Fingolimod

Fingolimod (INN, trade name Gilenya, Novartis) is an immunomodulating drug, mostly used for treating multiple sclerosis (MS). It has reduced the rate of relapses in relapsing-remitting multiple sclerosis by approximately one-half over a two-year period. Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction. Fingolimod (INN, trade name Gilenya, Novartis) is an immunomodulating drug, mostly used for treating multiple sclerosis (MS). It has reduced the rate of relapses in relapsing-remitting multiple sclerosis by approximately one-half over a two-year period. Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction. Fingolimod is used in the treatment of the relapsing form of multiple sclerosis. Its effect in those with primary progressive MS is not clear. It may also be used in chronic inflammatory demyelinating polyneuropathy. The most common side effects of fingolimod have been head colds, headache,increased gamma-glutamyl transfer (≤15%), Diarrhea (13%), nausea (13%), abdominal pain (11%) and fatigue. A few cases of skin cancer have been reported, which has also been reported in patients taking natalizumab (Tysabri), an approved MS drug. Fingolimod has also been associated with potentially fatal infections, bradycardia and, recently, a case of hemorrhaging focal encephalitis, an inflammation of the brain with bleeding. Two people died: one due to brain herpes infection, and a second one due to herpes zoster. It is unclear whether the drug was responsible for the events. At least three cases of progressive multifocal leukoencephalopathy had also occurred as of 2015. Fingolimod has also been known to cause macular edema, resulting in decreased vision. Therefore, frequent surveillance eye examinations are required while taking this medication. The European Medicines Agency has advised doctors to increase their level of monitoring of people after the first dose of the medicine. This includes electrocardiogram (ECG) monitoring before treatment and then continuously for the first six hours after the first dose, and measurement of blood pressure and heart rate every hour. It is derived from myriocin (ISP-1), a metabolite of the fungus Isaria sinclairii. It is a structural analogue of sphingosine and is phosphorylated by sphingosine kinases in the cell (most importantly sphingosine kinase 2). The molecular biology of phospho-fingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors, S1PR1. Phospho-fingolimod causes the internalization of S1P receptors, which sequesters lymphocytes in lymph nodes, preventing them from moving to the central nervous system and causing a relapse of multiple sclerosis. The unphosphorylated moiety of fingolimod, which is the predominant form of the drug in the body, is also an active molecule. Unphosphorylated fingolimod impairs the ability of cytotoxic CD8 T cells to kill their target cells by a different mechanism, which involves the arachidonic acid pathway, which is unrelated to sphigosine phosphate receptors. This has implications both for increasing susceptibility to viral infections as well as enhancing therapeutic efficacy in multiple sclerosis. Additionally, fingolimod shifts macrophages to an anti-inflammatory M2 phenotype. It modulates their proliferation, morphology, and cytokine release via inhibition of the transient receptor potential cation channel, subfamily M, member 7. (TRPM7). Finally, fingolimod has also been found to have other molecular targets and functions. Fingolimod has been reported to be a cannabinoid receptor antagonist, a cPLA2 inhibitor and a ceramide synthase inhibitor. It has also been reported to stimulate the repair process of glial cells and glial precursor cells after injury.