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31.
Cardiac safety assessment in drug development concerns the ventricular repolarization (represented by electrocardiogram (ECG) T‐wave) abnormalities of a cardiac cycle, which are widely believed to be linked with torsades de pointes, a potentially life‐threatening arrhythmia. The most often used biomarker for such abnormalities is the prolongation of the QT interval, which relies on the correct annotation of onset of QRS complex and offset of T‐wave on ECG. A new biomarker generated from a functional data‐based methodology is developed to quantify the T‐wave morphology changes from placebo to drug interventions. Comparisons of T‐wave‐form characters through a multivariate linear mixed model are made to assess cardiovascular risk of drugs. Data from a study with 60 subjects participating in a two‐period placebo‐controlled crossover trial with repeat ECGs obtained at baseline and 12 time points after interventions are used to illustrate this methodology; different types of wave form changes were characterized and motivated further investigation. Copyright © 2012 John Wiley & Sons, Ltd. 相似文献
32.
《Expert review of cardiovascular therapy》2013,11(7):853-861
In this review, the authors discuss the role of ECG in prediction of stroke. ECG plays an important role in detection of several stroke risk factors/predictors including atrial fibrillation and left ventricular hypertrophy; both are components of the Framingham Stroke Risk Score. Multiple other ECG traits have also emerged as potential predictors of stroke, namely cardiac electrical/structural remodeling – Q wave, QRS/QT duration, bundle blocks, P wave duration/amplitude/dispersion, other waveform angles and slopes; higher automaticity – ectopic beats; and re-entry – atrial tachyarrhythmia; and higher vulnerability to arrhythmia – heart rate and its variability. Most of these predictors are not ready for prime time yet; however, further research focusing on their role in risk stratification and prevention of stroke may be useful. In this article, the authors discuss the prevalence, mechanisms and clinical applications of traditional and novel ECG markers in the prevention and treatment of stroke. 相似文献
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Christoph Josef Spindelegger Konstantinos Papageorgiou Renate Grohmann Rolf Engel Waldemar Greil Anastasios Konstantinidis Marcus Willy Agelink Stefan Bleich Eckart Ruether Sermin Toto Siegfried Kasper 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2015,18(4)
35.
Dayimi Kaya Cem Guler Ali Metin Esen Irfan Barutcu Cetin Dincel 《Annals of noninvasive electrocardiology》2004,9(3):228-233
Background: Sildenafil citrate may have direct cardiac electrophysiological effects, and is possibly responsible for some cardiac events. The aim of our study was to investigate the effects of sildenafil citrate on QT dynamicity properties with a new QT analysis program showing even small changes in ventricular repolarization. Methods: Twenty‐four‐hour Holter electrocardiographic recordings were used to obtain the data in the predrug phase (1‐hour rest position before drug administration), and in the postdrug phase (1‐hour rest position, which began 60 minutes after 50 mg oral sildenafil citrate administration). With the special QT analysis program (Verda, Reynolds Medical Ltd., UK); mean values of RR, QT, QTo (corrected QT), J (the exponent of correction formula) and S (QT/RR plots slope) parameters together with QT variability indexes (QTVI) were calculated for study phases. Results: Mean ± SEM values for RR and QT were higher in postdrug phase than in predrug phase (RR: 845 ± 42 ms vs 816 ± 46 ms, P < 0.05; QT: 371 ± 8 ms vs 361 ± 9 ms, P < 0.05). However, sildenafil did not induce any significant change in mean ± SEM values for QTo, J, and S in postdrug phase compared with predrug phase (408 ± 10 ms vs 406 ± 8 ms, 0.474 ± 0.030 vs 0.433 ± 0.025, 0221 ± 0.020 vs 0.198 ± 0.017, respectively; P > 0.05). QTVIs were also not different in each phase (predrug: ?0.874 ± 0.071 vs postdrug: ?0.997 ± 0.067, P = 0.109). Conclusions: Fifty milligrams sildenafil does not affect QT dynamicity properties. The cardiac events associated with sildenafil could not be explained with ventricular arrhythmias. 相似文献
36.
BRL‐32872 is a new antiarrhythmic drug with balanced class‐III and class‐IV actions as categorized by the Vaughan‐Williams classification. BRL‐32872 blocks the rapid component of the cardiac delayed rectifier potassium channel IKr (IC50= 28 nM) and its molecular correlate HERG (“Human‐ether‐a‐go‐go related gene,” IC50 of 19.8 nM in cell lines) at low concentrations. It also inhibits the L‐type calcium current (ICa) at higher concentrations (IC50= 2.8 μM). This dual concentration‐dependent profile of action at higher concentrations may possibly prevent “torsades de pointes” ventricular arrhythmias, which is a dangerous side effect of many other class‐III antiarrhythmic drugs. With BRL‐32872, an excessive prolongation of the action potential duration and consecutive QTc prolongation is prevented by a concentration‐dependent increase of calcium channel block, resulting in the so‐called “bell‐shaped” profile of antiarrhythmic drug action. BRL‐32872 is very effective in the treatment of ventricular arrhythmias in animal models of cardiac ischemia. In the ischemic hearts of animals the drug significantly reduced early afterdepolarization and ventricular tachycardia. The antiarrhythmic effect of BRL‐32872 has not yet been demonstrated in humans. 相似文献
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38.
Response to flecainide test in Andersen‐Tawil syndrome with incessant ventricular tachycardia 下载免费PDF全文
39.
Laura Rabinovich-Guilatt Anna Elgart Lavi Erisson Sandra K Willsie Shoshi Tessler Ofra Barnett-Griness Amitkumar Pande Ofer Spiegelstein 《British journal of clinical pharmacology》2015,80(3):436-445
Aims
Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects.Methods
Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated.Results
AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration–effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience.Conclusion
Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen. 相似文献40.