OBJECTIVE: The sphingosine-1-phosphate receptor modulator fingolimod (FTY720) is known to elicit a negative chronotropic effect at treatment initiation that attenuates over time with continued dosing. The authors determined the effect of combining a single dose of fingolimod with steady-state atenolol or diltiazem on heart rate and mean arterial pressure. METHODS: In a partially randomized, single-blind, placebo-controlled, three-period, crossover study, 25 healthy subjects received (1) asingle oral 5-mg dose of fingolimod, (2) either 50 mg atenolol or 240 mg diltiazem once daily for 5 days, and (3) the antihypertensive for 5 days and a single dose of fingolimod on day 5. Telemetry and pharmacokinetic data were collected. RESULTS: The daytime mean heart rate nadir was 15% lower when fingolimod was combined with atenolol (42 +/- 7 bpm) compared with fingolimod alone (51 +/- 9 bpm) yielding a combination/monotherapy ratio of 0.85 (90%CI, 0.79-0.92). The daytime mean heart rate nadir from fingolimod alone (55 +/- 5 bpm) was not altered when combined with diltiazem (56 +/- 8 bpm) yielding a ratio of 0.99 (0.94-1.05). There was no clinically relevant change in mean arterial pressure when fingolimod was administered with atenolol or diltiazem compared with administration of the drugs alone in normotensive subjects. The pharmacokinetics of the drugs were not altered during coadministration. CONCLUSION: Adding fingolimod to a beta-blocker such as atenolol resulted in a moderately lower mean heart rate nadir compared with fingolimod alone. However, subjects who had a stronger negative chronotropic response to fingolimod alone (nadir < 50 bpm) had minimal or no further reduction in heart rate with the drug combination. Adding fingolimod to a calcium channel blocker such as diltiazem did not further lower the heart rate compared to fingolimod alone.
RCT Entities:
OBJECTIVE: The sphingosine-1-phosphate receptor modulator fingolimod (FTY720) is known to elicit a negative chronotropic effect at treatment initiation that attenuates over time with continued dosing. The authors determined the effect of combining a single dose of fingolimod with steady-state atenolol or diltiazem on heart rate and mean arterial pressure. METHODS: In a partially randomized, single-blind, placebo-controlled, three-period, crossover study, 25 healthy subjects received (1) a single oral 5-mg dose of fingolimod, (2) either 50 mg atenolol or 240 mg diltiazem once daily for 5 days, and (3) the antihypertensive for 5 days and a single dose of fingolimod on day 5. Telemetry and pharmacokinetic data were collected. RESULTS: The daytime mean heart rate nadir was 15% lower when fingolimod was combined with atenolol (42 +/- 7 bpm) compared with fingolimod alone (51 +/- 9 bpm) yielding a combination/monotherapy ratio of 0.85 (90%CI, 0.79-0.92). The daytime mean heart rate nadir from fingolimod alone (55 +/- 5 bpm) was not altered when combined with diltiazem (56 +/- 8 bpm) yielding a ratio of 0.99 (0.94-1.05). There was no clinically relevant change in mean arterial pressure when fingolimod was administered with atenolol or diltiazem compared with administration of the drugs alone in normotensive subjects. The pharmacokinetics of the drugs were not altered during coadministration. CONCLUSION: Adding fingolimod to a beta-blocker such as atenolol resulted in a moderately lower mean heart rate nadir compared with fingolimod alone. However, subjects who had a stronger negative chronotropic response to fingolimod alone (nadir < 50 bpm) had minimal or no further reduction in heart rate with the drug combination. Adding fingolimod to a calcium channel blocker such as diltiazem did not further lower the heart rate compared to fingolimod alone.
Authors: Ludwig Kappos; Jack Antel; Giancarlo Comi; Xavier Montalban; Paul O'Connor; Chris H Polman; Tomas Haas; Alexander A Korn; Goeril Karlsson; Ernst W Radue Journal: N Engl J Med Date: 2006-09-14 Impact factor: 91.245
Authors: Robert Schmouder; Denise Serra; Yibin Wang; John M Kovarik; John DiMarco; Thomas L Hunt; Marie-Claude Bastien Journal: J Clin Pharmacol Date: 2006-08 Impact factor: 3.126
Authors: Helio Tedesco-Silva; Mark D Pescovitz; Diane Cibrik; Michael A Rees; Shamkant Mulgaonkar; Barry D Kahan; Kristene K Gugliuzza; P R Rajagopalan; Ronaldo de M Esmeraldo; Hélène Lord; Maurizio Salvadori; Jennifer M Slade Journal: Transplantation Date: 2006-12-27 Impact factor: 4.939
Authors: Lev Koyrakh; Rafael Luján; Jose Colón; Christine Karschin; Yoshihisa Kurachi; Andreas Karschin; Kevin Wickman Journal: J Neurosci Date: 2005-12-07 Impact factor: 6.167
Authors: Ashis K Saha; Xiang Yu; Jian Lin; Mercedes Lobera; Anurag Sharadendu; Srinivas Chereku; Nili Schutz; Dalia Segal; Yael Marantz; Dilara McCauley; Scot Middleton; Jerry Siu; Roland W Bürli; Janet Buys; Michelle Horner; Kevin Salyers; Michael Schrag; Hugo M Vargas; Yang Xu; Michele McElvain; Han Xu Journal: ACS Med Chem Lett Date: 2010-11-09 Impact factor: 4.345
Authors: Zhiliang Xie; Min Chen; Swagata Goswami; Rajes Mani; Dasheng Wang; Samuel K Kulp; Chris C Coss; Larry J Schaaf; Fengyu Cui; John C Byrd; Ryan N Jennings; Karsten K Schober; Carrie Freed; Stephanie Lewis; Raphael Malbrue; Natarajan Muthusamy; Chad Bennett; William C Kisseberth; Mitch A Phelps Journal: AAPS J Date: 2020-07-16 Impact factor: 4.009