Abstract：
:All new molecular entities (NMEs) with targeted or indirect effects on the central nervous system (CNS) must be evaluated for their abuse liability as a part of their nonclinical development plan. Inherently key in the drug control review is the term "relative abuse liability". The basis for determination of drug control is critically dependent on the nonclinical assessment of the reinforcing attributes of the NME in animals (rat is the regulatory preferred species) in a standard operant conditioning paradigm. Pharmaceutical representatives without a background in behavioral analysis or operant conditioning models must weigh through conceptually-intriguing language and constructs that accurately convey and communicate the relative potential for abuse to drug regulatory experts in the field. Effective statutory language in the preclinical assessment of relative abuse liabilities for schedule control status reviews must be 1) specific; 2) concise; 3) familiar to the regulators; 4) unambiguous; 5) constructive; and 6) formalized with respect to both international and national drug control policies. In this review we attempt to define and highlight the importance of the statutory language used to report self-administration study results to both parties engaged in NDA approval process.
journal_name
J Pharmacol Toxicol Methodsjournal_title
Journal of pharmacological and toxicological methodsauthors
Gauvin DV,Zimmermann ZJ,Baird TJdoi
10.1016/j.vascn.2018.08.001subject
Has Abstractpub_date
2018-01-01 00:00:00pages
36-53issue
Pt 2eissn
1056-8719issn
1873-488Xpii
S1056-8719(18)30643-9journal_volume
94pub_type
杂志文章,评审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 variety of in vitro tests to replace the Draize test have been developed; however, there is no available method for assessing the full spectrum of Globally Harmonized System (GHS) categories. Human cornea-like three-dimensional (3D) reconstructed tissue models are the most promising in vitro systems. The...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2018.02.007
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：INTRODUCTION:The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) Cardiovascular Safety Subcommittee outlined a set of in vivo telemetry studies to determine how well this preclinical model identified compounds known to cause torsades de pointes (TdP) and prolong QT i...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2007.04.002
更新日期：2007-09-01 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：: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：:A method for the rapid detection of intracellular nitric oxide (NO) generation in dissociated cerebellar granule cells using dichlorofluorescin (DCFH) and flow cytometry was developed. DCFH can be oxidized specifically by NO and this was assessed by 1) the use of SIN-1 (10 nM-100 microM), an NO donor, that induced a c...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(97)00066-x
更新日期：1997-10-01 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：:Guinea pigs were sensitized with ovalbumin (i.p.) 14 days before use. In vivo airway hyperreactivity induced by ovalbumin inhalation was determined by challenging with aerosolized spasmogen (5-hydroxytryptamine [5-HT] methacholine, the thromboxane-mimetic, U-46619, or adenosine) 24 hr before (7 days with adenosine) an...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/1056-8719(95)00093-3
更新日期：1995-12-01 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
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: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：INTRODUCTION:The pig is one of the most valuable in vivo models in biomedical research, however with only a few well-accessible veins suitable for venipuncture. Moreover, most of the known methods of blood collection are suitable only for a limited time period. The aim of the study was to verify an improved method of l...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2019.106584
更新日期：2019-01-01 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:The aim of this investigation was to evaluate methods for increasing Caco-2 cell throughput for assessing drug intestinal absorption. The use of 6-, 12-, and 24-well membranes and the effect of membrane size on permeability and the integrity of the Caco-2 cell monolayer were assessed. In an effort to optim...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(01)00161-7
更新日期：2001-07-01 00:00:00
abstract：BACKGROUND:Animal models of allergy and bronchial hyperresponsiveness (BHR) are useful in researching pulmonary diseases and evaluating drug effects on the airways. Neonatally immunised rabbits exhibit several features of asthma as adults, including early and late airway responses following antigen challenge, oedema an...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2011.08.003
更新日期：2011-09-01 00:00:00
abstract：:The clinical value of coronary vasodilators in antianginal therapy depends on the ratio of their epicardial versus resistance coronary vessel actions. The coronary flow measured in standard isolated heart preparations, however, does not allow any conclusion about the function of epicardial vessels. Thus, we establishe...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(97)00096-8
更新日期：1997-12-01 00:00:00
abstract：INTRODUCTION:Methods to determine infarct size following ischemia-reperfusion injury include gross staining with triphenyltetrazolium chloride (TTC) and perfusion of colored dyes to demarcate the non-ischemic zone. Infarcted tissue (INF) can typically appear a mottled tan to brownish color, making a border between INF ...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2006.06.005
更新日期：2007-03-01 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:The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. METHODS:A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized sham...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2008.03.002
更新日期：2008-05-01 00:00:00
abstract：:Flavin-containing monooxygenases (FMOs) catalyze the oxidation of a diverse array of xenobiotic compounds. The purpose of this investigation was to develop a specific immunological probe to human hepatic flavin-containing monooxygenase (HLFMO3). An oligopetide corresponding to amino acid residues 257-270 of HLFMO3 was...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(97)00012-9
更新日期：1997-03-01 00:00:00
abstract：INTRODUCTION:There has been an increasing need to conduct investigative safety pharmacology studies to complement regulatory-required studies, particularly as it applies to a comprehensive assessment of cardiovascular (CV) risk. METHODS:We describe refined methodology using a combination of telemetry and direct signal...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2016.05.002
更新日期：2016-09-01 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：: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...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(00)00041-1
更新日期：1999-11-01 00:00:00
abstract：INTRODUCTION:Drug-induced QT prolongation is a major safety issue during drug development because it may lead to lethal ventricular arrhythmias. In this study, we evaluated the utility of multi-electrode arrays (MEA) with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to predict drug-induced QT p...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章,多中心研究
doi：10.1016/j.vascn.2015.12.002
更新日期：2016-03-01 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：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：:Many xenobiotics cause hepatobiliary toxicity and cholestasis in the rat. Initial assessment of hepatobiliary damage in rats can be accomplished by measuring serum concentrations of bile acids and bilirubin, serum activities of liver-associated enzymes such as 5'-nucleotidase, alkaline phosphatase, gamma-glutamyltrans...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章,评审
doi：10.1016/1056-8719(94)90024-8
更新日期：1994-02-01 00:00:00
abstract：:Fluorescent labeling of amine functional groups using dansyl chloride (DNS-Cl), and in sodium carbonate buffer, allowed the detection of 1 microg amounts of analytes. The methodology presented allows dansylation of primary, secondary, and tertiary amine groups at a temperature of 25 degrees C. The dansylation of terti...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/s1056-8719(01)00157-5
更新日期：2001-05-01 00:00:00
abstract：INDUCTION:Despite increasing acceptance of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in safety pharmacology, controversy remains about the physiological relevance of existing in vitro models for their mechanical testing. We hypothesize that existing signs of immaturity of the cell models re...
journal_title：Journal of pharmacological and toxicological methods
pub_type： 杂志文章
doi：10.1016/j.vascn.2020.106892
更新日期：2020-09-01 00:00:00
