Darapladib Binds to Lipoprotein-Associated Phospholipase A2 with Meaningful Interactions

Rok, Kyoung; Kim, Chul; Chang, Byung-Ha; An, Seong Soo A.; Shin, Jae Min; Yea, Sang Jun; Song, Mi Jin; No, Kyoung Tai; Lee, Jee Young

doi:10.5012/bkcs.2014.35.1.250

Cited by 3 publications

(1 citation statement)

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“…This drug has the IC 50 value of 0,25 nM. The IUPAC name of darapladib is N- [23] In vitro studies suggest that Lp-pLA 2 inhibition can inhibit at least some of the inflammatory and proatherogenic effects of LysoPC and OxNEFA. The selective inhibition of Lp-pLA 2 activity prevents the generation of Lyso-PC and Ox-NEFA, resulting in the inhibition of monocytes chemotaxis and the protection of macrophages againts cell death.…”

Section: |Discussionmentioning

confidence: 99%

Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague-Dawley rats

Heriansyah¹,

Wihastuti²,

Anita³

et al. 2016

Natl J Physiol Pharm Pharmacol

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Background: Atherosclerosis is a chronic inflammation disease that is caused by the interaction between monocyte and endothelial injury in tunica intima. One of the major factor of atherosclerosis is dyslipidemia. Chronic dyslipidemia, especially hypercholesterolemia, can directly alter endothelial cell through reactive oxygen species (ROS) production that oxidizes low-density lipoprotein (LDL) to become oxidized LDL (Ox-LDL). Proinflammatory cytokines, the products of perivascular adipocyte tissue (PVAT), may draw macrophage. Macrophage then engulfs Ox-LDL and becomes foam cell within tunica intima. Lipoprotein-associated phospholipase A 2 (Lp-pLA 2) is an enzyme that cleaves Ox-LDL to become proatherosclerotic products. Darapladib, an Lp-pLA 2 inhibitor, is expected to inhibit atherosclerotic lesion progressivity. Aims and Objective: To know the effects of darapladib on Ox-LDL level, PVAT thickness, and foam cell number. Materials and Methods: This study used in vivo posttest controlled group design with two time series. Thirty male Sprague-Dawley rats divided into two group based on time series (8 weeks and 16 weeks). Each time serial was divided into three groups which were: standard diet group ;high-fat diet group; and dyslipidemia model with darapladib administration group with dose of 200 mg/200 g body weight (BW). The parameters that was measured in this study were lipid profile [total cholesterol, LDL/very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL)], Ox-LDL level, number of foam cells, and PVAT thickness. Result: Ox-LDL level and foam cell number decreased significantly (p = 0.000 and p = 0.005, respectively), while PVAT thickness did not show significant difference (p = 0.912). Conclusion: In this, study, it has been proven that darapladib decreases Ox-LDL levels and foam cell numbers but not in PVAT thickness, even though a decreasing pattern was observed histologically. Further study needed to know the optimum dosage of darapladib administration.

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Section: |Discussionmentioning

confidence: 99%