التفاصيل البيبلوغرافية
| العنوان: |
The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. |
| المؤلفون: |
Gergely, P, Nuesslein-Hildesheim, B, Guerini, D, Brinkmann, V, Traebert, M, Bruns, C, Pan, S, Gray, NS, Hinterding, K, Cooke, NG, Groenewegen, A, Vitaliti, A, Sing, T, Luttringer, O, Yang, J, Gardin, A, Wang, N, Crumb Jr, WJ, Saltzman, M, Rosenberg, M |
| المصدر: |
British Journal of Pharmacology; Nov2012, Vol. 167 Issue 5, p1035-1047, 13p |
| مصطلحات موضوعية: |
SPHINGOSINE-1-phosphate, LYMPHOCYTES, HEART beat, IMMUNOLOGIC diseases, IMMUNOMODULATORS, PHARMACOKINETICS, PHARMACODYNAMICS, G protein coupled receptors |
| مستخلص: |
BACKGROUND AND PURPOSE BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P1 and S1P5 receptors. S1P1 receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data. EXPERIMENTAL APPROACH BAF312 was tested in a rat experimental autoimmune encephalomyelitis (EAE) model. Electrophysiological recordings of G-protein-coupled inwardly rectifying potassium (GIRK) channels were carried out in human atrial myocytes. A Phase I multiple-dose trial studied the pharmacokinetics, pharmacodynamics and safety of BAF312 in 48 healthy subjects. KEY RESULTS BAF312 effectively suppressed EAE in rats by internalizing S1P1 receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4+ T cells, Tnaïve, Tcentral memory and B cells within 4-6 h. Cell counts returned to normal ranges within a week after stopping treatment, in line with the elimination half-life of BAF312. Despite sparing S1P3 receptors (associated with bradycardia in mice), BAF312 induced rapid, transient (day 1 only) bradycardia in humans. BAF312-mediated activation of GIRK channels in human atrial myocytes can fully explain the bradycardia. CONCLUSION AND IMPLICATIONS This study illustrates species-specific differences in S1P receptor specificity for first-dose cardiac effects. Based on its profound but rapidly reversible inhibition of lymphocyte trafficking, BAF312 may have potential as a treatment for immune-mediated diseases. [ABSTRACT FROM AUTHOR] |
|
Copyright of British Journal of Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder