109 lines
41 KiB
Text
109 lines
41 KiB
Text
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" class="no-js no-jr">
|
|
<head>
|
|
<!-- For pinger, set start time and add meta elements. -->
|
|
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
|
|
|
<!-- Logger begin -->
|
|
<meta name="ncbi_db" content="books">
|
|
<meta name="ncbi_pdid" content="book-part">
|
|
<meta name="ncbi_acc" content="NBK547873">
|
|
<meta name="ncbi_domain" content="livertox">
|
|
<meta name="ncbi_report" content="reader">
|
|
<meta name="ncbi_type" content="fulltext">
|
|
<meta name="ncbi_objectid" content="">
|
|
<meta name="ncbi_pcid" content="/NBK547873/?report=reader">
|
|
<meta name="ncbi_pagename" content="Olaparib - LiverTox - NCBI Bookshelf">
|
|
<meta name="ncbi_bookparttype" content="chapter">
|
|
<meta name="ncbi_app" content="bookshelf">
|
|
<!-- Logger end -->
|
|
|
|
<!--component id="Page" label="meta"/-->
|
|
<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Olaparib - LiverTox - NCBI Bookshelf</title>
|
|
<meta charset="utf-8">
|
|
<meta name="apple-mobile-web-app-capable" content="no">
|
|
<meta name="viewport" content="initial-scale=1,minimum-scale=1,maximum-scale=1,user-scalable=no">
|
|
<meta name="jr-col-layout" content="auto">
|
|
<meta name="jr-prev-unit" content="/books/n/livertox/Olanzapine/?report=reader">
|
|
<meta name="jr-next-unit" content="/books/n/livertox/Olaratumab/?report=reader">
|
|
<meta name="bk-toc-url" content="/books/n/livertox/?report=toc">
|
|
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE">
|
|
<meta name="citation_inbook_title" content="LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]">
|
|
<meta name="citation_title" content="Olaparib">
|
|
<meta name="citation_publisher" content="National Institute of Diabetes and Digestive and Kidney Diseases">
|
|
<meta name="citation_date" content="2017/06/01">
|
|
<meta name="citation_pmid" content="31643209">
|
|
<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK547873/">
|
|
<link rel="schema.DC" href="http://purl.org/DC/elements/1.0/">
|
|
<meta name="DC.Title" content="Olaparib">
|
|
<meta name="DC.Type" content="Text">
|
|
<meta name="DC.Publisher" content="National Institute of Diabetes and Digestive and Kidney Diseases">
|
|
<meta name="DC.Date" content="2017/06/01">
|
|
<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK547873/">
|
|
<meta name="description" content="Olaparib is a small molecule inhibitor of poly ADP-ribose polymerase and is used as an antineoplastic agent in the therapy of refractory and advanced ovarian carcinoma. Olaparib therapy is associated with a low rate of transient elevations in serum aminotransferase during therapy and has not been linked to instances of clinically apparent liver injury.">
|
|
<meta name="og:title" content="Olaparib">
|
|
<meta name="og:type" content="book">
|
|
<meta name="og:description" content="Olaparib is a small molecule inhibitor of poly ADP-ribose polymerase and is used as an antineoplastic agent in the therapy of refractory and advanced ovarian carcinoma. Olaparib therapy is associated with a low rate of transient elevations in serum aminotransferase during therapy and has not been linked to instances of clinically apparent liver injury.">
|
|
<meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK547873/">
|
|
<meta name="og:site_name" content="NCBI Bookshelf">
|
|
<meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-livertox-lrg.png">
|
|
<meta name="twitter:card" content="summary">
|
|
<meta name="twitter:site" content="@ncbibooks">
|
|
<meta name="bk-non-canon-loc" content="/books/n/livertox/Olaparib/?report=reader">
|
|
<link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK547873/">
|
|
<link href="https://fonts.googleapis.com/css?family=Archivo+Narrow:400,700,400italic,700italic&subset=latin" rel="stylesheet" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/libs.min.css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/jr.min.css">
|
|
<meta name="format-detection" content="telephone=no">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css//books_print.min.css" type="text/css" media="print">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_reader.min.css" type="text/css">
|
|
<style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style>
|
|
|
|
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico">
|
|
<meta name="ncbi_phid" content="CE8E1B7C7D7E644100000000007F0068.m_5">
|
|
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3849091.css"></head>
|
|
<body>
|
|
<!-- Book content! -->
|
|
|
|
|
|
<div id="jr" data-jr-path="/corehtml/pmc/jatsreader/ptpmc_3.22/"><div class="jr-unsupported"><table class="modal"><tr><td><span class="attn inline-block"></span><br />Your browser does not support the NLM PubReader view.<br />Go to <a href="/pmc/about/pr-browsers/">this page</a> to see a list of supported browsers<br />or return to the <br /><a href="/books/NBK547873/?report=classic">regular view</a>.</td></tr></table></div><div id="jr-ui" class="hidden"><nav id="jr-head"><div class="flexh tb"><div id="jr-tb1"><a id="jr-links-sw" class="hidden" title="Links"><svg xmlns="http://www.w3.org/2000/svg" version="1.1" x="0px" y="0px" viewBox="0 0 70.6 85.3" style="enable-background:new 0 0 70.6 85.3;vertical-align:middle" xml:space="preserve" width="24" height="24">
|
|
<style type="text/css">.st0{fill:#939598;}</style>
|
|
<g>
|
|
<path class="st0" d="M36,0C12.8,2.2-22.4,14.6,19.6,32.5C40.7,41.4-30.6,14,35.9,9.8"></path>
|
|
<path class="st0" d="M34.5,85.3c23.2-2.2,58.4-14.6,16.4-32.5c-21.1-8.9,50.2,18.5-16.3,22.7"></path>
|
|
<path class="st0" d="M34.7,37.1c66.5-4.2-4.8-31.6,16.3-22.7c42.1,17.9,6.9,30.3-16.4,32.5h1.7c-66.2,4.4,4.8,31.6-16.3,22.7 c-42.1-17.9-6.9-30.3,16.4-32.5"></path>
|
|
</g>
|
|
</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"><a href="/books/n/livertox/Olanzapine/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="body"><div class="t">Olaparib</div><div class="j">LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]</div></div><div class="tail"><a href="/books/n/livertox/Olaratumab/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 h-55.484l-10.662,29.981c-4.065,11.431-12.794,20.627-24.001,25.274c-0.005,0.002-0.009,0.004-0.014,0.005 c-11.235,4.66-23.919,4.333-34.905-0.889l-28.723-13.653l-39.234,39.234l13.653,28.721c5.219,10.979,5.545,23.681,0.889,34.91 c-0.002,0.004-0.004,0.009-0.006,0.013c-4.649,11.214-13.834,19.931-25.271,23.998L50,228.257v55.485l29.98,10.661 c11.431,4.065,20.627,12.794,25.274,24c0.002,0.005,0.003,0.01,0.005,0.014c4.66,11.236,4.334,23.921-0.888,34.906l-13.654,28.723 l39.234,39.234l28.721-13.652c10.979-5.219,23.681-5.546,34.909-0.889c0.005,0.002,0.01,0.004,0.014,0.006 c11.214,4.649,19.93,13.833,23.998,25.271L228.257,462h55.484l10.595-29.79c4.103-11.538,12.908-20.824,24.216-25.525 c0.005-0.002,0.009-0.004,0.014-0.006c11.127-4.628,23.694-4.311,34.578,0.863l28.902,13.738l39.234-39.234l-13.66-28.737 c-5.214-10.969-5.539-23.659-0.886-34.877c0.002-0.005,0.004-0.009,0.006-0.014c4.654-11.225,13.848-19.949,25.297-24.021 L462,283.742z M256,331.546c-41.724,0-75.548-33.823-75.548-75.546s33.824-75.547,75.548-75.547 c41.723,0,75.546,33.824,75.546,75.547S297.723,331.546,256,331.546z"></path></svg></a><a id="jr-fip-sw" class="btn wsprkl hidden" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-rtoc-sw" class="btn wsprkl hidden" title="Table of Contents"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,20h10v8H20V20zM36,20h44v8H36V20zM20,37.33h10v8H20V37.33zM36,37.33h44v8H36V37.33zM20,54.66h10v8H20V54.66zM36,54.66h44v8H36V54.66zM20,72h10v8 H20V72zM36,72h44v8H36V72z"></path></svg></a></div></div></nav><nav id="jr-dash" class="noselect"><nav id="jr-dash" class="noselect"><div id="jr-pi" class="hidden"><a id="jr-pi-prev" class="hidden" title="Previous page"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a><div class="pginfo">Page <i class="jr-pg-pn">0</i> of <i class="jr-pg-lp">0</i></div><a id="jr-pi-next" class="hidden" title="Next page"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div><div id="jr-is-tb"><a id="jr-is-sw" class="btn wsprkl hidden" title="Switch between Figures/Tables strip and Progress bar"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><rect x="10" y="40" width="20" height="20"></rect><rect x="40" y="40" width="20" height="20"></rect><rect x="70" y="40" width="20" height="20"></rect></svg></a></div><nav id="jr-istrip" class="istrip hidden"><a id="jr-is-prev" href="#" class="hidden" title="Previous"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M80,40 60,65 80,90 70,90 50,65 70,40z M50,40 30,65 50,90 40,90 20,65 40,40z"></path><text x="35" y="25" textLength="60" style="font-size:25px">Prev</text></svg></a><a id="jr-is-next" href="#" class="hidden" title="Next"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,40 40,65 20,90 30,90 50,65 30,40z M50,40 70,65 50,90 60,90 80,65 60,40z"></path><text x="15" y="25" textLength="60" style="font-size:25px">Next</text></svg></a></nav><nav id="jr-progress"></nav></nav></nav><aside id="jr-links-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">NCBI Bookshelf</div></div><div class="cnt lol f1"><a href="/books/">Home</a><a href="/books/browse/">Browse All Titles</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://www.facebook.com/sharer/sharer.php?u=https://www.ncbi.nlm.nih.gov/books/NBK547873/"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24" preserveAspectRatio="none"><g><path d="M 17.996,32L 12,32 L 12,16 l-4,0 l0-5.514 l 4-0.002l-0.006-3.248C 11.993,2.737, 13.213,0, 18.512,0l 4.412,0 l0,5.515 l-2.757,0 c-2.063,0-2.163,0.77-2.163,2.209l-0.008,2.76l 4.959,0 l-0.585,5.514L 18,16L 17.996,32z"></path></g></svg> Share on Facebook</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://twitter.com/intent/tweet?url=https://www.ncbi.nlm.nih.gov/books/NBK547873/&text=Olaparib"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24"><g><path d="M 32,6.076c-1.177,0.522-2.443,0.875-3.771,1.034c 1.355-0.813, 2.396-2.099, 2.887-3.632 c-1.269,0.752-2.674,1.299-4.169,1.593c-1.198-1.276-2.904-2.073-4.792-2.073c-3.626,0-6.565,2.939-6.565,6.565 c0,0.515, 0.058,1.016, 0.17,1.496c-5.456-0.274-10.294-2.888-13.532-6.86c-0.565,0.97-0.889,2.097-0.889,3.301 c0,2.278, 1.159,4.287, 2.921,5.465c-1.076-0.034-2.088-0.329-2.974-0.821c-0.001,0.027-0.001,0.055-0.001,0.083 c0,3.181, 2.263,5.834, 5.266,6.438c-0.551,0.15-1.131,0.23-1.73,0.23c-0.423,0-0.834-0.041-1.235-0.118 c 0.836,2.608, 3.26,4.506, 6.133,4.559c-2.247,1.761-5.078,2.81-8.154,2.81c-0.53,0-1.052-0.031-1.566-0.092 c 2.905,1.863, 6.356,2.95, 10.064,2.95c 12.076,0, 18.679-10.004, 18.679-18.68c0-0.285-0.006-0.568-0.019-0.849 C 30.007,8.548, 31.12,7.392, 32,6.076z"></path></g></svg> Share on Twitter</a></div></aside><aside id="jr-rtoc-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Table of Content</div></div><div class="cnt lol f1"><a href="/books/n/livertox/?report=reader">Title Information</a><a href="/books/n/livertox/toc/?report=reader">Table of Contents Page</a></div></aside><aside id="jr-help-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Settings</div></div><div class="cnt f1"><div id="jr-typo-p" class="typo"><div><a class="sf btn wsprkl">A-</a><a class="lf btn wsprkl">A+</a></div><div><a class="bcol-auto btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 200 100" preserveAspectRatio="none"><text x="10" y="70" style="font-size:60px;font-family: Trebuchet MS, ArialMT, Arial, sans-serif" textLength="180">AUTO</text></svg></a><a class="bcol-1 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M15,25 85,25zM15,40 85,40zM15,55 85,55zM15,70 85,70z"></path></svg></a><a class="bcol-2 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M5,25 45,25z M55,25 95,25zM5,40 45,40z M55,40 95,40zM5,55 45,55z M55,55 95,55zM5,70 45,70z M55,70 95,70z"></path></svg></a></div></div><div class="lol"><a class="" href="/books/NBK547873/?report=classic">Switch to classic view</a><a href="/books/NBK547873/pdf/Bookshelf_NBK547873.pdf">PDF (115K)</a><a href="/books/NBK547873/?report=printable">Print View</a></div></div></aside><aside id="jr-bkhelp-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Help</div></div><div class="cnt f1 lol"><a id="jr-helpobj-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/help.xml" href="">Help</a><a href="mailto:info@ncbi.nlm.nih.gov?subject=PubReader%20feedback%20%2F%20NBK547873%20%2F%20sid%3ACE8B5AF87C7FFCB1_0191SID%20%2F%20phid%3ACE8E1B7C7D7E644100000000007F0068.4">Send us feedback</a><a id="jr-about-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/about.xml" href="">About PubReader</a></div></aside><aside id="jr-objectbox" class="thidden hidden"><div class="jr-objectbox-close wsprkl">✘</div><div class="jr-objectbox-inner cnt"><div class="jr-objectbox-drawer"></div></div></aside><nav id="jr-pm-left" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Previous Page</text></svg></nav><nav id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK547873_"><span class="title" itemprop="name">Olaparib</span></h1><p class="fm-aai"><a href="#_NBK547873_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="Olaparib.OVERVIEW"><h2 id="_Olaparib_OVERVIEW_">OVERVIEW</h2><div id="Olaparib.Introduction"><h3>Introduction</h3><p>Olaparib is a small molecule inhibitor of poly ADP-ribose polymerase and is used as an antineoplastic agent in the therapy of refractory and advanced ovarian carcinoma. Olaparib therapy is associated with a low rate of transient elevations in serum aminotransferase during therapy and has not been linked to instances of clinically apparent liver injury.</p></div><div id="Olaparib.Background"><h3>Background</h3><p>Olaparib (oh lap' a rib) is a small molecule inhibitor of poly adenine diphosphate (ADP)-ribose polymerase (PARP), an enzyme involved in DNA transcription and repair. Patients with mutations of the BRCA 1 and 2 genes are at increased risk for cancer, particularly ovarian and breast cancer in women. The BRCA gene encodes DNA repair enzymes, and tumor cells with BRCA mutations are dependent upon other DNA repair pathways and thus have an increased sensitivity to inhibition of PARP. Clinical trials of olaparib in women with BRCA 1 and 2 germline mutations and advanced, refractory ovarian carcinoma have shown response rates of 30% to 40% and prolongation of progression-free survival. Olaparib is also under evaluation as therapy for advanced breast cancer and other malignant diseases associated mutations in BRCA or other DNA repair enzymes. Olaparib received approval for use in the United States in 2014 for therapy of advanced and refractory ovarian carcinoma in women with BRAC 1 and 2 mutations. Olaparib is available in 50 mg capsules under the brand name Lynparza. The recommended dose is 400 mg by mouth twice daily. Lower doses are recommended for patients with renal impairment. Common side effects include anemia, fatigue, nausea, diarrhea, dyspepsia, abdominal pain, anorexia, cough, muscle and join pain, headache and rash. Uncommon, but potentially severe side effects include pneumonitis, myelodysplastic syndrome and embryo-fetal toxicity.</p></div><div id="Olaparib.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>In large clinical trials of olaparib, abnormalities in routine liver tests were uncommon with serum aminotransferase elevations occurring in 4% of patients and values above 5 times the upper limit of normal (ULN) in 1% or less. In trials of olaparib in patients with various advanced solid tumors there were no reports of hepatitis with jaundice or liver failure. Subsequent to its approval and more widescale use, there have been no published reports of clinically apparent liver injury attributed to olaparib.</p><p>Likelihood score: E (unlikely cause of clinically apparent liver injury).</p></div><div id="Olaparib.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>The mechanism of injury accounting for serum enzyme elevations during olaparib therapy is not known. Olaparib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. Because it is a substrate for CYP 3A4, olaparib is susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 3A activity.</p></div><div id="Olaparib.Outcome_and_Management"><h3>Outcome and Management</h3><p>Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) during olaparib therapy should lead to dose reduction or temporary cessation. There does not appear to be cross reactivity in risk for hepatic injury between olaparib and other PARP inhibitors such as rucaparib.</p><p>Drug Class: <a href="/books/n/livertox/AntineoplasticAgents/?report=reader">Antineoplastic Agents</a>, <a href="/books/n/livertox/ProteinKinaseInhibit/?report=reader">Protein Kinase Inhibitors</a></p><p>Other PARP Drugs: Niraparib, <a href="/books/n/livertox/Rucaparib/?report=reader">Rucaparib</a></p></div></div><div id="Olaparib.PRODUCT_INFORMATION"><h2 id="_Olaparib_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><div id="Olaparib.BPI" class="box boxed-text-box whole_rhythm hide-overflow"><p>
|
|
<b>REPRESENTATIVE TRADE NAMES</b>
|
|
</p><p>Olaparib – Lynparza®</p><p>
|
|
<b>DRUG CLASS</b>
|
|
</p><p>Antineoplastic Agents</p><p>
|
|
<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?label=all&query=Olaparib" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COMPLETE LABELING</a>
|
|
</p><p>Product labeling at DailyMed, National Library of Medicine, NIH</p></div></div><div id="Olaparib.CHEMICAL_FORMULA_AND_STRUCTURE"><h2 id="_Olaparib_CHEMICAL_FORMULA_AND_STRUCTURE_">CHEMICAL FORMULA AND STRUCTURE</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figOlaparibT1"><a href="/books/NBK547873/table/Olaparib.T1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figOlaparibT1" rid-ob="figobOlaparibT1"><img class="small-thumb" src="/books/NBK547873/table/Olaparib.T1/?report=thumb" src-large="/books/NBK547873/table/Olaparib.T1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="Olaparib.T1"><a href="/books/NBK547873/table/Olaparib.T1/?report=objectonly" target="object" rid-ob="figobOlaparibT1">Table</a></h4></div></div></div><div id="Olaparib.ANNOTATED_BIBLIOGRAPHY"><h2 id="_Olaparib_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 01 June 2017</p><p>Abbreviations used: PARP, poly adenine diphosphate-ribose polymerase</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Olaparib.R1">Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.<div><i>(Review of hepatotoxicity published in 1999 before the availability of protein kinase or PARP inhibitors such as olaparib).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R2">DeLeve LD. Kinase inhibitors. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.<div><i>(Review of hepatotoxicity of cancer chemotherapeutic agents discusses several kinase inhibitors including gefitinib, erlotinib and crizotinib, but not the PARP inhibitors such as olaparib).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R3">Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.<div><i>(Textbook of pharmacology and therapeutics).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R4">Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010; 376 (9737): 245-51. [<a href="https://pubmed.ncbi.nlm.nih.gov/20609468" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20609468</span></a>]<div><i>(Among 57 women with BRAC 1 or 2 mutations and advanced, refractory ovarian carcinoma treated with 400 vs 100 mg of olaparib twice daily, objective response rates were 33% vs 13%, while dose interruptions and reductions for adverse events were more frequent with the higher dose; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R5">Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010; 376 (9737): 235-44. [<a href="https://pubmed.ncbi.nlm.nih.gov/20609467" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20609467</span></a>]<div><i>(Among 54 women with BRCA 1 or 2 mutations and advanced, refractory breast cancer treated with 400 vs 100 mg of olaparib twice daily, objective response rates were 41% and 22%, while dose interruptions and reductions for adverse events were more frequent with the higher dose; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R6">Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12: 852-61. [<a href="https://pubmed.ncbi.nlm.nih.gov/21862407" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21862407</span></a>]<div><i>(In an open label trial of olaparib [400 mg twice daily] in women with advanced ovarian or breast cancer, objective responses occurred in 18 of 63 [29%] women with ovarian carcinoma, but none of 26 with breast cancer; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R7">Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012; 366: 1382-92. [<a href="https://pubmed.ncbi.nlm.nih.gov/22452356" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22452356</span></a>]<div><i>(Among 265 women with advanced ovarian cancer who had a partial or complete response to platinum based chemotherapy, progression free survival was higher with olaparib than placebo [8.4 vs 4.8 months], and adverse events included nausea [68% vs 35%], fatigue [49% vs 38%] and anemia [17% vs 5%], and "there were no unexpected changes in biochemical laboratory measurements").</i></div></div></li><li><div class="bk_ref" id="Olaparib.R8">Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 2012; 30: 372-9. [<a href="https://pubmed.ncbi.nlm.nih.gov/22203755" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22203755</span></a>]<div><i>(Among 97 women with BRCA 1 or 2 mutations and advanced ovarian cancer treated with olaparib [200 or 400 mg twice daily] or doxorubicin [intravenously every 28 days], progression free survival was similar in all 3 groups and specific adverse events were not mentioned).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R9">Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012; 483 (7391): 570-5. [<a href="/pmc/articles/PMC3349233/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3349233</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22460902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22460902</span></a>]<div><i>(Correlation of mutated cancer genes identified in cancer cell lines with their sensitivity to growth inhibition by antineoplastic agents revealed the possible role of PARP inhibition in several tumors including Ewing sarcoma).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R10">Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomized phase 2 trial. Lancet Oncol 2014; 15: 852-61. [<a href="https://pubmed.ncbi.nlm.nih.gov/24882434" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24882434</span></a>]<div><i>(Among 265 women with BRCA 1 or 2 mutations and relapsed, platinum-sensitive ovarian cancer treated with olaparib or placebo [Ledermann 2012], further follow up showed prolongation of progression free, but not overall survival with olaparib therapy and adverse events were similar to those previously reported).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R11">Ledford H. Resurrected cancer drug faces regulators. Nature 2014; 510 (7506): 454. [<a href="https://pubmed.ncbi.nlm.nih.gov/24965630" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24965630</span></a>]<div><i>(News report on olaparib, the initial PARP inhibitor, which in early clinical trials showed little effect on survival in women with ovarian carcinoma, but on reassessment limiting analysis to cases with BRCA mutations found evidence of an effect on cancer growth, reviving interest in pursuing olaparib as therapy of selected patients with ovarian cancer).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R12">Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244-50. [<a href="/pmc/articles/PMC6057749/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6057749</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25366685" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25366685</span></a>]<div><i>(Among 298 patients with refractory advanced cancers and BRCA 1 or 2 mutations treated with olaparib [400 mg twice daily], the overall objective response rate was 26% and was higher in women with ovarian [31%] than breast cancer [13%]; there were no liver related serious adverse events).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R13">Gunderson CC, Moore KN. Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Future Oncol 2015; 11: 747-57. [<a href="https://pubmed.ncbi.nlm.nih.gov/25757679" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25757679</span></a>]<div><i>(Review of the development, mechanism of action, clinical efficacy and safety of olaparib in ovarian cancer; mentions that the most frequent adverse events are gastrointestinal toxicity and myelosuppression; no mention of ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R14">Bao Z, Cao C, Geng X, Tian B, Wu Y, Zhang C, Chen Z, Li W, et al. Effectiveness and safety of poly (ADP-ribose) polymerase inhibitors in cancer therapy: A systematic review and meta-analysis. Oncotarget 2016; 7: 7629-39. [<a href="/pmc/articles/PMC4884943/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4884943</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26399274" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26399274</span></a>]<div><i>(Systematic review of the efficacy and safety of PARP inhibitors in cancer chemotherapy mentioned that in 5 placebo controlled trials, ALT elevations were no more frequent with the PARP inhibitors than in “controls”, but neither were any other adverse events).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R15">Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer 2016; 115: 1157-73. [<a href="/pmc/articles/PMC5104889/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5104889</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27736844" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27736844</span></a>]<div><i>(Review of role of BRCA 1 and 2 mutations in tumorigenesis and the mechanism of action of PARP inhibitors).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R16">Ledermann JA. PARP inhibitors in ovarian cancer. Ann Oncol 2016; 27 Suppl 1: i40-i44. [<a href="https://pubmed.ncbi.nlm.nih.gov/27141070" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27141070</span></a>]<div><i>(Review of possible role of PARP inhibitors in ovarian cancer; mentions that cells with defective BRCA proteins are deficient in repair of double-stranded breaks in DNA by homologous recombination and rely on other pathways, notably PARP that detects single DNA strand breaks and activates effector proteins to initiate repair).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R17">Ledermann JA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol 2016; 17: 1579-89. [<a href="https://pubmed.ncbi.nlm.nih.gov/27617661" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27617661</span></a>]<div><i>(Among 265 women with platinum-sensitive recurrent ovarian carcinoma treated with olaparib [400 mg twice daily] or placebo [Ledermann 2012], 5 year follow up showed little effect on median overall survival [29.8 vs 27.8 months]; there were no liver related severe adverse events requiring discontinuation).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R18">Olaparib (Lynparza) for advanced ovarian cancer. Med Lett Drugs Ther 2016; 58 (1489): e32-3. [<a href="https://pubmed.ncbi.nlm.nih.gov/26938702" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26938702</span></a>]<div><i>(Concise review of the mechanism of action, clinically efficacy, safety and costs of olaparib shortly after its approval in the US; does not mention ALT elevations or hepatotoxicity).</i></div></div></li><li><div class="bk_ref" id="Olaparib.R19">Domchek SM, Aghajanian C, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol 2016; 140: 199-203. [<a href="/pmc/articles/PMC4992984/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4992984</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26723501" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26723501</span></a>]<div><i>(Among 193 women with BRCA 1 or 2 mutations and advanced refractory ovarian cancer treated with olaparib [400 mg twice daily], 34% had an objective response and side effects were common, but only 3 patients [2%] developed ALT elevations above 5 times ULN and none had clinically apparent liver injury).</i></div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK547873_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">June 1, 2017</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="https://www.niddk.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Institute of Diabetes and Digestive and Kidney Diseases</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Olaparib. [Updated 2017 Jun 1].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/Olanzapine/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/livertox/Olaratumab/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="boxed-text" id="figobOlaparibBPI"><div id="Olaparib.BPI" class="box boxed-text-box whole_rhythm hide-overflow"><p>
|
|
<b>REPRESENTATIVE TRADE NAMES</b>
|
|
</p><p>Olaparib – Lynparza®</p><p>
|
|
<b>DRUG CLASS</b>
|
|
</p><p>Antineoplastic Agents</p><p>
|
|
<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?label=all&query=Olaparib" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COMPLETE LABELING</a>
|
|
</p><p>Product labeling at DailyMed, National Library of Medicine, NIH</p></div></article><article data-type="table-wrap" id="figobOlaparibT1"><div id="Olaparib.T1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547873/table/Olaparib.T1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Olaparib.T1_lrgtbl__"><table><thead><tr><th id="hd_h_Olaparib.T1_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">DRUG</th><th id="hd_h_Olaparib.T1_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">CAS REGISTRY NO.</th><th id="hd_h_Olaparib.T1_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_Olaparib.T1_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">STRUCTURE</th></tr></thead><tbody><tr><td headers="hd_h_Olaparib.T1_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Olaparib</td><td headers="hd_h_Olaparib.T1_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<b>
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/135261055" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">763113-22-0</a>
|
|
</b>
|
|
</td><td headers="hd_h_Olaparib.T1_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">C24-H23-F-N4-O3</td><td headers="hd_h_Olaparib.T1_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK547873/bin/Olaparib_structure.jpg" alt="Olaparib structure" /></div>
|
|
</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
|
|
|
|
|
|
|
|
|
|
<!-- Book content -->
|
|
|
|
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js"> </script>
|
|
|
|
|
|
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal107 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
|
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
|
|
|
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3968615.js" snapshot="books"></script></body>
|
|
</html>
|