Stereoselective cardiotoxic effects of terodiline
Clinical Pharmacology and Therapeutics, ISSN: 0009-9236, Vol: 60, Issue: 1, Page: 89-98
1996
- 43Citations
- 8Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations43
- Citation Indexes43
- 43
- CrossRef26
- Captures8
- Readers8
Article Description
Objective: To study the cardiovascular and electrocardiographic (EGG) effects of the R(+)- and S(-)enantiomers of terodiline. The racemic drug was previously used to treat detrusor instability but was withdrawn after it caused serious ventricular arrhythmias associated with prolongation of the QT interval. Methods: A double-blind, placebo-controlled, randomized crossover study was performed that involved nine healthy volunteers who were given single oral doses of racemic terodiline hydrochloride (200 mg), R(+)-terodiline hydrochloride (100 mg), S(-)-terodiline tartrate (100 mg), or placebo. Plasma concentrations of each enantiomer and cardiovascular and ECG effects, including QT intervals and QT dispersion, were measured over 14 days after each treatment. Results: Both racemic and A(S)-terodiline significantly increased QT interval, corrected QT interval (QT(c)), and QRS duration (all p < 0.05), without affecting QT dispersion. S(-)-Terodiline tartrate (100 mg) did not affect QT(c). Peak effects occurred 8 hours after dosing when increases in QT(c), from baseline (95% confidence intervals) were -3 (-20, 13) for placebo, 23 (8, 37) for racemic terodiline, 19 (6, 33) for R(S)-terodiline, and 0 (-10, 9) ms( 1/4 ) for S(-)-terodiline. Although differences were observed between the pharmacokinetics of the two enantiomers, these were not sufficient to account for the differences in ECG effects, and elimination half-lives were similar. Elimination of terodiline enantiomers was not significantly delayed in two genotypic poor metabolizers of debrisoquin (CYP2D6). Conclusions: QT prolongation associated with racemic terodiline is caused exclusively by the R(+)enantiomer, which therefore appears to be responsible for the ventricular arrhythmias caused by the drug.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0029776056&origin=inward; http://dx.doi.org/10.1016/s0009-9236(96)90171-x; http://www.ncbi.nlm.nih.gov/pubmed/8689817; http://doi.wiley.com/10.1016/S0009-9236(96)90171-X; http://dx.doi.org/10.1016/s0009-9236%2896%2990171-x; https://dx.doi.org/10.1016/s0009-9236%2896%2990171-x; https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1016/S0009-9236%2896%2990171-X
Wiley
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