Contributions
Abstract: EP1524
Type: ePoster
Abstract Category: Therapy - disease modifying - Risk management for disease modifying treatments
Background: Fingolimod is a commonly used immunomodulatory drug in multiple sclerosis (MS) escalation therapy. Clinical trials and post-marketing surveillance demonstrated that fingolimod is well tolerated and safe. One of the most relevant adverse events relate to the cardiac effects of fingolimod that include asymptomatic bradycardia and very rarely, second degree AV-conduction blocks.
Objectives: To further examine course and molecular pathways leading to heart rhythm modulation and to explore potential cardiac interactions of fingolimod with other agents used in symptomatic MS therapy. As representative drugs we used the antidepressant duloxetine, as selective serotonin-noradrenaline reuptake inhibitor, and the anti-spasticity drug tolterodine, a M2-muscarinergic receptor antagonist.
Methods: We performed extended long-term cardiac monitoring in C57/B6 mice by use of ECG-telemetry measurements with subcutaneously implanted transmitters. Effects of fingolimod on heart rate, RR-Interval and PR-time were recorded after i.p. injection of fingolimod alone or in combination with treatment by duloxetine or tolterodine. Cardiac tissue was analyzed for S1P-receptor subtype expression, and for GIRK1, a sub domain of the IKAch- potassium channel, responsible for bradycardia during fingolimod treatment.
Results: ECG-measurements showed a slight but significant HR-decrease during treatment with fingolimod, with a maximum at one hour post injection. AV-conduction blocks were not observed. Combination of fingolimod with duloxetine or tolterodine was associated with an attenuation of bradycardia. In older mice the decrease of HR occurred more rapidly and was more pronounced compared to those in younger mice. No significant change of PR-or RR-standard deviation was noted. We observed a reduced expression of cardiac S1P-subtype 3 receptors in fingolimod-treated mice. Notably, S1P3 expression correlated with higher age of the animals.
Conclusions: Combinatorial pharmacotherapies that include fingolimod and duloxetine or tolterodine are not associated with an increased risk for heart conduction abnormalities. Our finding that age may impact the expression and the internalisation of cardiac S1P-receptor subtype 3 might be relevant for future clinical monitoring and patient selection.
Disclosure: This study was partially funded by a scientific grant by Novartis
Abstract: EP1524
Type: ePoster
Abstract Category: Therapy - disease modifying - Risk management for disease modifying treatments
Background: Fingolimod is a commonly used immunomodulatory drug in multiple sclerosis (MS) escalation therapy. Clinical trials and post-marketing surveillance demonstrated that fingolimod is well tolerated and safe. One of the most relevant adverse events relate to the cardiac effects of fingolimod that include asymptomatic bradycardia and very rarely, second degree AV-conduction blocks.
Objectives: To further examine course and molecular pathways leading to heart rhythm modulation and to explore potential cardiac interactions of fingolimod with other agents used in symptomatic MS therapy. As representative drugs we used the antidepressant duloxetine, as selective serotonin-noradrenaline reuptake inhibitor, and the anti-spasticity drug tolterodine, a M2-muscarinergic receptor antagonist.
Methods: We performed extended long-term cardiac monitoring in C57/B6 mice by use of ECG-telemetry measurements with subcutaneously implanted transmitters. Effects of fingolimod on heart rate, RR-Interval and PR-time were recorded after i.p. injection of fingolimod alone or in combination with treatment by duloxetine or tolterodine. Cardiac tissue was analyzed for S1P-receptor subtype expression, and for GIRK1, a sub domain of the IKAch- potassium channel, responsible for bradycardia during fingolimod treatment.
Results: ECG-measurements showed a slight but significant HR-decrease during treatment with fingolimod, with a maximum at one hour post injection. AV-conduction blocks were not observed. Combination of fingolimod with duloxetine or tolterodine was associated with an attenuation of bradycardia. In older mice the decrease of HR occurred more rapidly and was more pronounced compared to those in younger mice. No significant change of PR-or RR-standard deviation was noted. We observed a reduced expression of cardiac S1P-subtype 3 receptors in fingolimod-treated mice. Notably, S1P3 expression correlated with higher age of the animals.
Conclusions: Combinatorial pharmacotherapies that include fingolimod and duloxetine or tolterodine are not associated with an increased risk for heart conduction abnormalities. Our finding that age may impact the expression and the internalisation of cardiac S1P-receptor subtype 3 might be relevant for future clinical monitoring and patient selection.
Disclosure: This study was partially funded by a scientific grant by Novartis