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PHARMACODYNAMICS |
From Exploratory Development, Novartis Pharmaceutical Corporation, East Hanover, New Jersey (Dr Schmouder, Ms Serra, Dr Wang, Dr Kovarik, Ms Bastien); Division of Cardiology, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia (Dr DiMarco); and PPD Development, Austin, Texas (Dr Hunt).
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: FTY720 • cardiac rate and rhythm • immunomodulators
FTY720 was effective in prolonging allograft survival in preclinical models of cardiac, renal, and hepatic transplantation.4 Furthermore, a synergistic effect was noted when FTY720 was used in combination with subtherapeutic or therapeutic doses of cyclosporine in a number of different allograft models.4 The results of phase II clinical studies demonstrated that FTY720 can be used effectively and safely in combination with classic immunosuppressive agents, including cyclosporine6 and everolimus.7
FTY720 has been well tolerated in comparative studies conducted in renal transplant recipients to date. However, a recurring finding in these trials has been a reduction in heart rate with initiation of FTY720 treatment.6–9 This negative chronotropic effect appears to be temporally associated with the first dose of FTY720. A nadir in heart rate is observed within 4 to 12 hours of drug administration, with heart rate recovering close to baseline within 48 hours after a single dose of FTY720.6–9 The mechanism underlying the effect of FTY720 on heart rate appears to be mediated by its capacity to agonize S1P receptors in the heart. Animal studies have shown that S1P receptors are present in the heart, especially in atrial myocytes, and that S1P can signal to these receptors, resulting in decreased heart rate.10–12 Koyrakh et al13 confirm that FTY720 shares these features with S1P, with both agents able to activate the cardiac G-protein-gated potassium channel I.
Decreased heart rate is a commonly reported adverse event experienced early in the posttransplant course and may be due to multiple factors, including increased vagal tone from general anesthesia, reduced gut function, and perioperative pain. In one clinical study with FTY720 following de novo renal transplantation, the rate of bradycardia adverse events in patients randomized to mycophenolate mofetil was 5%. In contrast, the rate of bradycardia in FTY720-treated subjects was 26% to 30%.6 The majority of these bradycardia events did not require medical intervention; however, 11% to 14% were treated with short courses of atropine and/or beta agonists. There was no measurable increase in mortality and/or cardiac morbidity in either the mycophenolate mofetil-treated or FTY720-treated groups.6–9,14
The current study was designed to measure the effect of FTY720 on cardiac rate and rhythm in healthy subjects. Although the effect of FTY720 on heart rate has been described briefly in renal transplant recipients,8,9 there are many confounding variables contributing to heart rate changes in transplant patients, such as autonomic and cardiovascular comorbidities and concomitant medications, which complicate the assessment of this dynamic effect of FTY720 in this patient group. Given these constraints, the current study used a placebo-controlled, randomized design to rigorously collect heart rate and rhythm data in healthy subjects. The purpose of this study was to definitively measure the effect of FTY720 on heart rate and rhythm and, in addition, to characterize the effect of interventions on these effects.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The in-center portion of the study included a 2-day placebo run-in phase; an 8-day treatment/evaluation phase during which subjects were randomized to receive once-daily dosing with FTY720 1.25 mg, FTY720 5 mg, or matching placebo for 7 days; and an end-of-study evaluation on day 8, after which participants were discharged from the study center. Subjects fasted overnight before administration of study medication at approximately 8:00 AM and consumed at least 200 mL of fluid every 4 hours during the waking hours of the study. Unless performing a study assessment, subjects were required to rest quietly in an upright position for 4 hours after administration of medication. In addition to cardiac monitoring described below, the study also measured the general tolerability of FTY720, its pharmacokinetics, and its effect on lymphocyte counts as reported previously.15
Assessments of Cardiac Function
Assessments of cardiac responses to FTY720 and placebo administration included 12-lead electrocardiography (ECG), Holter monitoring, telemetry, and pressor and exercise stress tests.
12-Lead ECG: Conduction Intervals
The primary pharmacodynamic measurement of the effect of FTY720 on conduction intervals used serial 12-lead ECG. Tracings were recorded every 2 hours over 24-hour intervals on the placebo baseline day –1 and the FTY720 or placebo treatment days 1 and 7. Conduction intervals (QRS, PQ, PR, RR, QT) were measured by manual digitization. The QT interval was corrected for heart rate (QTc) using Bazett's (QTcB), Frederica's (QTcF), and individual (QTcI) correction methods assuming a power model. Time-averaged QT or QTc intervals were derived by averaging the within-subject observations from 12-lead ECGs obtained over the course of the day.
Holter Monitoring: Total Daily Heartbeats, Arrhythmia Detection, Sinus Pauses, and Conduction Blocks
Five-lead Holter monitoring at baseline, day 1, and day 7 was used to measure the total number of heartbeats over a 24-hour period (8:00 AM to 8:00 AM) and to record the frequency and duration of sinus pauses, conduction blocks, and ectopy.
Telemetry: Safety, Hourly Mean Heart Rate, Events Outside of Holter Monitoring Intervals, and Heart Rate During Interventions
Telemetry was used to continuously monitor the heart rate of all subjects while they were in the study center from baseline through day 7. These data were continuously stored in a database, which allowed the calculation of a mean hourly heart rate by hour and day for each subject. The effect of FTY720 on the hearts' autonomic response to extrinsic factors was evaluated by the cold pressor test (CPT) and exercise stress test (EST) on days –2, 2, 4, and 6. The CPT was used to evaluate parasympathetic vagal function; typically, this test results in reduced heart rate. Resting heart rate was collected for a 10-minute interval, after which subjects immersed a hand in an ice bath for 2 minutes. Following immersion, subjects remained in a resting state while heart rate was collected over the next 10 minutes.
The EST employed a modified Bruce protocol and was used to evaluate cardiac response to sympathetic stimuli; typically, this protocol results in a staged increase in heart rate.16 Resting heart rate was collected for 10 minutes before exercise induction. Exercise intensity was then increased every 3 minutes over the following 12 minutes. Subjects were allowed to rest over the next 2 minutes, and heart rate continued to be monitored for a further 8 minutes.
Blood Pressure
Predose BP measured by automated cuff was collected daily throughout the study. In addition, standing and supine BP was collected predose and at 1, 2, 3, 4, 5, 6, 7, 8, and 10 hours after FTY720 or placebo administration on day 1. These data were used to construct 2 measures of effect: the mean area under the BP effect curve during the 12-hour period (AUE0–12) and the mean minimum blood pressure over the same period. Mean BP over the 12-hour period was derived by dividing the AUE0–12 by 12.
Statistical and Exposure–Response Analyses
Separate analysis of covariance (ANCOVA) was performed for each of the derived pharmacodynamic parameter data sets: hourly mean heart rate, cardiac conduction intervals, and BP, with treatment as a factor and baseline value as a covariate. P values and 95% confidence intervals (CIs) were derived from pairwise comparisons between treatments within the ANCOVA to evaluate treatment effect.
As reported previously, a 24-hour area under the FTY720 concentration-time curve (AUC0-24) was measured on days 1 and 7, and morning trough FTY720 blood levels were collected on days 2 through 6.15 A scatterplot of the day 1 AUC0-24 versus nadir heart rate was generated, and an inhibitory Emax model was fit to the data. The model was parameterized as follows: E = E0 – [(Emax · C)/EC50 + C)], where E0 is the nadir heart rate in the placebo group, Emax is the maximal effect of FTY720 on the nadir heart rate (ie, the lowest heart rate nadir), C is the FTY720 AUC0-24, and EC50 is the AUC0-24 at which half-maximal response occurs.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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To measure the time course of the rate-lowering effect of FTY720 on total daily heartbeats, telemetry data were used to construct mean hourly heart rates over the course of each day (Figure 1a,b). In the baseline period, all 3 groups had nearly identical 24-hour profiles of heart rate over time (data not shown). Administration of the first dose of FTY720, either 1.25 or 5 mg, on day 1 resulted in an acute, dose-dependent decrease in mean heart rate with a nadir observed at 3 to 4 hours postdose (Figure 1a). Compared with the placebo group, mean nadir heart rate decreased by 7.5 bpm (P < .001) and 10.6 bpm (P < .001) for the FTY720 1.25-mg and 5-mg dose groups, respectively. By 12 hours after the first FTY720 dose, the reduction in mean heart rate no longer appeared dose dependent, with both treatment groups displaying a similar 10-bpm decrease compared with the placebo group. When the placebo-treated group was compared with the FTY720 treatment groups at either day 1 or day 7, it did not appear that FTY720 disrupted the normal circadian pattern of heart rate (Figure 1a,b).
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FTY720 did not appear to increase the QT interval; no subject presented a QTcB or QTcF increase greater than 450 msec (male) or 470 msec (female), and no subject had a QTcB or QTcF change from baseline greater than 60 msec at any time in the study. The exposure–response scatterplots between FTY720 maximum concentration (Cmax) and mean QT interval at day 7 across subjects is shown in Figure 3. Cmax ranged from 3.6 to 28.4 ng/mL. The slope of the regression lines encompassing all subjects in the study was 0 or slightly negative for mean QtcI, QTcB, QTcF, and QT. There was no trend of increasing QTc over a wide FTY720 exposure range, suggesting that FTY720 does not prolong the QT interval (data not shown).
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Sinus Pauses and Conduction Blocks
On day 1 of treatment, there was an increased incidence of low-grade sinus pauses lasting 2 to 3 seconds in all groups; however, the frequency of this event was higher in FTY720 treatment groups and was dose dependent (25 and 116 events in the FTY720 1.25- and 5-mg groups, respectively, vs 13 in the placebo group). Inspection of the Holter records of these low-grade sinus pauses revealed that these events were almost entirely the result of sinus arrhythmia superimposed on transient periods of low nadir heart rate (32–35 bpm) in a small number of subjects. No high-grade sinus pauses greater than 3 seconds were detected in either FTY720 treatment group on day 1, and no sinus pauses were detected in any group by day 7.
No third-degree or second-degree type 2 atrioventricular (AV) blocks were observed during the study. Six subjects exhibited transient, second-degree, type 1 AV block (Wenckebach) events. Of these events, 3 occurred during the placebo run-in period, whereas the other 3 occurred in FTY720-treated subjects 1, 5, and 15 hours after administration on day 1. All subjects experiencing AV block were asymptomatic and required no medical intervention. No AV blocks were identified by Holter monitoring on day 7, and there were no new-onset AV blocks identified by telemetry on days 2 to 6.
Heart Rate Interventions
Cold Pressor Test
Using telemetry, the CPT evaluated the cardiac response to increased vagal stimuli in the setting of placebo or FTY720 treatment. On day –2, a slight slowing of heart rate of approximately 6 bpm in response to CPT was seen in all groups (data not shown); CPT data obtained from day 2 are shown in Figure 4. Although resting heart rate was reduced in both FTY720 groups, all 3 groups manifested a similar, approximately 5-bpm decrease in heart rate in response to the CPT. Similar CPT findings were seen on days 4 and 6 (data not shown).
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60 bpm vs 85 bpm). However, all 3 groups had very similar trajectories of heart rate increase in response to exercise. Both FTY720 1.25-mg and 5-mg treatment groups displayed a significantly greater percentage change (78%, P = .028 and 94%, P < .001, respectively) in heart rate (pretest heart rate vs maximum heart rate) when compared with the placebo group (62%). A similar pattern of response was also seen at days 4 and 6 (data not shown).
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Blood Pressure
On day 1, FTY720 5-mg treatment was associated with a significant decrease in systemic BP when compared with placebo (Table II); both the supine systolic and diastolic AUE0–12 decreased by approximately 5% to 6% (P < .028), and the supine systolic and diastolic minimum decreased by approximately 8% to 10% (P < .004). Mean supine BP over the 12-hour period postdose was 128/78 mm Hg in the placebo cohort and 122/74 mm Hg in the FTY720 5-mg treatment group. A similar magnitude of effect was measured for the standing BP. This effect of FTY720 on BP appeared to be dose related, with the FTY720 1.25-mg cohort manifesting a minimal effect on BP that was not statistically significant.
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Over the remaining 6 days of the study, both the morning supine mean systolic and diastolic BPs were similar in all groups. These mean data were nearly identical in the placebo and FTY720 1.25-mg cohorts. However, in the FTY720 5-mg treatment group, there was a trend for mean data to be slightly lower than in the other 2 groups by approximately 2 to 3 mm Hg. On the morning of the last day of treatment (day 7), the mean (SD) supine systolic and diastolic BPs for the 3 groups were as follows: placebo, 111(7)/66(5) mm Hg; FTY720 1.25 mg, 110 (9)/67(5) mm Hg; and FTY720 5 mg, 110(12)/66(7) mm Hg.
Heart Rate Exposure–Response Relationship
Figure 6 is a scatterplot of FTY720 AUC0–24 versus the nadir heart rate on day 1. Data from the placebo group are on the far left of the exposure axis, and the AUC in FTY720-treated subjects ranged from 15 to 111 ng·h/mL. The median (range) nadir heart rate occurred at 5 (2-22) hours in the placebo group, 18 (2-22) hours in FTY720 1.25-mg group, and 4 (2-22) hours in the FTY720 5-mg group. The corresponding group mean (SD) nadir heart rates were as follows: 58.1 (7.7), 50.6 (4.6), and 47.5 (5.3) bpm. The scatterplot suggests that a near-maximal acute effect on heart rate occurred at the 2 dose levels and exposures assessed in this study. The inhibitory Emax model estimated a baseline nadir (E0) for placebo-treated subjects of 58.0 bpm (coefficient of variation [CV] 2.3%), with a minimal heart rate (maximum effect, Emax) of 46.3 bpm (CV 5.5%). The model also estimated that the corresponding AUC0–24 for a half-maximal effect on heart rate nadir was 10.7 ng·h/mL (CV 96.8%).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Over the 7-day treatment course of this study, the mean heart rate in both FTY720 treatment groups was lower than in the placebo group. However, there are several lines of evidence that even at 7 days, the effect of FTY720 on the heart was beginning to wane. First, the total number of heartbeats per day had returned to within 3% of baseline values by day 7. Second, the higher rate of sinus pauses measured in the FTY720 treatment groups decreased to 0 by the last day of the study. In addition, the significantly prolonged mean PR interval seen at day 1 in those receiving FTY720 treatment had almost completely resolved by day 7. Finally, the difference in mean systolic and diastolic BP between the FTY720 5-mg and placebo groups had diminished to only 2 to 3 mm Hg by day 7. This attenuation of the effect of FTY720 on the heart with continued dosing is supported both by clinical6 and Holter17 data obtained from a phase II trial of FTY720 in de novo renal transplantation in which, beyond 2 weeks of treatment, mean heart rate was identical in the FTY720 and comparator groups. Although the mechanism of this adaptive, homoeostatic response of the heart is not fully elucidated, Matloubian et al18 showed that S1P receptors located on lymphocytes are internalized during FTY720 treatment and no longer available for signaling. S1P receptors on atrial myocytes responding in a similar way to chronic FTY720 dosing could explain this adaptive phenomenon.
Despite the fact that FTY720 treatment resulted in a new heart rate set point during the 7-day treatment period, FTY720-treated subjects displayed normal responses to both CPT and EST, indicating that vagal and adrenergic stimulatory responses were intact. Furthermore, normal circadian patterns in heart rate were observed over the 8-day monitoring period in subjects receiving FTY720. These data suggest that the response of the heart to both intrinsic and extrinsic autonomic stimuli is intact during multiple-dose FTY720 1.25 or 5 mg.
Holter monitoring demonstrated that FTY720 treatment was not associated with any atrial fibrillation or with an increase in the rate of ventricular ectopy. When administered at a 5-mg dose, FTY720 appeared to increase the frequency of premature atrial beats in some subjects on day 1; however, this treatment effect appeared to attenuate by day 7. In addition, a dose-dependent increase in the incidence of low-grade sinus pauses (2–3 seconds) was also apparent following the administration of the first dose of FTY720. This effect also diminished by day 7 of treatment, with no sinus pauses detectable in FTY720 treatment groups by day 7.
Asymptomatic and transient second-degree, type 1 AV block (Wenckebach) was detected in 6 subjects during the study. Half of these events occurred in the placebo group, whereas the other half occurred in FTY720-treated subjects on day 1 of treatment. No new-onset AV blocks were identified by telemetry on days 2 to 6. It is possible that these benign AV block events may be due to the effect of higher vagal tone associated with the stress of participating in a clinical trial involving intensive monitoring or may represent the background rate of this event in a relatively young and healthy population. However, given these events and the activity of FTY720 on the sinoatrial node, it is likely that FTY720 also has some AV nodal effects. The principal pharmacological effect of FTY720 appears to result in more refractory AV nodal conduction, similar to that seen with increased vagal tone. Human electrophysiology studies would help to better elucidate the AV nodal effects of FTY720.
The mean ECG QRS interval remained similar in the FTY720 and placebo groups. The ECG PR interval was increased on day 1 of FTY720 treatment. Consistent with the negative chronotropic effect of FTY720, a significant increase in the ECG RR interval was also observed with treatment. There was no consistent dose- or concentration-dependent effect of FTY720 on the QT interval. This finding is consistent with all in vitro studies with FTY720 to date, which show that the agent should have no effect on cardiac repolarization (data on file, Novartis Pharma AG, Basel, Switzerland).
FTY720 5-mg/d treatment was associated with a mild, significant, dose-dependent decrease in systemic BP of approximately 5% to 10% on the first day of treatment. Whereas this effect was clearly seen in the FTY720 5-mg cohort, the FTY720 1.25-mg cohort manifested this effect to a lesser, statistically nonsignificant degree. Over the remaining 6 days of daily dosing, it was difficult to detect a clear effect of FTY720 on BP, with a decrease of 2 to 3 mm Hg being observed at most. The mechanism of this acute, mild effect of FTY720 on BP is currently not known. One possibility is that the acute heart rate–reducing effect of FTY720 may have transiently lowered BP. Research on noncardiac effects of FTY720 (eg, vascular effects of the drug) is currently ongoing.
The findings of this study are consistent with those of clinical trials with FTY720 in maintenance renal transplant patients, which suggest that the agent mildly reduces heart rate.8,9 Similar to the current study, the effect of FTY720 on heart rate in renal transplant patients was temporally associated with administration of the first dose of the drug and a nadir heart rate at 4 to 12 hours postdose. Signs or symptoms of this lower heart rate returned close to baseline within the first 48 hours of treatment, and subsequent doses caused no further reduction. Most subjects experiencing bradycardia in these studies were asymptomatic and required no medical intervention; no further ECG abnormalities were observed, and there were no specific changes in BP values.8,9
In the current study, the effect of FTY720 on heart rate was dose dependent over the initial 4-hour period after dosing, with the effect diminishing over the following 12 hours. This effect was also observed following a single administration of FTY720 0.25 to 3.5 mg in stable renal transplant recipients8; however, no dose-dependent effect of FTY720 on heart rate was observed in renal transplant recipients following multiple dosing.9 These findings are consistent with the agonism of S1P receptors on the heart being an evident but relatively weak regulatory input to heart rate, which can be compensated for by competing regulatory pathways.
The mechanism of FTY720's effect on heart rate is becoming increasingly clear. In 1996, Bunemann et al19 reported the discovery of a G-protein-coupled receptor present in guinea pig atrial myocytes that was signaled by S1P. Three years later, Guo et al11 showed that S1P resulted in slowing of the rabbit sinoatrial node, and it was later proposed that S1P was a naturally occurring regulator of the heart.10 FTY720, in its phosphorylated in vivo form, shares both structural and functional homology to S1P.20 FTY720-phosphate targets multiple S1P receptors, including S1P1 and S1P3, with an EC50 almost identical to that of S1P.20 Recent studies have shown that the predominant S1P receptor on atrial myocytes is S1P3 and that FTY720-phosphate can efficiently signal this receptor.21,22 Thus, the current understanding of FTY720's capacity to decrease heart rate is that both S1P and FTY720-phosphate are agonists of S1P3 receptors on atrial myocytes; this agonism results in slowing of the sinoatrial node via activation of inwardly rectifying G-protein-activated potassium channels 1 and 4 (GIRK1/GIRK4) in atrial myocytes.10,13 In addition, FTY720 may have similar effects on the AV node, thus resulting in transient, benign, second-degree, type 1 AV block (Wenckebach).
We acknowledge that the findings in our study were obtained from healthy subjects and may not be directly transferable to patients, such as those receiving organ transplants, as many of these patients may have cardiovascular and autonomic dysfunction due to preexisting disease. However, this study provides useful data on the effect of FTY720 on the healthy human heart, supplying normative data that were not previously available. Furthermore, these data allow comparisons with ongoing and future studies with FTY720 in patients and can be used to guide future clinical trials with the drug in disease states for which patients have relatively normal heart function. The results of this study and of clinical trials conducted in stable renal transplant patients suggest that a mild to moderate, transient reduction in heart rate may be expected following the first dose of FTY720 treatment in normal subjects and in renal transplant recipients, and this effect of FTY720 on heart rate does not increase with continued dosing. Additional studies are currently under way to explore FTY720's effect on heart rate, rhythm, and function under various experimental conditions.
The principal author (R.S.) is an employee of Novartis Pharmaceuticals Corp.
Contributing authors D.S., Y.W., J.K., and M.B. are also employees of Novartis Pharmaceuticals Corp, and T.H. was supported by Novartis funding. The remaining contributor (J.D.) has no financial or personal relationships that could potentially be perceived as influencing the described research.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. Chiba K, Yanagawa Y, Masubuchi Y, et al. FTY720, a novel immunosuppressant, induces sequestration of circulating lymphocytes by acceleration of lymphocyte homing in rats: I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol. 1998;160: 5037–5044.
2. Brinkmann V, Pinschewer DD, Feng L, Chen S. FTY720: altered lymphocyte traffic results in allograft protection. Transplantation. 2001;72: 764–769.[Web of Science][Medline] [Order article via Infotrieve]
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5. Pinschewer DD, Ochsenbein AF, Odermatt B, Brinkmann V, Hengartner H, Zinkernagel RM. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol. 2000;164: 5761–5770.
6. Walker R, Ferguson RM, Mulgaonker S, et al. FTY720 with reduced cyclosporine exposure is efficacious in preventing rejection in renal transplantation: 12-month preliminary results. Presented at: World Congress of Nephrology; June 8-12, 2003; Berlin. Abstract T680.
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