Spijkers LJ, Alewijnse AE, Peters SL. FTY720 (Fingolimod) increases vascular tone and blood pressure in spontaneously hypertensive rats via inhibition of sphingosine kinase. Br J Pharmacol. 2012 Jan 17. doi: 10.1111/j.1476-5381.2012.01865.x. [Epub]
Background and purpose. FTY720 (Fingolimod) is a recently approved orally administered drug for the treatment of multiple sclerosis. Phase II and III clinical trials have demonstrated that this drug modestly increases blood pressure. We have previously shown that inhibition of sphingosine kinase increases vascular tone and blood pressure in hypertensive (high blood pressure), but not normotensive (normal) rats. Since FTY720 is reported to have sphingosine kinase inhibitory effects, we investigated whether FTY720 increases vascular tone and blood pressure only in hypertensive rats via this mechanism.
Experimental approach. The contractile and blood pressure modulating effects of FTY720 were studied in vivo and ex vivo (tissues taken from the animal) in age-matched normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Key results. Oral administration of FTY720 induced an increase in mean arterial pressure in hypertensive rats, whereas a decrease in blood pressure was observed in normal rats, as measured 24 hours after administration. In analogy to the sphingosine kinase inhibitor dimethylsphingosine (DMS), FTY720 induced major contractions in isolated carotid arteries from SHR, but not in those from WKY. In contrast, the phosphorylated form of FTY720 (FTY720-P, which is the active immunosuppressive drug that rapidly forms following injection of FTY720) did not induce contractions in isolated carotid arteries from SHR. FTY720-induced contractions (like DMS-induced contractions) proved to be endothelium-dependent and to be mediated by thromboxane A(2) , since these contractions could be inhibited by endothelium denudation (removal of the blood vessel lining cells), cyclooxygenase and thromboxane synthase inhibitors and by thromboxane receptor antagonism.
Conclusions and Implications. These data demonstrate that FTY720 increases vascular tone and blood pressure only in hypertensive rats, most likely due to its sphingosine kinase inhibitory effect.
Following the sad news of a number of deaths apparently following taken gilenya, this paper may gain increased importance. Whilst details about the deaths are sparse, according to Bloomberg Business Week there may have been problems with the heart and heart attacks.
It is known that Gilenya can cause your heart rate to slow down, particularly right after the first dose, with the drop being most significant at about six hours after the dose is taken. This is why doctors should monitor you during the first dose. Heart rate should to return to normal within one month of starting the medication, but feelings of dizziness and tiredness, or a slowed or uneven heartbeat should be reported to your doctor as should any pre-existing problems with blood pressure.
This research in rats indicates that whilst there may be a drop in blood pressure in normal rats, in rats that are genetically prone to high blood pressure can develop even higher blood pressure following gilenya. High blood pressure was caused by constriction of the artery and this causes the heart to work harder to circulate the blood. Hypertension can be associated with an increase risk of stroke and heart attack. In the rats asperin-like drugs could counteract the arterial constricting effects of fingolimod
At present more than 30,000 people have taken Gilenya and these deaths may be unrelated to the drug. Novartis are no doubt doing overtime to try and get to the bottom of this.
Following marketing of a drug, Pharmaceutical companies continue to perform “Pharmaco-vigilence” to spot any adverse effects that may be related to the drug. Death always ring alarm bells and need to be investigated. On a trial that Prof G did there was a death due to drowning. This was hardly likely to be drug-related but such things had to be reported just in case others cases occurred
We will keep you informed as this story develops.