Lack of effect of reboxetine on cardiac repolarization

Fleishaker, Joseph C.; Francom, Steven F.; Herman, Beth D.; Knuth, Dean W.; Azie, Nkechi

doi:10.1067/mcp.2001.117705

Cited by 27 publications

(14 citation statements)

References 17 publications

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“…A commonly used consistently positive control drug in this setting is moxifloxacin, a fluoroquinolone antibacterial, with a small mean effect on the QT interval in the range of 6 to 14 milliseconds. Manual techniques have historically been preferred in studies of drug-induced QT effects 14,17,29,35,36 and have clear benefits when used in patients with cardiovascular disease. 32 Because several doses of the investigational drug should be studied, this may result in a 4-or 5-way crossover design (placebo, positive control, and 2 to 3 doses of the drug).…”

Section: Discussionmentioning

confidence: 99%

Man Versus Machine: Is There an Optimal Method for QT Measurements in Thorough QT Studies?

Darpö

Agin

Kazierad

et al. 2006

The Journal of Clinical Pharma

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Electrocardiographic (ECG) recordings from 3 placebo-controlled thorough QT healthy volunteer studies were used to compare QT intervals obtained by manual measurement with those generated by ECG machines. The effect of the positive control was compared to placebo at each time point for data obtained from both sources. Both manual and automated techniques consistently demonstrated statistically significant prolongation of QTcF with the positive controls. The proportion of outlier values was small for both methods. The pairwise comparison between manual and automated uncorrected QT intervals demonstrated clear differences, with intervals derived from one machine on average 16 to 19 milliseconds shorter and from the other 7 milliseconds longer than the manually measured QT intervals, but these differences disappeared when analyzing QT change from baseline. Both manual and automated, commercially available QT algorithms demonstrated small statistically significant effects on the QTc interval induced by positive controls.

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Section: Discussionmentioning

confidence: 99%

Man Versus Machine: Is There an Optimal Method for QT Measurements in Thorough QT Studies?

Darpö

Agin

Kazierad

et al. 2006

The Journal of Clinical Pharma

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“…In addition, long-term treatment with reboxetine does not appear to result in greater weight gain than treatment with placebo (Thase and Bartlett, 2001). Although there are also reports of hyponatremia during treatment with reboxetine (Abdelrahman et al, 2003;Ranieri et al, 2000), it does not appear to alter cardiac conduction (Fleishaker et al, 2001). Treatment with reboxetine may result in increased blood pressure in some patients.…”

Section: Norepinephrine Reuptake Inhibitors (Nris)mentioning

confidence: 92%

Monoaminergic‐based Pharmacotherapy for Depression

Papakostas¹,

Fava²

2005

Biology of Depression

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Although recent advances in neuropharmacology, neuroendocrinology, molecular biology, and pharmacogenetics have been instrumental in bringing about potential treatments for depression which are fundamentally unrelated to their predecessors, including substance P antagonists, glutaminergic agents, and corticotropinreleasing factor (CRF) antagonists, nevertheless it was agents that influenced the function of monoamine receptors and transporters that were discovered initially by serendipity and then developed as treatments for depression. The development of such compounds also served as a framework for the understanding of depression as a medical illness affecting brain functioning. As a result of these efforts, our field has gained further understanding of the role of monoamines in depression. In previous chapters, the relevance of monoamines in the underlying pathophysiology of depression was reviewed. In the following chapter we will focus on describing the contemporary role of monoaminergic agents in the treatment of depression. 6.

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“…Effect of sibenadet on heart rate and uncorrected QT interval Sibenadet induced dose-dependent increases in heart rate after administration of a single dose giving least squares mean (95% CI) for maximum positive changes from baseline of 6 (2, 9), 13 (10, 17), 20 (17,23) and 28 (25, 31) beats min −1 for placebo, 250, 500 and 750 µg* of sibenadet, respectively. Maximum changes occurred in the first 10-15 min post dosing.…”

Section: Evaluation Of An Exercise-derived Sscf To Correct Qt For Thementioning

confidence: 99%

“…Therefore it is reasonable to postulate that the use of a SSCF derived from exercise was inappropriate and appeared to be over-correcting. Similarly, the use of an exercise-derived correction factor to correct QT interval for the heart rate effects of reboxetine was suggested to over-correct compared with the Fridericia method, which demonstrated little effect of reboxetine on QTc for heart rate effects [17].…”

Section: Figurementioning

confidence: 99%

Lack of correlation between exercise and sibenadet‐induced changes in heart rate corrected measurement of the QT interval

Newbold¹,

Sanders

Reele

2006

Brit J Clinical Pharma

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What is already known about this subject• When this study was conducted it was already known that the 'standard' methods of correcting the QT interval for hear t rate were not optimal and that bias could result in their use in certain circumstances, in particular when drugs or conditions also induced wide fluctuations in heart rate.• The use of subject specific correction methods had been advocated and whilst these had been shown to apparently correct QT interval over usual physiological heart rates, they had not been tested under conditions where drugs could potentially increase heart rate and 'standard' correction methods gave apparent increases in QT interval. Furthermore, subject specific correction methods had usually been generated over a normal physiological heart rate range and made the assumption that the relationship remained linear outside of this usual range. What this study adds• A subject specific correction factor for QT correction can be calculated from a wide range of heart rates using exercise testing and the relationships between QT and RR are unique for a given individual.• The generation of subject specific correction factors from ECGs collected under resting conditions is not a robust method.• That subject specific correction factors derived from exercise testing are not appropriate to apply to drugs (with no evidence to suggest effects on the QT interval) that induce increases in heart rate and that the relationship between the QT and RR interval during exercise is clearly different to the QT/RR relationship of a drug that increases heart rate. AimsWe sought to investigate subject specific QT interval correction factors (SSCF) determined at rest and after exercise and to determine the validity of these factors after the administration of a probe drug known to increase hear t rate without directly affecting cardiac repolarization. MethodsThirty-two healthy volunteers underwent graded exercise, multiple recordings of electrocardiogram during rest over a day and a treatment phase administering inhaled placebo or sibenadet (a β 2 -adrenoceptor/dopamine D 2 -receptor agonist) at 250, 500 or one of 750 or 1000 µ g. SSCF were determined from linear regression of plots of log RR interval vs. log QT after exercise (QTcX), rest (QTcR), and combined data (QTcC). The SSCFs along with Bazett & Fridericia corrections were applied to the ECGs after inhalation of sibenadet. ResultsSSCFs obtained from the combination of the exercise and resting day (mean QTcC = 0.41) and exercise alone (mean QTcX = 0.40) were similar with a good fit to the data (mean r 2 = 0.92 and 0.93, respectively) while data at rest resulted in a less pronounced slope (mean QTcR = 0.27) and poorer fit (mean r 2 = 0.52). After the administration of sibenadet, none of the SSCFs, Bazett or Fridericia corrections adequately corrected QT for heart rate induced changes. ConclusionsNeither a SSCF from exercise, Bazett's or Fridericia's correction factors, adequately corrected the QT interval after the administration of a sympathomimetic agoni...

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Lack of effect of reboxetine on cardiac repolarization

Cited by 27 publications

References 17 publications

Man Versus Machine: Is There an Optimal Method for QT Measurements in Thorough QT Studies?

Man Versus Machine: Is There an Optimal Method for QT Measurements in Thorough QT Studies?

Monoaminergic‐based Pharmacotherapy for Depression

Lack of correlation between exercise and sibenadet‐induced changes in heart rate corrected measurement of the QT interval

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