British Journal (british + journal)

Distribution by Scientific Domains

Selected Abstracts


Article first published online: 17 NOV 200
No abstract is available for this article. [source]


Article first published online: 17 NOV 200
No abstract is available for this article. [source]


Article first published online: 17 NOV 200
No abstract is available for this article. [source]


Article first published online: 17 NOV 200
No abstract is available for this article. [source]


Article first published online: 17 NOV 200
No abstract is available for this article. [source]

On the evolution of statistical methods as applied to clinical trials

D. Machin
Abstract. This paper describes how statistical methods have evolved in parallel with activities associated with randomized control trials. In particular we emphasize the pivotal role of two papers published in British Journal of Cancer, and the paper describing the Cox proportional hazards model. In addition, the importance of early papers on estimating the sample size required for trials is highlighted. Later developments including the increasing roles for competing risks, multilevel modelling and Bayesian methodologies are described. The interplay between computer software and statistical methodological developments is stressed. Finally some future directions are indicated. [source]

Commentary: Brunker C. (2006).

Assessment of sedated head-injured patients using the Glasgow Coma Scale: an audit
The Glasgow Coma Scale (GCS) is widely used to assess head-injured patients. However, patients with acute severe head injury are typically managed with varying doses of sedative drugs that may interfere with GCS assessments. There is a question as to whether GCS assessments are useful and justified when the patient is sedated. The limited literature available is briefly reviewed. The aim of the audit described in this paper was to gain an overview of current practice among the neuroscience intensive care units in the UK, in search of any consensus. Thirty questionnaires were distributed and 23 returned (a 77% response). The results show considerable variations in practice and, in particular, differences between those units that treat only neuroscience patients and those that manage general intensive care patients as well. This audit demonstrates a lack of clear consensus and highlights the need for more research. Abstract reprinted from the British Journal of Neuroscience Nursing, volume 2, Brunker C, ,Assessment of sedated head-injured patients using the Glasgow Coma Scale: an Audit.', pages 276,280. © 2006, reproduced with permission from MA Healthcare Limited. [source]

Latest news and product developments

PRESCRIBER, Issue 19 2007
Article first published online: 22 NOV 200
UK data suggest OCs may reduce cancer risk The latest analysis of the RCGP oral contraception (OC) study suggests that oral contraceptives may be associated with an overall reduction in the risk of cancer (Br Med J online: 11 September 2007; doi:10.1136/bmj.39289. 649410.55). The cohort of 46 000 women provided 744 000 woman-years for ever use of an oral contraceptive and 339 000 woman-years of never use. Longer use was associated with increasing risks of cervical (RR 2.73), and pituitary or CNS (RR 5.51) cancers, but decreasing risks of uterine (RR 0.57) and ovarian (RR 0.38) cancers. OC use was also associated with a lower overall risk of colorectal cancers. The overall risk of any cancer was reduced by 12 per cent (RR 0.88). CombAT two-year data Two-year data revealed at the 29th Congress of the Société Internationale d'Urologie in Paris in September show that dutasteride (Avodart) and tamsulosin combination therapy provides significantly improved symptom control in BPH compared with either therapy alone. The Combination therapy with Avodart (dutasteride) and tamsulosin (CombAT) study took over 4800 eligible men (age ,50 years with a prostate volume ,30cc, serum PSA level ,1.5-10ng per ml and IPSS ,12) who received placebo for four weeks before being randomised in a 1:1:1 ratio to either dutasteride monotherapy (0.5mg per day), tamsulosin monotherapy (0.4mg per day) or a combination of both drugs. At two years the primary efficacy end-point was achieved: combination therapy was significantly more effective than either monotherapy, and continuous improvement could be observed throughout the two years. The combination therapy was also well tolerated, although drug-related adverse events were more common with combination therapy (24 per cent) than either monotherapy (dutasteride 18 per cent, tamsulosin 14 per cent). Dutasteride, a 5-, reductase inhibitor, has been shown to be more effective for long-term use in men than tamsulosin, while tamsulosin, an alpha blocker, has been shown to be effective in the short term. CombAT is the first study to demonstrate that the combination therapy of both drugs could lead to greater symptom improvement over time than an alpha blocker alone. Aliskiren - new class of antihypertensive Novartis has introduced aliskiren (Rasilez), the first direct renin inhibitor for the treatment of hypertension. It is likely to be used in combination with other agents but is also licensed as monotherapy. The commonest adverse effect is diarrhoea. At the recommended dose of 150-300mg per day, a month's treatment costs £19.80-£23.80. MHRA updates drug safety advice The balance of benefit and risks from HRT may be more favourable for younger women, the MHRA says in its monthly bulletin, Drug Update (September 2007). GPs considering prescribing HRT should evaluate the potential risks and benefits for each individual, the MHRA says. The bulletin summarises the risks of cardiovascular events and cancers associated with HRT. Cardiovascular risk is a particular concern for women over 60, whose baseline risk is high; although evidence for the safety of HRT in younger women is limited, their baseline risk is lower. Overall, the lowest dose of HRT should be used for the shortest possible time, and HRT should be prescribed to prevent osteoporosis only when alternatives are not suitable. The MHRA also advises in the bulletin that: Individual risk of stroke, breast cancer and endometrial cancer should be considered before prescribing tibolone (Livial). Nasal formulations of desmopressin are no longer indicated for primary nocturnal enuresis; prescribers are reminded to adhere to product guidance on fluid intake. Patients and carers should be warned of the risk of psychiatric effects associated with corticosteroids; symptoms may develop within a few days or weeks in children and adults, and may be more common at higher doses. Patients taking steroids for more than three weeks are reminded not to stop treatment abruptly. A list of questions and answers for patients is available at The use of parenteral B vitamins plus ascorbic acid (Pabrinex) may rarely be associated with severe allergic reactions, but this should not preclude its use for patients who need it. Study claims statin switch may increase CV morbidity Switching patients from atorvastatin (Lipitor) to simvastatin may increase the risk of cardiovascular events, according to a UK study presented at the European Society of Cardiology Congress in Vienna. The analysis, from The Health Improvement Network database, included 11 520 patients taking atorvastatin for at least six months, of whom 2511 were switched to simvastatin. Switching was associated with a 30 per cent increase in the relative risk of cardiovascular events, though absolute figures have not been reported. Patients who were switched were also more likely to discontinue treatment (21 vs 8 per cent of those continuing atorvastatin). Details of the conduct of the study, which will be published in the British Journal of Cardiology, are not available. Glitazones controversy rumbles on New systematic reviews have fuelled the controversy over the cardiac safety of rosiglitazone and pioglitazone. A meta-analysis of four trials involving 14 291 patients and lasting one to four years found that rosiglitazone was associated with a significantly increased risk of myocardial infarction (relative risk, RR, 1.42) and heart failure (RR 2.09) but not cardiovascular mortality (RR 0.90) (J Am Med Assoc 2007;298:1189-95). The second review included 19 trials of pioglitazone involving 16 390 patients, with follow-up from four months to 3.5 years. Pioglitazone was associated with a lower risk of composite events (death, myocardial infarction, stroke; hazard ratio, HR, 0.82) but an increased risk of serious heart failure (HR 1.41) (J Am Med Assoc 2007;298: 1180-8). Neither review reported significant heterogeneity between the included studies. Another systematic review of eight controlled and cohort studies concluded that metformin is the only antidiabetic drug not associated with an increased risk of harm in patients with diabetes and heart failure (Br Med J Online First 30 August; doi:10.1136/bmj.39314. 620174.80). The Canadian authors found methodological problems with all studies, and concluded that results for sulphonylureas were conflicting due to differences between the studies. Asthma prescribing education Health professionals need more education about rational prescribing for children with asthma, say researchers from Australia (Arch Dis Child online: 4 September 2007; doi: 10. 1136/adc.2007.119834). Analysing trends in asthma medication prescriptions for children in the UK between 2000 and 2006, they found the proportion of steroid inhalers prescribed as combinations increased from 2.7 per cent in 2000 to 25 per cent in 2006. The authors say this excessive increase is inconsistent with guidance that steroid-only inhalers should be the mainstay for most people with asthma. Copyright © 2007 Wiley Interface Ltd [source]

Evolution of methodological standards in surgical trials

Carleen Ellis
Background: The Consolidated Standards of Reporting Trials (CONSORT) Statement outlines acceptable ways of performing and reporting clinical trials. The objective of the present study was to identify evolving patterns in the methodological standards of surgical trials. Methods: Compliance with 12 key standards from the CONSORT statement were evaluated in 490 trials published in either the ANZ Journal of Surgery or the British Journal of Surgery between January 1969 and December 2003. Results: There has been an irregular but progressive improvement in the methodological standards of published trials. The criteria with the greatest improvement related to estimation of sample size, randomization, concealment of the allocated intervention, baseline comparisons, and the method of expressing outcomes. Compliance rates were <50% for three criteria during the last decade of the review, that is, concealment of the allocated intervention, blindness of assessment, and the method of expressing outcomes. Conclusion: The results of surgical trials need to be interpreted with care. [source]

British Journal of Haematology

Papers to be published in forthcoming issues
No abstract is available for this article. [source]

British Journal of Haematology

Papers to be published in forthcoming issues
No abstract is available for this article. [source]

British Journal of Haematology

Papers to be published in forthcoming issues
No abstract is available for this article. [source]

Scholarship of Consequence: New Directions for the British Journal of Management

Mustafa F. Özbilgin
First page of article [source]

Glass Cliffs Are Not So Easily Scaled: On the Precariousness of Female CEOs' Positions

Michelle K. Ryan
Adams, Gupta and Leeth (British Journal of Management, 2008) question the universality of the glass cliff after finding no differences in US companies' financial performance either before or after the appointment of male and female CEOs. We agree that glass cliffs are neither universal nor ineluctable, but urge caution in interpreting this null result. This is because the nature and significance of women's precarious leadership positions becomes more apparent when one goes beyond archival financial data and compares the broad circumstances of male and female leaders. Here multiple strands of research suggest that above the glass ceiling the playing field for men and women is far from level. [source]

Changing Public Service Organizations: Current Perspectives and Future Prospects

Ewan Ferlie
As governments and public service organizations across the globe engage in strategies of institutional and organizational change, it is timely to examine current developments and a future research agenda for public governance and management. The paper commences with reflections on the state of the field, based on an analysis of papers published in the British Journal of Management over the last decade. While there was some variation apparent across the set, the ,typical' article was found to be influenced by the discipline of organizational behaviour, set within the health-care sector, using case-study methods within field-based studies, and investigating shifts in roles and relationships and the management of change. It has also in the past been UK-centric, though the journal editorial policy and our own article call for a stronger international and comparative focus in the future. The second section of the article summarizes the articles and themes contained in this collection of papers on public service organizations. The third section explores a possible research agenda for the future, arguing for the significance of public sector research for the understanding of management more generally, and for examining the interface between private and public organizations (an increasingly common phenomenon). We suggest the need to set public services research in policy and political contexts, and suggest this may reveal organizational processes of wide interest. We call for a wider set of disciplines to engage in public management research, and to engage in moving the agenda from the study of efficiency to effectiveness as defined by a variety of stakeholders. We address the issue of how far public management researchers should become directly engaged with the world of policy and suggest that whether researchers engage in Mode 1 or Mode 2 research, their work would benefit from a stronger theoretical base. [source]

Guidelines for reporting experiments involving animals: the ARRIVE guidelines

JC McGrath
British Journal of Pharmacology (BJP) is pleased to publish a new set of guidelines for reporting research involving animals, simultaneously with several other journals; the ,ARRIVE' guidelines (Animals in Research: Reporting In Vivo Experiments). This editorial summarizes the background to the guidelines, gives our view of their significance, considers aspects of specific relevance to pharmacology, re-states BJP's guidelines for authors on animal experiments and indicates our commitment to carrying on discussion of this important topic. We also invite feedback via the British Pharmacological Society website. [source]

Nitrite, NO and hypoxic vasodilation

Jason D Allen
The ability to deliver oxygen and other nutrients to working tissues at a rate acutely matched to demand is the quintessential function of the cardiovascular system. Thus, an understanding of the biochemical mechanisms involved in hypoxic vasodilation remains a major goal in vascular biology. Nitric oxide, its metabolites, and oxidation status are recognized as playing important roles in this process. Previous work examining how nitrite can be converted to bioactive nitric oxide (NO) under hypoxic conditions has focused on the role of the red blood cell and haemoglobin. In a recent issue of the British Journal of Pharmacology, Pinder et al. demonstrate that plasma nitrite, in the absence of haemoglobin, is capable of increasing the maximal dilation of rabbit aortic rings under hypoxic conditions. Furthermore, they demonstrate that this relaxation can occur with or without the endothelium. This observation, even if it is only a small proportion of the relaxant activity of nitrite, highlights how NO metabolites may be involved in a variety of mechanisms of vessel control. [source]

Mediators and receptors in the resolution of inflammation: drug targeting opportunities

AG Stewart
The active resolution of inflammation is recognized as offering new opportunities to generate novel anti-inflammatory agents. The emerging appreciation of the importance of active resolution in regulation of inflammation also creates an imperative to examine developing and existing agents for their potential to influence these pathways. This themed issue of the British Journal of Pharmacology contains papers that discuss the roles of annexin-1, lipoxins and related lipid products of fish oils as well as other mechanisms involved in active resolution and their receptor targets. This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit [source]

Persistent (current) in the face of adversity , A new class of cardiac anti-ischaemic compounds on the horizon?

David A Saint
Although a persistent component of the sodium current (INaP) was described in cardiac tissue about three decades ago, its physiological role and potential as a therapeutic target was not immediately apparent. Subsequent demonstrations that INaP is enhanced by hypoxia and ischaemia, and that Na+ influx via INaP may contribute to cellular damage, diastolic dysfunction and arrhythmias during ischaemia and reperfusion, raised interest in INaP as a target for anti-ischaemic drugs. Several agents have now been developed to clinical stages, which have INaP block as either their main action, or as a useful co-effect. In this issue of the British Journal of Pharmacology, Vacher et al. report the anti-ischaemic actions of F15845, which appears to exhibit the most selective block of INaP yet described. Its efficacy in animal models of angina raises the prospect of new, specific, INaP blockers that may represent a largely unexploited opportunity for a new class of anti-ischaemic compounds. [source]

Activation of the transient receptor potential vanilloid-1 (TRPV1) channel opens the gate for pain relief

G Jancsó
Pharmacological modulation of the transient receptor potential vanilloid-1 (TRPV1) receptor function offers a promising means of producing pain relief at the level of the primary sensory neuron. In this issue of the BJP, the pharmacological approaches and the available experimental data that focus on the TRPV1 receptor to achieve therapeutically useful alleviation of pain and inflammation are reviewed. The potentials to inactivate TRPV1 receptor function by site- and modality-specific TRPV1 antagonists, uncompetitive TRPV1 blockers and drugs interfering with TRPV1 sensitization, are evaluated. A crucial issue of producing pain relief at the level of the nocisensor remains whether it can be achieved solely through inactivation of the TRPV1 receptor or TRPV1 agonist-induced defunctionalization of the whole primary afferent neuron is required. The accumulated evidence indicates that both pharmacological modulation of the intracellular trafficking of the TRPV1 receptor and defunctionalization of the nocisensors by TRPV1 agonists are promising novel approaches to tame the TRPV1 receptor. British Journal of Pharmacology (2008) 155, 1139,1141; doi:fn1; published online 10 November 2008 [source]

Intra- and extrarenal arteries exhibit different profiles of contractile responses in high glucose conditions

K Nobe
Background and purpose: The renal artery (RA) has been extensively investigated for the assessment of renal vascular function/dysfunction; however, few studies have focused on the intrarenal vasculature. Experimental approach: We devised a microvascular force measurement system, which allowed us to measure contractions of interlobar arteries (ILA), isolated from within the mouse kidney and prepared without endothelium. Key results: KCl (50 mM) induced similar force development in the aorta and RA but responses in the ILA were about 50% lower. Treatment of RA with 10 ,M phenylephrine (PE), 10 nM U46619 (thromboxane A2 analogue) or 10 ,M prostaglandin F2, elicited a response greater than 150% of that induced by KCl. In ILA, 10 nM U46619 elicited a response that was 130% of the KCl-induced response; however, other agonists induced levels similar to that induced by KCl. High glucose conditions (22.2 mM glucose) significantly enhanced responses in RA and ILA to PE or U46619 stimulation. This enhancement was suppressed by rottlerin, a calcium-independent PKC inhibitor, indicating that glucose-dependent, enhanced small vessel contractility in the kidney was linked to the activation of calcium-independent PKC. Conclusion and implications: Extra- and intrarenal arteries exhibit different profiles of agonist-induced contractions. In ILA, only U46619 enhanced small vessel contractility in the kidney, which might lead to renal dysfunction and nephropathy through reduced intrarenal blood flow rate. A model has been established, which will allow the assessment of contractile responses of intrarenal arteries from murine models of renal disease, including type 2 diabetes. British Journal of Pharmacology (2008) 155, 1204,1213; doi:10.1038/bjp.2008.365; published online 22 September 2008 [source]

An endogenous regulator of inflammation, resolvin E1, modulates osteoclast differentiation and bone resorption

B S Herrera
Background and purpose: The inflammation-resolving lipid mediator resolvin E1 (RvE1) effectively stops inflammation-induced bone loss in vivo in experimental periodontitis. It was of interest to determine whether RvE1 has direct actions on osteoclast (OC) development and bone resorption. Experimental approach: Primary OC cultures derived from mouse bone marrow were treated with RvE1 and analysed for OC differentiation, cell survival and bone substrate resorption. Receptor binding was measured using radiolabelled RvE1. Nuclear factor (NF)-,B activation and Akt phosphorylation were determined with western blotting. Lipid mediator production was assessed with liquid chromatography tandem mass spectrometry. Key results: OC growth and resorption pit formation were markedly decreased in the presence of RvE1. OC differentiation was inhibited by RvE1 as demonstrated by decreased number of multinuclear OC, a delay in the time course of OC development and attenuation of receptor activator of NF-,B ligand-induced nuclear translocation of the p50 subunit of NF-,B. OC survival and apoptosis were not altered by RvE1. Messenger RNA for both receptors of RvE1, ChemR23 and BLT1 is expressed in OC cultures. Leukotriene B4 (LTB4) competed with [3H]RvE1 binding on OC cell membrane preparations, and the LTB4 antagonist U75302 prevented RvE1 inhibition of OC growth, indicating that BLT1 mediates RvE1 actions on OC. Primary OC synthesized the RvE1 precursor 18R -hydroxy-eicosapentaenoic acid and LTB4. Co-incubation of OC with peripheral blood neutrophils resulted in transcellular RvE1 biosynthesis. Conclusions and implications: These results indicate that RvE1 inhibits OC growth and bone resorption by interfering with OC differentiation. The bone-sparing actions of RvE1 are in addition to inflammation resolution, a direct action in bone remodelling. British Journal of Pharmacology (2008) 155, 1214,1223; doi:10.1038/bjp.2008.367; published online 22 September 2008 [source]

Neuropeptide Y Y2 receptor in health and disease

S L Parker
British Journal of Pharmacology (2008) 155, 1307; doi:10.1038/bjp.2008.376 [source]

Potential importance of alterations in hydrogen sulphide (H2S) bioavailability in diabetes

D J Lefer
British Journal of Pharmacology (2008) 155, 1308; doi:10.1038/bjp.2008.377 [source]

CGRP blockers in migraine therapy: where do they act?

L Edvinsson
Calcitonin gene-related peptide (CGRP) is expressed throughout the CNS and peripheral nervous system, consistent with control of vasodilatation, nociception, motor function, secretion and olfaction. ,CGRP is prominently localized in primary afferent C and A, fibres of spinal and trigeminal ganglia. Activation of the trigeminal nerve results in antidromic release of CGRP, acting through a CGRP1 receptor. Antagonists of CGRP1 receptors reduce signalling in the trigeminovascular pathway at multiple sites, putatively inside the blood,brain barrier. Other ways of interacting with CGRP mechanisms have appeared limiting the availability of CGRP in the circulation with a specific CGRP antibody or with a CGRP-binding RNA-Spiegelmer. Either way reduces neurogenic inflammation and attenuates signalling within the trigeminovascular pathway. Specific CGRP receptor blockade has been shown to reduce the effect of released CGRP and to abort acute migraine attacks. The novel approach of reducing available CGRP is limited by the blood,brain barrier; its usefulness may be more as prophylaxis rather than as acute treatment of migraine. British Journal of Pharmacology (2008) 155, 967,969; doi:fn1; published online 8 September 2008 [source]

Virodhamine relaxes the human pulmonary artery through the endothelial cannabinoid receptor and indirectly through a COX product

H Koz, owska
Background and purpose: The endocannabinoid virodhamine is a partial agonist at the cannabinoid CB1 receptor and a full agonist at the CB2 receptor, and relaxes rat mesenteric arteries through endothelial cannabinoid receptors. Its concentration in the periphery exceeds that of the endocannabinoid anandamide. Here, we examined the influence of virodhamine on the human pulmonary artery. Experimental approach: Isolated human pulmonary arteries were obtained during resections for lung carcinoma. Vasorelaxant effects of virodhamine were examined on endothelium-intact vessels precontracted with 5-HT or KCl. Key results: Virodhamine, unlike WIN 55,212-2, relaxed 5-HT-precontracted vessels concentration dependently. The effect of virodhamine was reduced by endothelium denudation, two antagonists of the endothelial cannabinoid receptor, cannabidiol and O-1918, and a high concentration of the CB1 receptor antagonist rimonabant (5 ,M), but only slightly attenuated by the NOS inhibitor L -NAME and not affected by a lower concentration of rimonabant (100 nM) or by the CB2 and vanilloid receptor antagonists SR 144528 and capsazepine, respectively. The COX inhibitor indomethacin and the fatty acid amide hydrolase inhibitor URB597 and combined administration of selective blockers of small (apamin) and intermediate and large (charybdotoxin) conductance Ca2+ -activated K+ channels attenuated virodhamine-induced relaxation. The vasorelaxant potency of virodhamine was lower in KCl- than in 5-HT-precontracted preparations. Conclusions and implications: Virodhamine relaxes the human pulmonary artery through the putative endothelial cannabinoid receptor and indirectly through a COX-derived vasorelaxant prostanoid formed from the virodhamine metabolite, arachidonic acid. One or both of these mechanisms may stimulate vasorelaxant Ca2+ -activated K+ channels. British Journal of Pharmacology (2008) 155, 1034,1042; doi:10.1038/bjp.2008.371; published online 22 September 2008 [source]

Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitro

M Aulí
Background and purpose: To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. Experimental approach: Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. Key results: Strips developed weak spontaneous rhythmic contractions (3.67±0.49 g, 2.54±0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 ,M). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1,100 ,M) inhibited spontaneous contractions. Latency of off-contractions and nicotine responses were reduced by NG -nitro- L -arginine (1 mM) and blocked after further addition of apamin (1 ,M) or the P2Y1 receptor antagonist MRS 2179 (10 ,M) and were unaffected by the P2X antagonist NF279 (10 ,M) or ,-chymotrypsin (10 U mL,1). Amplitude of on- and off-contractions was reduced by atropine (1 ,M) and the selective NK2 receptor antagonist Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (1 ,M). MRS 2179 reduced the amplitude of EFS on- and off-contractions without altering direct muscular contractions induced by ACh (1 nM,1 mM) or substance P (1 nM,10 ,M). Conclusions and implications: Latency of EFS-induced off-contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y1 receptors through apamin-sensitive K+ channels. EFS-induced on- and off-contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK2 receptors. Prejunctional P2Y1 receptors might modulate the activity of excitatory EMNs. P2Y1 and NK2 receptors might be therapeutic targets for colonic motor disorders. British Journal of Pharmacology (2008) 155, 1043,1055; doi:10.1038/bjp.2008.332; published online 1 September 2008 [source]

Epigenetic biomarkers in psychiatric disorders

J Peedicayil
The discovery of biomarkers in psychiatric disorders may help in the diagnosis, prevention and treatment of patients with these disorders. Here, I discuss the potential role of epigenetic biomarkers, that is, epigenetically altered genes and/or expression patterns of proteins or metabolites, in psychiatric disorders. Before epigenetic biomarkers can be clinically applied in these disorders, several issues need to be addressed. These include establishing a connection between biomarkers and the disease process; determining the predictive quality of the biomarkers; determining the effects of disease heterogeneity on the biomarkers; and identifying sample sources for the biomarkers that are easily accessible for testing. British Journal of Pharmacology (2008) 155, 795,796; doi:10.1038/bjp.2008.254; published online 23 June 2008 [source]

Kallikrein inhibitors limit kinin B2 antagonist-induced progression of oedematous to haemorrhagic pancreatitis in rats

T Griesbacher
Background and purpose: Exocrine hyperstimulation with caerulein is an established model for oedematous acute pancreatitis. Prevention of oedema formation by bradykinin B2 receptor antagonists induces a progression to a haemorrhagic course in this model. We have investigated whether increased kallikrein activity in the pancreas is responsible for vascular damage and whether this could be prevented by selective kallikrein inhibitors. Experimental approach: Caerulein was infused i.v. and vascular damage was assessed by histological evaluation and determination of haemoglobin accumulation in the tissue. In addition, oedema formation, tissue and plasma kallikrein (PK) activities and the endogenous kallikrein inhibitors ,1 -antitrypsin (,1 -AT) and ,2 -macroglobulin (,2 -M) were measured. Key results: Haemorrhagic lesions induced by icatibant in caerulein-induced pancreatitis were associated with a reduction in ,1 -AT and ,2 -M in the pancreas and a concomitant augmentation of tissue kallikrein (TK) activity. The TK inhibitor VA999024 (previously FE999024), or its combination with the PK inhibitor VA999026 (previously FE999026), inhibited oedema formation to the same extent but did not induce vascular damage. Furthermore, VA999024 inhibited TK activity. When icatibant was combined with VA999024 and VA999026, progression from oedematous to haemorrhagic pancreatitis was abolished. Conclusions and implications: Reduced oedema formation by B2 antagonists prevented influx of endogenous kallikrein inhibitors and led to an excessive activity of kallikrein in the pancreas leading to vascular damage. This can be prevented by a combined inhibition of both tissue-type and plasma-type kallikrein. Kallikrein inhibitors thus should be further evaluated for their therapeutic potential in preventing haemorrhagic lesions in acute pancreatitis. British Journal of Pharmacology (2008) 155, 865,874; doi:10.1038/bjp.2008.321; published online 11 August 2008 [source]

Cultured CD4T cells and primary human lymphocytes express hOATPs: intracellular accumulation of saquinavir and lopinavir

O Janneh
Background and purpose: Drug efflux tranporters (P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP)) limit the cellular uptake of human immunodeficiency virus protease inhibitors but the contribution of influx transporters in cells that (over)express P-gp or MRP is less clear. Here, we studied the expression of one influx transporter system, human organic anion-transporting polypeptide (hOATP), in some T-cell lines (CEM, CEMVBL, CEME1000) and in peripheral blood mononuclear cells (PBMCs) and examined the effects of manipulation of influx/efflux transporters on the uptake of saquinavir and lopinavir. Experimental approach: The expression of hOATPs was studied by PCR. We used hOATP substrate or inhibitor (estrone-3-sulphate (E-3-S) or montelukast, respectively) and inhibitors of P-gp (XR9576) and MRP (MK571 and frusemide) to study functional interactions between influx and efflux transporters in the uptake of saquinavir and lopinavir. Lipophilicity of the drugs was measured by octanol/saline partition coefficient. Key results: CEM cells, their variants and PBMCs express various hOATP isoforms, with OATP3A1 detected in all of the cells. MK571, XR9576 and frusemide increased the uptake of saquinavir and lopinavir. E-3-S and montelukast reduced the uptake of saquinavir and lopinavir in some, but not all, of the cells. Pretreatment of the cells with MK571, XR9576 or frusemide, followed by E-3-S co-incubation reduced the cellular accumulation of saquinavir and lopinavir. Lopinavir is much more lipophilic than saquinavir. Conclusions and implications: Human OATPs, MRP, P-gp and lipophilicity determine the cellular uptake and retention of saquinavir and lopinavir. These data may have important implications for drug,drug interactions, drug safety and efficacy. British Journal of Pharmacology (2008) 155, 875,883; doi:10.1038/bjp.2008.320; published online 18 August 2008 [source]