Abstract：
:In a typical flowchart for discovery of novel analgesic (or other) agents, a critical path often involves maximization of the separation of the therapeutic endpoint from known adverse-effect (AE) endpoint(s). Although strategies can easily be designed for in vitro paradigms such as high-throughput screening, extension to in vivo testing can represent a major obstacle to the rapid progression to the next step in development. The problem can be particularly acute when the assessment is required for oral dosing, and when it is not known if the therapeutic and AE mechanism(s) of action are the same. As a case in point, alpha(2)-adrenoceptor (alpha(2)-AR) agonists have potential therapeutic use as analgesics, but they also produce cardiovascular (CV) effects. However, whether the two effects are inexorably linked has not been resolved, particularly for oral administration. The present study used a novel method for comparing the CV effects produced by alpha(2)-AR agonists given by intraduodenal administration to anesthetized rats at fixed ratios of the oral antinociceptive ED(50) dose of each agonist. The technique provided a useful screen of compounds. In addition,there was no correlation between CV endpoints and alpha(2A)-AR affinity, suggesting that oral alpha(2)-AR-mediated analgesia and CV effects might be separable or that other mechanisms might be involved.
journal_name
J Pharmacol Toxicol Methodsjournal_title
Journal of pharmacological and toxicological methodsauthors
Li QS,Connelly CD,Codd EE,Raffa RBdoi
10.1016/s1056-8719(00)00041-1keywords:
subject
Has Abstractpub_date
1999-11-01 00:00:00pages
127-33issue
3eissn
1056-8719issn
1873-488Xpii
S1056-8719(00)00041-1journal_volume
42pub_type
杂志文章abstract：INTRODUCTION:Bioimpedance spectroscopy (BIS) has been used in human and large animal research to assess body fluid compartment volumes (BFC) such as total body water (TBW), extracellular fluid volume (ECFV), and intracellular fluid volume (ICFV). To date, the application of BIS for determination of BFC in small researc...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2012.02.001
更新日期：2012-03-01 00:00:00
abstract：:A radioimmunoassay of the undecapeptide substance P (SP) and its application in rabbit lung superfusate has been developed. The assay was based on the use of a radioactive tracer, 125I-SP-Tyr8, which showed, with an excess of antibodies, a specific binding greater than 90% and a nonspecific binding lower than 2%. This...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(98)00012-4
更新日期：1998-03-01 00:00:00
abstract：INTRODUCTION:Implantable telemetry enables continuous monitoring of physiological functions in freely moving animals and can greatly complement pharmacological research. Despite its miniaturization, a sensor/transmitter constitutes 5% or more of a mouse's bodyweight. The aim of the present study was to evaluate whether...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2017.02.002
更新日期：2017-01-01 00:00:00
abstract：INTRODUCTION:In vivo profiles of aldosterone synthase inhibitors (ASIs) have been investigated utilizing various rodent models. Due to lack of CYP17 activity, rodents produce corticosterone rather than cortisol as that of humans, which raised concern to their effectiveness in translational pharmacological characterizat...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2014.09.011
更新日期：2015-01-01 00:00:00
abstract：:Evaluation of angiotensin II (AII) receptor binding often necessitates freezing of the tissue of interest prior to assay of radioligand binding. This study evaluated the effects of freezing of various rat tissues at different rates on 125I-sarcosine1, isoleucine8 angiotensin II (125I-SI AII) binding to AII receptor su...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(94)00061-8
更新日期：1995-04-01 00:00:00
abstract：:Congestive heart failure (CHF) is a complex, multifactoral disease involving genetic and environmental factors that represents a large unmet medical need. There are currently many animal models of CHF that have provided some insight into the etiology of this disease. However, due to the complex interactions of environ...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(00)00099-x
更新日期：2000-03-01 00:00:00
abstract：:Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by vid...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2019.106611
更新日期：2019-01-01 00:00:00
abstract：INTRODUCTION:Multiple cardiac ion channels are prone to block by pharmaceutical compounds, and this can have large implications for cardiac safety. The effect of a compound on individual ion currents can now be measured in automated patch clamp screening assays. In-silico action potential models are proposed as one way...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2015.05.002
更新日期：2015-09-01 00:00:00
abstract：INTRODUCTION:The combined evaluation of physiology and behaviour allows a complete and more comprehensive pre-clinical assessment of central nervous system (CNS) function. An integrated video-telemetric electroencephalography (Video-tEEG) system, which allows the simultaneous and continuous recording of EEG and video i...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2010.04.004
更新日期：2010-07-01 00:00:00
abstract：:The isolated perfused mammalian heart preparation was established in 1897 by Oscar Langendorff. The method was developed on the basis of the isolated perfused frog heart established by Elias Cyon at the Carl Ludwig Institute of Physiology in Leipzig, Germany in 1866. Observations made using both methods at the end of ...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 历史文章,杂志文章,评审
doi：10.1016/j.vascn.2006.05.006
更新日期：2007-03-01 00:00:00
abstract：INTRODUCTION:Computational methods have been widely applied to toxicology across pharmaceutical, consumer product and environmental fields over the past decade. Progress in computational toxicology is now reviewed. METHODS:A literature review was performed on computational models for hepatotoxicity (e.g. for drug-indu...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章,评审
doi：10.1016/j.vascn.2013.12.003
更新日期：2014-03-01 00:00:00
abstract：:A model of gingival inflammation was performed in Sprague-Dawley rats weighing 180-200 g. Mechanical bamboo stick-induced injury was inflammatory when bacteria contaminated the sticks. Bacteria were first obtained from gingival fluid collected from a patient with adult periodontitis. Another strain from Institut Paste...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(94)90070-1
更新日期：1994-11-01 00:00:00
abstract：:The acetylcholine-evoked relaxation of rabbit isolated thoracic aorta precontracted by phenylephrine was studied. Phenylephrine caused a steady contraction that was maintained for 6 h. In the presence of calcium disodium ethylenediaminetetraacetate (EDTA) and ascorbic acid the contraction decreased with time. N(G)-Nit...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(99)00035-0
更新日期：1999-08-01 00:00:00
abstract：INTRODUCTION:In this paper the activity of cytoplasmatic antioxidant enzymes after multiple freeze-thaw cycles of samples of cytoplasm was assayed in order to characterise the limits that would be necessary to impose on experimental design. METHODS:The activities of antioxidant enzymes in samples of rat liver cytoplas...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2005.03.002
更新日期：2005-09-01 00:00:00
abstract：:Papaya latex-induced rat paw inflammation model for evaluating antiinflammatory activity has been developed and reported earlier. A number of drugs viz. aspirin, indomethacin, piroxicam, ibuprofen, prednisolone, levamisole, chloroquine, and boswellic acids showed antiinflammatory activity in this model. As the last th...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(94)90048-5
更新日期：1994-04-01 00:00:00
abstract：:We have developed a method for the rapid isolation of hepatocyte nuclei, which employs gentle homogenization and centrifugation conditions, and involves minimal processing time. The purified nuclei were morphologically unaltered when observed by light and electron microscopy. No significant contamination from cytoplas...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(97)00082-8
更新日期：1997-11-01 00:00:00
abstract：:Hemodynamic and biochemical changes were studied on 36 white ELCO-rabbits, seven adult older than 150 days, seven immatures between 21 and 27 days, and seven neonatals between 7 and 14 days. Five supplementary hearts of each age group served for preischemic biochemical values. Protection during 60 min of global ischem...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(93)90016-8
更新日期：1993-12-01 00:00:00
abstract：INTRODUCTION:Fosmidomycin is a phosphonic acid derivative originally isolated as a natural antibiotic from Streptomyces lavendulae. It was originally used as an antibiotic, and later on as an antimalarial drug. A simple, sensitive, selective and reproducible bioassay based on colorimetric method was developed for the d...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2010.02.012
更新日期：2010-05-01 00:00:00
abstract：INTRODUCTION:The aim of this experiment was to establish the usefulness of assessing temporal variability of the QT interval and changes in the T wave morphology in dogs as markers of pro-arrhythmic risk in humans. For this purpose, the electrocardiographic effects of astemizole and cisapride, two well known pro-arrhyt...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2008.03.001
更新日期：2008-05-01 00:00:00
abstract：INTRODUCTION:An increase in striatal dopamine is considered essential for the rewarding and reinforcing effects of drugs of abuse. We have developed and validated an ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the analysis of dopamine in rat brain extracellular fluid (...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2015.06.002
更新日期：2015-07-01 00:00:00
abstract：INTRODUCTION:The purpose of this study was to determine the sensitivity and specificity for predicting the liability of a compound to lengthen QTc using isolated, perfused guinea pig hearts (Langendorff preparation). METHODS:QTc (Fridericia correction) was calculated from bipolar transventricular electrograms. Hearts ...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2003.08.003
更新日期：2004-01-01 00:00:00
abstract：INTRODUCTION:Oxidative stress plays an important role in drug-induced toxicity. Oxidative stress-mediated toxicities can be detected using conventional animal models but their sensitivity is insufficient, and novel models to improve susceptibility to oxidative stress have been researched. In recent years, gene targetin...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2018.12.006
更新日期：2019-01-01 00:00:00
abstract：:The objective of this research is to determine whether the administration of a complete soft food formula to sub-lethal irradiated animals from three different transgenic mouse strains over a period of 21 consecutive days will have a significant impact on the clinical signs, and the general survival rate of the animal...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2014.12.003
更新日期：2015-01-01 00:00:00
abstract：:For the rapid assay of norepinephrine (NE) and its major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG) in the mouse brain, we developed a simple method using isocratic HPLC with coulometric detection. This method permits NE and MHPG assay within 5 min in one chromatographic run. Within-run coefficients of variati...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(94)90060-4
更新日期：1994-10-01 00:00:00
abstract：:"What do you know about Safety Pharmacology?" This is the question that was asked in 2000 with the inception of the Safety Pharmacology Society (SPS). There is now a widespread awareness of the role of safety pharmacology in drug discovery and increasing awareness among the wider community of methods and models used i...
journal_title：Journal of pharmacological and toxicological methods
pub_type：
doi：10.1016/j.vascn.2014.08.004
更新日期：2014-09-01 00:00:00
abstract：INTRODUCTION:MEKK1 is a 196-kDa serine-threonine kinase activated in response to a variety of stimuli, including EGF, lysophosphatidic acid, osmotic stress, UV light, and microtubule toxins. However, there are few reports about the expression level of MEKK1 in cancers. METHODS:In this report, a direct competitive ELIS...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2004.08.004
更新日期：2005-03-01 00:00:00
abstract：INTRODUCTION:A Tecan-based enzyme inhibition assay has been developed for the determination of atorvastatin-derived 'active' and 'total' (active inhibitors plus atorvastatin lactone and other potential inhibitors following base hydrolysis) 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitor concentratio...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2007.06.002
更新日期：2008-01-01 00:00:00
abstract：INTRODUCTION:Inhalation of antigen in atopic asthma induces early (EAR) and late asthmatic responses (LARs), inflammatory cell infiltration and airways hyperresponsiveness (AHR). Previously, we have established a protocol of sensitisation and subsequent ovalbumin (Ova) inhalation challenge in guinea-pigs which induced ...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2014.10.007
更新日期：2015-03-01 00:00:00
abstract：:In this study a new model of cerebral ischemia, based on a middle cerebral artery (MCA) thrombosis in rats is described. Furthermore, the effect of the novel plasminogen activator (SUN9216), a plasminogen-plasminogen activator chimera, comprising the fibrin kringle 1 domain of a plasminogen, and the two kringles, and ...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(93)90068-p
更新日期：1993-06-01 00:00:00
abstract：INTRODUCTION:Recently we have demonstrated that to the choice of tissue type is important in identifying I(Kr) and I(Ks)-induced prolongation of the action potential. However, the differential sensitivity of cardiac tissues to other ionic current blockers or modulators is relatively unknown. The aim of the present stud...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2007.06.005
更新日期：2008-01-01 00:00:00
