Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin

<!DOCTYPE html>     <html class="no-js" lang="en">  <head> <title>Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin - NASA/ADS</title>  <link rel="apple-touch-icon" sizes="180x180" href="//styles/favicon/apple-touch-icon.png" /> <link rel="icon" type="image/png" sizes="32x32" href="//styles/favicon/favicon-32x32.png" /> <link rel="icon" type="image/png" sizes="16x16" href="//styles/favicon/favicon-16x16.png" /> <link rel="manifest" href="//styles/favicon/site.webmanifest" /> <link rel="mask-icon" href="//styles/favicon/safari-pinned-tab.svg" color="#5bbad5" /> <meta name="apple-mobile-web-app-title" content="NASA ADS" /> <meta name="application-name" content="NASA ADS" /> <meta name="msapplication-TileColor" content="#ffc40d" /> <meta name="theme-color" content="#ffffff" />  <link rel="stylesheet" href="/styles/css/styles.css"> <meta name="robots" content="noarchive"> <link rel="canonical" href="http://ui.adsabs.harvard.edu/abs/2005PNAS..102.5507T/abstract"/> <meta name="description" content="Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the 伪-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.">  <meta property="og:type" content="article"> <meta property="og:title" content="Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin"> <meta property="og:site_name" content="NASA/ADS"> <meta property="og:description" content="Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the 伪-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication."> <meta property="og:url" content="https://ui.adsabs.harvard.edu/abs/2005PNAS..102.5507T/abstract"> <meta property="og:image" content="https://ui.adsabs.harvard.edu/styles/img/transparent_logo.svg"> <meta property="article:published_time" content="04/2005"> <meta property="article:author" content="Tate, Sarah K."> <meta property="article:author" content="Depondt, Chantal"> <meta property="article:author" content="Sisodiya, Sanjay M."> <meta property="article:author" content="Cavalleri, Gianpiero L."> <meta property="article:author" content="Schorge, Stephanie"> <meta property="article:author" content="Soranzo, Nicole"> <meta property="article:author" content="Thom, Maria"> <meta property="article:author" content="Sen, Arjune"> <meta property="article:author" content="Shorvon, Simon D."> <meta property="article:author" content="Sander, Josemir W."> <meta property="article:author" content="Wood, Nicholas W."> <meta property="article:author" content="Goldstein, David B.">  <meta name="citation_journal_title" content="Proceedings of the National Academy of Science"> <meta name="citation_authors" content="Tate, Sarah K.;Depondt, Chantal;Sisodiya, Sanjay M.;Cavalleri, Gianpiero L.;Schorge, Stephanie;Soranzo, Nicole;Thom, Maria;Sen, Arjune;Shorvon, Simon D.;Sander, Josemir W.;Wood, Nicholas W.;Goldstein, David B."> <meta name="citation_title" content="Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin"> <meta name="citation_date" content="04/2005"> <meta name="citation_volume" content="102"> <meta name="citation_issue" content="15"> <meta name="citation_firstpage" content="5507"> <meta name="citation_doi" content="10.1073/pnas.0407346102"> <meta name="citation_issn" content="0027-8424"> <meta name="citation_language" content="en"> <meta name="citation_keywords" content="GENETICS"> <meta name="citation_abstract_html_url" content="https://ui.adsabs.harvard.edu/abs/2005PNAS..102.5507T/abstract"> <meta name="citation_publication_date" content="04/2005"> <meta name="citation_pdf_url" content="https://ui.adsabs.harvard.edu/link_gateway/2005PNAS..102.5507T/PUB_PDF"> <meta name="citation_lastpage" content="5512" /> <link title="schema(PRISM)" rel="schema.prism" href="http://prismstandard.org/namespaces/1.2/basic/" /> <meta name="prism.publicationDate" content="04/2005" /> <meta name="prism.publicationName" content="PNAS" /> <meta name="prism.issn" content="0027-8424" /> <meta name="prism.volume" content="102" /> <meta name="prism.startingPage" content="5507" /> <meta name="prism.endingPage" content="5512" /> <link title="schema(DC)" rel="schema.dc" href="http://purl.org/dc/elements/1.1/" /> <meta name="dc.identifier" content="doi:10.1073/pnas.0407346102" /> <meta name="dc.date" content="04/2005" /> <meta name="dc.source" content="PNAS" /> <meta name="dc.title" content="Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin" /> <meta name="dc.creator" content="Tate, Sarah K."> <meta name="dc.creator" content="Depondt, Chantal"> <meta name="dc.creator" content="Sisodiya, Sanjay M."> <meta name="dc.creator" content="Cavalleri, Gianpiero L."> <meta name="dc.creator" content="Schorge, Stephanie"> <meta name="dc.creator" content="Soranzo, Nicole"> <meta name="dc.creator" content="Thom, Maria"> <meta name="dc.creator" content="Sen, Arjune"> <meta name="dc.creator" content="Shorvon, Simon D."> <meta name="dc.creator" content="Sander, Josemir W."> <meta name="dc.creator" content="Wood, Nicholas W."> <meta name="dc.creator" content="Goldstein, David B.">  <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:description" content="Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the 伪-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. 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<li class="author"><a href="/search/?q=author%3A%22Goldstein%2C+David+B.%22">Goldstein, David B.</a> </li> </ul> </div> <div class="s-abstract-text"> <h4 class="sr-only">Abstract</h4> <p> Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the 伪-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication. </p> </div> <br> <dl class="s-abstract-dl-horizontal"> <dt>Publication:</dt> <dd> <div id="article-publication">Proceedings of the National Academy of Science</div> </dd> <dt>Pub Date:</dt> <dd>April 2005</dd> <dt>DOI:</dt> <dd> <span> <a href="/link_gateway/2005PNAS..102.5507T/doi:10.1073/pnas.0407346102" target="_blank" rel="noopener">10.1073/pnas.0407346102</a> <i class="fa fa-external-link"></i> </span> </dd> <dt>Bibcode:</dt> <dd> <a href="/abs/2005PNAS..102.5507T/abstract"> 2005PNAS..102.5507T </a> <i class="icon-help" title="The bibcode is assigned by the ADS as a unique identifier for the paper."></i> </dd> <dt>Keywords:</dt> <dd> <ul class="list-inline"> <li>GENETICS</li> </ul> </dd> </dl> </article> </div> <div data-widget="ShowCitations"></div> <div data-widget="ShowReferences"></div> <div data-widget="ShowCoreads"></div> <div data-widget="ShowSimilar"></div> <div data-widget="ShowTableofcontents"></div> <div data-widget="ShowGraphics"></div> <div data-widget="ShowExportcitation" data-origin="abstract"></div> <div data-widget="ShowMetrics" data-allow-redirect="false"></div> <div data-widget="MetaTagsWidget"></div> </div> </div> </div> <div class="s-right-col-container col-xs-12 col-sm-12 col-md-3 col-lg-2 s-right-column" id="right-col-container" > <div data-widget="ShowResources"> <div data-reactroot="" class="s-right-col-widget-container" style="padding: 10px" > <div> <div class="resources__container"> <div class="resources__full__list"> <div class="resources__header__row"> <i class="fa fa-file-text-o" aria-hidden="true"> </i> <div class="resources__header__title">full text sources</div> </div> <div class="resources__content"> <div class="resources__content__title">Publisher</div> <div class="resources__content__links"> <span> <a href="/link_gateway/2005PNAS..102.5507T/PUB_PDF" rel="noopener" class="resources__content__link " > <i class="fa fa-file-pdf-o" aria-hidden="true"> </i> </a> <div class="resources__content__link__separator">|</div> </span> <span> <a href="/link_gateway/2005PNAS..102.5507T/PUB_HTML" rel="noopener" class="resources__content__link " > <i class="fa fa-file-text" aria-hidden="true"> </i> </a> </span> </div> </div> </div> </div> <div data-widget="ShowAssociated"> </div> </div> </div> </div> <div data-widget="ShowGraphicsSidebar"> </div> </div> </div> </div> </div> </div> </div> <div id="footer-container"> <div data-widget="FooterWidget"> <div class="footer s-footer"> <footer> <div class="__footer_wrapper"> <div class="__footer_brand"> 漏 The SAO/NASA Astrophysics Data System <div class="__footer_brand_extra"> <p> <i class="fa fa-envelope"></i> adshelp[at]cfa.harvard.edu </p> <p> The ADS is operated by the Smithsonian Astrophysical Observatory under NASA Cooperative Agreement <em>NNX16AC86A</em> </p> </div> <div class="__footer_brand_logos"> <a href="http://www.nasa.gov" target="_blank" rel="noopener"> <img src="/styles/img/nasa.svg" alt="NASA logo" id="nasa-logo"> </a> <a href="http://www.si.edu" target="_blank" rel="noopener"> <img id="smithsonian-logo" src="/styles/img/smithsonian.svg" alt="Smithsonian logo"> </a> <a href="https://www.cfa.harvard.edu/" target="_blank" rel="noopener"> <img src="/styles/img/cfa.png" title="Harvard Center for Astrophysics logo" id="cfa-logo"> </a> </div> </div> <div class="__footer_list"> <div class="__footer_list_title"> Resources </div> <ul class="__footer_links"> <li> <a href="/about/" target="_blank" rel="noopener"> <i class="fa fa-question-circle"></i> About ADS </a> </li> <li> <a href="//ui.adsabs.harvard.edu/help/" target="_blank" rel="noopener"> <i class="fa fa-info-circle"></i> ADS Help </a> </li> <li> <a href="//ui.adsabs.harvard.edu/help/whats_new/" target="_blank" rel="noopener"> <i class="fa fa-bullhorn"></i> What's New </a> </li> <li> <a href="/about/careers/" target="_blank" rel="noopener"> <i class="fa fa-group"></i> Careers@ADS </a> </li> </ul> </div> <div class="__footer_list"> <div class="__footer_list_title"> Social </div> <ul class="__footer_links"> <li> <a href="//twitter.com/adsabs" target="_blank" rel="noopener"> <i class="fa fa-twitter"></i> @adsabs </a> </li> <li> <a href="//ui.adsabs.harvard.edu/blog/" target="_blank" rel="noopener"> <i class="fa fa-newspaper-o"></i> ADS Blog </a> </li> </ul> </div> <div class="__footer_list"> <div class="__footer_list_title"> Project </div> <ul class="__footer_links"> <li> <a href="/core/never">Switch to full ADS</a> </li> <li> <a href="https://adsisdownorjustme.herokuapp.com/" target="_blank" rel="noopener">Is ADS down? 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// close any list of autocomplete values closeAllLists(); if (!val) { return false;} val = val.split(/\s+/); val = val[val.length - 1]; if (!val) { return false;} currentFocus = -1; // Create a DIV element that will contain the items (values): a = document.createElement("DIV"); a.setAttribute("id", this.id + "autocomplete-list"); a.setAttribute("class", "autocomplete-items"); // Append the DIV element as a child of the autocomplete container: this.parentNode.appendChild(a); for (i = 0; i < autoValues.length; i++) { // Check if the item starts with the same letters as the text field value: if (autoValues[i].match.substr(0, val.length).toUpperCase() == val.toUpperCase()) { // Create a DIV element for each matching element: b = document.createElement("DIV"); b.innerHTML = autoValues[i].label; if ("desc" in autoValues[i]) { b.innerHTML += " <i>" + autoValues[i].desc + "</i>"; } if (autoValues[i].value.startsWith(autoValues[i].match) ) { b.innerHTML += " | <strong>" + autoValues[i].match.substr(0, val.length) + "</strong>"; b.innerHTML += autoValues[i].match.substr(val.length); } // Insert a input field that will hold the current array item's value: b.innerHTML += "<input type='hidden' value='" + autoValues[i].value + "'>"; // Listen to clicks on the item value (DIV element): b.addEventListener("click", function(e) { var terms = searchBox.value.split(/\s+/); // Remove the current part of the input used for matching terms.pop(); // Insert the value for the autocomplete text field: terms.push(this.getElementsByTagName("input")[0].value); searchBox.value = terms.join(" "); // Move cursor position inside quotes/parenthesis if needed searchBox.focus(); if (searchBox.value[searchBox.value.length-1] === '"' || searchBox.value[searchBox.value.length-1] === ')') { searchBox.setSelectionRange(searchBox.value.length-1, searchBox.value.length-1); } // Close the list of autocompleted values closeAllLists(); }); a.appendChild(b); } } if (a.children.length > 0) { // By default, enter will select the first entry currentFocus = 0; addActive(a.children); } }); /*execute a function presses a key on the keyboard:*/ searchBox.addEventListener("keydown", function(e) { var x = document.getElementById(this.id + "autocomplete-list"); if (x) x = x.getElementsByTagName("div"); if (e.keyCode == 40) { // If the arrow DOWN key is pressed, increase the currentFocus variable: currentFocus++; addActive(x); } else if (e.keyCode == 38) { //up // If the arrow UP key is pressed, decrease the currentFocus variable: currentFocus--; /*and and make the current item more visible:*/ addActive(x); } else if (e.keyCode == 13) { // If the ENTER key is pressed: if (currentFocus > -1) { // Prevent the form from being submitted: e.preventDefault(); // Simulate a click on the "active" item: if (x) x[currentFocus].click(); currentFocus = -1; } } }); function addActive(x) { // Classify an item as "active": if (!x) return false; // Remove the "active" class on all items: removeActive(x); if (currentFocus >= x.length) currentFocus = 0; if (currentFocus < 0) currentFocus = (x.length - 1); // Add class "autocomplete-active": x[currentFocus].classList.add("autocomplete-active"); } function removeActive(x) { // Remove the "active" class from all autocomplete items: for (var i = 0; i < x.length; i++) { x[i].classList.remove("autocomplete-active"); } } function closeAllLists(elmnt) { // Close all autocomplete lists in the document, except the one passed as an argument: var x = document.getElementsByClassName("autocomplete-items"); for (var i = 0; i < x.length; i++) { if (elmnt != x[i] && elmnt != searchBox) { x[i].parentNode.removeChild(x[i]); } } } // Any other clicks in the document: document.addEventListener("click", function (e) { closeAllLists(e.target); }); } var autoList = [ { value: 'author:""', label: 'Author', match: 'author:"' }, { value: 'author:"^"', label: 'First Author', match: 'first author' }, { value: 'author:"^"', label: 'First Author', match: 'author:"^' }, { value: 'bibcode:""', label: 'Bibcode', desc: 'e.g. bibcode:1989ApJ...342L..71R', match: 'bibcode:"' }, { value: 'bibstem:""', label: 'Publication', desc: 'e.g. bibstem:ApJ', match: 'bibstem:"' }, { value: 'bibstem:""', label: 'Publication', desc: 'e.g. bibstem:ApJ', match: 'publication (bibstem)' }, { value: 'arXiv:', label: 'arXiv ID', match: 'arxiv:' }, { value: 'doi:', label: 'DOI', match: 'doi:' }, { value: 'full:""', label: 'Full text search', desc: 'title, abstract, and body', match: 'full:' }, { value: 'full:""', label: 'Full text search', desc: 'title, abstract, and body', match: 'fulltext' }, { value: 'full:""', label: 'Full text search', desc: 'title, abstract, and body', match: 'text' }, { value: 'year:', label: 'Year', match: 'year' }, { value: 'year:1999-2005', label: 'Year Range', desc: 'e.g. 1999-2005', match: 'year range' }, { value: 'aff:""', label: 'Affiliation', match: 'aff:' }, { value: 'abs:""', label: 'Search abstract + title + keywords', match: 'abs:' }, { value: 'database:astronomy', label: 'Limit to papers in the astronomy database', match: 'database:astronomy' }, { value: 'database:physics', label: 'Limit to papers in the physics database', match: 'database:physics' }, { value: 'title:""', label: 'Title', match: 'title:"' }, { value: 'orcid:', label: 'ORCiD identifier', match: 'orcid:' }, { value: 'object:', label: 'SIMBAD object (e.g. object:LMC)', match: 'object:' }, { value: 'property:refereed', label: 'Limit to refereed', desc: '(property:refereed)', match: 'refereed' }, { value: 'property:refereed', label: 'Limit to refereed', desc: '(property:refereed)', match: 'property:refereed' }, { value: 'property:notrefereed', label: 'Limit to non-refereed', desc: '(property:notrefereed)', match: 'property:notrefereed' }, { value: 'property:notrefereed', label: 'Limit to non-refereed', desc: '(property:notrefereed)', match: 'notrefereed' }, { value: 'property:eprint', label: 'Limit to eprints', desc: '(property:eprint)', match: 'eprint' }, { value: 'property:eprint', label: 'Limit to eprints', desc: '(property:eprint)', match: 'property:eprint' }, { value: 'property:openaccess', label: 'Limit to open access', desc: '(property:openaccess)', match: 'property:openaccess' }, { value: 'property:openaccess', label: 'Limit to open access', desc: '(property:openaccess)', match: 'openaccess' }, { value: 'doctype:software', label: 'Limit to software', desc: '(doctype:software)', match: 'software' }, { value: 'doctype:software', label: 'Limit to software', desc: '(doctype:software)', match: 'doctype:software' }, { value: 'property:inproceedings', label: 'Limit to papers in conference proceedings', desc: '(property:inproceedings)', match: 'proceedings' }, { value: 'property:inproceedings', label: 'Limit to papers in conference proceedings', desc: '(property:inproceedings)', match: 'property:inproceedings' }, { value: 'citations()', label: 'Citations', desc: 'Get papers citing your search result set', match: 'citations(' }, { value: 'references()', label: 'References', desc: 'Get papers referenced by your search result set', match: 'references(' }, { value: 'trending()', label: 'Trending', desc: 'Get papers most read by users who recently read your search result set', match: 'trending(' }, { value: 'reviews()', label: 'Review Articles', desc: 'Get most relevant papers that cite your search result set', match: 'reviews(' }, { value: 'useful()', label: 'Useful', desc: 'Get papers most frequently cited by your search result set', match: 'useful(' }, { value: 'similar()', label: 'Similar', desc: 'Get papers that have similar full text to your search result set', match: 'similar(' }, ]; // initiate the autocomplete function on the "q" element, and pass along the operators array as possible autocomplete values: inputBox = document.getElementById("q") if (inputBox) { inputBox.focus() // autofucs inputBox.setSelectionRange(inputBox.value.length, inputBox.value.length); // bring cursor to the end autocomplete(inputBox, autoList); } </script> <script> (function() { // turn off no-js if we have javascript document.documentElement.className = document.documentElement.className.replace("no-js", "js"); function getCookie(cname) { var name = cname + "="; var decodedCookie = decodeURIComponent(document.cookie); var ca = decodedCookie.split(';'); for (var i = 0; i < ca.length; i++) { var c = ca[i]; while (c.charAt(0) == ' ') { c = c.substring(1); } if (c.indexOf(name) == 0) { return c.substring(name.length, c.length); } } return ""; } (function() { // looks for the cookie, and sets true if its 'always' const coreCookie = getCookie('core') === 'always'; // only load bumblebee if we detect the core cookie and we are on abstract page if (coreCookie || (!(/^\/abs\//.test(document.location.pathname)) && !coreCookie)) { return; 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Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin - NASA/ADS