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Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="OBbiGBQOFQOCxqB8pisekKFiQvqhQ16K5oVnjrjafrB6rRHY2B5gOSbWoz8tJCE4">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="OBbiGBQOFQOCxqB8pisekKFiQvqhQ16K5oVnjrjafrB6rRHY2B5gOSbWoz8tJCE4">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="OBbiGBQOFQOCxqB8pisekKFiQvqhQ16K5oVnjrjafrB6rRHY2B5gOSbWoz8tJCE4">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="OBbiGBQOFQOCxqB8pisekKFiQvqhQ16K5oVnjrjafrB6rRHY2B5gOSbWoz8tJCE4">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="OBbiGBQOFQOCxqB8pisekKFiQvqhQ16K5oVnjrjafrB6rRHY2B5gOSbWoz8tJCE4">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="30880965">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://dx.doi.org/10.2147/IJN.S187139"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=7093&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=30880965&amp;db=pubmed&amp;nlmid=101263847"
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href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/30880965/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=30880965&amp;db=pubmed&amp;nlmid=101263847"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
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Free PMC article
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<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/30880965/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/30880965/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="30880965" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F30880965%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="OBbiGBQOFQOCxqB8pisekKFiQvqhQ16K5oVnjrjafrB6rRHY2B5gOSbWoz8tJCE4"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
Choose a collection:
</label><select id="collections-action-dialog-add-to-existing"
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Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice
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Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice
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<span class="authors-list-item "><a class="full-name"
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data-ga-label="Erik Őrfi">Erik Őrfi</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary, jszebeni2@gmail.com." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="SeroScience LCC., Cambridge, MA, USA, jszebeni2@gmail.com." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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><sup class="key">1</sup> Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary, jszebeni2@gmail.com.</li>
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><sup class="key">3</sup> TECOdevelopment GmbH, Rheinbach, Germany.</li>
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><sup class="key">4</sup> Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary.</li>
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><sup class="key">5</sup> Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.</li>
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><sup class="key">6</sup> Nanotechnology Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.</li>
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><sup class="key">7</sup> Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary, jszebeni2@gmail.com.</li>
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><sup class="key">8</sup> Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.</li>
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Purpose:
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Undesirable complement (C) activation by nanomedicines can entail an adverse immune reaction known as C activation-related pseudoallergy (CARPA) in sensitive patients. The syndrome includes cardiopulmonary, hemodynamic, and a variety of other physiological changes that have been well described in man, pigs, dogs, and rats. However, the information on CARPA is scarce and ambiguous in mice, a species widely used in preclinical studies. The present study aimed to fill this gap by exploring signs of CARPA in mice following i.v. administration of AmBisome and Abelcet, which are nano-formulations of Amphotericin B with high risk to cause CARPA.
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Materials and methods:
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Anesthetized NMRI mice were intravenously injected with liposomal amphotericin B (Abelcet and AmBisome; 30-300 mg phospholipid/kg), drug-free high cholesterol multilamellar vesicles (HC-MLV), and positive controls, cobra venom factor (CVF) and zymosan, followed by the measurement of blood pressure (BP), heart rate, white blood cell, and platelet counts and plasma thromboxane B2 (TXB2) levels. C activation was assessed by C3a ELISA, a C3 consumption assay (PAN-C3) and a modified sheep red blood cell hemolytic assay.
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</strong>
All test agents, except HC-MLV, caused transient hypertension, thrombocytopenia, and elevation of plasma TXB2, which were paralleled by significant rises of plasma C3a in CVF and zymosan-treated animals, wherein the initial hypertension turned into hypotension and shock. Abelcet and AmBisome caused minor, delayed rise of C3a that was not associated with hypertension. The C3a receptor inhibitor SB-290157 attenuated the hypertension caused by Abelcet and decreased the BP thereafter.
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</strong>
The parallelism between C3a anaphylatoxin production and severity of physiological changes caused by the different agents is consistent with CARPA underlying these changes. Although the reactive dose of liposomal phospholipids was substantially higher than that in other species (pigs, dogs), the mouse seems suitable for studying the mechanism of hypersensitivity reactions to liposomal formulations of amphotericin B, a frequent side effect of these drugs.
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Keywords:
</strong>
TXB2; anaphylatoxins; cholesterol; cobra venom factor; hypersensitivity; infusion reactions; platelets; zymosan.
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<div class="figure-caption-contents"><p> Schematic outline of the study… </p></div>
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<div class="figure-caption-contents"><p> Schematic outline of the study design. <b> Abbreviations: </b> BP, blood pressure; HR, heart rate. </p></div>
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Figure 1
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<div class="figure-caption-contents">Schematic outline of the study design. <b>Abbreviations:</b> BP, blood pressure; HR, heart rate.</div>
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<div class="figure-caption-contents"><p> Hemodynamic changes caused by complement activators and liposomes in male NMRI mice (n=56).… </p></div>
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Figure 2
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<div class="figure-caption-contents">Hemodynamic changes caused by complement activators and liposomes in male NMRI mice (n=56). <b>Note:</b> (<b>A</b>) Zymosan (30 mg/kg), (<b>B</b>) CVF 100 U/kg), (<b>C</b>) Abelcet (30 mg/kg), and (<b>D</b>) AmBisome (300 mg/kg) were administered as i.v. bolus at times indicated by the arrows. <b>Abbreviations:</b> CVF, cobra venom factor; NMRI, Naval Medical Research Institute.</div>
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<p> Figure 3 </p>
</strong>
<div class="figure-caption-contents"><p> Hematological changes ( <b> A </b> –… </p></div>
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<p> Figure 3 </p>
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<div class="figure-caption-contents"><p> Hematological changes ( <b> A </b> <b> C </b> ), TXB2 levels ( <b> D </b> ), complement… </p></div>
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Figure 3
</strong>
<div class="figure-caption-contents">Hematological changes (<b>A</b><b>C</b>), TXB2 levels (<b>D</b>), complement consumption (<b>E</b>), and plasma extravasation of Evans blue in various organs (<b>F</b>) of Zymosan-treated (30 mg/kg i.v.) male NMRI mice. <b>Notes:</b> The arrow indicates the time of treatment. The number of mice is n=35 for each time. Complement consumption was assessed using a modified sheep red blood cell hemolytic assay. The number of animals is eleven for the plasma extravasation test. Significant differences (*<i>P</i>&lt;0.05; **<i>P</i>&lt;0.01; ***<i>P</i>&lt;0.001) are shown in comparison to the baseline or vehicle treated control group in the case of extravasation. <b>Abbreviations:</b> NMRI, Naval Medical Research Institute; TXB2, thromboxane B2 levels.</div>
</figcaption>
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
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<strong class="figure-label">
<p> Figure 4 </p>
</strong>
<div class="figure-caption-contents"><p> Hematological effects of C activators… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 4 </p>
</strong>
<div class="figure-caption-contents"><p> Hematological effects of C activators and liposomes. <b> Notes: A </b> <b> D </b> show the… </p></div>
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Figure 4
</strong>
<div class="figure-caption-contents">Hematological effects of C activators and liposomes. <b>Notes: A</b><b>D</b> show the maximal changes of platelets, WBC, RBC and hematocrit, respectively, following injection of the C activators and liposomes, specified on the x-axis. n=811 mice for each assay. Significant differences (**<i>P</i>&lt;0.01; ***<i>P</i>&lt;0.001) relative to the group treated with saline (NS). *<sup>?</sup>HC-MLV interfered with the detection of WBC, these data are not reliable. <b>Abbreviations:</b> CVF, cobra venom factor; HC-MLV, high cholesterol multilamellar vesicles; RBC, red blood cell; WBC, white blood cell.</div>
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<strong class="figure-label">
<p> Figure 5 </p>
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<div class="figure-caption-contents"><p> Effects of C activators and… </p></div>
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<p> Figure 5 </p>
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<div class="figure-caption-contents"><p> Effects of C activators and liposomes on biomarkers of complement activation and TXB2… </p></div>
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<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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Figure 5
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<div class="figure-caption-contents">Effects of C activators and liposomes on biomarkers of complement activation and TXB2 levels. (<b>A</b>) Hemolytic C consumed, measured in a modified sheep red blood cell hemolytic assay, (<b>B</b>) C3 consumption evaluated by the PAN-C3 assay, and (<b>C</b>) mouse C3a, measured by mouse specific ELISA. (<b>D</b>) TXB2 levels measured by ELISA. n=811 mice for each assay. (<b>E</b>) The effects of Abelecet and AmBisome on plasma C3a measured at 3 minutes as well as 10, 20, and 30 minutes after treatment (the results for 1030 minutes are combined as C3a levels were similar at 10, 20, and 30 minutes). <b>Notes:</b> n=35 mice at each time. Significant differences (*<i>P</i>&lt;0.05; ***<i>P</i>&lt;0.001) relative to the group treated with saline (NS). <b>Abbreviations:</b> CVF, cobra venom factor; HC-MLV, high cholesterol multilamellar vesicles; RBC, red blood cell; TXB2, thromboxane B2 levels; WBC, white blood cell.</div>
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<p> Figure 6 </p>
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<div class="figure-caption-contents"><p> Effects of SB-290157 on the… </p></div>
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<p> Figure 6 </p>
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<div class="figure-caption-contents"><p> Effects of SB-290157 on the blood pressure and HR changes caused by Abelcet… </p></div>
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Figure 6
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<div class="figure-caption-contents">Effects of SB-290157 on the blood pressure and HR changes caused by Abelcet and comparison of the effects of Abelcet in NMRI and C57Bl/6N mice. Changes in mean arterial pressure (<b>A</b>) and HR (<b>B</b>) after pretreatment with SB-290157 at 10 mg/kg i.v. or its vehicle (5% DMSO in saline) and then administration of Abelcet at 30 mg/kg i.v. Comparison of changes in mean arterial pressure (<b>C</b>) and HR (<b>D</b>) in NMRI and C57Bl/6N mice after administration of Abelcet at 30 mg/kg i.v. <b>Note:</b> *<i>P</i>&lt;0.05; **<i>P</i>&lt;0.01; significant differences between the two groups. <b>Abbreviations:</b> HR, heart rate; MAP, mean arterial pressure; NMRI, Naval Medical Research Institute.</div>
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<p> Figure 7 </p>
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<div class="figure-caption-contents"><p> Double hit hypothesis of C… </p></div>
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<p> Figure 7 </p>
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<div class="figure-caption-contents"><p> Double hit hypothesis of C activator- and liposome-induced circulatory changes in mice. <b> Notes:… </b> </p></div>
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Figure 7
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<div class="figure-caption-contents">Double hit hypothesis of C activator- and liposome-induced circulatory changes in mice. <b>Notes:</b> Cells (blue) that can secrete vasoactive mediators (orange) can be stimulated either via anaphylatoxin-receptor (ATR, “AT hit”), or directly ((“C-independent hit”) leading to CARPA and C-independent pseudoallergy (CIPA)). Zymosan and CVF act via ATR, while AmBisome and Abelcet via a direct hit. The entailing physiological changes are listed on a black background. Italicized entries are hypothetical. <b>Abbreviations:</b> AT, anaphylatoxin; ATR, anaphylatoxin receptor; CARPA, C activation-related pseudoallergy; CIPA, C-independent pseudoallergy; CVF, cobra venom factor.</div>
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Szebeni J. Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology. 2005;216(23):106121.
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Szebeni J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol Immunol. 2014;61(2):163173.
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Dézsi L, Rosivall L, Hamar P, Szebeni J, Szénási G. Rodent models of complement activation-related pseudoallergy: inducers, symptoms, inhibitors and reaction mechanisms. Eur J Nanomed. 2015;7(1):15.
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Proctor LM, Moore TA, Monk PN, Sanderson SD, Taylor SM, Woodruff TM. Complement factors C3a and C5a have distinct hemodynamic effects in the rat. Int Immunopharmacol. 2009;9(6):800806.
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