balanced against efficiency. Case studies for which the inclusion of protein plasticity was crucial to success are noted along these lines. This allows us to identify scope and limitations of the current approaches, as well as guidelines for further developments.
Cost‐Effectiveness Analyses Throughout the Drug Development Life Cycle
Authors: Arnold Renée J.G.
Published: September 2010

Cost‐effectiveness analysis (CEA) is a systematic, quantitative method for summarizing health benefits and health resources of various treatment options into single numbers or ratios so that policy makers can choose among them. Computer modeling of cost‐effectiveness may play a significant role in informing the pharmaceutical decision‐making process throughout a product's life cycle, increasing the likelihood of reimbursement and broad use.
The Role of Permeability in DrugADME/PK, Interactions and Toxicity, and the Permeability‐Based Classification System (PCS)
Authors: Fagerholm Urban
Published: September 2010

Permeability (Pe) is one of the key determinants in the absorption, distribution, metabolism, excretion/pharmacokinetics (ADME/PK) of drugs and their metabolites. Predictions of ADME/PK, interactions, elimination routes, exposures, and toxicity require, therefore, that the role of permeability in different organs is considered, investigated and understood. That includes studies of and knowledge about the relation betweenPeand fraction absorbed (fa) (or fraction reabsorbed;fra) in various organs, and the interplay between passive permeability and active permeability, metabolism and solubility/dissolution. Relationships between passivePeandfain the human intestine, liver, renal tubuli (fra), and brain have been established, and these are the basis of the Permeability‐Based Classification System (PCS). This system demonstrates sigmoidalPeversusfaandfrarelationships of different shapes and shifts, and is divided into four permeability categories (very high/high/intermediate/low). Results show or indicate that the liver and brain have comparably high intrinsic passive uptake capacities, metabolism (rather than uptake, diffusion, and dissociation) is the general rate‐limiting step in hepatic metabolic clearance (CLH), and few high permeability compounds have dissolution‐limited gastrointestinalfa. Active transport processes contribute to the intestinal and hepatic uptake, and renal, biliary, and intestinal drug excretion, of many drugs with limited passivePe. Active transport could be clinically relevant for brain uptake of both low and high passive permeability compounds. Related drug–drug interactions and polymorphism appear most pronounced for drugs actively absorbed and excreted by the liver. Combined with intrinsic metabolic CL data, the PCS is useful for predictions of CLH, renal and biliary excretion potential, gut‐wall extraction ratio, oral bioavailability and effects of polymorphism, and for assessment of potential drug–drug or drug–metabolite interactions, and drug and metabolite organ/cell trapping.
Crystallographic Survey of Albumin Drug Interaction and Preliminary Applications in Cancer Chemotherapy
Authors: Carter Daniel C.
Published: September 2010

An overview of the results of a comprehensive crystallographic structural survey of drug binding to human albumin at atomic resolution is presented. More than 350 complexes were examined, ultimately producing more than 200 structures with representatives in every major therapeutic category. The survey indicated 12 independent drug‐binding locations dominated by the three sites located within subdomains IIA, IIIA, and IB. Site IB, the most structurally accommodating site on albumin, revealed a propensity for large heterocyclic ligands and showed the highest overall binding frequency at 49%. Details of IB ligand‐binding chemistry are presented for several ligands including the camptothecin, anthracyclin, and podophylotoxin families of oncology drugs. The results from the survey were used to establish a therapeutic drug combination approach that favorably alters the albumin‐based pharmacokinetics of several highly cytotoxic oncology drugs leading to marked improvements in safety and efficacy. Examples are presented for selected applications of improving the albumin‐based pharmacokinetics of this information in drug development to improving the safety and efficacy of highly cytotoxic drugs for several important families of oncology drugs.
Nanotechnology in Drug Delivery
Authors: Uchegbu Ijeoma F. , Schatzlein Andreas G.
Published: September 2010

Nanotechnology involves manipulating matter at the nanoscale (<1000 nm); that is, manipulations at less than thousandth of a millimeter, and for drug delivery applications this typically takes the form of creating nanoparticles (5 ∼ 800 nm) that are then used to package drug molecules and genes. By packaging pharmacologically active compounds within nanoparticles, nanomedicines are created. It is possible to control drug biodistribution and achieve therapeutic benefit with these nanomedicines. This chapter outlines the various chemistries and nanomedicine preparation strategies that have been used to produce nanoparticles and highlights the drug delivery benefits that are achievable from these nanoscale arrangements. The chemical compounds used to construct these nanomedicines are as follows: low molecular weight self‐assembling amphiphiles, self‐assembling amphiphilic polymers, polymer–drug conjugates, water insoluble polymers/cross‐linked polymers, dendrimers, and carbon nanotubes. Engineering of these particles has produced nanomedicines that target drugs and genes to tumors and improve the brain delivery of peptides and other molecules. These particles are also capable of promoting oral drug absorption and drug transport across other biological barriers such as the cornea and the skin. Only a few of these technologies are commercially available presently, such as liposomes (e.g., Doxil®), low molecular weight micelles (e.g., Fungizone®), and polymer–drug conjugates (Oncaspar®); but the therapeutic benefits being observed in both preclinical studies and early clinical testing suggest that more of these technologies will emerge into the patient arena in the future.
Antiplatelet Agents
Authors: Chackalamannil Samuel
Published: September 2010

In addition to their life‐sustaining role in hemostasis and wound healing, platelets play a central role in the pathogenesis of coronary artery, cerebrovascular, and peripheral vascular diseases. Under pathologic conditions such as rupture of an atherosclerotic plaque, the platelet activation mechanism and coagulation mechanism synergize in the formation of an occlusive thrombus leading to ischemic disorders such as acute coronary syndrome and stroke. Antiplatelet agents are the mainstay of pharmacological approach for the treatment of ischemic vascular disorders. Platelets have multiple cell‐surface receptors that, upon activation by specific ligands, trigger a cascade of cellular events resulting in the activation of the integrin glycoprotein (GP) IIb/IIIa receptors. Activated GP IIb/IIIa receptors cross‐link with fibrinogen causing platelet to aggregate. Aggregated platelets get trapped by fibrin meshwork, produced by the proteolysis of fibrinogen by thrombin. Cell‐surface platelet receptors have been the target of antiplatelet therapy. For example, aspirin, the most widely used antiplatelet agent, inhibit the biosynthesis of thromboxane A2, the endogenous agonist that activates thromboxane receptors. The ADP antagonists such as clopidogrel and ticlopidine inhibit ADP‐mediated activation of purinergic P2Y12receptors. Glycoprotein IIb/IIIa antagonists such as abciximab, eptifibatide, and tirofiban inhibit GP IIb/IIIa receptors, which involve the final common pathway of platelet aggregation. Phosphodiesterase inhibitors are less widely used antiplatelet agents that potentiate intracellular cyclic AMP levels. Promising newer antiplatelet agents such as thrombin receptor antagonists with reduced bleeding liability, third‐generation thienopyridine ADP antagonists with improved potency and reversible ADP antagonists are at advanced stage of development.
Atherosclerosis
II
:
HDL
Elevation
Authors: Ali Amjad , Hunt Julianne A. , Sinclair Peter J.
Published: September 2010

Atherosclerosis is an arterial disease associated with elevated plasma lipid levels and is a major cause of morbidity and mortality worldwide. Clinical trials have demonstrated that reduction of low‐density lipoprotein cholesterol (LDL‐C), as can be accomplished with HMG‐CoA reductase inhibitors (statins), leads to a reduction in coronary events and mortality by about 25%. Conversely, epidemiological evidence indicates that high‐density lipoprotein cholesterol (HDL‐C) levels have an inverse correlation with risk of coronary artery disease. The beneficial effects of HDL have been attributed to its involvement in the movement of cholesterol from the periphery to the liver as well as to its apparent antioxidant and anti‐inflammatory activities. Consequently, there is much interest in identifying therapeutic approaches to raising HDL that will be useful as a treatment for atherosclerosis and dyslipidemias. The properties and physiologic role of HDL, as well as approaches to increasing plasma HDL concentrations, will be summarized.
Drug Discovery in Non‐Life‐Threatening Disorders: Erectile Dysfunction, Insomnia, and Smoking Cessation
Authors: Rotella David P.
Published: September 2010

Drug discovery for non‐life‐threatening disorders is an active area of medicinal chemistry research. This chapter will describe the discovery and properties of phosphodiesterase 5 inhibitors for erectile dysfunction, the medicinal chemistry of agents for treatment of insomnia, and smoking cessation.
Immunosuppressive Agents for the Prevention of Transplantation Rejection
Authors: Pitts William J.
Published: September 2010

This chapter will focus on “small” molecule therapeutics that demonstrate useful immunosuppressant activity including established classes such as calcineurin inhibitors (cyclosporin A and tacrolimus),mTOR(mammaliantargetofrapamycin) agents (sirolimus, everolimus), and antiproliferative/antimetabolite agents (azathioprine, mycophenolic acid derivatives). This chapter will also introduce some agents with newer pharmacology mechanisms such as sphingosine receptor modulation (FTY720), inhibition of JAK3 (CP‐690,550), and inhibition of PKC θ (AEB071). Other agents useful in organ transplantation including glucocorticoids (such as prednisone and dexamethasone), nitrogen mustards (such as cyclophosphamide), and biologic agents (such as muromonab‐CD3, basiliximab, and daclizumab) are discussed elsewhere.
Natural Products as Cytotoxic Agents
Authors: Cutler Stephen J. , Cutler Horace G.
Published: September 2010

In the first decade of the twenty‐first century, the occurrence of cancers has increased not only in First World countries but also in those countries considered to have a lower standard of living, according to a world cancer report issued in 2008 for the IARC Nonserial Publication by Boyle and Levin. So widespread is cancer, in its various forms, that most adults have either had family members or had friends who have been afflicted by the disease. Projected figures for cancers indicate, in the aforementioned publication, that 12 million cancer cases were diagnosed in 2008 alone and that the number of cancer victims has doubled since 1978. Coupled to the psychological impact that a diagnosis has on an individual is the cost of treatment that must also be considered. Again, according to the National Cancer Institute (December 2008) these costs are estimated to be US$147 billion by 2020. An article, published inUSA Today, claims that new cancer cases in 2008 were projected to be 40,480. And the cost for elderly Medicare patients will be US$21.1 billion for 5 years of treatment for the period 2004–2009. Sadly, one in eight patients with advanced stages of cancer will turn down the offer of recommended care because of costs. While cases may have been misdiagnosed in the twentieth century, the sophisticated techniques available today give a clearer graph of the incidence of the disease. With advanced diagnostics, there has been a concomitant advance in anticancer chemotherapy.
PARP
Inhibitors As Anticancer Agents
Authors: Costantino Gabriele , Pellicciari Roberto
Published: September 2010

Poly(ADP‐ribosyl)ation is posttranslation covalent modification, which is operated by a family of enzymes whose founding member, named PARP‐1, has been involved in a variety of physiological as well as pathological processes. In particular, PARP‐1 is activated by DNA‐strand breaks, and is a key component of the DNA repairing machinery thus acting as a caretaker of genomic stability. Over the last decade, many evidence have accumulated suggesting that PARP inhibitors may find utility as cotherapy with DNA damaging agents in many preclinical models of cancer, and also as monotherapy in some important DNA repair defective tumors. These findings are now translating into clinically useful agents that are undergoing clinical trials. In this chapter, we review the diversity of the PARP family, the significance of poly(ADP‐ribosyl)ation in DNA repairing and the mechanism of PARP inhibitors in cancer therapy. Finally, an overview of the most promising PARP inhibitors under clinical evaluation is given.
TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS
Authors: Ghosh Arun K. , Anderson David D. , Mitsuya Hiroaki
Published: September 2010

Over the past two decades, HIV protease inhibitors have helped revolutionize the treatment of HIV/AIDS transforming this deadly ailment into a more manageable chronic infection. Due to intensive research in the area, a variety of protease inhibitors are now commercially available each of which possesses distinct characteristics and a unique tale of discovery. This manuscript reviews the design and development of the 10 currently available protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and darunavir. Special attention is given to the research efforts leading to their discovery and the successes and limitations of these drugs in the clinics. A brief review of the biology associated with the HIV‐1 protease target is provided in addition to a discussion of novel drug candidates currently under investigation.
β‐Lactam Antibiotics
Authors: Testero Sebastian A. , Fisher Jed F. , Mobashery Shahriar
Published: September 2010

The β‐lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β‐lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β‐lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β‐lactam resistance, alterations to the molecular targets of the β‐lactams (the penicillin binding proteins) and the use of enzymes (the β‐lactamases) capable of the hydrolytic deactivation of the β‐lactams are paramount. This review traces the historical development of β‐lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β‐lactams leading to the discovery of new generation β‐lactam antibacterials effective against the Gram‐negative and ‐positive bacterial pathogens of current medical concern.
Therapeutic Agents for the Treatment of Migraine
Authors: Dubowchik Gene M. , Macor John E.
Published: September 2010

Migraine is a debilitating condition, often with nearly unbearable throbbing pain, nausea, and greatly reduced thresholds to sensory stimulation. Despite the availability of specific acute medications (such as triptans), for over 15 years, migraine remains an undertreated condition. Although representing a revolution in headache therapy at the time, triptans have a number of shortcomings including cardiovascular side effects resulting from their inherent vasoconstrictive properties, and a significant proportion of refractory patients. CGRP antagonists appear to represent the next revolution in migraine therapy, with clinical safety issues shown to be comparable to placebo and 2 h response rates identical to the triptans. Preventative migraine therapy has been dominated by older drugs developed for other indications such as hypertension, epilepsy, and depression. These agents often have significant side effects. Drugs that act on other relevant mechanisms such as ion channels and nitric oxide generation have been developed and tested in the clinic. These have yet to emerge as rivals to the triptans. However, the pathophysiology of migraine is complex and combination therapies that target multiple mechanisms, including one or more of these, may turn out to be more efficacious than monotherapy. An important aspect of migraine therapy that has been addressed with only partial success is speed of onset. Intranasal and pulmonary delivery offer the potential for more rapid systemic exposure and perhaps faster onset of efficacy. Migraine patients are in particular need of improved nonoral drug delivery systems that can provide rapid relief of headache pain along with associated symptoms.
PET
and
SPECT
in Drug Development
Authors: Welch Andy , Pimlott Sally
Published: September 2010

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are noninvasive molecular imaging techniques that can be used to provide functional information in the living human body. They use radiolabeled compounds that bind to specific sites on a biological target, known as radiotracers, enabling us to visualize and characterize specific aspects of a biological process. This chapter describes these techniques and how they can be utilized in the drug development process.
Cotton
Authors: Wakelyn Phillip J. , Condon Brian , Thibodeaux Devron P.
Published: September 2010

Cotton is both a fiber and a food crop that is grown in about 130 countries in the world. About 60 countries cultivate at least 5000 ha and use about 2.5% of the world's total arable land area. In 2009/2010 in the world, about 103 million 217.7‐kg (480‐lb) bales [∼22.4 million metric tons (24.7 million tons)] of cotton fiber and 32.4 million metric tons (35.8 million tons) of cottonseed were produced. Cotton is the most important natural fiber (about 35% of the textile fiber consumed in the world in 2008) used to produce apparel, home furnishings, and industrial products. Cottonseed is one of the world's important oilseeds, used for vegetable oil, animal feed, and linters. About 95% of the world's cotton production is derived from varieties of upland cotton (Gossypium hirsutum) and about 5% is extra long staple cotton (“ELS”;G. barbadense). In 2010 biotech varieties make up more than 60% of the cotton grown in the world. Commercial cottons are white. There has been some interest in organic cotton (∼0.6% of world production) and naturally colored cottons (shades of brown and green are the main colors; only a trace is produced). The demand for more “sustainable” / “ecofriendly” cotton and cotton textiles continues to increase. The origin, biosynthesis, biology, development, production, harvesting, ginning, classification, physical properties, textile processing, morphology, physical structure, chemistry, reactivity, economic aspects, utilization, and health and safety are reviewed.
Graft Copolymers
Authors: Hadjichristidis N. , Pitsikalis M. , Iatrou H. , Driva P. , Chatzichristidi M. , Sakellariou G. , Lohse D.
Published: September 2010

This article deals with the synthesis by different strategies, molecular characterization, solution, and bulk properties as well as potential and industrial applications of graft copolymers.
Thermal Properties
Authors: Thompson Edward V.
Published: September 2010

Thermal properties of polymeric materials are always important and often critical in both processing stages and product uses. Most polymeric substances are processed and fabricated at elevated temperatures, often as a melt, necessitating the transfer of substantial quantities of heat first to the material to reach the desired temperatures and then to return to the formed or cured product to a solidified state at room temperature. This process can be slow and expensive. Heaters and heat‐exchange equipments must be carefully designed to ensure efficient and effective heat transfer. Accurate thermal property data are needed during the formation or curing processes and for the modeling steps such as extrusion or molding. The term thermal properties include a wide range of properties and phenomena. This article gives detailed data on four polymer properties: thermal conductivity, thermal diffusivity, specific heat capacity, and linear thermal expansivity. These properties are sometimes referred to as thermophysical properties.
Orientation
Authors: White James L. , Cakmak Mukerrem
Published: September 2010

The orientation of macromolecules in fabricated and naturally occurring polymers plays an important role in determining their performance, ranging from mechanical to optical characteristics. No laboratory for characterizing polymeric materials can be considered complete if it does not contain tools for characterizing orientation.
Calcium Channels
Authors: Bean Bruce P , McDonough Stefan I
Published: September 2010

Calcium channels are plasma membrane proteins containing calcium‐selective pores that are opened by depolarisation of the membrane voltage. They produce depolarisation‐induced calcium entry in neurons, muscle and other excitable cells, as well as some nonexcitable cells. Functions mediated by calcium channels include contraction of muscle, release of neurotransmitters and hormones by neurons and neuroendocrine cells, and control of gene transcription. Calcium channels are multi‐subunit proteins encoded by many separate genes, and the resulting proteins often govern distinct functional roles within a given cell type. They are targets for modulation by many intracellular signalling pathways including G proteins and phosphorylation. Calcium channels play pivotal roles in many human diseases, particularly of the cardiac and nervous systems, including pain, seizure, hypertension and migraine. Pharmacological blockers for some types of calcium channels are known, including clinically used drugs for hypertension and pain. In some cases such calcium channel blockers are highly selective for specific types of calcium channels, but there is great potential for developing more selective and more potent drugs targeting calcium channels.

Key Concepts:

Voltage‐gated calcium channels are proteins that selectively conduct calcium ions from the outside to the inside of the cell in response to a change in transmembrane voltage from more to less negative.

At the cellular level, calcium channels are a major link between electrical signalling and intracellular biochemical signalling. Calcium channel function is modulated strongly by a variety of intracellular enzymes and signalling pathways.

Many genes encode calcium channels. Different subtypes often carry out distinct physiological functions, via distinct cellular locations and biophysical properties.

Calcium channels govern physiological functions including neurotransmitter and hormone release, muscle contraction and the regulation of gene expression.

Calcium channel dysfunction contributes to diseases including cardiac arrhythmia, hypertension, chronic pain, epilepsy and migraine. They are under investigation for their role in diseases including autism, schizophrenia and bipolar spectrum disorder.
Neuroendocrine Parvocellular Neurons
Authors: Watts Alan G
Published: September 2010

Two sets of neuroendocrine neurons in the hypothalamus form a critical interface between the nervous and the endocrine systems. Neuroendocrine magnocellular neurons that release oxytocin and vasopressin from the neural lobe of the pituitary gland into the general vasculature constitute one of these sets; neuroendocrine parvocellular neurons comprise the other. These neurons release chemical signals into the hypophysial portal vasculature that then control the release of hormones from the anterior pituitary gland. These neurons form part of the neural network that generates pulsatile hormone release. However, more complex patterns of neuroendocrine release are enabled by more widely sourced neural afferents. In some cases, they are direct targets of feedback control by the hormones whose release neuroendocrine parvocellular neurons ultimately control.

Key Concepts:

Neuroendocrine parvicellular neurons release chemical signals (releasing factors) directly into the hypophysial portal vasculature.

Most of the body's hormones are released in pulsatile manner.

Feedback control of neuroendocrine activity is a key regulatory feature for neuroendocrine parvicellular neurons.

The brain contains complex neural networks that can influence the activity patterns of neuroendocrine parvicellular neurons.
Serotonin Receptors
Authors: Hoyer Daniel
Published: September 2010

Serotonin (5‐hydroxytryptamine, 5‐HT) receptors are found both in the central and peripheral nervous system as well as in a number of nonneuronal tissues in the gut, gastrointestinal, pulmonary, cardiovascular systems and blood cells. There are at least 15 different receptors organised in six families of theG protein‐coupled receptor(GPCR) type and one family of the Cys‐loop ligand‐gated channel type. Although the number of 5‐HT neurons in the brain is rather limited to the raphe system, projections occur across the brain and most receptors subtypes are largely distributed throughout the central nervous system (CNS). However, 95% of the 5‐HT is produced peripherally, especially in the gut, and most 5‐HT receptors are also present peripherally. It is to be expected that drugs targeting peripheral 5‐HT receptors will represent a wave of 5‐HT‐related therapies. 5‐HT has been implicated in the aetiology of a number of diseases such as migraine, hypertension, depression, anxiety, schizophrenia, irritable bowel syndrome, eating disorders and vomiting. Many of the current treatments for such disorders interact with the 5‐HT system.

Key Concepts:

Serotonin (5‐hydroxytryptamine, 5‐HT) is one of the oldest neurotransmitters. 5‐HT acts through a multitude of receptors in the brain and the periphery. Serotonin receptors are targeted by many drugs on the market or in clinical development for various central and peripheral pathologies such as depression, anxiety, schizophrenia, migraine, functional bowel disorders, chemotherapy‐induced emesis, eating disorders and others.
Locomotion
Authors: Grey MJ
Published: September 2010

Locomotion is an animal's ability to move itself from place to place. Locomotion requires the movements of the body or specialised parts of the body to generate propulsive forces on land, water or air. Muscles produce these forces in multicellular organisms. Muscle specialisation, mechanics and skeletal form combine to establish the speed, efficiency and endurance of locomotion. Most locomotor movements involve the rhythmic, co‐ordinated contractions of numerous muscles with the basic motor pattern provided by networks of neurons called central pattern generators (CPGs). In vertebrates, the integration of sensory information into CPGs occurs primarily within the spinal cord. However, the supraspinal integration of sensory information is more important in humans. Effective locomotion also requires the correct orientation of the body with respect to the environment, and this is particularly important in humans.

Key Concepts:

The type of motor unit used in locomotion is dependent on the speed of locomotion.

Specific muscle forces produced during locomotion are almost independent of body size.

Energy is stored and released by tendons.

Central pattern generators produce the rhythmic alternation flexion/extension bursts of muscle activity associated with locomotion.

Afferent feedback reinforces the locomotor muscle activity and controls the phase transition from stance to swing.

Locomotion is initiated by command neurons located in the brain stem and lateral hypothalamus.

Information from the somatosensory, vestibular and visual systems is used to provide stability for bipedal human walking.

Many of the concepts about the control of locomotion derived from animal studies apply to humans; however, human walking requires greater supraspinal control than that for other animals.
Bursa of Fabricius
Authors: Mustonen Laura , Alinikula Jukka , Lassila Olli , Nera Kalle‐Pekka
Published: September 2010

The bursa of Fabricius plays a central role in the development of the antibody‐producing B‐lymphocyte lineage in birds. It consists of more than 10 000 follicles surrounded by connective tissue. These follicles provide an appropriate microenvironment for generating a primary repertoire of antibodies. Immunoglobulin gene diversification is achieved by gene conversion and is antigen independent. Follicular B cells undergo very rapid cell division while expressing several genes also expressed in proliferating germinal centre B cells, such as
AID
,
UNG
,
Pax5
and
Bcl6
. Bursal B cell line DT40 provides a unique model system for gene‐targeting studies clarifying the B‐cell development, function and Ig diversification.

Key Concepts:

Bursa of Fabricius is the primary site for B‐cell development and antibody repertoire formation in birds.

Antibody diversification in the bursa of Fabricius is antigen independent and occurs mostly by Ig gene conversion.

Bursal derived DT40 B cell line provides a reverse genetic model to study molecular function of B cells.
Immunodeficiency, Primary: Affecting the Adaptive Immune System
Authors: Vihinen Mauno
Published: September 2010

Primary immunodeficiency (PID) is an intrinsic defect of the immune system. Patients with PID have increased susceptibility to recurrent and persistent infections, and they may also have autoimmune and cancer‐related symptoms. PIDs are mainly rare hereditary disorders of the immune system which often have serious consequences. Infections are the hallmarks of PIDs. Clinical descriptions have already been made for more than 200 PIDs, for which approximately 170 genetic aetiologies have been described. There are several different mechanisms behind PIDs. Some PIDs affect T‐ or B‐cell functions and when both cell types are affected lead to severe combined immunodeficiencies (SCIDs). Other PIDs affect major histocompatibility complex, antibody production, lymphocyte apoptosis, phagocytosis, complement cascade or the innate immune system.

Key Concepts:

Adaptive immunity is a specific and long‐lasting response of lymphocytes to antigens.

Combined immunodeficiency affects both B‐ and T cells.

Lymphocytes are white blood cells including B‐ and T cells.

Signal transduction is a process by which a cell converts one kind of signal or stimulus into another. In a signalling cascade an extracellular signal interacts with a cell surface receptor, which leads to a change in the level of a second messenger and ultimately a change in the cells functioning.