Universität zu Köln

Ritter, Christian, Svacina, Martin K. R., Bobylev, Ilja, Joshi, Abhijeet ORCID: 0000-0001-6750-1035, Schneider, Toni and Lehmann, Helmar C. (2017). Impact of Age and Polytherapy on Fingolimod Induced Bradycardia: a Preclinical Study. J. Neuroimmune Pharm., 12 (1). S. 204 - 210. NEW YORK: SPRINGER. ISSN 1557-1904

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Abstract

Fingolimod is a an oral disease modifying drug for relapsing remitting multiple sclerosis (MS) preventing egress of B and T cells from lymph nodes. Relevant first dose adverse events include bradycardia and atrioventricular conduction slowing. Cardiac side effects of fingolimod and combinational pharmacotherapy including duloxetine and tolterodine were monitored in mice of different age using implantable ECG telemetric systems. Cardiac tissue was assessed for S1P-receptor subtype (1 and 3), and for GIRK1 expression. Fingolimod led to a significant heart rate reduction within 60 min, which returned to baseline values within 24 h. In older mice bradycardia was more pronounced compared to younger mice. Atrioventricular conduction was not affected. Older mice showed a higher S1PR3 expression in a na < ve state and receptor expression was reduced after fingolimod administration. Combination with duloxetine or tolterodine alleviated fingolimod induced heart rate decrease. Our data provide preclinical evidence that negative chronotropic effects of fingolimod might be age dependent, possibly due to an altered expression and internalization of cardiac S1PR3 in older animals. This data could be relevant for future clinical monitoring and patient selection in the aging MS population. Combinational therapies of fingolimod and duloxetine or tolterodine are well tolerated and safe without an increased risk for pronounced bradycardia or arrhythmia.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ritter, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Svacina, Martin K. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bobylev, Ilja UNSPECIFIED UNSPECIFIED UNSPECIFIED Joshi, Abhijeet UNSPECIFIED orcid.org/0000-0001-6750-1035 UNSPECIFIED Schneider, Toni UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehmann, Helmar C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-238388
DOI:	10.1007/s11481-017-9727-8
Journal or Publication Title:	J. Neuroimmune Pharm.
Volume:	12
Number:	1
Page Range:	S. 204 - 210
Date:	2017
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1557-1904
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RELAPSING MULTIPLE-SCLEROSIS; HEART-RATE; OVERACTIVE BLADDER; RECEPTOR SUBTYPES; 1-PHOSPHATE; FTY720; ANTIMUSCARINICS; MANAGEMENT Multiple languages Neurosciences; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23838