Abstract:
INTRODUCTION:Understanding the appropriate application of telemetry and other technologies for nonclinical investigation of functional safety issues in the context of ongoing toxicology evaluations is a current industry challenge. One major issue is related to the potential impact of surgical implantation of a telemetry device on contemporarily established measures of drug toxicity, and potential for confounding pathological issues related to the systemic and local response of the experimental animal to the presence of a foreign body. This study was designed to evaluate the potential local and systemic impact of different implanted telemetry devices with varying requisite degrees of surgical complexity on general toxicology study endpoints. METHODS:Sixteen male beagle dogs 1) no surgical instrumentation [n=4], 2) Jacketed External Telemetry (JET) with femoral artery blood pressure implant (PA-C10 LA) [n=4], or 3) fully implantable (DSI-D70-CCTP) devices [n=8], were assigned to experimental groups and evaluated within the context of a standard repeat-dose toxicology design to determine the potential impact of these treatments on routine in-life and post-mortem toxicological endpoints. RESULTS:Device implantation, regardless of the level of invasiveness/complexity was without effect on any in-life safety parameter, including clinical chemistry and hematology, assessed in the experimental design. Histopathological findings were limited to the expected, primarily minimal to mild localized effects characteristic of a foreign body reaction (fibrosis, inflammation) in the area immediately in contact with the body of the transmitter device and associated sites of ECG lead and pressure catheter interface with local tissues. DISCUSSION:This study represents the first definitive evaluation of the influence of variably invasive telemetry device implantation on standardized, essential toxicology endpoints in the context of a simulated repeated dose experimental design. The data suggest that, when carefully evaluated, the local effects of implanted telemetry devices can be managed in the context of a standard Investigational New Drug (IND)-enabling toxicology study. This study provides support for the potential incorporation of unrestrained cardiovascular assessments via implanted or external telemetry into standard multi-dose toxicology studies.
journal_name
J Pharmacol Toxicol Methodsjournal_title
Journal of pharmacological and toxicological methodsauthors
Baird TJ,Bailie M,Patrick DJ,Moddrelle D,Yoder J,Gauvin DV,Dalton JAdoi
10.1016/j.vascn.2013.02.006subject
Has Abstractpub_date
2013-05-01 00:00:00pages
148-61issue
3eissn
1056-8719issn
1873-488Xpii
S1056-8719(13)00209-8journal_volume
67pub_type
杂志文章abstract::We report a simple fluorometric method for the continuous monitoring of mitochondrial membrane potential and cell viability in suspensions of hepatocytes exposed in vitro to cytotoxic agents. Suspensions of freshly isolated hepatocytes (10(6) cells/mL) preloaded with rhodamine 123 (Rh 123, 100 mumol/L) are transferred...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/1056-8719(95)00131-x
更新日期:1996-02-01 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: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:INTRODUCTION:In experimental pain research the effect of opioids is normally assessed by verbal subjective response to analgesia. However, as many confounders in pain assessment exist, objective bed-side assessment of the effect is highly warranted. Therefore, we aimed to assess the effect of morphine on three objectiv...
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.2015.01.005
更新日期:2015-05-01 00:00:00
abstract:INTRODUCTION:Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node--ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2005.02.003
更新日期:2006-01-01 00:00:00
abstract:INTRODUCTION:Drug-induced prolongation of the electrocardiographic QT interval (long QT syndrome) has been associated with increased risk of a serious ventricular arrhythmia, torsade de pointes. Inhibition of hERG, a cardiac potassium channel that controls action potential repolarization, is the most common cause of QT...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2008.10.004
更新日期:2009-01-01 00:00:00
abstract::The Safety Pharmacology Society organized a scientific session at its annual conference in 2017 to discuss the challenges and opportunities of the Comprehensive In-Vitro Proarrhythmia Assay (CiPA) paradigm. Our intention was to raise awareness of this initiative with its members and also to gauge the extent to which s...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章,评审
doi:10.1016/j.vascn.2018.06.005
更新日期:2018-01-01 00:00:00
abstract::In this article we review the value and utility of the minipig as an animal model in regulatory toxicity testing. Our review is based on detailed consideration of the comparative biology of the minipig, and of the practical features of toxicity testing in the minipig. The minipig presents a favourable profile as a non...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章,评审
doi:10.1016/j.vascn.2010.05.009
更新日期:2010-11-01 00:00:00
abstract:INTRODUCTION:Affymetrix oligonucleotide microarrays are widely used in basic and applied research (Lander, E.S., (1999). Array of hope. Nature Genetics 21, 3-4; Lockhart, D.J. & Winzeler, E.A. (2000) Genomics, gene expression and DNA arrays. Nature 405, 827-836.) The need for a significant amount of starting RNA has li...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2005.02.004
更新日期:2006-03-01 00:00:00
abstract:INTRODUCTION:Although therapeutically beneficial in the treatment of certain diseases, L-type calcium channel antagonism can result in unwanted off-target pharmacology leading to adverse drug reactions and to the termination of the development of otherwise promising compounds. In the present study three marketed calciu...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2016.11.002
更新日期:2017-01-01 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:INTRODUCTION:Voltage-sensitive optical (VSO) sensors offer a minimally invasive method to study the time course of repolarization of the cardiac action potential (AP). This Comprehensive in vitro Proarrhythmia Assay (CiPA) cross-platform study investigates protocol design and measurement variability of VSO sensors for ...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2019.106612
更新日期:2019-01-01 00:00:00
abstract:INTRODUCTION:The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different ph...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2007.05.002
更新日期:2007-09-01 00:00:00
abstract:INTRODUCTION:In the present study, a model was developed to determine the effect of secretase inhibition on beta-amyloid peptide (Abeta) levels in the cerebrospinal fluid (CSF) of freely moving adult rats. METHODS:Rats were chronically implanted with a cannula into the cisterna magna and CSF samples were collected at ...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2005.02.002
更新日期:2005-09-01 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: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:Opioid withdrawal syndrome is a critical component of opioid abuse and consists of a wide array of symptoms including increases in pain sensitivity (hyperalgesia). A reliable preclinical model of hyperalgesia during opioid withdrawal is needed to evaluate possible interventions to alleviate withdrawal. The...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2013.02.003
更新日期:2013-05-01 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::Escherichia coli produces a heat-stable (STa) enterotoxin that belongs to a family of peptides that mediate several diarrheal diseases, including traveler's diarrhea and epidemic diarrhea in infants and newborns. The STa enterotoxin consists of 18 or 19 amino acids and is encoded by genes specified on a transposon. In...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章,评审
doi:10.1016/1056-8719(92)90049-7
更新日期:1992-09-01 00:00:00
abstract:INTRODUCTION:Telemetry beagle dogs are the most frequently used species in cardiovascular telemetry assessments. However, beagle dogs may not be always suitable for all of the tests. Recently minipigs have received increased attention for these studies. Differences between the two species regarding the response of thei...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2014.03.172
更新日期:2014-07-01 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: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::Undesired immune responses against protein therapeutics may adversely affect the pharmacokinetics, efficacy, and safety of the product. The presence of anti-drug-antibodies (ADA) has been the key determinant of immunogenic responses. Here we describe the use of a capillary electrophoresis platform for the identificati...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2020.106872
更新日期:2020-01-01 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:The ability to quantify systemic concentrations of protein therapeutics is complicated by the presence of endogenous analyte, specific binding proteins, and nonspecific matrix components in biological matrices (Lee & Ma, 2007). Further complications can be introduced following pegylation whereby polyethyle...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2009.12.004
更新日期:2010-03-01 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::Two methods of measuring body temperature were compared in common marmosets. Subcutaneous temperatures were measured remotely via previously implanted subcutaneous microchips (Plexx BV, IPTT-100) prior to measurement of rectal temperature using a conventional rectal probe. Marmosets were treated with saline or the bra...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/s1056-8719(98)00030-6
更新日期:1998-07-01 00:00:00
abstract:INTRODUCTION:Reversible protein cysteine oxidation is recognised as a pivotal post-transitional modification that transduces physiological as well as pathological signalling. Pharmacological interventions that target specific sources of oxidant formation are currently being trialled to ascertain their potential ability...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2013.07.001
更新日期:2013-11-01 00:00:00
abstract:INTRODUCTION:Mouse models of chronic heart failure (HF) have been widely used in HF research. However, the current HF models most often use the C57BL/6 mouse strain and do not show the clinically relevant characteristics of pulmonary congestion. In this study, we developed a robust mouse model of HF in the BALB/c mouse...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2019.02.001
更新日期:2019-01-01 00:00:00