Abstract:
:Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Bass AS,Darpo B,Breidenbach A,Bruse K,Feldman HS,Garnes D,Hammond T,Haverkamp W,January C,Koerner J,Lawrence C,Leishman D,Roden D,Valentin JP,Vos MA,Zhou YY,Karluss T,Sager Pdoi
10.1038/bjp.2008.279subject
Has Abstractpub_date
2008-08-01 00:00:00pages
1491-501issue
7eissn
0007-1188issn
1476-5381pii
bjp2008279journal_volume
154pub_type
abstract:BACKGROUND AND PURPOSE:Red wine polyphenols (RWPs) inhibit the expression of vascular endothelial growth factor (VEGF), a major pro-angiogenic and pro-atherosclerotic factor, in vascular smooth muscle cells (VSMCs). The aim of this study was to identify which red wine polyphenols were inhibitory and to determine the me...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706843
更新日期:2006-10-01 00:00:00
abstract::1. Changes induced in the electrocorticogram by the bilateral perfusion of (+)-amphetamine into the mesencephalic reticular formation (MRF) have been studied in cat encéphale isolé preparations. 2. (+)-Amphetamine, applied for 5 min in the MRF, mimicked the electrocortical desynchronization induced by the perfusion of...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb08424.x
更新日期:1977-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Recombinant human erythropoietin (rHuEPO) is currently the mainstay of renal anaemia treatment. Recently, rHuEPO has been shown to provide pleiotrophic tissue protection in various pathological conditions. However, the benefits of rHuEPO beyond anaemia treatment are limited because it increases r...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2012.02123.x
更新日期:2013-01-01 00:00:00
abstract::1. The haemodynamic effects of propranolol, practolol and 4-hydroxypropranolol have been compared in anaesthetized dogs both at free heart rates and at heart rates fixed by electrical pacing. All three drugs produced a fall in heart rate at the lowest dose of 0.09 mg/kg.2. Practolol caused less change in dP/dt, cardia...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1972.tb08076.x
更新日期:1972-06-01 00:00:00
abstract::1. Pharmacological inhibitors of protein kinase A (PKA) and protein phosphatases 1/2A were used to determine whether basal L-type Ca(2+) current (I(Ca)) observed in the absence of exogenous beta-adrenergic receptor stimulation is sustained by PKA-mediated phosphorylation. Amphotericin B was used to record whole-cell I...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706809
更新日期:2006-08-01 00:00:00
abstract::Antidromic stimulation of sensory peripheral branches of the trigeminal system (mental nerve) leads to cutaneous vasodilatation and increases vascular permeability in the rat. Antidromic vasodilatation is observed only at high intensity stimulation (10 V, 15 Hz, 0.2 or 5 ms) supporting the participation of afferent C-...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb16144.x
更新日期:1985-03-01 00:00:00
abstract::The characteristics of the rat epidydimal adipocyte beta-adrenoceptor have been examined using lipolysis and cyclic AMP accumulation in adipocytes as well as adenylate cyclase activity in fat cell membranes. The pA2 values corrected for binding to bovine serum albumin of the selective antagonists betaxolol (beta 1-sel...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-01-01 00:00:00
abstract::1. Aggressive behaviour was elicited in rats that had been deprived of food for 20 h daily (starved), by chronic administration of Cannabis sativa extract or (-)-Delta(9)-trans-tetrahydrocannabinol.2. The influence of intraperitoneal (i.p.) or oral glucose administration, cold environment, acidosis, and corn, and prot...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1972.tb07317.x
更新日期:1972-04-01 00:00:00
abstract::1. The effects of varying H+ and other cation concentrations on phospholipase activity were investigated on two particulate fractions from human lung, corresponding to the mitochondrial and microsomal fractions. 2. Three 14C-labelled substrates, arachidonyl-phosphatidylcholine (PC), -phosphatidylethanolamine (PE) and ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb15826.x
更新日期:1990-07-01 00:00:00
abstract::1 The cardiovascular effects of intravenous desipramine (0.03 and 0.1 mg/kg), maprotiline (0.5 mg/kg), mianserin (1.0 and 3.0 mg/kg) and phentolamine (0.25 mg/kg) were examined and compared in pithed rats. Several experimental procedures were used in order to distinguish between the effects of the compounds on cardiac...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb10421.x
更新日期:1980-02-01 00:00:00
abstract::1 The putative 5-hydroxytryptamine (5-HT) receptor blocking drugs methysergide (10 mg/kg) and methergoline (5 mg/kg) were found to abolish some components of the hyperactivity syndrome, including head weaving and forepaw treading, which follow administration to rats of tranylcypromine (20 mg/kg) and L-tryptophan (100 ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1978.tb17290.x
更新日期:1978-10-01 00:00:00
abstract::Drug induced long QT syndrome (LQTS) can lead to cardiac arrhythmias and sudden death, and has emerged as a worldwide problem. Most drugs that cause this are thought to directly block a specific cardiac ion channel (KCNH2 or hERG) that carries the rapidly activating delayed rectifier potassium current, I(Kr). In this ...
journal_title:British journal of pharmacology
pub_type: 评论,杂志文章
doi:10.1038/sj.bjp.0706143
更新日期:2005-05-01 00:00:00
abstract::1. The effects of cocaine, 6-hydroxydopamine (6-OHDA), reserpine and 17-beta-oestradiol on the sensitivity of the rat anococcygeus muscle to noradrenaline (NA), acetylcholine (ACh) and KCl were investigated.2. Cocaine (10(-5)M) increased the sensitivity of the anococcygeus to NA (100-fold) but not to ACh or KCl.3. 6-O...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1973.tb17261.x
更新日期:1973-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The aggregation of α-synuclein is connected to the pathology of Parkinson's disease and prolyl oligopeptidase (PREP) accelerates the aggregation of α-synuclein in vitro. The aim of this study was to investigate the effects of a PREP inhibitor, KYP-2047, on α-synuclein aggregation in cell lines ov...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2012.01846.x
更新日期:2012-06-01 00:00:00
abstract::1. Antilaminin IgG decreased the dF/dt of mouse isolated atria and inhibited the mechanical effect of acetylcholine in a non-competitive fashion. 2. Inhibitors of nicotinic and muscarinic cholinoceptors impaired the negative inotropic action of antilaminin IgG in mouse isolated atria. Hemicholinium and tetrodotoxin al...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1989.tb11964.x
更新日期:1989-06-01 00:00:00
abstract::The position of dose-response curves for histamine-induced accumulation of [3H]-inositol 1-phosphate ([3H]-IP1) in lithium-treated slices of guinea-pig brain prelabelled with [3H]-inositol differed significantly between cerebellum (EC50 5.1 +/- 1.0 microM) and cerebral cortex (EC50 16.3 +/- 0.7 microM). The Hill coeff...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1986.tb11186.x
更新日期:1986-12-01 00:00:00
abstract::1 The effects of diltiazem on smooth muscle cells of the canine basilar artery were investigated by means of microelectrode, double sucrose gap and isometric tension recording methods. 2 The mean membrane potential of the smooth muscle cells was -49.8 mV and they were electrically quiescent. Diltiazem (over 10(-5) M) ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1982.tb09162.x
更新日期:1982-03-01 00:00:00
abstract::The pharmaceutical industry is testing new potential drugs for their propensity to prolong human cardiac repolarization, and regards this as a sign of proarrhythmic risk. Many studies have dethroned the common perception that prolonged repolarization is a reliable surrogate marker for torsades de pointes (TdP) arrhyth...
journal_title:British journal of pharmacology
pub_type: 评论,杂志文章
doi:10.1038/sj.bjp.0707299
更新日期:2007-08-01 00:00:00
abstract::1. A technique for the close-arterial administration of substances to the rat stomach in vivo has been developed. 2. Intra-arterial infusion of platelet-activating factor (Paf, 10-50 ng kg-1 min-1 for 10 min) induced macroscopically assessed damage in the corpus mucosa, characterized as vasocongestion and necrosis. 3....
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11425.x
更新日期:1988-01-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The Rho GTPase, Rac1, is involved in the pathogenesis of neuropathic pain induced by malformation of dendritic spines in the spinal dorsal horn (sDH) neurons. In the present study, the contribution of spinal Rac1 to peripheral inflammatory pain was studied. EXPERIMENTAL APPROACH:Effects of s.c. ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13413
更新日期:2016-03-01 00:00:00
abstract::The variety of factors and events involved in neurodegeneration renders the subject a major challenge. Neurodegenerative disorders include a number of different pathological conditions, which share similar critical metabolic processes, such as protein aggregation and oxidative stress, both of which are associated with...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/sj.bjp.0706416
更新日期:2005-12-01 00:00:00
abstract::Animal and epidemiological studies suggest that polyphenol constituents of red wine possess antioxidant activities that favour protection against cardiovascular disease - the so-called. 'French paradox' - and possibly, central nervous system disorders such as Alzheimer's disease (AD) and ischaemia. In the present stud...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703626
更新日期:2000-10-01 00:00:00
abstract::Until recently, hydrogen sulfide (H2 S) was exclusively viewed a toxic gas and an environmental hazard, with its toxicity primarily attributed to the inhibition of mitochondrial Complex IV, resulting in a shutdown of mitochondrial electron transport and cellular ATP generation. Work over the last decade established mu...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bph.12369
更新日期:2014-04-01 00:00:00
abstract::1 Dose-related increases in airways resistance (Raw) and decreases in dynamic lung compliance (Cdyn) were recorded in guinea-pigs and rats following intravenous injection of propranolol and of the cardioselective beta-adrenoceptor blocking drugs, atenolol and practolol. 2 The bronchoconstriction reached a peak in 2 to...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1979.tb10846.x
更新日期:1979-07-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Pancreatic cancer is a solid tumour that is often fatal. Hence, there is an urgent need to identify new drug targets for this disease. Highly proliferating cancer cells have an increased demand for nutrients and, therefore, need to up-regulate selective amino acid transporters. Here, we investiga...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13616
更新日期:2016-12-01 00:00:00
abstract::1 The metabolism of prostacyclin (PGI2) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) was studied in cell-free homogenates of rat, rabbit and guinea-pig kidney. 2 Rabbit kidney converted both PGI2 and 6-keto PGF1 alpha to a stable metabolite with chromatographic and biological activity identical to that of aut...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1983.tb10507.x
更新日期:1983-05-01 00:00:00
abstract::1. The vasodilator response to acetylcholine (ACh) was investigated in the aortic arches of the leopard frog (Rana pipiens). 2. With adrenaline pre-constricted preparations, both ACh and sodium nitroprusside (SNP) caused concentration-dependent relaxations. Damage to the endothelial layer abolished relaxations to ACh,...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15568.x
更新日期:1996-07-01 00:00:00
abstract::1 A newly synthesized substance P (SP) analogue, (D-Pro2, D-Trp7,9)-SP, specifically antagonizes the contractile effects of SP on the guinea-pig isolated taenia coli. In addition, previous studies had indicated that the SP analogue per se is capable of contracting this preparation. The results of the present study on ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1982.tb09348.x
更新日期:1982-12-01 00:00:00
abstract::The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit. Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]-prazosin from specific binding s...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb09437.x
更新日期:1985-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Imiquimod is an immunomodulator approved for the treatment of basal cell carcinoma and has adverse side effects, including taste disturbances. Paracrine transmission, representing cell-cell communication within taste buds, has the potential to shape the final signals that taste buds transmit to t...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13567
更新日期:2016-11-01 00:00:00