AIMS: To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac-sotalol. METHODS: The effect of rac-sotalol on QT interval duration was studied in 10 patients after single oral administration (160 mg) and after 6-day multiple oral dosing (80 mg two or three times daily). In order to separate the pure Class III effect from the bradycardia-related QT prolongation, heart rate/QT relationship was preliminarly assessed in each patient after the administration of a pure beta-adrenoceptor blocker (propranolol, 80 mg orally). Repolarization changes were quantified as percent difference between the measured QT and the expected QT on the basis of the individual heart rate/QT relationship. RESULTS: In all patients QT interval prolongation was linearly correlated with rac-sotalol log plasma concentration. The maximal QT prolongation and peak plasma concentration were not significantly different following acute and chronic administrations (QT effect: +18.1+/-6.3% vs +14.2+/-3.3%; peak concentration: 1.64+/-0.49 mg l(-1) vs 1.83+/-0.66 mg l(-1)). Line slopes were also unchanged following chronic treatment (21.8+/-8.9 vs 21.1+/-9.2). In four cases a significant rightward shift of the line occurred during repeated administrations, consistent with the appearance of pharmacodynamic tolerance. The inconstancy of this change in responsiveness may either be ascribed to a genetically determined individual susceptibility or to a variable interplay between Class III effect, gradual QT prolongation due to long-term beta-adrenoceptor blockade and tolerance development. CONCLUSIONS: During maintenance treatment with rac-solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.
AIMS: To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac-sotalol. METHODS: The effect of rac-sotalol on QT interval duration was studied in 10 patients after single oral administration (160 mg) and after 6-day multiple oral dosing (80 mg two or three times daily). In order to separate the pure Class III effect from the bradycardia-related QT prolongation, heart rate/QT relationship was preliminarly assessed in each patient after the administration of a pure beta-adrenoceptor blocker (propranolol, 80 mg orally). Repolarization changes were quantified as percent difference between the measured QT and the expected QT on the basis of the individual heart rate/QT relationship. RESULTS: In all patientsQT interval prolongation was linearly correlated with rac-sotalol log plasma concentration. The maximal QT prolongation and peak plasma concentration were not significantly different following acute and chronic administrations (QT effect: +18.1+/-6.3% vs +14.2+/-3.3%; peak concentration: 1.64+/-0.49 mg l(-1) vs 1.83+/-0.66 mg l(-1)). Line slopes were also unchanged following chronic treatment (21.8+/-8.9 vs 21.1+/-9.2). In four cases a significant rightward shift of the line occurred during repeated administrations, consistent with the appearance of pharmacodynamic tolerance. The inconstancy of this change in responsiveness may either be ascribed to a genetically determined individual susceptibility or to a variable interplay between Class III effect, gradual QT prolongation due to long-term beta-adrenoceptor blockade and tolerance development. CONCLUSIONS: During maintenance treatment with rac-solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.
Authors: V Gotta; F Cools; K van Ammel; D J Gallacher; S A G Visser; F Sannajust; P Morissette; M Danhof; P H van der Graaf Journal: Br J Pharmacol Date: 2015-07-21 Impact factor: 8.739
Authors: James P Tsikouris; Michael J Peeters; Craig D Cox; Gary E Meyerrose; Charles F Seifert Journal: Ann Noninvasive Electrocardiol Date: 2006-01 Impact factor: 1.468