| Autor: |
Pagan, Fernando L., Hebron, Michaeline L., Wilmarth, Barbara, Torres-Yaghi, Yasar, Lawler, Abigail, Mundel, Elizabeth E., Yusuf, Nadia, Starr, Nathan J., Arellano, Joy, Howard, Helen H., Peyton, Margo, Matar, Sara, Liu, Xiaoguang, Fowler, Alan J., Schwartz, Sorell L., Ahn, Jaeil, Moussa, Charbel |
| Předmět: |
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| Zdroj: |
Pharmacology Research & Perspectives; Apr2019, Vol. 7 Issue 2, p1-N.PAG, 12p |
| Abstrakt: |
Nilotinib is a broad-based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c-Abl) and discoidin domain receptors (DDR1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson's disease (PD). We previously showed that Nilotinib penetrates the blood-brain barrier (BBB) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies (DLB). We performed a physiologically based population pharmacokinetic/pharmacodynamic (popPK/PD) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open-label random single dose (RSD) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose-independent manner and 200 mg Nilotinib increases the level of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha-synuclein and appears to reduce CSF oligomeric: total alpha-synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha-synuclein. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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