Publications by authors named "David J Gallacher"

55 Publications

Seizure-induced Torsades de pointes:In a canine drug-induced long-QT1 model.

J Pharmacol Toxicol Methods 2021 Jun 10:107086. Epub 2021 Jun 10.

Janssen Research & Development, Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address:

Introduction: People with epilepsy are at heightened risk of sudden death compared to the general population. The leading cause of epilepsy-related premature mortality is a sudden unexpected death in epilepsy (SUDEP). The mechanism of SUDEP remains largely unresolved and the lack of preclinical models to study the potential mechanism underlying SUDEP is a problem.

Method: By combining electroencephalographic (EEG) and electrocardiogram (ECG) measurements within a well described LQT1 dog model, we investigated the effect of the proconvulsive compound pentylenetetrazol (PTZ), and its link to the induction of Torsades de Pointes (TdP).

Results: Pre-treatment with the potent and selective I blocker JNJ 282 induced a pronounced QT (QTc) prolongation in anaesthetized dogs (Long QT syndrome type 1 or LQT1 group) compared to dogs that were not treated (control group). Subsequent PTZ administration induced spiking on the EEG signal and seizures in both groups, but only R-on-T, salvo and TdP were observed in dogs of the LQT1 group.

Conclusion: Our results show that a proconvulsive drug can trigger TdP-like cardiac arrhythmias, in conditions of compromised repolarization in the heart (I blockade). In man, TdP arrythmia's can often lead to ventricular fibrillation (VF) and sudden death. This observation suggests that long QT-intervals (genetic or drug induced) could potentially be one of the risk factors for SUDEP in epileptic patients.
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http://dx.doi.org/10.1016/j.vascn.2021.107086DOI Listing
June 2021

Comparison of the Simulated Response of Three Human Stem Cell-Derived Cardiomyocytes Models and Data Under 15 Drug Actions.

Front Pharmacol 2021 15;12:604713. Epub 2021 Mar 15.

Department of Computer Science, University of Oxford, Oxford, United Kingdom.

Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM models (Koivumäki2018, Kernik2019, and Paci2020) to simulated drug action, and compare simulation results against data for 15 drugs. First, simulations were conducted considering 15 drugs, using a simple pore-block model and experimental data for seven ion channels. Similarities and differences were analyzed in the responses of the three models to drugs, in terms of Ca transient duration (CTD) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na (I), L-type Ca (I), and rapid delayed rectifying K (I) currents was quantified. Finally, we compared the drug-induced effects on CTD against the corresponding experiments. The observed CTD changes were overall consistent among the models, all three showing changes of smaller magnitudes compared to the ones measured . For example, sparfloxacin 10 µM induced +42% CTD prolongation , and +17% (Koivumäki2018), +6% (Kernik2019), and +9% (Paci2020) . Different arrhythmic events were observed following drug application, mainly for drugs affecting I. Paci2020 and Kernik2019 showed only repolarization failure, while Koivumäki2018 also displayed early and delayed afterdepolarizations. The spontaneous activity was suppressed by Na blockers and by drugs with similar effects on I and I in Koivumäki2018 and Paci2020, while only by strong I blockers, e.g. nisoldipine, in Kernik2019. These results were confirmed by the sensitivity analysis. To conclude, The CTD changes observed are qualitatively consistent with our data, although our simulations show differences in drug responses across the hSC-CM models, which could stem from variability in the experimental data used in their construction.
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http://dx.doi.org/10.3389/fphar.2021.604713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033762PMC
March 2021

The resting membrane potential of hSC-CM in a syncytium is more hyperpolarised than that of isolated cells.

Channels (Austin) 2021 Dec;15(1):239-252

Department of Biomedical Sciences, University of Antwerp , Antwerp, Belgium.

Human-induced pluripotent stem cell (hiPSC) and stem cell (hSC) derived cardiomyocytes (CM) are gaining popularity as in vitro model for cardiology and pharmacology studies. A remaining flaw of these cells, as shown by single-cell electrophysiological characterization, is a more depolarized resting membrane potential (RMP) compared to native CM. Most reports attribute this to a lower expression of the Kir2.1 potassium channel that generates the I current. However, most RMP recordings are obtained from isolated hSC/hiPSC-CMs whereas in a more native setting these cells are interconnected with neighboring cells by connexin-based gap junctions, forming a syncytium. Hereby, these cells are electrically connected and the total pool of I increases. Therefore, the input resistance (Ri) of interconnected cells is lower than that of isolated cells. During patch clamp experiments pipettes need to be well attached or sealed to the cell, which is reflected in the seal resistance (Rs), because a nonspecific ionic current can leak through this pipette-cell contact or seal and balance out small currents within the cell such as I. By recording the action potential of isolated hSC-CMs and that of hSC-CMs cultured in small monolayers, we show that the RMP of hSC-CMs in monolayer is approximately -20 mV more hyperpolarized compared to isolated cells. Accordingly, adding carbenoxolone, a connexin channel blocker, isolates the cell that is patch clamped from its neighboring cells of the monolayer and depolarizes the RMP. The presented data show that the recorded RMP of hSC-CMs in a syncytium is more negative than that determined from isolated hSC/hiPSC-CMs, most likely because the active pool of Kir2.1 channels increased.
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http://dx.doi.org/10.1080/19336950.2021.1871815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817136PMC
December 2021

Utility of Normalized TdP Score System in Drug Proarrhythmic Potential Assessment: A Blinded in vitro Study of CiPA Drugs.

Clin Pharmacol Ther 2021 Jun 29;109(6):1606-1617. Epub 2020 Dec 29.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.

Drugs that prolong QT may cause torsade de pointes (TdP). However, translation of nonclinical assessment of QT prolongation or hERG channel, targeted by QT-prolonging drugs, into clinical TdP risk has been insufficient to date. In this blinded study, we confirmed the utility of a Normalized TdP Score System in predicting drug-induced TdP risks among 34 drugs, including 28 with low, intermediate, and high TdP risks under the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative plus six compounds with names blinded to the investigators, using the rabbit ventricular wedge assay. Concentration-dependent TdP scores were determined by drug-induced changes in QT, T , and proarrhythmias. Disclosure of the names and testing concentrations was made after completion of the experiments and report to the sponsors. Drugs' normalized TdP scores were calculated thereafter based on their respective free clinical maximum concentration (C ). Drugs' normalized TdP scores were calculated and ranked for 33 drugs, excluding 1 investigational drug, and the TdP risks of the 28 CiPA drugs were correctly distinguished according to their respective categories of low, intermediate, and high TdP risks under the CiPA initiative. Accordingly, we are able to propose the cutoff values of the normalized TdP scores at 1 × C : ≤ 0, > 0 to < 0.65 and ≥ 0.65, respectively, for low, intermediate, and high risk. This blinded study supports utility of our Normalized TdP Score System in predicting drug-induced TdP risks in 33 drugs, including 28 used for characterization of other assays under the CiPA initiative. However, these results need to be replicated in other laboratories.
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http://dx.doi.org/10.1002/cpt.2133DOI Listing
June 2021

Pharmacological Profile of the Sodium Current in Human Stem Cell-Derived Cardiomyocytes Compares to Heterologous Nav1.5+β1 Model.

Front Pharmacol 2019 11;10:1374. Epub 2019 Dec 11.

Laboratory of Molecular, Cellular, and Network Excitability, University of Antwerp, Antwerp, Belgium.

The cardiac Nav1.5 mediated sodium current (I) generates the upstroke of the action potential in atrial and ventricular myocytes. Drugs that modulate this current can therefore be antiarrhythmic or proarrhythmic, which requires preclinical evaluation of their potential drug-induced inhibition or modulation of Nav1.5. Since Nav1.5 assembles with, and is modulated by, the auxiliary β1-subunit, this subunit can also affect the channel's pharmacological response. To investigate this, the effect of known Nav1.5 inhibitors was compared between COS-7 cells expressing Nav1.5 or Nav1.5+β1 using whole-cell voltage clamp experiments. For the open state class Ia blockers ajmaline and quinidine, and class Ic drug flecainide, the affinity did not differ between both models. For class Ib drugs phenytoin and lidocaine, which are inactivated state blockers, the affinity decreased more than a twofold when β1 was present. Thus, β1 did not influence the affinity for the class Ia and Ic compounds but it did so for the class Ib drugs. Human stem cell-derived cardiomyocytes (hSC-CMs) are a promising translational cell source for models that express a representative repertoire of channels and auxiliary proteins, including β1. Therefore, we subsequently evaluated the same drugs for their response on the I in hSC-CMs. Consequently, it was expected and confirmed that the drug response of I in hSC-CMs compares best to I expressed by Nav1.5+β1.
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http://dx.doi.org/10.3389/fphar.2019.01374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917651PMC
December 2019

Role of Kv7.2/Kv7.3 and M muscarinic receptors in the regulation of neuronal excitability in hiPSC-derived neurons.

Eur J Pharmacol 2019 Sep 22;858:172474. Epub 2019 Jun 22.

Non-Clinical Safety, Discovery, Product Development & Supply, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.

The Kv7 family of voltage-dependent non-inactivating potassium channels is composed of five members, of which four are expressed in the CNS. Kv7.2, 7.3 and 7.5 are responsible for the M-current, which plays a critical role in the regulation of neuronal excitability. Stimulation of M muscarinic acetylcholine receptor, M receptor, increases neuronal excitability by suppressing the M-current generated by the Kv7 channel family. The M-current modulation via M receptor is well-described in in vitro assays using cell lines and in native rodent tissue. However, this mechanism was not yet reported in human induced pluripotent stem cells (hiPSC) derived neurons. In the present study, we investigated the effects of both agonists and antagonists of Kv7.2/7.3 channel and M receptor in hiPSC derived neurons and in primary rat cortical neuronal cells. The role of M receptors in the modulation of neuronal excitability could be demonstrated in both rat primary and hiPSC neurons. The M receptors agonist, xanomeline, increased neuronal excitability in both rat cortical and the hiPSC neuronal cells. Furthermore, M receptor agonist-induced neuronal excitability in vitro was reduced by an agonist of Kv7.2/7.3 in both neuronal cells. These results show that hiPSC derived neurons recreate the modulation of the M-current by the muscarinic receptor in hiPSC neurons similarly to rat native neurons. Thus, hiPSC neurons could be a useful human-based cell assay for characterization of drugs that affect neuronal excitability and/or induce seizure activity by modulation of M receptors or inhibition of Kv7 channels.
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http://dx.doi.org/10.1016/j.ejphar.2019.172474DOI Listing
September 2019

Assessing Drug-Induced Long QT and Proarrhythmic Risk Using Human Stem-Cell-Derived Cardiomyocytes in a Ca2+ Imaging Assay: Evaluation of 28 CiPA Compounds at Three Test Sites.

Toxicol Sci 2019 08;170(2):345-356

Janssen Pharmaceutica NV (J&J), 2340 Beerse, Belgium.

The goal of this research consortium including Janssen, MSD, Ncardia, FNCR/LBR, and Health and Environmental Sciences Institute (HESI) was to evaluate the utility of an additional in vitro assay technology to detect potential drug-induced long QT and torsade de pointes (TdP) risk by monitoring cytosolic free Ca2+ transients in human stem-cell-derived cardiomyocytes (hSC-CMs). The potential proarrhythmic risks of the 28 comprehensive in vitro proarrhythmia assay (CiPA) drugs linked to low, intermediate, and high clinical TdP risk were evaluated in a blinded manner using Ca2+-sensitive fluorescent dye assay recorded from a kinetic plate reader system (Hamamatsu FDSS/µCell and FDSS7000) in 2D cultures of 2 commercially available hSC-CM lines (Cor.4U and CDI iCell Cardiomyocytes) at 3 different test sites. The Ca2+ transient assay, performed at the 3 sites using the 2 different hSC-CMs lines, correctly detected potential drug-induced QT prolongation among the 28 CiPA drugs and detected cellular arrhythmias-like/early afterdepolarization in 7 of 8 high TdP-risk drugs (87.5%), 6 of 11 intermediate TdP-risk drugs (54.5%), and 0 of 9 low/no TdP-risk drugs (0%). The results were comparable among the 3 sites and from 2 hSC-CM cell lines. The Ca2+ transient assay can serve as a user-friendly and higher throughput alternative to complement the microelectrode array and voltage-sensing optical action potential recording assays used in the HESI-CiPA study for in vitro assessment of drug-induced long QT and TdP risk.
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http://dx.doi.org/10.1093/toxsci/kfz102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657578PMC
August 2019

Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking.

Stem Cell Reports 2018 12;11(6):1365-1377

Global Safety Pharmacology, Non-Clinical Safety, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising cardiac safety platform, demonstrated by numerous validation studies using drugs with known cardiac adverse effects in humans. However, the challenge remains to implement hiPSC-CMs into cardiac de-risking of new chemical entities (NCEs) during preclinical drug development. Here, we used the calcium transient screening assay in hiPSC-CMs to develop a hazard score system for cardiac electrical liabilities. Tolerance interval calculations and evaluation of different classes of cardio-active drugs enabled us to develop a weighted scoring matrix. This approach allowed the translation of various pharmacological effects in hiPSC-CMs into a single hazard label (no, low, high, or very high hazard). Evaluation of 587 internal NCEs and good translation to ex vivo and in vivo models for a subset of these NCEs highlight the value of the cardiac hazard scoring in facilitating the selection of compounds during early drug safety screening.
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http://dx.doi.org/10.1016/j.stemcr.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294263PMC
December 2018

Prognostic value of electrocardiographic time intervals and QT rate dependence in hypertrophic cardiomyopathy.

J Electrocardiol 2018 Nov - Dec;51(6):1077-1083. Epub 2018 Sep 12.

Department of Cardiovascular Diseases, University Hospitals Leuven, Belgium; Department of Cardiovascular Sciences, University of Leuven, Belgium.

Introduction: Preventing sudden cardiac death (SCD) is one of the main goals in hypertrophic cardiomyopathy (HCM). Many variables have been proposed, however the European and American guidelines do not incorporate any ECG or Holter monitoring derived variables other than the presence of ventricular arrhythmia in their risk stratification models. In the present study we evaluated electrocardiographic parameters in risk stratification of HCM.

Methods And Results: Novel electrocardiographic parameters including the index of cardio-electrophysiological balance (iCEB), individualized QT correction (QTi) and QT rate dependence were evaluated along with established risk factors. A composite endpoint of SCD was defined as out of hospital cardiac arrest, appropriate ICD shock and sustained ventricular tachycardia. Cox regression analysis was used to evaluate predictors of SCD. Out of the 466 HCM patients, 31 reached the composite endpoint during a follow up of 75 ± 86 months. In a multivariate model, nor iCEB, QTi or QT rate dependence were predictors of SCD. Only male gender (p < 0.01; OR 13.1; CI 1.74-98.83), negative T waves in the inferior leads (p = 0.04; OR 2.51; CI 1.03-6.13) and familial sudden death (p < 0.01; OR 3.03; CI 1.39-6.59) were significant predictors. On top of either the ESC risk score or the 3 traditional 'American risk factors', only male gender was a significant predictor of SCD.

Conclusion: No ECG or Holter monitoring parameters added in risk stratification for SCD in HCM. However, male gender and negative T waves in the inferior leads are promising novel markers to evaluate in larger cohorts.
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http://dx.doi.org/10.1016/j.jelectrocard.2018.09.005DOI Listing
October 2019

Impact of calcium-sensitive dyes on the beating properties and pharmacological responses of human iPS-derived cardiomyocytes using the calcium transient assay.

J Pharmacol Toxicol Methods 2018 May - Jun;91:80-86. Epub 2018 Feb 6.

Global Safety Pharmacology, Preclinical Safety & Development, Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. Electronic address:

Introduction: Calcium-based screening of hiPS-CMs is a useful preclinical safety evaluation platform with the ability to generate robust signals that facilitates high-throughput screening and data analysis. However, due to the potential inherent toxicities, it is important to understand potential effects of different calcium-sensitive dyes on the hiPS-CMs model.

Methods: We compared three calcium-sensitive fluorescence dyes (Cal520, ACTOne and Calcium 5) for their impact on the variability, the beating properties and the pharmacological responses of hiPS-CMs using the Hamamatsu FDSS/μCell imaging platform. Direct effects of three dyes on the electrophysiological properties of hiPS-CMs were evaluated with the multi-electrode array (MEA) Axion Maestro platform.

Results: We propose a specific experimental protocol for each dye which gives the most optimal assay conditions to minimize variability and possible adverse effects. We showed that Cal520 had the smallest effect on hiPS-CMs together with the longest-lasting stable amplitude signal (up to 4 h). Although all dyes had a (minor) acute effect on hiPS-CMs, in the form of reduced beat rate and prolonged field potential duration, the selection of the dye did not influence the pharmacological response of four cardioactive drugs (dofetilide, moxifloxacin, nimodipine and isoprenaline).

Discussion: In conclusion, we have documented that different calcium sensitive dyes have only minor direct (acute) effects on hiPS-CMs with Cal520 showing the least effects and the longest lasting signal amplitude. Importantly, drug-induced pharmacological responses in hiPS-CMs were comparable between the three dyes. These findings should help further improve the robustness of the hiPS-CMs-based calcium transient assay as a predictive, preclinical cardiac safety evaluation tool.
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http://dx.doi.org/10.1016/j.vascn.2018.02.004DOI Listing
September 2018

A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate.

J Med Chem 2018 01 20;61(1):207-223. Epub 2017 Dec 20.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01279DOI Listing
January 2018

Response of Robyns to the Tse's letter to editor.

Ann Noninvasive Electrocardiol 2017 11;22(6)

Department of Cardiovascular Diseases, University Hospitals, Leuven, Belgium.

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http://dx.doi.org/10.1111/anec.12515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931848PMC
November 2017

Human Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

Front Physiol 2017 12;8:668. Epub 2017 Sep 12.

Computational Cardiovascular Science Group, Department of Computer Science, University of OxfordOxford, United Kingdom.

Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC/Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca/late Na currents and Na/Ca-exchanger, reduced Na/K-pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na and Ca currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca-transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.
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http://dx.doi.org/10.3389/fphys.2017.00668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601077PMC
September 2017

Application of a systems pharmacology model for translational prediction of hERG-mediated QTc prolongation.

Pharmacol Res Perspect 2016 12 17;4(6):e00270. Epub 2016 Nov 17.

Systems Pharmacology Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands; Certara Quantitative Systems Pharmacology Canterbury United Kingdom.

Drug-induced QTc interval prolongation ( QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only). Scaling parameters for translational in vivo extrapolation of drug effects were derived based on the assumption of system-specific myocardial ion channel densities and transduction of ion channel block: the operational efficacy (transduction of hERG block) in dogs was drug specific (1-19% hERG block corresponded to ≥10 msec QTc). System-specific maximal achievable QTc was estimated to 28% from baseline in both dog and human, while %hERG block leading to half-maximal effects was 58% lower in human, suggesting a higher contribution of hERG-mediated potassium current to cardiac repolarization. These results suggest that differences in sensitivity to drug-induced QTc prolongation may be well explained by drug- and system-specific differences in operational efficacy (transduction of hERG block), consistent with experimental reports. The proposed scaling approach may thus assist the translational risk assessment of QTc prolongation in different species and patient populations, if mediated by the hERG channel.
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http://dx.doi.org/10.1002/prp2.270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226282PMC
December 2016

Chronic drug-induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell-derived cardiomyocytes.

Br J Pharmacol 2017 Nov 8;174(21):3766-3779. Epub 2017 Feb 8.

Preclinical Development and Safety, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.

Background And Purpose: In the pharmaceutical industry risk assessments of chronic cardiac safety liabilities are mostly performed during late stages of preclinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity.

Experimental Approach: Video microscopy-based motion field imaging was applied to evaluate the chronic effect (over 72 h) of cardiotoxic drugs on the contractile motion of hiPS-CMs. In parallel, the release of cardiac troponin I (cTnI), heart fatty acid binding protein (FABP3) and N-terminal pro-brain natriuretic peptide (NT-proBNP) was analysed from cell medium, and transcriptional profiling of hiPS-CMs was done at the end of the experiment.

Key Results: Different cardiotoxic drugs altered the contractile motion properties of hiPS-CMs together with increasing the release of cardiac biomarkers. FABP3 and cTnI were shown to be potential surrogates to predict cardiotoxicity in hiPS-CMs, whereas NT-proBNP seemed to be a less valuable biomarker. Furthermore, drug-induced cardiotoxicity produced by chronic exposure of hiPS-CMs to arsenic trioxide, doxorubicin or panobinostat was associated with different profiles of changes in contractile parameters, biomarker release and transcriptional expression.

Conclusion And Implications: We have shown that a parallel assessment of motion field imaging-derived contractile properties, release of biomarkers and transcriptional changes can detect diverse mechanisms of chronic drug-induced cardiac liabilities in hiPS-CMs. Hence, hiPS-CMs could potentially improve and accelerate cardiovascular de-risking of compounds at earlier stages of drug discovery.

Linked Articles: This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.
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http://dx.doi.org/10.1111/bph.13713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647189PMC
November 2017

KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting.

Nat Commun 2016 10 12;7:12795. Epub 2016 Oct 12.

Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster, Muenster D-48149, Germany.

Most small-molecule inhibitors of voltage-gated ion channels display poor subtype specificity because they bind to highly conserved residues located in the channel's central cavity. Using a combined approach of scanning mutagenesis, electrophysiology, chemical ligand modification, chemical cross-linking, MS/MS-analyses and molecular modelling, we provide evidence for the binding site for adamantane derivatives and their putative access pathway in Kv7.1/KCNE1 channels. The adamantane compounds, exemplified by JNJ303, are highly potent gating modifiers that bind to fenestrations that become available when KCNE1 accessory subunits are bound to Kv7.1 channels. This mode of regulation by auxiliary subunits may facilitate the future development of potent and highly subtype-specific Kv channel inhibitors.
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http://dx.doi.org/10.1038/ncomms12795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064022PMC
October 2016

Assessment of drug-induced proarrhythmia: The importance of study design in the rabbit left ventricular wedge model.

J Pharmacol Toxicol Methods 2016 Sep-Oct;81:151-60. Epub 2016 Jun 29.

Lankenau Institute for Medical Research, Wynnewood, PA, USA.

In the present study, we investigated an impact of the stimulation rate on the detection of the proarrhythmic potential of 10 reference compounds with effects on different cardiac ion channels in the isolated arterially-perfused rabbit left ventricular wedge preparation. The compounds were tested in the wedge model using two distinct protocols; including baseline stimulation at 1-Hz followed by a brief period at 0.5-Hz, either without an additional brief period of 2-Hz stimulation (i.e. Protocol 1) or with 2-Hz stimulation (i.e. Protocol 2). As expected, QT-prolonging drugs (ibutilide and quinidine) prolonged the QT interval, similarly increased the Torsades de Pointes (TdP) score, and elicited early afterdepolarizations (EADs) in both protocols. HMR1556 and JNJ-303 (IKs blockers) also prolonged the QT interval up to 1μM similarly in both protocols. Nifedipine (Ca(2+) antagonist) shortened the QT interval, and reduced force of contraction similarly in both protocols. However, Na(+) channel blockers (Ia, Ib, Ic) widened the QRS duration more in Protocol 2 than in Protocol 1. Furthermore, it was only possible to detect non-TdP-like ventricular tachycardia/fibrillation (VT/VF) induced by Na(+) blockers and by QT-shortening drugs (levcromakalim and mallotoxin) using the 2-Hz stimulation (Protocol 2). Our data suggest that the inclusion of a brief period of fast stimulation at 2Hz is critical for detecting drug-induced slowing of conduction (QRS widening), QT shortening and associated (non-TdP-like) VT/VF, which are distinct from the QT prolongation/TdP proarrhythmia in isolated, arterially-perfused rabbit left ventricular wedges.
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http://dx.doi.org/10.1016/j.vascn.2016.06.006DOI Listing
May 2017

Common respiratory conditions of the newborn.

Breathe (Sheff) 2016 Mar;12(1):30-42

Department of Child Health, School of Medicine, Cardiff University, Cardiff, UK.

Key Points: Respiratory distress is a common presenting feature among newborn infants.Prompt investigation to ascertain the underlying diagnosis and appropriate subsequent management is important to improve outcomes.Many of the underlying causes of respiratory distress in a newborn are unique to this age group.A chest radiograph is crucial to assist in diagnosis of an underlying cause.

Educational Aims: To inform readers of the common respiratory problems encountered in neonatology and the evidence-based management of these conditions.To enable readers to develop a framework for diagnosis of an infant with respiratory distress. The first hours and days of life are of crucial importance for the newborn infant as the infant adapts to the extra-uterine environment. The newborn infant is vulnerable to a range of respiratory diseases, many unique to this period of early life as the developing fluid-filled fetal lungs adapt to the extrauterine environment. The clinical signs of respiratory distress are important to recognise and further investigate, to identify the underlying cause. The epidemiology, diagnostic features and management of common neonatal respiratory conditions are covered in this review article aimed at all healthcare professionals who come into contact with newborn infants.
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http://dx.doi.org/10.1183/20734735.000716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818233PMC
March 2016

Functional and Transcriptional Characterization of Histone Deacetylase Inhibitor-Mediated Cardiac Adverse Effects in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Stem Cells Transl Med 2016 May 31;5(5):602-12. Epub 2016 Mar 31.

Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica, Beerse, Belgium.

Unlabelled: Histone deacetylase (HDAC) inhibitors possess therapeutic potential to reverse aberrant epigenetic changes associated with cancers, neurological diseases, and immune disorders. Unfortunately, clinical studies with some HDAC inhibitors displayed delayed cardiac adverse effects, such as atrial fibrillation and ventricular tachycardia. However, the underlying molecular mechanism(s) of HDAC inhibitor-mediated cardiotoxicity remains poorly understood and is difficult to detect in the early stages of preclinical drug development because of a delayed onset of effects. In the present study, we show for the first time in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) that HDAC inhibitors (dacinostat, panobinostat, vorinostat, entinostat, and tubastatin-a) induce delayed dose-related cardiac dysfunction at therapeutic concentrations associated with cardiac adverse effects in humans. HDAC inhibitor-mediated delayed effects on the beating properties of hiPS-CMs developed after 12 hours by decreasing the beat rate, shortening the field potential duration, and inducing arrhythmic behavior under form of sustained contractions and fibrillation-like patterns. Transcriptional changes that are common between the cardiotoxic HDAC inhibitors but different from noncardiotoxic treatments identified cardiac-specific genes and pathways related to structural and functional changes in cardiomyocytes. Combining the functional data with epigenetic changes in hiPS-CMs allowed us to identify molecular targets that might explain HDAC inhibitor-mediated cardiac adverse effects in humans. Therefore, hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and support identification of better HDAC inhibitors with an improved benefit-risk profile.

Significance: Histone deacetylase (HDAC) inhibitors are a promising class of drugs to treat certain cancers, autoimmune, and neurodegenerative diseases. However, treated patients can experience various cardiac adverse events such as hearth rhythm disorders. This study found that human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) can predict cardiac adverse events in patients caused by HDAC inhibitors. Furthermore, transcriptional changes at the level of gene expression supported the effects on the beating properties of hiPS-CMs and highlight targets that might cause these cardiac adverse effects. hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and to support development of safer HDAC inhibitors.
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http://dx.doi.org/10.5966/sctm.2015-0279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835253PMC
May 2016

Respiratory Microbiome of New-Born Infants.

Front Pediatr 2016 23;4:10. Epub 2016 Feb 23.

Department of Child Health, School of Medicine, Cardiff University , Cardiff , UK.

The respiratory tract, once believed to be sterile, harbors diverse bacterial communities. The role of microorganisms within health and disease is slowly being unraveled. Evidence points to the neonatal period as a critical time for establishing stable bacterial communities and influencing immune responses important for long-term respiratory health. This review summarizes the evidence of early airway and lung bacterial colonization and the role the microbiome has on respiratory health in the short and long term. The challenges of neonatal respiratory microbiome studies and future research directions are also discussed.
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http://dx.doi.org/10.3389/fped.2016.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762994PMC
March 2016

The respiratory consequences of early-term birth and delivery by caesarean sections.

Paediatr Respir Rev 2016 Jun 23;19:49-55. Epub 2015 Dec 23.

Department of Child Health, School of Medicine, Cardiff University, Cardiff, UK. Electronic address:

In England and Wales, 19% of live births in 2012 were at 37-38 weeks' gestation, equating to nearly 140 000 early-term births each year. Since caesarean sections (CS) are often performed at early-term gestations, this accounts for some of the increased proportion of the early-term births. Infants born early-term are at an increased risk of neonatal respiratory morbidity particularly if they are delivered by caesarean section. The long term lung function data are limited but available data suggest that early-term delivery is associated with respiratory morbidity in childhood. CS also appears to be associated with increased neonatal morbidity and future development of respiratory symptoms. However, future studies need to confirm the independent effects of caesarean sections and early-term deliveries particularly for long term outcomes as both are likely to affect the respiratory system differently.
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http://dx.doi.org/10.1016/j.prrv.2015.12.002DOI Listing
June 2016

High Throughput Measurement of Ca++ Dynamics in Human Stem Cell-Derived Cardiomyocytes by Kinetic Image Cytometery: A Cardiac Risk Assessment Characterization Using a Large Panel of Cardioactive and Inactive Compounds.

Toxicol Sci 2015 Dec 9;148(2):503-16. Epub 2015 Sep 9.

*Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Pharmaceutical NV, B2340 Beerse, Belgium;

Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as a powerful in vitro model for cardiac safety assessment which may allow for better identification of compounds with poor arrhythmogenic liability profiles early in the drug discovery process. Here, we describe our examination of the Kinetic Image Cytometer (KIC) system's ability to predict adverse compound effects using hiPS-CMs and a library of 53 compounds, the majority of which are known to be cardioactive compounds, and several negative controls. The KIC provides a high throughput method for analyzing intracellular calcium transients. In the cardiomyocyte, intracellular calcium transients integrate the electrochemical signals of the action potential (AP) with the molecular signaling pathways regulating contraction. Drug-induced alterations in the shape and duration of AP result in changes to the shape and duration of the intracellular calcium transient. By examining calcium transient dynamics in hiPS-CMs, KIC can be used as a phenotypic screen to assess compound effects across multiple ion channel types (MITs), detecting MITs, calcium handling and signaling effects. The results of this blinded study indicate that using hiPS-CMs, KIC is able to accurately detect drug-induced changes in Ca(2+) transient dynamics (ie, duration and beat rate) and therefore, may be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase.
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http://dx.doi.org/10.1093/toxsci/kfv201DOI Listing
December 2015

Evaluation of Index of Cardio-Electrophysiological Balance (iCEB) as a New Biomarker for the Identification of Patients at Increased Arrhythmic Risk.

Ann Noninvasive Electrocardiol 2016 May 25;21(3):294-304. Epub 2015 Aug 25.

Department of Cardiovascular Diseases, University Hospitals, Leuven, Belgium.

Background: Recently a new risk marker for drug-induced arrhythmias called index of cardio-electrophysiological balance (iCEB), measured as QT interval divided by QRS duration, was evaluated in an animal model. It was hypothesized that iCEB is equivalent to the cardiac wavelength λ (λ = effective refractory period (ERP) x conduction velocity) and that an increased or decreased value of iCEB would potentially predict an increased susceptibility to TdP or non-TdP mediated VT/VF, respectively.

Methods: First, the correlation between QT interval and ERP was evaluated by invasively measuring ERP during a ventricular stimulation protocol in humans (N = 40). Then the effect of administration of sotalol and flecainide on iCEB was measured in 40 patients with supraventricular tachycardias. Finally iCEB was assessed in carriers of a long QT syndrome (LQTS, N = 70) or Brugada syndrome (BrS, N = 57) mutation and compared them with genotype negative family members (N = 65).

Results: The correlation between QT interval and ERP was established (Pearson R(2) = 0.25) which suggests that iCEB≈ERPxCV≈QT/QRS. Sotalol administration increased iCEB (+ 0.23; P = 0.01), while it decreased with the administration of flecainide (-0.21, P = 0.03). In the LQTS group iCEB was increased (5.22 ± 0.93, P < 0.0001) compared to genotype negative family members (4.24 ± 0.5), while it was decreased in the BrS group (3.52 ± 0.43, P < 0.0001).

Conclusions: Our data suggest that iCEB (QT/QRS) is a simple but effective ECG surrogate of cardiac wavelength. iCEB is increased in situations that predispose to TdP and is decreased in situations that predispose to non-TdP mediated VT/VF. Therefore, iCEB might serve as a noninvasive and readily measurable marker to detect increased arrhythmic risk.
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http://dx.doi.org/10.1111/anec.12309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931457PMC
May 2016

Renal studies in safety pharmacology and toxicology: A survey conducted in the top 15 pharmaceutical companies.

J Pharmacol Toxicol Methods 2015 Sep-Oct;75:101-10. Epub 2015 Jan 29.

Safety Pharmacology Centre of Excellence, Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.

Introduction: With the recent development of more sensitive biomarkers to assess kidney injury preclinically, a survey was designed i) to investigate what strategies are used to investigate renal toxicity in both ICH S7A compliant Safety Pharmacology (SP) studies after a single dose of a compound and within repeat-dose toxicity studies by large pharmaceutical companies today; ii) to understand whether renal SP studies have impact or utility in drug development and/or if it may be more appropriate to assess renal effects after multiple doses of compounds; iii) to ascertain how much mechanistic work is performed by the top 15 largest pharmaceutical companies (as determined by R&D revenue size); iv) to gain an insight into the impact of the validation of DIKI biomarkers and their introduction in the safety evaluation paradigm; and v) to understand the impact of renal/urinary safety study data on progression of projects.

Methods: Two short anonymous surveys were submitted to SP leaders of the top 15 pharmaceutical companies, as defined by 2012 R&D portfolio size. Fourteen multiple choice questions were designed to explore the strategies used to investigate renal effects in both ICH S7A compliant SP studies and within toxicology studies.

Results: A 67% and 60% response rate was obtained in the first and second surveys, respectively. Nine out of ten respondent companies conduct renal excretory measurements (eg. urine analysis) in toxicology studies whereas only five out of ten conduct specific renal SP studies; and all of those 5 also conduct the renal excretory measurements in toxicology studies. These companies measure and/or calculate a variety of parameters as part of these studies, and also on a case by case basis include regulatory qualified and non-qualified DIKI biomarkers. Finally, only one company has used renal/urinary functional data alone to stop a project, whereas the majority of respondents combine renal data with other target organ assessments to form an integrated decision-making set.

Conclusion: These short surveys highlighted areas of similarity: a) urinary measurements are most commonly taken on repeat-dose toxicity studies, and b) renal SP studies are less often utilised. The two major differences are a) lack of consistent use of DIKI biomarkers in urinary safety studies and b) the way large pharmaceutical companies assess renal function. Finally, suggestions were made to improve the safety assessment methods for determining the safety of compounds with potential renal liability.
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http://dx.doi.org/10.1016/j.vascn.2015.01.004DOI Listing
July 2016

Sensitivity of pharmacokinetic-pharmacodynamic analysis for detecting small magnitudes of QTc prolongation in preclinical safety testing.

J Pharmacol Toxicol Methods 2015 Mar-Apr;72:1-10. Epub 2014 Dec 31.

Systems Pharmacology, Leiden Academic Center of Drug Research (LACDR), Leiden University, Leiden, The Netherlands. Electronic address:

Introduction: Preclinical concentration-effect (pharmacokinetic-pharmacodynamic, PKPD) modeling has successfully quantified QT effects of several drugs known for significant QT prolongation. This study investigated its sensitivity for detecting small magnitudes of QT-prolongation in a typical preclinical cardiovascular (CV) safety study in the conscious telemetered dog (crossover study in 4-8 animals receiving a vehicle and three dose levels). Results were compared with conventional statistical analysis (analysis of covariance, ANCOVA).

Methods: A PKPD model predicting individual QTc was first developed from vehicle arms of 28 typical CV studies and one positive control study (sotalol). The model quantified between-animal, inter-occasion and within-animal variability and described QTc over 24h as a function of circadian variation and drug concentration. This "true" model was used to repeatedly (n = 500) simulate studies with typical drug-induced QTc prolongation (∆QTc) of 1 to 12 ms at high-dose peak concentrations. Simulated studies were re-analyzed by both PKPD analysis (with varying complexity) and ANCOVA. Sensitivity (power) was calculated as the percentage of studies in which a significant (α = 0.05) drug effect was found. One simulation scenario did not include a concentration-effect relationship and served to investigate false-positive rates. Exposure-effect relationships were derived from both PKPD analysis (linear concentration-effect) and ANCOVA (linear trend test for dose) and compared.

Results: PKPD analysis/ANCOVA had a sensitivity of 80% to detect the effects of 7/13 ms (n = 4), 5/10 ms (n = 6) and 4.5/8 ms (n = 8), respectively. The false-positive rate was much higher using ANCOVA (40%) compared to PKPD analysis (1%). Typical drug effects were more precisely predicted using estimated concentration-effect slopes (± 1.5-2.8 ms) than dose-effect slopes (± 3.3-3.7 ms).

Discussion: Preclinical PKPD analysis can increase the confidence in the quantification of small QTc effects and potentially allow reducing the number of animals while maintaining the required study sensitivity. This underscores the value of PKPD modeling in preclinical safety testing.
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http://dx.doi.org/10.1016/j.vascn.2014.12.008DOI Listing
December 2015

Characterization of an anesthetized dog model of transient cardiac ischemia and rapid pacing: a pilot study for preclinical assessment of the potential for proarrhythmic risk of novel drug candidates.

J Pharmacol Toxicol Methods 2015 Mar-Apr;72:72-84. Epub 2014 Oct 23.

Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, Belgium.

Introduction: Preclinical proarrhythmic risk assessment of drug candidates is focused predominantly on arrhythmias arising from repolarization abnormalities. However, drug-induced cardiac conduction slowing is associated with significant risk of life-threatening ventricular arrhythmias, particularly in a setting of cardiac ischemia. Therefore, we optimized and characterized an anesthetized dog model to evaluate the potential proarrhythmic risk of drug candidates in ischemic heart disease patients.

Methods: Anesthetized dogs were instrumented with atrial and ventricular epicardial electrodes for pacing and measurement of conduction times, and a balloon occluder and flow probe placed around the left anterior descending coronary artery (LAD) distal to the first branch. Conduction times, ECG intervals and incidence of arrhythmias were assessed serially at the end of each dose infusion (flecainide: 0.32, 0.63, 1.25, 2.5 and 5mg/kg, i.v.; dofetilide:1.25, 2.5, 5, 10 and 20 μg/kg, i.v.; or vehicle; n=6/group) both during normal flow (with and without rapid pacing) and during 5-min LAD occlusion (with and without rapid pacing). Compound X, a development candidate with mild conduction slowing activity, was also evaluated.

Results: Flecainide produced pronounced, dose-dependent slowing of conduction that was exacerbated during ischemia and rapid pacing. In addition, ventricular tachycardia (VT) and fibrillation (VF) occurred in 4 of 6 dogs (3 VF @ 0.63 mg/kg; 1VT @ 2.5mg/kg). In contrast, no animals in the vehicle group developed arrhythmias. Dofetilide, a potent IKr blocker that does not slow conduction, prolonged QT interval but did not cause further conduction slowing during ischemia with or without pacing and there were no arrhythmias. Compound X, like flecainide, produced marked conduction slowing and arrhythmias (VT, VF) during ischemia and pacing.

Discussion: This model may be useful to more accurately define shifts in safety margins in a setting of ischemia and increased cardiac demand for drugs that slow conduction.
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http://dx.doi.org/10.1016/j.vascn.2014.10.006DOI Listing
December 2015

The concordance between nonclinical and phase I clinical cardiovascular assessment from a cross-company data sharing initiative.

Toxicol Sci 2014 Dec 21;142(2):427-35. Epub 2014 Sep 21.

*AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.

It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new molecules. The growth of translational safety offers a promising approach to improve the probability of success for new molecules. Here we describe a cross-company initiative to determine the concordance between the conscious telemetered dog and phase I outcome for 3 cardiovascular parameters. The data indicate that, in the context of the methods applied in this analysis, the ability to detect compounds that affect the corrected QT interval (QTc) was good within the 10-30x exposure range but the predictive or detective value for heart rate and diastolic blood pressure was poor. These findings may highlight opportunities to refine both the animal and the clinical study designs, as well as refocusing the assessment of value of dog cardiovascular assessments beyond phase 1. This investigation has also highlighted key considerations for cross-company data sharing and presents a unique learning opportunity to improve future translational projects.
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http://dx.doi.org/10.1093/toxsci/kfu198DOI Listing
December 2014

Effect of sitagliptin treatment on metabolism and cardiac function in genetic diabetic mice.

Eur J Pharmacol 2014 Jan 6;723:175-80. Epub 2014 Jan 6.

Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium. Electronic address:

To investigate the chronic effect of sitagliptin (7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-(3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate, SIT) on metabolism and cardiac function in genetic diabetic Akita mice, 10 weeks old Akita mice were either exposed for 4 months to a high fat and high cholesterol (HF-HC) diet, with or without 10mg/kg/day SIT, or were fed for 3 months with the same diet with or without 50mg/kg/day SIT. SIT treatment of Akita mice at either a low or high dose did not affect body or liver weight. A significant increase in subcutaneous and gonadal fat mass was only observed for the 50mg/kg/day dose of SIT. Furthermore, only the 50mg/kg/day SIT dose resulted in an improvement of glycemic control, as evidenced by a decrease in fasting blood HbA1c levels and an increase in plasma adiponectin levels. Echocardiographic analysis revealed that Akita mice kept on the HF-HC diet with 10mg/kg/day of SIT for 4 months showed an increase in ejection fraction and fractional shortening, whereas the higher dose (50mg/kg/day) had no effect on these parameters, but instead induced left ventricular (LV) hypertrophy as evidenced by an enlarged LV internal diameter, volume and mass. Thus, in the diabetic Akita mouse SIT is cardioprotective at a low dose (10mg/kg/day), whereas improvement of glycemic control requires a higher dose (50mg/kg/day) which, however, induces LV hypertrophy. This mouse model may thus be useful to study the safety of anti-diabetic drugs.
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http://dx.doi.org/10.1016/j.ejphar.2013.12.036DOI Listing
January 2014

A translational assessment of preclinical versus clinical tools for the measurement of cardiac contractility: comparison of LV dP/dt(max) with echocardiography in telemetry implanted beagle dogs.

J Pharmacol Toxicol Methods 2014 Jan-Feb;69(1):17-23. Epub 2013 Oct 16.

Translational Sciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.

Introduction: Regarding evaluation of drug-induced changes in left ventricular contractility in safety pharmacology there is still a gap in knowledge between preclinically and clinically used measurements.

Methods: As a step towards translation of preclinical to clinical outcomes, this study in telemetered dogs was initiated to compare indexes of contractility, such as LV dP/dt(max) (contractility measured as the maximum raise of pressure in the left ventricle) and LV dP/dt(max)/P (contractility measured as the maximum raise of pressure in the left ventricle, corrected for pressure) (telemetry; both commonly preclinically used) and EF (ejection fraction) and FS (fractional shortening) (echocardiography; both commonly clinically used). Different inotropic states were induced by minoxidil, milrinone, isoprenaline, clonidine, atenolol and verapamil.

Results: Both techniques demonstrated reproducible changes in contractility which showed a clear linear association. A change in LV dP/dt(max) of 1000 mmHg/s (in the range of 2500 to 7500 mmHg/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of approximately 6%. A change of 10/s LV dP/dt(max)/P (in the range of 35 to 85/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of 7%.

Discussion: The correlation found in this study could potentially enable a better--translational--assessment of the clinical relevance of changes in contractility indices measured with telemetry devices in preclinical safety studies.
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http://dx.doi.org/10.1016/j.vascn.2013.10.003DOI Listing
September 2014

Effect of rosiglitazone on liver structure and function in genetically diabetic Akita mice.

Basic Clin Pharmacol Toxicol 2013 Nov 11;113(5):353-60. Epub 2013 Jul 11.

Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.

Genetically diabetic Akita mice, kept on a high-fat and high-cholesterol diet, and treated with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (10 mg/kg per day during 4 months), displayed rosiglitazone-induced side effects, similar to those observed in patients, including weight and fat gain and early signs of hypertrophic cardiomyopathy. As several cases of hepatotoxicity were reported in patients receiving rosiglitazone treatment, this study evaluated whether rosiglitazone also induced hepatotoxicity in these diabetic animals. Liver structure and function was analysed in wild-type and rosiglitazone-treated and untreated Akita mice, kept for 4 months on the high-fat and high-cholesterol diet. Decreased circulating levels of the liver enzymes aspartate and alanine aminotransferase and increased levels of alkaline phosphatases were observed upon rosiglitazone treatment, whereas liver weight was markedly increased. Rosiglitazone administration was associated with liver steatosis, as demonstrated by triglyceride accumulation. However, gene expression of steatosis markers in liver tissue was not markedly affected by rosiglitazone treatment, while expression of fatty acid transport protein was reduced by rosiglitazone treatment, suggesting an impairment of the fatty acid β-oxidation pathway. mRNA expression of pro- and anti-oxidant enzymes and liver 3-nitrotyrosine content was not affected. Furthermore, gene and protein expression of macrophage markers and of cell adhesion molecules did not indicate progression to steatohepatitis, whereas an unaltered collagen deposition did not suggest steatofibrosis. In conclusion, rosiglitazone treatment of diabetic Akita mice induced liver steatosis without, however, progression to more advanced stages of liver disease.
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http://dx.doi.org/10.1111/bcpt.12104DOI Listing
November 2013