Fingolimod hydrochloride

Expert Opin Drug Saf. 2014 Jul;13(7):989-98.

Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis.[Pubmed: 24935480]

Fingolimod (Gilenya®, FTY720) is an oral sphingosine-1-phosphate analogue that was approved by the FDA in 2010 for the treatment of relapsing forms of multiple sclerosis (MS).
METHODS AND RESULTS:
Fingolimod's mechanism of action is primarily related to lymphocyte sequestration in primary and secondary lymphoid tissues. Phase III trials demonstrated a reduction in annualized relapse rate and MRI progression in fingolimod-treated subjects compared with both placebo and IFN-β-treated subjects. Frequent adverse effects include fatigue, gastrointestinal disturbance, headache and upper respiratory tract infection. More serious, but rare, adverse events associated with fingolimod include atrioventricular block, symptomatic bradycardia, herpetic viral infections and macular edema. We discuss the mechanism of action, pharmacokinetics, clinical efficacy and safety profile of fingolimod in patients with relapsing MS.
CONCLUSIONS:
Fingolimod is an effective treatment for relapsing MS and its oral route of administration may be preferred by some. Fingolimod is generally well tolerated but requires diligence in patient selection and monitoring. Additional information is needed regarding risk of infection, malignancy and rebound disease with long-term use of fingolimod.

Chinese Journal of Tissue Engineering Research, 2014 ,18 (11):1712-7.

Fingolimod hydrochloride suppresses inflammatory reaction of blood vessels after balloon injury of the carotid artery[Reference: WebLink]

METHODS AND RESULTS:
Hematoxylin-eosin staining showed that the proliferation of blood vessel was remarkable in the balloon injury group, but attenuated in the drug intervention group. The appearance of blood vessels was normal in the blank control group and negative control group. Real-time fluorescent quantitative PCRrevealed that cyclooxygenase 2 and prostaglandin E2 mRNA expression levels were significantly lower in the drug intervention group than those in the balloon injury group at 7 days(P 0.05). Cyclooxygenase 2 and prostaglandin E2 mRNA expression levels were significantly higher in the balloon injury group and drug intervention group than those in the blank control group and negative control group at the same time point(P 0.05). Western blot assay results revealed that sphingosine1-phosphate receptor 1 expression was high in early stage of injury, and then reduced in late stage of injury. In particular, protein expression further decreased after drug intervention.
CONCLUSIONS:
Results indicated that Fingolimod hydrochloride suppressed inflammatory reaction of injured blood vessels and lessened the stenosis of injured blood vessels by regulating cyclooxygenase 2 and prostaglandin E2 mRNA expression using sphingosine1-phosphate receptor 1.

Arch Pharm Res. 2016 Dec;39(12):1644-1652.

P21 (Cdc42/Rac)-activated kinase 1 (pak1) is associated with cardiotoxicity induced by antihistamines.[Pubmed: 27681411 ]

Astemizole, a non-sedating histamine H1 receptor blocker, is widely known to cause cardiac arrhythmia, which prolongs the QT interval. However, the precise molecular mechanism involved in antihistamine-induced cardiovascular adverse effects other than hERG channel inhibition is still unclear.
METHODS AND RESULTS:
In this study, we used DNA microarray analysis to detect the mechanisms involved in life-threatening adverse effects caused by astemizole. Rat primary cardiomyocytes were treated with various concentrations of astemizole for 24 h and the corresponding cell lysates were analyzed using a DNA microarray. Astemizole altered the expression profiles of genes involved in calcium transport/signaling. Using qRT-PCR analysis, we demonstrated that, among those genes, p21 (Cdc42/Rac)-activated kinase 1 (pak1) mRNA was downregulated by treatment with terfenadine and astemizole. Astemizole also reduced pak1 protein levels in rat cardiomyocytes. In addition, astemizole decreased pak1 mRNA and protein levels in H9c2 cells and induced an increase in cell surface area (hypertrophy) and cytotoxicity. Fingolimod hydrochloride (FTY720), a pak1 activator, inhibited astemizole-induced hypertrophy and cytotoxicity in H9c2 cells.
CONCLUSIONS:
These results suggest that antihistamine-induced cardiac adverse effects are associated with pak1 expression and function.

J Pharm Pharmacol. 2016 Oct;68(10):1268-77.

Fingolimod hydrochloride gel shows promising therapeutic effects in a mouse model of atopic dermatitis.[Pubmed: 27465785 ]

To assess the efficacy of topically applied 2% hydroxypropyl cellulose gels containing 0.5% Fingolimod hydrochloride (FNGL) with or without 6% colloidal oatmeal in an in vivo model of atopic dermatitis (AD).
METHODS AND RESULTS:
AD-like lesions were induced in SKH1/Hr hairless mice and were treated with FNGL gels, non-medicated base gels and Elidel(®) cream for 6 weeks. The severity/improvement of the lesions was assessed regularly using the Eczema Area and Severity Index (EASI), pH of the skin, transepidermal water loss, g/m(2) /h (TEWL), humidity and temperature. At the end of the experiments, the plasma levels of cytokines, FNGL and white blood cells were determined. The EASI score was almost unchanged for the vehicle-only groups compared to before the treatments, whereas the medicated groups showed a significant decrease in the overall EASI score (P < 0.01), although there was non-significant differences among them (P > 0.081). Both the FNGL groups also showed a significant (P ˂ 0.05) reduction in blood WBC.
CONCLUSIONS:
This study shows that the gels containing 0.50% FNGL and FNGL 0.50% plus 6% colloidal oatmeal have potential for the treatment of AD. The presence of colloidal oatmeal may provide additional benefits.