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  1. Article ; Online: Electrocardiographic biomarkers to confirm drug's electrophysiological effects used for proarrhythmic risk prediction under CiPA.

    Vicente, Jose / Hosseini, Meisam / Johannesen, Lars / Strauss, David G

    Journal of electrocardiology

    2017  Volume 50, Issue 6, Page(s) 808–813

    Abstract: The ECG plays a critical role in the thorough QT study. This clinical study is part of the assessment of proarrhythmic potential of drugs under the current regulatory paradigm. While the current paradigm has been successful in preventing drugs with ... ...

    Abstract The ECG plays a critical role in the thorough QT study. This clinical study is part of the assessment of proarrhythmic potential of drugs under the current regulatory paradigm. While the current paradigm has been successful in preventing drugs with unexpected QT prolongation or torsade risk from reaching the market, the focus on QT prolongation has likely resulted in potentially beneficial compounds with minimal torsade risk being dropped from development. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new mechanistic-based paradigm for cardiac safety evaluation of drugs. The fourth component of CiPA uses ECG data in phase 1 clinical studies to confirm there are no unanticipated ion channel effects compared to nonclinical data. The J-Tpeak interval was identified as the best biomarker for differentiating QTc prolonging drugs with predominant hERG block from drugs with multichannel (hERG plus late sodium and/or calcium block). This manuscript describes ECG methods for J-Tpeak assessment and their relationship with the features of new ECG biomarkers for detecting multichannel effects under CiPA.
    MeSH term(s) Algorithms ; Arrhythmias, Cardiac/chemically induced ; Arrhythmias, Cardiac/diagnosis ; Biomarkers/analysis ; Calcium Channel Blockers/pharmacology ; Electrocardiography/methods ; Electrophysiological Phenomena ; Heart Conduction System/drug effects ; Heart Rate/drug effects ; Heart Rate/physiology ; Humans ; Ion Channels/drug effects ; Long QT Syndrome/chemically induced ; Long QT Syndrome/diagnosis ; Phenethylamines/pharmacology ; Potassium Channel Blockers/pharmacology ; Quinidine/pharmacology ; Ranolazine/pharmacology ; Sodium Channel Blockers/pharmacology ; Sulfonamides/pharmacology ; Torsades de Pointes/chemically induced ; Torsades de Pointes/diagnosis ; Verapamil/pharmacology
    Chemical Substances Biomarkers ; Calcium Channel Blockers ; Ion Channels ; Phenethylamines ; Potassium Channel Blockers ; Sodium Channel Blockers ; Sulfonamides ; Ranolazine (A6IEZ5M406) ; Verapamil (CJ0O37KU29) ; Quinidine (ITX08688JL) ; dofetilide (R4Z9X1N2ND)
    Language English
    Publishing date 2017-11
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 410286-1
    ISSN 1532-8430 ; 0022-0736
    ISSN (online) 1532-8430
    ISSN 0022-0736
    DOI 10.1016/j.jelectrocard.2017.08.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 701: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk.

    Johannesen, Lars / Vicente, Jose / Hosseini, Meisam / Strauss, David G

    PloS one

    2016  Volume 11, Issue 12, Page(s) e0166925

    Abstract: Background: Prolongation of the heart rate corrected QT (QTc) interval is a sensitive marker of torsade de pointes risk; however it is not specific as QTc prolonging drugs that block inward currents are often not associated with torsade. Recent work ... ...

    Abstract Background: Prolongation of the heart rate corrected QT (QTc) interval is a sensitive marker of torsade de pointes risk; however it is not specific as QTc prolonging drugs that block inward currents are often not associated with torsade. Recent work demonstrated that separate analysis of the heart rate corrected J-Tpeakc (J-Tpeakc) and Tpeak-Tend intervals can identify QTc prolonging drugs with inward current block and is being proposed as a part of a new cardiac safety paradigm for new drugs (the "CiPA" initiative).
    Methods: In this work, we describe an automated measurement methodology for assessment of the J-Tpeakc and Tpeak-Tend intervals using the vector magnitude lead. The automated measurement methodology was developed using data from one clinical trial and was evaluated using independent data from a second clinical trial.
    Results: Comparison between the automated and the prior semi-automated measurements shows that the automated algorithm reproduces the semi-automated measurements with a mean difference of single-deltas <1 ms and no difference in intra-time point variability (p for all > 0.39). In addition, the time-profile of the baseline and placebo-adjusted changes are within 1 ms for 63% of the time-points (86% within 2 ms). Importantly, the automated results lead to the same conclusions about the electrophysiological mechanisms of the studied drugs.
    Conclusions: We have developed an automated algorithm for assessment of J-Tpeakc and Tpeak-Tend intervals that can be applied in clinical drug trials. Under the CiPA initiative this ECG assessment would determine if there are unexpected ion channel effects in humans compared to preclinical studies. The algorithm is being released as open-source software.
    Trial registration: NCT02308748 and NCT01873950.
    MeSH term(s) Algorithms ; Arrhythmias, Cardiac/chemically induced ; Arrhythmias, Cardiac/physiopathology ; Automation/methods ; Drug-Related Side Effects and Adverse Reactions/physiopathology ; Electrocardiography/methods ; Heart Conduction System/drug effects ; Heart Rate/drug effects ; Humans ; Long QT Syndrome/chemically induced ; Long QT Syndrome/physiopathology ; Pharmaceutical Preparations/administration & dosage ; Risk ; Torsades de Pointes/chemically induced ; Torsades de Pointes/physiopathology
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2016
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0166925
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Automated T-wave Delineator Algorithm for J-t

    Hosseini, Meisam / Johannesen, Lars / Vicente, Jose / Strauss, David G

    Journal of electrocardiology

    2016  Volume 49, Issue 6, Page(s) 935–936

    Language English
    Publishing date 2016-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 410286-1
    ISSN 1532-8430 ; 0022-0736
    ISSN (online) 1532-8430
    ISSN 0022-0736
    DOI 10.1016/j.jelectrocard.2016.09.036
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 701: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Correction: Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.

    Vicente, Jose / Johannesen, Lars / Hosseini, Meisam / Mason, Jay W / Sager, Philip T / Pueyo, Esther / Strauss, David G

    PloS one

    2018  Volume 13, Issue 5, Page(s) e0197952

    Abstract: This corrects the article DOI: 10.1371/journal.pone.0163619.]. ...

    Abstract [This corrects the article DOI: 10.1371/journal.pone.0163619.].
    Language English
    Publishing date 2018-05-21
    Publishing country United States
    Document type Journal Article ; Published Erratum
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0197952
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Order via subito

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    Inter-library loan at ZB MED

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  5. Article ; Online: Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.

    Vicente, Jose / Johannesen, Lars / Hosseini, Meisam / Mason, Jay W / Sager, Philip T / Pueyo, Esther / Strauss, David G

    PloS one

    2016  Volume 11, Issue 12, Page(s) e0163619

    Abstract: Background: Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e ... ...

    Abstract Background: Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.
    Methods and results: In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001).
    Conclusions: Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.
    Trial registration: NCT02308748 and NCT01873950.
    MeSH term(s) Adult ; Biomarkers/metabolism ; Calcium Channel Blockers/pharmacology ; Cross-Over Studies ; Electrocardiography/methods ; Ether-A-Go-Go Potassium Channels/metabolism ; Female ; Heart/drug effects ; Heart Rate/drug effects ; Humans ; Lidocaine/pharmacology ; Long QT Syndrome/metabolism ; Male ; Mexiletine/pharmacology ; Phenethylamines/pharmacology ; Potassium Channel Blockers/pharmacology ; Sodium/metabolism ; Sodium Channel Blockers/pharmacology ; Sulfonamides/pharmacology ; Torsades de Pointes/metabolism ; Verapamil/pharmacology
    Chemical Substances Biomarkers ; Calcium Channel Blockers ; Ether-A-Go-Go Potassium Channels ; Phenethylamines ; Potassium Channel Blockers ; Sodium Channel Blockers ; Sulfonamides ; Mexiletine (1U511HHV4Z) ; Lidocaine (98PI200987) ; Sodium (9NEZ333N27) ; Verapamil (CJ0O37KU29) ; dofetilide (R4Z9X1N2ND)
    Language English
    Publishing date 2016-12-30
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0163619
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Kategorien

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