Abstract：
:The origins of safety pharmacology are grounded upon observations that organ functions (like organ structures) can be toxicological targets in humans exposed to novel therapeutic agents, and that drug effects on organ functions (unlike organ structures) are not readily detected by standard toxicological testing. Safety pharmacology is " em leader those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relationship to exposure in the therapeutic range and above em leader " [International Conference on Harmonization (ICH) S7A guidelines; Safety Pharmacology Studies for Human Pharmaceuticals]. This publication provides a comprehensive review of the history of safety pharmacology, international regulatory guidelines that govern the practices of this important field, and the scientific challenges that are being faced by its rapid emergence in pharmaceutical development. The criticality of identifying undesired adverse effects of new drugs in nonclinical models, which reflect the overall human condition, is reflected in the importance of generating an integrated and accurate assessment of possible human risk. The conundrum posed by the challenge of formulating a reliable risk assessment is the importance of improving and enhancing the safe progression of new drugs to the marketplace, while preventing unnecessary delays (or discontinuances), based on nonclinical findings that are not relevant or interpretable in terms of clinical response or human risk.
journal_name
J Pharmacol Toxicol Methodsjournal_title
Journal of pharmacological and toxicological methodsauthors
Bass A,Kinter L,Williams Pdoi
10.1016/j.vascn.2004.02.007keywords:
subject
Has Abstractpub_date
2004-05-01 00:00:00pages
145-51issue
3eissn
1056-8719issn
1873-488Xpii
S1056-8719(04)00022-Xjournal_volume
49pub_type
杂志文章,评审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：:This article outlines a strategy for collecting accurate data for the determination of the sensitivity, specificity and predictive value of safety pharmacology models. This entails performing a retrospective analysis on commonly used safety pharmacology endpoints and an objective assessment of new non-clinical models....
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2009.05.011
更新日期：2009-09-01 00:00:00
abstract：:A sensitive and precise gas chromatography-mass spectrometry method with selected ion monitoring has been developed for determination of ketamine in the brain using chlorpheniramine as an internal standard. The assay is based on the acid extraction of brain homogenate with hexane and ethyl ether with subsequent alkali...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(99)00023-4
更新日期：1999-04-01 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:A custom designed HD exposure system was used to deliver controlled inhaled doses to an animal model through an endotracheal tube. METHODS:Target HD vapor challenges were generated by a temperature controlled bubbler/aerosol trap, while concentration was monitored near real-time by gas chromatography. Ani...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2014.09.009
更新日期：2015-01-01 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:Drug-induced cardiovascular effects identified in conscious cynomolgus monkeys equipped with tethers and prepared for radiotelemetry were compared with results from anesthetized non-human primate (cynomolgus and rhesus) models. METHODS:Remifentanil (4.0 microg/kg, bolus), esmolol (2.0 mg/kg, bolus) and do...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2008.05.004
更新日期：2008-09-01 00:00:00
abstract：:The aim of the present study was to formulate a simple chemically defined medium for the in vitro growth of rat two-cell embryos to blastocysts. Embryos from day 2 pregnant rats were retrieved and placed in paraffin oil-covered droplets of "rat two-cell embryo culture medium" (R2ECM) containing combinations of various...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(00)00084-8
更新日期：2000-05-01 00:00:00
abstract：:Buffers used to incubate cells for pharmacological or toxicological studies are usually of very simple composition, far from the composition of biological fluids or cell culture media. Comparative studies on taurine uptake levels by cultured cells show that a new CO2-Independent Medium (CIM) is suitable for incubating...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(98)00020-3
更新日期：1998-06-01 00:00:00
abstract：:Regulation of brain temperature during and after cerebral ischemia plays an important role in the evolution of neuronal damage. Therefore, it is essential to maintain brain temperature at 37 degrees C during and after the ischemic insult. To get information about brain temperature during the experimental procedure, re...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(92)90016-t
更新日期：1992-03-01 00:00:00
abstract：INTRODUCTION:A credible animal overactive bladder model used in basic research is an indispensable harbinger of safe and ethical clinical trials on human subjects. Our objective was to develop a new animal model of a hyperactive bladder that will be void of inflammatory urothelium lesions and display significant sensit...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2015.04.006
更新日期：2015-07-01 00:00:00
abstract：:Electrical field stimulation (EFS, 2.5 Hz, 60 V, 1 ms, trains of 5 sec every 5 min) of the rat external urethral sphincter (EUS) produced contractile responses characterized by a "slow" tonic contraction on which was superimposed a series of phasic "twitch-like" contractions. Both responses were abolished by tetrodoto...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(92)90052-3
更新日期：1992-09-01 00:00:00
abstract：INTRODUCTION:The standard Ficoll-Hypaque method used to isolate peripheral blood mononuclear cells (PBMC) gives very variable results when used with cynomolgus monkey blood. We have improved the method by using special cell processing tubes (CP-tubes), originally developed for clinical use. METHODS:Blood samples were ...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2004.04.003
更新日期：2004-09-01 00:00:00
abstract：INTRODUCTION:Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dep...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2016.10.004
更新日期：2017-01-01 00:00:00
abstract：INTRODUCTION:The cytochrome P450 CYP26 family of retinoic acid (RA) metabolizing enzymes, comprising CYP26A1, CYP26B1, and CYP26C1 is critical for establishing patterns of RA distribution during embryonic development and retinoid homeostasis in the adult. All three members of this family can metabolize all trans-RA. CY...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2011.08.005
更新日期：2011-11-01 00:00:00
abstract：:A wipe sampling procedure followed by a simple ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous quantification of six cytotoxic drugs: 5-fluorouracil (5FU), doxorubicin (DOXO), epirubicin (EPI), ifosfamide (IF), cyclophosphamide (CP) an...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2019.106652
更新日期：2020-01-01 00:00:00
abstract：INTRODUCTION:Most preclinical trials are designed to identify potential torsadogenicity test only for surrogates of torsade de pointes, most commonly prolongation of the heart rate corrected QT interval (QTc). This study was conducted to determine which correction method best accounts for the effects of changes in the ...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2005.04.013
更新日期：2006-03-01 00:00:00
abstract：:A method for determination of cis-diaminedichloroplatinum (II) (cisplatin) in ultrafiltered plasma, cell, and tumour samples is described. Cisplatin separation was carried out on a reversed-phase column using methanol-acetonitrile-water as the mobile phase. The flow rate was maintained constant at 1.6 mL/min and analy...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2005.06.005
更新日期：2005-11-01 00:00:00
abstract：INTRODUCTION:A large number of drugs from a variety of pharmacological classes have been demonstrated to cause adverse effects on cardiac rhythm, including the life-threatening arrhythmia Torsades de Pointes. These side effects are often associated with prolongation of the QT interval and are mediated via blockade of t...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2006.09.003
更新日期：2007-05-01 00:00:00
abstract：INTRODUCTION:Although the effects of relatively high concentrations of endotoxin on endothelial activation/dysfunction and kidney markers has been described in literature, detailed insight in the LPS concentration-effect relationship, the magnitude, variability and timing of the response, and potential effects of endot...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章,随机对照试验
doi：10.1016/j.vascn.2017.10.004
更新日期：2018-01-01 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:Increase of serum alanine aminotransferase (ALT) activity is widely used as a surrogate marker for tissue damage. Two ALT isoforms, ALT1 and ALT2, have been cloned recently in mammals. The study investigated the source of elevated ALT activity in serum of dogs treated with a hepatotoxic compound. METHODS:...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2009.09.001
更新日期：2009-11-01 00:00:00
abstract：:A tissue preparation is described which makes it possible to examine the effect of drugs on the nerves that control both longitudinal and circular muscles of the small intestine. The preparation consists of a segment of rat ileum set up to measure the tension developed in the longitudinal muscle and intraluminal press...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(96)00110-4
更新日期：1996-11-01 00:00:00
abstract：INTRODUCTION:In vitro metabolism models such as liver microsomes represent an important tool for the development of novel radioligands. Comparability and physiological relevance of in vitro metabolism data critically depend on the careful evaluation and optimization of assay protocols. We therefore investigated the inf...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2018.11.005
更新日期：2019-01-01 00:00:00
abstract：:The U.S. Food & Drug Administration (FDA) has issued a final guidance document on the preclinical determination of abuse potential that must be conducted in animals for all new molecular entities (NMEs) submitted for a new drug application (NDA). Under statutory restrictions government guidance documents serve only as...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2017.11.005
更新日期：2018-01-01 00:00:00
abstract：:Investigations of the coupling between contraction and relaxation (contraction-relaxation [CRC] process) in isometric conditions are essential in determining whether pharmacologic interventions or cardiac diseases specifically modify isometric relaxation (intrinsic lusitropic effect) or change it in proportion with th...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(99)00044-1
更新日期：1999-09-01 00:00:00
abstract：:There are three major assays that must be conducted in standard investigational new drug (IND) -enabling ototoxicity study designs: 1) functional acoustic threshold measurements (Auditory Brainstem Respsonse, ABR); 2) otohistopathology and 3) cytocochleograms. We provide evidence to demonstrate the unreliability of au...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章,评审
doi：10.1016/j.vascn.2017.09.254
更新日期：2017-01-01 00:00:00
abstract：INTRODUCTION:Laboratory investigations into cholestatic liver disease and the effects of cholemia on organ function are long-standing subjects of scientific enquiry. A widely-used strategy to investigate these topics relies on animal-based research using experimental animal models. Targeted inactivation of the spgp gen...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2004.06.002
更新日期：2004-11-01 00:00:00
abstract：INTRODUCTION:Gastrointestinal (GI) motility disorders include many clinical manifestations associated with various pathologies. They are widespread and can be considered a primary symptom or can be associated to other diseases, such as Parkinson's disease. Understanding the type and site of GI dysmotility is crucial to...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2014.08.003
更新日期：2014-09-01 00:00:00
abstract：:Multiple ECG analysis strategies are used in safety pharmacology in a framework focused on accurate ECG complex interval quantification and arrhythmia detection. Automated arrhythmia detection is commonly used in the clinic and adapted tools may be used to facilitate analysis of large non-clinical datasets in safety p...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章,评审
doi：10.1016/j.vascn.2010.06.005
更新日期：2010-09-01 00:00:00
