CINXE.COM

<!DOCTYPE html> <html class="client-nojs vector-feature-language-in-header-enabled vector-feature-language-in-main-page-header-disabled vector-feature-page-tools-pinned-disabled vector-feature-toc-pinned-clientpref-1 vector-feature-main-menu-pinned-disabled vector-feature-limited-width-clientpref-1 vector-feature-limited-width-content-enabled vector-feature-custom-font-size-clientpref-1 vector-feature-appearance-pinned-clientpref-1 vector-feature-night-mode-enabled skin-theme-clientpref-day vector-sticky-header-enabled vector-toc-available" lang="en" dir="ltr"> <head> <meta charset="UTF-8"> <title>Additive effect - Wikipedia</title> <script>(function(){var className="client-js vector-feature-language-in-header-enabled vector-feature-language-in-main-page-header-disabled vector-feature-page-tools-pinned-disabled vector-feature-toc-pinned-clientpref-1 vector-feature-main-menu-pinned-disabled vector-feature-limited-width-clientpref-1 vector-feature-limited-width-content-enabled vector-feature-custom-font-size-clientpref-1 vector-feature-appearance-pinned-clientpref-1 vector-feature-night-mode-enabled skin-theme-clientpref-day vector-sticky-header-enabled vector-toc-available";var cookie=document.cookie.match(/(?:^|; )enwikimwclientpreferences=([^;]+)/);if(cookie){cookie[1].split('%2C').forEach(function(pref){className=className.replace(new RegExp('(^| )'+pref.replace(/-clientpref-\w+$|[^\w-]+/g,'')+'-clientpref-\\w+( |$)'),'$1'+pref+'$2');});}document.documentElement.className=className;}());RLCONF={"wgBreakFrames":false,"wgSeparatorTransformTable":["",""],"wgDigitTransformTable":["",""],"wgDefaultDateFormat":"dmy","wgMonthNames":["","January","February","March","April","May","June","July","August","September","October","November","December"],"wgRequestId":"a53dff83-5bd8-4428-b363-82b6815c6f4c","wgCanonicalNamespace":"","wgCanonicalSpecialPageName":false,"wgNamespaceNumber":0,"wgPageName":"Additive_effect","wgTitle":"Additive effect","wgCurRevisionId":1256458693,"wgRevisionId":1256458693,"wgArticleId":70103474,"wgIsArticle":true,"wgIsRedirect":false,"wgAction":"view","wgUserName":null,"wgUserGroups":["*"],"wgCategories":["All articles with unsourced statements","Articles with unsourced statements from May 2022","Pharmacology"],"wgPageViewLanguage":"en","wgPageContentLanguage":"en","wgPageContentModel":"wikitext","wgRelevantPageName":"Additive_effect","wgRelevantArticleId":70103474,"wgIsProbablyEditable":true,"wgRelevantPageIsProbablyEditable":true,"wgRestrictionEdit":[],"wgRestrictionMove":[],"wgRedirectedFrom":"Synergy_(pharmacology)","wgNoticeProject":"wikipedia","wgCiteReferencePreviewsActive":false,"wgFlaggedRevsParams":{"tags":{"status":{"levels":1}}},"wgMediaViewerOnClick":true,"wgMediaViewerEnabledByDefault":true,"wgPopupsFlags":0,"wgVisualEditor":{"pageLanguageCode":"en","pageLanguageDir":"ltr","pageVariantFallbacks":"en"},"wgMFDisplayWikibaseDescriptions":{"search":true,"watchlist":true,"tagline":false,"nearby":true},"wgWMESchemaEditAttemptStepOversample":false,"wgWMEPageLength":30000,"wgInternalRedirectTargetUrl":"/wiki/Additive_effect#Detection_of_synergy","wgEditSubmitButtonLabelPublish":true,"wgULSPosition":"interlanguage","wgULSisCompactLinksEnabled":false,"wgVector2022LanguageInHeader":true,"wgULSisLanguageSelectorEmpty":false,"wgWikibaseItemId":"Q112228119","wgCheckUserClientHintsHeadersJsApi":["brands","architecture","bitness","fullVersionList","mobile","model","platform","platformVersion"],"GEHomepageSuggestedEditsEnableTopics":true,"wgGETopicsMatchModeEnabled":false,"wgGELevelingUpEnabledForUser":false}; RLSTATE={"ext.globalCssJs.user.styles":"ready","site.styles":"ready","user.styles":"ready","ext.globalCssJs.user":"ready","user":"ready","user.options":"loading","ext.cite.styles":"ready","skins.vector.search.codex.styles":"ready","skins.vector.styles":"ready","skins.vector.icons":"ready","ext.wikimediamessages.styles":"ready","ext.visualEditor.desktopArticleTarget.noscript":"ready","ext.uls.interlanguage":"ready","wikibase.client.init":"ready"};RLPAGEMODULES=["mediawiki.action.view.redirect","ext.cite.ux-enhancements","site","mediawiki.page.ready","mediawiki.toc","skins.vector.js","ext.centralNotice.geoIP","ext.centralNotice.startUp","ext.gadget.ReferenceTooltips","ext.gadget.switcher","ext.urlShortener.toolbar","ext.centralauth.centralautologin","ext.popups","ext.visualEditor.desktopArticleTarget.init","ext.visualEditor.targetLoader","ext.echo.centralauth","ext.eventLogging","ext.wikimediaEvents","ext.navigationTiming","ext.uls.interface","ext.cx.eventlogging.campaigns","ext.cx.uls.quick.actions","wikibase.client.vector-2022","ext.checkUser.clientHints","ext.quicksurveys.init","ext.growthExperiments.SuggestedEditSession"];</script> <script>(RLQ=window.RLQ||[]).push(function(){mw.loader.impl(function(){return["user.options@12s5i",function($,jQuery,require,module){mw.user.tokens.set({"patrolToken":"+\\","watchToken":"+\\","csrfToken":"+\\"}); }];});});</script> <link rel="stylesheet" href="/w/load.php?lang=en&modules=ext.cite.styles%7Cext.uls.interlanguage%7Cext.visualEditor.desktopArticleTarget.noscript%7Cext.wikimediamessages.styles%7Cskins.vector.icons%2Cstyles%7Cskins.vector.search.codex.styles%7Cwikibase.client.init&only=styles&skin=vector-2022"> <script async="" src="/w/load.php?lang=en&modules=startup&only=scripts&raw=1&skin=vector-2022"></script> <meta name="ResourceLoaderDynamicStyles" content=""> <link rel="stylesheet" href="/w/load.php?lang=en&modules=site.styles&only=styles&skin=vector-2022"> <meta name="generator" content="MediaWiki 1.44.0-wmf.21"> <meta name="referrer" content="origin"> <meta name="referrer" content="origin-when-cross-origin"> <meta name="robots" content="max-image-preview:standard"> <meta name="format-detection" content="telephone=no"> <meta name="viewport" content="width=1120"> <meta property="og:title" content="Additive effect - Wikipedia"> <meta property="og:type" content="website"> <link rel="alternate" media="only screen and (max-width: 640px)" href="//en.m.wikipedia.org/wiki/Additive_effect#Detection_of_synergy"> <link rel="alternate" type="application/x-wiki" title="Edit this page" href="/w/index.php?title=Additive_effect&action=edit"> <link rel="apple-touch-icon" href="/static/apple-touch/wikipedia.png"> <link rel="icon" href="/static/favicon/wikipedia.ico"> <link rel="search" type="application/opensearchdescription+xml" href="/w/rest.php/v1/search" title="Wikipedia (en)"> <link rel="EditURI" type="application/rsd+xml" href="//en.wikipedia.org/w/api.php?action=rsd"> <link rel="canonical" href="https://en.wikipedia.org/wiki/Additive_effect#Detection_of_synergy"> <link rel="license" href="https://creativecommons.org/licenses/by-sa/4.0/deed.en"> <link rel="alternate" type="application/atom+xml" title="Wikipedia Atom feed" href="/w/index.php?title=Special:RecentChanges&feed=atom"> <link rel="dns-prefetch" href="//meta.wikimedia.org" /> <link rel="dns-prefetch" href="login.wikimedia.org"> </head> <body class="skin--responsive skin-vector skin-vector-search-vue mediawiki ltr sitedir-ltr mw-hide-empty-elt ns-0 ns-subject mw-editable page-Additive_effect rootpage-Additive_effect skin-vector-2022 action-view"><a class="mw-jump-link" href="#bodyContent">Jump to content</a> <div class="vector-header-container"> <header class="vector-header mw-header"> <div class="vector-header-start"> <nav class="vector-main-menu-landmark" aria-label="Site"> <div id="vector-main-menu-dropdown" class="vector-dropdown vector-main-menu-dropdown vector-button-flush-left vector-button-flush-right" title="Main menu" > <input type="checkbox" id="vector-main-menu-dropdown-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-vector-main-menu-dropdown" class="vector-dropdown-checkbox " aria-label="Main menu" > <label id="vector-main-menu-dropdown-label" for="vector-main-menu-dropdown-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only " aria-hidden="true" ><span class="vector-icon mw-ui-icon-menu mw-ui-icon-wikimedia-menu"></span> <span class="vector-dropdown-label-text">Main menu</span> </label> <div class="vector-dropdown-content"> <div id="vector-main-menu-unpinned-container" class="vector-unpinned-container"> <div id="vector-main-menu" class="vector-main-menu vector-pinnable-element"> <div class="vector-pinnable-header vector-main-menu-pinnable-header vector-pinnable-header-unpinned" data-feature-name="main-menu-pinned" data-pinnable-element-id="vector-main-menu" data-pinned-container-id="vector-main-menu-pinned-container" data-unpinned-container-id="vector-main-menu-unpinned-container" > <div class="vector-pinnable-header-label">Main menu</div> <button class="vector-pinnable-header-toggle-button vector-pinnable-header-pin-button" data-event-name="pinnable-header.vector-main-menu.pin">move to sidebar</button> <button class="vector-pinnable-header-toggle-button vector-pinnable-header-unpin-button" data-event-name="pinnable-header.vector-main-menu.unpin">hide</button> </div> <div id="p-navigation" class="vector-menu mw-portlet mw-portlet-navigation" > <div class="vector-menu-heading"> Navigation </div> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="n-mainpage-description" class="mw-list-item"><a href="/wiki/Main_Page" title="Visit the main page [z]" accesskey="z"><span>Main page</span></a></li><li id="n-contents" class="mw-list-item"><a href="/wiki/Wikipedia:Contents" title="Guides to browsing Wikipedia"><span>Contents</span></a></li><li id="n-currentevents" class="mw-list-item"><a href="/wiki/Portal:Current_events" title="Articles related to current events"><span>Current events</span></a></li><li id="n-randompage" class="mw-list-item"><a href="/wiki/Special:Random" title="Visit a randomly selected article [x]" accesskey="x"><span>Random article</span></a></li><li id="n-aboutsite" class="mw-list-item"><a href="/wiki/Wikipedia:About" title="Learn about Wikipedia and how it works"><span>About Wikipedia</span></a></li><li id="n-contactpage" class="mw-list-item"><a href="//en.wikipedia.org/wiki/Wikipedia:Contact_us" title="How to contact Wikipedia"><span>Contact us</span></a></li> </ul> </div> </div> <div id="p-interaction" class="vector-menu mw-portlet mw-portlet-interaction" > <div class="vector-menu-heading"> Contribute </div> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="n-help" class="mw-list-item"><a href="/wiki/Help:Contents" title="Guidance on how to use and edit Wikipedia"><span>Help</span></a></li><li id="n-introduction" class="mw-list-item"><a href="/wiki/Help:Introduction" title="Learn how to edit Wikipedia"><span>Learn to edit</span></a></li><li id="n-portal" class="mw-list-item"><a href="/wiki/Wikipedia:Community_portal" title="The hub for editors"><span>Community portal</span></a></li><li id="n-recentchanges" class="mw-list-item"><a href="/wiki/Special:RecentChanges" title="A list of recent changes to Wikipedia [r]" accesskey="r"><span>Recent changes</span></a></li><li id="n-upload" class="mw-list-item"><a href="/wiki/Wikipedia:File_upload_wizard" title="Add images or other media for use on Wikipedia"><span>Upload file</span></a></li><li id="n-specialpages" class="mw-list-item"><a href="/wiki/Special:SpecialPages"><span>Special pages</span></a></li> </ul> </div> </div> </div> </div> </div> </div> </nav> <a href="/wiki/Main_Page" class="mw-logo"> <img class="mw-logo-icon" src="/static/images/icons/wikipedia.png" alt="" aria-hidden="true" height="50" width="50"> <span class="mw-logo-container skin-invert"> <img class="mw-logo-wordmark" alt="Wikipedia" src="/static/images/mobile/copyright/wikipedia-wordmark-en.svg" style="width: 7.5em; height: 1.125em;"> <img class="mw-logo-tagline" alt="The Free Encyclopedia" src="/static/images/mobile/copyright/wikipedia-tagline-en.svg" width="117" height="13" style="width: 7.3125em; height: 0.8125em;"> </span> </a> </div> <div class="vector-header-end"> <div id="p-search" role="search" class="vector-search-box-vue vector-search-box-collapses vector-search-box-show-thumbnail vector-search-box-auto-expand-width vector-search-box"> <a href="/wiki/Special:Search" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only search-toggle" title="Search Wikipedia [f]" accesskey="f"><span class="vector-icon mw-ui-icon-search mw-ui-icon-wikimedia-search"></span> <span>Search</span> </a> <div class="vector-typeahead-search-container"> <div class="cdx-typeahead-search cdx-typeahead-search--show-thumbnail cdx-typeahead-search--auto-expand-width"> <form action="/w/index.php" id="searchform" class="cdx-search-input cdx-search-input--has-end-button"> <div id="simpleSearch" class="cdx-search-input__input-wrapper" data-search-loc="header-moved"> <div class="cdx-text-input cdx-text-input--has-start-icon"> <input class="cdx-text-input__input" type="search" name="search" placeholder="Search Wikipedia" aria-label="Search Wikipedia" autocapitalize="sentences" title="Search Wikipedia [f]" accesskey="f" id="searchInput" > <span class="cdx-text-input__icon cdx-text-input__start-icon"></span> </div> <input type="hidden" name="title" value="Special:Search"> </div> <button class="cdx-button cdx-search-input__end-button">Search</button> </form> </div> </div> </div> <nav class="vector-user-links vector-user-links-wide" aria-label="Personal tools"> <div class="vector-user-links-main"> <div id="p-vector-user-menu-preferences" class="vector-menu mw-portlet emptyPortlet" > <div class="vector-menu-content"> <ul class="vector-menu-content-list"> </ul> </div> </div> <div id="p-vector-user-menu-userpage" class="vector-menu mw-portlet emptyPortlet" > <div class="vector-menu-content"> <ul class="vector-menu-content-list"> </ul> </div> </div> <nav class="vector-appearance-landmark" aria-label="Appearance"> <div id="vector-appearance-dropdown" class="vector-dropdown " title="Change the appearance of the page's font size, width, and color" > <input type="checkbox" id="vector-appearance-dropdown-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-vector-appearance-dropdown" class="vector-dropdown-checkbox " aria-label="Appearance" > <label id="vector-appearance-dropdown-label" for="vector-appearance-dropdown-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only " aria-hidden="true" ><span class="vector-icon mw-ui-icon-appearance mw-ui-icon-wikimedia-appearance"></span> <span class="vector-dropdown-label-text">Appearance</span> </label> <div class="vector-dropdown-content"> <div id="vector-appearance-unpinned-container" class="vector-unpinned-container"> </div> </div> </div> </nav> <div id="p-vector-user-menu-notifications" class="vector-menu mw-portlet emptyPortlet" > <div class="vector-menu-content"> <ul class="vector-menu-content-list"> </ul> </div> </div> <div id="p-vector-user-menu-overflow" class="vector-menu mw-portlet" > <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="pt-sitesupport-2" class="user-links-collapsible-item mw-list-item user-links-collapsible-item"><a data-mw="interface" href="https://donate.wikimedia.org/?wmf_source=donate&wmf_medium=sidebar&wmf_campaign=en.wikipedia.org&uselang=en" class=""><span>Donate</span></a> </li> <li id="pt-createaccount-2" class="user-links-collapsible-item mw-list-item user-links-collapsible-item"><a data-mw="interface" href="/w/index.php?title=Special:CreateAccount&returnto=Additive+effect" title="You are encouraged to create an account and log in; however, it is not mandatory" class=""><span>Create account</span></a> </li> <li id="pt-login-2" class="user-links-collapsible-item mw-list-item user-links-collapsible-item"><a data-mw="interface" href="/w/index.php?title=Special:UserLogin&returnto=Additive+effect" title="You're encouraged to log in; however, it's not mandatory. [o]" accesskey="o" class=""><span>Log in</span></a> </li> </ul> </div> </div> </div> <div id="vector-user-links-dropdown" class="vector-dropdown vector-user-menu vector-button-flush-right vector-user-menu-logged-out" title="Log in and more options" > <input type="checkbox" id="vector-user-links-dropdown-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-vector-user-links-dropdown" class="vector-dropdown-checkbox " aria-label="Personal tools" > <label id="vector-user-links-dropdown-label" for="vector-user-links-dropdown-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only " aria-hidden="true" ><span class="vector-icon mw-ui-icon-ellipsis mw-ui-icon-wikimedia-ellipsis"></span> <span class="vector-dropdown-label-text">Personal tools</span> </label> <div class="vector-dropdown-content"> <div id="p-personal" class="vector-menu mw-portlet mw-portlet-personal user-links-collapsible-item" title="User menu" > <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="pt-sitesupport" class="user-links-collapsible-item mw-list-item"><a href="https://donate.wikimedia.org/?wmf_source=donate&wmf_medium=sidebar&wmf_campaign=en.wikipedia.org&uselang=en"><span>Donate</span></a></li><li id="pt-createaccount" class="user-links-collapsible-item mw-list-item"><a href="/w/index.php?title=Special:CreateAccount&returnto=Additive+effect" title="You are encouraged to create an account and log in; however, it is not mandatory"><span class="vector-icon mw-ui-icon-userAdd mw-ui-icon-wikimedia-userAdd"></span> <span>Create account</span></a></li><li id="pt-login" class="user-links-collapsible-item mw-list-item"><a href="/w/index.php?title=Special:UserLogin&returnto=Additive+effect" title="You're encouraged to log in; however, it's not mandatory. [o]" accesskey="o"><span class="vector-icon mw-ui-icon-logIn mw-ui-icon-wikimedia-logIn"></span> <span>Log in</span></a></li> </ul> </div> </div> <div id="p-user-menu-anon-editor" class="vector-menu mw-portlet mw-portlet-user-menu-anon-editor" > <div class="vector-menu-heading"> Pages for logged out editors <a href="/wiki/Help:Introduction" aria-label="Learn more about editing"><span>learn more</span></a> </div> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="pt-anoncontribs" class="mw-list-item"><a href="/wiki/Special:MyContributions" title="A list of edits made from this IP address [y]" accesskey="y"><span>Contributions</span></a></li><li id="pt-anontalk" class="mw-list-item"><a href="/wiki/Special:MyTalk" title="Discussion about edits from this IP address [n]" accesskey="n"><span>Talk</span></a></li> </ul> </div> </div> </div> </div> </nav> </div> </header> </div> <div class="mw-page-container"> <div class="mw-page-container-inner"> <div class="vector-sitenotice-container"> <div id="siteNotice"></div> </div> <div class="vector-column-start"> <div class="vector-main-menu-container"> <div id="mw-navigation"> <nav id="mw-panel" class="vector-main-menu-landmark" aria-label="Site"> <div id="vector-main-menu-pinned-container" class="vector-pinned-container"> </div> </nav> </div> </div> <div class="vector-sticky-pinned-container"> <nav id="mw-panel-toc" aria-label="Contents" data-event-name="ui.sidebar-toc" class="mw-table-of-contents-container vector-toc-landmark"> <div id="vector-toc-pinned-container" class="vector-pinned-container"> <div id="vector-toc" class="vector-toc vector-pinnable-element"> <div class="vector-pinnable-header vector-toc-pinnable-header vector-pinnable-header-pinned" data-feature-name="toc-pinned" data-pinnable-element-id="vector-toc" > <h2 class="vector-pinnable-header-label">Contents</h2> <button class="vector-pinnable-header-toggle-button vector-pinnable-header-pin-button" data-event-name="pinnable-header.vector-toc.pin">move to sidebar</button> <button class="vector-pinnable-header-toggle-button vector-pinnable-header-unpin-button" data-event-name="pinnable-header.vector-toc.unpin">hide</button> </div> <ul class="vector-toc-contents" id="mw-panel-toc-list"> <li id="toc-mw-content-text" class="vector-toc-list-item vector-toc-level-1"> <a href="#" class="vector-toc-link"> <div class="vector-toc-text">(Top)</div> </a> </li> <li id="toc-History" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#History"> <div class="vector-toc-text"> <span class="vector-toc-numb">1</span> <span>History</span> </div> </a> <ul id="toc-History-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Types_of_Additive_Effect" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Types_of_Additive_Effect"> <div class="vector-toc-text"> <span class="vector-toc-numb">2</span> <span>Types of Additive Effect</span> </div> </a> <button aria-controls="toc-Types_of_Additive_Effect-sublist" class="cdx-button cdx-button--weight-quiet cdx-button--icon-only vector-toc-toggle"> <span class="vector-icon mw-ui-icon-wikimedia-expand"></span> <span>Toggle Types of Additive Effect subsection</span> </button> <ul id="toc-Types_of_Additive_Effect-sublist" class="vector-toc-list"> <li id="toc-Equivalent_or_overlapping_actions" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Equivalent_or_overlapping_actions"> <div class="vector-toc-text"> <span class="vector-toc-numb">2.1</span> <span>Equivalent or overlapping actions</span> </div> </a> <ul id="toc-Equivalent_or_overlapping_actions-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Independent_actions" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Independent_actions"> <div class="vector-toc-text"> <span class="vector-toc-numb">2.2</span> <span>Independent actions</span> </div> </a> <ul id="toc-Independent_actions-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> <li id="toc-Common_misconceptions" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Common_misconceptions"> <div class="vector-toc-text"> <span class="vector-toc-numb">3</span> <span>Common misconceptions</span> </div> </a> <ul id="toc-Common_misconceptions-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Clinical_Significance" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Clinical_Significance"> <div class="vector-toc-text"> <span class="vector-toc-numb">4</span> <span>Clinical Significance</span> </div> </a> <button aria-controls="toc-Clinical_Significance-sublist" class="cdx-button cdx-button--weight-quiet cdx-button--icon-only vector-toc-toggle"> <span class="vector-icon mw-ui-icon-wikimedia-expand"></span> <span>Toggle Clinical Significance subsection</span> </button> <ul id="toc-Clinical_Significance-sublist" class="vector-toc-list"> <li id="toc-Detection_of_synergy" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Detection_of_synergy"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.1</span> <span>Detection of synergy</span> </div> </a> <ul id="toc-Detection_of_synergy-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Detection_of_antagonism" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Detection_of_antagonism"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.2</span> <span>Detection of antagonism</span> </div> </a> <ul id="toc-Detection_of_antagonism-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Combination_therapy" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Combination_therapy"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.3</span> <span>Combination therapy</span> </div> </a> <ul id="toc-Combination_therapy-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Optimal_dosing" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Optimal_dosing"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.4</span> <span>Optimal dosing</span> </div> </a> <ul id="toc-Optimal_dosing-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> <li id="toc-Adverse_Effects" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Adverse_Effects"> <div class="vector-toc-text"> <span class="vector-toc-numb">5</span> <span>Adverse Effects</span> </div> </a> <button aria-controls="toc-Adverse_Effects-sublist" class="cdx-button cdx-button--weight-quiet cdx-button--icon-only vector-toc-toggle"> <span class="vector-icon mw-ui-icon-wikimedia-expand"></span> <span>Toggle Adverse Effects subsection</span> </button> <ul id="toc-Adverse_Effects-sublist" class="vector-toc-list"> <li id="toc-ACEI_and_potassium-sparing_diuretics" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#ACEI_and_potassium-sparing_diuretics"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.1</span> <span>ACEI and potassium-sparing diuretics</span> </div> </a> <ul id="toc-ACEI_and_potassium-sparing_diuretics-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-NSAIDs_and_glucocorticoids" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#NSAIDs_and_glucocorticoids"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.2</span> <span>NSAIDs and glucocorticoids</span> </div> </a> <ul id="toc-NSAIDs_and_glucocorticoids-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> <li id="toc-See_also" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#See_also"> <div class="vector-toc-text"> <span class="vector-toc-numb">6</span> <span>See also</span> </div> </a> <ul id="toc-See_also-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-References" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#References"> <div class="vector-toc-text"> <span class="vector-toc-numb">7</span> <span>References</span> </div> </a> <ul id="toc-References-sublist" class="vector-toc-list"> </ul> </li> </ul> </div> </div> </nav> </div> </div> <div class="mw-content-container"> <main id="content" class="mw-body"> <header class="mw-body-header vector-page-titlebar"> <nav aria-label="Contents" class="vector-toc-landmark"> <div id="vector-page-titlebar-toc" class="vector-dropdown vector-page-titlebar-toc vector-button-flush-left" title="Table of Contents" > <input type="checkbox" id="vector-page-titlebar-toc-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-vector-page-titlebar-toc" class="vector-dropdown-checkbox " aria-label="Toggle the table of contents" > <label id="vector-page-titlebar-toc-label" for="vector-page-titlebar-toc-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only " aria-hidden="true" ><span class="vector-icon mw-ui-icon-listBullet mw-ui-icon-wikimedia-listBullet"></span> <span class="vector-dropdown-label-text">Toggle the table of contents</span> </label> <div class="vector-dropdown-content"> <div id="vector-page-titlebar-toc-unpinned-container" class="vector-unpinned-container"> </div> </div> </div> </nav> <h1 id="firstHeading" class="firstHeading mw-first-heading"><span class="mw-page-title-main">Additive effect</span></h1> <div id="p-lang-btn" class="vector-dropdown mw-portlet mw-portlet-lang" > <input type="checkbox" id="p-lang-btn-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-p-lang-btn" class="vector-dropdown-checkbox mw-interlanguage-selector" aria-label="Go to an article in another language. Available in 2 languages" > <label id="p-lang-btn-label" for="p-lang-btn-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--action-progressive mw-portlet-lang-heading-2" aria-hidden="true" ><span class="vector-icon mw-ui-icon-language-progressive mw-ui-icon-wikimedia-language-progressive"></span> <span class="vector-dropdown-label-text">2 languages</span> </label> <div class="vector-dropdown-content"> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li class="interlanguage-link interwiki-ar mw-list-item"><a href="https://ar.wikipedia.org/wiki/%D8%A3%D8%AB%D8%B1_%D9%85%D8%B6%D8%A7%D9%81" title="أثر مضاف – Arabic" lang="ar" hreflang="ar" data-title="أثر مضاف" data-language-autonym="العربية" data-language-local-name="Arabic" class="interlanguage-link-target"><span>العربية</span></a></li><li class="interlanguage-link interwiki-ru mw-list-item"><a href="https://ru.wikipedia.org/wiki/%D0%90%D0%B4%D0%B4%D0%B8%D1%82%D0%B8%D0%B2%D0%BD%D1%8B%D0%B9_%D1%8D%D1%84%D1%84%D0%B5%D0%BA%D1%82" title="Аддитивный эффект – Russian" lang="ru" hreflang="ru" data-title="Аддитивный эффект" data-language-autonym="Русский" data-language-local-name="Russian" class="interlanguage-link-target"><span>Русский</span></a></li> </ul> <div class="after-portlet after-portlet-lang"><span class="wb-langlinks-edit wb-langlinks-link"><a href="https://www.wikidata.org/wiki/Special:EntityPage/Q112228119#sitelinks-wikipedia" title="Edit interlanguage links" class="wbc-editpage">Edit links</a></span></div> </div> </div> </div> </header> <div class="vector-page-toolbar"> <div class="vector-page-toolbar-container"> <div id="left-navigation"> <nav aria-label="Namespaces"> <div id="p-associated-pages" class="vector-menu vector-menu-tabs mw-portlet mw-portlet-associated-pages" > <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="ca-nstab-main" class="selected vector-tab-noicon mw-list-item"><a href="/wiki/Additive_effect" title="View the content page [c]" accesskey="c"><span>Article</span></a></li><li id="ca-talk" class="vector-tab-noicon mw-list-item"><a href="/wiki/Talk:Additive_effect" rel="discussion" title="Discuss improvements to the content page [t]" accesskey="t"><span>Talk</span></a></li> </ul> </div> </div> <div id="vector-variants-dropdown" class="vector-dropdown emptyPortlet" > <input type="checkbox" id="vector-variants-dropdown-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-vector-variants-dropdown" class="vector-dropdown-checkbox " aria-label="Change language variant" > <label id="vector-variants-dropdown-label" for="vector-variants-dropdown-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet" aria-hidden="true" ><span class="vector-dropdown-label-text">English</span> </label> <div class="vector-dropdown-content"> <div id="p-variants" class="vector-menu mw-portlet mw-portlet-variants emptyPortlet" > <div class="vector-menu-content"> <ul class="vector-menu-content-list"> </ul> </div> </div> </div> </div> </nav> </div> <div id="right-navigation" class="vector-collapsible"> <nav aria-label="Views"> <div id="p-views" class="vector-menu vector-menu-tabs mw-portlet mw-portlet-views" > <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="ca-view" class="selected vector-tab-noicon mw-list-item"><a href="/wiki/Additive_effect"><span>Read</span></a></li><li id="ca-edit" class="vector-tab-noicon mw-list-item"><a href="/w/index.php?title=Additive_effect&action=edit" title="Edit this page [e]" accesskey="e"><span>Edit</span></a></li><li id="ca-history" class="vector-tab-noicon mw-list-item"><a href="/w/index.php?title=Additive_effect&action=history" title="Past revisions of this page [h]" accesskey="h"><span>View history</span></a></li> </ul> </div> </div> </nav> <nav class="vector-page-tools-landmark" aria-label="Page tools"> <div id="vector-page-tools-dropdown" class="vector-dropdown vector-page-tools-dropdown" > <input type="checkbox" id="vector-page-tools-dropdown-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-vector-page-tools-dropdown" class="vector-dropdown-checkbox " aria-label="Tools" > <label id="vector-page-tools-dropdown-label" for="vector-page-tools-dropdown-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet" aria-hidden="true" ><span class="vector-dropdown-label-text">Tools</span> </label> <div class="vector-dropdown-content"> <div id="vector-page-tools-unpinned-container" class="vector-unpinned-container"> <div id="vector-page-tools" class="vector-page-tools vector-pinnable-element"> <div class="vector-pinnable-header vector-page-tools-pinnable-header vector-pinnable-header-unpinned" data-feature-name="page-tools-pinned" data-pinnable-element-id="vector-page-tools" data-pinned-container-id="vector-page-tools-pinned-container" data-unpinned-container-id="vector-page-tools-unpinned-container" > <div class="vector-pinnable-header-label">Tools</div> <button class="vector-pinnable-header-toggle-button vector-pinnable-header-pin-button" data-event-name="pinnable-header.vector-page-tools.pin">move to sidebar</button> <button class="vector-pinnable-header-toggle-button vector-pinnable-header-unpin-button" data-event-name="pinnable-header.vector-page-tools.unpin">hide</button> </div> <div id="p-cactions" class="vector-menu mw-portlet mw-portlet-cactions emptyPortlet vector-has-collapsible-items" title="More options" > <div class="vector-menu-heading"> Actions </div> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="ca-more-view" class="selected vector-more-collapsible-item mw-list-item"><a href="/wiki/Additive_effect"><span>Read</span></a></li><li id="ca-more-edit" class="vector-more-collapsible-item mw-list-item"><a href="/w/index.php?title=Additive_effect&action=edit" title="Edit this page [e]" accesskey="e"><span>Edit</span></a></li><li id="ca-more-history" class="vector-more-collapsible-item mw-list-item"><a href="/w/index.php?title=Additive_effect&action=history"><span>View history</span></a></li> </ul> </div> </div> <div id="p-tb" class="vector-menu mw-portlet mw-portlet-tb" > <div class="vector-menu-heading"> General </div> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="t-whatlinkshere" class="mw-list-item"><a href="/wiki/Special:WhatLinksHere/Additive_effect" title="List of all English Wikipedia pages containing links to this page [j]" accesskey="j"><span>What links here</span></a></li><li id="t-recentchangeslinked" class="mw-list-item"><a href="/wiki/Special:RecentChangesLinked/Additive_effect" rel="nofollow" title="Recent changes in pages linked from this page [k]" accesskey="k"><span>Related changes</span></a></li><li id="t-upload" class="mw-list-item"><a href="//en.wikipedia.org/wiki/Wikipedia:File_Upload_Wizard" title="Upload files [u]" accesskey="u"><span>Upload file</span></a></li><li id="t-permalink" class="mw-list-item"><a href="/w/index.php?title=Additive_effect&oldid=1256458693" title="Permanent link to this revision of this page"><span>Permanent link</span></a></li><li id="t-info" class="mw-list-item"><a href="/w/index.php?title=Additive_effect&action=info" title="More information about this page"><span>Page information</span></a></li><li id="t-cite" class="mw-list-item"><a href="/w/index.php?title=Special:CiteThisPage&page=Additive_effect&id=1256458693&wpFormIdentifier=titleform" title="Information on how to cite this page"><span>Cite this page</span></a></li><li id="t-urlshortener" class="mw-list-item"><a href="/w/index.php?title=Special:UrlShortener&url=https%3A%2F%2Fen.wikipedia.org%2Fwiki%2FAdditive_effect%23Detection_of_synergy"><span>Get shortened URL</span></a></li><li id="t-urlshortener-qrcode" class="mw-list-item"><a href="/w/index.php?title=Special:QrCode&url=https%3A%2F%2Fen.wikipedia.org%2Fwiki%2FAdditive_effect%23Detection_of_synergy"><span>Download QR code</span></a></li> </ul> </div> </div> <div id="p-coll-print_export" class="vector-menu mw-portlet mw-portlet-coll-print_export" > <div class="vector-menu-heading"> Print/export </div> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="coll-download-as-rl" class="mw-list-item"><a href="/w/index.php?title=Special:DownloadAsPdf&page=Additive_effect&action=show-download-screen" title="Download this page as a PDF file"><span>Download as PDF</span></a></li><li id="t-print" class="mw-list-item"><a href="/w/index.php?title=Additive_effect&printable=yes" title="Printable version of this page [p]" accesskey="p"><span>Printable version</span></a></li> </ul> </div> </div> <div id="p-wikibase-otherprojects" class="vector-menu mw-portlet mw-portlet-wikibase-otherprojects" > <div class="vector-menu-heading"> In other projects </div> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li id="t-wikibase" class="wb-otherproject-link wb-otherproject-wikibase-dataitem mw-list-item"><a href="https://www.wikidata.org/wiki/Special:EntityPage/Q112228119" title="Structured data on this page hosted by Wikidata [g]" accesskey="g"><span>Wikidata item</span></a></li> </ul> </div> </div> </div> </div> </div> </div> </nav> </div> </div> </div> <div class="vector-column-end"> <div class="vector-sticky-pinned-container"> <nav class="vector-page-tools-landmark" aria-label="Page tools"> <div id="vector-page-tools-pinned-container" class="vector-pinned-container"> </div> </nav> <nav class="vector-appearance-landmark" aria-label="Appearance"> <div id="vector-appearance-pinned-container" class="vector-pinned-container"> <div id="vector-appearance" class="vector-appearance vector-pinnable-element"> <div class="vector-pinnable-header vector-appearance-pinnable-header vector-pinnable-header-pinned" data-feature-name="appearance-pinned" data-pinnable-element-id="vector-appearance" data-pinned-container-id="vector-appearance-pinned-container" data-unpinned-container-id="vector-appearance-unpinned-container" > <div class="vector-pinnable-header-label">Appearance</div> <button class="vector-pinnable-header-toggle-button vector-pinnable-header-pin-button" data-event-name="pinnable-header.vector-appearance.pin">move to sidebar</button> <button class="vector-pinnable-header-toggle-button vector-pinnable-header-unpin-button" data-event-name="pinnable-header.vector-appearance.unpin">hide</button> </div> </div> </div> </nav> </div> </div> <div id="bodyContent" class="vector-body" aria-labelledby="firstHeading" data-mw-ve-target-container> <div class="vector-body-before-content"> <div class="mw-indicators"> </div> <div id="siteSub" class="noprint">From Wikipedia, the free encyclopedia</div> </div> <div id="contentSub"><div id="mw-content-subtitle"><span class="mw-redirectedfrom">(Redirected from <a href="/w/index.php?title=Synergy_(pharmacology)&redirect=no" class="mw-redirect" title="Synergy (pharmacology)">Synergy (pharmacology)</a>)</span></div></div> <div id="mw-content-text" class="mw-body-content"><div class="mw-content-ltr mw-parser-output" lang="en" dir="ltr"><p><b>Additive effect</b> in <a href="/wiki/Pharmacology" title="Pharmacology">pharmacology</a> describes the situation when the combining effects of two drugs equal the sum of the effects of the two drugs acting independently.<sup id="cite_ref-1" class="reference"><a href="#cite_note-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-2" class="reference"><a href="#cite_note-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> The concept of additive effect is derived from the concept of <a href="/wiki/Synergy#Biological_sciences" title="Synergy">synergy</a>. It was introduced by the scientists in pharmacology and <a href="/wiki/Biochemistry" title="Biochemistry">biochemistry</a> fields in the process of understanding the synergistic interaction between drugs and chemicals over the century. </p><p>Additive effect often occurs when two similar drugs are taken together to achieve the same degree of therapeutic effect while reducing the specific <a href="/wiki/Adverse_effect" title="Adverse effect">adverse effect</a> of one particular drug. For example, <a href="/wiki/Aspirin/paracetamol/caffeine" title="Aspirin/paracetamol/caffeine">aspirin, paracetamol, and caffeine</a> are formulated together to treat pain caused by tension headaches and <a href="/wiki/Migraine" title="Migraine">migraine</a>. </p><p>Additive effect can be used to detect synergy as it can be considered as the baseline effect in methods determining whether drugs have synergistic effect. Synergistic effect is similar to additive effect, having a combination effect greater than additive effect. It can produce an effect of 2+2 > 4 when two drugs are used together. Additive effect can also be found in a majority of <a href="/wiki/Combination_therapy" title="Combination therapy">combination therapies</a>, although synergistic effect is more common. If the combination of two drugs in combination therapy has an effect lower than the sum of the effects of the two drugs acting independently, also known as <a href="/wiki/Antagonism_(chemistry)" title="Antagonism (chemistry)">antagonistic effect</a>, the drugs will seldom be prescribed together in the same therapy. </p><p>Drug or chemical combinations with additive effects can cause adverse effects. For example, co-administration of <a href="/wiki/Nonsteroidal_anti-inflammatory_drug" title="Nonsteroidal anti-inflammatory drug">non-steroidal anti-inflammatory drugs</a> (NSAIDs) and <a href="/wiki/Glucocorticoid" title="Glucocorticoid">glucocorticoids</a> increases the risk of gastric bleeding.<sup id="cite_ref-:0_3-0" class="reference"><a href="#cite_note-:0-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> </p> <meta property="mw:PageProp/toc" /> <div class="mw-heading mw-heading2"><h2 id="History">History</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=1" title="Edit section: History"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The concept of additive effect is derived from the concept of drug synergy. Thus, the origin of additive effect dates back to the early twentieth century when the search for synergy started. During the search for synergy, the models of <a href="/wiki/Loewe_additivity" title="Loewe additivity">Loewe additivity</a> and <a href="https://de.wikipedia.org/wiki/Bliss_independence" class="extiw" title="de:Bliss independence">Bliss independence</a> were proposed.<sup id="cite_ref-4" class="reference"><a href="#cite_note-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup> These models are capable of measuring the effects of drug combinations. Hence, Loewe additivity and Bliss independence were developed to determine whether an effect of a drug combination is synergistic or antagonistic. During the construction of these models, the concept of additive effect was introduced as the baseline for the determination of synergy and antagonism. </p> <div class="mw-heading mw-heading2"><h2 id="Types_of_Additive_Effect">Types of Additive Effect</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=2" title="Edit section: Types of Additive Effect"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Additive effects can occur with drugs with either equivalent or overlapping actions, or independent actions. </p> <div class="mw-heading mw-heading3"><h3 id="Equivalent_or_overlapping_actions">Equivalent or overlapping actions</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=3" title="Edit section: Equivalent or overlapping actions"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Many of the drugs in the same class exert additive effect as they have a similar therapeutic <a href="/wiki/Mechanism_of_action" title="Mechanism of action">mechanism of action</a>. For example, the <a href="/wiki/Calcium_carbonate" title="Calcium carbonate">calcium carbonate</a>, <a href="/wiki/Magnesium" title="Magnesium">magnesium</a>, and <a href="/wiki/Aluminium" title="Aluminium">aluminium</a> salts are all <a href="/wiki/Antacid" title="Antacid">antacids</a> with the mechanism of using the <a href="/wiki/Negative_ion" class="mw-redirect" title="Negative ion">negative ion</a> to <a href="/wiki/Neutralization_(chemistry)" title="Neutralization (chemistry)">neutralize</a> the acid in the stomach.<sup id="cite_ref-5" class="reference"><a href="#cite_note-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup> The antacids have no interaction between them, so they would be considered to have additive effect when taken together. </p><p>Drugs that are in the same class, but do not have the same target, may also act additively by interacting with different targets in the same pathway. For example, <a href="/wiki/Propofol" title="Propofol">propofol</a> and <a href="/wiki/Sevoflurane" title="Sevoflurane">sevoflurane</a> can both produce <a href="/wiki/Anesthesia" title="Anesthesia">anesthetic effects</a>.<sup id="cite_ref-6" class="reference"><a href="#cite_note-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup> Propofol can potentiate the activity of <a href="/wiki/GABAA_receptor" title="GABAA receptor">GABA<sub>A</sub> receptor</a> and act on α, β and γ subunits,<sup id="cite_ref-7" class="reference"><a href="#cite_note-7"><span class="cite-bracket">[</span>7<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-8" class="reference"><a href="#cite_note-8"><span class="cite-bracket">[</span>8<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-9" class="reference"><a href="#cite_note-9"><span class="cite-bracket">[</span>9<span class="cite-bracket">]</span></a></sup> while sevoflurane enhances the response of the GABA<sub>A</sub> receptor to endogenous GABA by binding to the α1-subunit.<sup id="cite_ref-10" class="reference"><a href="#cite_note-10"><span class="cite-bracket">[</span>10<span class="cite-bracket">]</span></a></sup> By using Dixon up-down method, a trial has shown that the effect in producing anesthetic effects between propofol and sevoflurane is additive.<sup id="cite_ref-11" class="reference"><a href="#cite_note-11"><span class="cite-bracket">[</span>11<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Independent_actions">Independent actions</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=4" title="Edit section: Independent actions"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Two drugs having different targets in unrelated pathways that ultimately result in the desired therapeutic result are considered to have additive effects with independent actions. For example, <a href="/wiki/Artemisinin" title="Artemisinin">artemisinin</a> and <a href="/wiki/Curcumin" title="Curcumin">curcumin</a> both exert <a href="/wiki/Antimalarial_medication" title="Antimalarial medication">antimalarial</a> effects. Artemisinin works by being metabolized in the body into active metabolites. The metabolites would then create <a href="/wiki/Reactive_oxygen_species" title="Reactive oxygen species">reactive oxygen species(ROS)</a> that damage the parasites and kill them.<sup id="cite_ref-12" class="reference"><a href="#cite_note-12"><span class="cite-bracket">[</span>12<span class="cite-bracket">]</span></a></sup> The mechanism of action of curcumin remains largely unknown, but the antiparasitic effect is believed to be associated with the potentiation of innate and adaptive <a href="/wiki/Immunological_response" class="mw-redirect" title="Immunological response">immunological responses</a>.<sup id="cite_ref-13" class="reference"><a href="#cite_note-13"><span class="cite-bracket">[</span>13<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-14" class="reference"><a href="#cite_note-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup> The combined effects of artemisinin and curcumin each contribute to the death of parasites via different mechanisms and the effect is shown to be additive by fractional inhibitory concentrations.<sup id="cite_ref-15" class="reference"><a href="#cite_note-15"><span class="cite-bracket">[</span>15<span class="cite-bracket">]</span></a></sup> </p><p>Drugs with the same target in different sites that produce additive effects are also considered as independent action. For example, <a href="/wiki/Doxorubicin" title="Doxorubicin">doxorubicin</a> and <a href="/wiki/Trabectedin" title="Trabectedin">trabectedin</a> can both produce <a href="/wiki/Anticancer" class="mw-redirect" title="Anticancer">anticancer effect</a>.<sup id="cite_ref-16" class="reference"><a href="#cite_note-16"><span class="cite-bracket">[</span>16<span class="cite-bracket">]</span></a></sup> Doxorubicin is a <a href="/wiki/Intercalation_(biochemistry)" title="Intercalation (biochemistry)">DNA intercalator</a> that prefers to bind to AT regions,<sup id="cite_ref-17" class="reference"><a href="#cite_note-17"><span class="cite-bracket">[</span>17<span class="cite-bracket">]</span></a></sup> while trabectedin forms <a href="/wiki/Guanine" title="Guanine">guanine</a> adduct in DNA to disrupt DNA repair system.<sup id="cite_ref-18" class="reference"><a href="#cite_note-18"><span class="cite-bracket">[</span>18<span class="cite-bracket">]</span></a></sup> A recent study has shown that doxorubicin and trabectedin do not hinder each other and could produce an additive anticancer effect.<sup id="cite_ref-19" class="reference"><a href="#cite_note-19"><span class="cite-bracket">[</span>19<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading2"><h2 id="Common_misconceptions">Common misconceptions</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=5" title="Edit section: Common misconceptions"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The concept of additive effect is analogous to the concept of simple addition in mathematics. However, the additive effect is not simply the <a href="/wiki/Summation" title="Summation">arithmetic summation</a> of two (or more) drugs in most cases.<sup id="cite_ref-20" class="reference"><a href="#cite_note-20"><span class="cite-bracket">[</span>20<span class="cite-bracket">]</span></a></sup> For an additive inhibition effect, drug A and drug B could each inhibit 20% individually, but the additive effect is not 40%. The effect cannot be simply arithmetic because if drug A and drug B each inhibits 60% cannot theoretically exert an inhibitory effect of 120%. With 60% inhibitory effect each, the remaining function would be at (1-60%)×(1-60%)=16%, meaning the additive inhibitory effect would be 84%. Since the application of additive effect is commonly seen in clinical practice, avoiding the common misconceptions of additive effect is crucial to understanding the clinical significance of additive effect.<sup class="noprint Inline-Template Template-Fact" style="white-space:nowrap;">[<i><a href="/wiki/Wikipedia:Citation_needed" title="Wikipedia:Citation needed"><span title="This claim needs references to reliable sources. (May 2022)">citation needed</span></a></i>]</sup> </p> <div class="mw-heading mw-heading2"><h2 id="Clinical_Significance">Clinical Significance</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=6" title="Edit section: Clinical Significance"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <div class="mw-heading mw-heading3"><h3 id="Detection_of_synergy">Detection of synergy</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=7" title="Edit section: Detection of synergy"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>One of the typical uses of additive effect is to detect synergy.<sup id="cite_ref-21" class="reference"><a href="#cite_note-21"><span class="cite-bracket">[</span>21<span class="cite-bracket">]</span></a></sup> Additive effect can be considered as the baseline effect in methods of determining the presence of synergistic effect between two or more drugs. Synergistic effect is similar to additive effect. The only difference is it has a combination effect greater than additive effect. To be brief, synergy can produce an effect of 2 + 2 > 4 when drugs are used in combination.<sup id="cite_ref-22" class="reference"><a href="#cite_note-22"><span class="cite-bracket">[</span>22<span class="cite-bracket">]</span></a></sup> The combination of <a href="/wiki/Angiotensin_II_receptor_blocker" title="Angiotensin II receptor blocker">angiotensin II receptor antagonist (ARB)</a>, <a href="/wiki/Candesartan" title="Candesartan">Candesartan-cilexetil</a>, and <a href="/wiki/ACE_inhibitor" title="ACE inhibitor">angiotensin-converting enzyme inhibitor (ACEI)</a>, Ramipril, demonstrates a synergistic effect in reducing <a href="/wiki/Blood_pressure" title="Blood pressure">systolic blood pressure</a>.<sup id="cite_ref-:1_23-0" class="reference"><a href="#cite_note-:1-23"><span class="cite-bracket">[</span>23<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Detection_of_antagonism">Detection of antagonism</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=8" title="Edit section: Detection of antagonism"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The other use of additive effect is to detect antagonism. Similarly, additive effect can be considered as the baseline effect in methods of determining the presence of antagonistic effect between drugs. Pharmacists can confirm the presence of antagonism when the combination effect of drugs is less than additive effect. The combination of <a href="/wiki/Aspirin" title="Aspirin">acetylsalicylic acid</a> and <a href="/wiki/Ibuprofen" title="Ibuprofen">ibuprofen</a> demonstrates an antagonistic effect in relieving pain and <a href="/wiki/Inflammation" title="Inflammation">inflammation</a>.<sup id="cite_ref-:0_3-1" class="reference"><a href="#cite_note-:0-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Combination_therapy">Combination therapy</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=9" title="Edit section: Combination therapy"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The most common clinical usage of additive effect in pharmacology is combination therapy. Two or more therapeutic agents are used in combination therapy to treat a single disease. Different drugs in the same combination therapy act on different biological and biochemical pathways in the body to produce an additive effect. </p><p>An example of combination therapy demonstrating additive effect is the use of <a href="/wiki/Beta2-adrenergic_agonist" title="Beta2-adrenergic agonist">β-2 adrenergic receptor agonists</a> together with <a href="/wiki/Corticosteroid" title="Corticosteroid">inhaled corticosteroids</a>. This is a treatment for two commonly seen <a href="/wiki/Respiratory_disease" title="Respiratory disease">pulmonary diseases</a>, <a href="/wiki/Asthma" title="Asthma">asthma</a> and <a href="/wiki/Chronic_obstructive_pulmonary_disease" title="Chronic obstructive pulmonary disease">chronic obstructive pulmonary disease</a>. β-2 adrenergic receptor agonists act as <a href="/wiki/Bronchodilator" title="Bronchodilator">bronchodilators</a>, having an effect of inducing bronchodilation to relieve bronchoconstriction; Inhaled corticosteroids act as anti-inflammatory drugs to decrease the inflammatory response. The two drugs act on different sites in the body. The corticosteroids also reverse and restore the function and number of β-2 adrenergic receptors in patients’ lungs <a href="/wiki/In_vivo" title="In vivo">in vivo</a>. Meanwhile, the combined activity of two drugs resolves the problem of reduced sensitivity in some patients with chronic obstructive pulmonary disease towards inhaled corticosteroids.<sup id="cite_ref-24" class="reference"><a href="#cite_note-24"><span class="cite-bracket">[</span>24<span class="cite-bracket">]</span></a></sup> A common drug from this example can be found is <a href="/wiki/Fluticasone/salmeterol" title="Fluticasone/salmeterol">Seretide®</a>, containing a long-acting β-2 adrenergic receptor agonist named as <a href="/wiki/Salmeterol" title="Salmeterol">Salmeterol</a> and a corticosteroid named as <a href="/wiki/Fluticasone" title="Fluticasone">Fluticasone</a>.<sup id="cite_ref-25" class="reference"><a href="#cite_note-25"><span class="cite-bracket">[</span>25<span class="cite-bracket">]</span></a></sup> </p><p>Additive interaction can also be found in combination therapy for treating <a href="/wiki/Hypertension" title="Hypertension">hypertension</a>. The combination of angiotensin II receptor blockers (ARBs) and <a href="/wiki/Calcium_channel_blocker" title="Calcium channel blocker">calcium channel blockers</a> (CCBs) is one of the suggested antihypertensive therapies. ARBs inhibit the action of <a href="/wiki/Angiotensin" title="Angiotensin">angiotensin II</a> to decrease fluid retention and blood volume to decrease blood pressure, reduce <a href="/wiki/Vasoconstriction" title="Vasoconstriction">vasoconstriction</a> to decrease <a href="/wiki/Vascular_resistance" title="Vascular resistance">peripheral vascular resistance</a>, and prevent vascular <a href="/wiki/Fibrosis" title="Fibrosis">fibrosis</a> to decrease vascular stiffness. CCBs are <a href="/wiki/Vasodilation" title="Vasodilation">vasodilators</a> inhibiting <a href="/wiki/L-type_calcium_channel" title="L-type calcium channel">L-type voltage-operated calcium channels</a> in the blood vessels to alleviate vasoconstriction resulting in a decrease in peripheral vascular resistance. The two types of drugs act on different pathways to produce an additive effect on lowering blood pressure without any increase in adverse effects.<sup id="cite_ref-26" class="reference"><a href="#cite_note-26"><span class="cite-bracket">[</span>26<span class="cite-bracket">]</span></a></sup> This combination, with ARB, <a href="/wiki/Valsartan" title="Valsartan">valsartan</a>, and CCB, <a href="/wiki/Amlodipine" title="Amlodipine">amlodipine</a>, is a common treatment in high-risk hypertensive patients, especially the elderly.<sup id="cite_ref-27" class="reference"><a href="#cite_note-27"><span class="cite-bracket">[</span>27<span class="cite-bracket">]</span></a></sup> </p><p>The treatment for another common disease, primary <a href="/wiki/Hypercholesterolemia" title="Hypercholesterolemia">hypercholesterolemia</a>, also demonstrates additive effect. Plant sterol-ester margarine and a common type of <a href="/wiki/Lipid-lowering_agent" title="Lipid-lowering agent">antihyperlipidaemic</a> drug, <a href="/wiki/Cerivastatin" title="Cerivastatin">cerivastatin</a>, have an additive effect in reducing <a href="/wiki/Low-density_lipoprotein" title="Low-density lipoprotein">LDL cholesterol</a>, without significant interaction between the two drugs.<sup id="cite_ref-28" class="reference"><a href="#cite_note-28"><span class="cite-bracket">[</span>28<span class="cite-bracket">]</span></a></sup> Another drug combination with additive effect for hypercholesterolemia is <a href="/wiki/Niacin_(substance)" class="mw-redirect" title="Niacin (substance)">niacin</a> (<a href="/wiki/Vitamin_B3" title="Vitamin B3">vitamin B3</a>) and <a href="/wiki/Simvastatin" title="Simvastatin">simvastatin</a>. This drug combination is also known as <a href="/wiki/Niacin/simvastatin" title="Niacin/simvastatin">Simcor</a> commercially. Niacin can reduce the secretion of LDL cholesterol and very-low-density lipoprotein cholesterol (VLDL cholesterol). On the other hand, simvastatin can reduce the synthesis of LDL cholesterol and <a href="/wiki/Triglyceride" title="Triglyceride">triglycerides</a>, and increase the level of <a href="/wiki/High-density_lipoprotein" title="High-density lipoprotein">high-density lipoprotein cholesterol (HDL cholesterol)</a>. Together, niacin and simvastatin reduce the level of LDL cholesterol and increases the level of HDL cholesterol,<sup id="cite_ref-:1_23-1" class="reference"><a href="#cite_note-:1-23"><span class="cite-bracket">[</span>23<span class="cite-bracket">]</span></a></sup> therefore managing hypercholesterolemia effectively. </p> <div class="mw-heading mw-heading3"><h3 id="Optimal_dosing">Optimal dosing</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=10" title="Edit section: Optimal dosing"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Additive interaction or additive effect can be found in the treatment of the majority of common diseases. The combination of drugs with different effects has the benefit of using each drug at its optimal dose.<sup id="cite_ref-29" class="reference"><a href="#cite_note-29"><span class="cite-bracket">[</span>29<span class="cite-bracket">]</span></a></sup> This decreases the possibility of using a higher dose of a single medication if the previous dose is ineffective in treating diseases or relieving symptoms. The significance of using drugs with optimal dose is lowering the occurrence of intolerable side effects, adverse reactions, and possible <a href="/wiki/Drug_toxicity" class="mw-redirect" title="Drug toxicity">drug toxicity</a> in patient's body. This increases the safe use of drugs and increases patient compliance with the therapy.<sup id="cite_ref-30" class="reference"><a href="#cite_note-30"><span class="cite-bracket">[</span>30<span class="cite-bracket">]</span></a></sup> </p><p>One of the examples is the use of calcium channel blocker and beta-blocker. They are drugs that can be used to treat stable <a href="/wiki/Angina" title="Angina">angina</a>. They can both decrease the frequency of angina, aiming to relieve the symptoms of angina. There are controlled, double blind clinical trials and studies involving patients with preserved left ventricular function demonstrating that the combination of calcium channel blocker and beta blocker has an additive cardio depressant effects when comparing with either drug class alone.<sup id="cite_ref-31" class="reference"><a href="#cite_note-31"><span class="cite-bracket">[</span>31<span class="cite-bracket">]</span></a></sup> The combination therapy is used when a single medication fails to produce a therapeutic effect. Choosing the optimal dose of the two medications in the combination therapy prevents the use of an extreme high dose of a single medication alone, leading to adverse effects. </p> <div class="mw-heading mw-heading2"><h2 id="Adverse_Effects">Adverse Effects</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=11" title="Edit section: Adverse Effects"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Drug combinations with additive effects have the potential to cause adverse effects. Adverse effects induced by drug combinations are not uncommon. The risk of having adverse effects is increased when the drug combination with additive effect has the same adverse effect. Thus, some drug combinations with additive effect are avoided. Below are commonly seen drug combinations with additive effect causing adverse effects. </p> <div class="mw-heading mw-heading3"><h3 id="ACEI_and_potassium-sparing_diuretics">ACEI and potassium-sparing diuretics</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=12" title="Edit section: ACEI and potassium-sparing diuretics"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>An example demonstrating how drug combination with additive effect can cause adverse effects is the co-administration of ACEI and <a href="/wiki/Potassium-sparing_diuretic" title="Potassium-sparing diuretic">potassium-sparing diuretics</a>.<sup id="cite_ref-:0_3-2" class="reference"><a href="#cite_note-:0-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> Despite having different mechanisms of action, the drugs are able to reduce potassium excretion from the body. Hence, both ACEI and potassium-sparing diuretics have the side effect of <a href="/wiki/Hyperkalemia" title="Hyperkalemia">hyperkalemia</a>. When two drugs are used together, the risk of having hyperkalemia is doubled. Since hyperkalemia has the potential to cause <a href="/wiki/Arrhythmia" title="Arrhythmia">arrhythmia</a> and <a href="/wiki/Metabolic_acidosis" title="Metabolic acidosis">metabolic acidosis</a>, the combination of ACEI and potassium-sparing diuretics is avoided. </p> <div class="mw-heading mw-heading3"><h3 id="NSAIDs_and_glucocorticoids">NSAIDs and glucocorticoids</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=13" title="Edit section: NSAIDs and glucocorticoids"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Another example is the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids.<sup id="cite_ref-:0_3-3" class="reference"><a href="#cite_note-:0-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> Although NSAIDs and glucocorticoids have different mechanisms of action, the drugs are able to diminish the protective effect of gastric mucosa from gastric acid.<sup id="cite_ref-32" class="reference"><a href="#cite_note-32"><span class="cite-bracket">[</span>32<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-33" class="reference"><a href="#cite_note-33"><span class="cite-bracket">[</span>33<span class="cite-bracket">]</span></a></sup> As a result, the concomitant use of NSAIDs and glucocorticoids increases the risk of gastric bleeding and worsens <a href="/wiki/Peptic_ulcer_disease" title="Peptic ulcer disease">peptic ulcer disease</a>. As a result, the combination of NSAIDs and glucocorticoids is not recommended. </p> <div class="mw-heading mw-heading2"><h2 id="See_also">See also</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=14" title="Edit section: See also"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <ul><li><a href="/wiki/Antibiotic_synergy" title="Antibiotic synergy">Antibiotic synergy</a></li></ul> <div class="mw-heading mw-heading2"><h2 id="References">References</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Additive_effect&action=edit&section=15" title="Edit section: References"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <style data-mw-deduplicate="TemplateStyles:r1239543626">.mw-parser-output .reflist{margin-bottom:0.5em;list-style-type:decimal}@media screen{.mw-parser-output .reflist{font-size:90%}}.mw-parser-output .reflist .references{font-size:100%;margin-bottom:0;list-style-type:inherit}.mw-parser-output .reflist-columns-2{column-width:30em}.mw-parser-output .reflist-columns-3{column-width:25em}.mw-parser-output .reflist-columns{margin-top:0.3em}.mw-parser-output .reflist-columns ol{margin-top:0}.mw-parser-output .reflist-columns li{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .reflist-upper-alpha{list-style-type:upper-alpha}.mw-parser-output .reflist-upper-roman{list-style-type:upper-roman}.mw-parser-output .reflist-lower-alpha{list-style-type:lower-alpha}.mw-parser-output .reflist-lower-greek{list-style-type:lower-greek}.mw-parser-output .reflist-lower-roman{list-style-type:lower-roman}</style><div class="reflist"> <div class="mw-references-wrap mw-references-columns"><ol class="references"> <li id="cite_note-1"><span class="mw-cite-backlink"><b><a href="#cite_ref-1">^</a></b></span> <span class="reference-text"><style data-mw-deduplicate="TemplateStyles:r1238218222">.mw-parser-output cite.citation{font-style:inherit;word-wrap:break-word}.mw-parser-output .citation q{quotes:"\"""\"""'""'"}.mw-parser-output .citation:target{background-color:rgba(0,127,255,0.133)}.mw-parser-output .id-lock-free.id-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/6/65/Lock-green.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-limited.id-lock-limited a,.mw-parser-output .id-lock-registration.id-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/d/d6/Lock-gray-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-subscription.id-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/a/aa/Lock-red-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .cs1-ws-icon a{background:url("//upload.wikimedia.org/wikipedia/commons/4/4c/Wikisource-logo.svg")right 0.1em center/12px no-repeat}body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-free a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-limited a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-registration a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-subscription a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .cs1-ws-icon a{background-size:contain;padding:0 1em 0 0}.mw-parser-output .cs1-code{color:inherit;background:inherit;border:none;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;color:var(--color-error,#d33)}.mw-parser-output .cs1-visible-error{color:var(--color-error,#d33)}.mw-parser-output .cs1-maint{display:none;color:#085;margin-left:0.3em}.mw-parser-output .cs1-kern-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right{padding-right:0.2em}.mw-parser-output .citation .mw-selflink{font-weight:inherit}@media screen{.mw-parser-output .cs1-format{font-size:95%}html.skin-theme-clientpref-night .mw-parser-output .cs1-maint{color:#18911f}}@media screen and (prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output .cs1-maint{color:#18911f}}</style><cite id="CITEREFGovernment_of_Canada2019" class="citation web cs1">Government of Canada, Canadian Centre for Occupational Health and Safety (2019). <a rel="nofollow" class="external text" href="https://www.ccohs.ca/oshanswers/chemicals/synergism.html">"Synergism and related terms : OSH Answers"</a>. <i>www.ccohs.ca</i><span class="reference-accessdate">. Retrieved <span class="nowrap">2022-03-26</span></span>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=unknown&rft.jtitle=www.ccohs.ca&rft.atitle=Synergism+and+related+terms+%3A+OSH+Answers&rft.date=2019&rft.aulast=Government+of+Canada&rft.aufirst=Canadian+Centre+for+Occupational+Health+and+Safety&rft_id=https%3A%2F%2Fwww.ccohs.ca%2Foshanswers%2Fchemicals%2Fsynergism.html&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-2"><span class="mw-cite-backlink"><b><a href="#cite_ref-2">^</a></b></span> <span class="reference-text">Rowland, M., & Tozer, T. (2011). <i>Clinical pharmacokinetics and pharmacodynamics [electronic resource]</i> : Concepts and applications (4th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.</span> </li> <li id="cite_note-:0-3"><span class="mw-cite-backlink">^ <a href="#cite_ref-:0_3-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-:0_3-1"><sup><i><b>b</b></i></sup></a> <a href="#cite_ref-:0_3-2"><sup><i><b>c</b></i></sup></a> <a href="#cite_ref-:0_3-3"><sup><i><b>d</b></i></sup></a></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFCascorbi2012" class="citation journal cs1">Cascorbi, Ingolf (2012). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444856">"Drug interactions--principles, examples and clinical consequences"</a>. <i>Deutsches Ärzteblatt International</i>. <b>109</b> (<span class="nowrap">33–</span>34): <span class="nowrap">546–</span>555, quiz 556. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.3238%2Farztebl.2012.0546">10.3238/arztebl.2012.0546</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1866-0452">1866-0452</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444856">3444856</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/23152742">23152742</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Deutsches+%C3%84rzteblatt+International&rft.atitle=Drug+interactions--principles%2C+examples+and+clinical+consequences&rft.volume=109&rft.issue=%3Cspan+class%3D%22nowrap%22%3E33%E2%80%93%3C%2Fspan%3E34&rft.pages=%3Cspan+class%3D%22nowrap%22%3E546-%3C%2Fspan%3E555%2C+quiz+556&rft.date=2012&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC3444856%23id-name%3DPMC&rft.issn=1866-0452&rft_id=info%3Apmid%2F23152742&rft_id=info%3Adoi%2F10.3238%2Farztebl.2012.0546&rft.aulast=Cascorbi&rft.aufirst=Ingolf&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC3444856&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-4"><span class="mw-cite-backlink"><b><a href="#cite_ref-4">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFGrecoBravoParsons1995" class="citation journal cs1">Greco, W. R.; Bravo, G.; Parsons, J. C. (1995). <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/7568331">"The search for synergy: a critical review from a response surface perspective"</a>. <i>Pharmacological Reviews</i>. <b>47</b> (2): <span class="nowrap">331–</span>385. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0031-6997">0031-6997</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/7568331">7568331</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Pharmacological+Reviews&rft.atitle=The+search+for+synergy%3A+a+critical+review+from+a+response+surface+perspective&rft.volume=47&rft.issue=2&rft.pages=%3Cspan+class%3D%22nowrap%22%3E331-%3C%2Fspan%3E385&rft.date=1995&rft_id=info%3Apmid%2F7568331&rft.issn=0031-6997&rft.aulast=Greco&rft.aufirst=W.+R.&rft.au=Bravo%2C+G.&rft.au=Parsons%2C+J.+C.&rft_id=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F7568331&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-5"><span class="mw-cite-backlink"><b><a href="#cite_ref-5">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFMatonBurton1999" class="citation journal cs1">Maton, P. N.; Burton, M. E. (1999). <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/10400401">"Antacids revisited: a review of their clinical pharmacology and recommended therapeutic use"</a>. <i>Drugs</i>. <b>57</b> (6): <span class="nowrap">855–</span>870. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.2165%2F00003495-199957060-00003">10.2165/00003495-199957060-00003</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0012-6667">0012-6667</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/10400401">10400401</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:46960343">46960343</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Drugs&rft.atitle=Antacids+revisited%3A+a+review+of+their+clinical+pharmacology+and+recommended+therapeutic+use&rft.volume=57&rft.issue=6&rft.pages=%3Cspan+class%3D%22nowrap%22%3E855-%3C%2Fspan%3E870&rft.date=1999&rft.issn=0012-6667&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A46960343%23id-name%3DS2CID&rft_id=info%3Apmid%2F10400401&rft_id=info%3Adoi%2F10.2165%2F00003495-199957060-00003&rft.aulast=Maton&rft.aufirst=P.+N.&rft.au=Burton%2C+M.+E.&rft_id=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F10400401&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-6"><span class="mw-cite-backlink"><b><a href="#cite_ref-6">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFBrohanGoudra2017" class="citation journal cs1">Brohan, Janette; Goudra, Basavana G. (2017-10-01). <a rel="nofollow" class="external text" href="https://doi.org/10.1007/s40263-017-0463-7">"The Role of GABA Receptor Agonists in Anesthesia and Sedation"</a>. <i>CNS Drugs</i>. <b>31</b> (10): <span class="nowrap">845–</span>856. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1007%2Fs40263-017-0463-7">10.1007/s40263-017-0463-7</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1179-1934">1179-1934</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/29039138">29039138</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:207486777">207486777</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=CNS+Drugs&rft.atitle=The+Role+of+GABA+Receptor+Agonists+in+Anesthesia+and+Sedation&rft.volume=31&rft.issue=10&rft.pages=%3Cspan+class%3D%22nowrap%22%3E845-%3C%2Fspan%3E856&rft.date=2017-10-01&rft.issn=1179-1934&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A207486777%23id-name%3DS2CID&rft_id=info%3Apmid%2F29039138&rft_id=info%3Adoi%2F10.1007%2Fs40263-017-0463-7&rft.aulast=Brohan&rft.aufirst=Janette&rft.au=Goudra%2C+Basavana+G.&rft_id=https%3A%2F%2Fdoi.org%2F10.1007%2Fs40263-017-0463-7&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-7"><span class="mw-cite-backlink"><b><a href="#cite_ref-7">^</a></b></span> <span class="reference-text">Sanna, E., Garau, F., & Harris, R. (1995). Novel properties of homomeric beta 1 gamma-aminobutyric acid type A receptors: Actions of the anesthetics propofol and pentobarbital. <i>Molecular Pharmacology</i>, <i>47(2)</i>, 213.</span> </li> <li id="cite_note-8"><span class="mw-cite-backlink"><b><a href="#cite_ref-8">^</a></b></span> <span class="reference-text">Jones, M., Harrison, N., Pritchett, D., & Hales, T. (1995). Modulation of the GABAA receptor by propofol is independent of the gamma subunit. <i>The Journal of Pharmacology and Experimental Therapeutics, 274</i>(2), 962-968.</span> </li> <li id="cite_note-9"><span class="mw-cite-backlink"><b><a href="#cite_ref-9">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFLamReynolds1998" class="citation journal cs1">Lam, Dennis W; Reynolds, James N (1998). <a rel="nofollow" class="external text" href="https://dx.doi.org/10.1016/s0006-8993(97)01334-6">"Modulatory and direct effects of propofol on recombinant GABAA receptors expressed in Xenopus oocytes: Influence of α- and γ2-subunits"</a>. <i>Brain Research</i>. <b>784</b> (<span class="nowrap">1–</span>2): <span class="nowrap">179–</span>187. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs0006-8993%2897%2901334-6">10.1016/s0006-8993(97)01334-6</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0006-8993">0006-8993</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/9518600">9518600</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:140204274">140204274</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Brain+Research&rft.atitle=Modulatory+and+direct+effects+of+propofol+on+recombinant+GABAA+receptors+expressed+in+Xenopus+oocytes%3A+Influence+of+%CE%B1-+and+%CE%B32-subunits&rft.volume=784&rft.issue=%3Cspan+class%3D%22nowrap%22%3E1%E2%80%93%3C%2Fspan%3E2&rft.pages=%3Cspan+class%3D%22nowrap%22%3E179-%3C%2Fspan%3E187&rft.date=1998&rft.issn=0006-8993&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A140204274%23id-name%3DS2CID&rft_id=info%3Apmid%2F9518600&rft_id=info%3Adoi%2F10.1016%2Fs0006-8993%2897%2901334-6&rft.aulast=Lam&rft.aufirst=Dennis+W&rft.au=Reynolds%2C+James+N&rft_id=http%3A%2F%2Fdx.doi.org%2F10.1016%2Fs0006-8993%2897%2901334-6&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-10"><span class="mw-cite-backlink"><b><a href="#cite_ref-10">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFGarciaKoleskyJenkins2010" class="citation journal cs1">Garcia, Paul; Kolesky, Scott; Jenkins, Andrew (2010-03-01). <a rel="nofollow" class="external text" href="https://dx.doi.org/10.2174/157015910790909502">"General Anesthetic Actions on GABAA Receptors"</a>. <i>Current Neuropharmacology</i>. <b>8</b> (1): <span class="nowrap">2–</span>9. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.2174%2F157015910790909502">10.2174/157015910790909502</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1570-159X">1570-159X</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866459">2866459</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/20808541">20808541</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Current+Neuropharmacology&rft.atitle=General+Anesthetic+Actions+on+GABAA+Receptors&rft.volume=8&rft.issue=1&rft.pages=%3Cspan+class%3D%22nowrap%22%3E2-%3C%2Fspan%3E9&rft.date=2010-03-01&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC2866459%23id-name%3DPMC&rft.issn=1570-159X&rft_id=info%3Apmid%2F20808541&rft_id=info%3Adoi%2F10.2174%2F157015910790909502&rft.aulast=Garcia&rft.aufirst=Paul&rft.au=Kolesky%2C+Scott&rft.au=Jenkins%2C+Andrew&rft_id=http%3A%2F%2Fdx.doi.org%2F10.2174%2F157015910790909502&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-11"><span class="mw-cite-backlink"><b><a href="#cite_ref-11">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFHarrisLazarJohansenSebel2006" class="citation journal cs1">Harris, R.; Lazar, O.; Johansen, J.; Sebel, P. (2006-06-01). <a rel="nofollow" class="external text" href="https://doi.org/10.1097%2F00000542-200606000-00011">"Interaction of Propofol and Sevoflurane on Loss of Consciousness and Movement to Skin Incision during General Anesthesia"</a>. <i>Anesthesiology</i>. <b>104</b> (6): <span class="nowrap">1170–</span>1175. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://doi.org/10.1097%2F00000542-200606000-00011">10.1097/00000542-200606000-00011</a></span>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0003-3022">0003-3022</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16732087">16732087</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:7164486">7164486</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Anesthesiology&rft.atitle=Interaction+of+Propofol+and+Sevoflurane+on+Loss+of+Consciousness+and+Movement+to+Skin+Incision+during+General+Anesthesia&rft.volume=104&rft.issue=6&rft.pages=%3Cspan+class%3D%22nowrap%22%3E1170-%3C%2Fspan%3E1175&rft.date=2006-06-01&rft.issn=0003-3022&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A7164486%23id-name%3DS2CID&rft_id=info%3Apmid%2F16732087&rft_id=info%3Adoi%2F10.1097%2F00000542-200606000-00011&rft.aulast=Harris&rft.aufirst=R.&rft.au=Lazar%2C+O.&rft.au=Johansen%2C+J.&rft.au=Sebel%2C+P.&rft_id=https%3A%2F%2Fdoi.org%2F10.1097%252F00000542-200606000-00011&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-12"><span class="mw-cite-backlink"><b><a href="#cite_ref-12">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFNovaesSartiniRodriguesGonçalves2016" class="citation journal cs1">Novaes, Rômulo Dias; Sartini, Marcus Vinicius Pessoa; Rodrigues, João Paulo Ferreira; Gonçalves, Reggiani Vilela; Santos, Eliziária Cardoso; Souza, Raquel Lopes Martins; Caldas, Ivo Santana (2016). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879395">"Curcumin Enhances the Anti-Trypanosoma cruzi Activity of Benznidazole-Based Chemotherapy in Acute Experimental Chagas Disease"</a>. <i>Antimicrobial Agents and Chemotherapy</i>. <b>60</b> (6): <span class="nowrap">3355–</span>3364. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1128%2FAAC.00343-16">10.1128/AAC.00343-16</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0066-4804">0066-4804</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879395">4879395</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/27001816">27001816</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Antimicrobial+Agents+and+Chemotherapy&rft.atitle=Curcumin+Enhances+the+Anti-Trypanosoma+cruzi+Activity+of+Benznidazole-Based+Chemotherapy+in+Acute+Experimental+Chagas+Disease&rft.volume=60&rft.issue=6&rft.pages=%3Cspan+class%3D%22nowrap%22%3E3355-%3C%2Fspan%3E3364&rft.date=2016&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC4879395%23id-name%3DPMC&rft.issn=0066-4804&rft_id=info%3Apmid%2F27001816&rft_id=info%3Adoi%2F10.1128%2FAAC.00343-16&rft.aulast=Novaes&rft.aufirst=R%C3%B4mulo+Dias&rft.au=Sartini%2C+Marcus+Vinicius+Pessoa&rft.au=Rodrigues%2C+Jo%C3%A3o+Paulo+Ferreira&rft.au=Gon%C3%A7alves%2C+Reggiani+Vilela&rft.au=Santos%2C+Elizi%C3%A1ria+Cardoso&rft.au=Souza%2C+Raquel+Lopes+Martins&rft.au=Caldas%2C+Ivo+Santana&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC4879395&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-13"><span class="mw-cite-backlink"><b><a href="#cite_ref-13">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFAllam2009" class="citation journal cs1">Allam, Gamal (2009). <a rel="nofollow" class="external text" href="https://linkinghub.elsevier.com/retrieve/pii/S0171298508001563">"Immunomodulatory effects of curcumin treatment on murine schistosomiasis mansoni"</a>. <i>Immunobiology</i>. <b>214</b> (8): <span class="nowrap">712–</span>727. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fj.imbio.2008.11.017">10.1016/j.imbio.2008.11.017</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/19249123">19249123</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Immunobiology&rft.atitle=Immunomodulatory+effects+of+curcumin+treatment+on+murine+schistosomiasis+mansoni&rft.volume=214&rft.issue=8&rft.pages=%3Cspan+class%3D%22nowrap%22%3E712-%3C%2Fspan%3E727&rft.date=2009&rft_id=info%3Adoi%2F10.1016%2Fj.imbio.2008.11.017&rft_id=info%3Apmid%2F19249123&rft.aulast=Allam&rft.aufirst=Gamal&rft_id=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0171298508001563&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-14"><span class="mw-cite-backlink"><b><a href="#cite_ref-14">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFJagetiaAggarwal2007" class="citation journal cs1">Jagetia, Ganesh Chandra; Aggarwal, Bharat B. (2007-01-25). <a rel="nofollow" class="external text" href="http://link.springer.com/10.1007/s10875-006-9066-7">"<span class="cs1-kern-left"></span>"Spicing Up" of the Immune System by Curcumin"</a>. <i>Journal of Clinical Immunology</i>. <b>27</b> (1): <span class="nowrap">19–</span>35. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1007%2Fs10875-006-9066-7">10.1007/s10875-006-9066-7</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0271-9142">0271-9142</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/17211725">17211725</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:21586221">21586221</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Journal+of+Clinical+Immunology&rft.atitle=%22Spicing+Up%22+of+the+Immune+System+by+Curcumin&rft.volume=27&rft.issue=1&rft.pages=%3Cspan+class%3D%22nowrap%22%3E19-%3C%2Fspan%3E35&rft.date=2007-01-25&rft.issn=0271-9142&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A21586221%23id-name%3DS2CID&rft_id=info%3Apmid%2F17211725&rft_id=info%3Adoi%2F10.1007%2Fs10875-006-9066-7&rft.aulast=Jagetia&rft.aufirst=Ganesh+Chandra&rft.au=Aggarwal%2C+Bharat+B.&rft_id=http%3A%2F%2Flink.springer.com%2F10.1007%2Fs10875-006-9066-7&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-15"><span class="mw-cite-backlink"><b><a href="#cite_ref-15">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFNandakumarNagarajVathsalaRangarajan2006" class="citation journal cs1">Nandakumar, Dalavaikodihalli Nanjaiah; Nagaraj, Viswanathan Arun; Vathsala, Palakkod Govindan; Rangarajan, Pundi; Padmanaban, Govindarajan (2006). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472230">"Curcumin-Artemisinin Combination Therapy for Malaria"</a>. <i>Antimicrobial Agents and Chemotherapy</i>. <b>50</b> (5): <span class="nowrap">1859–</span>1860. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1128%2FAAC.50.5.1859-1860.2006">10.1128/AAC.50.5.1859-1860.2006</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0066-4804">0066-4804</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472230">1472230</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16641461">16641461</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Antimicrobial+Agents+and+Chemotherapy&rft.atitle=Curcumin-Artemisinin+Combination+Therapy+for+Malaria&rft.volume=50&rft.issue=5&rft.pages=%3Cspan+class%3D%22nowrap%22%3E1859-%3C%2Fspan%3E1860&rft.date=2006&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC1472230%23id-name%3DPMC&rft.issn=0066-4804&rft_id=info%3Apmid%2F16641461&rft_id=info%3Adoi%2F10.1128%2FAAC.50.5.1859-1860.2006&rft.aulast=Nandakumar&rft.aufirst=Dalavaikodihalli+Nanjaiah&rft.au=Nagaraj%2C+Viswanathan+Arun&rft.au=Vathsala%2C+Palakkod+Govindan&rft.au=Rangarajan%2C+Pundi&rft.au=Padmanaban%2C+Govindarajan&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC1472230&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-16"><span class="mw-cite-backlink"><b><a href="#cite_ref-16">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFDangFuZhangLiu2021" class="citation journal cs1">Dang, Jingyi; Fu, Jun; Zhang, Zhao; Liu, Dong; Cheng, Debin; Fan, Hongbin (2021). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756232">"Comparison between trabectedin and doxorubicin in soft-tissue sarcomas: a systematic review and meta-analysis"</a>. <i>Annals of Translational Medicine</i>. <b>9</b> (24): 1764. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://doi.org/10.21037%2Fatm-21-6033">10.21037/atm-21-6033</a></span>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/2305-5839">2305-5839</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756232">8756232</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/35071458">35071458</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Annals+of+Translational+Medicine&rft.atitle=Comparison+between+trabectedin+and+doxorubicin+in+soft-tissue+sarcomas%3A+a+systematic+review+and+meta-analysis&rft.volume=9&rft.issue=24&rft.pages=1764&rft.date=2021&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC8756232%23id-name%3DPMC&rft.issn=2305-5839&rft_id=info%3Apmid%2F35071458&rft_id=info%3Adoi%2F10.21037%2Fatm-21-6033&rft.aulast=Dang&rft.aufirst=Jingyi&rft.au=Fu%2C+Jun&rft.au=Zhang%2C+Zhao&rft.au=Liu%2C+Dong&rft.au=Cheng%2C+Debin&rft.au=Fan%2C+Hongbin&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC8756232&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-17"><span class="mw-cite-backlink"><b><a href="#cite_ref-17">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFKelloggScarsdaleFornari1998" class="citation journal cs1">Kellogg, G. E.; Scarsdale, J. N.; Fornari, F. A. (1998). <a rel="nofollow" class="external text" href="https://dx.doi.org/10.1093/nar/26.20.4721">"Identification and hydropathic characterization of structural features affecting sequence specificity for doxorubicin intercalation into DNA double-stranded polynucleotides"</a>. <i>Nucleic Acids Research</i>. <b>26</b> (20): <span class="nowrap">4721–</span>4732. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1093%2Fnar%2F26.20.4721">10.1093/nar/26.20.4721</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0305-1048">0305-1048</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC147880">147880</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/9753742">9753742</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Nucleic+Acids+Research&rft.atitle=Identification+and+hydropathic+characterization+of+structural+features+affecting+sequence+specificity+for+doxorubicin+intercalation+into+DNA+double-stranded+polynucleotides&rft.volume=26&rft.issue=20&rft.pages=%3Cspan+class%3D%22nowrap%22%3E4721-%3C%2Fspan%3E4732&rft.date=1998&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC147880%23id-name%3DPMC&rft.issn=0305-1048&rft_id=info%3Apmid%2F9753742&rft_id=info%3Adoi%2F10.1093%2Fnar%2F26.20.4721&rft.aulast=Kellogg&rft.aufirst=G.+E.&rft.au=Scarsdale%2C+J.+N.&rft.au=Fornari%2C+F.+A.&rft_id=http%3A%2F%2Fdx.doi.org%2F10.1093%2Fnar%2F26.20.4721&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-18"><span class="mw-cite-backlink"><b><a href="#cite_ref-18">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFZewail-FooteLiKohnBearss2001" class="citation journal cs1">Zewail-Foote, Maha; Li, Ven-Shun; Kohn, Harold; Bearss, David; Guzman, Mary; Hurley, Laurence H (2001). <a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs1074-5521%2801%2900071-0">"The inefficiency of incisions of ecteinascidin 743–DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent"</a>. <i>Chemistry & Biology</i>. <b>8</b> (11): <span class="nowrap">1033–</span>1049. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs1074-5521%2801%2900071-0">10.1016/s1074-5521(01)00071-0</a></span>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1074-5521">1074-5521</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/11731295">11731295</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Chemistry+%26+Biology&rft.atitle=The+inefficiency+of+incisions+of+ecteinascidin+743%E2%80%93DNA+adducts+by+the+UvrABC+nuclease+and+the+unique+structural+feature+of+the+DNA+adducts+can+be+used+to+explain+the+repair-dependent+toxicities+of+this+antitumor+agent&rft.volume=8&rft.issue=11&rft.pages=%3Cspan+class%3D%22nowrap%22%3E1033-%3C%2Fspan%3E1049&rft.date=2001&rft.issn=1074-5521&rft_id=info%3Apmid%2F11731295&rft_id=info%3Adoi%2F10.1016%2Fs1074-5521%2801%2900071-0&rft.aulast=Zewail-Foote&rft.aufirst=Maha&rft.au=Li%2C+Ven-Shun&rft.au=Kohn%2C+Harold&rft.au=Bearss%2C+David&rft.au=Guzman%2C+Mary&rft.au=Hurley%2C+Laurence+H&rft_id=https%3A%2F%2Fdoi.org%2F10.1016%252Fs1074-5521%252801%252900071-0&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-19"><span class="mw-cite-backlink"><b><a href="#cite_ref-19">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFHemanta_BaruahColin_G._BarryUlrich_Bierbach2004" class="citation journal cs1">Hemanta Baruah; Colin G. Barry; Ulrich Bierbach (2004). <a rel="nofollow" class="external text" href="https://dx.doi.org/10.2174/1568026043387313">"Platinum-Intercalator Conjugates: From DNA-Targeted Cisplatin Derivatives to Adenine Binding Complexes as Potential Modulators of Gene Regulation"</a>. <i>Current Topics in Medicinal Chemistry</i>. <b>4</b> (15): <span class="nowrap">1537–</span>1549. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.2174%2F1568026043387313">10.2174/1568026043387313</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1568-0266">1568-0266</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/15579095">15579095</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Current+Topics+in+Medicinal+Chemistry&rft.atitle=Platinum-Intercalator+Conjugates%3A+From+DNA-Targeted+Cisplatin+Derivatives+to+Adenine+Binding+Complexes+as+Potential+Modulators+of+Gene+Regulation&rft.volume=4&rft.issue=15&rft.pages=%3Cspan+class%3D%22nowrap%22%3E1537-%3C%2Fspan%3E1549&rft.date=2004&rft.issn=1568-0266&rft_id=info%3Apmid%2F15579095&rft_id=info%3Adoi%2F10.2174%2F1568026043387313&rft.au=Hemanta+Baruah&rft.au=Colin+G.+Barry&rft.au=Ulrich+Bierbach&rft_id=http%3A%2F%2Fdx.doi.org%2F10.2174%2F1568026043387313&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-20"><span class="mw-cite-backlink"><b><a href="#cite_ref-20">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFChou2006" class="citation journal cs1">Chou, Ting-Chao (2006). <a rel="nofollow" class="external text" href="https://dx.doi.org/10.1124/pr.58.3.10">"Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies"</a>. <i>Pharmacological Reviews</i>. <b>58</b> (3): <span class="nowrap">621–</span>681. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1124%2Fpr.58.3.10">10.1124/pr.58.3.10</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0031-6997">0031-6997</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16968952">16968952</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:7055257">7055257</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Pharmacological+Reviews&rft.atitle=Theoretical+Basis%2C+Experimental+Design%2C+and+Computerized+Simulation+of+Synergism+and+Antagonism+in+Drug+Combination+Studies&rft.volume=58&rft.issue=3&rft.pages=%3Cspan+class%3D%22nowrap%22%3E621-%3C%2Fspan%3E681&rft.date=2006&rft.issn=0031-6997&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A7055257%23id-name%3DS2CID&rft_id=info%3Apmid%2F16968952&rft_id=info%3Adoi%2F10.1124%2Fpr.58.3.10&rft.aulast=Chou&rft.aufirst=Ting-Chao&rft_id=http%3A%2F%2Fdx.doi.org%2F10.1124%2Fpr.58.3.10&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-21"><span class="mw-cite-backlink"><b><a href="#cite_ref-21">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFRoellReifMotsinger-Reif2017" class="citation journal cs1">Roell, Kyle R.; Reif, David M.; Motsinger-Reif, Alison A. (2017). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397413">"An Introduction to Terminology and Methodology of Chemical Synergy—Perspectives from Across Disciplines"</a>. <i>Frontiers in Pharmacology</i>. <b>8</b>: 158. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://doi.org/10.3389%2Ffphar.2017.00158">10.3389/fphar.2017.00158</a></span>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1663-9812">1663-9812</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397413">5397413</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/28473769">28473769</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Frontiers+in+Pharmacology&rft.atitle=An+Introduction+to+Terminology+and+Methodology+of+Chemical+Synergy%E2%80%94Perspectives+from+Across+Disciplines&rft.volume=8&rft.pages=158&rft.date=2017&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC5397413%23id-name%3DPMC&rft.issn=1663-9812&rft_id=info%3Apmid%2F28473769&rft_id=info%3Adoi%2F10.3389%2Ffphar.2017.00158&rft.aulast=Roell&rft.aufirst=Kyle+R.&rft.au=Reif%2C+David+M.&rft.au=Motsinger-Reif%2C+Alison+A.&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC5397413&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-22"><span class="mw-cite-backlink"><b><a href="#cite_ref-22">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFGovernment_of_Canada2022" class="citation web cs1">Government of Canada, Canadian Centre for Occupational Health and Safety (2022). <a rel="nofollow" class="external text" href="https://www.ccohs.ca/oshanswers/chemicals/synergism.html">"Synergism and related terms : OSH Answers"</a>. <i>www.ccohs.ca</i><span class="reference-accessdate">. Retrieved <span class="nowrap">2022-03-16</span></span>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=unknown&rft.jtitle=www.ccohs.ca&rft.atitle=Synergism+and+related+terms+%3A+OSH+Answers&rft.date=2022&rft.aulast=Government+of+Canada&rft.aufirst=Canadian+Centre+for+Occupational+Health+and+Safety&rft_id=https%3A%2F%2Fwww.ccohs.ca%2Foshanswers%2Fchemicals%2Fsynergism.html&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-:1-23"><span class="mw-cite-backlink">^ <a href="#cite_ref-:1_23-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-:1_23-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFJiaZhuMaCao2009" class="citation journal cs1">Jia, Jia; Zhu, Feng; Ma, Xiaohua; Cao, Zhiwei W.; Li, Yixue X.; Chen, Yu Zong (2009). <a rel="nofollow" class="external text" href="https://dx.doi.org/10.1038/nrd2683">"Mechanisms of drug combinations: interaction and network perspectives"</a>. <i>Nature Reviews Drug Discovery</i>. <b>8</b> (2): <span class="nowrap">111–</span>128. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1038%2Fnrd2683">10.1038/nrd2683</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1474-1776">1474-1776</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/19180105">19180105</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:54466254">54466254</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Nature+Reviews+Drug+Discovery&rft.atitle=Mechanisms+of+drug+combinations%3A+interaction+and+network+perspectives&rft.volume=8&rft.issue=2&rft.pages=%3Cspan+class%3D%22nowrap%22%3E111-%3C%2Fspan%3E128&rft.date=2009&rft.issn=1474-1776&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A54466254%23id-name%3DS2CID&rft_id=info%3Apmid%2F19180105&rft_id=info%3Adoi%2F10.1038%2Fnrd2683&rft.aulast=Jia&rft.aufirst=Jia&rft.au=Zhu%2C+Feng&rft.au=Ma%2C+Xiaohua&rft.au=Cao%2C+Zhiwei+W.&rft.au=Li%2C+Yixue+X.&rft.au=Chen%2C+Yu+Zong&rft_id=http%3A%2F%2Fdx.doi.org%2F10.1038%2Fnrd2683&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-24"><span class="mw-cite-backlink"><b><a href="#cite_ref-24">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFJohnson2004" class="citation journal cs1">Johnson, Malcolm (2004). <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16113435">"Interactions between corticosteroids and beta2-agonists in asthma and chronic obstructive pulmonary disease"</a>. <i>Proceedings of the American Thoracic Society</i>. <b>1</b> (3): <span class="nowrap">200–</span>206. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1513%2Fpats.200402-010MS">10.1513/pats.200402-010MS</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1546-3222">1546-3222</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16113435">16113435</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Proceedings+of+the+American+Thoracic+Society&rft.atitle=Interactions+between+corticosteroids+and+beta2-agonists+in+asthma+and+chronic+obstructive+pulmonary+disease&rft.volume=1&rft.issue=3&rft.pages=%3Cspan+class%3D%22nowrap%22%3E200-%3C%2Fspan%3E206&rft.date=2004&rft.issn=1546-3222&rft_id=info%3Apmid%2F16113435&rft_id=info%3Adoi%2F10.1513%2Fpats.200402-010MS&rft.aulast=Johnson&rft.aufirst=Malcolm&rft_id=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F16113435&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-25"><span class="mw-cite-backlink"><b><a href="#cite_ref-25">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite class="citation web cs1"><a rel="nofollow" class="external text" href="https://www.mims.com/hongkong/drug/info/seretide?type=full">"Seretide Full Prescribing Information, Dosage & Side Effects | MIMS Hong Kong"</a>. <i>www.mims.com</i><span class="reference-accessdate">. Retrieved <span class="nowrap">2022-04-18</span></span>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=unknown&rft.jtitle=www.mims.com&rft.atitle=Seretide+Full+Prescribing+Information%2C+Dosage+%26+Side+Effects+%7C+MIMS+Hong+Kong&rft_id=https%3A%2F%2Fwww.mims.com%2Fhongkong%2Fdrug%2Finfo%2Fseretide%3Ftype%3Dfull&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-26"><span class="mw-cite-backlink"><b><a href="#cite_ref-26">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFVolpeTocci2012" class="citation journal cs1">Volpe, Massimo; Tocci, Giuliano (2012). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383291">"Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic"</a>. <i>Vascular Health and Risk Management</i>. <b>8</b>: <span class="nowrap">371–</span>380. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://doi.org/10.2147%2FVHRM.S28359">10.2147/VHRM.S28359</a></span>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1178-2048">1178-2048</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383291">3383291</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/22745561">22745561</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Vascular+Health+and+Risk+Management&rft.atitle=Rationale+for+triple+fixed-dose+combination+therapy+with+an+angiotensin+II+receptor+blocker%2C+a+calcium+channel+blocker%2C+and+a+thiazide+diuretic&rft.volume=8&rft.pages=%3Cspan+class%3D%22nowrap%22%3E371-%3C%2Fspan%3E380&rft.date=2012&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC3383291%23id-name%3DPMC&rft.issn=1178-2048&rft_id=info%3Apmid%2F22745561&rft_id=info%3Adoi%2F10.2147%2FVHRM.S28359&rft.aulast=Volpe&rft.aufirst=Massimo&rft.au=Tocci%2C+Giuliano&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC3383291&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-27"><span class="mw-cite-backlink"><b><a href="#cite_ref-27">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFKostis2010" class="citation journal cs1">Kostis, John B. (2010). <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/19433970">"Antihypertensive therapy with CCB/ARB combination in older individuals: focus on amlodipine/valsartan combination"</a>. <i>American Journal of Therapeutics</i>. <b>17</b> (2): <span class="nowrap">188–</span>196. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1097%2FMJT.0b013e3181a2ba2d">10.1097/MJT.0b013e3181a2ba2d</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/1536-3686">1536-3686</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/19433970">19433970</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:205809141">205809141</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=American+Journal+of+Therapeutics&rft.atitle=Antihypertensive+therapy+with+CCB%2FARB+combination+in+older+individuals%3A+focus+on+amlodipine%2Fvalsartan+combination&rft.volume=17&rft.issue=2&rft.pages=%3Cspan+class%3D%22nowrap%22%3E188-%3C%2Fspan%3E196&rft.date=2010&rft.issn=1536-3686&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A205809141%23id-name%3DS2CID&rft_id=info%3Apmid%2F19433970&rft_id=info%3Adoi%2F10.1097%2FMJT.0b013e3181a2ba2d&rft.aulast=Kostis&rft.aufirst=John+B.&rft_id=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F19433970&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-28"><span class="mw-cite-backlink"><b><a href="#cite_ref-28">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFSimons2002" class="citation journal cs1">Simons, Leon A. (2002). <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/12356387">"Additive effect of plant sterol-ester margarine and cerivastatin in lowering low-density lipoprotein cholesterol in primary hypercholesterolemia"</a>. <i>The American Journal of Cardiology</i>. <b>90</b> (7): <span class="nowrap">737–</span>740. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs0002-9149%2802%2902600-0">10.1016/s0002-9149(02)02600-0</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0002-9149">0002-9149</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/12356387">12356387</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=The+American+Journal+of+Cardiology&rft.atitle=Additive+effect+of+plant+sterol-ester+margarine+and+cerivastatin+in+lowering+low-density+lipoprotein+cholesterol+in+primary+hypercholesterolemia&rft.volume=90&rft.issue=7&rft.pages=%3Cspan+class%3D%22nowrap%22%3E737-%3C%2Fspan%3E740&rft.date=2002&rft.issn=0002-9149&rft_id=info%3Apmid%2F12356387&rft_id=info%3Adoi%2F10.1016%2Fs0002-9149%2802%2902600-0&rft.aulast=Simons&rft.aufirst=Leon+A.&rft_id=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F12356387&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-29"><span class="mw-cite-backlink"><b><a href="#cite_ref-29">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite class="citation web cs1"><a rel="nofollow" class="external text" href="https://www.merckmanuals.com/home/cancer/prevention-and-treatment-of-cancer/combination-cancer-therapy">"Combination Cancer Therapy - Cancer"</a>. <i>Merck Manuals Consumer Version</i><span class="reference-accessdate">. Retrieved <span class="nowrap">2022-03-16</span></span>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=unknown&rft.jtitle=Merck+Manuals+Consumer+Version&rft.atitle=Combination+Cancer+Therapy+-+Cancer&rft_id=https%3A%2F%2Fwww.merckmanuals.com%2Fhome%2Fcancer%2Fprevention-and-treatment-of-cancer%2Fcombination-cancer-therapy&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-30"><span class="mw-cite-backlink"><b><a href="#cite_ref-30">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFShenfield1982" class="citation journal cs1">Shenfield, G. M. (1982). <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/7049658">"Fixed combination drug therapy"</a>. <i>Drugs</i>. <b>23</b> (6): <span class="nowrap">462–</span>480. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.2165%2F00003495-198223060-00003">10.2165/00003495-198223060-00003</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0012-6667">0012-6667</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/7049658">7049658</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:25856967">25856967</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Drugs&rft.atitle=Fixed+combination+drug+therapy&rft.volume=23&rft.issue=6&rft.pages=%3Cspan+class%3D%22nowrap%22%3E462-%3C%2Fspan%3E480&rft.date=1982&rft.issn=0012-6667&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A25856967%23id-name%3DS2CID&rft_id=info%3Apmid%2F7049658&rft_id=info%3Adoi%2F10.2165%2F00003495-198223060-00003&rft.aulast=Shenfield&rft.aufirst=G.+M.&rft_id=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F7049658&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-31"><span class="mw-cite-backlink"><b><a href="#cite_ref-31">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFLeonRosingBonowEpstein1985" class="citation journal cs1">Leon, Martin B.; Rosing, Douglas R.; Bonow, Robert O.; Epstein, Stephen E. (1985-01-25). <a rel="nofollow" class="external text" href="https://www.ajconline.org/article/0002-9149(85)90615-0/abstract">"Combination therapy with calcium-channel blockers and beta blockers for chronic stable angina pectoris"</a>. <i>American Journal of Cardiology</i>. <b>55</b> (3): <span class="nowrap">B69 –</span> <span class="nowrap">B80</span>. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2F0002-9149%2885%2990615-0">10.1016/0002-9149(85)90615-0</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0002-9149">0002-9149</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/2857518">2857518</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=American+Journal+of+Cardiology&rft.atitle=Combination+therapy+with+calcium-channel+blockers+and+beta+blockers+for+chronic+stable+angina+pectoris&rft.volume=55&rft.issue=3&rft.pages=%3Cspan+class%3D%22nowrap%22%3EB69+-%3C%2Fspan%3E+%3Cspan+class%3D%22nowrap%22%3EB80%3C%2Fspan%3E&rft.date=1985-01-25&rft.issn=0002-9149&rft_id=info%3Apmid%2F2857518&rft_id=info%3Adoi%2F10.1016%2F0002-9149%2885%2990615-0&rft.aulast=Leon&rft.aufirst=Martin+B.&rft.au=Rosing%2C+Douglas+R.&rft.au=Bonow%2C+Robert+O.&rft.au=Epstein%2C+Stephen+E.&rft_id=https%3A%2F%2Fwww.ajconline.org%2Farticle%2F0002-9149%2885%2990615-0%2Fabstract&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-32"><span class="mw-cite-backlink"><b><a href="#cite_ref-32">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFHsiangNgLuChen2010" class="citation journal cs1">Hsiang, Kuo-Wei; Ng, Yee-Yung; Lu, Ching-Liang; Chen, Tseng-Shing; Lin, Hsiao-Yi; Luo, Jiing-Chyuan; Wu, Jia-Min; Lin, Han-Chieh; Chang, Full-Young; Lee, Shou-Dong (2010). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997316">"Corticosteroids therapy and peptic ulcer disease in nephrotic syndrome patients: Steroid therapy and peptic ulcer disease"</a>. <i>British Journal of Clinical Pharmacology</i>. <b>70</b> (5): <span class="nowrap">756–</span>761. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1111%2Fj.1365-2125.2010.03752.x">10.1111/j.1365-2125.2010.03752.x</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997316">2997316</a></span>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=British+Journal+of+Clinical+Pharmacology&rft.atitle=Corticosteroids+therapy+and+peptic+ulcer+disease+in+nephrotic+syndrome+patients%3A+Steroid+therapy+and+peptic+ulcer+disease&rft.volume=70&rft.issue=5&rft.pages=%3Cspan+class%3D%22nowrap%22%3E756-%3C%2Fspan%3E761&rft.date=2010&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC2997316%23id-name%3DPMC&rft_id=info%3Adoi%2F10.1111%2Fj.1365-2125.2010.03752.x&rft.aulast=Hsiang&rft.aufirst=Kuo-Wei&rft.au=Ng%2C+Yee-Yung&rft.au=Lu%2C+Ching-Liang&rft.au=Chen%2C+Tseng-Shing&rft.au=Lin%2C+Hsiao-Yi&rft.au=Luo%2C+Jiing-Chyuan&rft.au=Wu%2C+Jia-Min&rft.au=Lin%2C+Han-Chieh&rft.au=Chang%2C+Full-Young&rft.au=Lee%2C+Shou-Dong&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC2997316&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> <li id="cite_note-33"><span class="mw-cite-backlink"><b><a href="#cite_ref-33">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFDrina2017" class="citation journal cs1">Drina, Musa (2017-06-01). <a rel="nofollow" class="external text" href="https://www.nps.org.au/australian-prescriber/articles/peptic-ulcer-disease-and-non-steroidal-anti-inflammatory-drugs">"Peptic ulcer disease and non-steroidal anti-inflammatory drugs"</a>. <i>Australian Prescriber</i>. <b>40</b> (3): <span class="nowrap">91–</span>93. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.18773%2Faustprescr.2017.037">10.18773/austprescr.2017.037</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478398">5478398</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/28798512">28798512</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Australian+Prescriber&rft.atitle=Peptic+ulcer+disease+and+non-steroidal+anti-inflammatory+drugs&rft.volume=40&rft.issue=3&rft.pages=%3Cspan+class%3D%22nowrap%22%3E91-%3C%2Fspan%3E93&rft.date=2017-06-01&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC5478398%23id-name%3DPMC&rft_id=info%3Apmid%2F28798512&rft_id=info%3Adoi%2F10.18773%2Faustprescr.2017.037&rft.aulast=Drina&rft.aufirst=Musa&rft_id=https%3A%2F%2Fwww.nps.org.au%2Faustralian-prescriber%2Farticles%2Fpeptic-ulcer-disease-and-non-steroidal-anti-inflammatory-drugs&rfr_id=info%3Asid%2Fen.wikipedia.org%3AAdditive+effect" class="Z3988"></span></span> </li> </ol></div></div>    </div><noscript><img src="https://login.wikimedia.org/wiki/Special:CentralAutoLogin/start?useformat=desktop&type=1x1&usesul3=0" alt="" width="1" height="1" style="border: none; position: absolute;"></noscript> <div class="printfooter" data-nosnippet="">Retrieved from "<a dir="ltr" href="https://en.wikipedia.org/w/index.php?title=Additive_effect&oldid=1256458693#Detection_of_synergy">https://en.wikipedia.org/w/index.php?title=Additive_effect&oldid=1256458693#Detection_of_synergy</a>"</div></div> <div id="catlinks" class="catlinks" data-mw="interface"><div id="mw-normal-catlinks" class="mw-normal-catlinks"><a href="/wiki/Help:Category" title="Help:Category">Category</a>: <ul><li><a href="/wiki/Category:Pharmacology" title="Category:Pharmacology">Pharmacology</a></li></ul></div><div id="mw-hidden-catlinks" class="mw-hidden-catlinks mw-hidden-cats-hidden">Hidden categories: <ul><li><a href="/wiki/Category:All_articles_with_unsourced_statements" title="Category:All articles with unsourced statements">All articles with unsourced statements</a></li><li><a href="/wiki/Category:Articles_with_unsourced_statements_from_May_2022" title="Category:Articles with unsourced statements from May 2022">Articles with unsourced statements from May 2022</a></li></ul></div></div> </div> </main> </div> <div class="mw-footer-container"> <footer id="footer" class="mw-footer" > <ul id="footer-info"> <li id="footer-info-lastmod"> This page was last edited on 10 November 2024, at 01:00<span class="anonymous-show"> (UTC)</span>.</li> <li id="footer-info-copyright">Text is available under the <a href="/wiki/Wikipedia:Text_of_the_Creative_Commons_Attribution-ShareAlike_4.0_International_License" title="Wikipedia:Text of the Creative Commons Attribution-ShareAlike 4.0 International License">Creative Commons Attribution-ShareAlike 4.0 License</a>; additional terms may apply. By using this site, you agree to the <a href="https://foundation.wikimedia.org/wiki/Special:MyLanguage/Policy:Terms_of_Use" class="extiw" title="foundation:Special:MyLanguage/Policy:Terms of Use">Terms of Use</a> and <a href="https://foundation.wikimedia.org/wiki/Special:MyLanguage/Policy:Privacy_policy" class="extiw" title="foundation:Special:MyLanguage/Policy:Privacy policy">Privacy Policy</a>. Wikipedia® is a registered trademark of the <a rel="nofollow" class="external text" href="https://wikimediafoundation.org/">Wikimedia Foundation, Inc.</a>, a non-profit organization.</li> </ul> <ul id="footer-places"> <li id="footer-places-privacy"><a href="https://foundation.wikimedia.org/wiki/Special:MyLanguage/Policy:Privacy_policy">Privacy policy</a></li> <li id="footer-places-about"><a href="/wiki/Wikipedia:About">About Wikipedia</a></li> <li id="footer-places-disclaimers"><a href="/wiki/Wikipedia:General_disclaimer">Disclaimers</a></li> <li id="footer-places-contact"><a href="//en.wikipedia.org/wiki/Wikipedia:Contact_us">Contact Wikipedia</a></li> <li id="footer-places-wm-codeofconduct"><a href="https://foundation.wikimedia.org/wiki/Special:MyLanguage/Policy:Universal_Code_of_Conduct">Code of Conduct</a></li> <li id="footer-places-developers"><a href="https://developer.wikimedia.org">Developers</a></li> <li id="footer-places-statslink"><a href="https://stats.wikimedia.org/#/en.wikipedia.org">Statistics</a></li> <li id="footer-places-cookiestatement"><a href="https://foundation.wikimedia.org/wiki/Special:MyLanguage/Policy:Cookie_statement">Cookie statement</a></li> <li id="footer-places-mobileview"><a href="//en.m.wikipedia.org/w/index.php?title=Additive_effect&mobileaction=toggle_view_mobile#Detection_of_synergy" class="noprint stopMobileRedirectToggle">Mobile view</a></li> </ul> <ul id="footer-icons" class="noprint"> <li id="footer-copyrightico"><a href="https://www.wikimedia.org/" class="cdx-button cdx-button--fake-button cdx-button--size-large cdx-button--fake-button--enabled"><picture><source media="(min-width: 500px)" srcset="/static/images/footer/wikimedia-button.svg" width="84" height="29"><img src="/static/images/footer/wikimedia.svg" width="25" height="25" alt="Wikimedia Foundation" lang="en" loading="lazy"></picture></a></li> <li id="footer-poweredbyico"><a href="https://www.mediawiki.org/" class="cdx-button cdx-button--fake-button cdx-button--size-large cdx-button--fake-button--enabled"><picture><source media="(min-width: 500px)" srcset="/w/resources/assets/poweredby_mediawiki.svg" width="88" height="31"><img src="/w/resources/assets/mediawiki_compact.svg" alt="Powered by MediaWiki" lang="en" width="25" height="25" loading="lazy"></picture></a></li> </ul> </footer> </div> </div> </div> <div class="vector-header-container vector-sticky-header-container"> <div id="vector-sticky-header" class="vector-sticky-header"> <div class="vector-sticky-header-start"> <div class="vector-sticky-header-icon-start vector-button-flush-left vector-button-flush-right" aria-hidden="true"> <button class="cdx-button cdx-button--weight-quiet cdx-button--icon-only vector-sticky-header-search-toggle" tabindex="-1" data-event-name="ui.vector-sticky-search-form.icon"><span class="vector-icon mw-ui-icon-search mw-ui-icon-wikimedia-search"></span> <span>Search</span> </button> </div> <div role="search" class="vector-search-box-vue vector-search-box-show-thumbnail vector-search-box"> <div class="vector-typeahead-search-container"> <div class="cdx-typeahead-search cdx-typeahead-search--show-thumbnail"> <form action="/w/index.php" id="vector-sticky-search-form" class="cdx-search-input cdx-search-input--has-end-button"> <div class="cdx-search-input__input-wrapper" data-search-loc="header-moved"> <div class="cdx-text-input cdx-text-input--has-start-icon"> <input class="cdx-text-input__input" type="search" name="search" placeholder="Search Wikipedia"> <span class="cdx-text-input__icon cdx-text-input__start-icon"></span> </div> <input type="hidden" name="title" value="Special:Search"> </div> <button class="cdx-button cdx-search-input__end-button">Search</button> </form> </div> </div> </div> <div class="vector-sticky-header-context-bar"> <nav aria-label="Contents" class="vector-toc-landmark"> <div id="vector-sticky-header-toc" class="vector-dropdown mw-portlet mw-portlet-sticky-header-toc vector-sticky-header-toc vector-button-flush-left" > <input type="checkbox" id="vector-sticky-header-toc-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-vector-sticky-header-toc" class="vector-dropdown-checkbox " aria-label="Toggle the table of contents" > <label id="vector-sticky-header-toc-label" for="vector-sticky-header-toc-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only " aria-hidden="true" ><span class="vector-icon mw-ui-icon-listBullet mw-ui-icon-wikimedia-listBullet"></span> <span class="vector-dropdown-label-text">Toggle the table of contents</span> </label> <div class="vector-dropdown-content"> <div id="vector-sticky-header-toc-unpinned-container" class="vector-unpinned-container"> </div> </div> </div> </nav> <div class="vector-sticky-header-context-bar-primary" aria-hidden="true" ><span class="mw-page-title-main">Additive effect</span></div> </div> </div> <div class="vector-sticky-header-end" aria-hidden="true"> <div class="vector-sticky-header-icons"> <a href="#" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only" id="ca-talk-sticky-header" tabindex="-1" data-event-name="talk-sticky-header"><span class="vector-icon mw-ui-icon-speechBubbles mw-ui-icon-wikimedia-speechBubbles"></span> <span></span> </a> <a href="#" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only" id="ca-subject-sticky-header" tabindex="-1" data-event-name="subject-sticky-header"><span class="vector-icon mw-ui-icon-article mw-ui-icon-wikimedia-article"></span> <span></span> </a> <a href="#" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only" id="ca-history-sticky-header" tabindex="-1" data-event-name="history-sticky-header"><span class="vector-icon mw-ui-icon-wikimedia-history mw-ui-icon-wikimedia-wikimedia-history"></span> <span></span> </a> <a href="#" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only mw-watchlink" id="ca-watchstar-sticky-header" tabindex="-1" data-event-name="watch-sticky-header"><span class="vector-icon mw-ui-icon-wikimedia-star mw-ui-icon-wikimedia-wikimedia-star"></span> <span></span> </a> <a href="#" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only" id="ca-edit-sticky-header" tabindex="-1" data-event-name="wikitext-edit-sticky-header"><span class="vector-icon mw-ui-icon-wikimedia-wikiText mw-ui-icon-wikimedia-wikimedia-wikiText"></span> <span></span> </a> <a href="#" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only" id="ca-ve-edit-sticky-header" tabindex="-1" data-event-name="ve-edit-sticky-header"><span class="vector-icon mw-ui-icon-wikimedia-edit mw-ui-icon-wikimedia-wikimedia-edit"></span> <span></span> </a> <a href="#" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--icon-only" id="ca-viewsource-sticky-header" tabindex="-1" data-event-name="ve-edit-protected-sticky-header"><span class="vector-icon mw-ui-icon-wikimedia-editLock mw-ui-icon-wikimedia-wikimedia-editLock"></span> <span></span> </a> </div> <div class="vector-sticky-header-buttons"> <button class="cdx-button cdx-button--weight-quiet mw-interlanguage-selector" id="p-lang-btn-sticky-header" tabindex="-1" data-event-name="ui.dropdown-p-lang-btn-sticky-header"><span class="vector-icon mw-ui-icon-wikimedia-language mw-ui-icon-wikimedia-wikimedia-language"></span> <span>2 languages</span> </button> <a href="#" class="cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--action-progressive" id="ca-addsection-sticky-header" tabindex="-1" data-event-name="addsection-sticky-header"><span class="vector-icon mw-ui-icon-speechBubbleAdd-progressive mw-ui-icon-wikimedia-speechBubbleAdd-progressive"></span> <span>Add topic</span> </a> </div> <div class="vector-sticky-header-icon-end"> <div class="vector-user-links"> </div> </div> </div> </div> </div> <div class="mw-portlet mw-portlet-dock-bottom emptyPortlet" id="p-dock-bottom"> <ul> </ul> </div> <script>(RLQ=window.RLQ||[]).push(function(){mw.config.set({"wgHostname":"mw-web.codfw.main-6fd9bbc867-vqrwh","wgBackendResponseTime":134,"wgPageParseReport":{"limitreport":{"cputime":"0.350","walltime":"0.397","ppvisitednodes":{"value":2157,"limit":1000000},"postexpandincludesize":{"value":89003,"limit":2097152},"templateargumentsize":{"value":638,"limit":2097152},"expansiondepth":{"value":12,"limit":100},"expensivefunctioncount":{"value":2,"limit":500},"unstrip-depth":{"value":1,"limit":20},"unstrip-size":{"value":128865,"limit":5000000},"entityaccesscount":{"value":0,"limit":400},"timingprofile":["100.00% 335.303 1 -total"," 80.97% 271.478 1 Template:Reflist"," 43.65% 146.345 26 Template:Cite_journal"," 26.43% 88.611 4 Template:Cite_web"," 17.26% 57.874 1 Template:Citation_needed"," 11.53% 38.671 1 Template:Fix"," 7.42% 24.864 2 Template:Category_handler"," 1.71% 5.736 1 Template:Delink"," 0.70% 2.342 1 Template:Fix/category"," 0.53% 1.766 2 Template:Main_other"]},"scribunto":{"limitreport-timeusage":{"value":"0.222","limit":"10.000"},"limitreport-memusage":{"value":5084434,"limit":52428800}},"cachereport":{"origin":"mw-web.codfw.main-7b4fff7949-5mwds","timestamp":"20250326151107","ttl":2592000,"transientcontent":false}}});});</script> <script type="application/ld+json">{"@context":"https:\/\/schema.org","@type":"Article","name":"Additive effect","url":"https:\/\/en.wikipedia.org\/wiki\/Additive_effect#Detection_of_synergy","sameAs":"http:\/\/www.wikidata.org\/entity\/Q112228119","mainEntity":"http:\/\/www.wikidata.org\/entity\/Q112228119","author":{"@type":"Organization","name":"Contributors to Wikimedia projects"},"publisher":{"@type":"Organization","name":"Wikimedia Foundation, Inc.","logo":{"@type":"ImageObject","url":"https:\/\/www.wikimedia.org\/static\/images\/wmf-hor-googpub.png"}},"datePublished":"2022-02-18T06:35:18Z","dateModified":"2024-11-10T01:00:49Z"}</script> </body> </html>