bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and Magnetic Properties of New Octahedral Iron(II) Complexes
Authors: Weber Birgit , Kaps Eike , Obel Jaroslava , Bauer Wolfgang
Published: May 2008

The reaction of iron(II) acetate with the tetradentate Schiff base like ligands H2L1 ((E,E)‐[{diethyl 2,2′‐[1,2‐phenylenebis‐(iminomethylidyne)]bis[3‐oxobutanato]}]) and H2L2 ([([3,3′]‐[1,2‐phenylenebis(iminomethylidyne)]bis(2,4‐pentane‐dionato)(2‐)‐N,N′,O2,O2′]) in the presence of 1‐meim (1‐methylimidazole) or 2‐meim (2‐methylimidazole) leads to the formation of pentacoordinated or octahedral complexes depending on the used reaction conditions. Two pentacoordinated and four octahedral iron(II) complexes of the composition [FeL1(1‐meim)2] (1), [FeL2(1‐meim)] (2), [FeL2(1‐meim)2] (3), [FeL2(1‐meim)2](DMF) (3(DMF)), [FeL1(2‐meim)](MeOH)0.5 (4) and [FeL1(2‐meim)2] (5) were isolated and structurally characterized. For the 2‐meim complexes a hydrogen bond network between the imidazole N‐H hydrogen and the carbonyl oxygen of the equatorial ligand is formed, while for the 1‐meim derivatives only weak van der Waals interactions are observed. Magnetic measurements were performed on all samples. As expected, the pentacoordinated complexes remain in the high‐spin state in the whole temperature range investigated. For the octahedral complexes, 1 and 5 are pure high‐spin complexes while for 3 and 3(DMF) spin transition behaviour is observed.
Continuous Preparation of Calcite, Aragonite and Vaterite, and of Magnesium‐Substituted Amorphous Calcium Carbonate (Mg‐ACC)
Authors: Nebel H. , Epple Matthias
Published: May 2008

The three water‐free calcium carbonate polymorphs calcite, aragonite and vaterite were prepared from aqueous solutions without additives using standard laboratory equipment in a continuous process. Variation parameters were the way of mixing, the solution concentrations, and the reactor residence time. The samples were crystallographically and chemically pure, but a thorough elemental analysis revealed the presence of small amounts of sodium carbonate which was not detectable by X‐ray powder diffraction. The continuous process avoids the inherent variability of batch syntheses. By adapting the crystallization parameters, magnesium‐substituted amorphous calcium carbonate (molar ratio of Mg:Ca of 1:2.68) was prepared in this continuous process.
(Cyclopentadienyl)trioxorhenium(VII) – no Match for Methyltrioxorhenium (MTO)
Authors: Högerl Manuel , Kühn Fritz E.
Published: May 2008

Together with a further improvement of the synthesis of (cyclopentadienyl)trioxorhenium(VII), CpReO3, its reaction chemistry and catalytic activity is also revisited in greater detail. However, in spite of the high catalytic activity of the homologous methyltrioxorhenium(VII) (MTO) and the related CpMo(O2)X, (X = R, Hal, etc.) it is seen that CpReO3 suffers greatly from the lability of the Cp‐Re bond under oxidative conditions and in the presence of electron donor ligands. (Cyclopentadienyl)trioxorhenium(VII) although accessible very conveniently, neither matches the rich reaction chemistry of its pentamethylcyclopentadienyl derivative, Cp*ReO3 nor the catalytic versatility of MTO.
Expression of homothorax and extradenticle mRNA in the legs of the crustacean Parhyale hawaiensis: evidence for a reversal of gene expression regulation in the pancrustacean lineage
Authors: Prpic Nikola-Michael , Telford Maximilian J.
Published: May 2008

In Drosophila leg development, the extradenticle (exd) gene is expressed ubiquitously and its co-factor homothorax (hth) is restricted to the proximal leg portion. This condition is conserved in other insect species but is reversed in chelicerates and myriapods. As the region of co-expression does not differ in the two groups and transcripts from both are necessary for function, this difference in expression is likely to be functionally neutral. Here, we report the expression patterns of exd and hth in a crustacean, the amphipod shrimp Parhyale hawaiensis. The patterns in P. hawaiensis are similar to the insect patterns, supporting the close relationship between crustaceans and insects in the taxon Tetraconata. However, mRNA expression of exd in P. hawaiensis is weak in the distal leg parts, thus being intermediate between the complete lack of distal exd expression in chelicerates and myriapods and the strong distal exd expression in insects. Our data suggest that the reversal of the gene expression regulation of hth and exd occurred in the pancrustacean lineage.
Effect of High Intensity Ultrasound on Crystallization Behavior of Anhydrous Milk Fat
Authors: Martini S. , Suzuki A. H. , Hartel R. W.
Published: May 2008

The need to eliminate trans‐fatty acids from foods’ formulation resulted in the exploration of new lipid sources and alternative processing conditions that will improve the physicochemical characteristics and nutritional qualities of lipid‐based foods. In general, the physicochemical characteristics of lipid networks depend on the microstructure and crystallization behavior of the system. The objective of this work was to use high intensity ultrasound (HIU) as an additional processing condition to alter the crystallization behavior of a lipid model system (anhydrous milk fat). Results show that HIU application not only decreases the induction time of crystallization (faster crystallization) at a constant crystallization temperature, but also generates smaller crystals. In addition, higher viscosities are obtained when samples are crystallized after HIU application. The degree of supercooling, ultrasound application settings and a combination of both parameters influence the degree of ultrasound effect on the crystallization behavior.
Modulation of Olive Oil Quality Using NaCl as Extraction Coadjuvant
Authors: Pérez Ana G. , Romero Carmen , Yousfi Khaled , García José M.
Published: May 2008

The use of four concentrations of common salt (NaCl) used as coadjuvant for the extraction of virgin olive oil has been tested on a laboratory scale and the quality attributes of the oils obtained were compared to those obtained with talc as coadjuvant. The oils extracted from Picual fruits after NaCl addition were not significantly affected in terms of the physicochemical requirements established for extra virgin olive oil, the best level of quality of this produce. Addition of NaCl during the extraction process was positively correlated with the presence of o‐diphenol compounds and the stability of the oils obtained. Moreover the use of NaCl resulted in a significant increase in contents of pigments (β‐carotene, lutein and chlorophylls a and b) and volatile compounds in the oils.
E2‐mediated cathepsin D (CTSD) activation involves looping of distal enhancer elements
Authors: Bretschneider Nancy , Kangaspeska Sara , Seifert Martin , Reid George , Gannon Frank , Denger Stefanie
Published: May 2008

Estrogen receptor alpha (ERα) is a ligand dependent transcription factor that regulates the expression of target genes through interacting with cis‐acting estrogen response elements (EREs). However, only a minority of ERα binding sites are located within the proximal promoter regions of responsive genes. Here we report the characterization of an ERE located 9kbp upstream of the TSS of the cathepsin D gene (CTSD) that up‐regulates CTSD expression upon estrogen stimulation in MCF‐7 cells. Using ChIP, we show recruitment of ERα and phosphorylated PolII at the CTSD distal enhancer region. Moreover, we determine the kinetics of transient CpG methylation on the promoter region of CTSD and for the first time, at a distal enhancer element. We show that ERα is crucial for long‐distance regulation of CTSD expression involving a looping mechanism.
Fishing in the mild West: democratic peace and militarised interstate disputes in the transatlantic community
Authors: HELLMANN GUNTHER , HERBORTH BENJAMIN
Published: May 2008

According to many of its proponents, the proposition that democracies do not fight each other is ‘as close as anything we have to an empirical law’. However, there have been several incidents among solidified liberal democracies where force was threatened or even used. Since these inter-democratic militarised interstate disputes (MIDs) almost always took place in the context of fisheries disputes, we examine two of these conflicts in detail: the cod wars between Iceland and Britain between the 1950s and the 1970s and the turbot war between Canada and Spain. We ask why these fisheries conflicts became militarised in the first place but did not escalate further. In both cases it was actually the presumed impossibility of a more violent escalation which led the parties to use force in the first place. Moreover, the (limited) use of force was almost always accompanied by the efforts of the parties involved to achieve some formalisation of international rules in the context of expanding regimes. Having demonstrated how some of the more prominent causal mechanisms stipulated by democratic peace theorists fail to convincingly account of these cases, we refrain from concluding that any of this falsifies the democratic peace proposition. However, in conclusion we do call into question the premises of the falsificationist methodology underlying much of the democratic peace debate on both theoretical and metholdological grounds. Reframing the democratic peace proposition in terms of a large-scale process of descuritisation, we contend, allows us to understand better how democratic interstate interaction remains inherently conflictive and possibly still subject to process of resecuritisation.
Meteor wind radar observations of gravity wave momentum fluxes and their forcing toward the Mesospheric Semiannual Oscillation
Authors: Antonita T. Maria , Ramkumar Geetha , Kumar Karanam Kishore , Deepa V.
Published: May 2008

Wind measurements from continuous meteor radar observations during June 2004–May 2007 are used to estimate the gravity wave momentum fluxes in the Mesosphere Lower Thermosphere (MLT) region over Trivandrum (8.5°N, 76.9°E), a low‐latitude station in India. The radial velocity variances in the 82–98 km height region, which are mainly caused by gravity waves, measured by the meteor radar are used to determine the gravity wave momentum fluxes. Using a novel method proposed by Hocking (2005), altitude profiles of momentum fluxes of short period (less than 2–3 h) gravity waves are estimated for three continuous years. Seasonal variation in the gravity wave momentum fluxes showed semi annual variation with equinoctial maximum and solstitial minimum. By using estimated gravity wave momentum fluxes, an attempt is made to quantify their contribution in driving the Mesospheric Semi Annual Oscillation (MSAO). The mean flow acceleration estimated from the divergence of gravity wave momentum fluxes is compared with the observed mean flow acceleration computed from monthly mean zonal winds during six MSAO cycles over three years. This comparison reveled that the gravity wave contribution toward the westerly phase of MSAO varies from ∼20–60% while that toward the easterly phase varies from ∼30–70%. Variations are observed from cycle‐to‐cycle in the gravity wave forcing toward both phases of MSAO. The significance of the present study lies in estimating the gravity wave momentum fluxes in the MLT region and quantifying their contribution toward the generation of MSAO over the low‐latitude for the first time.
Hydrodynamic planetary thermosphere model: 1. Response of the Earth's thermosphere to extreme solar EUV conditions and the significance of adiabatic cooling
Authors: Tian Feng , Kasting James F. , Liu Han‐Li , Roble Raymond G.
Published: May 2008

It has been suggested that the exobase temperature of early terrestrial planetary atmosphere could have reached over 10,000 K. Although such high exobase temperatures should have caused the major gases at the exobase to experience fast Jeans escape, and the entire thermosphere should have experienced hydrodynamic flow, hydrostatic equilibrium was assumed to be valid in this earlier model. In this paper we develop a multicomponent hydrodynamic thermosphere model to self‐consistently study the Earth's thermosphere under extreme solar EUV conditions. The model is validated against observations and other models for the present Earth's thermosphere. Simulations show that if forced in hydrostatic equilibrium and maintaining the current composition, the Earth's thermosphere could experience a fast transition to an atmospheric blowoff state when exposed to solar EUV radiation stronger than certain critical flux. When hydrodynamic flow and its associated adiabatic cooling are included, atmospheric blowoff is prevented and Earth's exobase temperature decreases with increasing solar EUV beyond the critical solar EUV flux. Simulations show that the transition of the thermosphere from the hydrostatic equilibrium regime to the hydrodynamic regime occurs when the exobase temperature reaches 7000 to 8000 K if atomic O and N dominate the upper thermosphere. The fast variations of the bulk motion velocities under different exobase temperatures suggest that the adiabatic cooling effect could have kept the exobase temperature lower than ∼1000 K if light gases such as atomic hydrogen were the dominant species in the Earth's thermosphere. We propose that hydrodynamic flow and associated adiabatic cooling should exist in the thermospheres of a broad range of early and/or close‐in terrestrial type planets and that the adiabatic cooling effect must be included in the energy balance in order to correctly estimate their thermospheric structures and their evolutionary paths.
On the roles of the northeast cold surge, the Borneo vortex, the Madden‐Julian Oscillation, and the Indian Ocean Dipole during the extreme 2006/2007 flood in southern Peninsular Malaysia
Authors: Tangang Fredolin T. , Juneng Liew , Salimun Ester , Vinayachandran P. N. , Seng Yap Kok , Reason C. J. C. , Behera S. K. , Yasunari T.
Published: May 2008

The mid‐December 2006 to late January 2007 flood in southern Peninsular Malaysia was the worst flood in a century and was caused by three extreme precipitation episodes. These extreme precipitation events were mainly associated with strong northeasterly winds over the South China Sea. In all cases, the northeasterlies penetrated anomalously far south and followed almost a straight trajectory. The elevated terrain over Sumatra and southern Peninsular Malaysia caused low‐level convergence. The strong easterly winds near Java associated with the Rossby wave‐type response to Madden‐Julian Oscillation (MJO) inhibited the counter‐clockwise turning of the northeasterlies and the formation of the Borneo vortex, which, in turn, enhanced the low‐level convergence over the region. The abrupt termination of the Indian Ocean Dipole (IOD) in December 2006 played a secondary role as warmer equatorial Indian Ocean helped in the MJO formation.
Pharmacology of stimulants prohibited by the World Anti‐Doping Agency (WADA)
Authors: Docherty J R
Published: May 2008

This review examines the pharmacology of stimulants prohibited by the World Anti‐Doping Agency (WADA). Stimulants that increase alertness/reduce fatigue or activate the cardiovascular system can include drugs like ephedrine available in many over‐the‐counter medicines. Others such as amphetamines, cocaine and hallucinogenic drugs, available on prescription or illegally, can modify mood. A total of 62 stimulants (61 chemical entities) are listed in the WADA List, prohibited in competition. Athletes may have stimulants in their body for one of three main reasons: inadvertent consumption in a propriety medicine; deliberate consumption for misuse as a recreational drug and deliberate consumption to enhance performance. The majority of stimulants on the list act on the monoaminergic systems: adrenergic (sympathetic, transmitter noradrenaline), dopaminergic (transmitter dopamine) and serotonergic (transmitter serotonin, 5‐HT). Sympathomimetic describes agents, which mimic sympathetic responses, and dopaminomimetic and serotoninomimetic can be used to describe actions on the dopamine and serotonin systems. However, many agents act to mimic more than one of these monoamines, so that a collective term of monoaminomimetic may be useful. Monoaminomimietic actions of stimulants can include blockade of re‐uptake of neurotransmitter, indirect release of neurotransmitter, direct activation of monoaminergic receptors. Many of the stimulants are amphetamines or amphetamine derivatives, including agents with abuse potential as recreational drugs. A number of agents are metabolized to amphetamine or metamphetamine. In addition to the monoaminomimetic agents, a small number of agents with different modes of action are on the list. A number of commonly used stimulants are not considered as Prohibited Substances.

British Journal of Pharmacology(2008)154, 606–622; doi:fn1
Gene doping: the hype and the reality
Authors: Wells D J
Published: May 2008

Some spectacular results from genetic manipulation of laboratory rodents and increasing developments in human gene therapy raise the spectre of genetic modification or ‘gene doping’ in sports. Candidate targets include the induction of muscle hypertrophy through overexpression of specific splice variants of insulin‐like growth factor‐1 or blockade of the action of myostatin, increasing oxygen delivery by raising the hematocrit through the use of erythropoietin, induction of angiogenesis with vascular endothelial growth factors or related molecules and changes in muscle phenotype through expression of peroxisome‐proliferator‐activated receptor‐ delta and associated molecules. Some of these potential genetic enhancements, particularly where the genetic modification and its action are confined to the muscles, may be undetectable using current tests. This had lead to exaggerated predictions that gene doping in athletics will be common within the next few years. However, a review of the methods of gene transfer and the current ‘state of the art’ in development of genetic treatments for human disease show that the prospects for gene doping remain essentially theoretical at present. Despite this conclusion, it will be important to continue to monitor improvements in the technology and to develop methods of detection, particularly those based on identifying patterns of changes in response to doping as opposed to the detection of specific agents.

British Journal of Pharmacology (2008) 154, 623–631; doi:fn1; published online 21 April 2008
Indirect androgen doping by oestrogen blockade in sports
Authors: Handelsman D J
Published: May 2008

Androgens can increase muscular mass and strength and remain the most frequently abused and widely available drugs used in sports doping. Banning the administration of natural or synthetic androgens has led to a variety of strategies to circumvent the ban of the most effective ergogenic agents for power sports. Among these, a variety of indirect androgen doping strategies aiming to produce a sustained rise in endogenous testosterone have been utilized. These include oestrogen blockade by drugs that act as oestrogen receptor antagonists (antioestrogen) or aromatase inhibitors. The physiological and pharmacological basis for the effects of oestrogen blockade in men, but not women, are reviewed.

British Journal of Pharmacology (2008) 154, 598–605; doi:fn1; published online 21 April 2008
Regulation of muscle mass by growth hormone and IGF‐I
Authors: Velloso C P
Published: May 2008

Growth hormone (GH) is widely used as a performance‐enhancing drug. One of its best‐characterized effects is increasing levels of circulating insulin‐like growth factor I (IGF‐I), which is primarily of hepatic origin. It also induces synthesis of IGF‐I in most non‐hepatic tissues. The effects of GH in promoting postnatal body growth are IGF‐I dependent, but IGF‐I‐independent functions are beginning to be elucidated. Although benefits of GH administration have been reported for those who suffer from GH deficiency, there is currently very little evidence to support an anabolic role for supraphysiological levels of systemic GH or IGF‐I in skeletal muscle of healthy individuals. There may be other performance‐enhancing effects of GH. In contrast, the hypertrophic effects of muscle‐specific IGF‐I infusion are well documented in animal models and muscle cell culture systems. Studies examining the molecular responses to hypertrophic stimuli in animals and humans frequently cite upregulation of IGF‐I messenger RNA or immunoreactivity. The circulatory/systemic (endocrine) and local (autocrine/paracrine) effects of GH and IGF‐I may have distinct effects on muscle mass regulation.

British Journal of Pharmacology (2008) 154, 557–568; doi:fn1
Drugs in sport: a scientist–athlete's perspective: from ambition to neurochemistry
Authors: Spedding M , Spedding C
Published: May 2008

This article, by the United Kingdom's last Olympic Marathon Medal winner, Charlie Spedding, and his brother, the pharmacologist, Michael Spedding, covers the difficulties posed by the availability of powerful drugs to ameliorate athletic performance, from an athlete's perspective, particularly in view of the fact that performances are becoming highly optimised with less margin for further physiological improvement. The authors have had long athletic careers and argue that doping not only devalues performance but sport, and exercise, as a whole. Furthermore, the neurotrophic and metabolic changes involved in exercise and training, which can be modified by drugs, are central to health and reflect a part of the epidemic in obesity.

British Journal of Pharmacology (2008) 154, 496–501; doi:fn1
The rush to adrenaline: drugs in sport acting on the β‐adrenergic system
Authors: Davis E , Loiacono R , Summers R J
Published: May 2008

Athletes attempt to improve performance with drugs that act on the β‐adrenergic system directly or indirectly. Of three β‐adrenoceptor (AR) subtypes, the β2‐AR is the main target in sport; they have bronchodilator and anabolic actions and enhance anti‐inflammatory actions of corticosteroids. Although demonstrable in animal experiments and humans, there is little evidence that these properties can significantly improve performance in trained athletes. Their actions may also be compromised by receptor desensitization and by common, naturally occurring receptor mutations (polymorphisms) that can influence receptor signalling and desensitization properties in individuals. Indirectly acting agents affect release and reuptake of noradrenaline and adrenaline, thereby influencing all AR subtypes including the three β‐ARs. These agents can have potent psychostimulant effects that provide an illusion of better performance that does not usually translate into improvement in practice. Amphetamines and cocaine also have considerable potential for cardiac damage. β‐AR antagonists (β‐blockers) are used in sports that require steadiness and accuracy, such as archery and shooting, where their ability to reduce heart rate and muscle tremor may improve performance. They have a deleterious effect in endurance sports because they reduce physical performance and maximum exercise load. Recent studies have identified that many β‐AR antagonists not only block the actions of agonists but also activate other (mitogen‐activated PK) signalling pathways influencing cell growth and fate. The concept that many compounds previously regarded as ‘blockers’ may express their own spectrum of pharmacological properties has potentially far‐reaching consequences for the use of drugs both therapeutically and illicitly.

British Journal of Pharmacology(2008)154, 584–597; doi:fn2
Pharmacology of anabolic steroids
Authors: Kicman A T
Published: May 2008

Athletes and bodybuilders have recognized for several decades that the use of anabolic steroids can promote muscle growth and strength but it is only relatively recently that these agents are being revisited for clinical purposes. Anabolic steroids are being considered for the treatment of cachexia associated with chronic disease states, and to address loss of muscle mass in the elderly, but nevertheless their efficacy still needs to be demonstrated in terms of improved physical function and quality of life. In sport, these agents are performance enhancers, this being particularly apparent in women, although there is a high risk of virilization despite the favourable myotrophic–androgenic dissociation that many xenobiotic steroids confer. Modulation of androgen receptor expression appears to be key to partial dissociation, with consideration of both intracellular steroid metabolism and the topology of the bound androgen receptor interacting with co‐activators. An anticatabolic effect, by interfering with glucocorticoid receptor expression, remains an attractive hypothesis. Behavioural changes by non‐genomic and genomic pathways probably help motivate training. Anabolic steroids continue to be the most common adverse finding in sport and, although apparently rare, designer steroids have been synthesized in an attempt to circumvent the dope test. Doping with anabolic steroids can result in damage to health, as recorded meticulously in the former German Democratic Republic. Even so, it is important not to exaggerate the medical risks associated with their administration for sporting or bodybuilding purposes but to emphasize to users that an attitude of personal invulnerability to their adverse effects is certainly misguided.

British Journal of Pharmacology(2008)154, 502–521; doi:fn1
Drugs in Sport
Authors: McGrath J C , Cowan D A
Published: May 2008

This themed issue of the British Journal of Pharmacology has been compiled and edited by Ian McGrath, Regius Professor of Physiology at University of Glasgow and David Cowan, Director of the Drug Control Centre at King's College London. It contains 11 articles covering the mechanisms of action of the major groups of drugs used illicitly in sport. The articles, written by experts in how drugs work, set out where drugs can or cannot affect sporting performance, how this relates to their legitimate medicinal use, their other detrimental effects and how they can be detected. Publication coincides with Olympic year, when sport is highlighted in the public mind and much speculation is made concerning the use of drugs. The articles provide a framework of expert, accurate knowledge to inform and facilitate these debates and to help to overcome the ill‐informed and dangerous anecdotal information by which sports men and women are persuaded to misuse drugs in the mistaken belief that this will improve their performance without present or future ill effects. A unique article is included by the Spedding brothers, Mike with a long career in drug discovery and Charlie, the 1984 Los Angeles Olympic Marathon Bronze Medallist and still the English National Marathon record holder. From their unique experience, they describe the insidious and unfair way that drug‐assisted performance undermines the ethos of sport and endangers the vital place of sport in maintaining the health of the population.

British Journal of Pharmacology (2008) 154, 493–495; doi:fn11
Acetylcholine beyond neurons: the non‐neuronal cholinergic system in humans
Authors: Wessler I , Kirkpatrick C J
Published: May 2008

Animal life is controlled by neurons and in this setting cholinergic neurons play an important role. Cholinergic neurons release ACh, which via nicotinic and muscarinic receptors (n‐ and mAChRs) mediate chemical neurotransmission, a highly integrative process. Thus, the organism responds to external and internal stimuli to maintain and optimize survival and mood. Blockade of cholinergic neurotransmission is followed by immediate death. However, cholinergic communication has been established from the beginning of life in primitive organisms such as bacteria, algae, protozoa, sponge and primitive plants and fungi, irrespective of neurons. Tubocurarine‐ and atropine‐sensitive effects are observed in plants indicating functional significance. All components of the cholinergic system (ChAT, ACh, n‐ and mAChRs, high‐affinity choline uptake, esterase) have been demonstrated in mammalian non‐neuronal cells, including those of humans. Embryonic stem cells (mice), epithelial, endothelial and immune cells synthesize ACh, which via differently expressed patterns of n‐ and mAChRs modulates cell activities to respond to internal or external stimuli. This helps to maintain and optimize cell function, such as proliferation, differentiation, formation of a physical barrier, migration, and ion and water movements. Blockade of n‐ and mACHRs on non‐innervated cells causes cellular dysfunction and/or cell death. Thus, cholinergic signalling in non‐neuronal cells is comparable to cholinergic neurotransmission. Dysfunction of the non‐neuronal cholinergic system is involved in the pathogenesis of diseases. Alterations have been detected in inflammatory processes and a pathobiologic role of non‐neuronal ACh in different diseases is discussed. The present article reviews recent findings about the non‐neuronal cholinergic system in humans.

British Journal of Pharmacology (2008) 154, 1558–1571; doi:10.1038/bjp.2008.185; published online 26 May 2008
Intrapulmonary and intravenous administrations of dihydroergotamine mesylate have similar cardiovascular effects in the conscious dog
Authors: Shrewsbury S B , Stonerook M , Okikawa J K
Published: May 2008

Background and purpose:

The effects of intrapulmonary artery (i.p.a.) administration of dihydroergotamine mesylate (DHE) were evaluated.

Experimental approach:

Conscious beagle dogs (n=4) were given DHE via the i.p.a. or i.v. route as two 0.014 mg kg−1 doses and a 0.14 mg kg−1 dose given 60 min apart. A recovery period of 45 h occurred before crossover to the alternative route. Physiological parameters were monitored by telemetry or direct measurement, and venous blood samples were collected for pharmacokinetic assessments.

Key results:

No meaningful differences between i.v. and i.p.a. treatments were observed for heart rate, systemic pressures and vascular pressures. Aortic resistance increased 8, 27 and 70%, respectively, following three doses of i.v. DHE compared with 11, 37 and 57%, respectively, with i.p.a. DHE. Carotid artery resistance increased 22, 40 and 87%, respectively, following three doses of i.v. DHE, compared with 17, 45 and 67%, respectively, following i.p.a. DHE. Increases in coronary artery resistance were of similar magnitude following i.v. and i.p.a. DHE administration. Increases in left ventricular systolic and diastolic pressures were seen following all doses of i.v. and i.p.a. DHE. Changes following DHE 0.014 mg kg−1 were minimal and not clinically significant. With DHE 0.14 mg kg−1 by either route, emesis was the most common adverse event.

Conclusions and implications:

DHE has comparable effects delivered via simulated deep inhalation (i.p.a.) or i.v. administration. The risk of cardiovascular complications is unlikely to be greater following inhalation of DHE.

British Journal of Pharmacology (2008) 154, 1254–1265; doi:10.1038/bjp.2008.187; published online 26 May 2008
Involvement of organic anion transporting polypeptides in the toxicity of hydrophilic pravastatin and lipophilic fluvastatin in rat skeletal myofibres
Authors: Sakamoto K , Mikami H , Kimura J
Published: May 2008

Background and purpose:

There is a discrepancy in the adverse effect of 3‐hydroxy‐3‐methylglutaryl–CoA reductase inhibitors, statins between the clinical reports and the studies using skeletal muscle cell models. In the clinical reports, both hydrophilic and lipophilic statins induce myotoxicity, whereas inin vitroexperiments using cell lines of myoblasts, lipophilic, but not hydrophilic, statins exert myotoxicity. We investigated the cause of this discrepancy.

Experimental approach:

Skeletal myofibres, fibroblasts and satellite cells were isolated from rat flexor digitorum brevis (FDB) muscles. Using these primary cultured cells as well as the L6 myoblast cell line, we compared the toxicity of hydrophilic pravastatin and lipophilic fluvastatin. The mRNA expression levels of possible drug transporters for statins were also examined in these cells using reverse transcriptase‐PCR.

Key results:

In the skeletal myofibres, both pravastatin and fluvastatin induced vacuolation and cell death, whereas in the mononuclear cells only fluvastatin, but not pravastatin, was toxic. mRNA of the organic anion transporting polypeptides (Oatp) 1a4 and Oatp2b1 were expressed in the skeletal myofibres, but not in mononucleate cells. Estrone‐3‐sulphate, a substrate for Oatps, attenuated the effects of pravastatin and fluvastatin in skeletal myofibres; p‐aminohippuric acid, a substrate for the organic anion transporters (Oats), but not Oatps, failed to do so.

Conclusions and implications:

The statin transporters Oatp1a4 and Oatp2b1 are expressed in rat skeletal myofibres, but not in satellite cells, fibroblasts or in L6 myoblasts. This is probably why hydrophilic pravastatin affects skeletal muscle, but not skeletal myoblasts.

British Journal of Pharmacology(2008)154, 1482–1490; doi:10.1038/bjp.2008.192; published online 26 May 2008
Effects of a non‐selective COX inhibitor and selective COX‐2 inhibitors on contractility of human and porcine uretersin vitroandin vivo
Authors: Chaignat V , Danuser H , Stoffel M H , Z'Brun S , Studer U E , Mevissen M
Published: May 2008

Background and purpose:

Anti‐inflammatory drugs are used in the treatment of acute renal colic. The aim of this study was to investigate the effects of selective COX‐2 inhibitors and the non‐selective COX inhibitor diclofenac on contractility of human and porcine uretersin vitroandin vivo, respectively. COX‐1 and COX‐2 receptors were identified in human ureter and kidney.

Experimental approach:

Human ureter samples were used alongside anin vivopig model with or without partial ureteral obstruction. COX‐1 and COX‐2 receptors were located in human ureters by immunohistochemistry.

Key results:

Diclofenac and valdecoxib significantly decreased the amplitude of electrically‐stimulated contractions in human uretersin vitro, the maximal effect (Vmax) being 120 and 14%, respectively. Valdecoxib was more potent in proximal specimens of human ureter (EC50=7.3 × 10−11 M) than in distal specimens (EC50=7.4 × 10−10 M), and theVmaxwas more marked in distal specimens (22.5%) than in proximal specimens (8.0%)in vitro. In thein vivopig model, parecoxib, when compared to the effect of its solvent, significantly decreased the maximal amplitude of contractions (Amax) in non‐obstructed ureters but not in obstructed ureters. Diclofenac had no effect on spontaneous contractions of porcine ureterin vivo. COX‐1 and COX‐2 receptors were found to be expressed in proximal and distal human ureter and in tubulus epithelia of the kidney.

Conclusions and implications:

Selective COX‐2 inhibitors decrease the contractility of non‐obstructed, but not obstructed, ureters of the pigin vivo, but have a minimal effect on electrically‐induced contractions of human uretersin vitro.

British Journal of Pharmacology(2008)154, 1297–1307; doi:10.1038/bjp.2008.193; published online 26 May 2008
Auranofin promotes retinoic acid‐ or dihydroxyvitamin D3‐mediated cell differentiation of promyelocytic leukaemia cells by increasing histone acetylation
Authors: Park S J , Kim M , Kim N H , Oh M K , Cho J K , Jin J Y , Kim I S
Published: May 2008

Background and purpose:

To investigate the molecular mechanism for the effect of auranofin on the induction of cell differentiation, the cellular events associated with differentiation were analysed in acute promyelocytic leukaemia (APL) cells.

Experimental approach:

The APL blasts from leukaemia patients and NB4 cells were cotreated with auroanofin and all‐trans‐retinoic acid (ATRA) at suboptimal concentration. The HL‐60 cells were treated with auroanofin and a subeffective dose of 1α,25‐dihydroxyvitamin D3 (1,25(OH)2 vit D3) in combination. The effect of auroanofin was investigated on histone acetylation at the promoter of differentiation‐associated genes and expression of cell cycle regulators.

Key results:

Treatment with auroanofin and ATRA cooperatively induced granulocytic differentiation of fresh APL blasts isolated from patients and NB4 cells. The combined treatment also increased reorganization of nuclear PML bodies and histone acetylation at the promoter of the RARβ2 gene. Auroanofin also promoted monocytic differentiation of the HL‐60 cells triggered by subeffective concentration of 1,25(OH)2 vit D3. The combined treatment of auroanofin and 1,25(OH)2 vit D3 stimulated histone acetylation at p21 promoters and increased the accumulation of cells in the G0/G1 phase. Consistent with this, the expressions of p21, p27 and PTEN were increased and the levels of cyclin A, Cdk2 and Cdk4 were decreased. Furthermore, the hypophosphorylated form of pRb was markedly increased in cotreated cells.

Conclusions and implications:

These findings indicate that auroanofin in combination with low doses of either ATRA or 1,25(OH)2 vit D3 promotes APL cell differentiation by enhancing histone acetylation and the expression of differentiation‐associated genes.

British Journal of Pharmacology (2008) 154, 1196–1205; doi:10.1038/bjp.2008.197; published online 26 May 2008
Anti‐convulsive and anti‐epileptic properties of brivaracetam (ucb 34714), a high‐affinity ligand for the synaptic vesicle protein, SV2A
Authors: Matagne A , Margineanu D‐G , Kenda B , Michel P , Klitgaard H
Published: May 2008

Background and purpose:

Screening of 12 000 compounds for binding affinity to the synaptic vesicle protein 2A (SV2A), identified a high‐affinity pyrrolidone derivative, brivaracetam (ucb 34714). This study examined its pharmacological profile in variousin vitroandin vivomodels of seizures and epilepsy, to evaluate its potential as a new antiepileptic drug.

Experimental approach:

The effects of brivaracetam and levetiracetam on epileptiform activity and seizure expression were examined in rat hippocampal slices, corneally kindled mice, audiogenic seizure–susceptible mice, maximal electroshock and pentylenetetrazol seizures in mice, hippocampal‐kindled rats, amygdala‐kindled rats and genetic absence epilepsy rats.

Key results:

Brivaracetam and levetiracetam reduced epileptiform responses in rat hippocampal slices, brivaracetam being most potent. Brivaracetam also differed from levetiracetam by its ability to protect against seizures in normal mice induced by a maximal electroshock or maximal dose of pentylenetetrazol. In corneally kindled mice and hippocampal‐kindled rats, brivaracetam induced potent protection against secondarily generalized motor seizures and showed anti‐kindling properties superior to levetiracetam. In amygdala‐kindled rats, brivaracetam induced a significant suppression in motor‐seizure severity and, contrary to levetiracetam, reduced the after‐discharge at a higher dose. Audiogenic seizure–susceptible mice were protected more potently against the expression of clonic convulsions by brivaracetam than by levetiracetam. Brivaracetam induced a more complete suppression of spontaneous spike‐and‐wave discharges in genetic absence epilepsy rats than levetiracetam.

Conclusions and implications:

Brivaracetam has higher potency and efficacy than levetiracetam as an anti‐seizure and anti‐epileptogenic agent in various experimental models of epilepsy, and a wide therapeutic index.

British Journal of Pharmacology(2008)154, 1662–1671; doi:fn1; published online 26 May 2008
Aldosterone induces endothelial dysfunction in resistance arteries from normotensive and hypertensive rats by increasing thromboxane A2 and prostacyclin
Authors: Xavier F E , Aras‐López R , Arroyo‐Villa I , Del Campo L , Salaices M , Rossoni L V , Ferrer M , Balfagón G
Published: May 2008

Background and purpose:

The present study was designed to assess whether cyclooxygenase‐2 (COX‐2) activation is involved in the effects of chronic aldosterone treatment on endothelial function of mesenteric resistance arteries (MRA) from Wistar‐Kyoto (WKY) and spontaneously hypertensive rats (SHR).

Experimental approach:

Relaxation to acetylcholine was measured in MRA from both untreated and aldosterone‐treated strains. Vasomotor responses to prostacyclin and U46619 were also analysed. Release of 6‐oxo‐prostaglandin (PG)F1α and thromboxane B2 (TxB2) was determined by enzyme immunoassay. COX‐2 protein expression was measured by western blot.

Key results:

Aldosterone reduced acetylcholine relaxation in MRA from both strains. In MRA from both aldosterone‐treated strains the COX‐1/2 or COX‐2 inhibitor (indomethacin and NS‐398, respectively), TxA2 synthesis inhibitor (furegrelate), prostacyclin synthesis inhibitor (tranylcypromine) or TxA2/ PGH2 receptor antagonist (SQ 29 548), but not COX‐1 inhibitor SC‐560, increased acetylcholine relaxation. In untreated rats this response was increased only in SHR. Prostacyclin elicited a biphasic vasomotor response: lower concentrations elicited relaxation, whereas higher concentrations elicited contraction that was reduced by SQ 29 548. Aldosterone increased the acetylcholine‐stimulated production of 6‐oxo‐PGF1α and TxB2 in MRA from both strains. COX‐2 expression was higher in both strains of rats treated with aldosterone.

Conclusions and implications:

Chronic treatment with aldosterone impaired endothelial function in MRA under normotensive and hypertensive conditions by increasing COX‐2‐derived prostacyclin and thromboxane A2. As endothelial dysfunction participates in the pathogenesis of many cardiovascular disorders we hypothesize that anti‐inflammatory drugs, specifically COX‐2 inhibitors, could ameliorate vascular damage in patients with elevated aldosterone production.

British Journal of Pharmacology (2008) 154, 1225–1235; doi:10.1038/bjp.2008.200; published online 26 May 2008
Ethyl pyruvate modulates acute inflammatory reactions in human endothelial cells in relation to the NF‐κB pathway
Authors: Johansson A‐S , Johansson‐Haque K , Okret S , Palmblad J
Published: May 2008

Background and purpose:

Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Ethanol (EtOH) reduces host defence systems, including cell adhesion. However, well‐known side effects of EtOH limit its clinical use as an anti‐inflammatory drug. Instead, ethyl pyruvate (EtP) may represent a better alternative. Here, we compared effects of EtP and EtOH on neutrophil recruitment and activation of human umbilical vein endothelial cells (HUVECs).

Experimental approach:

Adhesion of neutrophils to HUVEC monolayers, surface expression of intercellular cell adhesion molecule, E‐selectin, vascular cell adhesion molecule, release of interleukin (IL)‐8 and granulocyte colony‐stimulating factor (G‐CSF) from HUVECs were assessed as well as translocation of interleukin‐1 receptor‐associated kinase (IRAK‐1), the nuclear factor‐kappa B (NF‐κB) subunits p50, p65 and IκB‐α. NF‐κB activation was analysed with a luciferase reporter plasmid. Cells were stimulated with IL‐1β, lipopolysaccharide (LPS) or tumour necrosis factor‐α.

Key results:

EtP was several‐fold more potent than EtOH in reducing adhesion of neutrophils to activated HUVECs, generation of IL‐8 or G‐CSF and surface expression of the adhesion molecules. This last reaction was decreased by EtP even when added after cytokines or LPS. Translocation of IRAK‐1, IκBα and the NF‐κB p65 subunit to the HUVEC nucleus was inhibited by EtP for all stimuli, whereas the diminished p50 translocation was stimulus specific. When p65 was constitutively expressed in Cos7 cells, stimulation of an NF‐κB‐dependent reporter gene was not affected by EtP, suggesting that EtP acted upstream of gene activation.

Conclusions and implications:

EtP impedes adhesive, secretory and signalling events typical of the early inflammatory response in endothelial cells, suggesting EtP as a possible treatment for acute inflammatory conditions.

British Journal of Pharmacology (2008) 154, 1318–1326; doi:10.1038/bjp.2008.201; published online 26 May 2008
Anti‐inflammatory effects of dimemorfan on inflammatory cells and LPS‐induced endotoxin shock in mice
Authors: Wang Y‐H , Shen Y‐C , Liao J‐F , Li C‐H , Chou C‐Y , Liou K‐T , Chou Y‐C
Published: May 2008

Background and purpose:

Dimemorfan (a σ1 receptor agonist) showed neuroprotective properties in animal models of inflammation‐mediated neurodegenerative conditions, but its effects on inflammatory cells and systemic inflammation remain unclear.

Experimental approach:

The effects of dimemorfan on phorbol‐12‐myristate‐13‐acetate (PMA)‐ and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP)‐ induced neutrophils and lipopolysaccharide (LPS)‐activated microglial cells, as well as LPS‐induced endotoxin shock in mice were elucidated.

Key results:

Dimemorfan decreased PMA‐ and fMLP‐induced production of reactive oxygen species (ROS) and CD11b expression in neutrophils, through mechanisms independent of σ1 receptors, possibly by blocking ROS production and G‐protein‐mediated intracellular calcium increase. Dimemorfan also inhibited LPS‐induced ROS and nitric oxide (NO) production, as well as that of monocyte chemoattractant protein‐1 and tumour necrosis factor‐alpha (TNF‐α), by inhibition of NADPH oxidase (NOX) activity and suppression of iNOS up‐regulation through interfering with nuclear factor kappa‐B (NF‐κB) signalling in microglial cells. Treatment in vivo with dimemorfan (1 and 5 mg kg−1, i.p., at three successive times after LPS) decreased plasma TNF‐α, and neutrophil infiltration and oxidative stress in the lung and liver.

Conclusions and implications:

Our results suggest that dimemorfan acts via σ1 receptor‐independent mechanisms to modulate intracellular calcium increase, NOX activity, and NF‐κB signalling, resulting in inhibition of iNOS expression and NO production, and production of pro‐inflammatory cytokines. These effects may contribute its anti‐inflammatory action and protective effects against endotoxin shock in mice.

British Journal of Pharmacology (2008) 154, 1327–1338; doi:10.1038/bjp.2008.202; published online 26 May 2008
Strategies to reduce the risk of drug‐induced QT interval prolongation: a pharmaceutical company perspective
Authors: Pollard C E , Valentin J‐P , Hammond T G
Published: May 2008

Drug‐induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the ‘Thorough QT/QTc Study’—as defined in the clinical regulatory guidance (ICH E14)—are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least anin vivoQT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG andin vivonon‐clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high‐benefit drugs for serious indications may never be marketed.

British Journal of Pharmacology(2008)154, 1538–1543; doi:fn1; published online 26 May 2008