Effect of fingolimod on cardiac autonomic regulation in patients with multiple sclerosis

The safety profile of S1P receptor modulators is considered better than other classes of immunomodulators and was further improved by the development of up-titration regimens to mitigate first-dose effects. S1P receptor modulators display similar pharmacodynamic effects but have very different pharmacokinetic profiles. Drugs with a rapid elimination are of interest in case of opportunistic infections or pregnancy, whereas the need of re-initiation of up-titration in case of treatment interruption can present a challenge.

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“…After three months, o.d. dosing with fingolimod shifts cardiac autonomic regulation towards sympathetic predominance, particularly in men [110].…”

Section: Adverse Effects On Hr and Av Conductionmentioning

confidence: 99%

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Juif

Kraehenbuehl

Dingemanse

2016

Expert Opinion on Drug Metabolism & Toxicology

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“…Previously, we reported a decrease in overall HRV, suggesting increased sympathetic cardiac regulation, during 3 months of fingolimod treatment (Simula et al. ). According to our current findings, however, this seems to be asymmetric, as overall HRV (i.e., TP and SDNN) decreased more at night than during the day.…”

Section: Discussionmentioning

confidence: 66%

Modulation of sphingosine receptors influences circadian pattern of cardiac autonomic regulation

Simula

Laitinen

et al. 2016

Physiol Rep

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Fingolimod is an oral sphingosine‐1‐phospate (S1P) receptor modulator for the treatment of relapsing‐remitting multiple sclerosis (RRMS). In addition to therapeutic effects on lymphoid and neural tissue, fingolimod influences cardiovascular system by specific S1P‐receptor modulation. The effects of S1P‐receptor modulation on the endogenous circadian pattern of cardiac autonomic regulation (CAR), however, are not known. We examined the effects of fingolimod on the circadian pattern of CAR. Ambulatory 24‐h ECG recordings were undertaken in 27 RRMS patients before fingolimod (baseline), at the day of fingolimod initiation (1D) and after 3 months of fingolimod treatment (3M). The mean time between two consecutive R‐peaks (RR‐interval) and mean values for measures of heart rate variability (HRV) in time‐ and frequency domain were calculated from ECG recording at daytime and nighttime. The mean night:day‐ratio of RR‐interval was 1.23 ± 0.12 at baseline, decreased temporarily at 1D (1.16 ± 0.12; P < 0.01) and was higher at 3M (1.32 ± 0.11; P < 0.001) than at baseline. The night:day‐ratio of HRV parameters reflecting parasympathetic cardiac regulation (pNN50, rMSSD, HFnu) decreased at 1D but recovered back to baseline at 3M (P < 0.05 for all). On the other hand, the night:day‐ratio of TP, a parameter reflecting overall HRV gradually decreased and was lower at 3M than at baseline (P < 0.05). Our findings suggest that physiological relation between the circadian pattern of RR‐interval and overall HRV as well as parasympathetic cardiac regulation becomes uncoupled during fingolimod treatment. In addition, fingolimod shifts the circadian equilibrium of CAR toward greater daytime dominance of overall HRV. Accordingly, S1P‐receptor modulation influences circadian pattern of CAR.

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“…Interestingly, the immunoactive substance sphingosine-1-phosphate (S1P) is increased in plasma and CSF of patients with acute TBE (Kulakowska et al 2014). As the immune-modulator fingolimod, which inhibits S1P signaling, leads to an increase in parasympathetic regulation in humans (Simula et al 2015), elevation of SP1 in TBE could be an explanation for the predominant sympathetic innervations in our TBE patients.…”

Section: Discussionmentioning

confidence: 87%

Autonomic and peripheral nervous system function in acute tick‐borne encephalitis

et al. 2016

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ObjectivesTick‐borne encephalitis (TBE) is an emerging flaviviral zoonosis in Central and Eastern Europe. TBE can present as meningitis, meningoencephalitis, or meningoencephalomyelitis. Dysfunction of the autonomic (ANS) and peripheral motoric and sensory nervous system (PNS) might contribute to acute and long‐term complications. We aimed to examine, whether the ANS and PNS are affected in acute TBE.MethodsFourteen patients with acute TBE, 17 with diabetic polyneuropathy (d‐PNP), and 30 healthy controls (HC) were examined in our single‐center, prospective study. ANS and PNS function was assessed by time‐ and frequency‐domain parameters of the heart rate (HR) variability at rest and deep respiration, and by sural and tibial nerve neurography. Primary endpoint was the HR variability at rest measured by root mean square of the successive differences (RMSSD). Autonomic symptoms and quality of life (QoL) were assessed by questionnaires.ResultsTick‐borne encephalitis patients had a lower RMSSD at rest (TBE 13.1 ± 7.0, HC 72.7 ± 48.3; P < 0.001) and deep respiration (TBE 42.8 ± 27.0, HC 109.7 ± 68.8; P < 0.01), an increased low‐frequency to high‐frequency power component ratio at rest (TBE 4.0 ± 4.0, HC 0.8 ± 0.5; P < 0.001), and a higher minimal heart rate at rest (TBE 85.4 ± 7.0, HC 69.5 ± 8.5; P < 0.001), all similar to patients with d‐PNP, indicating sympathovagal imbalance with increased sympathetic activation. Compared to HC, sural and tibial nerve conduction velocities and action potential amplitudes were reduced, ANS symptoms were more frequent, and QoL was lower in patients with TBE.ConclusionsThe ANS and to a lesser degree the PNS are affected by acute TBE, which could potentially contribute to short‐ and long‐term morbidity.

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Effect of fingolimod on cardiac autonomic regulation in patients with multiple sclerosis

Cited by 22 publications

References 28 publications

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Modulation of sphingosine receptors influences circadian pattern of cardiac autonomic regulation

Autonomic and peripheral nervous system function in acute tick‐borne encephalitis

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