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Teuku Heriansyah - One of the best experts on this subject based on the ideXlab platform.
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Lp-PLA 2 Selective Inhibitor (Darapladib) Effect In Lowering The Expression Level Of IL-1B And IL-6 In The Renal At Type 2 Diabetes Mellitus
Vascular health and risk management, 2019Co-Authors: Titin Andri Wihastuti, Fitria Nugraha Aini, Cholid Tri Tjahjono, Yuni Hendrati Sulfia, Zuhrotus Sholichah, Teuku HeriansyahAbstract:Purpose The aim of this study is to prove that type 2 diabetes mellitus can induce increasing inflammation marker in renal and that the provision of Darapladib as Lp-LA2 Inhibitor agents can inhibit inflammation that were measured from the expression of IL-1B and IL-6- type cytokine in renal. This study also discusses the correlation between IL-1B and IL-6- type cytokine expression in renal. Methods Thirty Sprague-Dawley (SD) rats were divided into three main groups; those are negative control group (NC), Type 2 Diabetes Mellitus group (T2DM) given high fat diet (HFD) with streptozotocin intraperitoneal injection (35mg/kg BW) and diabetes mellitus + Darapladib group (DM + DP). Each group was treated within two serial treatment time: 8 weeks and 16 weeks. Expressions of IL-1B and IL-6- type cytokine in renal were the markers that we measured by immunofluorosense method. Results The administration of Darapladib can significantly decrease the expression of IL-1B- type cytokine (p ANOVA = 0.029, p < 0.005) measured in rats' renal both at weeks 8 and 16 in the T2DM group. The Expression of IL-6- type cytokine also showed a significant difference after treated with Darapladib both at weeks 8 and 16 in T2DM group with p-value of ANOVA = 0.033, p < 0.005. The Pearson correlation showed a strong correlation (linear regression value was r2 = 0.743). Conclusion Our results show that atherosclerosis caused by inflammation in renal T2DM SD rats could be inhibited by the administration of Darapladib.
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Reduction in Vasa Vasorum Angiogenesis by Lp-PLA2 Selective Inhibitor Through The HIF-1α and VEGF Expression Under Dyslipidemic Conditions in Atherosclerosis Pathogenesis.
Cardiovascular & hematological agents in medicinal chemistry, 2019Co-Authors: Teuku Heriansyah, Nafisa Nafisatuzzamrudah, Fitria Nugraha Aini, Muhammad Ridwan, Rozah F. Primardhika, Maya Wijayanti, Rachmad S. Bekti, Titin Andri WihastutiAbstract:BACKGROUND Atherosclerosis is a chronic inflammatory disease which may lead to major cardiovascular events. The primary cause of atherosclerosis is Dyslipidemia. The increased level of lipid profile triggers endothelial dysfunction. This results in inflammation with the recruitment of monocyte, macrophage, T lymphocyte, and Mast cells secreted by an Lp-PLA2 enzyme which causes binding between macrophage and oxidized LDL. This binding results in the formation of foam cells and also the migration of smooth muscle cells. Following that, an Lp-PLA2 receptor hydrolizes OxPC which results in LysoPC and OxNEFA, bioactive compounds which stimulate the progression of atherosclerosis plaques. This process leads to cell hypoxia, which may result in the increase of HIF-1α and VEGF expressions and induction of vasa vasorum angiogenesis. Employing Darapladib as an agent of Lp-PLA2 selective inhibitors, this study aimed to find out the effect of Darapladib as an Lp- PLA2 selective inhibitor agent on the formation of vasa vasorum angiogenesis and the decrease of HIF-1α and VEGF expression in aortic tissue of rats with dyslipidemia. METHOD A true laboratory experiment with a randomized post-test control group design used 30 male spraque dowley rats as animal models which were divided into 6 groups: Normal 8 weeks, Normal 16 weeks, Dyslipidemia (DL) 8 weeks, Dyslipidemia (DL) 16 weeks, Dyslipidemia with Darapladib treatment (DLDP) 8 weeks and Dyslipidemia with Darapladib treatment (DLDP) 16 weeks. The data measured in this study were the lipid profile (total cholesterol, HDL, and LDL). Using EnzyChrom TM kit, hematoxylin eosin, and double-labelling immunofluorescene, the levels of lipid profile, vasa vasorum, HIF-1α and VEGF were measured. RESULTS The study results which were analyzed using NOVA test showed that with Darapladib administration, there was a significant decrease in vasa vasorum angiogenesis (p=0.000), HIF-1α (p=0.005) and VEGF (p=0.009) expression in each time series. This result proves that Lp-PLA2 inhibitor reduces inflammatory process. CONCLUSION Darapladib injection as an Lp-PLA2 selective inhibitor correlates with the decreasing vasa vasorum angiogenesis through alteration in HIF-1α and VEGF expressions in the aorta of high fat diet rats. We recommend further experiments to determine the effectiveness of Darapladib with earlier time series in the atherosclerosis process.
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Darapladib inhibits atherosclerosis development in type 2 diabetes mellitus sprague dawley rat model
Endocrine Regulations, 2018Co-Authors: Titin Andri Wihastuti, Sri Andarini, Teuku Heriansyah, Yuni Hendrati Sulfia, Zuhrotus Sholichah, Hanifa Hanifa, Aditya Angela Adam, Jeki Refialdinata, Nurul Cholifah LutfianaAbstract:OBJECTIVE Increase in the low-density lipoprotein (LDL) level in diabetes mellitus and atherosclerosis is related to lipoprotein associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is an enzyme that produces lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (oxNEFA). LysoPC regulates inflammation mediators, including intra-cellular adhesion molecule-1 (ICAM-1). Darapladib is known as a Lp-PLA2 specific inhibitor. The aim of this study was to reveal the effect of Darapladib on the foam cell number, inducible nitric oxide synthase (iNOS), and ICAM-1 expression in aorta at early stages of the atherosclerosis in type 2 diabetes mellitus Sprague-Dawley rat model. METHODS Thirty Sprague-Dawley male rats were divided into 3 main groups: control, rats with type 2 diabetes mellitus (T2DM), and T2DM rats treated with Darapladib (T2DM-DP). Each group was divided into 2 subgroups according the time of treatment: 8-week and 16-week treatment group. Fasting blood glucose, insulin resistance, and lipid profile were measured and analyzed to ensure T2DM model. The foam cells number were detected using hematoxylin-eosin (HE) staining and the expression of iNOS and ICAM-1 was analyzed using double immunofluorescence staining. RESULTS Induction of T2DM in male Sprague-Dawley rats after high fat diet and streptozotocin injection was confirmed by elevated levels of total cholesterol and LDL and increased fasting glucose and insulin levels compared to controls after both times of treatment. Moreover, T2DM in rats induced a significant increase (p<0.05) in the foam cells number and iNOS and ICAM-1 expression in aorta compared to controls after both treatment times. Darapladib treatment significantly reduced (p<0.05) foam cells number as well as iNOS expression in aorta in rats with T2DM after both treatment times. A significant decrease (p<0.05) in ICAM-1 expression in aorta was observed after Darapladib treatment in rats with T2DM only after 8 weeks of treatment. CONCLUSION Our data indicate that Darapladib can decrease the foam cells number, iNOS, and ICAM-1 expression in aorta at the early stages of atherosclerosis in T2DM rat model.
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Darapladib inhibits atherosclerosis development in type 2 diabetes mellitus Sprague-Dawley rat model.
Endocrine regulations, 2018Co-Authors: Titin Andri Wihastuti, Sri Andarini, Teuku Heriansyah, Yuni Hendrati Sulfia, Zuhrotus Sholichah, Hanifa Hanifa, Aditya Angela Adam, Jeki Refialdinata, Nurul Cholifah LutfianaAbstract:OBJECTIVE Increase in the low-density lipoprotein (LDL) level in diabetes mellitus and atherosclerosis is related to lipoprotein associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is an enzyme that produces lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (oxNEFA). LysoPC regulates inflammation mediators, including intra-cellular adhesion molecule-1 (ICAM-1). Darapladib is known as a Lp-PLA2 specific inhibitor. The aim of this study was to reveal the effect of Darapladib on the foam cell number, inducible nitric oxide synthase (iNOS), and ICAM-1 expression in aorta at early stages of the atherosclerosis in type 2 diabetes mellitus Sprague-Dawley rat model. METHODS Thirty Sprague-Dawley male rats were divided into 3 main groups: control, rats with type 2 diabetes mellitus (T2DM), and T2DM rats treated with Darapladib (T2DM-DP). Each group was divided into 2 subgroups according the time of treatment: 8-week and 16-week treatment group. Fasting blood glucose, insulin resistance, and lipid profile were measured and analyzed to ensure T2DM model. The foam cells number were detected using hematoxylin-eosin (HE) staining and the expression of iNOS and ICAM-1 was analyzed using double immunofluorescence staining. RESULTS Induction of T2DM in male Sprague-Dawley rats after high fat diet and streptozotocin injection was confirmed by elevated levels of total cholesterol and LDL and increased fasting glucose and insulin levels compared to controls after both times of treatment. Moreover, T2DM in rats induced a significant increase (p
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decreasement of lysophosphatidylcholine level nf kb expression intima media thickness and improvement of insulin resistance by Darapladib treatment in vivo studies of type 2 diabetes mellitus sprague dawley rat model
Asian Journal of Pharmaceutical and Clinical Research, 2017Co-Authors: Titin Andri Wihastuti, Dinda Zahra Putri Andiyani, Sri Andarini, Teuku HeriansyahAbstract:Objective: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme with several pro-inflammatory properties that involved in pathogenesis of atherosclerosis, but some investigation shows controversial views regarding its biological role. We examined the effect of selective inhibitor of Lp-PLA2 (Darapladib) to the inflammation marker, intima-media thickness (IMT), and insulin resistance (IR) of type 2 diabetes mellitus (T2DM) rat model. This study aimed to measure lysophosphatidylcholine (lyso-PC) in serum and aortic tissue, nuclear factor kappa B (NF-IoB) expression, IMT, and IR with Darapladib treatment in a T2DM rat model.Methods: 30 Sprague-Dawley rats were randomly divided into normal group, T2DM group and T2DM with Darapladib treatment. Induction of T2DM was done by giving high-fat diet and low dose injection of streptozotocin. Blood glucose level and insulin plasma concentration were measured to calculate IR. 8 weeks and 16 weeks after treatment, we compared lyso-PC level, NF-IoB expression, and IMT.Results: Darapladib significantly decreased lyso-PC level, NF-IoB expression, and IMT at two serial treatments. Darapladib treatment group exhibited significant reduction of IR (0.64±0.11 vs. 2.07±0.16, at 8 weeks; and 0.93±0.08 vs. 6.48±0.55 at 16 weeks) compared with T2DM group.Conclusions: These data suggested that Lp-PLA2 played a role in inflammation process, atherosclerosis, and IR occurring in metabolic disorder.
Titin Andri Wihastuti - One of the best experts on this subject based on the ideXlab platform.
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Lp-PLA 2 Selective Inhibitor (Darapladib) Effect In Lowering The Expression Level Of IL-1B And IL-6 In The Renal At Type 2 Diabetes Mellitus
Vascular health and risk management, 2019Co-Authors: Titin Andri Wihastuti, Fitria Nugraha Aini, Cholid Tri Tjahjono, Yuni Hendrati Sulfia, Zuhrotus Sholichah, Teuku HeriansyahAbstract:Purpose The aim of this study is to prove that type 2 diabetes mellitus can induce increasing inflammation marker in renal and that the provision of Darapladib as Lp-LA2 Inhibitor agents can inhibit inflammation that were measured from the expression of IL-1B and IL-6- type cytokine in renal. This study also discusses the correlation between IL-1B and IL-6- type cytokine expression in renal. Methods Thirty Sprague-Dawley (SD) rats were divided into three main groups; those are negative control group (NC), Type 2 Diabetes Mellitus group (T2DM) given high fat diet (HFD) with streptozotocin intraperitoneal injection (35mg/kg BW) and diabetes mellitus + Darapladib group (DM + DP). Each group was treated within two serial treatment time: 8 weeks and 16 weeks. Expressions of IL-1B and IL-6- type cytokine in renal were the markers that we measured by immunofluorosense method. Results The administration of Darapladib can significantly decrease the expression of IL-1B- type cytokine (p ANOVA = 0.029, p < 0.005) measured in rats' renal both at weeks 8 and 16 in the T2DM group. The Expression of IL-6- type cytokine also showed a significant difference after treated with Darapladib both at weeks 8 and 16 in T2DM group with p-value of ANOVA = 0.033, p < 0.005. The Pearson correlation showed a strong correlation (linear regression value was r2 = 0.743). Conclusion Our results show that atherosclerosis caused by inflammation in renal T2DM SD rats could be inhibited by the administration of Darapladib.
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Reduction in Vasa Vasorum Angiogenesis by Lp-PLA2 Selective Inhibitor Through The HIF-1α and VEGF Expression Under Dyslipidemic Conditions in Atherosclerosis Pathogenesis.
Cardiovascular & hematological agents in medicinal chemistry, 2019Co-Authors: Teuku Heriansyah, Nafisa Nafisatuzzamrudah, Fitria Nugraha Aini, Muhammad Ridwan, Rozah F. Primardhika, Maya Wijayanti, Rachmad S. Bekti, Titin Andri WihastutiAbstract:BACKGROUND Atherosclerosis is a chronic inflammatory disease which may lead to major cardiovascular events. The primary cause of atherosclerosis is Dyslipidemia. The increased level of lipid profile triggers endothelial dysfunction. This results in inflammation with the recruitment of monocyte, macrophage, T lymphocyte, and Mast cells secreted by an Lp-PLA2 enzyme which causes binding between macrophage and oxidized LDL. This binding results in the formation of foam cells and also the migration of smooth muscle cells. Following that, an Lp-PLA2 receptor hydrolizes OxPC which results in LysoPC and OxNEFA, bioactive compounds which stimulate the progression of atherosclerosis plaques. This process leads to cell hypoxia, which may result in the increase of HIF-1α and VEGF expressions and induction of vasa vasorum angiogenesis. Employing Darapladib as an agent of Lp-PLA2 selective inhibitors, this study aimed to find out the effect of Darapladib as an Lp- PLA2 selective inhibitor agent on the formation of vasa vasorum angiogenesis and the decrease of HIF-1α and VEGF expression in aortic tissue of rats with dyslipidemia. METHOD A true laboratory experiment with a randomized post-test control group design used 30 male spraque dowley rats as animal models which were divided into 6 groups: Normal 8 weeks, Normal 16 weeks, Dyslipidemia (DL) 8 weeks, Dyslipidemia (DL) 16 weeks, Dyslipidemia with Darapladib treatment (DLDP) 8 weeks and Dyslipidemia with Darapladib treatment (DLDP) 16 weeks. The data measured in this study were the lipid profile (total cholesterol, HDL, and LDL). Using EnzyChrom TM kit, hematoxylin eosin, and double-labelling immunofluorescene, the levels of lipid profile, vasa vasorum, HIF-1α and VEGF were measured. RESULTS The study results which were analyzed using NOVA test showed that with Darapladib administration, there was a significant decrease in vasa vasorum angiogenesis (p=0.000), HIF-1α (p=0.005) and VEGF (p=0.009) expression in each time series. This result proves that Lp-PLA2 inhibitor reduces inflammatory process. CONCLUSION Darapladib injection as an Lp-PLA2 selective inhibitor correlates with the decreasing vasa vasorum angiogenesis through alteration in HIF-1α and VEGF expressions in the aorta of high fat diet rats. We recommend further experiments to determine the effectiveness of Darapladib with earlier time series in the atherosclerosis process.
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Darapladib inhibits atherosclerosis development in type 2 diabetes mellitus sprague dawley rat model
Endocrine Regulations, 2018Co-Authors: Titin Andri Wihastuti, Sri Andarini, Teuku Heriansyah, Yuni Hendrati Sulfia, Zuhrotus Sholichah, Hanifa Hanifa, Aditya Angela Adam, Jeki Refialdinata, Nurul Cholifah LutfianaAbstract:OBJECTIVE Increase in the low-density lipoprotein (LDL) level in diabetes mellitus and atherosclerosis is related to lipoprotein associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is an enzyme that produces lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (oxNEFA). LysoPC regulates inflammation mediators, including intra-cellular adhesion molecule-1 (ICAM-1). Darapladib is known as a Lp-PLA2 specific inhibitor. The aim of this study was to reveal the effect of Darapladib on the foam cell number, inducible nitric oxide synthase (iNOS), and ICAM-1 expression in aorta at early stages of the atherosclerosis in type 2 diabetes mellitus Sprague-Dawley rat model. METHODS Thirty Sprague-Dawley male rats were divided into 3 main groups: control, rats with type 2 diabetes mellitus (T2DM), and T2DM rats treated with Darapladib (T2DM-DP). Each group was divided into 2 subgroups according the time of treatment: 8-week and 16-week treatment group. Fasting blood glucose, insulin resistance, and lipid profile were measured and analyzed to ensure T2DM model. The foam cells number were detected using hematoxylin-eosin (HE) staining and the expression of iNOS and ICAM-1 was analyzed using double immunofluorescence staining. RESULTS Induction of T2DM in male Sprague-Dawley rats after high fat diet and streptozotocin injection was confirmed by elevated levels of total cholesterol and LDL and increased fasting glucose and insulin levels compared to controls after both times of treatment. Moreover, T2DM in rats induced a significant increase (p<0.05) in the foam cells number and iNOS and ICAM-1 expression in aorta compared to controls after both treatment times. Darapladib treatment significantly reduced (p<0.05) foam cells number as well as iNOS expression in aorta in rats with T2DM after both treatment times. A significant decrease (p<0.05) in ICAM-1 expression in aorta was observed after Darapladib treatment in rats with T2DM only after 8 weeks of treatment. CONCLUSION Our data indicate that Darapladib can decrease the foam cells number, iNOS, and ICAM-1 expression in aorta at the early stages of atherosclerosis in T2DM rat model.
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Darapladib inhibits atherosclerosis development in type 2 diabetes mellitus Sprague-Dawley rat model.
Endocrine regulations, 2018Co-Authors: Titin Andri Wihastuti, Sri Andarini, Teuku Heriansyah, Yuni Hendrati Sulfia, Zuhrotus Sholichah, Hanifa Hanifa, Aditya Angela Adam, Jeki Refialdinata, Nurul Cholifah LutfianaAbstract:OBJECTIVE Increase in the low-density lipoprotein (LDL) level in diabetes mellitus and atherosclerosis is related to lipoprotein associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is an enzyme that produces lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (oxNEFA). LysoPC regulates inflammation mediators, including intra-cellular adhesion molecule-1 (ICAM-1). Darapladib is known as a Lp-PLA2 specific inhibitor. The aim of this study was to reveal the effect of Darapladib on the foam cell number, inducible nitric oxide synthase (iNOS), and ICAM-1 expression in aorta at early stages of the atherosclerosis in type 2 diabetes mellitus Sprague-Dawley rat model. METHODS Thirty Sprague-Dawley male rats were divided into 3 main groups: control, rats with type 2 diabetes mellitus (T2DM), and T2DM rats treated with Darapladib (T2DM-DP). Each group was divided into 2 subgroups according the time of treatment: 8-week and 16-week treatment group. Fasting blood glucose, insulin resistance, and lipid profile were measured and analyzed to ensure T2DM model. The foam cells number were detected using hematoxylin-eosin (HE) staining and the expression of iNOS and ICAM-1 was analyzed using double immunofluorescence staining. RESULTS Induction of T2DM in male Sprague-Dawley rats after high fat diet and streptozotocin injection was confirmed by elevated levels of total cholesterol and LDL and increased fasting glucose and insulin levels compared to controls after both times of treatment. Moreover, T2DM in rats induced a significant increase (p
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decreasement of lysophosphatidylcholine level nf kb expression intima media thickness and improvement of insulin resistance by Darapladib treatment in vivo studies of type 2 diabetes mellitus sprague dawley rat model
Asian Journal of Pharmaceutical and Clinical Research, 2017Co-Authors: Titin Andri Wihastuti, Dinda Zahra Putri Andiyani, Sri Andarini, Teuku HeriansyahAbstract:Objective: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme with several pro-inflammatory properties that involved in pathogenesis of atherosclerosis, but some investigation shows controversial views regarding its biological role. We examined the effect of selective inhibitor of Lp-PLA2 (Darapladib) to the inflammation marker, intima-media thickness (IMT), and insulin resistance (IR) of type 2 diabetes mellitus (T2DM) rat model. This study aimed to measure lysophosphatidylcholine (lyso-PC) in serum and aortic tissue, nuclear factor kappa B (NF-IoB) expression, IMT, and IR with Darapladib treatment in a T2DM rat model.Methods: 30 Sprague-Dawley rats were randomly divided into normal group, T2DM group and T2DM with Darapladib treatment. Induction of T2DM was done by giving high-fat diet and low dose injection of streptozotocin. Blood glucose level and insulin plasma concentration were measured to calculate IR. 8 weeks and 16 weeks after treatment, we compared lyso-PC level, NF-IoB expression, and IMT.Results: Darapladib significantly decreased lyso-PC level, NF-IoB expression, and IMT at two serial treatments. Darapladib treatment group exhibited significant reduction of IR (0.64±0.11 vs. 2.07±0.16, at 8 weeks; and 0.93±0.08 vs. 6.48±0.55 at 16 weeks) compared with T2DM group.Conclusions: These data suggested that Lp-PLA2 played a role in inflammation process, atherosclerosis, and IR occurring in metabolic disorder.
Joel L. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Effect of Darapladib Treatment on Endarterectomy Carotid Plaque Lipoprotein-Associated Phospholipase A2 Activity: A Randomized, Controlled Trial
2016Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Yi Shi, Colin H MacpheeAbstract:Background: The aim of this study was to assess the effects of Darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity. Methods: Patients undergoing elective carotid endarterectomy were randomized to Darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. Results: Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52 % and 81%, respectively, versus placebo (both P,0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P,0.0001), which equated to a 52 % and 80 % decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with Darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P,0.001) and caspase-8 (P,0.05) activity were found to be significantly lower in the Darapladib 80-mg group versus placebo. No major safety concerns were identified in the study. Conclusions: Short-term treatment (1464 days) with Darapladib produced a robust, dose-dependent reduction in plasm
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Effect of Darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial.
PLOS ONE, 2014Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Colin H MacpheeAbstract:Background The aim of this study was to assess the effects of Darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity. Methods Patients undergoing elective carotid endarterectomy were randomized to Darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. Results Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P
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effect of Darapladib treatment on endarterectomy carotid plaque lipoprotein associated phospholipase a2 activity a randomized controlled trial
PLOS ONE, 2014Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Yi Shi, Colin H MacpheeAbstract:Background The aim of this study was to assess the effects of Darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity. Methods Patients undergoing elective carotid endarterectomy were randomized to Darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. Results Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with Darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the Darapladib 80-mg group versus placebo. No major safety concerns were identified in the study. Conclusions Short-term treatment (14±4 days) with Darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, Darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized. Trial Registration Information Name of Registry 1: ClinicalTrials.gov Registry Number 1: NCT01916720 Trial URL in Registry Database 1: www.clinicaltrials.gov/ct2/show/NCT01916720 Name of Registry 2: GSK Clinical Study Register Registry Number 2∶480848/010 Trial URL in Registry Database 2: www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=480848%2F010&studyId=74F5DB65-4661-4FA8-91D4-EBF78D769F24&compound=Darapladib&type=Compound&letterrange=A-F
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Effect of Darapladib treatment (14±4 days) on plaque and plasma lipoprotein-associated phospholipase A2 activity.
2014Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Yi Shi, Colin H MacpheeAbstract:Vertical bars for plaque and plasma data points represent 97.5% and 95% confidence intervals (CI), respectively. Baseline plasma Lp-PLA2 activity levels are provided in Table 1. At Day 15, plasma Lp-PLA2 activity levels (mean ± SD) for placebo, 40 mg Darapladib, and 80 mg Darapladib were 141.4±39.3, 63.4±28.3, and 27.0±11.4 nmol/min/ml, respectively. At Day 15, plaque Lp-PLA2 activity levels (mean ± SEM) for placebo, 40 mg Darapladib, and 80 mg Darapladib were 0.94±0.14, 0.26±0.13, and 0.11±0.14 nmol/min/mg protein, respectively.
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The influence of Darapladib treatment (14±4 days) on plaque (A) caspase-3 activity and (B) caspase-8 activity (mean ± SEM).
2014Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Yi Shi, Colin H MacpheeAbstract:P values represent comparisons of Darapladib 80 mg with placebo. AU, activity units.
Colin H Macphee - One of the best experts on this subject based on the ideXlab platform.
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Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for Darapladib.
PloS one, 2017Co-Authors: Astrid Yeo, Colin H Macphee, Liling Warren, Jennifer L. Aponte, Dana Fraser, Karen S. King, Kelley A. Johansson, Allison Barnes, Richard Y DaviesAbstract:Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA(2)) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in s ...
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Retinal pathology is associated with increased blood-retina barrier permeability in a diabetic and hypercholesterolaemic pig model: Beneficial effects of the LpPLA2 inhibitor Darapladib.
Diabetes & vascular disease research, 2017Co-Authors: Nimish K Acharya, Eric L Goldwaser, George A Godsey, Mary C Kosciuk, Robert L. Wilensky, Colin H Macphee, Theresa A. Freeman, X Qi, Hao Wu, Venkat VenkataramanAbstract:Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood-brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta1-42 peptide in pyramidal neurons. Treatment with Darapladib (GlaxoSmithKline, SB480848), an inhibitor of lipoprotein-associated phospholipase-A2, alleviated these effects. Here, investigation of the effects of chronic diabetes mellitus and hypercholesterolaemia on the pig retina revealed a corresponding increased permeability of the blood-retina barrier coupled with a leak of plasma components into the retina, alterations in retinal architecture, selective IgG binding to neurons in the ganglion cell layer, thinning of retinal layers due to cell loss and increased glial fibrillary acidic protein expression in Müller cells, all of which were curtailed by treatment with Darapladib. These findings suggest that chronic diabetes mellitus and hypercholesterolaemia induces increased blood-retina barrier permeability that may be linked to altered expression of blood-retina barrier-associated tight junction proteins, claudin and occludin, leading to structural changes in the retina consistent with diabetic retinopathy. Additionally, results suggest that drugs with vascular anti-inflammatory properties, such as Darapladib, may have beneficial effects on eye diseases strongly linked to vascular abnormalities such as diabetic retinopathy and age-related macular degeneration.
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Effect of Darapladib Treatment on Endarterectomy Carotid Plaque Lipoprotein-Associated Phospholipase A2 Activity: A Randomized, Controlled Trial
2016Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Yi Shi, Colin H MacpheeAbstract:Background: The aim of this study was to assess the effects of Darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity. Methods: Patients undergoing elective carotid endarterectomy were randomized to Darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. Results: Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52 % and 81%, respectively, versus placebo (both P,0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P,0.0001), which equated to a 52 % and 80 % decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with Darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P,0.001) and caspase-8 (P,0.05) activity were found to be significantly lower in the Darapladib 80-mg group versus placebo. No major safety concerns were identified in the study. Conclusions: Short-term treatment (1464 days) with Darapladib produced a robust, dose-dependent reduction in plasm
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Effect of Darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial.
PLOS ONE, 2014Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Colin H MacpheeAbstract:Background The aim of this study was to assess the effects of Darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity. Methods Patients undergoing elective carotid endarterectomy were randomized to Darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. Results Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P
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effect of Darapladib treatment on endarterectomy carotid plaque lipoprotein associated phospholipase a2 activity a randomized controlled trial
PLOS ONE, 2014Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Yi Shi, Colin H MacpheeAbstract:Background The aim of this study was to assess the effects of Darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity. Methods Patients undergoing elective carotid endarterectomy were randomized to Darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. Results Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with Darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the Darapladib 80-mg group versus placebo. No major safety concerns were identified in the study. Conclusions Short-term treatment (14±4 days) with Darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, Darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized. Trial Registration Information Name of Registry 1: ClinicalTrials.gov Registry Number 1: NCT01916720 Trial URL in Registry Database 1: www.clinicaltrials.gov/ct2/show/NCT01916720 Name of Registry 2: GSK Clinical Study Register Registry Number 2∶480848/010 Trial URL in Registry Database 2: www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=480848%2F010&studyId=74F5DB65-4661-4FA8-91D4-EBF78D769F24&compound=Darapladib&type=Compound&letterrange=A-F
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Post-hoc analyses of Darapladib, an oral Lp-PLA(2) inhibitor, in phase III cardiovascular outcomes trials may inform investigation in diabetic macular edema
Investigative Ophthalmology & Visual Science, 2015Co-Authors: Rachel E. Williams, Salim Janmohamed, John I Wurzelmann, Harvey D White, Shawn Patrick Shearn, Lars Wallentin, Michael Dowd, Greg Cicconetti, Megan M MclaughlinAbstract:Post-hoc analyses of Darapladib, an oral Lp-PLA(2) inhibitor, in phase III cardiovascular outcomes trials may inform investigation in diabetic macular edema
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Characterization of cardiovascular endpoints, impact of event adjudication and effects of Darapladib in the STABILITY trial
European Heart Journal, 2015Co-Authors: Claes Held, Harvey D White, Richard Y Davies, R. Stewart, S. H. Sampson, Karen Chiswell, Ulrika Bodén, K.w. Mahaffey, Lars WallentinAbstract:Characterization of cardiovascular endpoints, impact of event adjudication and effects of Darapladib in the STABILITY trial
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Effect of Darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.
JAMA, 2014Co-Authors: Michelle L. O'donoghue, Harvey D White, Elizabeth Tarka, Eugene Braunwald, Dylan L. Steen, Mary Ann Lukas, P. Gabriel Steg, Judith S. Hochman, Christoph Bode, Aldo P. MaggioniAbstract:hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the Darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the Darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the Darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%).
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Darapladib for preventing ischemic events in stable coronary heart disease
The New England Journal of Medicine, 2014Co-Authors: Harvey D White, Ralph A.h. Stewart, Claes Held, Elizabeth Tarka, Rebekkah Brown, Richard Y Davies, Andrzej Budaj, Robert A Harrington, Gabriel P StegAbstract:Background Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2. Methods In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily Darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). Results During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the Darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the Darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02). Conclusions In patients with stable coronary heart disease, Darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).
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Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome
American heart journal, 2011Co-Authors: Michelle L. O'donoghue, Harvey D White, Eugene Braunwald, Judith S. Hochman, Christoph Bode, Aldo P. Maggioni, Patrick W. Serruys, Ph. Gabriel Steg, Douglas Weaver, Joel L. JohnsonAbstract:Background Higher levels of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) are associated with a higher risk of cardiovascular events and may play a causal role in atherogenesis. Darapladib inhibits Lp-PLA 2 activity in plasma and in arterial plaques and may confer clinical benefit in preventing cardiovascular events. Study Design The SOLID-TIMI 52 trial is a randomized, double-blind, placebo-controlled, multicenter, event-driven trial. Approximately 13,000 subjects are being randomized to Darapladib (160 mg enteric-coated tablet daily) or matching placebo within 30 days of hospitalization with an acute coronary syndrome. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points include major and total coronary events, individual components of the primary end point, and all-cause mortality. The study will continue until approximately 1,500 primary end point events have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be approximately 3 years, with a total study duration of approximately 4.1 years. Conclusions The SOLID-TIMI 52 trial will determine the clinical benefit of direct inhibition of Lp-PLA 2 activity with Darapladib in patients after an acute coronary syndrome.
