bluuebunny/crossref_metadata_2025 huggingface dataset:
Archaeo‐geophysical methods in the Templo del Escalonado, Cahuachi, Nasca (Peru)
Authors: Rizzo Enzo , Masini Nicola , Lasaponara Rosa , Orefici Giuseppe
Published: September 2010

The application of geophysical prospection methods to detect earthen remains is one of the major challenging issues to be addressed in archaeological investigations. The subtle geophysical contrast between earthen buried remains and the surroundings makes the detection of archaeological features very difficult. In this paper, we address this challenge using a multi‐technique approach. The integration of different geophysical methods has been used to identify archaeological remains in Cahuach, Peru, which is the largest adobe ceremonial centre in the world. The investigations herein presented are focused on two different geophysical campaigns carried out in 2008 in an area of the Templo del Escalonado, which is highly representative of the whole archaeological site. It is a desert environment where the archaeological features are covered by sand and alluvial material.

The geophysical prospection, required by the archaeologists to guide excavation planning, was performed using both ground‐penetrating radar (GPR) and geomagnetics with a gradiometer system. The first allowed the detection of significant anomalies, the latter confirmed the presence of these anomalies and also provided additional features not visible from GPR.

Trial excavations were carried out in correspondence of some anomalies. The archaeologists unearthed a ceremonial offering in correspondence of an anomaly detected using both GPR and geomagnetic methods. Moreover, an altar and precious archaeological materials were discovered in the area characterized by a magnetic anomaly. From an archaeological perspective, these findings were very significant, because they enabled us to cast new light on the Templo del Escalonado.

From a geophysical perspective, our results pointed out the high potentiality of magnetic and GPR techniques to detect, investigate and document adobe archaeological remains in a desert environmental setting.
Fertilisation phosphatée et potassique dans la culture du pois sec
Authors: Lafond J. , Pageau D.
Published: September 2010

In Quebec, the P recommendations for dry peas (Pisum sativum L.) are nearly three times higher than those in western Canada, while recommendations for K are at least 20% lower. The objective of this project was to re-evaluate the P and K needs of dry peas under the climatic conditions of the Saguenay-Lac-Saint-Jean region (Quebec, Canada) in soils with a range of soil P and K availabilities. The treatments consisted of four P rates (0, 20, 40, 80 and 160 kg P2O5 ha–1) and three K rates (0, 50 and 150 kg K2O ha–1). The trials were conducted at two sites over 3 yr. Site 1 was classified as low in P availability and site 2 as medium according to the soil analysis. Both sites had a medium level of soil K availability. Grain yields increased significantly, by 6%, with increasing fertilizer P (3246 to 3437 kg ha–1). Potassium fertilization had no significant effect on grain yields. Grain yields were also 37% higher in the highest soil P site. This low response of the crop to mineral fertilizers was attributed to the significant soil contribution to crop P and K needs. Soil tests have also indicated an enrichment of P and K with large inputs of mineral fertilizers. Thus, a rate of 30-35 kg P2O5 ha–1 for P poor soils would be sufficient to meet the crop needs. For soils with moderate levels of K (201-400 kg K ha–1), a rate of 50 kg K2O ha–1 would be sufficient to meet the crop needs and to maintain the soil fertility. Key words: Enrichment, efficiency, phosphorus, potassium, Pisum sativum L.
Response of broccoli (Brassica oleracea var. italica) yield and hollow stem to plant density, trickle irrigation and transplanting date
Authors: Sanderson K R. , Fillmore S. A. E.
Published: September 2010

Maximizing yield and quality of processing broccoli (Brassica oleracea L. var. italica) is critical to successful production in Atlantic Canada. Field studies were conducted from 2004 to 2006 to evaluate the effect of plant density and trickle irrigation on the yields and incidence of hollow stem for early and late transplanting of broccoli. Treatments consisted of five plant densities ranging from 3.17 to 6.35 plants m–2. Each plant density was either not irrigated or trickle irrigated to maintain at least 25 mm total precipitation per week. The highest marketable yield was achieved at 5.56 plants m–2 when grown in an early transplanting with trickle irrigation in a single row with 90 cm between the row and 20 cm within the row. Overall, earlier transplanting dates were more productive. Trickle irrigation increased marketable yield by an average of 12% over the 3 yr of tests. Average head weight, head diameter, and the incidence of hollow stem decreased as plant density increased. Leaf tissue N was not affected by plant density, trickle irrigation or transplanting date.Key words: Brassica oleracea L. italica, plant density, yield, growth
Consistency of long-term marketable yield of carrot and onion cultivars in muck (organic) soil in relation to seasonal weather
Authors: Tesfaendrias M. T. , McDonald M. R. , Warland J.
Published: September 2010

To identify carrot and onion cultivars that provide consistent marketable yields, we tracked the yields of five fresh market carrot [(Daucus carota L. subsp. sativus (Hoffm.) Arcang.] and six onion (Allium cepa L.) cultivars for at least 13 yr. Relationships between long-term weather variables and marketable yields were also investigated. The effects of cultivar, year and cultivar × year interactions on yield of carrots and onions were assessed. Cultivar and year had significant effects on carrot and onion yields, while the interaction was significant in only one of four data sets of carrot yield. Carrot cv. Cellobunch (95.4 t ha–1) and onion cv. Corona (74.1 t ha–1) had the highest mean marketable yields over the years studied. There was a slight positive correlation between mean yield of the assessed carrots and maximum temperatures in September (r = 0.44). Mean carrot yield was also somewhat negatively correlated with total rainfall in July (r = –0.43) and with number of days with rain in August (r = –0.43) and September (r = –0.44). Most onion cultivars showed stronger relationships between marketable yield and various weather patterns. Marketable yield of onions increased with an increase in the number of days with rainfall in June (r = 0.57). The mean marketable yield of the six onion cultivars decreased in relation to temperatures ≥30°C in June (r = –0.55) and August (r = –0.53). The mean yield of all the onions in the trials was negatively correlated (r = –0.78) with growing degree days (base 5°C, May to August). The results indicated that the data from long-term cultivar trials can be used to identify cultivars that yield well despite seasonal variations in weather. Key words: Daucus carota, Allium cepa, temperature, rainfall
Commercial generations of Brassica napus cause greater yield loss in Triticum aestivum, than volunteer B. napus generations
Authors: Seerey N J , Shirtliffe S J
Published: September 2010

Volunteer canola (Brassica napus L.) has become a common weed in producer fields, due to the large area cropped, and inherent harvest losses. Commonly grown B. napus varieties which segregate in subsequent generations to create volunteers with unknown competitive capabilities are developed by hybrid genetics. The objective of this study was to evaluate the effect of volunteer B. napus variety and generation on competition yield loss in hard red spring wheat (Triticum aestivum L.). Two hybrid and one open-pollinated B. napus varieties with three consecutive generations produced from each variety were grown at varying densities in a wheat stand over 5 site-years. Yield loss depended on the density of B. napus in relation to total plant density. Generational differences in B. napus seedlings resulted in differences in wheat yield losses. Brassica napus densities at maturity provided a more robust model of wheat yield loss, as there were differences in wheat yield losses due to the interaction of generation and variety of B. napus. Commercial seed generations were the most competitive plants, while volunteer generations were less competitive. The amount of yield loss caused by volunteer B. napus was highly variable. The availability of low-priced herbicides, and the competitive ability of volunteer B. napus may allow for economic thresholds concerning weed control to be surpassed at low densities of volunteer B. napus populations. Key words: Competition, hybrid, open-pollinated, volunteer weed, seedling mortality, mature density, seedling density, feral
Basal branching in field pea cultivars and yield-density relationships
Authors: Spies J. M. , Warkentin T. , Shirtliffe S.
Published: September 2010

The current recommended plant density in field pea (Pisum sativum L.) in western Canada is 88 plants m–2. This rate may exceed the optimum for yield in cultivars with more basal branching than typical. The objective of this research was to determine how the seed yield of pea cultivars differing in basal branching ability responds to changes in plant density. Ten pea cultivars were sown at target plant populations of 10, 30, 90, 120, and 150 plant m–2 for 3 yr at Rosthern and Saskatoon, Saskatchewan. At very low plant densities there was greater than a twofold difference in branching potential between cultivars (range 0.85 to 1.99 branches plant–1). Increasing field pea plant density reduced branching by 0.097 branches for each additional plant. The response of yield to plant density differed, as the forage cultivars 40-10 and CDC Sonata reached their potential yield at lower densities, while Courier required higher densities to reach the same proportion of yield. Field pea cultivars with greater basal branching achieved their maximum yield at lower plant densities compared with cultivars with low basal branching. The optimum economic plant density for the pea cultivars ranged from 59 to 84 plants m–2, which is below the current recommended plant density. However, with the exception of the forage cultivars and the low-branching cultivar Courier, the optimum seeding rate was within 8% of 88 seeds m–2. It is recommended that pea growers avoid low-branching pea cultivars and seed at a rate of 88 viable seeds m–2.Key words: Basal branching, seeding rate, plant density, light interception, leafed pea, semi-leafless pea, forage pea
Bayesian data analysis for agricultural experiments
Authors: Che X. , Xu S.
Published: September 2010

Data collected in agricultural experiments can be analyzed in many different ways using different models. The most commonly used models are the linear model and the generalized linear model. The maximum likelihood method is often used for data analysis. However, this method may not be able to handle complicated models, especially multiple level hierarchical models. The Bayesian method partitions complicated models into simple components, each of which may be formulated analytically. Therefore, the Bayesian method is capable of handling very complicated models. The Bayesian method itself may not be more complicated than the maximum likelihood method, but the analysis is time consuming, because numerical integration involved in Bayesian analysis is almost exclusively accomplished based on Monte Carlo simulations, the so called Markov Chain Monte Carlo (MCMC) algorithm. Although the MCMC algorithm is intuitive and straightforward to statisticians, it may not be that simple to agricultural scientists, whose main purpose is to implement the method and interpret the results. In this review, we provide the general concept of Bayesian analysis and the MCMC algorithm in a way that can be understood by non-statisticians. We also demonstrate the implementation of the MCMC algorithm using professional software packages such as the MCMC procedure in SAS software. Three datasets from agricultural experiments were analyzed to demonstrate the MCMC algorithm.Key words: Bayesian method, Generalized linear model, Markov Chain Monte Carlo, SAS, WinBUGS
OAC Derkeller common bean
Authors: Smith T. H. , Michaels T. E. , Pauls K. P.
Published: September 2010

OAC Derkeller (CFIA registration no. 6594) is a determinate bush dark red kidney bean (Phaseolus vulgaris L.) cultivar with early maturity and good yield potential. Seed has good cooking and canning quality.Key words: Phaseolus vulgaris L., kidney bean, common bean, cultivar description
Influence of N fertilization method on weed growth, grain yield and grain protein concentration in no-till winter wheat
Authors: Beres B. L. , Harker K. N. , Clayton G. W. , Bremer E. , O’Donovan T. T. , Blackshaw R. E. , Smith A. M.
Published: September 2010

Applying polymer-coated urea (PCU) instead of uncoated urea may benefit winter wheat (Triticum aestivum L.) production by reducing weed growth or increasing grain yield and protein concentration. Field trials were conducted for 3 yr under rainfed and irrigated conditions in Lethbridge and 2 yr under rainfed conditions in Lacombe to determine potential benefits of substituting urea with PCU for typical winter wheat production practices in Alberta. Four factors were included in each experiment: (1) urea type (urea, PCU and a 50:50 blend of urea and PCU), (2) application method (fall side-band vs. spring broadcast), (3) N rate (1× and 1.5× recommended N rate), and (4) herbicide application (none vs. full). Herbicide application substantially reduced weed biomass at all site-years, but only increased average grain yield by 9%. Dicot weed biomass was not affected by fertilizer treatment, but monocot weed biomass was less for fall banded than spring broadcast application and less for urea than PCU or blend at the 1× N rate. Over all site-years, substitution of 50 or 100% of urea with PCU increased grain yield by an average of 4.3% and reduced protein concentration by 1.3%. Substitution of urea with PCU had the largest impact at the site-year with most severe drought stress, indicating that PCU benefits were probably due to factors other than reduced N loss. Further study is required to evaluate potential benefits from substitution of urea with PCU over a wide range of environmental conditions.Key words: Triticum aestivum, nitrogen fertilizer, placement, timing, split N, grain protein concentration, polymer-coated urea
Best Practices in Clinical Decision Support
Authors: Phansalkar Shobha , Bloomrosen Meryl , Jenders Robert , Bobb Anne , Halamka John , Kuperman Gilad , Payne Thomas , Teasdale S. , Vaida A. J. , Bates D. W. , Wright Adam
Published: September 2010

Background: Evidence demonstrates that clinical decision support (CDS) is a powerful tool for improving healthcare quality and ensuring patient safety. However, implementing and maintaining effective decision support interventions presents multiple technical and organizational challenges.

Purpose: To identify best practices for CDS, using the domain of preventive care reminders as an example.

Methods: We assembled a panel of experts in CDS and held a series of facilitated online and in-person discussions. We analyzed the results of these discussions using a grounded theory method to elicit themes and best practices.

Results: Eight best practice themes were identified as important: deliver CDS in the most appropriate ways, develop effective governance structures, consider use of incentives, be aware of workflow, keep content current, monitor and evaluate impact, maintain high quality data, and consider sharing content. Keys themes within each of these areas were also described.

Conclusion: Successful implementation of CDS requires consideration of both technical and socio-technical factors. The themes identified in this study provide guidance on crucial factors that need consideration when CDS is implemented across healthcare settings. These best practice themes may be useful for developers, implementers, and users of decision support.
Impact of brine-induced stratification on the glacial carbon cycle
Authors: Bouttes N. , Paillard D. , Roche D. M.
Published: September 2010

Abstract. During the cold period of the Last Glacial Maximum (LGM, about 21 000 years ago) atmospheric CO2 was around 190 ppm, much lower than the pre-industrial concentration of 280 ppm. The causes of this substantial drop remain partially unresolved, despite intense research. Understanding the origin of reduced atmospheric CO2 during glacial times is crucial to comprehend the evolution of the different carbon reservoirs within the Earth system (atmosphere, terrestrial biosphere and ocean). In this context, the ocean is believed to play a major role as it can store large amounts of carbon, especially in the abyss, which is a carbon reservoir that is thought to have expanded during glacial times. To create this larger reservoir, one possible mechanism is to produce very dense glacial waters, thereby stratifying the deep ocean and reducing the carbon exchange between the deep and upper ocean. The existence of such very dense waters has been inferred in the LGM deep Atlantic from sediment pore water salinity and δ18O inferred temperature. Based on these observations, we study the impact of a brine mechanism on the glacial carbon cycle. This mechanism relies on the formation and rapid sinking of brines, very salty water released during sea ice formation, which brings salty dense water down to the bottom of the ocean. It provides two major features: a direct link from the surface to the deep ocean along with an efficient way of setting a strong stratification. We show with the CLIMBER-2 carbon-climate model that such a brine mechanism can account for a significant decrease in atmospheric CO2 and contribute to the glacial-interglacial change. This mechanism can be amplified by low vertical diffusion resulting from the brine-induced stratification. The modeled glacial distribution of oceanic δ13C as well as the deep ocean salinity are substantially improved and better agree with reconstructions from sediment cores, suggesting that such a mechanism could have played an important role during glacial times.
The cold frontal depression that affected the area of Cyprus between 28 and 29 January 2008
Authors: Nicolaides K. , Orphanou A. , Savvidou K. , Michaelides S. , Tsitouri M.
Published: September 2010

Abstract. The baroclinic depression that affected the area of Cyprus during the cold period, between 28 and 29 January 2008 was thoroughly studied and is presented in the present paper. A small perturbation on a northwesterly flow to the north of Cyprus has initiated the generation of the depression and in 24 h this developed into a deep baroclinic system. This depression was associated with intense weather phenomena, such as heavy thunderstorms with hail and near gale force winds. Strong cold advection resulted in a significant temperature decrease; precipitation even in lower altitudes was in the form of snow, while the accumulated rainfall corresponded to the 25% of the monthly normal. January 2008 is considered as a dry month, despite the fact that, on the average, January is considered as the wettest month of the year. In this study, the evolution and development of the depression was investigated from synoptic, dynamic, energetic and thermodynamic perspectives, in order to enhance our knowledge on the life cycle and behaviour of similar depressions over the area with extreme characteristics.
A numerical study of glacier advance over deforming till
Authors: Leysinger Vieli G. J.-M. C. , Gudmundsson G. H.
Published: September 2010

Abstract. The advance of a glacier over a deforming sediment layer is analysed numerically. We treat this problem as a contact problem involving two slowly-deforming viscous bodies. The surface evolution of the two bodies, and of the contact interface between them, is followed through time. Using various different non-linear till rheologies, we show how the mode of advance depends on the relative effective viscosities of ice and till. Three modes of advances are observed: (1) overriding, where the glacier advances through ice deformation only and without deforming the sediment; (2) plug-flow, where the sediment is strongly deformed, the ice moves forward as a block and a bulge is built in front of the glacier; and (3) mixed-flow, where the glacier advances through both ice and sediment deformation. For the cases of both overriding and mixed-flow, an inverse depth-age relationship within the ice is obtained. A series of model experiments show the contrast in effective viscosity between ice and till to be the single most important model parameter defining the mode of advance and the resulting thickness distribution of the till. Our model experiments indicate that the thickness of the deforming till layer is greatest close to the glacier front. Measurements of till thickness taken in such locations may not be representative of deforming till thickness elsewhere. Given sufficiently large contrast in effective viscosity between ice and till, a sediment bulge is formed in front of the glacier. During glacier advance, the bulge quickly reaches a steady state form strongly resembling single-crested push moraines. Inspection of particle paths within the sediment bulge, shows that particles within the till travel at a different speed from the bulge itself, and the push moraine to advance as a form-conserving non-linear wave.
Cadmium‐Carbonic Anhydrase
Authors: Xu Yan , Supuran Claudiu T , Morel François M M
Published: September 2010

Cadmium‐carbonic anhydrase (CDCA1) is a ζ‐carbonic anhydrase (CA) isolated from the marine diatom
Thalassiosira weissflogii
, which naturally uses Cd as its metal cofactor. Its homolog gene has been found in a number of diatom species as well as natural assemblages. The expression of
cdca1
gene at both transcript and protein levels is regulated by pH/
p
CO
2
and Cd and Zn availabilities in seawater. The amino acid sequence contains a triple repeat with high identity among repeats, and each single repeat is a functional CA and a structural mimic of a functional β‐CA dimer. CDCA1 incorporates either Zn or Cd at its active site and readily exchanges one with the other. The metal cofactor is tetrahedrally coordinated by two Cys, a His, and a water molecule and an open conformation is adapted at the active site when the metal is absent. The catalytic efficiencies of both the Cd‐ and Zn‐bound CDCA1 are pH dependent and the Zn‐bound CDCA1 is more active than the Cd‐bound CDCA1.
Combinatorial Chemistry and Multiple Parallel Synthesis
Authors: Mitscher Lester A. , Aubé Jeffrey , Dutta Apurba , Golden Jennifer E.
Published: September 2010

The current state of the art in drug seeking through applications of combinatorial chemical and multiple parallel synthetic methods is reviewed with examples culled from the contemporaneous literature.
Therapeutic Agents Acting on
RNA
Targets
Authors: Rife Jason P.
Published: September 2010

There are many therapeutics that target RNA, such as streptomycin, gentamicin, and tetracycline; some of them have been in existence for many years. All of them bind to ribosomal RNA and alter normal ribosome function. The modern strategies of drug discovery and design pertain nearly exclusively to protein targets. However, the field of drug discovery for RNA targets is maturing rapidly, largely due to the exciting ribosome/drug complexes that have recently been solved. Potential RNA drug targets abound for bacterial, viral, and cellular systems. Nevertheless, questions remain as to whether or not compounds can be found that simultaneously satisfy RNA binding and pharmacological properties, such as absorption and membrane permeation. The range of interactions observed, from Coulombic to hydrophobic, and the predicted “drug‐like” qualities of several ribosome binding antibiotics, suggest that the discovery of drugs that target RNA can be a general phenomenon.
Thyroid Hormones and Thyromimetics
Authors: Malm Johan , Grover Gary J.
Published: September 2010

This chapter will provide an overview on the recent design principles and structure–activity relationship of thyroid hormones and thyromimetics. The prospects for the treatment of metabolic diseases, hypo‐ and hyperthyroidism, and cardiac disease with pharmacologically selective thyromimetics are considerable if cardiovascular acceleration and other adverse events can be avoided.
Fundamentals of Steroid Chemistry and Biochemistry
Authors: Brueggemeier Robert W. , Li Pui‐Kai
Published: September 2010

Steroids are a unique class of chemical compounds found throughout the animal and plant kingdom. This class includes sterols such as cholesterol and ergosterol, bile acids, and steroid hormones. Chemical research on steroids began with isolation and structure determination, and major research efforts focused on total synthesis and on the development of numerous reactions for modifying the steroid scaffold. Methods in microbial transformations of steroids were developed in order 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.
Agents Acting on Prostanoid and Thromboxane Receptors
Authors: Hall Adrian , Peace Simon , Swarbrick Martin E.
Published: September 2010

This chapter covers recent developments in the prostaglandin and thromboxane research area, with particular focus on the medicinal chemistry aspects. Each of the receptors is discussed in turn with progress and medicinal chemistry strategies discussed for both agonists and antagonists. Clinical development compounds are highlighted.
Retinoids
Authors: Dawson Marcia I.
Published: September 2010

Retinoid drugs find major applications in the topical treatment of cutaneous proliferative disorders such as acne, psoriasis, and photoaging and cutaneous cancers such as cutaneous T‐cell lymphoma (CTCL) and Kaposi's sarcoma. Oral retinoids are successfully used to treat nodular/cystic acne, systemic CTCL, and acute promyelocytic leukemia. This overview of available retinoid drugs and those in the preclinical or clinical pipeline covers their development, indications, clinical trial results, adverse effects, and pharmacology/metabolism. Retinoids have been described historically and functionally in the context of interaction with their nuclear receptors—retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—in inducing gene transcription. RAR‐selective retinoids or their prodrugs include first‐generation all‐trans‐retinoic acid (tretinoin) and its 13‐cisisomer (isotretinoin), and second‐generation acitretin and its ethyl ester (etretinate), both having an aromatic 2,3,6‐trimethyl‐4‐methoxyphenyl terminus. Third‐generation more aromatic analogs include ethyl ester tazarotene (Tazorac®) and adapalene (Differin®), both selective for RAR subtypes β and γ, and RARα‐selective pipeline candidates Am80 and NRX 195183, which are in clinical trials. RAR and RXR transcriptional panagonist 9‐cis‐retinoic acid is next and is followed by RXR‐selective bexarotene (Targretin™) and two RXR‐selective clinical trial candidates, 9cUAB and NRX 194204. The fourth generation includes three compounds that may have applications in the treatment or prevention of cancer. While originally considered as retinoids, such asN‐(4‐hydroxyphenyl) retinamide, or as retinoid‐related or derived, such as ST1926 (AHPC) and SHetA2, they subsequently were found to function independently of the RARs and RXRs in inhibiting cancer cell proliferation and inducing apoptosis.
SNPs: Single Nucleotide Polymorphisms and Pharmacogenomics: Individually Designed Drug Therapy
Authors: Maitland‐van der Zee Anke‐Hilse , Puckett Brian J. , Terra Steven G. , Walker Joe
Published: September 2010

Pharmacogenetics is literally a combination of pharmacology and genetics. Pharmacogenetics is the study of how an individual's genetic makeup may influence response to medications. This chapter describes examples of pharmacogenetic interactions, and the role pharmacogenetics plays and might play in clinical practice.
Synthetic Antibacterial Agents
Authors: Anand Nitya , Remers William A.
Published: September 2010

Synthetic antibacterial compounds are divided into topical and systemic agents. Topical agents are called disinfectants or antiseptics depending on how they are used. They show little selectivity between the microbes and the host. Nevertheless, they are indispensable in hospitals, public health, and the home.

The development of systemic antibacterial agents had a strong dye connection. Ehrlich's development of selective staining methods led him to propose that dyes may also have selective toxicity for microbes, and to coin the term chemotherapy. Domagk's discovery of antibacterial activity for the azo dye prontosil led to the first effective chemotherapeutic agent, sulfanilamide. This compound provided an excellent lead for structural modification and ushered in the modern era of chemotherapy and drug design. The discovery that sulfonamides act through folate inhibition resulted in the development of dihydrofolate reductase inhibitors such as trimethoprim.

The availability of synthetic antibacterials and antibiotics, which were discovered almost concurrently, provided major advances in control of bacterial infections; however, the rise in bacterial resistance prompted the search for newer classes of agents. This search provided fluoroquinolines and oxazolidones.

There are also synthetic antibacterials with niche needs, such as nitrofurans and methenamine, which are used for urinary tract infections.
Antidepressants
Authors: Glennon Richard A. , Iversen Leslie
Published: September 2010

This chapter reviews the antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure–activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by agents that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin‐selective reuptake inhibitors or mixed norepinephrine/serotonin reuptake inhibitors that possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions, including phobias and the treatment of generalized anxiety disorder (GAD). Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolitesin vivo. All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of 5‐HT1Areceptors) and/or alterations in the expression of neurotrophic factors (e.g., brain‐derived neurotrophic factor, vascular endothelial growth factor) associated with changes in neurogenesis in certain brain regions. New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, corticotrophin releasing factor receptors, or agonists/antagonists for galanin receptors.
New Strategies for Natural Products Lead Generation
Authors: Carter Guy T. , Bernan Valerie S. , Koehn Frank E.
Published: September 2010

Microbial sources of natural products are increasingly valued for their chemical diversity and access to biosynthetic pathways. It appears that an incredible repository of untapped microbial life and associated chemical diversity remain to be exploited. Molecular techniques such as “metagenomics” are beginning to provide access to cryptic biosynthetic pathways, which are also revealing new chemistry. Refined libraries of natural products with well‐characterized components provide enhanced value as screening sources. These libraries continue to provide new chemical entities that inform biological processes and provide leads for therapeutic agents. There is a renaissance of phenotypic screening that promises to uncover numerous new links between secondary metabolites and their roles in biology. Genomic methods are growing in value as our understanding of biosynthetic processes at the molecular level expands. Screening of DNA sequences for pathways that yield particular chemistries is now a reality for certain types of biosynthetic processes, especially type I polyketide synthases and nonribosomally produced peptides.
ADMETIn VitroProfiling: Utility and Applications in Lead Discovery
Authors: Kerns Edward H. , Di Li , Carter Guy T.
Published: September 2010

ADMET properties are a vital integral part of drug discovery because they determine the pharmacokinetics and safety of clinical development candidates. Diverse ADMET profiling assays have been developed and implemented to provide property data for drug discovery team decision making. Their utility and applications in lead discovery include the following: lead selection, diagnosis of poor PK, guidance for structure modification, solving specific project team property issues, providing accurate biological data for SAR, selecting compounds forin vivoPK and PD studies, and improving dosing for optimum exposurein vivo. ADMET properties are discussed along with case studies and assays.
Structural Alerts for Toxicity
Authors: Blagg Julian
Published: September 2010

This chapter summarizes structural alerts where there is a significant weight of evidence that their incorporation into a drug candidate molecule is likely to result in a higher than average incidence of attrition due to adverse safety/or toxicity findings. The mechanism of formation of reactive metabolites from each structural alert is summarized. The structure–toxicity relationships and the boundary of definition for each structural alert are discussed. The benefits of low exposure and alternative routes of metabolism are highlighted along with screening methods to manage the risks associated with structural alerts.
Docking and Scoring in Drug Discovery
Authors: Spyrakis Francesca , Cozzini Pietro , Kellogg Glen Eugene
Published: September 2010

The rational development of new lead compounds requires good understanding of the relationship between all the actors involved in a binding event (protein, ligand, water, metal ions, cofactors, etc.). Computational methods attempt to reproduce and predict the behavior of nature even though this can be very difficult. The docking/scoring paradigm is probably the most widespread and potentially useful computer‐aided technique used in the discovery of new drugs. This paradigm can be analyzed as the sum of a “geometric” problem, that is, the implementation of algorithms to find the possible positions of a ligand in a receptor cavity, and a “chemistry” problem, that is, the evaluation of the solution list using good and realistic energy functions. In this chapter, we deal with the panorama of docking and scoring approaches and the related software packages. After a general introduction, some basic principles about the goodness and limits of experimental data used for computational simulations are described. Then an exhaustive examination of the most common docking methods and packages is carried out followed by an analysis of scoring functions developed to date, including the evolving consensus scoring approach. Next, several problems with the paradigm and their state‐of‐the‐art partial solutions are discussed, including active site water, ionization states, tautomerization, flexibility, and the probability of more than one “correct” solution. Particular attention is paid for the upside and the downside of the problem in a short user guide for the docking and scoring beginner, followed by a conclusions and outlook.
Angiotensin‐Converting Enzyme Inhibitors
Authors: Petrillo Edward W.
Published: September 2010

The discovery of captopril, the first orally active angiotensin‐converting enzyme inhibitor, showed that blockade of the renin‐angiotensin system effectively lowers blood pressure in a wide spectrum of patients with hypertension. Captopril was designed using a hypothetical model of the enzyme active site that subsequently guided the design of new classes of inhibitors. Because ACE inhibitors retard the progression of cardiovascular disease and the complications of diabetes, leading to an overall reduction in mortality, they have become one of the most widely used drug classes in cardiovascular medicine. New genetic and structural evidence has revealed that ACE has two functional catalytic domains with differences that may be exploited in the future to design inhibitors with superior properties.
Anticoagulants
Authors: Henry Brian L. , Desai Umesh R.
Published: September 2010

Thrombotic disorders are a major cause of morbidity and mortality in humans. Examples of thrombotic disorders include pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, acute myocardial infarction, unstable angina, and cerebrovascular thrombosis. Anticoagulants are the mainstay of treatment and prevention of these disorders. The most widely used anticoagulants include unfractionated heparin, low molecular weight heparins and warfarin. Newer agents introduced in the past decade include bivalirudin, fondaparinux, and argatroban. Mechanistically, these anticoagulants either directly inhibit thrombin or indirectly reduce the activity of thrombin and factor Xa. Several new molecules have been recently designed to directly inhibit thrombin and factor Xa with high potency and considerable selectivity, of which dabigatran and rivaroxaban were approved for clinical use in few countries in 2008. Molecules being pursued in clinical trials include AZD0837, LB‐30870, otamixaban, apixaban, YM‐150, and others. Ximelagatran, which was introduced in 2004 as a direct thrombin inhibitor, was taken off the market within 20 months due to significant hepatotoxicity. Indirect anticoagulants utilize the antithrombin‐mediated conformational activation and bridging mechanisms for inhibiting coagulation enzymes. Among the indirect anticoagulants that are currently being investigated in clinical trials are a biotinylated idraparinux and SR123781. Over the last two decades, major conceptual strides have been made including the design of the first anticoagulant based solely on factor Xa inhibition (fondaparinux) and the establishment of the paradigm that anticoagulation is possible without frequent laboratory monitoring (ximelagatran). Current work attempts to establish other concepts such as the dual inhibition of free and clot‐bound thrombin by a heparin‐based molecule (ORG42675) and the applicability of neutral P1‐group containing active site‐directed molecules as effective inhibitors of coagulation enzymes (rivaroxaban). To date, no molecule has been designed that satisfies all the properties of an ideal anticoagulant including a broad therapeutic window, absence of bleeding risk, no requirement for frequent coagulation monitoring, oral bioavailability, availability of an effective antidote, lack of hepatoxicity and absence other adverse effects. Yet, the newer agents are likely to be more attractive than the heparin‐ and coumarin‐based therapy. In this chapter, we review the structure, design, and mechanism of action of clinically used and new potential anticoagulants. Special emphasis is placed on the molecular interaction of anticoagulants with their targets.
The Role of Translational Medicine and Predictive Biomarkers in the Development of Novel, Innovative Treatments for the Management of Chronic Heart Failure:APharmaceutical Industry Perspective
Authors: Douglas Stephen A. , Feuerstein Giora Z.
Published: September 2010

Chronic heart failure (CHF) represents one of the few cardiovascular diseases with an incidence that continues to rise. While the socio‐economic burden associated with this malignant disease remains high, recent attempts to develop novel, differentiated therapies for the management of CHF (ET‐1, TNFα, dual ACE/NEP inhibitors) have met with failure due to lack of differentiated efficacy and/or safety concerns. Such disappointments have drawn attention to the difficulties faced today in (a) the selection of the most appropriate, innovative targets for the management of this disease; (b) the development of predictive biomarkers that validate the target, define compound pharmacodynamic/‐kinetic (safety/efficacy) relationships, catalog disease modification, and/or assist in patient selection/stratification; and (c) optimal CHF clinical trial design. The present commentary discusses the role of Translational Medicine in the preclinical and clinical CHF Drug Discovery process and details how this emerging scientific discipline can be best used to minimize investment risk/cost.
Nuclear Hormone Receptor Medicinal Chemistry
Authors: Cheng Peter T.W. , Kick Ellen , Mukherjee Ranjan
Published: September 2010

This chapter will be focused on recent advances in the medicinal chemistry of agonist, antagonist, and modulator ligands of selected nuclear hormone receptors (NHRs) that are of special interest in the metabolic diseases therapeutic area (diabetes, obesity and dyslipidemia/atherosclerosis). These NHRs include established biological targets such as the peroxisome proliferator‐activated receptors (PPARs), the liver X receptors (LXRs), and the farnesoid X receptors (FXRs), for which ligands have reached either clinical development or have been approved for clinical usage. Other more recent targets of interest to metabolic diseases include HNF and Rev‐erb.
Anti‐Inflammatory Glucocorticoids
Authors: Avery Mitchell A. , Chittiboyina Amar G.
Published: September 2010

Glucocorticoids are the first line medication used in the treatment of afflictions ranging from the moderate skin rash to severe acute inflammatory disorders. They exert their activity through binding to the glucocorticoid receptor, a ligand‐dependent transcription factor, and result in either activation or repression of a large set of glucocorticoid responsive genes. The
glucocorticoid receptor
(
GR
) is a cytoplasmic protein of complex structure that is associated with various heat shock proteins (e.g., hsp 90). The desired immunosuppressive effect is apparently due largely to the downregulation of a variety of proinflammatory factors, whereas adverse reactions such as corticoid‐induced diabetes and osteoporosis could be connected to the inappropriate activation of genes involved in the control of metabolic processes. The discovery of selective receptor modulators, which maintain beneficial therapeutic activity together with a diminished risk of side effects, focuses on ligands that lead to repression rather than activation of genes targeted by the glucocorticoid receptor. Current drug‐screening programs have yielded a number of molecules including steroidal as well as nonsteroidal compounds, which preferentially induce receptor‐mediated repression.
Diabetes Drugs: Present and Emerging
Authors: Tilley Jefferson , Grimsby Joseph , Erickson Shawn , Berthel Steven
Published: September 2010

This chapter includes a summary of the mechanism of action, history, and ADME properties compounds selected from four classes of marketed drugs for the treatment of type 2 diabetes. These include the biguanides (metformin), α‐glucosylase inhibitors, sulfonylureas, and glinides. In addition, a discussion of several advanced, emerging classes of drugs together with lead structures is provided. The mechanistic classes of emerging drugs include inhibitors of the sodium glucose cotransporter 2 (SGLT2), glucokinase activators (GKAs), inhibitors of fructose‐1,6‐bisphosphatase (FPase), inhibitors of 11‐β‐sterol dehydrogenase (11‐β‐HSD1), agonists acting on the G‐coupled‐protein receptor GPR119, and mimics of the sirtuin family member SIRT1.
Kinase Inhibitors: Approved Drugs and Clinical Candidates
Authors: Bradbury Robert H.
Published: September 2010

During the past two decades, protein kinases involved in a wide range of cellular signaling pathways have proved a tractable class of oncology drug target, and by the end of 2008 nine small‐molecule kinase inhibitors had been approved by regulatory authorities for treatment of human hematological or solid tumors. The majority of protein kinase inhibitors that have progressed to clinical evaluation target the adenosine triphosphate binding site. After a brief overview of design of the pioneering Bcr‐Abl kinase inhibitor imatinib, this chapter is structured around the effect of kinase inhibitor drugs on the “hallmarks of cancer,” the acquired cellular capabilities that collectively promote malignant growth of solid tumors. The chapter continues by reviewing growth factor and antiangiogenic kinase inhibitors, approaches that have now been validated in large‐scale clinical trials, and then proceeds to discuss inhibitors implicated in the cell cycle, survival signaling, and tissue invasion and metastasis. Reviewed in the chapter are approximately 20 oncology kinase drug targets and 60 associated inhibitors with disclosed chemical structures that have been approved by regulatory authorities or are undergoing clinical trials. Synopses of evolution from lead to candidate drug distilled from original articles illustrate themes in kinase inhibitor medicinal chemistry.
CNSCancers
Authors: Graeme Robertson
Published: September 2010

CNS tumors represent a diverse collection of tumor types driven by a range of signaling inputs that often generate highly aggressive and at the same time heterogeneous tumor types. The effect of these tumors is particularly dramatic and impacts on children as well as adults. Malignant CNS tumors are characterized by being highly heterogeneous, aggressive, and frequently invasive, leading to poor overall patient survival times. As CNS tumors present within the nervous system, there are particular challenges in the development of effective molecular‐targeted therapies in dealing not only with the aggressive nature of these tumors and their ability to evade treatment but also, particularly, with maintaining normal neuronal and brain functions. Compounding this is the need to deliver systemically small molecules or other agents such as vaccines and for immunotherapy approaches to confront the complexity of the relationship between the nervous system and the immune system.

Research to find effective treatments for CNS tumors is being facilitated by two key inputs both of which are reviewed in this chapter; first, a much greater understanding of tumor pathobiology and the potential role of developmental signaling pathways and tumor stem‐like cells, and by the development of animal models that more adequately represent endpoints measurable in the clinic. Together, these advances should assist in the selection of better targets and the optimization of better compounds to progress into clinical trials.