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class="institution">Faculty of Medicine and Health, School of Pharmacy, The University of Sydney</div>, Sydney, NSW, <div class="country">Australia</div></div> </div> <div class="info-card-search-label"> Search for other works by this author on: </div> <div class="info-card-search info-card-search-internal"> <a href="/jpp/search-results?f_Authors=Jane+R+Hanrahan" rel="nofollow">Oxford Academic</a> </div> <div class="info-card-search info-card-search-google"> <a href="http://scholar.google.com/scholar?q=author:%22Hanrahan Jane R%22">Google Scholar</a> </div> </div> </span> </span> <span class="al-author-name-more js-flyout-wrap"> <button type="button" class="linked-name js-linked-name-trigger btn-as-link">Joanna E Harnett</button><span class='delimiter'></span> <span class="al-author-info-wrap arrow-up"> <div class="info-card-author authorInfo_OUP_ArticleTop_Info_Widget"> <div class="name-role-wrap"> <div class="info-card-name"> Joanna E Harnett <span class="info-card-footnote"><span class="xrefLink" id="jumplink-cor1"></span><a href="javascript:;" reveal-id="cor1" data-open="cor1" class="link link-ref link-reveal xref-default"></a></span> </div> </div> <div class="info-card-affilitation"> <div class="aff"><div class="institution">Faculty of Medicine and Health, School of Pharmacy, The University of Sydney</div>, Sydney, NSW, <div class="country">Australia</div></div><div class="aff"><div class="institution">Faculty of Health, Australian Research Centre of Complementary and Integrative Medicine, University of Technology Sydney</div>, Ultimo, NSW, <div class="country">Australia</div></div> </div> <div class="info-author-correspondence"> <div content-id="cor1"><strong>Correspondence</strong> Joanna E. Harnett, The School of Pharmacy, Badham Building A16, Science Rd, Camperdown, NSW 2006, Australia E-mail: <a href="mailto:joanna.harnett@sydney.edu.au" target="_blank">joanna.harnett@sydney.edu.au</a></div> </div> <div class="info-card-location"> <a id="contrib-orcid-0000-0001-9904-2144" href="https://orcid.org/0000-0001-9904-2144"> <img class="orchid-icon" alt="ORCID logo" aria-hidden="true" src="//oup.silverchair-cdn.com/Themes/Silver/app/img/mini-icon.png"/>  https://orcid.org/0000-0001-9904-2144 </a> </div> <div class="info-card-search-label"> Search for other works by this author on: </div> <div class="info-card-search info-card-search-internal"> <a href="/jpp/search-results?f_Authors=Joanna+E+Harnett" rel="nofollow">Oxford Academic</a> </div> <div class="info-card-search info-card-search-google"> <a href="http://scholar.google.com/scholar?q=author:%22Harnett Joanna E%22">Google Scholar</a> </div> </div> </span> </span> </div> </div> <div class="pub-history-wrap clearfix js-history-dropdown-wrap"> <div class="pub-history-row clearfix"> <div class="ww-citation-primary"><em>Journal of Pharmacy and Pharmacology</em>, Volume 72, Issue 1, January 2020, Pages 1–16, <a href='https://doi.org/10.1111/jphp.13182'>https://doi.org/10.1111/jphp.13182</a></div> </div> <div class="pub-history-row clearfix"> <div class="ww-citation-date-wrap"> <div class="citation-label">Published:</div> <div class="citation-date">01 January 2020</div> </div> <a href="javascript:;" class="history-label js-history-dropdown-trigger st-article-history at-ArticleHistory"> <span>Article history</span><i class="icon-general-arrow-filled-down arrow-icon"></i> </a> </div> <div class="ww-history js-history-entries-wrap at-history-entries-wrap"> <div class="history-entry at-history-entry"> <div class="wi-state">Received:</div> <div class="wi-date">24 July 2019</div> </div> <div class="history-entry at-history-entry"> <div class="wi-state">Accepted:</div> <div class="wi-date">23 September 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widget-ArticleFulltext widget-instance-OUP_Article_FullText_Widget"> <div class="module-widget"> <div class="widget-items" data-widgetname="ArticleFulltext"> <h2 scrollto-destination=491205013 id="491205013" class="abstract-title js-splitscreen-abstract-title" data-legacy-id=jphp13182-abs-0001>Abstract</h2> <section class="abstract"><div class=" sec"><div class="title">Objectives</div><p class="chapter-para"><em>Annona muricata</em>, also known as graviola, soursop and guanabana, has been widely utilised for the treatment of a range of cancers. The mechanism of action and the efficacy of <em>A. muricata</em> and its constituents in the treatment of cancer have been comprehensively reviewed. The aim of this systematic review was to summarise the available literature that reports on factors related to the safety and tolerability of <em>A. muricata</em> leaf extract and its acetogenins.</p></div><div class=" sec"><div class="title">Methods</div><p class="chapter-para"><em>In-vitro</em>, preclinical animal studies and human studies of any design written in any language were included. Studies that evaluated <em>A. muricata</em> leaf extract and its constituents were searched through the databases Pubmed, Medline and Embase from inception to April 2019. The elaborated item 4 of Consolidated Standards of Reporting Trials statement and Animals in Research: Reporting <em>In vivo</em> Experiments guidelines were used to evaluate the quality of the studies.</p></div><div class=" sec"><div class="title">Key findings</div><p class="chapter-para">The results suggest that <em>A. muricata</em> and its constituents have hepatoprotective, neurotoxic, antinociceptive, anti-ulcerative and chemopreventive effects. The dose and duration used in animal studies demonstrating toxicity may not directly translate into the effects in humans. Studies included in this review were judged to be of medium to high quality.</p></div><div class=" sec"><div class="title">Conclusions</div><p class="chapter-para">The overall outcome of the current review suggests that <em>A. muricata</em> has a favourable safety and tolerability profile. Future studies investigating its use in people diagnosed with a range of cancers are warranted.</p></div></section> <div class="article-metadata-panel clearfix at-ArticleMetadata"></div> <div class="kwd-group"><a class="kwd-part kwd-main" href="javascript:;" data-keyword="acetogenins">acetogenins</a>, <a class="kwd-part kwd-main" href="javascript:;" data-keyword=""Annona muricata""><em>Annona muricata</em></a>, <a class="kwd-part kwd-main" href="javascript:;" data-keyword=""pharmacological effect"">pharmacological effect</a>, <a class="kwd-part kwd-main" href="javascript:;" data-keyword="safety">safety</a>, <a class="kwd-part kwd-main" href="javascript:;" data-keyword="tolerability">tolerability</a></div> <h2 scrollto-destination=491205015 id="491205015" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0005>Introduction</h2> <p class="chapter-para">There has been a trend over the last two decades by people diagnosed with cancer in their use of natural products to complement or as an alternative to standard care.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0001"></span><a href="javascript:;" reveal-id="jphp13182-bib-0001" data-open="jphp13182-bib-0001" class="link link-ref link-reveal xref-bibr">1</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0002"></span><a href="javascript:;" reveal-id="jphp13182-bib-0002" data-open="jphp13182-bib-0002" class="link link-ref link-reveal xref-bibr">2</a>]</sup> To date, there is limited research exploring the efficacy and safety of many of these products.</p><p class="chapter-para"><em>Annona muricata</em>, also known as graviola, soursop and guanabana,<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0003"></span><a href="javascript:;" reveal-id="jphp13182-bib-0003" data-open="jphp13182-bib-0003" class="link link-ref link-reveal xref-bibr">3</a>]</sup> has been increasingly used by people diagnosed with cancer. This plant is distributed in tropical areas of Central and South America, Africa and south-east Asia<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0003"></span><a href="javascript:;" reveal-id="jphp13182-bib-0003" data-open="jphp13182-bib-0003" class="link link-ref link-reveal xref-bibr">3</a>]</sup> as a small evergreen tree that grows around 4 to 8 m tall and produces green spiny heart-shaped fruit.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0003"></span><a href="javascript:;" reveal-id="jphp13182-bib-0003" data-open="jphp13182-bib-0003" class="link link-ref link-reveal xref-bibr">3</a>]</sup> The bark, fruit, seed and leaves have been traditionally used for the management of a wide variety of diseases such as malaria, diabetes and parasitosis.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0004"></span><a href="javascript:;" reveal-id="jphp13182-bib-0004" data-open="jphp13182-bib-0004" class="link link-ref link-reveal xref-bibr">4</a>]</sup> Currently, <em>A. muricata</em> is widely utilised by people diagnosed with cancer. A Jamaican study investigating the perceptions of people diagnosed with cancer about self-medicating with medicinal plants found that 60% of the participants (<em>n</em> = 80) reported using <em>A. muricata</em> for the treatment of a range of cancers, predominately breast and prostate cancer.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0005"></span><a href="javascript:;" reveal-id="jphp13182-bib-0005" data-open="jphp13182-bib-0005" class="link link-ref link-reveal xref-bibr">5</a>]</sup> Similar results were showed in specialty oncology clinics in Trinidad with <em>A. muricata</em> being used by 80.9% of people living with breast, prostate and colorectal cancer (<em>n</em> = 150).<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0006"></span><a href="javascript:;" reveal-id="jphp13182-bib-0006" data-open="jphp13182-bib-0006" class="link link-ref link-reveal xref-bibr">6</a>]</sup> In addition, results of a cross-sectional study suggest that 14% of liver cancer patients in Peru (<em>n</em> = 88) had taken <em>A. muricata</em> to manage their cancer-related symptoms.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0007"></span><a href="javascript:;" reveal-id="jphp13182-bib-0007" data-open="jphp13182-bib-0007" class="link link-ref link-reveal xref-bibr">7</a>]</sup> Despite such prevalent use, only a limited number of randomised controlled trials (RCTs) for <em>A. muricata</em> have been published and these have been in the setting of colorectal cancer.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></p><p class="chapter-para">However, <em>A. muricata</em> and its constituents have been widely studied for their anticancer properties and efficacy and both <em>in-vivo</em> and <em>in-vitro</em> data have been comprehensively reviewed.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0010 jphp13182-bib-0011 jphp13182-bib-0012"></span><a href="javascript:;" reveal-id="jphp13182-bib-0010 jphp13182-bib-0011 jphp13182-bib-0012" data-open="jphp13182-bib-0010 jphp13182-bib-0011 jphp13182-bib-0012" class="link link-ref link-reveal xref-bibr">10–12</a>]</sup> Although all aerial parts of <em>A. muricata</em> are used in traditional medicine practices, the leaf is the most widely used in current commercially available products. The acetogenins have been identified as one of the main bioactive constituents of <em>A. muricata</em>.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0010"></span><a href="javascript:;" reveal-id="jphp13182-bib-0010" data-open="jphp13182-bib-0010" class="link link-ref link-reveal xref-bibr">10</a>]</sup> Previous reviews have reported some safety and tolerability data specifically focused on preclinical studies.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0010"></span><a href="javascript:;" reveal-id="jphp13182-bib-0010" data-open="jphp13182-bib-0010" class="link link-ref link-reveal xref-bibr">10</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0011"></span><a href="javascript:;" reveal-id="jphp13182-bib-0011" data-open="jphp13182-bib-0011" class="link link-ref link-reveal xref-bibr">11</a>]</sup> However, to date, a systematic and comprehensive review of the safety and tolerability of <em>A. muricata</em> obtained from both preclinical and human studies has not been reported. The aim of this review was to summarise available literature that reports on factors related to the safety and tolerability of <em>A. muricata</em> leaf extract and its acetogenins. The primary objective was to identify the pharmacological effects of <em>A. muricata</em> leaf extract on major body systems from a safety and tolerability perspective. The secondary objective was to summarise the available pharmacokinetic data of <em>A. muricata</em> constituents.</p> <h2 scrollto-destination=491205020 id="491205020" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0006>Methods</h2> <h3 scrollto-destination=491205022 id="491205022" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0007>Inclusion criteria</h3> <p class="chapter-para">Studies which evaluated the specific pharmacological effects of <em>A. muricata</em> on major body systems, pharmacokinetic and human case studies were included. <em>In-vitro</em> studies and preclinical animal studies or <em>in-vivo</em> human studies of any design written in any language that evaluated <em>A. muricata</em> leaf extract or acetogenins isolated from <em>A. muricata</em> were included.</p> <h3 scrollto-destination=491205025 id="491205025" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0008>Exclusion criteria</h3> <p class="chapter-para">Animal and <em>in-vitro</em> studies which evaluated only the efficacy of <em>A. muricata</em> in cancer, with no information directly inform the safety and tolerability, or which cannot be directly translated to clinically relevant data were excluded. Studies which utilised whole plant extract, or extract other than leaf (e.g. fruit, pericarp, seeds and root), synthetic acetogenins, folate-modified acetogenins, acetogenins extracted from species other than <em>A. muricata</em> or evaluated multiple ingredient herbal medicines were also excluded. Epidemiological, ethnobotanical, ethnopharmacological studies and reviews were not included. Articles which measured serum antioxidant enzymes were excluded as these are indicators of generic systemic effects and not specific to major body system.</p> <h3 scrollto-destination=491205029 id="491205029" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0009>Search strategy</h3> <p class="chapter-para">A systematic search was conducted via the databases Pubmed, Medline and Embase. Articles published from inception to 22 April 2019 were searched. The search terms include the following: graviola OR soursop OR <em>A. muricata</em> OR guanabana OR acetogenins OR annonacin OR bullatacin AND pharmacokinetics OR administration OR distribution OR metabolism OR elimination OR bioavailability OR p-glycoprotein OR CYP 450 OR clearance OR half-life OR synergistic effect OR interactions OR drug interactions OR cancer OR side effects OR toxicity OR LD<sub>50</sub> OR physiological effects OR renal OR renoprotective OR nephrotoxic OR kidney OR hepatic OR hepatoprotective OR hepatotoxic OR liver OR cardiac OR cardioprotective OR cardiotoxic OR heart OR gastrointestinal OR gastroprotective OR antiulcerative OR brain OR neuroprotective OR neurotoxic Or neurological OR lungs OR respiratory OR case study OR case report OR clinical trials OR trials.</p><p class="chapter-para">Two authors agreed on the search terms, inclusion and exclusion criteria. One author conducted the systematic search and two authors reviewed the included articles.</p> <h3 scrollto-destination=491205035 id="491205035" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0010>Data extraction</h3> <p class="chapter-para"><em>In-vitro</em>,<em> preclinical and clinical studies</em> were classified into pharmacological, human and pharmacokinetic studies. Data extracted from toxicity studies included the author, publication year, animal tested, solvent of leaf extract, origin, dosage range, sample size, administration route, duration of treatment, main results/outcomes and pharmacological outcome. The data extracted from studies reporting the pharmacological effects included the author, publication year, animal or cell line tested, solvent of leaf extract or acetogenin tested, origin, dose range, sample size, experimental design of treatment group, duration and pharmacological outcome. For human studies, author, publication year, study design, <em>A. muricata</em> formulation, origin, dosage, duration, study population, concurrent medication or therapy, sample size, biomarkers assessed, main outcomes and adverse effects were recorded. For pharmacokinetic studies, the author, publication year, animal tested, constituent analysed, study design, main outcome (including pharmacokinetic parameters) and interpretation were recorded.</p><p class="chapter-para">The Animals in Research: Reporting <em>In vivo</em> Experiments (ARRIVE) guidelines were employed to review the quality of included animal studies in regards to methodology and the reporting of results.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0013"></span><a href="javascript:;" reveal-id="jphp13182-bib-0013" data-open="jphp13182-bib-0013" class="link link-ref link-reveal xref-bibr">13</a>]</sup> Toxicity, mortality, and side effect data were recorded as adverse effects. To assess the quality of RCTs, the elaborated item 4 of Consolidated Standards of Reporting Trials (CONSORT) statement was employed.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0014"></span><a href="javascript:;" reveal-id="jphp13182-bib-0014" data-open="jphp13182-bib-0014" class="link link-ref link-reveal xref-bibr">14</a>]</sup> Two authors independently assessed the quality of included trials, and any discrepancies were discussed before arriving at consensus.</p> <h2 scrollto-destination=491205040 id="491205040" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0011>Results</h2> <p class="chapter-para">A total of 1741 articles were identified from the three databases and 12 articles were identified from other sources. After screening through abstracts and titles, 264 records were selected. After duplicates were removed, a total of 165 articles were screened. Of these, 66 full-text articles were assessed for eligibility and 27 articles were excluded due to not meeting the inclusion criteria (<span class="xrefLink" id="jumplink-jphp13182-fig-0001"></span><a href="javascript:;" data-modal-source-id="jphp13182-fig-0001" class="link xref-fig">Figure 1</a>). A total 39 articles were included for full review.</p> <a id="491205044" scrollto-destination="491205044"></a> <div data-id="jphp13182-fig-0001" data-content-id="jphp13182-fig-0001" class="fig fig-section js-fig-section" swap-content-for-modal="true"><div class="graphic-wrap"><img class="content-image" src="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/jpp/72/1/10.1111_jphp.13182/5/m_jphp13182-fig-0001.jpeg?Expires=1734460764&Signature=jKJ0nsfO6RdI50MwWLz-bCYwjKXWVqrwtncMD-E9lqVeg0HFv3nPwUOb63Te0GU-Ut9mQppPv24QzjT9cS68bHpuCvwiXH~bf6nzsVdkGb8ZB5TodMAydEcS7OHHDdzNEd1-HkeWxoqMo555IVXCqwcc29PgOLALd280U47kxYFTIdTQhn7TjkPcuoXu4~y8orDSbeoryoW5342YIJGQeZNoOU05PNqhrDXQU8n~iEaVWB6c8AYb1me8qSDLGqqsvfZaoydEy6aD4gcReX31TmiNoQDsy4xWtr35SsIGa6NqYuJhyxyzJd1F1~o8~mXijs3OyzlgRSZoopRWzLRS6A__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA" alt="PRISMA flowchart of literature search." data-path-from-xml="jphp13182-fig-0001.tif" /><div class="graphic-bottom"><div class="label fig-label" id="label-491205044">Figure 1</div><div class="caption fig-caption"><p class="chapter-para">PRISMA flowchart of literature search.</p></div><div class="ajax-articleAbstract-exclude-regex fig-orig original-slide figure-button-wrap"><a class="fig-view-orig js-view-large at-figureViewLarge openInAnotherWindow" role="button" aria-describedby="label-491205044" href="/view-large/figure/491205044/jphp13182-fig-0001.tif" data-path-from-xml="jphp13182-fig-0001.tif" target="_blank">Open in new tab</a><a class="download-slide" role="button" aria-describedby="label-491205044" data-section="491205044" href="/DownloadFile/DownloadImage.aspx?image=https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/jpp/72/1/10.1111_jphp.13182/5/jphp13182-fig-0001.jpeg?Expires=1734460764&Signature=3TA6uatDL-WyzTY69EifT3t4G-ZRmWTqmXKVo4DLHS4kJc3lsWItndnxtmxdDfocEtz~x545zGEW4NW5FthDmtN-D7QH~RzhibETzNZRd7YiXwo6gYwIy2FbvM5hr94K8oykrP8kMpPdpVftF71imNozaK5QPnQrvS4wHH2joqpFcL9YLf4W7nkw7zJxRJjIm~5XvziEkgtlXKF17F4dReluWptiLGEng-N5oZFrCa-AWywDnDnN4RNyLpOvyUu7x8Sh0aAgnuntAvLqLWvTl1xVKUoic6yI247ATsSMeiuDStQNhDUpFYu2RchGbdDGoFQhxeZfBVng96GCPoSbtg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA&sec=491205044&ar=6121999&xsltPath=~/UI/app/XSLT&imagename=&siteId=6329" data-path-from-xml="jphp13182-fig-0001.tif">Download slide</a></div></div></div></div><p class="chapter-para">Of the 39 included studies, 32 evaluated the pharmacological effects of <em>A. muricata</em>, two studied the pharmacokinetics of annonacin and five evaluated the safety and efficacy of <em>A. muricata</em> use in humans. The study types include animal studies (<em>n</em> = 26), <em>in-vitro</em> studies (<em>n</em> = 8) and human studies (<em>n</em> = 5). Within animal studies, only mice (<em>n</em> = 14) and rats (<em>n</em> = 13) were studied. The route of administration in animal studies included oral (<em>n</em> = 19), intraperitoneal (<em>n</em> = 2), intravenous (<em>n</em> = 4) and topical (<em>n</em> = 1). All human studies evaluated orally administered <em>A. muricata</em>. Formulations evaluated include ethanolic leaf extract (<em>n</em> = 9), aqueous leaf extract (<em>n</em> = 8), methanolic leaf extract (<em>n</em> = 4), ethyl acetate leaf extract (<em>n</em> = 2), hydroalcoholic leaf extract (<em>n</em> = 2), a leaf extract with undisclosed solvent (<em>n</em> = 1), commercially available products (<em>n</em> = 5), annonacin extracted from <em>A. muricata</em> (<em>n</em> = 7), dry leaves in boiled water (<em>n</em> = 1) and leaf extract with increasing polarity of solvent (<em>n</em> = 1). The longest duration of therapy in animal studies was 16 weeks.</p><p class="chapter-para">Studies which evaluated the pharmacological effect of <em>A. muricata</em> were classified into 15 categories including toxicity (<span class="xrefLink" id="jumplink-jphp13182-tbl-0001"></span><a href="javascript:;" reveal-id="jphp13182-tbl-0001" data-open="jphp13182-tbl-0001" class="link link-reveal link-table xref-fig">Table 1</a>), neurological, hepatic, renal, gastrointestinal, cardiac, haematological, reproductive (<span class="xrefLink" id="jumplink-jphp13182-tbl-0002"></span><a href="javascript:;" reveal-id="jphp13182-tbl-0002" data-open="jphp13182-tbl-0002" class="link link-reveal link-table xref-fig">Table 2</a>), hypoglycaemic, hypotensive, antinociceptive, anti-inflammatory, chemopreventive (<span class="xrefLink" id="jumplink-jphp13182-tbl-0003"></span><a href="javascript:;" reveal-id="jphp13182-tbl-0003" data-open="jphp13182-tbl-0003" class="link link-reveal link-table xref-fig">Table 3</a>) and drug and metabolic enzyme interactions (<span class="xrefLink" id="jumplink-jphp13182-tbl-0004"></span><a href="javascript:;" reveal-id="jphp13182-tbl-0004" data-open="jphp13182-tbl-0004" class="link link-reveal link-table xref-fig">Table 4</a>).</p> <a id="491205054" scrollto-destination="491205054"></a> <div content-id="jphp13182-tbl-0001" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0001" data-id="jphp13182-tbl-0001"><span class="label title-label" id="label-43357">Table 1</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205054" aria-describedby="label-43357"> Open in new tab </a></div><div class="caption caption-id-" id="caption-43357"><p class="chapter-para">Toxicity of <em>Annona muricata</em> leaf extract</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-43357" aria-describedby="
 caption-43357"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Administration route and duration of treatment<span aria-hidden="true" style="display: none;"> . </span></th><th>Main results/outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="7">Toxicity</td></tr><tr><td> Acesio NO <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015" data-open="jphp13182-bib-0015" class="link link-ref link-reveal xref-bibr">15</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>1000–2000 mg/kg<span class="xrefLink" id="jumplink-jphp13182-note-0001"></span><a href="javascript:;" reveal-id="jphp13182-note-0001" data-open="jphp13182-note-0001" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>Oral over 24 h</td><td>All treatment groups died 24 h after treatment</td><td>Dose at ≥1000 mg/kg resulted in the death of mice 24 h after treatment</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Mice</td><td>Aqueous (Nigeria)</td><td>25–3200 mg/kg (<em>n</em> = 64)</td><td>Intraperitoneal over 48 h</td><td>Dose of >200 mg/kg were toxic and/or lethal to mice</td><td>LD<sub>50</sub> value is 155 ± 20 mg/kg</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>500–3000 mg/kg (<em>n</em> = 50)</td><td>Oral over 48 h</td><td>–</td><td>Oral LD<sub>50</sub> was 1670 mg/kg</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>2000–5000 mg/kg (<em>n</em> = 12)</td><td>Oral over 14 days</td><td>No mortality or changes in behaviour. No visible lesions in macroscopic pathology</td><td>LD<sub>50</sub> should be greater than >5000 mg/kg</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>200–800 mg/kg (<em>n</em> = 30) daily</td><td>Oral over 4 weeks</td><td>No signs of toxicity and death. No significant differences in weight</td><td>Relatively safe up to 800 mg/kg</td></tr><tr><td> Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Rats</td><td>Ethyl acetate (Malaysia)</td><td>1000–2000 mg/kg (<em>n</em> = 12)</td><td>Oral over 14 days</td><td>No mortality or signs of toxicity. No changes in all biochemical parameters and histology results</td><td>Oral LD<sub>50</sub> should be >2000 mg/kg</td></tr><tr><td> Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Mice</td><td>Methanolic (India)</td><td>2000 mg/kg (<em>n</em> = 5)</td><td>Oral over 14 days</td><td>No mortality or signs of toxicity</td><td>Oral dose is safe up to 2000 mg/kg</td></tr><tr><td> Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>Rats</td><td>Methanolic (Nigeria)</td><td>10 mg/kg–5000 mg/kg (<em>n</em> = 9)</td><td>Oral over 24 h</td><td>No mortality at a dose up to 5000 mg/kg</td><td>Oral LD<sub>50</sub> in rats should be >5000 mg/kg</td></tr><tr><td> Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>Rats</td><td>Methanolic (Nigeria)</td><td>250–1000 mg/kg (<em>n</em> = 15)</td><td>Oral over 28 days</td><td>Various changes in serum creatinine and sodium. Increase in relative liver weight. (All values were within reference range.) Mild noxious effect in liver and kidney histopathology</td><td>Chronic consumption of high-dose AM is potentially hepatotoxic</td></tr><tr><td> Somsak V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100–4000 mg/kg (<em>n</em> = 15)</td><td>Oral over 7 days</td><td>No mortality. Behavioural signs of toxicity observed at 4000 mg/kg</td><td>LD<sub>50</sub> was estimated to be ≥2500 mg/kg</td></tr><tr><td> Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>10–2000 mg/kg (<em>n</em> = 36)</td><td>Intraperitoneal over 14 days</td><td>Doses ≥500 mg/kg demonstrated CNS depressant effect. 50% mortality at 1000 mg/kg dose</td><td>LD<sub>50</sub> is 1092 mg/kg</td></tr><tr><td> Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Mice</td><td>Ethanolic GLE (USA); AEF; FEF</td><td>2000 mg/kg AEF (<em>n</em> = 5);<br />2000 mg/kg FEF (<em>n</em> = 5);<br />2000 mg/kg GLE (<em>n</em> = 5)</td><td>Oral<span class="xrefLink" id="jumplink-jphp13182-note-0001"></span><a href="javascript:;" reveal-id="jphp13182-note-0001" data-open="jphp13182-note-0001" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>No mortality or signs of toxicity in GLE and FEF group. All AEF group died</td><td>High-dose acetogenin are potentially toxic</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Administration route and duration of treatment<span aria-hidden="true" style="display: none;"> . </span></th><th>Main results/outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="7">Toxicity</td></tr><tr><td> Acesio NO <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015" data-open="jphp13182-bib-0015" class="link link-ref link-reveal xref-bibr">15</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>1000–2000 mg/kg<span class="xrefLink" id="jumplink-jphp13182-note-0001"></span><a href="javascript:;" reveal-id="jphp13182-note-0001" data-open="jphp13182-note-0001" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>Oral over 24 h</td><td>All treatment groups died 24 h after treatment</td><td>Dose at ≥1000 mg/kg resulted in the death of mice 24 h after treatment</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Mice</td><td>Aqueous (Nigeria)</td><td>25–3200 mg/kg (<em>n</em> = 64)</td><td>Intraperitoneal over 48 h</td><td>Dose of >200 mg/kg were toxic and/or lethal to mice</td><td>LD<sub>50</sub> value is 155 ± 20 mg/kg</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>500–3000 mg/kg (<em>n</em> = 50)</td><td>Oral over 48 h</td><td>–</td><td>Oral LD<sub>50</sub> was 1670 mg/kg</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>2000–5000 mg/kg (<em>n</em> = 12)</td><td>Oral over 14 days</td><td>No mortality or changes in behaviour. No visible lesions in macroscopic pathology</td><td>LD<sub>50</sub> should be greater than >5000 mg/kg</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>200–800 mg/kg (<em>n</em> = 30) daily</td><td>Oral over 4 weeks</td><td>No signs of toxicity and death. No significant differences in weight</td><td>Relatively safe up to 800 mg/kg</td></tr><tr><td> Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Rats</td><td>Ethyl acetate (Malaysia)</td><td>1000–2000 mg/kg (<em>n</em> = 12)</td><td>Oral over 14 days</td><td>No mortality or signs of toxicity. No changes in all biochemical parameters and histology results</td><td>Oral LD<sub>50</sub> should be >2000 mg/kg</td></tr><tr><td> Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Mice</td><td>Methanolic (India)</td><td>2000 mg/kg (<em>n</em> = 5)</td><td>Oral over 14 days</td><td>No mortality or signs of toxicity</td><td>Oral dose is safe up to 2000 mg/kg</td></tr><tr><td> Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>Rats</td><td>Methanolic (Nigeria)</td><td>10 mg/kg–5000 mg/kg (<em>n</em> = 9)</td><td>Oral over 24 h</td><td>No mortality at a dose up to 5000 mg/kg</td><td>Oral LD<sub>50</sub> in rats should be >5000 mg/kg</td></tr><tr><td> Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>Rats</td><td>Methanolic (Nigeria)</td><td>250–1000 mg/kg (<em>n</em> = 15)</td><td>Oral over 28 days</td><td>Various changes in serum creatinine and sodium. Increase in relative liver weight. (All values were within reference range.) Mild noxious effect in liver and kidney histopathology</td><td>Chronic consumption of high-dose AM is potentially hepatotoxic</td></tr><tr><td> Somsak V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100–4000 mg/kg (<em>n</em> = 15)</td><td>Oral over 7 days</td><td>No mortality. Behavioural signs of toxicity observed at 4000 mg/kg</td><td>LD<sub>50</sub> was estimated to be ≥2500 mg/kg</td></tr><tr><td> Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>10–2000 mg/kg (<em>n</em> = 36)</td><td>Intraperitoneal over 14 days</td><td>Doses ≥500 mg/kg demonstrated CNS depressant effect. 50% mortality at 1000 mg/kg dose</td><td>LD<sub>50</sub> is 1092 mg/kg</td></tr><tr><td> Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Mice</td><td>Ethanolic GLE (USA); AEF; FEF</td><td>2000 mg/kg AEF (<em>n</em> = 5);<br />2000 mg/kg FEF (<em>n</em> = 5);<br />2000 mg/kg GLE (<em>n</em> = 5)</td><td>Oral<span class="xrefLink" id="jumplink-jphp13182-note-0001"></span><a href="javascript:;" reveal-id="jphp13182-note-0001" data-open="jphp13182-note-0001" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>No mortality or signs of toxicity in GLE and FEF group. All AEF group died</td><td>High-dose acetogenin are potentially toxic</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0001"></span><div content-id="jphp13182-note-0001" class="footnote"><span class="fn"><p class="chapter-para">AEF, acetogenin-enriched fraction; AM, <em>Annona muricata</em>; CNS, central nervous system; FEF, flavonoid-enriched fraction; GLE, graviola leaf extract; LD<sub>50</sub>, median lethal dose; <em>n</em>, sample size.</p><p class="chapter-para"><sup>a</sup><em>n</em> = unreported. <sup>b</sup>Unspecified duration.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0001" data-id="jphp13182-tbl-0001"><span class="label title-label" id="label-43357">Table 1</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205054" aria-describedby="label-43357"> Open in new tab </a></div><div class="caption caption-id-" id="caption-43357"><p class="chapter-para">Toxicity of <em>Annona muricata</em> leaf extract</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-43357" aria-describedby="
 caption-43357"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Administration route and duration of treatment<span aria-hidden="true" style="display: none;"> . </span></th><th>Main results/outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="7">Toxicity</td></tr><tr><td> Acesio NO <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015" data-open="jphp13182-bib-0015" class="link link-ref link-reveal xref-bibr">15</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>1000–2000 mg/kg<span class="xrefLink" id="jumplink-jphp13182-note-0001"></span><a href="javascript:;" reveal-id="jphp13182-note-0001" data-open="jphp13182-note-0001" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>Oral over 24 h</td><td>All treatment groups died 24 h after treatment</td><td>Dose at ≥1000 mg/kg resulted in the death of mice 24 h after treatment</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Mice</td><td>Aqueous (Nigeria)</td><td>25–3200 mg/kg (<em>n</em> = 64)</td><td>Intraperitoneal over 48 h</td><td>Dose of >200 mg/kg were toxic and/or lethal to mice</td><td>LD<sub>50</sub> value is 155 ± 20 mg/kg</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>500–3000 mg/kg (<em>n</em> = 50)</td><td>Oral over 48 h</td><td>–</td><td>Oral LD<sub>50</sub> was 1670 mg/kg</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>2000–5000 mg/kg (<em>n</em> = 12)</td><td>Oral over 14 days</td><td>No mortality or changes in behaviour. No visible lesions in macroscopic pathology</td><td>LD<sub>50</sub> should be greater than >5000 mg/kg</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>200–800 mg/kg (<em>n</em> = 30) daily</td><td>Oral over 4 weeks</td><td>No signs of toxicity and death. No significant differences in weight</td><td>Relatively safe up to 800 mg/kg</td></tr><tr><td> Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Rats</td><td>Ethyl acetate (Malaysia)</td><td>1000–2000 mg/kg (<em>n</em> = 12)</td><td>Oral over 14 days</td><td>No mortality or signs of toxicity. No changes in all biochemical parameters and histology results</td><td>Oral LD<sub>50</sub> should be >2000 mg/kg</td></tr><tr><td> Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Mice</td><td>Methanolic (India)</td><td>2000 mg/kg (<em>n</em> = 5)</td><td>Oral over 14 days</td><td>No mortality or signs of toxicity</td><td>Oral dose is safe up to 2000 mg/kg</td></tr><tr><td> Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>Rats</td><td>Methanolic (Nigeria)</td><td>10 mg/kg–5000 mg/kg (<em>n</em> = 9)</td><td>Oral over 24 h</td><td>No mortality at a dose up to 5000 mg/kg</td><td>Oral LD<sub>50</sub> in rats should be >5000 mg/kg</td></tr><tr><td> Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>Rats</td><td>Methanolic (Nigeria)</td><td>250–1000 mg/kg (<em>n</em> = 15)</td><td>Oral over 28 days</td><td>Various changes in serum creatinine and sodium. Increase in relative liver weight. (All values were within reference range.) Mild noxious effect in liver and kidney histopathology</td><td>Chronic consumption of high-dose AM is potentially hepatotoxic</td></tr><tr><td> Somsak V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100–4000 mg/kg (<em>n</em> = 15)</td><td>Oral over 7 days</td><td>No mortality. Behavioural signs of toxicity observed at 4000 mg/kg</td><td>LD<sub>50</sub> was estimated to be ≥2500 mg/kg</td></tr><tr><td> Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>10–2000 mg/kg (<em>n</em> = 36)</td><td>Intraperitoneal over 14 days</td><td>Doses ≥500 mg/kg demonstrated CNS depressant effect. 50% mortality at 1000 mg/kg dose</td><td>LD<sub>50</sub> is 1092 mg/kg</td></tr><tr><td> Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Mice</td><td>Ethanolic GLE (USA); AEF; FEF</td><td>2000 mg/kg AEF (<em>n</em> = 5);<br />2000 mg/kg FEF (<em>n</em> = 5);<br />2000 mg/kg GLE (<em>n</em> = 5)</td><td>Oral<span class="xrefLink" id="jumplink-jphp13182-note-0001"></span><a href="javascript:;" reveal-id="jphp13182-note-0001" data-open="jphp13182-note-0001" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>No mortality or signs of toxicity in GLE and FEF group. All AEF group died</td><td>High-dose acetogenin are potentially toxic</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Administration route and duration of treatment<span aria-hidden="true" style="display: none;"> . </span></th><th>Main results/outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="7">Toxicity</td></tr><tr><td> Acesio NO <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015" data-open="jphp13182-bib-0015" class="link link-ref link-reveal xref-bibr">15</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>1000–2000 mg/kg<span class="xrefLink" id="jumplink-jphp13182-note-0001"></span><a href="javascript:;" reveal-id="jphp13182-note-0001" data-open="jphp13182-note-0001" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>Oral over 24 h</td><td>All treatment groups died 24 h after treatment</td><td>Dose at ≥1000 mg/kg resulted in the death of mice 24 h after treatment</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Mice</td><td>Aqueous (Nigeria)</td><td>25–3200 mg/kg (<em>n</em> = 64)</td><td>Intraperitoneal over 48 h</td><td>Dose of >200 mg/kg were toxic and/or lethal to mice</td><td>LD<sub>50</sub> value is 155 ± 20 mg/kg</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>500–3000 mg/kg (<em>n</em> = 50)</td><td>Oral over 48 h</td><td>–</td><td>Oral LD<sub>50</sub> was 1670 mg/kg</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>2000–5000 mg/kg (<em>n</em> = 12)</td><td>Oral over 14 days</td><td>No mortality or changes in behaviour. No visible lesions in macroscopic pathology</td><td>LD<sub>50</sub> should be greater than >5000 mg/kg</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>200–800 mg/kg (<em>n</em> = 30) daily</td><td>Oral over 4 weeks</td><td>No signs of toxicity and death. No significant differences in weight</td><td>Relatively safe up to 800 mg/kg</td></tr><tr><td> Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Rats</td><td>Ethyl acetate (Malaysia)</td><td>1000–2000 mg/kg (<em>n</em> = 12)</td><td>Oral over 14 days</td><td>No mortality or signs of toxicity. No changes in all biochemical parameters and histology results</td><td>Oral LD<sub>50</sub> should be >2000 mg/kg</td></tr><tr><td> Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Mice</td><td>Methanolic (India)</td><td>2000 mg/kg (<em>n</em> = 5)</td><td>Oral over 14 days</td><td>No mortality or signs of toxicity</td><td>Oral dose is safe up to 2000 mg/kg</td></tr><tr><td> Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>Rats</td><td>Methanolic (Nigeria)</td><td>10 mg/kg–5000 mg/kg (<em>n</em> = 9)</td><td>Oral over 24 h</td><td>No mortality at a dose up to 5000 mg/kg</td><td>Oral LD<sub>50</sub> in rats should be >5000 mg/kg</td></tr><tr><td> Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>Rats</td><td>Methanolic (Nigeria)</td><td>250–1000 mg/kg (<em>n</em> = 15)</td><td>Oral over 28 days</td><td>Various changes in serum creatinine and sodium. Increase in relative liver weight. (All values were within reference range.) Mild noxious effect in liver and kidney histopathology</td><td>Chronic consumption of high-dose AM is potentially hepatotoxic</td></tr><tr><td> Somsak V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100–4000 mg/kg (<em>n</em> = 15)</td><td>Oral over 7 days</td><td>No mortality. Behavioural signs of toxicity observed at 4000 mg/kg</td><td>LD<sub>50</sub> was estimated to be ≥2500 mg/kg</td></tr><tr><td> Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>10–2000 mg/kg (<em>n</em> = 36)</td><td>Intraperitoneal over 14 days</td><td>Doses ≥500 mg/kg demonstrated CNS depressant effect. 50% mortality at 1000 mg/kg dose</td><td>LD<sub>50</sub> is 1092 mg/kg</td></tr><tr><td> Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Mice</td><td>Ethanolic GLE (USA); AEF; FEF</td><td>2000 mg/kg AEF (<em>n</em> = 5);<br />2000 mg/kg FEF (<em>n</em> = 5);<br />2000 mg/kg GLE (<em>n</em> = 5)</td><td>Oral<span class="xrefLink" id="jumplink-jphp13182-note-0001"></span><a href="javascript:;" reveal-id="jphp13182-note-0001" data-open="jphp13182-note-0001" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>No mortality or signs of toxicity in GLE and FEF group. All AEF group died</td><td>High-dose acetogenin are potentially toxic</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0001"></span><div content-id="jphp13182-note-0001" class="footnote"><span class="fn"><p class="chapter-para">AEF, acetogenin-enriched fraction; AM, <em>Annona muricata</em>; CNS, central nervous system; FEF, flavonoid-enriched fraction; GLE, graviola leaf extract; LD<sub>50</sub>, median lethal dose; <em>n</em>, sample size.</p><p class="chapter-para"><sup>a</sup><em>n</em> = unreported. <sup>b</sup>Unspecified duration.</p></span></div></div></div></div> <a id="491205056" scrollto-destination="491205056"></a> <div content-id="jphp13182-tbl-0002" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0002" data-id="jphp13182-tbl-0002"><span class="label title-label" id="label-43357">Table 2</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205056" aria-describedby="label-43357"> Open in new tab </a></div><div class="caption caption-id-" id="caption-43357"><p class="chapter-para">Neurological, hepatic, renal, gastrointestinal, cardiac, haematological and reproductive effect of <em>Annona muricata</em> leaf extract and/or acetogenins from <em>A. muricata</em></p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-43357" aria-describedby="
 caption-43357"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/cell line tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract or acetogenin tested (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="6">Neurological</td></tr><tr><td> Champy P <em>et al</em>. (2004) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>]</sup></td><td>Rats</td><td>Annonacin extracted from root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td char=".">3.8–7.6 mg/kg per day (<em>n</em> = 14)</td><td>Intravenous annonacin was administered to rats for 28 days</td><td>Annonacin penetrated and accumulated in brain, demonstrated neurodegeneration without behavioural changes</td></tr><tr><td> Escobar-Khondiker M <em>et al</em>. (2007) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0033"></span><a href="javascript:;" reveal-id="jphp13182-bib-0033" data-open="jphp13182-bib-0033" class="link link-ref link-reveal xref-bibr">33</a>]</sup></td><td>Embryonic rats’ striatal neurons</td><td>Annonacin extracted from leaf and root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>25–100 n<span class="small-caps">m</span></td><td>Striatal neurons were incubated with annonacin for 48 h</td><td>Annonacin is neurotoxic, it increases tau proteins accumulation and redistribution</td></tr><tr><td> Hollerhage M <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0034"></span><a href="javascript:;" reveal-id="jphp13182-bib-0034" data-open="jphp13182-bib-0034" class="link link-ref link-reveal xref-bibr">34</a>]</sup></td><td>Human LUHMES cells</td><td>Dried leaves, and stems; ethyl acetate pulp extract (Brazil)</td><td char=".">0.01–10 μg/ml</td><td>Neurons were incubated with different samples for 48 h</td><td>AM dietary supplements are neurotoxic</td></tr><tr><td> Lannuzel A <em>et al</em>. (2003) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0035"></span><a href="javascript:;" reveal-id="jphp13182-bib-0035" data-open="jphp13182-bib-0035" class="link link-ref link-reveal xref-bibr">35</a>]</sup></td><td>Embryonic rats’ mesencephalonic neurons</td><td>Annonacin extracted from root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>1–100 n<span class="small-caps">m</span></td><td>Neurons were incubated with samples for 24 h</td><td>Annonacin is neurotoxic</td></tr><tr><td> Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>25–100 mg/kg (<em>n</em> = 108)</td><td>Intraperitoneal annonacin was administered for 30 min before behavioural test</td><td>Sedative, anxiolytic and anticonvulsant-like effect</td></tr><tr><td colspan="6">Hepatic</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>(Egypt)<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Hepatotoxicity was induced by DMBA. AM was either simultaneously or post-treated for 2 weeks<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>c</sup></a></td><td>Hepatoprotective</td></tr><tr><td> Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>Rats</td><td>Commercially available product (Brazil)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Hepatotoxicity was induced by MSG. AM was then administered orally for another 4 weeks</td><td>Hepatoprotective</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Rats</td><td>Aqueous (Nigeria)</td><td>100 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for the 4 weeks</td><td>Hepatoprotective</td></tr><tr><td> Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>]</sup></td><td>Rats</td><td>Aqueous (Ghana)</td><td>50–400 mg/kg per day (<em>n</em> = 40)</td><td>Hepatotoxicity was induced by either CCl<sub>4</sub> or acetaminophen. AM was pretreated orally for 1 day and continued for 7 days</td><td>Hepatoprotective</td></tr><tr><td> Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup></td><td>Rats</td><td>Aqueous (Ghana)</td><td>100–800 mg/kg (<em>n</em> = 10)</td><td>Hyperbilirubinaemia was induced by PHZ. Hepatotoxicity and hyperbilirubinaemia were induced by co-administration of PHZ and CCl<sub>4</sub>. AM was administered either one day prior to or after PHZ induction. Treatment duration was 7 days</td><td>Bilirubin-lowering and hepatoprotective effect</td></tr><tr><td> Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis and hepatotoxicity were induced by injecting <em>B. fimus</em>. Mice were either pretreated with AM orally for 2 h or 7 days</td><td>Hepatotoxic (with or without peritonitis induction) and increased hepatotoxicity with peritonitis infection</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Hepatotoxicity was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Hepatoprotective</td></tr><tr><td> George VC <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>]</sup></td><td>Hepatic cell (WRL-68)</td><td>Methanolic (India)</td><td char=".">12.5–100 μg/ml</td><td>Hepatic cells were incubated with NaAsO<sub>2</sub> and AM for 24 h</td><td>Hepatoprotective</td></tr><tr><td> Usunomena U and Ngozi (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup></td><td>Rats</td><td>Ethanolic (Nigeria)</td><td>200 mg/kg (<em>n</em> = 12)</td><td>Hepatic fibrosis was induced by DMN. AM was co-administered orally for 14 consecutive days</td><td>Hepatoprotective</td></tr><tr><td colspan="6">Renal</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>(Egypt)<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Nephrotoxicity was induced by DMBA. AM was either simultaneously or post-treated for 2 weeks</td><td>Nephroprotective</td></tr><tr><td> Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis and renal damage were induced by injecting Bacillus firmus. Mice were either pretreated with AM orally for 2 h or 7 days</td><td>Nephrotoxic effect (with or without peritonitis induction) and increased nephrotoxicity with peritonitis infection</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Nephrotoxicity was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Nephroprotective</td></tr><tr><td colspan="6">Gastrointestinal</td></tr><tr><td> Bento EB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>]</sup></td><td>Mice</td><td>Hydroalcoholic (Brazil)</td><td>50–400 mg/kg (<em>n</em> = 60)</td><td>Gastric ulcer was induced either by absolute ethanol, acidified ethanol or indomethacin. Animals were pretreated with AM orally</td><td>Gastroprotective</td></tr><tr><td> Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Rats</td><td>Ethanolic (Malaysia)</td><td>10–300 mg/kg (<em>n</em> = 24)</td><td>Gastric ulcer was induced by ethanol. AM was pretreated orally for 1 h</td><td>Gastroprotective</td></tr><tr><td> Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Rats</td><td>Ethyl acetate (Malaysia)</td><td>200–400 mg/kg (<em>n</em> = 12)</td><td>Gastric ulcer was induced by ethanol. AM was pretreated orally for 1 h</td><td>Gastroprotective</td></tr><tr><td colspan="6">Cardiac</td></tr><tr><td> Bipat R <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0038"></span><a href="javascript:;" reveal-id="jphp13182-bib-0038" data-open="jphp13182-bib-0038" class="link link-ref link-reveal xref-bibr">38</a>]</sup></td><td>Guinea pig atria</td><td>Aqueous (Suriname)</td><td char=".">0.001–1 mg/ml (<em>n</em> = not reported)</td><td>Ischaemic-reperfusion injured atria was incubated with AM for 6 min</td><td>Positive inotropic properties without causing damage to myocytes</td></tr><tr><td colspan="6">Haematological</td></tr><tr><td> George VC <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>]</sup></td><td>Human erythrocytes</td><td>Methanolic (India)</td><td char=".">12.5–100 μg/ml</td><td>Erythrocytes were incubated with NaAsO<sub>2</sub> and AM for 2.5 h</td><td>Protective against haemolysis</td></tr><tr><td> Pautus S <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup></td><td>Mice</td><td>Annonacin and annonacinone isolated from AM seeds</td><td>20 μ<span class="small-caps">m</span> (<em>n</em> = 7)</td><td>Annonacinone was administered to the FeCl<sub>3</sub>-occluded mesenteric vessels in mice model</td><td>Annonacinone potentiates the fibrinolytic action of tPA</td></tr><tr><td colspan="6">Reproductive</td></tr><tr><td> Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>Rats</td><td>Commercially available leaf extract (Brazil)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Testicular toxicity was induced by MSG. AM was later administered orally for another 4 weeks</td><td>Protective against testicular toxicity</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/cell line tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract or acetogenin tested (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="6">Neurological</td></tr><tr><td> Champy P <em>et al</em>. (2004) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>]</sup></td><td>Rats</td><td>Annonacin extracted from root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td char=".">3.8–7.6 mg/kg per day (<em>n</em> = 14)</td><td>Intravenous annonacin was administered to rats for 28 days</td><td>Annonacin penetrated and accumulated in brain, demonstrated neurodegeneration without behavioural changes</td></tr><tr><td> Escobar-Khondiker M <em>et al</em>. (2007) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0033"></span><a href="javascript:;" reveal-id="jphp13182-bib-0033" data-open="jphp13182-bib-0033" class="link link-ref link-reveal xref-bibr">33</a>]</sup></td><td>Embryonic rats’ striatal neurons</td><td>Annonacin extracted from leaf and root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>25–100 n<span class="small-caps">m</span></td><td>Striatal neurons were incubated with annonacin for 48 h</td><td>Annonacin is neurotoxic, it increases tau proteins accumulation and redistribution</td></tr><tr><td> Hollerhage M <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0034"></span><a href="javascript:;" reveal-id="jphp13182-bib-0034" data-open="jphp13182-bib-0034" class="link link-ref link-reveal xref-bibr">34</a>]</sup></td><td>Human LUHMES cells</td><td>Dried leaves, and stems; ethyl acetate pulp extract (Brazil)</td><td char=".">0.01–10 μg/ml</td><td>Neurons were incubated with different samples for 48 h</td><td>AM dietary supplements are neurotoxic</td></tr><tr><td> Lannuzel A <em>et al</em>. (2003) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0035"></span><a href="javascript:;" reveal-id="jphp13182-bib-0035" data-open="jphp13182-bib-0035" class="link link-ref link-reveal xref-bibr">35</a>]</sup></td><td>Embryonic rats’ mesencephalonic neurons</td><td>Annonacin extracted from root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>1–100 n<span class="small-caps">m</span></td><td>Neurons were incubated with samples for 24 h</td><td>Annonacin is neurotoxic</td></tr><tr><td> Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>25–100 mg/kg (<em>n</em> = 108)</td><td>Intraperitoneal annonacin was administered for 30 min before behavioural test</td><td>Sedative, anxiolytic and anticonvulsant-like effect</td></tr><tr><td colspan="6">Hepatic</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>(Egypt)<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Hepatotoxicity was induced by DMBA. AM was either simultaneously or post-treated for 2 weeks<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>c</sup></a></td><td>Hepatoprotective</td></tr><tr><td> Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>Rats</td><td>Commercially available product (Brazil)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Hepatotoxicity was induced by MSG. AM was then administered orally for another 4 weeks</td><td>Hepatoprotective</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Rats</td><td>Aqueous (Nigeria)</td><td>100 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for the 4 weeks</td><td>Hepatoprotective</td></tr><tr><td> Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>]</sup></td><td>Rats</td><td>Aqueous (Ghana)</td><td>50–400 mg/kg per day (<em>n</em> = 40)</td><td>Hepatotoxicity was induced by either CCl<sub>4</sub> or acetaminophen. AM was pretreated orally for 1 day and continued for 7 days</td><td>Hepatoprotective</td></tr><tr><td> Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup></td><td>Rats</td><td>Aqueous (Ghana)</td><td>100–800 mg/kg (<em>n</em> = 10)</td><td>Hyperbilirubinaemia was induced by PHZ. Hepatotoxicity and hyperbilirubinaemia were induced by co-administration of PHZ and CCl<sub>4</sub>. AM was administered either one day prior to or after PHZ induction. Treatment duration was 7 days</td><td>Bilirubin-lowering and hepatoprotective effect</td></tr><tr><td> Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis and hepatotoxicity were induced by injecting <em>B. fimus</em>. Mice were either pretreated with AM orally for 2 h or 7 days</td><td>Hepatotoxic (with or without peritonitis induction) and increased hepatotoxicity with peritonitis infection</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Hepatotoxicity was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Hepatoprotective</td></tr><tr><td> George VC <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>]</sup></td><td>Hepatic cell (WRL-68)</td><td>Methanolic (India)</td><td char=".">12.5–100 μg/ml</td><td>Hepatic cells were incubated with NaAsO<sub>2</sub> and AM for 24 h</td><td>Hepatoprotective</td></tr><tr><td> Usunomena U and Ngozi (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup></td><td>Rats</td><td>Ethanolic (Nigeria)</td><td>200 mg/kg (<em>n</em> = 12)</td><td>Hepatic fibrosis was induced by DMN. AM was co-administered orally for 14 consecutive days</td><td>Hepatoprotective</td></tr><tr><td colspan="6">Renal</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>(Egypt)<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Nephrotoxicity was induced by DMBA. AM was either simultaneously or post-treated for 2 weeks</td><td>Nephroprotective</td></tr><tr><td> Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis and renal damage were induced by injecting Bacillus firmus. Mice were either pretreated with AM orally for 2 h or 7 days</td><td>Nephrotoxic effect (with or without peritonitis induction) and increased nephrotoxicity with peritonitis infection</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Nephrotoxicity was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Nephroprotective</td></tr><tr><td colspan="6">Gastrointestinal</td></tr><tr><td> Bento EB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>]</sup></td><td>Mice</td><td>Hydroalcoholic (Brazil)</td><td>50–400 mg/kg (<em>n</em> = 60)</td><td>Gastric ulcer was induced either by absolute ethanol, acidified ethanol or indomethacin. Animals were pretreated with AM orally</td><td>Gastroprotective</td></tr><tr><td> Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Rats</td><td>Ethanolic (Malaysia)</td><td>10–300 mg/kg (<em>n</em> = 24)</td><td>Gastric ulcer was induced by ethanol. AM was pretreated orally for 1 h</td><td>Gastroprotective</td></tr><tr><td> Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Rats</td><td>Ethyl acetate (Malaysia)</td><td>200–400 mg/kg (<em>n</em> = 12)</td><td>Gastric ulcer was induced by ethanol. AM was pretreated orally for 1 h</td><td>Gastroprotective</td></tr><tr><td colspan="6">Cardiac</td></tr><tr><td> Bipat R <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0038"></span><a href="javascript:;" reveal-id="jphp13182-bib-0038" data-open="jphp13182-bib-0038" class="link link-ref link-reveal xref-bibr">38</a>]</sup></td><td>Guinea pig atria</td><td>Aqueous (Suriname)</td><td char=".">0.001–1 mg/ml (<em>n</em> = not reported)</td><td>Ischaemic-reperfusion injured atria was incubated with AM for 6 min</td><td>Positive inotropic properties without causing damage to myocytes</td></tr><tr><td colspan="6">Haematological</td></tr><tr><td> George VC <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>]</sup></td><td>Human erythrocytes</td><td>Methanolic (India)</td><td char=".">12.5–100 μg/ml</td><td>Erythrocytes were incubated with NaAsO<sub>2</sub> and AM for 2.5 h</td><td>Protective against haemolysis</td></tr><tr><td> Pautus S <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup></td><td>Mice</td><td>Annonacin and annonacinone isolated from AM seeds</td><td>20 μ<span class="small-caps">m</span> (<em>n</em> = 7)</td><td>Annonacinone was administered to the FeCl<sub>3</sub>-occluded mesenteric vessels in mice model</td><td>Annonacinone potentiates the fibrinolytic action of tPA</td></tr><tr><td colspan="6">Reproductive</td></tr><tr><td> Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>Rats</td><td>Commercially available leaf extract (Brazil)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Testicular toxicity was induced by MSG. AM was later administered orally for another 4 weeks</td><td>Protective against testicular toxicity</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0002"></span><div content-id="jphp13182-note-0002" class="footnote"><span class="fn"><p class="chapter-para">AM, <em>Annona muricata</em>; CCl<sub>4</sub>, carbon tetrachloride; DMBA, 7,12-dimethylbenz(a)anthracene; DMN, dimethylnitrosamine; FeCl<sub>3</sub>, Iron (III) chloride; LUHMES, Lund human mesencephalic neurons; MSG, monosodium glutamate; NaAsO<sub>2</sub>, sodium arsenite; <em>n</em>, sample size; PHZ, phenylhydrazine; STZ, streptozotocin; tPA, tissue plasminogen activator. <sup>a</sup>Unreported origin. <sup>b</sup>Unreported solvent used. <sup>c</sup>Unreported route.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0002" data-id="jphp13182-tbl-0002"><span class="label title-label" id="label-43357">Table 2</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205056" aria-describedby="label-43357"> Open in new tab </a></div><div class="caption caption-id-" id="caption-43357"><p class="chapter-para">Neurological, hepatic, renal, gastrointestinal, cardiac, haematological and reproductive effect of <em>Annona muricata</em> leaf extract and/or acetogenins from <em>A. muricata</em></p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-43357" aria-describedby="
 caption-43357"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/cell line tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract or acetogenin tested (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="6">Neurological</td></tr><tr><td> Champy P <em>et al</em>. (2004) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>]</sup></td><td>Rats</td><td>Annonacin extracted from root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td char=".">3.8–7.6 mg/kg per day (<em>n</em> = 14)</td><td>Intravenous annonacin was administered to rats for 28 days</td><td>Annonacin penetrated and accumulated in brain, demonstrated neurodegeneration without behavioural changes</td></tr><tr><td> Escobar-Khondiker M <em>et al</em>. (2007) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0033"></span><a href="javascript:;" reveal-id="jphp13182-bib-0033" data-open="jphp13182-bib-0033" class="link link-ref link-reveal xref-bibr">33</a>]</sup></td><td>Embryonic rats’ striatal neurons</td><td>Annonacin extracted from leaf and root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>25–100 n<span class="small-caps">m</span></td><td>Striatal neurons were incubated with annonacin for 48 h</td><td>Annonacin is neurotoxic, it increases tau proteins accumulation and redistribution</td></tr><tr><td> Hollerhage M <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0034"></span><a href="javascript:;" reveal-id="jphp13182-bib-0034" data-open="jphp13182-bib-0034" class="link link-ref link-reveal xref-bibr">34</a>]</sup></td><td>Human LUHMES cells</td><td>Dried leaves, and stems; ethyl acetate pulp extract (Brazil)</td><td char=".">0.01–10 μg/ml</td><td>Neurons were incubated with different samples for 48 h</td><td>AM dietary supplements are neurotoxic</td></tr><tr><td> Lannuzel A <em>et al</em>. (2003) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0035"></span><a href="javascript:;" reveal-id="jphp13182-bib-0035" data-open="jphp13182-bib-0035" class="link link-ref link-reveal xref-bibr">35</a>]</sup></td><td>Embryonic rats’ mesencephalonic neurons</td><td>Annonacin extracted from root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>1–100 n<span class="small-caps">m</span></td><td>Neurons were incubated with samples for 24 h</td><td>Annonacin is neurotoxic</td></tr><tr><td> Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>25–100 mg/kg (<em>n</em> = 108)</td><td>Intraperitoneal annonacin was administered for 30 min before behavioural test</td><td>Sedative, anxiolytic and anticonvulsant-like effect</td></tr><tr><td colspan="6">Hepatic</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>(Egypt)<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Hepatotoxicity was induced by DMBA. AM was either simultaneously or post-treated for 2 weeks<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>c</sup></a></td><td>Hepatoprotective</td></tr><tr><td> Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>Rats</td><td>Commercially available product (Brazil)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Hepatotoxicity was induced by MSG. AM was then administered orally for another 4 weeks</td><td>Hepatoprotective</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Rats</td><td>Aqueous (Nigeria)</td><td>100 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for the 4 weeks</td><td>Hepatoprotective</td></tr><tr><td> Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>]</sup></td><td>Rats</td><td>Aqueous (Ghana)</td><td>50–400 mg/kg per day (<em>n</em> = 40)</td><td>Hepatotoxicity was induced by either CCl<sub>4</sub> or acetaminophen. AM was pretreated orally for 1 day and continued for 7 days</td><td>Hepatoprotective</td></tr><tr><td> Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup></td><td>Rats</td><td>Aqueous (Ghana)</td><td>100–800 mg/kg (<em>n</em> = 10)</td><td>Hyperbilirubinaemia was induced by PHZ. Hepatotoxicity and hyperbilirubinaemia were induced by co-administration of PHZ and CCl<sub>4</sub>. AM was administered either one day prior to or after PHZ induction. Treatment duration was 7 days</td><td>Bilirubin-lowering and hepatoprotective effect</td></tr><tr><td> Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis and hepatotoxicity were induced by injecting <em>B. fimus</em>. Mice were either pretreated with AM orally for 2 h or 7 days</td><td>Hepatotoxic (with or without peritonitis induction) and increased hepatotoxicity with peritonitis infection</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Hepatotoxicity was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Hepatoprotective</td></tr><tr><td> George VC <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>]</sup></td><td>Hepatic cell (WRL-68)</td><td>Methanolic (India)</td><td char=".">12.5–100 μg/ml</td><td>Hepatic cells were incubated with NaAsO<sub>2</sub> and AM for 24 h</td><td>Hepatoprotective</td></tr><tr><td> Usunomena U and Ngozi (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup></td><td>Rats</td><td>Ethanolic (Nigeria)</td><td>200 mg/kg (<em>n</em> = 12)</td><td>Hepatic fibrosis was induced by DMN. AM was co-administered orally for 14 consecutive days</td><td>Hepatoprotective</td></tr><tr><td colspan="6">Renal</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>(Egypt)<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Nephrotoxicity was induced by DMBA. AM was either simultaneously or post-treated for 2 weeks</td><td>Nephroprotective</td></tr><tr><td> Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis and renal damage were induced by injecting Bacillus firmus. Mice were either pretreated with AM orally for 2 h or 7 days</td><td>Nephrotoxic effect (with or without peritonitis induction) and increased nephrotoxicity with peritonitis infection</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Nephrotoxicity was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Nephroprotective</td></tr><tr><td colspan="6">Gastrointestinal</td></tr><tr><td> Bento EB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>]</sup></td><td>Mice</td><td>Hydroalcoholic (Brazil)</td><td>50–400 mg/kg (<em>n</em> = 60)</td><td>Gastric ulcer was induced either by absolute ethanol, acidified ethanol or indomethacin. Animals were pretreated with AM orally</td><td>Gastroprotective</td></tr><tr><td> Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Rats</td><td>Ethanolic (Malaysia)</td><td>10–300 mg/kg (<em>n</em> = 24)</td><td>Gastric ulcer was induced by ethanol. AM was pretreated orally for 1 h</td><td>Gastroprotective</td></tr><tr><td> Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Rats</td><td>Ethyl acetate (Malaysia)</td><td>200–400 mg/kg (<em>n</em> = 12)</td><td>Gastric ulcer was induced by ethanol. AM was pretreated orally for 1 h</td><td>Gastroprotective</td></tr><tr><td colspan="6">Cardiac</td></tr><tr><td> Bipat R <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0038"></span><a href="javascript:;" reveal-id="jphp13182-bib-0038" data-open="jphp13182-bib-0038" class="link link-ref link-reveal xref-bibr">38</a>]</sup></td><td>Guinea pig atria</td><td>Aqueous (Suriname)</td><td char=".">0.001–1 mg/ml (<em>n</em> = not reported)</td><td>Ischaemic-reperfusion injured atria was incubated with AM for 6 min</td><td>Positive inotropic properties without causing damage to myocytes</td></tr><tr><td colspan="6">Haematological</td></tr><tr><td> George VC <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>]</sup></td><td>Human erythrocytes</td><td>Methanolic (India)</td><td char=".">12.5–100 μg/ml</td><td>Erythrocytes were incubated with NaAsO<sub>2</sub> and AM for 2.5 h</td><td>Protective against haemolysis</td></tr><tr><td> Pautus S <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup></td><td>Mice</td><td>Annonacin and annonacinone isolated from AM seeds</td><td>20 μ<span class="small-caps">m</span> (<em>n</em> = 7)</td><td>Annonacinone was administered to the FeCl<sub>3</sub>-occluded mesenteric vessels in mice model</td><td>Annonacinone potentiates the fibrinolytic action of tPA</td></tr><tr><td colspan="6">Reproductive</td></tr><tr><td> Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>Rats</td><td>Commercially available leaf extract (Brazil)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Testicular toxicity was induced by MSG. AM was later administered orally for another 4 weeks</td><td>Protective against testicular toxicity</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/cell line tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract or acetogenin tested (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="6">Neurological</td></tr><tr><td> Champy P <em>et al</em>. (2004) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>]</sup></td><td>Rats</td><td>Annonacin extracted from root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td char=".">3.8–7.6 mg/kg per day (<em>n</em> = 14)</td><td>Intravenous annonacin was administered to rats for 28 days</td><td>Annonacin penetrated and accumulated in brain, demonstrated neurodegeneration without behavioural changes</td></tr><tr><td> Escobar-Khondiker M <em>et al</em>. (2007) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0033"></span><a href="javascript:;" reveal-id="jphp13182-bib-0033" data-open="jphp13182-bib-0033" class="link link-ref link-reveal xref-bibr">33</a>]</sup></td><td>Embryonic rats’ striatal neurons</td><td>Annonacin extracted from leaf and root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>25–100 n<span class="small-caps">m</span></td><td>Striatal neurons were incubated with annonacin for 48 h</td><td>Annonacin is neurotoxic, it increases tau proteins accumulation and redistribution</td></tr><tr><td> Hollerhage M <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0034"></span><a href="javascript:;" reveal-id="jphp13182-bib-0034" data-open="jphp13182-bib-0034" class="link link-ref link-reveal xref-bibr">34</a>]</sup></td><td>Human LUHMES cells</td><td>Dried leaves, and stems; ethyl acetate pulp extract (Brazil)</td><td char=".">0.01–10 μg/ml</td><td>Neurons were incubated with different samples for 48 h</td><td>AM dietary supplements are neurotoxic</td></tr><tr><td> Lannuzel A <em>et al</em>. (2003) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0035"></span><a href="javascript:;" reveal-id="jphp13182-bib-0035" data-open="jphp13182-bib-0035" class="link link-ref link-reveal xref-bibr">35</a>]</sup></td><td>Embryonic rats’ mesencephalonic neurons</td><td>Annonacin extracted from root<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a></td><td>1–100 n<span class="small-caps">m</span></td><td>Neurons were incubated with samples for 24 h</td><td>Annonacin is neurotoxic</td></tr><tr><td> Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>25–100 mg/kg (<em>n</em> = 108)</td><td>Intraperitoneal annonacin was administered for 30 min before behavioural test</td><td>Sedative, anxiolytic and anticonvulsant-like effect</td></tr><tr><td colspan="6">Hepatic</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>(Egypt)<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Hepatotoxicity was induced by DMBA. AM was either simultaneously or post-treated for 2 weeks<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>c</sup></a></td><td>Hepatoprotective</td></tr><tr><td> Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>Rats</td><td>Commercially available product (Brazil)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Hepatotoxicity was induced by MSG. AM was then administered orally for another 4 weeks</td><td>Hepatoprotective</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Rats</td><td>Aqueous (Nigeria)</td><td>100 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for the 4 weeks</td><td>Hepatoprotective</td></tr><tr><td> Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>]</sup></td><td>Rats</td><td>Aqueous (Ghana)</td><td>50–400 mg/kg per day (<em>n</em> = 40)</td><td>Hepatotoxicity was induced by either CCl<sub>4</sub> or acetaminophen. AM was pretreated orally for 1 day and continued for 7 days</td><td>Hepatoprotective</td></tr><tr><td> Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup></td><td>Rats</td><td>Aqueous (Ghana)</td><td>100–800 mg/kg (<em>n</em> = 10)</td><td>Hyperbilirubinaemia was induced by PHZ. Hepatotoxicity and hyperbilirubinaemia were induced by co-administration of PHZ and CCl<sub>4</sub>. AM was administered either one day prior to or after PHZ induction. Treatment duration was 7 days</td><td>Bilirubin-lowering and hepatoprotective effect</td></tr><tr><td> Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis and hepatotoxicity were induced by injecting <em>B. fimus</em>. Mice were either pretreated with AM orally for 2 h or 7 days</td><td>Hepatotoxic (with or without peritonitis induction) and increased hepatotoxicity with peritonitis infection</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Hepatotoxicity was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Hepatoprotective</td></tr><tr><td> George VC <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>]</sup></td><td>Hepatic cell (WRL-68)</td><td>Methanolic (India)</td><td char=".">12.5–100 μg/ml</td><td>Hepatic cells were incubated with NaAsO<sub>2</sub> and AM for 24 h</td><td>Hepatoprotective</td></tr><tr><td> Usunomena U and Ngozi (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup></td><td>Rats</td><td>Ethanolic (Nigeria)</td><td>200 mg/kg (<em>n</em> = 12)</td><td>Hepatic fibrosis was induced by DMN. AM was co-administered orally for 14 consecutive days</td><td>Hepatoprotective</td></tr><tr><td colspan="6">Renal</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>(Egypt)<span class="xrefLink" id="jumplink-jphp13182-note-0002"></span><a href="javascript:;" reveal-id="jphp13182-note-0002" data-open="jphp13182-note-0002" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>b</sup></a></td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Nephrotoxicity was induced by DMBA. AM was either simultaneously or post-treated for 2 weeks</td><td>Nephroprotective</td></tr><tr><td> Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis and renal damage were induced by injecting Bacillus firmus. Mice were either pretreated with AM orally for 2 h or 7 days</td><td>Nephrotoxic effect (with or without peritonitis induction) and increased nephrotoxicity with peritonitis infection</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Nephrotoxicity was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Nephroprotective</td></tr><tr><td colspan="6">Gastrointestinal</td></tr><tr><td> Bento EB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>]</sup></td><td>Mice</td><td>Hydroalcoholic (Brazil)</td><td>50–400 mg/kg (<em>n</em> = 60)</td><td>Gastric ulcer was induced either by absolute ethanol, acidified ethanol or indomethacin. Animals were pretreated with AM orally</td><td>Gastroprotective</td></tr><tr><td> Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Rats</td><td>Ethanolic (Malaysia)</td><td>10–300 mg/kg (<em>n</em> = 24)</td><td>Gastric ulcer was induced by ethanol. AM was pretreated orally for 1 h</td><td>Gastroprotective</td></tr><tr><td> Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Rats</td><td>Ethyl acetate (Malaysia)</td><td>200–400 mg/kg (<em>n</em> = 12)</td><td>Gastric ulcer was induced by ethanol. AM was pretreated orally for 1 h</td><td>Gastroprotective</td></tr><tr><td colspan="6">Cardiac</td></tr><tr><td> Bipat R <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0038"></span><a href="javascript:;" reveal-id="jphp13182-bib-0038" data-open="jphp13182-bib-0038" class="link link-ref link-reveal xref-bibr">38</a>]</sup></td><td>Guinea pig atria</td><td>Aqueous (Suriname)</td><td char=".">0.001–1 mg/ml (<em>n</em> = not reported)</td><td>Ischaemic-reperfusion injured atria was incubated with AM for 6 min</td><td>Positive inotropic properties without causing damage to myocytes</td></tr><tr><td colspan="6">Haematological</td></tr><tr><td> George VC <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>]</sup></td><td>Human erythrocytes</td><td>Methanolic (India)</td><td char=".">12.5–100 μg/ml</td><td>Erythrocytes were incubated with NaAsO<sub>2</sub> and AM for 2.5 h</td><td>Protective against haemolysis</td></tr><tr><td> Pautus S <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup></td><td>Mice</td><td>Annonacin and annonacinone isolated from AM seeds</td><td>20 μ<span class="small-caps">m</span> (<em>n</em> = 7)</td><td>Annonacinone was administered to the FeCl<sub>3</sub>-occluded mesenteric vessels in mice model</td><td>Annonacinone potentiates the fibrinolytic action of tPA</td></tr><tr><td colspan="6">Reproductive</td></tr><tr><td> Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>Rats</td><td>Commercially available leaf extract (Brazil)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Testicular toxicity was induced by MSG. AM was later administered orally for another 4 weeks</td><td>Protective against testicular toxicity</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0002"></span><div content-id="jphp13182-note-0002" class="footnote"><span class="fn"><p class="chapter-para">AM, <em>Annona muricata</em>; CCl<sub>4</sub>, carbon tetrachloride; DMBA, 7,12-dimethylbenz(a)anthracene; DMN, dimethylnitrosamine; FeCl<sub>3</sub>, Iron (III) chloride; LUHMES, Lund human mesencephalic neurons; MSG, monosodium glutamate; NaAsO<sub>2</sub>, sodium arsenite; <em>n</em>, sample size; PHZ, phenylhydrazine; STZ, streptozotocin; tPA, tissue plasminogen activator. <sup>a</sup>Unreported origin. <sup>b</sup>Unreported solvent used. <sup>c</sup>Unreported route.</p></span></div></div></div></div> <a id="491205058" scrollto-destination="491205058"></a> <div content-id="jphp13182-tbl-0003" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0003" data-id="jphp13182-tbl-0003"><span class="label title-label" id="label-79237">Table 3</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205058" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Hypoglycaemic, hypotensive, antinociceptive, anti-inflammatory and chemopreventive effect of <em>Annona muricata</em> leaf extract and/or acetogenins from <em>A. muricata</em></p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/compound tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="6">Hypoglycaemic effect</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Rats</td><td>Aqueous (Nigeria)</td><td>100 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for the 4-consecutive week</td><td>Hypoglycaemic</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>AM (single dose) was administered orally in normoglycemic rats</td><td>No effect on BGL in normoglycemic rats</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Hypoglycaemic</td></tr><tr><td> Justino AB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0042"></span><a href="javascript:;" reveal-id="jphp13182-bib-0042" data-open="jphp13182-bib-0042" class="link link-ref link-reveal xref-bibr">42</a>]</sup></td><td>Inhibition of α-amylase and α-glucosidase</td><td>increasing polarity of solvent (Brazil)</td><td char=".">0.00–80 μg/ml for α-amylase;<br />0.00–1500 μg/ml for α-glucosidase</td><td>AM was incubated with α-amylase and α-glucosidase for 30 min</td><td>Ethyl acetate and n-butanol fraction demonstrated inhibitory effect</td></tr><tr><td colspan="6">Hypotensive effect</td></tr><tr><td> Nwokocha CR <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup></td><td>Rats</td><td>Aqueous (Jamaica)</td><td char=".">9.17–48.53 mg/kg (<em>n</em> = 15)</td><td>Graded doses of AM were administered intravenously in 10 min apart in anesthetised normotensive rats</td><td>Hypotensive in normotensive rats. No effect on heart rate</td></tr><tr><td colspan="6">Antinociceptive</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>100–400 mg/kg (<em>n</em> = 72)</td><td>Nociception was induced by either oral acetic acid or subplantar injection of formalin or exposure to hot-plate. Animals were pretreated with AM orally for 1 h</td><td>Antinociceptive</td></tr><tr><td> Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Rats; mice</td><td>Ethanolic (Malaysia)</td><td>10–300 mg/kg (mice <em>n</em> = 48);<br />(rats <em>n</em> = 24)</td><td>Nociception in mice was induced by either administration of acetic acid or exposure to hot-plate. Nociception in rats were induced by subcutaneous injection of formalin into the paw. Animals were pretreated with AM orally for 1 h</td><td>Antinociceptive</td></tr><tr><td colspan="6">Anti-inflammatory</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Rats</td><td>Ethanolic (Brazil)</td><td>100–400 mg/kg (<em>n</em> = 36)</td><td>Inflammation was induced by either subplantar injection of carrageenan (oedema) or intrapleural administration of carrageenan (pleurisy). Animals were pretreated with oral AM for 1 h</td><td>Anti-inflammatory</td></tr><tr><td colspan="6">Chemopreventive</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>Unreported (Egypt)</td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Mammary carcinogenesis was induced by DMBA. AM was simultaneously administered for 2 weeks</td><td>Chemopreventive</td></tr><tr><td> Hamizah S <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup></td><td>Mice</td><td>Ethanolic (Malaysia)</td><td>30–300 mg/kg (<em>n</em> = 90)</td><td>Skin papillomagenesis was initiated by topical DMBA, followed by repeated application of croton oil for promotion. AM was topically applied either 7 days prior and 7 days after DMBA administration, or co-applied with croton oil (twice weekly), or applied both 7 days prior and 7 days after DMBA and twice weekly. Duration of the study was 10 weeks</td><td>Chemopreventive potential</td></tr><tr><td> Minari JB and Okeke (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup></td><td>Mice</td><td>Ethanolic (Nigeria)</td><td>50–200 mg/ml per day (<em>n</em> = 18)</td><td>AM was administered orally in adjunct with DMBA for 6 weeks</td><td>Prevent against DNA damage</td></tr><tr><td> Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Mice</td><td>Methanolic (India)</td><td>200–400 mg/kg per day (<em>n</em> = 12)</td><td>Lung cancer was induced by benzo[a]pyrene. AM was pretreated orally for 1 week and continued for 16 weeks</td><td>Chemopreventive potential</td></tr><tr><td colspan="6">Effects on radiopharmaceuticals</td></tr><tr><td> Holanda CM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></td><td>Rats</td><td>Hydroalcoholic<span class="xrefLink" id="jumplink-jphp13182-note-0003"></span><a href="javascript:;" reveal-id="jphp13182-note-0003" data-open="jphp13182-note-0003" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> (Brazil)</td><td>25 mg/kg (<em>n</em> = 12)</td><td>Rats were injected with 99mTc-DMSA (for renal imaging) or 99mTc-sodium phytate (for liver and spleen imaging). Rats were pretreated with oral AM daily for 10 days</td><td>Negatively influence 99mTc-DMSA intake in bladder, kidney and blood</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/compound tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="6">Hypoglycaemic effect</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Rats</td><td>Aqueous (Nigeria)</td><td>100 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for the 4-consecutive week</td><td>Hypoglycaemic</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>AM (single dose) was administered orally in normoglycemic rats</td><td>No effect on BGL in normoglycemic rats</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Hypoglycaemic</td></tr><tr><td> Justino AB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0042"></span><a href="javascript:;" reveal-id="jphp13182-bib-0042" data-open="jphp13182-bib-0042" class="link link-ref link-reveal xref-bibr">42</a>]</sup></td><td>Inhibition of α-amylase and α-glucosidase</td><td>increasing polarity of solvent (Brazil)</td><td char=".">0.00–80 μg/ml for α-amylase;<br />0.00–1500 μg/ml for α-glucosidase</td><td>AM was incubated with α-amylase and α-glucosidase for 30 min</td><td>Ethyl acetate and n-butanol fraction demonstrated inhibitory effect</td></tr><tr><td colspan="6">Hypotensive effect</td></tr><tr><td> Nwokocha CR <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup></td><td>Rats</td><td>Aqueous (Jamaica)</td><td char=".">9.17–48.53 mg/kg (<em>n</em> = 15)</td><td>Graded doses of AM were administered intravenously in 10 min apart in anesthetised normotensive rats</td><td>Hypotensive in normotensive rats. No effect on heart rate</td></tr><tr><td colspan="6">Antinociceptive</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>100–400 mg/kg (<em>n</em> = 72)</td><td>Nociception was induced by either oral acetic acid or subplantar injection of formalin or exposure to hot-plate. Animals were pretreated with AM orally for 1 h</td><td>Antinociceptive</td></tr><tr><td> Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Rats; mice</td><td>Ethanolic (Malaysia)</td><td>10–300 mg/kg (mice <em>n</em> = 48);<br />(rats <em>n</em> = 24)</td><td>Nociception in mice was induced by either administration of acetic acid or exposure to hot-plate. Nociception in rats were induced by subcutaneous injection of formalin into the paw. Animals were pretreated with AM orally for 1 h</td><td>Antinociceptive</td></tr><tr><td colspan="6">Anti-inflammatory</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Rats</td><td>Ethanolic (Brazil)</td><td>100–400 mg/kg (<em>n</em> = 36)</td><td>Inflammation was induced by either subplantar injection of carrageenan (oedema) or intrapleural administration of carrageenan (pleurisy). Animals were pretreated with oral AM for 1 h</td><td>Anti-inflammatory</td></tr><tr><td colspan="6">Chemopreventive</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>Unreported (Egypt)</td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Mammary carcinogenesis was induced by DMBA. AM was simultaneously administered for 2 weeks</td><td>Chemopreventive</td></tr><tr><td> Hamizah S <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup></td><td>Mice</td><td>Ethanolic (Malaysia)</td><td>30–300 mg/kg (<em>n</em> = 90)</td><td>Skin papillomagenesis was initiated by topical DMBA, followed by repeated application of croton oil for promotion. AM was topically applied either 7 days prior and 7 days after DMBA administration, or co-applied with croton oil (twice weekly), or applied both 7 days prior and 7 days after DMBA and twice weekly. Duration of the study was 10 weeks</td><td>Chemopreventive potential</td></tr><tr><td> Minari JB and Okeke (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup></td><td>Mice</td><td>Ethanolic (Nigeria)</td><td>50–200 mg/ml per day (<em>n</em> = 18)</td><td>AM was administered orally in adjunct with DMBA for 6 weeks</td><td>Prevent against DNA damage</td></tr><tr><td> Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Mice</td><td>Methanolic (India)</td><td>200–400 mg/kg per day (<em>n</em> = 12)</td><td>Lung cancer was induced by benzo[a]pyrene. AM was pretreated orally for 1 week and continued for 16 weeks</td><td>Chemopreventive potential</td></tr><tr><td colspan="6">Effects on radiopharmaceuticals</td></tr><tr><td> Holanda CM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></td><td>Rats</td><td>Hydroalcoholic<span class="xrefLink" id="jumplink-jphp13182-note-0003"></span><a href="javascript:;" reveal-id="jphp13182-note-0003" data-open="jphp13182-note-0003" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> (Brazil)</td><td>25 mg/kg (<em>n</em> = 12)</td><td>Rats were injected with 99mTc-DMSA (for renal imaging) or 99mTc-sodium phytate (for liver and spleen imaging). Rats were pretreated with oral AM daily for 10 days</td><td>Negatively influence 99mTc-DMSA intake in bladder, kidney and blood</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0003"></span><div content-id="jphp13182-note-0003" class="footnote"><span class="fn"><p class="chapter-para">AM, <em>Annona muricata</em>; BGL, blood glucose level; DMBA, 7,12-dimethylbenz(a)anthracene; n, sample size; STZ, streptozotocin. <sup>a</sup>Confirmed leaf extract after contacting author.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0003" data-id="jphp13182-tbl-0003"><span class="label title-label" id="label-79237">Table 3</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205058" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Hypoglycaemic, hypotensive, antinociceptive, anti-inflammatory and chemopreventive effect of <em>Annona muricata</em> leaf extract and/or acetogenins from <em>A. muricata</em></p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/compound tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="6">Hypoglycaemic effect</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Rats</td><td>Aqueous (Nigeria)</td><td>100 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for the 4-consecutive week</td><td>Hypoglycaemic</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>AM (single dose) was administered orally in normoglycemic rats</td><td>No effect on BGL in normoglycemic rats</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Hypoglycaemic</td></tr><tr><td> Justino AB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0042"></span><a href="javascript:;" reveal-id="jphp13182-bib-0042" data-open="jphp13182-bib-0042" class="link link-ref link-reveal xref-bibr">42</a>]</sup></td><td>Inhibition of α-amylase and α-glucosidase</td><td>increasing polarity of solvent (Brazil)</td><td char=".">0.00–80 μg/ml for α-amylase;<br />0.00–1500 μg/ml for α-glucosidase</td><td>AM was incubated with α-amylase and α-glucosidase for 30 min</td><td>Ethyl acetate and n-butanol fraction demonstrated inhibitory effect</td></tr><tr><td colspan="6">Hypotensive effect</td></tr><tr><td> Nwokocha CR <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup></td><td>Rats</td><td>Aqueous (Jamaica)</td><td char=".">9.17–48.53 mg/kg (<em>n</em> = 15)</td><td>Graded doses of AM were administered intravenously in 10 min apart in anesthetised normotensive rats</td><td>Hypotensive in normotensive rats. No effect on heart rate</td></tr><tr><td colspan="6">Antinociceptive</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>100–400 mg/kg (<em>n</em> = 72)</td><td>Nociception was induced by either oral acetic acid or subplantar injection of formalin or exposure to hot-plate. Animals were pretreated with AM orally for 1 h</td><td>Antinociceptive</td></tr><tr><td> Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Rats; mice</td><td>Ethanolic (Malaysia)</td><td>10–300 mg/kg (mice <em>n</em> = 48);<br />(rats <em>n</em> = 24)</td><td>Nociception in mice was induced by either administration of acetic acid or exposure to hot-plate. Nociception in rats were induced by subcutaneous injection of formalin into the paw. Animals were pretreated with AM orally for 1 h</td><td>Antinociceptive</td></tr><tr><td colspan="6">Anti-inflammatory</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Rats</td><td>Ethanolic (Brazil)</td><td>100–400 mg/kg (<em>n</em> = 36)</td><td>Inflammation was induced by either subplantar injection of carrageenan (oedema) or intrapleural administration of carrageenan (pleurisy). Animals were pretreated with oral AM for 1 h</td><td>Anti-inflammatory</td></tr><tr><td colspan="6">Chemopreventive</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>Unreported (Egypt)</td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Mammary carcinogenesis was induced by DMBA. AM was simultaneously administered for 2 weeks</td><td>Chemopreventive</td></tr><tr><td> Hamizah S <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup></td><td>Mice</td><td>Ethanolic (Malaysia)</td><td>30–300 mg/kg (<em>n</em> = 90)</td><td>Skin papillomagenesis was initiated by topical DMBA, followed by repeated application of croton oil for promotion. AM was topically applied either 7 days prior and 7 days after DMBA administration, or co-applied with croton oil (twice weekly), or applied both 7 days prior and 7 days after DMBA and twice weekly. Duration of the study was 10 weeks</td><td>Chemopreventive potential</td></tr><tr><td> Minari JB and Okeke (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup></td><td>Mice</td><td>Ethanolic (Nigeria)</td><td>50–200 mg/ml per day (<em>n</em> = 18)</td><td>AM was administered orally in adjunct with DMBA for 6 weeks</td><td>Prevent against DNA damage</td></tr><tr><td> Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Mice</td><td>Methanolic (India)</td><td>200–400 mg/kg per day (<em>n</em> = 12)</td><td>Lung cancer was induced by benzo[a]pyrene. AM was pretreated orally for 1 week and continued for 16 weeks</td><td>Chemopreventive potential</td></tr><tr><td colspan="6">Effects on radiopharmaceuticals</td></tr><tr><td> Holanda CM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></td><td>Rats</td><td>Hydroalcoholic<span class="xrefLink" id="jumplink-jphp13182-note-0003"></span><a href="javascript:;" reveal-id="jphp13182-note-0003" data-open="jphp13182-note-0003" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> (Brazil)</td><td>25 mg/kg (<em>n</em> = 12)</td><td>Rats were injected with 99mTc-DMSA (for renal imaging) or 99mTc-sodium phytate (for liver and spleen imaging). Rats were pretreated with oral AM daily for 10 days</td><td>Negatively influence 99mTc-DMSA intake in bladder, kidney and blood</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/compound tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="6">Hypoglycaemic effect</td></tr><tr><td> Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Rats</td><td>Aqueous (Nigeria)</td><td>100 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for the 4-consecutive week</td><td>Hypoglycaemic</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>AM (single dose) was administered orally in normoglycemic rats</td><td>No effect on BGL in normoglycemic rats</td></tr><tr><td> Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Rats</td><td>Aqueous (Cameroon)</td><td>100–200 mg/kg (<em>n</em> = 10)</td><td>Diabetes was induced by STZ. AM was then administered orally for 4 consecutive weeks</td><td>Hypoglycaemic</td></tr><tr><td> Justino AB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0042"></span><a href="javascript:;" reveal-id="jphp13182-bib-0042" data-open="jphp13182-bib-0042" class="link link-ref link-reveal xref-bibr">42</a>]</sup></td><td>Inhibition of α-amylase and α-glucosidase</td><td>increasing polarity of solvent (Brazil)</td><td char=".">0.00–80 μg/ml for α-amylase;<br />0.00–1500 μg/ml for α-glucosidase</td><td>AM was incubated with α-amylase and α-glucosidase for 30 min</td><td>Ethyl acetate and n-butanol fraction demonstrated inhibitory effect</td></tr><tr><td colspan="6">Hypotensive effect</td></tr><tr><td> Nwokocha CR <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup></td><td>Rats</td><td>Aqueous (Jamaica)</td><td char=".">9.17–48.53 mg/kg (<em>n</em> = 15)</td><td>Graded doses of AM were administered intravenously in 10 min apart in anesthetised normotensive rats</td><td>Hypotensive in normotensive rats. No effect on heart rate</td></tr><tr><td colspan="6">Antinociceptive</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Mice</td><td>Ethanolic (Brazil)</td><td>100–400 mg/kg (<em>n</em> = 72)</td><td>Nociception was induced by either oral acetic acid or subplantar injection of formalin or exposure to hot-plate. Animals were pretreated with AM orally for 1 h</td><td>Antinociceptive</td></tr><tr><td> Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Rats; mice</td><td>Ethanolic (Malaysia)</td><td>10–300 mg/kg (mice <em>n</em> = 48);<br />(rats <em>n</em> = 24)</td><td>Nociception in mice was induced by either administration of acetic acid or exposure to hot-plate. Nociception in rats were induced by subcutaneous injection of formalin into the paw. Animals were pretreated with AM orally for 1 h</td><td>Antinociceptive</td></tr><tr><td colspan="6">Anti-inflammatory</td></tr><tr><td> de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Rats</td><td>Ethanolic (Brazil)</td><td>100–400 mg/kg (<em>n</em> = 36)</td><td>Inflammation was induced by either subplantar injection of carrageenan (oedema) or intrapleural administration of carrageenan (pleurisy). Animals were pretreated with oral AM for 1 h</td><td>Anti-inflammatory</td></tr><tr><td colspan="6">Chemopreventive</td></tr><tr><td> Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Mice</td><td>Unreported (Egypt)</td><td>50–200 mg/kg per day (<em>n</em> = 30)</td><td>Mammary carcinogenesis was induced by DMBA. AM was simultaneously administered for 2 weeks</td><td>Chemopreventive</td></tr><tr><td> Hamizah S <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup></td><td>Mice</td><td>Ethanolic (Malaysia)</td><td>30–300 mg/kg (<em>n</em> = 90)</td><td>Skin papillomagenesis was initiated by topical DMBA, followed by repeated application of croton oil for promotion. AM was topically applied either 7 days prior and 7 days after DMBA administration, or co-applied with croton oil (twice weekly), or applied both 7 days prior and 7 days after DMBA and twice weekly. Duration of the study was 10 weeks</td><td>Chemopreventive potential</td></tr><tr><td> Minari JB and Okeke (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup></td><td>Mice</td><td>Ethanolic (Nigeria)</td><td>50–200 mg/ml per day (<em>n</em> = 18)</td><td>AM was administered orally in adjunct with DMBA for 6 weeks</td><td>Prevent against DNA damage</td></tr><tr><td> Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Mice</td><td>Methanolic (India)</td><td>200–400 mg/kg per day (<em>n</em> = 12)</td><td>Lung cancer was induced by benzo[a]pyrene. AM was pretreated orally for 1 week and continued for 16 weeks</td><td>Chemopreventive potential</td></tr><tr><td colspan="6">Effects on radiopharmaceuticals</td></tr><tr><td> Holanda CM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></td><td>Rats</td><td>Hydroalcoholic<span class="xrefLink" id="jumplink-jphp13182-note-0003"></span><a href="javascript:;" reveal-id="jphp13182-note-0003" data-open="jphp13182-note-0003" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> (Brazil)</td><td>25 mg/kg (<em>n</em> = 12)</td><td>Rats were injected with 99mTc-DMSA (for renal imaging) or 99mTc-sodium phytate (for liver and spleen imaging). Rats were pretreated with oral AM daily for 10 days</td><td>Negatively influence 99mTc-DMSA intake in bladder, kidney and blood</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0003"></span><div content-id="jphp13182-note-0003" class="footnote"><span class="fn"><p class="chapter-para">AM, <em>Annona muricata</em>; BGL, blood glucose level; DMBA, 7,12-dimethylbenz(a)anthracene; n, sample size; STZ, streptozotocin. <sup>a</sup>Confirmed leaf extract after contacting author.</p></span></div></div></div></div> <a id="491205059" scrollto-destination="491205059"></a> <div content-id="jphp13182-tbl-0004" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0004" data-id="jphp13182-tbl-0004"><span class="label title-label" id="label-79237">Table 4</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205059" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Drugs and metabolic enzyme interactions of <em>Annona muricata</em> leaf extract and/or acetogenins from <em>A. muricata</em></p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/cell line tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract or acetogenin tested (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Ko Y <em>et al</em>. (2011) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0045"></span><a href="javascript:;" reveal-id="jphp13182-bib-0045" data-open="jphp13182-bib-0045" class="link link-ref link-reveal xref-bibr">45</a>]</sup></td><td>ERα-positive MCF-7 cell</td><td>Annonacin from AM leaf (Taiwan)</td><td char=".">0.01–1 μ<span class="small-caps">m</span></td><td>Annonacin and the combination of annonacin and 4-hydroxytamoxifen was incubated with cell lines for 48 h</td><td>Additive effect of annonacin and 4-hydroxytamoxifen</td></tr><tr><td>Kuete V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0046"></span><a href="javascript:;" reveal-id="jphp13182-bib-0046" data-open="jphp13182-bib-0046" class="link link-ref link-reveal xref-bibr">46</a>]</sup></td><td>Drug-sensitive leukaemia and its p-glycoprotein-overexpressing subline</td><td>Methanolic leaf, seeds and pericarp extract (Cameroon)</td><td>Unreported</td><td>Cells were incubated with AM sample for 24 or 48 h</td><td>AM is not actively transported by p-glycoprotein</td></tr><tr><td>Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis was induced by injecting <em>B. fimus</em>. Mice were co-administered with AM and aspirin orally 2 h prior to peritonitis induction</td><td>Additive anti-inflammatory effect of AM and aspirin</td></tr><tr><td>Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Mice</td><td>Ethanolic GLE (USA); AEF; FEF</td><td>GLE 100 mg/kg (<em>n</em> = 6);<br />AEF 100 mg/kg (<em>n</em> = 6);<br />FEF 100 mg/kg (<em>n</em> = 6)</td><td>Human prostate cancer cell line was injected to mice (15 days prior to treatment). Different fraction of AM was administered orally for 4 weeks</td><td>Synergistic interactions between flavonoids and acetogenins to confer maximum therapeutic benefits</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/cell line tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract or acetogenin tested (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Ko Y <em>et al</em>. (2011) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0045"></span><a href="javascript:;" reveal-id="jphp13182-bib-0045" data-open="jphp13182-bib-0045" class="link link-ref link-reveal xref-bibr">45</a>]</sup></td><td>ERα-positive MCF-7 cell</td><td>Annonacin from AM leaf (Taiwan)</td><td char=".">0.01–1 μ<span class="small-caps">m</span></td><td>Annonacin and the combination of annonacin and 4-hydroxytamoxifen was incubated with cell lines for 48 h</td><td>Additive effect of annonacin and 4-hydroxytamoxifen</td></tr><tr><td>Kuete V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0046"></span><a href="javascript:;" reveal-id="jphp13182-bib-0046" data-open="jphp13182-bib-0046" class="link link-ref link-reveal xref-bibr">46</a>]</sup></td><td>Drug-sensitive leukaemia and its p-glycoprotein-overexpressing subline</td><td>Methanolic leaf, seeds and pericarp extract (Cameroon)</td><td>Unreported</td><td>Cells were incubated with AM sample for 24 or 48 h</td><td>AM is not actively transported by p-glycoprotein</td></tr><tr><td>Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis was induced by injecting <em>B. fimus</em>. Mice were co-administered with AM and aspirin orally 2 h prior to peritonitis induction</td><td>Additive anti-inflammatory effect of AM and aspirin</td></tr><tr><td>Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Mice</td><td>Ethanolic GLE (USA); AEF; FEF</td><td>GLE 100 mg/kg (<em>n</em> = 6);<br />AEF 100 mg/kg (<em>n</em> = 6);<br />FEF 100 mg/kg (<em>n</em> = 6)</td><td>Human prostate cancer cell line was injected to mice (15 days prior to treatment). Different fraction of AM was administered orally for 4 weeks</td><td>Synergistic interactions between flavonoids and acetogenins to confer maximum therapeutic benefits</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0004"></span><div content-id="jphp13182-note-0004" class="footnote"><span class="fn"><p class="chapter-para">AEF, acetogenin-enriched fraction; AM, <em>Annona muricata</em>; FEF, flavonoid-enriched fraction; GLE, graviola leaf extract; <em>n</em>, sample size; N/A, not applicable; ss, statistically significant.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0004" data-id="jphp13182-tbl-0004"><span class="label title-label" id="label-79237">Table 4</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205059" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Drugs and metabolic enzyme interactions of <em>Annona muricata</em> leaf extract and/or acetogenins from <em>A. muricata</em></p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/cell line tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract or acetogenin tested (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Ko Y <em>et al</em>. (2011) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0045"></span><a href="javascript:;" reveal-id="jphp13182-bib-0045" data-open="jphp13182-bib-0045" class="link link-ref link-reveal xref-bibr">45</a>]</sup></td><td>ERα-positive MCF-7 cell</td><td>Annonacin from AM leaf (Taiwan)</td><td char=".">0.01–1 μ<span class="small-caps">m</span></td><td>Annonacin and the combination of annonacin and 4-hydroxytamoxifen was incubated with cell lines for 48 h</td><td>Additive effect of annonacin and 4-hydroxytamoxifen</td></tr><tr><td>Kuete V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0046"></span><a href="javascript:;" reveal-id="jphp13182-bib-0046" data-open="jphp13182-bib-0046" class="link link-ref link-reveal xref-bibr">46</a>]</sup></td><td>Drug-sensitive leukaemia and its p-glycoprotein-overexpressing subline</td><td>Methanolic leaf, seeds and pericarp extract (Cameroon)</td><td>Unreported</td><td>Cells were incubated with AM sample for 24 or 48 h</td><td>AM is not actively transported by p-glycoprotein</td></tr><tr><td>Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis was induced by injecting <em>B. fimus</em>. Mice were co-administered with AM and aspirin orally 2 h prior to peritonitis induction</td><td>Additive anti-inflammatory effect of AM and aspirin</td></tr><tr><td>Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Mice</td><td>Ethanolic GLE (USA); AEF; FEF</td><td>GLE 100 mg/kg (<em>n</em> = 6);<br />AEF 100 mg/kg (<em>n</em> = 6);<br />FEF 100 mg/kg (<em>n</em> = 6)</td><td>Human prostate cancer cell line was injected to mice (15 days prior to treatment). Different fraction of AM was administered orally for 4 weeks</td><td>Synergistic interactions between flavonoids and acetogenins to confer maximum therapeutic benefits</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal/cell line tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Solvent of leaf extract or acetogenin tested (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dose range (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental design of treatment group and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Pharmacological outcome<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Ko Y <em>et al</em>. (2011) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0045"></span><a href="javascript:;" reveal-id="jphp13182-bib-0045" data-open="jphp13182-bib-0045" class="link link-ref link-reveal xref-bibr">45</a>]</sup></td><td>ERα-positive MCF-7 cell</td><td>Annonacin from AM leaf (Taiwan)</td><td char=".">0.01–1 μ<span class="small-caps">m</span></td><td>Annonacin and the combination of annonacin and 4-hydroxytamoxifen was incubated with cell lines for 48 h</td><td>Additive effect of annonacin and 4-hydroxytamoxifen</td></tr><tr><td>Kuete V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0046"></span><a href="javascript:;" reveal-id="jphp13182-bib-0046" data-open="jphp13182-bib-0046" class="link link-ref link-reveal xref-bibr">46</a>]</sup></td><td>Drug-sensitive leukaemia and its p-glycoprotein-overexpressing subline</td><td>Methanolic leaf, seeds and pericarp extract (Cameroon)</td><td>Unreported</td><td>Cells were incubated with AM sample for 24 or 48 h</td><td>AM is not actively transported by p-glycoprotein</td></tr><tr><td>Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Mice</td><td>Aqueous (Thailand)</td><td>100 mg/kg (<em>n</em> = 12)</td><td>Peritonitis was induced by injecting <em>B. fimus</em>. Mice were co-administered with AM and aspirin orally 2 h prior to peritonitis induction</td><td>Additive anti-inflammatory effect of AM and aspirin</td></tr><tr><td>Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Mice</td><td>Ethanolic GLE (USA); AEF; FEF</td><td>GLE 100 mg/kg (<em>n</em> = 6);<br />AEF 100 mg/kg (<em>n</em> = 6);<br />FEF 100 mg/kg (<em>n</em> = 6)</td><td>Human prostate cancer cell line was injected to mice (15 days prior to treatment). Different fraction of AM was administered orally for 4 weeks</td><td>Synergistic interactions between flavonoids and acetogenins to confer maximum therapeutic benefits</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0004"></span><div content-id="jphp13182-note-0004" class="footnote"><span class="fn"><p class="chapter-para">AEF, acetogenin-enriched fraction; AM, <em>Annona muricata</em>; FEF, flavonoid-enriched fraction; GLE, graviola leaf extract; <em>n</em>, sample size; N/A, not applicable; ss, statistically significant.</p></span></div></div></div></div><p class="chapter-para">Of the 12 toxicity tests reported,<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015 jphp13182-bib-0016 jphp13182-bib-0017 jphp13182-bib-0018 jphp13182-bib-0019 jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022 jphp13182-bib-0023 jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015 jphp13182-bib-0016 jphp13182-bib-0017 jphp13182-bib-0018 jphp13182-bib-0019 jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022 jphp13182-bib-0023 jphp13182-bib-0024" data-open="jphp13182-bib-0015 jphp13182-bib-0016 jphp13182-bib-0017 jphp13182-bib-0018 jphp13182-bib-0019 jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022 jphp13182-bib-0023 jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">15–24</a>]</sup> only one study reported behavioural signs of toxicity in mice at an oral dose of 4000 mg/kg in response to aqueous leaf extract which included paw licking, salivation, stretching and reduced activity.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup> In mice studies, the calculated intraperitoneal LD<sub>50</sub> varied from 155 mg/kg for aqueous leaf extract to 1092 mg/kg for ethanolic leaf extract.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup> The oral LD<sub>50</sub> of mice was calculated to be 1670 mg/kg in response to ethanolic leaf extract.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup> However, one study suggested that the mice oral LD<sub>50</sub> is ≥2500 mg/kg using aqueous leaf extract.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup> In the rat model studies, there was no calculated LD<sub>50</sub>, and it was estimated to be >5000 mg/kg in response to aqueous and methanolic leaf extract.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup> However, chronic consumption of high dose <em>A. muricata</em> methanolic leaf extract in rats had the potential to cause hepatotoxicity as evidenced by liver histology and a significant change in relative liver weight without affecting any liver enzymes level.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></p><p class="chapter-para">Nine studies investigated the effects of <em>A. muricata</em> leaf extract on liver function.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0025 jphp13182-bib-0026 jphp13182-bib-0027 jphp13182-bib-0028 jphp13182-bib-0029 jphp13182-bib-0030 jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025 jphp13182-bib-0026 jphp13182-bib-0027 jphp13182-bib-0028 jphp13182-bib-0029 jphp13182-bib-0030 jphp13182-bib-0031" data-open="jphp13182-bib-0025 jphp13182-bib-0026 jphp13182-bib-0027 jphp13182-bib-0028 jphp13182-bib-0029 jphp13182-bib-0030 jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">25–31</a>]</sup> Among the studies investigating hepatic effects, eight studies demonstrated a hepatoprotective effect of <em>A. muricata</em> leaf extracts<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0025 jphp13182-bib-0026 jphp13182-bib-0027 jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025 jphp13182-bib-0026 jphp13182-bib-0027 jphp13182-bib-0028" data-open="jphp13182-bib-0025 jphp13182-bib-0026 jphp13182-bib-0027 jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">25–28</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup> while one study demonstrated a hepatotoxic effect with no substantial differences in the dose, formulation or route of administration.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup> Three <em>in-vitro</em> and one animal study identified neurotoxic effects (<em>n</em> = 4),<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032 jphp13182-bib-0033 jphp13182-bib-0034 jphp13182-bib-0035"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032 jphp13182-bib-0033 jphp13182-bib-0034 jphp13182-bib-0035" data-open="jphp13182-bib-0032 jphp13182-bib-0033 jphp13182-bib-0034 jphp13182-bib-0035" class="link link-ref link-reveal xref-bibr">32–35</a>]</sup> with the animal study using annonacin at a dose of 3.8–7.6 mg/kg per day when administrated intravenously to rats for 28 days. One animal study utilised ethanolic leaf extract at a dose of 25–100 mg/kg demonstrated sedative, anxiolytic and anticonvulsant-like effect.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup> Antiulcerative (<em>n</em> = 3)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup> effects of <em>A. muricata</em> hydroalcoholic, ethanolic and ethyl acetate leaf extracts were identified when administered orally over the dose range of 10–400 mg/kg. Of the three studies which investigated <em>A. muricata</em> leaf extract in renal effect,<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup> two studies demonstrated a nephroprotective effect,<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup> while one demonstrated a nephrotoxic effect<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup> with no substantial differences in the dose, formulation or route of administration. There were limited data reported on the cardiac (<em>n</em> = 1),<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0038"></span><a href="javascript:;" reveal-id="jphp13182-bib-0038" data-open="jphp13182-bib-0038" class="link link-ref link-reveal xref-bibr">38</a>]</sup> haematological (<em>n</em> = 2)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0030"></span><a href="javascript:;" reveal-id="jphp13182-bib-0030" data-open="jphp13182-bib-0030" class="link link-ref link-reveal xref-bibr">30</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup> and reproductive (<em>n</em> = 1)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup> effect of <em>A. muricata</em> leaf extract.</p><p class="chapter-para">There were consistent results demonstrating the antinociceptive (<em>n</em> = 2)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup> effect of <em>A. muricata</em> in a rats and mice model using the ethanolic leaf extract at a dose range of 10–400 mg/kg. Chemopreventive effects of <em>A. muricata</em> were also demonstrated across four studies<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup> utilising mice model, with ethanolic and methanolic leaf extracts at a dose range of 30–400 mg/kg. A hypoglycaemic effect was demonstrated in an <em>in-vitro</em> study<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0042"></span><a href="javascript:;" reveal-id="jphp13182-bib-0042" data-open="jphp13182-bib-0042" class="link link-ref link-reveal xref-bibr">42</a>]</sup> and in rat models utilising aqueous leaf extract at a dose range of 100–200 mg/kg<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup> without affecting the blood glucose level in normoglycemic rats.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup> There was limited data demonstrating hypotensive (<em>n</em> = 1)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup> or anti-inflammatory (<em>n</em> = 1)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup> effects or effect of <em>A. muricata</em> on radiopharmaceuticals (<em>n</em> = 1).<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></p><p class="chapter-para">An <em>in-vitro</em> study demonstrated a drug and metabolic enzyme interaction that resulted in an additive effect of annonacin to 4-hydroxytamoxifen through the inhibition of MCF-7 breast cancer cell line survival.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0045"></span><a href="javascript:;" reveal-id="jphp13182-bib-0045" data-open="jphp13182-bib-0045" class="link link-ref link-reveal xref-bibr">45</a>]</sup> An additive anti-inflammatory effect between oral aqueous <em>A. muricata</em> leaf extract and aspirin was demonstrated in a mice model study at a dose of 100 mg/kg.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup> Interactions were also reported between acetogenins and flavonoids isolated from <em>A. muricata</em>.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup> The oral combination of these constituents conferred a maximal therapeutic effect against prostate cancer cell xenograft mice.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup> One in-vitro study also demonstrated that the constituents of <em>A. muricata</em> were not actively transported by p-glycoprotein.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0046"></span><a href="javascript:;" reveal-id="jphp13182-bib-0046" data-open="jphp13182-bib-0046" class="link link-ref link-reveal xref-bibr">46</a>]</sup></p><p class="chapter-para">As presented in <span class="xrefLink" id="jumplink-jphp13182-tbl-0005"></span><a href="javascript:;" reveal-id="jphp13182-tbl-0005" data-open="jphp13182-tbl-0005" class="link link-reveal link-table xref-fig">Table 5</a>, a range of human studies including RCTs (<em>n</em> = 3),<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup> double-blind RCT (<em>n</em> = 1)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup> and a case report (<em>n</em> = 1)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0049"></span><a href="javascript:;" reveal-id="jphp13182-bib-0049" data-open="jphp13182-bib-0049" class="link link-ref link-reveal xref-bibr">49</a>]</sup> were conducted for a duration of one to nine months utilising an oral ethanolic leaf extract at a range of doses from 180 to 540 mg daily. One case report used dry <em>A. muricata</em> leaves boiled in water.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0049"></span><a href="javascript:;" reveal-id="jphp13182-bib-0049" data-open="jphp13182-bib-0049" class="link link-ref link-reveal xref-bibr">49</a>]</sup> These studies evaluated the pharmacological effects of an <em>A. muricata</em> leaf extract in people with diabetes (<em>n</em> = 1),<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup> breast cancer (<em>n</em> = 1)<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0049"></span><a href="javascript:;" reveal-id="jphp13182-bib-0049" data-open="jphp13182-bib-0049" class="link link-ref link-reveal xref-bibr">49</a>]</sup> and colorectal cancer (<em>n</em> = 3).<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup> The adverse effect of nausea (<em>n</em> = 3), mild epigastric burn (<em>n</em> = 2), anal pain (<em>n</em> = 1) and patient condition deterioration (<em>n</em> = 1).</p> <a id="491205065" scrollto-destination="491205065"></a> <div content-id="jphp13182-tbl-0005" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0005" data-id="jphp13182-tbl-0005"><span class="label title-label" id="label-79237">Table 5</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205065" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Human studies</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design<span aria-hidden="true" style="display: none;"> . </span></th><th>AM formulation (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dosage and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Study population<span aria-hidden="true" style="display: none;"> . </span></th><th>Concurrent medication or therapy (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Biomarkers assessed<span aria-hidden="true" style="display: none;"> . </span></th><th>Main outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Adverse effect<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Arroyo J <em>et al</em>. (2009) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup></td><td>DB-RCT</td><td>Ethanolic leaf extract</td><td>180 mg/day;<br />360 mg/day;<br />540 mg/day for 30 days</td><td>Type 2 diabetes (BGL: 185–291 mg/dl)</td><td>Glibenclamide 5 mg/day (<em>n</em> = 10);<br />Glibenclamide 10 mg/day (<em>n</em> = 10);<br />Glibenclamide 15 mg/day (<em>n</em> = 10)</td><td>BGL, ALP, lipid profile and serum creatinine</td><td>Dose-dependent hypoglycaemic effect of AM; no changes in other parameters</td><td>Mild epigastric burn (<em>n</em> = 2);<br />nausea (<em>n</em> = 3)</td></tr><tr><td>Hansra DM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0049"></span><a href="javascript:;" reveal-id="jphp13182-bib-0049" data-open="jphp13182-bib-0049" class="link link-ref link-reveal xref-bibr">49</a>]</sup></td><td>Case report</td><td>10–12 dry leaves boiled in water for 5–7 min</td><td>8 oz daily for 9 months</td><td>80-year-old female with metastatic breast cancer (lung and liver metastases)</td><td>Capecitabine 2500 mg/day</td><td>AST, ALT, CEA, CA27-29, CA15-3 and PET/CT imaging</td><td>Reduction in liver enzymes and cancer biomarkers. PET/CT scan demonstrated improvement with stable disease</td><td>Nil</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>]</sup></td><td>RCT/ex-vivo study</td><td>Ethanolic leaf extract (unknown)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Colorectal cancer patient >30 years who had undergone primary tumour resection</td><td>In AM group (<em>n</em> = 14), 80% received chemotherapy</td><td>Cytotoxicity of venous blood sample towards colorectal and human embryonic kidney cell lines, total energy intake, BMI and haemoglobin level</td><td>Blood sample demonstrated an increase in cell viability in HEK cell line, decrease in cell viability in colorectal cancer DLD-1, but not in COLO205 cell line<br />No changes in other parameters</td><td>Not reported</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup></td><td>RCT</td><td>Ethanolic leaf extract (Indonesia)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Colorectal cancer patient >30 years who had undergone primary tumour resection</td><td>In AM group (<em>n</em> = 14), 80% received chemotherapy</td><td>Full blood count, albumin, AST, ALT, creatinine and blood urea nitrogen</td><td>No changes of all measured parameters</td><td>Anal pain (<em>n</em> = 1);<br />condition deteriorated (<em>n</em> = 1)</td></tr><tr><td>Surono IS <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></td><td>RCT</td><td>Ethanolic leaf extract (Indonesia)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Postresection colorectal cancer out-patient who are >30 years</td><td>In AM group (<em>n</em> = 13), 54% received either chemotherapy and/or radiotherapy</td><td>Serum TNF-α, IL-10, IFN-γ, COX-2</td><td>No difference in all parameters. Strong correlation between TNF-α and IL-10 level, and a significant correlation between IFN-γ and IL-10</td><td>Unreported</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design<span aria-hidden="true" style="display: none;"> . </span></th><th>AM formulation (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dosage and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Study population<span aria-hidden="true" style="display: none;"> . </span></th><th>Concurrent medication or therapy (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Biomarkers assessed<span aria-hidden="true" style="display: none;"> . </span></th><th>Main outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Adverse effect<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Arroyo J <em>et al</em>. (2009) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup></td><td>DB-RCT</td><td>Ethanolic leaf extract</td><td>180 mg/day;<br />360 mg/day;<br />540 mg/day for 30 days</td><td>Type 2 diabetes (BGL: 185–291 mg/dl)</td><td>Glibenclamide 5 mg/day (<em>n</em> = 10);<br />Glibenclamide 10 mg/day (<em>n</em> = 10);<br />Glibenclamide 15 mg/day (<em>n</em> = 10)</td><td>BGL, ALP, lipid profile and serum creatinine</td><td>Dose-dependent hypoglycaemic effect of AM; no changes in other parameters</td><td>Mild epigastric burn (<em>n</em> = 2);<br />nausea (<em>n</em> = 3)</td></tr><tr><td>Hansra DM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0049"></span><a href="javascript:;" reveal-id="jphp13182-bib-0049" data-open="jphp13182-bib-0049" class="link link-ref link-reveal xref-bibr">49</a>]</sup></td><td>Case report</td><td>10–12 dry leaves boiled in water for 5–7 min</td><td>8 oz daily for 9 months</td><td>80-year-old female with metastatic breast cancer (lung and liver metastases)</td><td>Capecitabine 2500 mg/day</td><td>AST, ALT, CEA, CA27-29, CA15-3 and PET/CT imaging</td><td>Reduction in liver enzymes and cancer biomarkers. PET/CT scan demonstrated improvement with stable disease</td><td>Nil</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>]</sup></td><td>RCT/ex-vivo study</td><td>Ethanolic leaf extract (unknown)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Colorectal cancer patient >30 years who had undergone primary tumour resection</td><td>In AM group (<em>n</em> = 14), 80% received chemotherapy</td><td>Cytotoxicity of venous blood sample towards colorectal and human embryonic kidney cell lines, total energy intake, BMI and haemoglobin level</td><td>Blood sample demonstrated an increase in cell viability in HEK cell line, decrease in cell viability in colorectal cancer DLD-1, but not in COLO205 cell line<br />No changes in other parameters</td><td>Not reported</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup></td><td>RCT</td><td>Ethanolic leaf extract (Indonesia)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Colorectal cancer patient >30 years who had undergone primary tumour resection</td><td>In AM group (<em>n</em> = 14), 80% received chemotherapy</td><td>Full blood count, albumin, AST, ALT, creatinine and blood urea nitrogen</td><td>No changes of all measured parameters</td><td>Anal pain (<em>n</em> = 1);<br />condition deteriorated (<em>n</em> = 1)</td></tr><tr><td>Surono IS <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></td><td>RCT</td><td>Ethanolic leaf extract (Indonesia)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Postresection colorectal cancer out-patient who are >30 years</td><td>In AM group (<em>n</em> = 13), 54% received either chemotherapy and/or radiotherapy</td><td>Serum TNF-α, IL-10, IFN-γ, COX-2</td><td>No difference in all parameters. Strong correlation between TNF-α and IL-10 level, and a significant correlation between IFN-γ and IL-10</td><td>Unreported</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0005"></span><div content-id="jphp13182-note-0005" class="footnote"><span class="fn"><p class="chapter-para">ALP, alkaline phosphatase; ALT, alanine aminotransferase; AM, <em>Annona muricata</em>; AST, aspartate aminotransferase; BGL, Blood glucose level; BMI, body mass index; CA15-3, cancer antigen 15-3; CA27-29, cancer antigen 27-29; CEA, carcinoembryonic antigen; COX-2, cyclooxygenase-2; DB-RCT, double-blind randomised controlled trial; IFN-γ, interferon-γ; IL-10, interleukin-10; <em>n</em>, sample size; PET/CT, positron emission tomography–computed tomography; RCT, randomised controlled trial; TNF-α, tumour necrosis factor-α. <sup>a</sup>Contains 3.6 mg/kg acetogenin.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0005" data-id="jphp13182-tbl-0005"><span class="label title-label" id="label-79237">Table 5</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205065" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Human studies</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design<span aria-hidden="true" style="display: none;"> . </span></th><th>AM formulation (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dosage and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Study population<span aria-hidden="true" style="display: none;"> . </span></th><th>Concurrent medication or therapy (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Biomarkers assessed<span aria-hidden="true" style="display: none;"> . </span></th><th>Main outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Adverse effect<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Arroyo J <em>et al</em>. (2009) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup></td><td>DB-RCT</td><td>Ethanolic leaf extract</td><td>180 mg/day;<br />360 mg/day;<br />540 mg/day for 30 days</td><td>Type 2 diabetes (BGL: 185–291 mg/dl)</td><td>Glibenclamide 5 mg/day (<em>n</em> = 10);<br />Glibenclamide 10 mg/day (<em>n</em> = 10);<br />Glibenclamide 15 mg/day (<em>n</em> = 10)</td><td>BGL, ALP, lipid profile and serum creatinine</td><td>Dose-dependent hypoglycaemic effect of AM; no changes in other parameters</td><td>Mild epigastric burn (<em>n</em> = 2);<br />nausea (<em>n</em> = 3)</td></tr><tr><td>Hansra DM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0049"></span><a href="javascript:;" reveal-id="jphp13182-bib-0049" data-open="jphp13182-bib-0049" class="link link-ref link-reveal xref-bibr">49</a>]</sup></td><td>Case report</td><td>10–12 dry leaves boiled in water for 5–7 min</td><td>8 oz daily for 9 months</td><td>80-year-old female with metastatic breast cancer (lung and liver metastases)</td><td>Capecitabine 2500 mg/day</td><td>AST, ALT, CEA, CA27-29, CA15-3 and PET/CT imaging</td><td>Reduction in liver enzymes and cancer biomarkers. PET/CT scan demonstrated improvement with stable disease</td><td>Nil</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>]</sup></td><td>RCT/ex-vivo study</td><td>Ethanolic leaf extract (unknown)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Colorectal cancer patient >30 years who had undergone primary tumour resection</td><td>In AM group (<em>n</em> = 14), 80% received chemotherapy</td><td>Cytotoxicity of venous blood sample towards colorectal and human embryonic kidney cell lines, total energy intake, BMI and haemoglobin level</td><td>Blood sample demonstrated an increase in cell viability in HEK cell line, decrease in cell viability in colorectal cancer DLD-1, but not in COLO205 cell line<br />No changes in other parameters</td><td>Not reported</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup></td><td>RCT</td><td>Ethanolic leaf extract (Indonesia)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Colorectal cancer patient >30 years who had undergone primary tumour resection</td><td>In AM group (<em>n</em> = 14), 80% received chemotherapy</td><td>Full blood count, albumin, AST, ALT, creatinine and blood urea nitrogen</td><td>No changes of all measured parameters</td><td>Anal pain (<em>n</em> = 1);<br />condition deteriorated (<em>n</em> = 1)</td></tr><tr><td>Surono IS <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></td><td>RCT</td><td>Ethanolic leaf extract (Indonesia)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Postresection colorectal cancer out-patient who are >30 years</td><td>In AM group (<em>n</em> = 13), 54% received either chemotherapy and/or radiotherapy</td><td>Serum TNF-α, IL-10, IFN-γ, COX-2</td><td>No difference in all parameters. Strong correlation between TNF-α and IL-10 level, and a significant correlation between IFN-γ and IL-10</td><td>Unreported</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design<span aria-hidden="true" style="display: none;"> . </span></th><th>AM formulation (origin)<span aria-hidden="true" style="display: none;"> . </span></th><th><em>Annona muricata</em> dosage and duration<span aria-hidden="true" style="display: none;"> . </span></th><th>Study population<span aria-hidden="true" style="display: none;"> . </span></th><th>Concurrent medication or therapy (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Biomarkers assessed<span aria-hidden="true" style="display: none;"> . </span></th><th>Main outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Adverse effect<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Arroyo J <em>et al</em>. (2009) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup></td><td>DB-RCT</td><td>Ethanolic leaf extract</td><td>180 mg/day;<br />360 mg/day;<br />540 mg/day for 30 days</td><td>Type 2 diabetes (BGL: 185–291 mg/dl)</td><td>Glibenclamide 5 mg/day (<em>n</em> = 10);<br />Glibenclamide 10 mg/day (<em>n</em> = 10);<br />Glibenclamide 15 mg/day (<em>n</em> = 10)</td><td>BGL, ALP, lipid profile and serum creatinine</td><td>Dose-dependent hypoglycaemic effect of AM; no changes in other parameters</td><td>Mild epigastric burn (<em>n</em> = 2);<br />nausea (<em>n</em> = 3)</td></tr><tr><td>Hansra DM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0049"></span><a href="javascript:;" reveal-id="jphp13182-bib-0049" data-open="jphp13182-bib-0049" class="link link-ref link-reveal xref-bibr">49</a>]</sup></td><td>Case report</td><td>10–12 dry leaves boiled in water for 5–7 min</td><td>8 oz daily for 9 months</td><td>80-year-old female with metastatic breast cancer (lung and liver metastases)</td><td>Capecitabine 2500 mg/day</td><td>AST, ALT, CEA, CA27-29, CA15-3 and PET/CT imaging</td><td>Reduction in liver enzymes and cancer biomarkers. PET/CT scan demonstrated improvement with stable disease</td><td>Nil</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>]</sup></td><td>RCT/ex-vivo study</td><td>Ethanolic leaf extract (unknown)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Colorectal cancer patient >30 years who had undergone primary tumour resection</td><td>In AM group (<em>n</em> = 14), 80% received chemotherapy</td><td>Cytotoxicity of venous blood sample towards colorectal and human embryonic kidney cell lines, total energy intake, BMI and haemoglobin level</td><td>Blood sample demonstrated an increase in cell viability in HEK cell line, decrease in cell viability in colorectal cancer DLD-1, but not in COLO205 cell line<br />No changes in other parameters</td><td>Not reported</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup></td><td>RCT</td><td>Ethanolic leaf extract (Indonesia)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Colorectal cancer patient >30 years who had undergone primary tumour resection</td><td>In AM group (<em>n</em> = 14), 80% received chemotherapy</td><td>Full blood count, albumin, AST, ALT, creatinine and blood urea nitrogen</td><td>No changes of all measured parameters</td><td>Anal pain (<em>n</em> = 1);<br />condition deteriorated (<em>n</em> = 1)</td></tr><tr><td>Surono IS <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></td><td>RCT</td><td>Ethanolic leaf extract (Indonesia)</td><td>300 mg/day<span class="xrefLink" id="jumplink-jphp13182-note-0005"></span><a href="javascript:;" reveal-id="jphp13182-note-0005" data-open="jphp13182-note-0005" class="link link-ref link-reveal xref-fn js-xref-fn"><sup>a</sup></a> for 8 weeks</td><td>Postresection colorectal cancer out-patient who are >30 years</td><td>In AM group (<em>n</em> = 13), 54% received either chemotherapy and/or radiotherapy</td><td>Serum TNF-α, IL-10, IFN-γ, COX-2</td><td>No difference in all parameters. Strong correlation between TNF-α and IL-10 level, and a significant correlation between IFN-γ and IL-10</td><td>Unreported</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0005"></span><div content-id="jphp13182-note-0005" class="footnote"><span class="fn"><p class="chapter-para">ALP, alkaline phosphatase; ALT, alanine aminotransferase; AM, <em>Annona muricata</em>; AST, aspartate aminotransferase; BGL, Blood glucose level; BMI, body mass index; CA15-3, cancer antigen 15-3; CA27-29, cancer antigen 27-29; CEA, carcinoembryonic antigen; COX-2, cyclooxygenase-2; DB-RCT, double-blind randomised controlled trial; IFN-γ, interferon-γ; IL-10, interleukin-10; <em>n</em>, sample size; PET/CT, positron emission tomography–computed tomography; RCT, randomised controlled trial; TNF-α, tumour necrosis factor-α. <sup>a</sup>Contains 3.6 mg/kg acetogenin.</p></span></div></div></div></div><p class="chapter-para">Only two studies (<span class="xrefLink" id="jumplink-jphp13182-tbl-0006"></span><a href="javascript:;" reveal-id="jphp13182-tbl-0006" data-open="jphp13182-tbl-0006" class="link link-reveal link-table xref-fig">Table 6</a>) were found that reported on the pharmacokinetics of <em>A. muricata</em> constituents in rats,<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup> and the main focus was the constituent annonacin. This constituent was found to have a low bioavailability (<em>F</em> = 3.2 ± 0.3%) and limited penetration of the blood brain barrier.</p> <a id="491205067" scrollto-destination="491205067"></a> <div content-id="jphp13182-tbl-0006" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0006" data-id="jphp13182-tbl-0006"><span class="label title-label" id="label-79237">Table 6</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205067" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Pharmacokinetics of acetogenins from <em>Annona muricata</em></p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Constituent analysed<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Main outcome<span aria-hidden="true" style="display: none;"> . </span></th><th>Interpretation<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Bonneau N <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>]</sup></td><td>Rats</td><td>Annonacin extracted from AM seeds</td><td>Annonacin was administered IV (0.5 mg/kg) (<em>n</em> = 6) or orally (<em>n</em> = 6) (10 mg/kg) to rats</td><td>IV <em>t</em><sub>1/2</sub> = 15.2 ± 1.1 h;<br />oral <em>t</em><sub>1/2</sub> = 4.8 ± 0.7;<br /><em>F</em> = 3.2 ± 0.3%</td><td>Low bioavailability of annonacin</td></tr><tr><td>Bonneau N <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></td><td>Rats</td><td>Annonacin extracted from AM seeds</td><td>Annonacin was administered via IV (0.5 mg/kg; <em>n</em> = 17) or orally (10 mg/kg) (<em>n</em> = 8) or orally (100 mg/kg) (<em>n</em> = 5)</td><td>Amount of annonacin in brain:<br />IV:<br />0.5 mg/kg: 12.5 × 10<sup>−4</sup>% (at 24 h);<br />0.5 mg/kg: 8.4 × 10<sup>−4</sup>% (48 h)<br />Oral:<br />10 mg/kg: 1.1 × 10<sup>−4</sup>% (at 48 h);<br />100 mg/kg: 0.8 × 10<sup>−4</sup>% (at 24 h)</td><td>Limited blood brain barrier penetration</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Constituent analysed<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Main outcome<span aria-hidden="true" style="display: none;"> . </span></th><th>Interpretation<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Bonneau N <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>]</sup></td><td>Rats</td><td>Annonacin extracted from AM seeds</td><td>Annonacin was administered IV (0.5 mg/kg) (<em>n</em> = 6) or orally (<em>n</em> = 6) (10 mg/kg) to rats</td><td>IV <em>t</em><sub>1/2</sub> = 15.2 ± 1.1 h;<br />oral <em>t</em><sub>1/2</sub> = 4.8 ± 0.7;<br /><em>F</em> = 3.2 ± 0.3%</td><td>Low bioavailability of annonacin</td></tr><tr><td>Bonneau N <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></td><td>Rats</td><td>Annonacin extracted from AM seeds</td><td>Annonacin was administered via IV (0.5 mg/kg; <em>n</em> = 17) or orally (10 mg/kg) (<em>n</em> = 8) or orally (100 mg/kg) (<em>n</em> = 5)</td><td>Amount of annonacin in brain:<br />IV:<br />0.5 mg/kg: 12.5 × 10<sup>−4</sup>% (at 24 h);<br />0.5 mg/kg: 8.4 × 10<sup>−4</sup>% (48 h)<br />Oral:<br />10 mg/kg: 1.1 × 10<sup>−4</sup>% (at 48 h);<br />100 mg/kg: 0.8 × 10<sup>−4</sup>% (at 24 h)</td><td>Limited blood brain barrier penetration</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0006"></span><div content-id="jphp13182-note-0006" class="footnote"><span class="fn"><p class="chapter-para">AM, Annona muricata; <em>F</em>, bioavailability; IV, intravenous; <em>n</em>, sample size; <em>t</em><sub>1/2</sub>, half-life.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0006" data-id="jphp13182-tbl-0006"><span class="label title-label" id="label-79237">Table 6</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205067" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Pharmacokinetics of acetogenins from <em>Annona muricata</em></p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Constituent analysed<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Main outcome<span aria-hidden="true" style="display: none;"> . </span></th><th>Interpretation<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Bonneau N <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>]</sup></td><td>Rats</td><td>Annonacin extracted from AM seeds</td><td>Annonacin was administered IV (0.5 mg/kg) (<em>n</em> = 6) or orally (<em>n</em> = 6) (10 mg/kg) to rats</td><td>IV <em>t</em><sub>1/2</sub> = 15.2 ± 1.1 h;<br />oral <em>t</em><sub>1/2</sub> = 4.8 ± 0.7;<br /><em>F</em> = 3.2 ± 0.3%</td><td>Low bioavailability of annonacin</td></tr><tr><td>Bonneau N <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></td><td>Rats</td><td>Annonacin extracted from AM seeds</td><td>Annonacin was administered via IV (0.5 mg/kg; <em>n</em> = 17) or orally (10 mg/kg) (<em>n</em> = 8) or orally (100 mg/kg) (<em>n</em> = 5)</td><td>Amount of annonacin in brain:<br />IV:<br />0.5 mg/kg: 12.5 × 10<sup>−4</sup>% (at 24 h);<br />0.5 mg/kg: 8.4 × 10<sup>−4</sup>% (48 h)<br />Oral:<br />10 mg/kg: 1.1 × 10<sup>−4</sup>% (at 48 h);<br />100 mg/kg: 0.8 × 10<sup>−4</sup>% (at 24 h)</td><td>Limited blood brain barrier penetration</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Study<span aria-hidden="true" style="display: none;"> . </span></th><th>Animal tested<span aria-hidden="true" style="display: none;"> . </span></th><th>Constituent analysed<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design (<em>n</em>)<span aria-hidden="true" style="display: none;"> . </span></th><th>Main outcome<span aria-hidden="true" style="display: none;"> . </span></th><th>Interpretation<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Bonneau N <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>]</sup></td><td>Rats</td><td>Annonacin extracted from AM seeds</td><td>Annonacin was administered IV (0.5 mg/kg) (<em>n</em> = 6) or orally (<em>n</em> = 6) (10 mg/kg) to rats</td><td>IV <em>t</em><sub>1/2</sub> = 15.2 ± 1.1 h;<br />oral <em>t</em><sub>1/2</sub> = 4.8 ± 0.7;<br /><em>F</em> = 3.2 ± 0.3%</td><td>Low bioavailability of annonacin</td></tr><tr><td>Bonneau N <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></td><td>Rats</td><td>Annonacin extracted from AM seeds</td><td>Annonacin was administered via IV (0.5 mg/kg; <em>n</em> = 17) or orally (10 mg/kg) (<em>n</em> = 8) or orally (100 mg/kg) (<em>n</em> = 5)</td><td>Amount of annonacin in brain:<br />IV:<br />0.5 mg/kg: 12.5 × 10<sup>−4</sup>% (at 24 h);<br />0.5 mg/kg: 8.4 × 10<sup>−4</sup>% (48 h)<br />Oral:<br />10 mg/kg: 1.1 × 10<sup>−4</sup>% (at 48 h);<br />100 mg/kg: 0.8 × 10<sup>−4</sup>% (at 24 h)</td><td>Limited blood brain barrier penetration</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0006"></span><div content-id="jphp13182-note-0006" class="footnote"><span class="fn"><p class="chapter-para">AM, Annona muricata; <em>F</em>, bioavailability; IV, intravenous; <em>n</em>, sample size; <em>t</em><sub>1/2</sub>, half-life.</p></span></div></div></div></div><p class="chapter-para">The quality of 26 animal studies are presented in <span class="xrefLink" id="jumplink-jphp13182-tbl-0007"></span><a href="javascript:;" reveal-id="jphp13182-tbl-0007" data-open="jphp13182-tbl-0007" class="link link-reveal link-table xref-fig">Table 7</a> highlighting that while most of the ARRIVE criteria were met, only two studies described the allocation of animals to experimental groups,<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup> four reported baseline data of animals<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup> and 12 reported the adverse effects.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015 jphp13182-bib-0016 jphp13182-bib-0017 jphp13182-bib-0018 jphp13182-bib-0019 jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022 jphp13182-bib-0023 jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015 jphp13182-bib-0016 jphp13182-bib-0017 jphp13182-bib-0018 jphp13182-bib-0019 jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022 jphp13182-bib-0023 jphp13182-bib-0024" data-open="jphp13182-bib-0015 jphp13182-bib-0016 jphp13182-bib-0017 jphp13182-bib-0018 jphp13182-bib-0019 jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022 jphp13182-bib-0023 jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">15–24</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></p> <a id="491205069" scrollto-destination="491205069"></a> <div content-id="jphp13182-tbl-0007" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0007" data-id="jphp13182-tbl-0007"><span class="label title-label" id="label-79237">Table 7</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205069" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Quality assessment of animal studies</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th><span aria-hidden="true" style="display: none;"> . </span></th><th colspan="9">Methods<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="4">Results<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Author-year<span aria-hidden="true" style="display: none;"> . </span></th><th>Ethical statement<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental procedures<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental animals<span aria-hidden="true" style="display: none;"> . </span></th><th>Housing and husbandry<span aria-hidden="true" style="display: none;"> . </span></th><th>Sample size<span aria-hidden="true" style="display: none;"> . </span></th><th>Allocating animals to experimental groups<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Statistical methods<span aria-hidden="true" style="display: none;"> . </span></th><th>Baseline data<span aria-hidden="true" style="display: none;"> . </span></th><th>Numbers analysed<span aria-hidden="true" style="display: none;"> . </span></th><th>Outcomes and estimation<span aria-hidden="true" style="display: none;"> . </span></th><th>Adverse events<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>P</td><td>N</td></tr><tr><td>Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Acesio NO <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015" data-open="jphp13182-bib-0015" class="link link-ref link-reveal xref-bibr">15</a>]</sup></td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Arthur FKN <em>et al</em>. 2012 <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>P</td><td>Y</td><td>N</td></tr><tr><td>Bento EB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Bonneau N <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Bonneau N <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Champy P <em>et al</em>. (2004) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Hamizah S <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Holanda CM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Minari JB and Okeke (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>P</td><td>N</td></tr><tr><td>Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Nwokocha CR <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup></td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Pautus S <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td></tr><tr><td>Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>N</td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Somsak V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>Usunomena U and Ngozi (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>P</td><td>Y</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th><span aria-hidden="true" style="display: none;"> . </span></th><th colspan="9">Methods<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="4">Results<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Author-year<span aria-hidden="true" style="display: none;"> . </span></th><th>Ethical statement<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental procedures<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental animals<span aria-hidden="true" style="display: none;"> . </span></th><th>Housing and husbandry<span aria-hidden="true" style="display: none;"> . </span></th><th>Sample size<span aria-hidden="true" style="display: none;"> . </span></th><th>Allocating animals to experimental groups<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Statistical methods<span aria-hidden="true" style="display: none;"> . </span></th><th>Baseline data<span aria-hidden="true" style="display: none;"> . </span></th><th>Numbers analysed<span aria-hidden="true" style="display: none;"> . </span></th><th>Outcomes and estimation<span aria-hidden="true" style="display: none;"> . </span></th><th>Adverse events<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>P</td><td>N</td></tr><tr><td>Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Acesio NO <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015" data-open="jphp13182-bib-0015" class="link link-ref link-reveal xref-bibr">15</a>]</sup></td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Arthur FKN <em>et al</em>. 2012 <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>P</td><td>Y</td><td>N</td></tr><tr><td>Bento EB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Bonneau N <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Bonneau N <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Champy P <em>et al</em>. (2004) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Hamizah S <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Holanda CM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Minari JB and Okeke (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>P</td><td>N</td></tr><tr><td>Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Nwokocha CR <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup></td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Pautus S <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td></tr><tr><td>Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>N</td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Somsak V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>Usunomena U and Ngozi (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>P</td><td>Y</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0007"></span><div content-id="jphp13182-note-0007" class="footnote"><span class="fn"><p class="chapter-para">N, no; P, partial; Y, yes.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0007" data-id="jphp13182-tbl-0007"><span class="label title-label" id="label-79237">Table 7</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205069" aria-describedby="label-79237"> Open in new tab </a></div><div class="caption caption-id-" id="caption-79237"><p class="chapter-para">Quality assessment of animal studies</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-79237" aria-describedby="
 caption-79237"><thead><tr><th><span aria-hidden="true" style="display: none;"> . </span></th><th colspan="9">Methods<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="4">Results<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Author-year<span aria-hidden="true" style="display: none;"> . </span></th><th>Ethical statement<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental procedures<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental animals<span aria-hidden="true" style="display: none;"> . </span></th><th>Housing and husbandry<span aria-hidden="true" style="display: none;"> . </span></th><th>Sample size<span aria-hidden="true" style="display: none;"> . </span></th><th>Allocating animals to experimental groups<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Statistical methods<span aria-hidden="true" style="display: none;"> . </span></th><th>Baseline data<span aria-hidden="true" style="display: none;"> . </span></th><th>Numbers analysed<span aria-hidden="true" style="display: none;"> . </span></th><th>Outcomes and estimation<span aria-hidden="true" style="display: none;"> . </span></th><th>Adverse events<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>P</td><td>N</td></tr><tr><td>Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Acesio NO <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015" data-open="jphp13182-bib-0015" class="link link-ref link-reveal xref-bibr">15</a>]</sup></td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Arthur FKN <em>et al</em>. 2012 <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>P</td><td>Y</td><td>N</td></tr><tr><td>Bento EB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Bonneau N <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Bonneau N <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Champy P <em>et al</em>. (2004) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Hamizah S <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Holanda CM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Minari JB and Okeke (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>P</td><td>N</td></tr><tr><td>Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Nwokocha CR <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup></td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Pautus S <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td></tr><tr><td>Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>N</td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Somsak V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>Usunomena U and Ngozi (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>P</td><td>Y</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th><span aria-hidden="true" style="display: none;"> . </span></th><th colspan="9">Methods<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="4">Results<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Author-year<span aria-hidden="true" style="display: none;"> . </span></th><th>Ethical statement<span aria-hidden="true" style="display: none;"> . </span></th><th>Study design<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental procedures<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental animals<span aria-hidden="true" style="display: none;"> . </span></th><th>Housing and husbandry<span aria-hidden="true" style="display: none;"> . </span></th><th>Sample size<span aria-hidden="true" style="display: none;"> . </span></th><th>Allocating animals to experimental groups<span aria-hidden="true" style="display: none;"> . </span></th><th>Experimental outcomes<span aria-hidden="true" style="display: none;"> . </span></th><th>Statistical methods<span aria-hidden="true" style="display: none;"> . </span></th><th>Baseline data<span aria-hidden="true" style="display: none;"> . </span></th><th>Numbers analysed<span aria-hidden="true" style="display: none;"> . </span></th><th>Outcomes and estimation<span aria-hidden="true" style="display: none;"> . </span></th><th>Adverse events<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Abd El-Kaream SA (2019) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0025"></span><a href="javascript:;" reveal-id="jphp13182-bib-0025" data-open="jphp13182-bib-0025" class="link link-ref link-reveal xref-bibr">25</a>]</sup></td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>P</td><td>N</td></tr><tr><td>Abd-Ella EM <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>]</sup></td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Acesio NO <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0015"></span><a href="javascript:;" reveal-id="jphp13182-bib-0015" data-open="jphp13182-bib-0015" class="link link-ref link-reveal xref-bibr">15</a>]</sup></td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>Adewole SO and Ojewole (2008) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Arthur FKN <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0027"></span><a href="javascript:;" reveal-id="jphp13182-bib-0027" data-open="jphp13182-bib-0027" class="link link-ref link-reveal xref-bibr">27</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Arthur FKN <em>et al</em>. 2012 <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0028"></span><a href="javascript:;" reveal-id="jphp13182-bib-0028" data-open="jphp13182-bib-0028" class="link link-ref link-reveal xref-bibr">28</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>P</td><td>Y</td><td>N</td></tr><tr><td>Bento EB <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0036"></span><a href="javascript:;" reveal-id="jphp13182-bib-0036" data-open="jphp13182-bib-0036" class="link link-ref link-reveal xref-bibr">36</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Bitar R <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Bonneau N <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0050"></span><a href="javascript:;" reveal-id="jphp13182-bib-0050" data-open="jphp13182-bib-0050" class="link link-ref link-reveal xref-bibr">50</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Bonneau N <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0051"></span><a href="javascript:;" reveal-id="jphp13182-bib-0051" data-open="jphp13182-bib-0051" class="link link-ref link-reveal xref-bibr">51</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Champy P <em>et al</em>. (2004) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0032"></span><a href="javascript:;" reveal-id="jphp13182-bib-0032" data-open="jphp13182-bib-0032" class="link link-ref link-reveal xref-bibr">32</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>P</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>de Sousa OV <em>et al</em>. (2010) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0017"></span><a href="javascript:;" reveal-id="jphp13182-bib-0017" data-open="jphp13182-bib-0017" class="link link-ref link-reveal xref-bibr">17</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Florence NT <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Hamid RA <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0037"></span><a href="javascript:;" reveal-id="jphp13182-bib-0037" data-open="jphp13182-bib-0037" class="link link-ref link-reveal xref-bibr">37</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>N</td><td>P</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Hamizah S <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Holanda CM <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup></td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td></tr><tr><td>Minari JB and Okeke (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0041"></span><a href="javascript:;" reveal-id="jphp13182-bib-0041" data-open="jphp13182-bib-0041" class="link link-ref link-reveal xref-bibr">41</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>P</td><td>N</td></tr><tr><td>Moghadamtousi SZ <em>et al</em>. (2014) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0019"></span><a href="javascript:;" reveal-id="jphp13182-bib-0019" data-open="jphp13182-bib-0019" class="link link-ref link-reveal xref-bibr">19</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Nwokocha CR <em>et al</em>. (2012) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0043"></span><a href="javascript:;" reveal-id="jphp13182-bib-0043" data-open="jphp13182-bib-0043" class="link link-ref link-reveal xref-bibr">43</a>]</sup></td><td>Y</td><td>P</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Pautus S <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0039"></span><a href="javascript:;" reveal-id="jphp13182-bib-0039" data-open="jphp13182-bib-0039" class="link link-ref link-reveal xref-bibr">39</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Rajesh V and Baby Kala (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0020"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020" data-open="jphp13182-bib-0020" class="link link-ref link-reveal xref-bibr">20</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>Y</td></tr><tr><td>Sherif HB <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0021"></span><a href="javascript:;" reveal-id="jphp13182-bib-0021" data-open="jphp13182-bib-0021" class="link link-ref link-reveal xref-bibr">21</a>]</sup></td><td>N</td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Somsak V <em>et al</em>. (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0022" data-open="jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">22</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td></tr><tr><td>Souza DO <em>et al</em>. (2018) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0023"></span><a href="javascript:;" reveal-id="jphp13182-bib-0023" data-open="jphp13182-bib-0023" class="link link-ref link-reveal xref-bibr">23</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td></tr><tr><td>Usunomena U and Ngozi (2016) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0031"></span><a href="javascript:;" reveal-id="jphp13182-bib-0031" data-open="jphp13182-bib-0031" class="link link-ref link-reveal xref-bibr">31</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Yang C <em>et al</em>. (2015) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup></td><td>Y</td><td>Y</td><td>Y</td><td>P</td><td>P</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>P</td><td>Y</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0007"></span><div content-id="jphp13182-note-0007" class="footnote"><span class="fn"><p class="chapter-para">N, no; P, partial; Y, yes.</p></span></div></div></div></div><p class="chapter-para">The quality of the human studies is presented in <span class="xrefLink" id="jumplink-jphp13182-tbl-0008"></span><a href="javascript:;" reveal-id="jphp13182-tbl-0008" data-open="jphp13182-tbl-0008" class="link link-reveal link-table xref-fig">Table 8</a> illustrating that all reported the Latin binomial name, parts of plant, the extraction solvent used, dosage, duration and route, and content of product. However, none of the studies reported the registration and licensed use of the product, purity testing and practitioner involved.</p> <a id="491205071" scrollto-destination="491205071"></a> <div content-id="jphp13182-tbl-0008" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0008" data-id="jphp13182-tbl-0008"><span class="label title-label" id="label-62875">Table 8</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205071" aria-describedby="label-62875"> Open in new tab </a></div><div class="caption caption-id-" id="caption-62875"><p class="chapter-para">Quality assessment of human studies</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-62875" aria-describedby="
 caption-62875"><thead><tr><th><span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Herbal medicinal product name<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="4">Characteristics of the herbal products<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Dosage regimen and quantitative description<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Qualitative testing<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">Placebo group<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">Practitioner<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Author-year<span aria-hidden="true" style="display: none;"> . </span></th><th>Latin binomial name<span aria-hidden="true" style="display: none;"> . </span></th><th>Brand name or extract name and manufacturer<span aria-hidden="true" style="display: none;"> . </span></th><th>Licensed or registration<span aria-hidden="true" style="display: none;"> . </span></th><th>Parts of plant used<span aria-hidden="true" style="display: none;"> . </span></th><th>Type of product used<span aria-hidden="true" style="display: none;"> . </span></th><th>Extraction solvent<span aria-hidden="true" style="display: none;"> . </span></th><th>Authentication of raw material<span aria-hidden="true" style="display: none;"> . </span></th><th>Dosage, duration and route<span aria-hidden="true" style="display: none;"> . </span></th><th>Product content<span aria-hidden="true" style="display: none;"> . </span></th><th>Quantity of standardised constituents<span aria-hidden="true" style="display: none;"> . </span></th><th>Chemical fingerprint<span aria-hidden="true" style="display: none;"> . </span></th><th>Special testing/purity testing<span aria-hidden="true" style="display: none;"> . </span></th><th>Standardisation<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Arroyo J <em>et al</em>. (2009) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>N</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>]</sup></td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Surono IS <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th><span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Herbal medicinal product name<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="4">Characteristics of the herbal products<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Dosage regimen and quantitative description<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Qualitative testing<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">Placebo group<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">Practitioner<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Author-year<span aria-hidden="true" style="display: none;"> . </span></th><th>Latin binomial name<span aria-hidden="true" style="display: none;"> . </span></th><th>Brand name or extract name and manufacturer<span aria-hidden="true" style="display: none;"> . </span></th><th>Licensed or registration<span aria-hidden="true" style="display: none;"> . </span></th><th>Parts of plant used<span aria-hidden="true" style="display: none;"> . </span></th><th>Type of product used<span aria-hidden="true" style="display: none;"> . </span></th><th>Extraction solvent<span aria-hidden="true" style="display: none;"> . </span></th><th>Authentication of raw material<span aria-hidden="true" style="display: none;"> . </span></th><th>Dosage, duration and route<span aria-hidden="true" style="display: none;"> . </span></th><th>Product content<span aria-hidden="true" style="display: none;"> . </span></th><th>Quantity of standardised constituents<span aria-hidden="true" style="display: none;"> . </span></th><th>Chemical fingerprint<span aria-hidden="true" style="display: none;"> . </span></th><th>Special testing/purity testing<span aria-hidden="true" style="display: none;"> . </span></th><th>Standardisation<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Arroyo J <em>et al</em>. (2009) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>N</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>]</sup></td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Surono IS <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0008"></span><div content-id="jphp13182-note-0008" class="footnote"><span class="fn"><p class="chapter-para">N, no; P, partial; Y, yes.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="jphp13182-tbl-0008" data-id="jphp13182-tbl-0008"><span class="label title-label" id="label-62875">Table 8</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/491205071" aria-describedby="label-62875"> Open in new tab </a></div><div class="caption caption-id-" id="caption-62875"><p class="chapter-para">Quality assessment of human studies</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-62875" aria-describedby="
 caption-62875"><thead><tr><th><span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Herbal medicinal product name<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="4">Characteristics of the herbal products<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Dosage regimen and quantitative description<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Qualitative testing<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">Placebo group<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">Practitioner<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Author-year<span aria-hidden="true" style="display: none;"> . </span></th><th>Latin binomial name<span aria-hidden="true" style="display: none;"> . </span></th><th>Brand name or extract name and manufacturer<span aria-hidden="true" style="display: none;"> . </span></th><th>Licensed or registration<span aria-hidden="true" style="display: none;"> . </span></th><th>Parts of plant used<span aria-hidden="true" style="display: none;"> . </span></th><th>Type of product used<span aria-hidden="true" style="display: none;"> . </span></th><th>Extraction solvent<span aria-hidden="true" style="display: none;"> . </span></th><th>Authentication of raw material<span aria-hidden="true" style="display: none;"> . </span></th><th>Dosage, duration and route<span aria-hidden="true" style="display: none;"> . </span></th><th>Product content<span aria-hidden="true" style="display: none;"> . </span></th><th>Quantity of standardised constituents<span aria-hidden="true" style="display: none;"> . </span></th><th>Chemical fingerprint<span aria-hidden="true" style="display: none;"> . </span></th><th>Special testing/purity testing<span aria-hidden="true" style="display: none;"> . </span></th><th>Standardisation<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Arroyo J <em>et al</em>. (2009) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>N</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>]</sup></td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Surono IS <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th><span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Herbal medicinal product name<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="4">Characteristics of the herbal products<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Dosage regimen and quantitative description<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="3">Qualitative testing<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">Placebo group<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">Practitioner<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Author-year<span aria-hidden="true" style="display: none;"> . </span></th><th>Latin binomial name<span aria-hidden="true" style="display: none;"> . </span></th><th>Brand name or extract name and manufacturer<span aria-hidden="true" style="display: none;"> . </span></th><th>Licensed or registration<span aria-hidden="true" style="display: none;"> . </span></th><th>Parts of plant used<span aria-hidden="true" style="display: none;"> . </span></th><th>Type of product used<span aria-hidden="true" style="display: none;"> . </span></th><th>Extraction solvent<span aria-hidden="true" style="display: none;"> . </span></th><th>Authentication of raw material<span aria-hidden="true" style="display: none;"> . </span></th><th>Dosage, duration and route<span aria-hidden="true" style="display: none;"> . </span></th><th>Product content<span aria-hidden="true" style="display: none;"> . </span></th><th>Quantity of standardised constituents<span aria-hidden="true" style="display: none;"> . </span></th><th>Chemical fingerprint<span aria-hidden="true" style="display: none;"> . </span></th><th>Special testing/purity testing<span aria-hidden="true" style="display: none;"> . </span></th><th>Standardisation<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>Arroyo J <em>et al</em>. (2009) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0048"></span><a href="javascript:;" reveal-id="jphp13182-bib-0048" data-open="jphp13182-bib-0048" class="link link-ref link-reveal xref-bibr">48</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>N</td><td>N</td><td>N</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>]</sup></td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Indrawati L <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr><tr><td>Surono IS <em>et al</em>. (2017) <sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>]</sup></td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>Y</td><td>Y</td><td>N</td><td>Y</td><td>Y</td><td>N</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-jphp13182-note-0008"></span><div content-id="jphp13182-note-0008" class="footnote"><span class="fn"><p class="chapter-para">N, no; P, partial; Y, yes.</p></span></div></div></div></div> <h2 scrollto-destination=491205072 id="491205072" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0012>Discussion</h2> <p class="chapter-para">The principal finding of this review suggests that while there are only limited data about the pharmacological effects of <em>A. muricata</em> leaf extract and its acetogenins, the hepatoprotective, neurotoxic, antiulcerative, antinociceptive and chemopreventive effects were observed across several studies. <em>Annona muricata</em> leaf extract also demonstrated hypoglycaemic effects in diabetic model, but not in normoglycaemic model. The pharmacokinetics data were limited and suggested that annonacin has low bioavailability and low ability to cross the blood brain barrier.</p><p class="chapter-para">The studies in this review were judged to be of medium to high quality. However, only a very few animal studies applied randomization methodology.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0016"></span><a href="javascript:;" reveal-id="jphp13182-bib-0016" data-open="jphp13182-bib-0016" class="link link-ref link-reveal xref-bibr">16</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0018"></span><a href="javascript:;" reveal-id="jphp13182-bib-0018" data-open="jphp13182-bib-0018" class="link link-ref link-reveal xref-bibr">18</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022"></span><a href="javascript:;" reveal-id="jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022" data-open="jphp13182-bib-0020 jphp13182-bib-0021 jphp13182-bib-0022" class="link link-ref link-reveal xref-bibr">20–22</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0026"></span><a href="javascript:;" reveal-id="jphp13182-bib-0026" data-open="jphp13182-bib-0026" class="link link-ref link-reveal xref-bibr">26</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0029"></span><a href="javascript:;" reveal-id="jphp13182-bib-0029" data-open="jphp13182-bib-0029" class="link link-ref link-reveal xref-bibr">29</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0040"></span><a href="javascript:;" reveal-id="jphp13182-bib-0040" data-open="jphp13182-bib-0040" class="link link-ref link-reveal xref-bibr">40</a>]</sup> More sophisticated randomization allocation methods and blinding of researchers are needed to improve the internal validity of the studies and confidence in the interpretation of the findings.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0052"></span><a href="javascript:;" reveal-id="jphp13182-bib-0052" data-open="jphp13182-bib-0052" class="link link-ref link-reveal xref-bibr">52</a>]</sup> None of the human studies included in this review reported essential information about the purity testing of the <em>A. muricata</em>, such as heavy metals, and microbial and pesticide contaminations.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0014"></span><a href="javascript:;" reveal-id="jphp13182-bib-0014" data-open="jphp13182-bib-0014" class="link link-ref link-reveal xref-bibr">14</a>]</sup></p><p class="chapter-para">The rigour of the systematic search methodology and quality assessment of the included studies provides an exhaustive report of the current available data regarding the safety and tolerability of <em>A. muricata</em> leaf extracts. Excluding herbal remedies that contained <em>A. muricata</em> with other herbal ingredients from our review in an attempt to reduce the ambiguity around the interpretation of pharmacological data is a unique approach that has facilitated a more specific focus on <em>A. muricata</em> itself. However, this may have excluded important information about any synergistic effects inherent to the traditional use of multiple ingredient herbal medicines. The variation in study type, animal model, information reported, administration route and solvent utilised in the included studies may create difficulty in generalising results.</p><p class="chapter-para">Our results are consistent with earlier reviews,<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0004"></span><a href="javascript:;" reveal-id="jphp13182-bib-0004" data-open="jphp13182-bib-0004" class="link link-ref link-reveal xref-bibr">4</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0010 jphp13182-bib-0011 jphp13182-bib-0012"></span><a href="javascript:;" reveal-id="jphp13182-bib-0010 jphp13182-bib-0011 jphp13182-bib-0012" data-open="jphp13182-bib-0010 jphp13182-bib-0011 jphp13182-bib-0012" class="link link-ref link-reveal xref-bibr">10–12</a>]</sup> in respect to identifying consistent reports of the antiulcerative, anti-inflammatory, antinociceptive and chemopreventive effects of <em>A. muricata</em> leaf extract. This review focused on summarising clinically relevant data to add to the body of knowledge about the safety and tolerability of <em>A. muricata</em> leaf extract. To date, there has been a gap in such knowledge, despite the large amount of mechanism of action data. Unlike previous reviews, this review summarised the potential synergistic effects and drug interactions of <em>A. muricata</em> leaf extract. One of the included studies demonstrated the protective effect of flavonoids and acetogenins to counteract the fatal effect of acetogenins.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup> This protective effect was proposed to be conferred by the flavonoid rutin acting as a p-glycoprotein inducer to increase acetogenins efflux in brain.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0024"></span><a href="javascript:;" reveal-id="jphp13182-bib-0024" data-open="jphp13182-bib-0024" class="link link-ref link-reveal xref-bibr">24</a>]</sup> This demonstrated the importance of utilising the leaf extract instead of isolated acetogenins. An important finding of this review was that the <em>A. muricata</em> leaf extract may potentially affect the biodistribution of the radiopharmaceutical 99mTc-DMSA.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0044"></span><a href="javascript:;" reveal-id="jphp13182-bib-0044" data-open="jphp13182-bib-0044" class="link link-ref link-reveal xref-bibr">44</a>]</sup> Such information potentially has important implications for people who choose to use <em>A. muricata</em> concurrently during medical imaging. Previous reviews and a case–control study conducted in Guadeloupe raised the concern over the neurotoxicity of <em>A. muricata</em> and its acetogenins.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0004"></span><a href="javascript:;" reveal-id="jphp13182-bib-0004" data-open="jphp13182-bib-0004" class="link link-ref link-reveal xref-bibr">4</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0053"></span><a href="javascript:;" reveal-id="jphp13182-bib-0053" data-open="jphp13182-bib-0053" class="link link-ref link-reveal xref-bibr">53</a>]</sup> A limited number of preclinical studies utilising other parts of <em>A. muricata</em> such as root, bark and fruit juice,<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0054 jphp13182-bib-0055 jphp13182-bib-0056"></span><a href="javascript:;" reveal-id="jphp13182-bib-0054 jphp13182-bib-0055 jphp13182-bib-0056" data-open="jphp13182-bib-0054 jphp13182-bib-0055 jphp13182-bib-0056" class="link link-ref link-reveal xref-bibr">54–56</a>]</sup> have also demonstrated its neurotoxicity. However, the current study is focused on the leaf extract and identified only <em>in-vitro</em> and animal studies that supported its proposed neurological adverse effect. The dose, formulation and duration from these studies may not be directly translatable into human clinical trials. A limitation of this study relates to the reductionist approach applied to identify data related specially to the acetogenins of <em>A. muricata</em>, while not considering the flavonoids and phenol compounds of <em>A. muricata</em> which may also contribute to its pharmacological effects.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0012"></span><a href="javascript:;" reveal-id="jphp13182-bib-0012" data-open="jphp13182-bib-0012" class="link link-ref link-reveal xref-bibr">12</a>]</sup></p><p class="chapter-para">In regards to human studies, the results of our review indicate that <em>A. muricata</em> leaf extract was safe in an oral dose up to 540 mg/day when taken for up to 30 days. Although there were four RCTs conducted, it is important to note that three of those investigated <em>A. muricata</em>'s effect on people with postresection colorectal cancer.<sup>[<span class="xrefLink" id="jumplink-jphp13182-bib-0008"></span><a href="javascript:;" reveal-id="jphp13182-bib-0008" data-open="jphp13182-bib-0008" class="link link-ref link-reveal xref-bibr">8</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0009"></span><a href="javascript:;" reveal-id="jphp13182-bib-0009" data-open="jphp13182-bib-0009" class="link link-ref link-reveal xref-bibr">9</a>,<span class="xrefLink" id="jumplink-jphp13182-bib-0047"></span><a href="javascript:;" reveal-id="jphp13182-bib-0047" data-open="jphp13182-bib-0047" class="link link-ref link-reveal xref-bibr">47</a>]</sup> Hence, high quality human studies conducted according to the elaborated item 4 of CONSORT statement, investigating more diverse populations of people living with different types of cancers are warranted for assessing the quality of safety and tolerability of <em>A. muricata</em> leaf extract.</p> <h2 scrollto-destination=491205078 id="491205078" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0013>Conclusion</h2> <p class="chapter-para">In conclusion, the pharmacological effects of <em>A. muricata</em> leaf extracts and acetogenins isolated from <em>A. muricata</em> on major body systems suggests a favourable safety profile. Further studies investigating these findings in humans living with a range of cancers are required to build on the findings of this review.</p> <h2 scrollto-destination=491205080 id="491205080" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0014>Declaration</h2> <h3 scrollto-destination=491205081 id="491205081" class="section-title js-splitscreen-section-title" data-legacy-id=jphp13182-sec-0015>Conflict of interest</h3> <p class="chapter-para">There is no conflict of interest.</p> <h2 scrollto-destination=491205083 id="491205083" class="backreferences-title js-splitscreen-backreferences-title" data-legacy-id=jphp13182-bibl-0001>References</h2> <div class="ref-list js-splitview-ref-list"><div content-id="jphp13182-bib-0001" class="js-splitview-ref-item" data-legacy-id="jphp13182-bib-0001"><div class="refLink-parent"><span class="refLink"><a name="jumplink-jphp13182-bib-0001" href="javascript:;" aria-label="jumplink-jphp13182-bib-0001" data-id=""></a></span></div><div class="ref false"><div id="ref-auto-jphp13182-bib-0001" class="ref-content " data-id="jphp13182-bib-0001"><div class="mixed-citation citation"><p class="mixed-citation-compatibility"><span class="person-group"><span class="name string-name"><div class="surname">Yates</div> <div class="given-names">JS</div></span> et al. </span> <div class="article-title">Prevalence of complementary and alternative medicine use in cancer patients during treatment</div>. <div class="source ">Support Care Cancer</div> <div class="year">2005</div>; 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