bluuebunny/crossref_metadata_2025_split huggingface dataset:
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