Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a PLA2G7 Gene Polymorphism of Val279Phe

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/wit...

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Veröffentlicht in:Circulation Journal 2013, Vol.77(6), pp.1518-1525
Hauptverfasser: Daida, Hiroyuki, Iwase, Takayuki, Yagi, Shigeru, Ando, Hidekazu, Nakajima, Hiromu
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container_issue 6
container_start_page 1518
container_title Circulation Journal
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creator Daida, Hiroyuki
Iwase, Takayuki
Yagi, Shigeru
Ando, Hidekazu
Nakajima, Hiromu
description Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed. Methods and Results: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40mg (n=28), 80mg (n=28), or 160mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P
doi_str_mv 10.1253/circj.CJ-12-0813
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This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed. Methods and Results: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40mg (n=28), 80mg (n=28), or 160mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P&lt;0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted. Conclusions: Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA  (Circ J 2013; 77: 1518–1525)2.</description><identifier>ISSN: 1346-9843</identifier><identifier>EISSN: 1347-4820</identifier><identifier>DOI: 10.1253/circj.CJ-12-0813</identifier><identifier>PMID: 23439604</identifier><language>eng</language><publisher>Japan: The Japanese Circulation Society</publisher><subject>1-Alkyl-2-acetylglycerophosphocholine Esterase ; Adult ; Aged, 80 and over ; Amino Acid Substitution ; Asian Continental Ancestry Group ; Atherosclerosis ; Benzaldehydes - administration &amp; dosage ; Benzaldehydes - adverse effects ; Darapladib ; Dose-Response Relationship, Drug ; Double-Blind Method ; Dyslipidemia ; Dyslipidemias - drug therapy ; Dyslipidemias - enzymology ; Dyslipidemias - genetics ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration &amp; dosage ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects ; Japan ; Lipoprotein-associated phospholipase A2 ; Male ; Middle Aged ; Mutation, Missense ; Oximes - administration &amp; dosage ; Oximes - adverse effects ; Phospholipase A2 Inhibitors - administration &amp; dosage ; Phospholipase A2 Inhibitors - adverse effects ; Phospholipases A2 - blood ; Phospholipases A2 - genetics ; Polymorphism, Single Nucleotide ; V279F</subject><ispartof>Circulation Journal, 2013, Vol.77(6), pp.1518-1525</ispartof><rights>2013 THE JAPANESE CIRCULATION SOCIETY</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c452t-a95c647bd3ec639ea9491256b714a14ad891e6e33f9c5280d0b691114ec76aaf3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1881,4021,27921,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23439604$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Daida, Hiroyuki</creatorcontrib><creatorcontrib>Iwase, Takayuki</creatorcontrib><creatorcontrib>Yagi, Shigeru</creatorcontrib><creatorcontrib>Ando, Hidekazu</creatorcontrib><creatorcontrib>Nakajima, Hiromu</creatorcontrib><title>Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a PLA2G7 Gene Polymorphism of Val279Phe</title><title>Circulation Journal</title><addtitle>Circ J</addtitle><description>Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed. Methods and Results: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40mg (n=28), 80mg (n=28), or 160mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P&lt;0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted. Conclusions: Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA  (Circ J 2013; 77: 1518–1525)2.</description><subject>1-Alkyl-2-acetylglycerophosphocholine Esterase</subject><subject>Adult</subject><subject>Aged, 80 and over</subject><subject>Amino Acid Substitution</subject><subject>Asian Continental Ancestry Group</subject><subject>Atherosclerosis</subject><subject>Benzaldehydes - administration &amp; dosage</subject><subject>Benzaldehydes - adverse effects</subject><subject>Darapladib</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Dyslipidemia</subject><subject>Dyslipidemias - drug therapy</subject><subject>Dyslipidemias - enzymology</subject><subject>Dyslipidemias - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration &amp; dosage</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects</subject><subject>Japan</subject><subject>Lipoprotein-associated phospholipase A2</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation, Missense</subject><subject>Oximes - administration &amp; dosage</subject><subject>Oximes - adverse effects</subject><subject>Phospholipase A2 Inhibitors - administration &amp; dosage</subject><subject>Phospholipase A2 Inhibitors - adverse effects</subject><subject>Phospholipases A2 - blood</subject><subject>Phospholipases A2 - genetics</subject><subject>Polymorphism, Single Nucleotide</subject><subject>V279F</subject><issn>1346-9843</issn><issn>1347-4820</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkU1v1DAQhiMEoqVw54R85ECKHSdOfIy224XVSuTAxzGaOBPilRMH24vIL-PvkXSXVrLsGfuZV-N5o-gto7csyfhHpZ063m72MUtiWjD-LLpmPM3jtEjo84dYxLJI-VX0yvsjpYmkmXwZXSU85VLQ9Dr6u-06VIHYjtyBg8lAqxtiR1IZ8AOQg57s5GxAPcal91ZpCNiSqrd-6q3RE3gkZUJKFfRvHWaiR7KHCUZc7u9mvxC6xUErUkHQOAb_gfzQoSfbP5OxDoJ1MylHMLPXfu0CSHUok11OdjgiqayZB-umXvthff0OJsll1ePr6EUHxuOby3kTfbvfft18ig9fdp835SFWaZaEGGSmRJo3LUcluESQqVwmJ5qcpbCstpAMBXLeSZUlBW1pIyRjLEWVC4CO30Tvz7rLEH6d0Id60F6hMcsP7cnXjGeCF4VgxYLSM6qc9d5hV09OD-DmmtF6tat-sKve7JesXu1aSt5d1E_NgO1jwX9_FuD-DBx9gJ_4CIALWhm8KOZ5LdbtSfkJ6MHVOPJ_sims4A</recordid><startdate>2013</startdate><enddate>2013</enddate><creator>Daida, Hiroyuki</creator><creator>Iwase, Takayuki</creator><creator>Yagi, Shigeru</creator><creator>Ando, Hidekazu</creator><creator>Nakajima, Hiromu</creator><general>The Japanese Circulation Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>2013</creationdate><title>Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a PLA2G7 Gene Polymorphism of Val279Phe</title><author>Daida, Hiroyuki ; Iwase, Takayuki ; Yagi, Shigeru ; Ando, Hidekazu ; Nakajima, Hiromu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c452t-a95c647bd3ec639ea9491256b714a14ad891e6e33f9c5280d0b691114ec76aaf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>1-Alkyl-2-acetylglycerophosphocholine Esterase</topic><topic>Adult</topic><topic>Aged, 80 and over</topic><topic>Amino Acid Substitution</topic><topic>Asian Continental Ancestry Group</topic><topic>Atherosclerosis</topic><topic>Benzaldehydes - administration &amp; dosage</topic><topic>Benzaldehydes - adverse effects</topic><topic>Darapladib</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Dyslipidemia</topic><topic>Dyslipidemias - drug therapy</topic><topic>Dyslipidemias - enzymology</topic><topic>Dyslipidemias - genetics</topic><topic>Female</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration &amp; dosage</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects</topic><topic>Japan</topic><topic>Lipoprotein-associated phospholipase A2</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation, Missense</topic><topic>Oximes - administration &amp; dosage</topic><topic>Oximes - adverse effects</topic><topic>Phospholipase A2 Inhibitors - administration &amp; dosage</topic><topic>Phospholipase A2 Inhibitors - adverse effects</topic><topic>Phospholipases A2 - blood</topic><topic>Phospholipases A2 - genetics</topic><topic>Polymorphism, Single Nucleotide</topic><topic>V279F</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Daida, Hiroyuki</creatorcontrib><creatorcontrib>Iwase, Takayuki</creatorcontrib><creatorcontrib>Yagi, Shigeru</creatorcontrib><creatorcontrib>Ando, Hidekazu</creatorcontrib><creatorcontrib>Nakajima, Hiromu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation Journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Daida, Hiroyuki</au><au>Iwase, Takayuki</au><au>Yagi, Shigeru</au><au>Ando, Hidekazu</au><au>Nakajima, Hiromu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a PLA2G7 Gene Polymorphism of Val279Phe</atitle><jtitle>Circulation Journal</jtitle><addtitle>Circ J</addtitle><date>2013</date><risdate>2013</risdate><volume>77</volume><issue>6</issue><spage>1518</spage><epage>1525</epage><pages>1518-1525</pages><issn>1346-9843</issn><eissn>1347-4820</eissn><abstract>Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed. Methods and Results: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40mg (n=28), 80mg (n=28), or 160mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P&lt;0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted. Conclusions: Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA  (Circ J 2013; 77: 1518–1525)2.</abstract><cop>Japan</cop><pub>The Japanese Circulation Society</pub><pmid>23439604</pmid><doi>10.1253/circj.CJ-12-0813</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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subjects 1-Alkyl-2-acetylglycerophosphocholine Esterase
Adult
Aged, 80 and over
Amino Acid Substitution
Asian Continental Ancestry Group
Atherosclerosis
Benzaldehydes - administration & dosage
Benzaldehydes - adverse effects
Darapladib
Dose-Response Relationship, Drug
Double-Blind Method
Dyslipidemia
Dyslipidemias - drug therapy
Dyslipidemias - enzymology
Dyslipidemias - genetics
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage
Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects
Japan
Lipoprotein-associated phospholipase A2
Male
Middle Aged
Mutation, Missense
Oximes - administration & dosage
Oximes - adverse effects
Phospholipase A2 Inhibitors - administration & dosage
Phospholipase A2 Inhibitors - adverse effects
Phospholipases A2 - blood
Phospholipases A2 - genetics
Polymorphism, Single Nucleotide
V279F
title Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a PLA2G7 Gene Polymorphism of Val279Phe
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