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<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id>
<journal-title>Frontiers in Pharmacology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Pharmacol.</abbrev-journal-title>
<issn pub-type="epub">1663-9812</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
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<article-meta>
<article-id pub-id-type="publisher-id">1360932</article-id>
<article-id pub-id-type="doi">10.3389/fphar.2024.1360932</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Pharmacology</subject>
<subj-group>
<subject>Systematic Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Effects of Dl-3-n-butylphthalide on neurological function, hemodynamics and Hcy concentration in cerebral hemorrhage: a systematic review and meta-analysis</article-title>
<alt-title alt-title-type="left-running-head">Ma et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fphar.2024.1360932">10.3389/fphar.2024.1360932</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Ma</surname>
<given-names>Yingqi</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2541164/overview"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Guo</surname>
<given-names>Chenchen</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="fn" rid="fn1">
<sup>&#x2020;</sup>
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<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Yiguo</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="fn" rid="fn1">
<sup>&#x2020;</sup>
</xref>
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<contrib contrib-type="author" corresp="yes">
<name>
<surname>Liu</surname>
<given-names>Xinxin</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2703484/overview"/>
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<aff id="aff1">
<sup>1</sup>
<institution>First School of Clinical Medicine</institution>, <institution>Shandong University of Traditional Chinese Medicine</institution>, <addr-line>Jinan</addr-line>, <addr-line>Shandong</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University</institution>, <institution>Shandong First Medical University and Shandong Academy of Medical Sciences</institution>, <addr-line>Jinan</addr-line>, <country>China</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Experimental Research Center</institution>, <institution>China Academy of Chinese Medical Sciences</institution>, <addr-line>Beijing</addr-line>, <country>China</country>
</aff>
<aff id="aff4">
<sup>4</sup>
<institution>Centre for Evidence-Based Chinese Medicine</institution>, <institution>Beijing University of Chinese Medicine</institution>, <addr-line>Beijing</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/8132/overview">Francisco Lopez-Munoz</ext-link>, Camilo Jos&#xe9; Cela University, Spain</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1051152/overview">Xiao Lin</ext-link>, Wenzhou Medical University, China</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1060634/overview">Christine R&#xf6;mer</ext-link>, Bielefeld University, Germany</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Xinxin Liu, <email>lxxmedical@126.com</email>
</corresp>
<fn fn-type="equal" id="fn1">
<label>
<sup>&#x2020;</sup>
</label>
<p>These authors have contributed equally to this work</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>30</day>
<month>05</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1360932</elocation-id>
<history>
<date date-type="received">
<day>31</day>
<month>01</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>06</day>
<month>05</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Ma, Guo, Wang and Liu.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Ma, Guo, Wang and Liu</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>Dl-3-n-Butylphthalide (NBP) has emerged as a potential therapeutic agent for cerebral hemorrhage, despite not being included in current guideline recommendations. Investigating the underlying physiological and pathological mechanisms of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment remains a critical area of research.</p>
</sec>
<sec>
<title>Objective</title>
<p>This review aims to evaluate the efficacy of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment and elucidate its potential biological mechanisms, thereby providing evidence to support treatment optimization.</p>
</sec>
<sec>
<title>Methods</title>
<p>A comprehensive search of seven electronic databases (PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP, and Wanfang Database) was conducted for studies published up to September 2023. Screening and data extraction were performed by a team of researchers. The Cochrane collaboration tool was utilized for risk bias assessment, and Revman 5.3 along with Stata 17.0 were employed for statistical analysis.</p>
</sec>
<sec>
<title>Outcomes</title>
<p>We searched 254 literature, and 19 were included in this meta-analysis. The results showed that Dl-3-n-Butylphthalide improved the clinical efficacy rate (RR &#x003D; 1.25, 95% CI 1.19&#x2013;1.31; <italic>p</italic> &#x003D; 0.00), quality of life (MD &#x003D; 13.93, 95% CI: 11.88&#x2013;15.98; <italic>p</italic> &#x003D; 0.000), increased cerebral blood flow and velocity, reduced cerebral edema volume, Hcy concentration, and did not have obvious adverse reactions (RR &#x003D; 0.68, 95% CI: 0.39&#x2013;1.18; <italic>p</italic> &#x003D; 0.10).</p>
</sec>
<sec>
<title>Conclusion</title>
<p>This meta-analysis is the first to demonstrate the potential of Dl-3-n-Butylphthalide in treating cerebral hemorrhage. It suggests that Dl-3-n-Butylphthalide may alleviate clinical symptoms by modulating neurological function and improving hemodynamics. Our findings provide robust evidence for incorporating Dl-3-n-Butylphthalide into cerebral hemorrhage treatment strategies, potentially guiding future clinical practice and research.</p>
<p>
<bold>Systematic Review Registration: <ext-link ext-link-type="uri" xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID&#x003D;355114, Identifier CRD42022355114.">https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID&#x003D;355114, Identifier CRD42022355114.</ext-link>
</bold>
</p>
</sec>
</abstract>
<kwd-group>
<kwd>Dl-3-n-butylphthalide</kwd>
<kwd>cerebral hemorrhage</kwd>
<kwd>neurological function</kwd>
<kwd>meta-analysis</kwd>
<kwd>systematic review</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Ethnopharmacology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>Cerebral hemorrhage, a severe form of stroke, is categorized into non-traumatic and traumatic types. It typically manifests with sudden local neurological dysfunction and potential elevations in intracranial pressure. Clinical symptoms often include nausea, vomiting, headache, increased blood pressure, and cognitive impairment (<xref ref-type="bibr" rid="B25">Hwang et al., 2023</xref>; <xref ref-type="bibr" rid="B53">Romero and Rojas-Serrano, 2023</xref>). Non-traumatic intracerebral hemorrhage (ICH) primarily results from ruptured arterial vessels, frequently occurring in the basal ganglia or thalamic regions. The predominant cause is cerebral small vessel diseases (CSVD), affecting small arteries. Conditions such as cerebral amyloid angiopathy (CAA) and hypertensive arteriosclerosis are common examples (<xref ref-type="bibr" rid="B10">DeSimone et al., 2017</xref>; <xref ref-type="bibr" rid="B16">Gil-Garcia et al., 2022</xref>). Approximately 20% of ICH cases arise from other etiologies, including arteriovenous malformations, spongiomas, or fistulas (<xref ref-type="bibr" rid="B54">Sallinen et al., 2020</xref>). ICH constitutes about 20% of all stroke incidents and remains a significant cause of morbidity and mortality globally, with mortality rates reaching up to 50% (<xref ref-type="bibr" rid="B45">Poon et al., 2014</xref>; <xref ref-type="bibr" rid="B20">Hemphill et al., 2015</xref>).The incidence of ICH varies regionally, with the Global Burden of Disease Study reporting that 80% of global brain hemorrhages occur in low-and middle-income countries (<xref ref-type="bibr" rid="B31">Krishnamurthi et al., 2014</xref>). By 2050, the incidence is projected to increase by 35.2%. The aging population trend suggests that the proportion of cerebral hemorrhage patients over 80 years will rise by 2.5 times (<xref ref-type="bibr" rid="B58">Steiner et al., 2016</xref>). Traumatic intracerebral hemorrhage results from external head impacts, often leading to contusions in the frontal and temporal lobes. Concurrently, patients may exhibit neuroimaging signs of traumatic subarachnoid hemorrhage, epidural hematoma, subdural hematoma, or skull fractures (<xref ref-type="bibr" rid="B2">Cepeda et al., 2015</xref>).</p>
<p>Early hematoma expansion is a prevalent and grave complication in cerebral hemorrhage patients, often indicating a dismal prognosis (<xref ref-type="bibr" rid="B5">Chen et al., 2015</xref>). To mitigate hematoma growth, clinicians administer hemostatic agents such as tranexamic acid, recombinant activated factor VII (rFVIIa), and prothrombin complex concentrate (PCC). However, these treatments minimally impact the improvement of clinical symptoms and lack sufficient evidence to demonstrate effects on functional outcomes or mortality reduction (<xref ref-type="bibr" rid="B57">Steiner and Bsel, 2010</xref>; <xref ref-type="bibr" rid="B15">Garg and Biller, 2019</xref>). The &#x201c;mass effect,&#x201d; inflammatory responses, and iron-induced secondary damage (<xref ref-type="bibr" rid="B29">Jiang et al., 2020</xref>) necessitate medical interventions targeting secondary injury. These include anti-inflammatory agents (<xref ref-type="bibr" rid="B26">Ironside et al., 2021</xref>) and iron chelating agents (<xref ref-type="bibr" rid="B52">Ramadhan et al., 2023</xref>). Surgical evacuation of the hematoma represents a therapeutic approach for cerebral hemorrhage. Yet, current evidence scarcely supports that surgery or pharmacological treatment substantially decreases mortality or morbidity associated with cerebral hemorrhage (<xref ref-type="bibr" rid="B65">Wilkinson et al., 2018a</xref>; <xref ref-type="bibr" rid="B66">Wilkinson et al., 2018b</xref>; <xref ref-type="bibr" rid="B9">de Oliveira Manoel, 2020</xref>). Therefore, exploring novel methods to enhance neuroinflammation management and neural function recovery post-cerebral hemorrhage is imperative.</p>
<p>In mitigating adverse neurological outcomes and mortality among cerebral hemorrhage patients, prompt diagnosis and swift implementation of suitable interventions are vital (<xref ref-type="bibr" rid="B51">Rabinstein, 2017</xref>). Despite extensive clinical research in recent years investigating optimal treatment strategies for cerebral hemorrhage, including Western medicine and surgical approaches, definitive evidence-based medical guidance for managing this condition remains elusive. Enhancing patient survival and quality of life continues to present significant challenges, underscoring the urgent necessity for novel therapeutic agents to augment current clinical outcomes (<xref ref-type="bibr" rid="B1">Al-Kawaz et al., 2020</xref>; <xref ref-type="bibr" rid="B16">Gil-Garcia et al., 2022</xref>; <xref ref-type="bibr" rid="B40">Magid-Bernstein et al., 2022</xref>; <xref ref-type="bibr" rid="B55">Sheth, 2023</xref>).</p>
<p>NBP, commonly known as butylphthalide, is an organic compound derived from celery oil. In 2002, the China Food and Drug Administration (CFDA) approved NBP for the treatment of cerebral infarction (<xref ref-type="bibr" rid="B62">Wang et al., 2018</xref>). Numerous studies have identified NBP as a promising neuroprotective agent, effective in treating heart failure, ischemic stroke, Parkinsonism syndrome, Alzheimer&#x2019;s disease, and other neurologic disorders associated with cognitive dysfunction (<xref ref-type="bibr" rid="B49">Qiu et al., 2018</xref>; <xref ref-type="bibr" rid="B62">Wang et al., 2018</xref>; <xref ref-type="bibr" rid="B13">Gao et al., 2019</xref>; <xref ref-type="bibr" rid="B33">Li et al., 2022</xref>; <xref ref-type="bibr" rid="B22">Hu et al., 2023</xref>). Previous meta-analyses highlight NBP&#x2019;s role in cerebrovascular disease treatment, including reducing inflammation, mitigating oxidative stress, and enhancing vascular endothelial function (<xref ref-type="bibr" rid="B37">Liu et al., 2023</xref>). Its neuroprotective effects in cerebrovascular diseases, corroborated by extensive animal studies, are attributed to a range of biomolecular mechanisms (<xref ref-type="bibr" rid="B8">Cheng et al., 2019</xref>; <xref ref-type="bibr" rid="B36">Liu et al., 2021</xref>; <xref ref-type="bibr" rid="B7">Chen X. et al., 2022a</xref>; <xref ref-type="bibr" rid="B14">Gao et al., 2022</xref>).</p>
<p>
<xref ref-type="bibr" rid="B59">Tu et al. (2020)</xref> discovered that NBP may mitigate neurological impairment following localized cerebral hemorrhage by fostering neovascularization near the hemorrhage site. NBP can diminish brain cell apoptosis, safeguard neuronal cells, and repair neurological function, primarily through the upregulation of UBIAD1 expression. However, there has been limited investigation into the therapeutic potential of this compound in experimental models of hemorrhagic stroke (<xref ref-type="bibr" rid="B44">Pi et al., 2021</xref>).</p>
<p>To our knowledge, no meta-analysis has specifically addressed the efficacy of NBP in treating cerebral hemorrhage. This study serves as a reference for clinicians considering NBP as a therapeutic option for this condition.</p>
</sec>
<sec id="s2" sec-type="methods">
<title>2 Methods</title>
<p>This study has been registered on the PROSPERO platform (Registration No. CRD42022355114, <ext-link ext-link-type="uri" xlink:href="https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=355114">https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID&#x003D;355114</ext-link>).</p>
<sec id="s2-1">
<title>2.1 Eligibility criteria</title>
<sec id="s2-1-1">
<title>2.1.1 Inclusion criteria and exclusion criteria</title>
<p>
<list list-type="simple">
<list-item>
<p>(1) Patients: All included patients must conform to the established Western medical diagnostic criteria for cerebral hemorrhage; Age &#x2265;18 years old. Meanwhile, patients with severe cardiac, hepatic, or renal insufficiency; patients with malignant tumors or severe organic lesions; patients with severe neurological dysfunction or a history of psychiatric disorders; patients with autoimmune diseases, diabetes mellitus, and acute infectious diseases; and patients with allergy to NBP were excluded.</p>
</list-item>
<list-item>
<p>(2) Interventions: The treatment group was given NBP injection (25&#xa0;mL/bid) or NBP soft capsule (0.2&#xa0;g/tid) on top of the control group.</p>
</list-item>
<list-item>
<p>(3) Comparisons: The control group was given routine treatment (maintaining stable vital signs, mannitol dehydration, maintaining water electrolytes, acid-base balance, nutritional support, and nutritional brain cells).</p>
</list-item>
<list-item>
<p>(4) Outcome measures: &#x2460;Clinical efficiency; &#x2461;Incidence of adverse reactions; &#x2462;National Institutes of Health Stroke Scale (NIHSS); &#x2463;Activity of Daily Living Scale (ADLS); &#x2464;Mean cerebral blood flow (MCBF); &#x2465;Mean cerebral blood flow velocity (MBFV); &#x2466;Cerebral edema volume; &#x2467;Hcy concentration; &#x2468;SP concentration.</p>
</list-item>
<list-item>
<p>(5) Studies: Randomized Controlled Trials (RCTs). The following were excluded: case reports, conference papers and animal studies, etc.;</p>
</list-item>
</list>
</p>
</sec>
</sec>
<sec id="s2-2">
<title>2.2 Literature search</title>
<p>Seven electronic databases including PubMed, Web of Science, Embase, Cochrane Library, CNKI, VIP, and Wanfang Database were searched by computer from the establishment of the database to September 2023. Pubmed search strategy: (((((((Cerebral Hemorrhage [MeSH Terms])) OR (Cerebral Hemorrhage [Title/Abstract])) OR (Cerebrum Hemorrhage [Title/Abstract])) OR (Cerebral Parenchymal Hemorrhage [Title/Abstract])) OR (Intracerebral Hemorrhage [Title/Abstract])) OR (Cerebral Brain Hemorrhage [Title/Abstract])) AND ((((((((3-n-butylphthalide [MeSH Terms])) OR (3-n-butylphthalide [Title/Abstract])) OR (DL-3-n-butylphthalide [Title/Abstract])) OR (l-NBP cpd [Title/Abstract])) OR (N-butylphthalide [Title/Abstract])) OR (butylphthalide [Title/Abstract])) OR ((S)-(&#x2212;)-3-butylphthalide [Title/Abstract])).</p>
</sec>
<sec id="s2-3">
<title>2.3 Literature screening and data extraction</title>
<p>We imported the retrieved literature into EndNote 20.1 and excluded those not meeting the eligibility criteria. Two researchers, C-C G and Y-G W, independently reviewed the titles and abstracts to identify studies suitable for analysis. Concurrently, all full texts meeting the inclusion criteria were downloaded and independently assessed. Researchers C-C G and Y-Q M utilized Excel 2021 to collate and organize the baseline characteristics of the selected studies, which included the first author, publication year, sample size, region, study design, participants&#x2019; gender and age, blood loss, intervention types, treatment duration, and outcomes. The results were cross-verified, and any discrepancies were resolved through discussion between the parties involved. If necessary, a third researcher (Y-Q M) was available to assist in resolving any disagreements.</p>
</sec>
<sec id="s2-4">
<title>2.4 Quality evaluation</title>
<p>Two researchers, Y-G W and C-C G, evaluated the quality of the included studies utilizing the Revman5.3 Risk of Bias assessment tool. The assessment criteria encompassed random sequence generation, allocation concealment, blinding (including implementer and participant blinding, as well as outcome evaluator blinding), incomplete outcome data, selective reporting, and other potential sources of bias. Based on this quality assessment, the risk levels were categorized as &#x201c;low risk,&#x201d; &#x201c;high risk,&#x201d; or &#x201c;unclear risk.&#x201d; In cases of disagreement, the two researchers engaged in discussions, and a third researcher, X-X L, intervened as necessary to make a final determination.</p>
</sec>
<sec id="s2-5">
<title>2.5 Statistical analysis</title>
<p>The meta-analysis was conducted using Stata 17.0 software. Overall parameter estimates were presented as 95% confidence intervals (95% CI), with <italic>p</italic>-values less than 0.05 indicating statistical significance. (1) The I<sup>2</sup> test was employed to assess heterogeneity among studies. A fixed-effect model was applied when heterogeneity was low (<italic>p</italic> &#x003e; 0.1, I<sup>2</sup> &#x003c; 50%). In contrast, a random-effects model was chosen in cases of high heterogeneity (<italic>p</italic> &#x003c; 0.1, I<sup>2</sup> &#x003e; 50%). (2) The effect size for binary variables was measured using Relative Risk (RR), and Mean Difference (MD) for continuous variables. Standardized Mean Difference (SMD) was utilized when the included studies employed different measurement instruments, whereas Weighted Mean Difference (WMD) was used otherwise.</p>
</sec>
<sec id="s2-6">
<title>2.6 Sensitivity analysis</title>
<p>To assess the stability and reliability of the outcome indicators, sensitivity analysis was conducted. In instances of high heterogeneity, a Galbraith plot was utilized to identify the sources of significant heterogeneity in each study.</p>
</sec>
<sec id="s2-7">
<title>2.7 Meta-regression analysis</title>
<p>Meta-regression analysis was conducted on variables such as age, sex, and route of administration in studies comprising more than ten reports, to determine their correlation with the effect size.</p>
</sec>
<sec id="s2-8">
<title>2.8 Publication bias</title>
<p>If the funnel plot exhibits asymmetry or the Egger test indicates publication bias (<italic>p</italic> &#x003c; 0.05), it becomes necessary to assess the stability and reliability of the outcome indicators. In such cases, the &#x201c;Trim and Fill&#x201d; method is employed to estimate the combined effect size while adjusting for publication bias.</p>
</sec>
</sec>
<sec id="s3" sec-type="results">
<title>3 Results</title>
<sec id="s3-1">
<title>3.1 Results of literature search</title>
<p>A comprehensive computer search yielded 254 studies. After the exclusion of 70 duplicates, the titles, abstracts, and full texts of the remaining 184 articles were meticulously reviewed. Studies that failed to meet the inclusion criteria were subsequently excluded. Ultimately, 19 studies qualified for inclusion. The detailed retrieval process is illustrated in <xref ref-type="fig" rid="F1">Figure 1</xref>.</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>Flow chart of literature screening.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g001.tif"/>
</fig>
</sec>
<sec id="s3-2">
<title>3.2 Baseline characteristics</title>
<p>The selected studies, published between 2017 and 2023, exclusively involved Chinese patients. This meta-analysis incorporated 19 randomized controlled trials (<xref ref-type="bibr" rid="B64">Wang Y. et al., 2021a</xref>; <xref ref-type="bibr" rid="B48">Qian, 2021</xref>; <xref ref-type="bibr" rid="B35">Liu et al., 2018</xref>; <xref ref-type="bibr" rid="B43">Pang et al., 2010</xref>; <xref ref-type="bibr" rid="B21">hongli, 2019</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B68">yan et al., 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>; <xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>; <xref ref-type="bibr" rid="B3">Chen et al., 2018</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>; <xref ref-type="bibr" rid="B69">yang et al., 2020</xref>; <xref ref-type="bibr" rid="B34">Lin, 2021</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B12">fang, 2017</xref>; <xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>; <xref ref-type="bibr" rid="B4">Chen et al., 2023</xref>), with 17 published in Chinese and two in English. The studies collectively enrolled 1959 patients diagnosed with cerebral hemorrhage, aged between 46 and 73 years. The sample sizes varied, ranging from 60 (<xref ref-type="bibr" rid="B43">Pang et al., 2010</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B12">fang, 2017</xref>) to 192 (<xref ref-type="bibr" rid="B3">Chen et al., 2018</xref>). Among these, 1742 patients were diagnosed with ICH (<xref ref-type="bibr" rid="B48">Qian, 2021</xref>; <xref ref-type="bibr" rid="B35">Liu et al., 2018</xref>; <xref ref-type="bibr" rid="B43">Pang et al., 2010</xref>; <xref ref-type="bibr" rid="B21">hongli, 2019</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B68">yan et al., 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>; <xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>; <xref ref-type="bibr" rid="B3">Chen et al., 2018</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>; <xref ref-type="bibr" rid="B69">yang et al., 2020</xref>; <xref ref-type="bibr" rid="B34">Lin, 2021</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B12">fang, 2017</xref>; <xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>), while 217 patients had traumatic intracerebral hemorrhage (<xref ref-type="bibr" rid="B64">Wang Y. et al., 2021a</xref>; <xref ref-type="bibr" rid="B4">Chen et al., 2023</xref>). The intervention in all studies was a combination of NBP and conventional therapy. <xref ref-type="table" rid="T1">Table 1</xref> presents the baseline characteristics of these studies.</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>Baseline characteristics of the included studies.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Study</th>
<th align="left">disease</th>
<th align="left">Region</th>
<th align="left">study type</th>
<th align="left">Sample Size</th>
<th align="left">Gender(%F)</th>
<th align="left">Age[mean(SD)]</th>
<th align="left">Intracranial bleeding (ml)</th>
<th align="left">Course of hypertension (yd)</th>
<th align="left">Onset time(h)</th>
<th align="left">Intervention</th>
<th align="left">Dose/Duration(days)</th>
<th align="left">follow-up time(days)</th>
<th align="left">Outcomes</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Wang YH, <font color="#FE0191">et al.,</font> 2021 (<xref ref-type="bibr" rid="B64">Wang et al., 2021a</xref>)</td>
<td align="left">HICH</td>
<td align="left">Zhejiang</td>
<td align="left">RCT</td>
<td align="left">115</td>
<td align="left">40.87</td>
<td align="left">T:60.21 &#xb1; 10.61 C:61.41 &#xb1; 9.85</td>
<td align="left">NA</td>
<td align="left">T: 6.95 &#xb1; 2.17 C:6.79 &#xb1; 1.86</td>
<td align="left">T:7.32 &#xb1; 1.95 C:7.65 &#xb1; 2.03</td>
<td align="left">T:NBP injection &#x2b; nimodipine; C: nimodipine</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2461;&#x2462;</td>
</tr>
<tr>
<td align="left">Zhang Q 2021 (<xref ref-type="bibr" rid="B48">Qian, 2021</xref>)</td>
<td align="left">ICH</td>
<td align="left">Henan</td>
<td align="left">RCT</td>
<td align="left">88</td>
<td align="left">35.23</td>
<td align="left">T:56.37 &#xb1; 3.07 C:54.12 &#xb1; 2.34</td>
<td align="left">T:30.06 &#xb1; 5.14 C:29.34 &#xb1; 4.35</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP soft capsule &#x2b; Nimodipine; C: Nimodipine</td>
<td align="left">0.2&#xa0;g/tid 70d</td>
<td align="left">NA</td>
<td align="left">&#x2463;&#x2464;&#x2465;</td>
</tr>
<tr>
<td align="left">Liu CY, <font color="#FE0191">et al.,</font> 2018 (<xref ref-type="bibr" rid="B35">Liu et al., 2018</xref>)</td>
<td align="left">aSAH</td>
<td align="left">Hubei</td>
<td align="left">RCT</td>
<td align="left">63</td>
<td align="left">58.73</td>
<td align="left">T:46.9 &#xb1; 10.8 C:50.1 &#xb1; 10.8</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; CT; C:CT</td>
<td align="left">25&#xa0;ml/bid 7d</td>
<td align="left">28</td>
<td align="left">&#x2460;</td>
</tr>
<tr>
<td align="left">Pang QJ, <font color="#FE0191">et al.,</font> 2010 (<xref ref-type="bibr" rid="B43">Pang et al., 2010</xref>)</td>
<td align="left">HICH</td>
<td align="left">Hebei</td>
<td align="left">RCT</td>
<td align="left">60</td>
<td align="left">41.67</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP soft capsule &#x2b; CT; C: CT</td>
<td align="left">0.2&#xa0;g/tid 20d</td>
<td align="left">21</td>
<td align="left">&#x2460;&#x2463;</td>
</tr>
<tr>
<td align="left">Xu HL 2019 (<xref ref-type="bibr" rid="B21">hongli, 2019</xref>)</td>
<td align="left">SCH</td>
<td align="left">Henan</td>
<td align="left">RCT</td>
<td align="left">98</td>
<td align="left">39.79</td>
<td align="left">T:58&#x223c;79 C:57&#x223c;80</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:2&#x223c;12 C:2&#x223c;16</td>
<td align="left">T:NBP injection &#x2b; naloxone; C: naloxone</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;</td>
</tr>
<tr>
<td align="left">Han HB <font color="#FE0191">et al.,</font> 2021 (<xref ref-type="bibr" rid="B19">Han et al., 2021</xref>)</td>
<td align="left">SCH</td>
<td align="left">Henan</td>
<td align="left">RCT</td>
<td align="left">110</td>
<td align="left">63.64</td>
<td align="left">T:67.55 &#xb1; 3.56 C:68.43 &#xb1; 3.67</td>
<td align="left">T:41.43 &#xb1; 4.82 C:43.64 &#xb1; 4.75</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; HOT; C: HOT</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2461;&#x2462;&#x2463;&#x2464;&#x2465;&#x2468;</td>
</tr>
<tr>
<td align="left">Liu Y<sub>a</sub>, <font color="#FE0191">et al.,</font> 2021 (<xref ref-type="bibr" rid="B68">yan et al., 2021</xref>)</td>
<td align="left">ICH</td>
<td align="left">Neimenggu</td>
<td align="left">RCT</td>
<td align="left">140</td>
<td align="left">42.14</td>
<td align="left">T:68.9 &#xb1; 1.2 C:68.7 &#xb1; 1.2</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; oxiracetam; C: oxiracetam</td>
<td align="left">25&#xa0;ml/bid 21d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2463;</td>
</tr>
<tr>
<td align="left">Shi L, <font color="#FE0191">et al.,</font> 2022 (<xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>)</td>
<td align="left">SCH</td>
<td align="left">Shandong</td>
<td align="left">RCT</td>
<td align="left">84</td>
<td align="left">46.43</td>
<td align="left">T:73.51 &#xb1; 9.14 C:73.89 &#xb1; 9.35</td>
<td align="left">T:18.50 &#xb1; 2.65 C:18.21 &#xb1; 2.77</td>
<td align="left">T:8.65 &#xb1; 3.24 C:8.89 &#xb1; 3.16</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; oxiracetam; C: oxiracetam</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2461;&#x2462;&#x2463;</td>
</tr>
<tr>
<td align="left">Qian QQ, <font color="#FE0191">et al.,</font> 2017 (<xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>)</td>
<td align="left">SCH</td>
<td align="left">Hebei</td>
<td align="left">RCT</td>
<td align="left">130</td>
<td align="left">42.31</td>
<td align="left">T:66.5 &#xb1; 3.2 C:66.8 &#xb1; 3.9</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:7.7 &#xb1; 3.0 C:6.8 &#xb1; 3.1</td>
<td align="left">T:NBP injection &#x2b; naloxone; C: naloxone</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2462;&#x2467;</td>
</tr>
<tr>
<td align="left">Chen FY, <font color="#FE0191">et al.,</font> 2018 (<xref ref-type="bibr" rid="B3">Chen et al., 2018</xref>)</td>
<td align="left">ICH</td>
<td align="left">Zhejiang</td>
<td align="left">RCT</td>
<td align="left">192</td>
<td align="left">41.15</td>
<td align="left">T:52.11 &#xb1; 9.82 C:52.80 &#xb1; 10.51</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:21.35 &#xb1; 10.52 C:22.12 &#xb1; 11.24</td>
<td align="left">T:NBP injection &#x2b; CT; C: CT</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2462;</td>
</tr>
<tr>
<td align="left">Huang ZY, <font color="#FE0191">et al.,</font> 2022 (<xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>)</td>
<td align="left">ICH&#x26;PI</td>
<td align="left">Guangdong</td>
<td align="left">RCT</td>
<td align="left">124</td>
<td align="left">37.09</td>
<td align="left">T:56.54 &#xb1; 6.28 C:56.47 &#xb1; 6.32</td>
<td align="left">T:35.84 &#xb1; 3.43 C:35.78 &#xb1; 3.41</td>
<td align="left">NA</td>
<td align="left">T:21.39 &#xb1; 3.34 C:21.35 &#xb1; 3.28</td>
<td align="left">T:NBP injection &#x2b;CT; C: CT</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2461;&#x2462;</td>
</tr>
<tr>
<td align="left">Liu Y<sub>b</sub>, <font color="#FE0191">et al.,</font> 2020 (<xref ref-type="bibr" rid="B69">yang et al., 2020</xref>)</td>
<td align="left">HICH</td>
<td align="left">Anhui</td>
<td align="left">RCT</td>
<td align="left">100</td>
<td align="left">49</td>
<td align="left">T:76 &#xb1; 3 C:77 &#xb1; 3</td>
<td align="left">T:25 &#xb1; 4 C:26 &#xb1; 3</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP soft capsule &#x2b; edaravone; C: edaravone</td>
<td align="left">0.2&#xa0;g/tid 28d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2464;&#x2465;</td>
</tr>
<tr>
<td align="left">Lin Q 2021 (<xref ref-type="bibr" rid="B34">Lin, 2021</xref>)</td>
<td align="left">HICH</td>
<td align="left">Zhejiang</td>
<td align="left">RCT</td>
<td align="left">180</td>
<td align="left">45</td>
<td align="left">T:72.25 &#xb1; 2.22 C:71.19 &#xb1; 2.36</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; oxiracetam; C: oxiracetam</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2461;</td>
</tr>
<tr>
<td align="left">Guo WC, <font color="#FE0191">et al.,</font> 2022 (<xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>)</td>
<td align="left">HICH</td>
<td align="left">Guangdong</td>
<td align="left">RCT</td>
<td align="left">60</td>
<td align="left">31.67</td>
<td align="left">T:56.39 &#xb1; 6.91 C:53.61 &#xb1; 6.57</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; MICLD; C:MICLD</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2462;&#x2466;&#x2467;&#x2468;</td>
</tr>
<tr>
<td align="left">Jian F 2017 (<xref ref-type="bibr" rid="B12">fang, 2017</xref>)</td>
<td align="left">HICH</td>
<td align="left">Chongqing</td>
<td align="left">RCT</td>
<td align="left">60</td>
<td align="left">41.67</td>
<td align="left">35&#x223c;72</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP soft capsule &#x2b; CT; C: CT</td>
<td align="left">0.2&#xa0;g/tid 28d</td>
<td align="left">NA</td>
<td align="left">&#x2460;</td>
</tr>
<tr>
<td align="left">Jia YH, <font color="#FE0191">et al.,</font> 2017 (<xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>)</td>
<td align="left">HICH</td>
<td align="left">Shanxi</td>
<td align="left">RCT</td>
<td align="left">80</td>
<td align="left">45</td>
<td align="left">T:63.7 &#xb1; 8.4 C:64.2 &#xb1; 7.5</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; CT; C: CT</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">28</td>
<td align="left">&#x2460;&#x2466;&#x2467;&#x2468;</td>
</tr>
<tr>
<td align="left">Huang F, <font color="#FE0191">et al.,</font> 2021 (<xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>)</td>
<td align="left">HICH</td>
<td align="left">Hunan</td>
<td align="left">RCT</td>
<td align="left">110</td>
<td align="left">39.09</td>
<td align="left">T:72.74 &#xb1; 8.15 C:71.34 &#xb1; 7.43</td>
<td align="left">T:38.13 &#xb1; 6.75 C:36.34 &#xb1; 5.43</td>
<td align="left">T:7.34 &#xb1; 3.43 C:7.84 &#xb1; 4.26</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; oxiracetam; C: oxiracetam</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2462;&#x2463;&#x2466;&#x2467;&#x2468;</td>
</tr>
<tr>
<td align="left">Ji XT, <font color="#FE0191">et al.,</font> 2017 (<xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>)</td>
<td align="left">HICH</td>
<td align="left">Hainan</td>
<td align="left">RCT</td>
<td align="left">63</td>
<td align="left">42.86</td>
<td align="left">T:59.92 &#xb1; 5.87 C:61.03 &#xb1; 5.72</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; Xingnaojing injection; C: Xingnaojing injection</td>
<td align="left">25&#xa0;ml/bid 14d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2462;&#x2465;&#x2466;</td>
</tr>
<tr>
<td align="left">Chen H, <font color="#FE0191">et al.,</font> 2023 (<xref ref-type="bibr" rid="B4">Chen et al., 2023</xref>)</td>
<td align="left">SAH</td>
<td align="left">Hunan</td>
<td align="left">RCT</td>
<td align="left">102</td>
<td align="left">43.14</td>
<td align="left">T:62.52 &#xb1; 12.38 C:63.24 &#xb1; 12.77</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">T:NBP injection &#x2b; nimodipine; C: nimodipine</td>
<td align="left">25&#xa0;ml/bid 10d</td>
<td align="left">NA</td>
<td align="left">&#x2460;&#x2465;</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Note: ICH: intracerebral hemorrhage; HICH: Hypertensive intracerebral hemorrhage; aSAH: Aneurysmal subarachnoid hemorrhage; SCH: senile cerebral haemorrhage; ICH&#x26;PI; Cerebral hemorrhage complicated with pulmonary infection; SAH: subarachnoid hemorrhage; CT: conventional therapy; HOT: Hyperbaric Oxygen Therapy; MICLD: minimally invasive catheter suction liquefaction drainage; RCT: Randomized controlled trial; NA: Not applicable;&#x2460;Clinical efficiency;&#x2461;Incidence of adverse reactions; &#x2462;NIHSS scores; &#x2463;ADL scores; &#x2464;MCBF; &#x2465;MBFV; &#x2466;cerebral edema volume; &#x2467;Hcy concentration; &#x2468;SP concentration.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3-3">
<title>3.3 Literature quality evaluation</title>
<p>A total of seven studies (<xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B48">Qian, 2021</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>; <xref ref-type="bibr" rid="B4">Chen et al., 2023</xref>) employed the random number table method for participant allocation. Nine studies (<xref ref-type="bibr" rid="B64">Wang Y. et al., 2021a</xref>; <xref ref-type="bibr" rid="B35">Liu et al., 2018</xref>; <xref ref-type="bibr" rid="B43">Pang et al., 2010</xref>; <xref ref-type="bibr" rid="B21">hongli, 2019</xref>; <xref ref-type="bibr" rid="B3">Chen et al., 2018</xref>; <xref ref-type="bibr" rid="B34">Lin, 2021</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B12">fang, 2017</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>) only specified the use of &#x201c;random&#x201d; without further detail. One study (<xref ref-type="bibr" rid="B68">yan et al., 2021</xref>) allocated participants according to different treatment groups. Another study (<xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>) used a lottery system for grouping, and one study (<xref ref-type="bibr" rid="B69">yang et al., 2020</xref>) divided participants based on odd and even numbers. None of the studies exhibited evidence of selective reporting. One study (<xref ref-type="bibr" rid="B35">Liu et al., 2018</xref>) provided detailed information on patient dropouts and missed follow-ups, including the primary reasons for these occurrences. These aspects are illustrated in <xref ref-type="fig" rid="F2">Figure 2</xref>, <xref ref-type="fig" rid="F3">3</xref>.</p>
<fig id="F2" position="float">
<label>FIGURE 2</label>
<caption>
<p>Risk of bias plot of included literature.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g002.tif"/>
</fig>
<fig id="F3" position="float">
<label>FIGURE 3</label>
<caption>
<p>Summary of risk of bias in the included literature.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g003.tif"/>
</fig>
</sec>
<sec id="s3-4">
<title>3.4 Analysis of outcomes</title>
<sec id="s3-4-1">
<title>3.4.1 Clinical efficiency</title>
<p>Out of the 19 studies included, 17 (<xref ref-type="bibr" rid="B64">Wang Y. et al., 2021a</xref>; <xref ref-type="bibr" rid="B43">Pang et al., 2010</xref>; <xref ref-type="bibr" rid="B21">hongli, 2019</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B68">yan et al., 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>; <xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>; <xref ref-type="bibr" rid="B3">Chen et al., 2018</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>; <xref ref-type="bibr" rid="B69">yang et al., 2020</xref>; <xref ref-type="bibr" rid="B34">Lin, 2021</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B12">fang, 2017</xref>; <xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>; <xref ref-type="bibr" rid="B4">Chen et al., 2023</xref>) evaluated clinical response rates, showing a statistically significant difference between the two groups. In compliance with the criteria for meta-analysis inclusion, these 17 studies (n &#x003D; 1808) were analyzed. The analysis revealed that NBP enhanced the clinical efficacy rate (RR &#x003D; 1.25, 95% CI: 1.19&#x2013;1.31; <italic>p</italic> &#x003D; 0.00; Q (13) &#x003D; 10; <italic>p</italic> &#x003D; 0.04; I<sup>2</sup> &#x003D; 41.6%). The results are presented in <xref ref-type="fig" rid="F4">Figure 4</xref>.</p>
<fig id="F4" position="float">
<label>FIGURE 4</label>
<caption>
<p>Meta-analysisof clinical efficiency.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g004.tif"/>
</fig>
</sec>
<sec id="s3-4-2">
<title>3.4.2 Incidence of adverse reactions</title>
<p>Five studies (<xref ref-type="bibr" rid="B64">Wang Y. et al., 2021a</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B34">Lin, 2021</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>) investigated the incidence of adverse reactions, such as nausea and vomiting. Two of these studies (<xref ref-type="bibr" rid="B34">Lin, 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>) reported statistical differences in comparisons before and after treatment between groups, suggesting that NBP may reduce the incidence of adverse reactions. However, three other studies (<xref ref-type="bibr" rid="B64">Wang Y. et al., 2021a</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>) found that NBP did not significantly decrease adverse reactions. In the meta-analysis, which included five eligible studies with a total of 613 participants, the results indicated no statistically significant difference in adverse outcomes (RR &#x003D; 0.68, 95% CI: 0.39&#x2013;1.18; <italic>p</italic> &#x003D; 0.17; Q (4) &#x003D; 7.83; <italic>p</italic> &#x003D; 0.10, I<sup>2</sup> &#x003D; 48.89). These findings are illustrated in <xref ref-type="fig" rid="F5">Figure 5</xref>.</p>
<fig id="F5" position="float">
<label>FIGURE 5</label>
<caption>
<p>Meta-analysis of incidence of adverse reactions.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g005.tif"/>
</fig>
</sec>
<sec id="s3-4-3">
<title>3.4.3 NIHSS score</title>
<p>Nine studies (<xref ref-type="bibr" rid="B64">Wang Y. et al., 2021a</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>; <xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>; <xref ref-type="bibr" rid="B3">Chen et al., 2018</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>), with a total of 988 participants evaluated the NIHSS score. Among these, one study (<xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>) observed a decreasing trend in the NIHSS score (<italic>p</italic> &#x003c; 0.05). The remaining eight studies (<xref ref-type="bibr" rid="B64">Wang Y. et al., 2021a</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>; <xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>; <xref ref-type="bibr" rid="B3">Chen et al., 2018</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2022</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>) reported statistically significant differences between groups (<italic>p</italic> &#x003c; 0.01). The aggregated results indicated that NBP contributed to a reduction in the NIHSS score (MD &#x003D; &#x2212;6.00, 95% CI: &#x2212;8.65 to &#x2212;3.34; <italic>p</italic> &#x003D; 0.00; Q (8) &#x003D; 832.39; <italic>p</italic> &#x003D; 0.00; I<sup>2</sup> &#x003D; 99.04%). These findings are depicted in <xref ref-type="fig" rid="F6">Figure 6</xref>.</p>
<fig id="F6" position="float">
<label>FIGURE 6</label>
<caption>
<p>Meta-analysis of NIHSS score.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g006.tif"/>
</fig>
</sec>
<sec id="s3-4-4">
<title>3.4.4 ADL score</title>
<p>Six studies (<xref ref-type="bibr" rid="B48">Qian, 2021</xref>; <xref ref-type="bibr" rid="B43">Pang et al., 2010</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B68">yan et al., 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>), with a total of 592 participants evaluated the Activities of Daily Living (ADL) score. Among these, three studies (<xref ref-type="bibr" rid="B48">Qian, 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>; <xref ref-type="bibr" rid="B70">Zhang et al. 2021</xref>; <xref ref-type="bibr" rid="B56">Shi and Chen 2022</xref>; <xref ref-type="bibr" rid="B23">Huang et al., 2021</xref>) indicated an increasing trend in the ADL score (<italic>p</italic> &#x003c; 0.05). Three studies (<xref ref-type="bibr" rid="B43">Pang et al., 2010</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B68">yan et al., 2021</xref>) demonstrated statistically significant differences in the ADL score between groups (<italic>p</italic> &#x003c; 0.01). The aggregated results revealed that NBP positively influenced the ADL score, MD &#x003D; 13.93, 95% CI: 11.88&#x2013;15.98 (<italic>p</italic> &#x003D; 0.00), Q (5) &#x003D; 21.02 (<italic>p</italic> &#x003D; 0.00), I<sup>2</sup> &#x003D; 76.21%, as depicted in <xref ref-type="fig" rid="F7">Figure 7</xref>.</p>
<fig id="F7" position="float">
<label>FIGURE 7</label>
<caption>
<p>Meta-analysis of ADL score.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g007.tif"/>
</fig>
</sec>
<sec id="s3-4-5">
<title>3.4.5 Hemodynamic indicators</title>
<sec id="s3-4-5-1">
<title>3.4.5.1 Mean cerebral blood flow (MCBF)</title>
<p>Three studies (<xref ref-type="bibr" rid="B48">Qian, 2021</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B69">yang et al., 2020</xref>), comprising a total of 298 participants, assessed MCBF. The findings revealed a statistically significant difference in blood flow between groups. Specifically, NBP was associated with an increase in MCBF. MD &#x003D; 2.79, 95% CI:1.83&#x2013;3.74 (<italic>p</italic> &#x003D; 0.00). Q (2) &#x003D; 16.76 (<italic>p</italic> &#x003D; 0.00), I<sup>2</sup> &#x003D; 88.06%, as depicted in <xref ref-type="fig" rid="F8">Figure 8</xref>.</p>
<fig id="F8" position="float">
<label>FIGURE 8</label>
<caption>
<p>Meta-analysis results of the MCBF.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g008.tif"/>
</fig>
</sec>
<sec id="s3-4-5-2">
<title>3.4.5.2 Mean cerebral blood flow velocity (MBFV)</title>
<p>Five studies (<xref ref-type="bibr" rid="B48">Qian, 2021</xref>; <xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B69">yang et al., 2020</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>; <xref ref-type="bibr" rid="B4">Chen et al., 2023</xref>), involving a total of 463 participants, examined the MBFV. The analysis indicated a statistically significant difference in MBFV between groups. Specifically, NBP was found to increase the MBFV. SMD &#x003D; 1.64, 95% CI:1.10&#x2013;2.19 (<italic>p</italic> &#x003D; 0.00). Q (4) &#x003D; 25.98 (<italic>p</italic> &#x003D; 0.00), I<sup>2</sup> &#x003D; 84.61%, as illustrated in <xref ref-type="fig" rid="F9">Figure 9</xref>.</p>
<fig id="F9" position="float">
<label>FIGURE 9</label>
<caption>
<p>Meta-analysis of the MBFV.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g009.tif"/>
</fig>
</sec>
</sec>
<sec id="s3-4-6">
<title>3.4.6 Cerebral edema volume</title>
<p>Four studies (<xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>), encompassing 311 participants, evaluated the volume of cerebral edema. Among these, two studies (<xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>) indicated a decreasing trend in cerebral edema volume (<italic>p</italic> &#x003c; 0.05). In contrast, two studies (<xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>; <xref ref-type="bibr" rid="B27">Ji and Zhou, 2017</xref>) demonstrated statistically significant differences in cerebral edema volume between groups (<italic>p</italic> &#x003c; 0.01). The cumulative results suggest that NBP may reduce cerebral edema volume in patients with cerebral hemorrhage. SMD &#x003D; &#x2212;1.98, 95% CI: &#x2212;2.25 &#x223c; &#x2212;1.71 (<italic>p</italic> &#x003D; 0.00), Q (3) &#x003D; 4.27 (<italic>p</italic> &#x003D; 0.23), I<sup>2</sup> &#x003D; 29.80%, <xref ref-type="fig" rid="F10">Figure 10</xref>.</p>
<fig id="F10" position="float">
<label>FIGURE 10</label>
<caption>
<p>Meta-analysisof cerebral edema volume.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g010.tif"/>
</fig>
</sec>
<sec id="s3-4-7">
<title>3.4.7 Hcy concentration</title>
<p>Four studies (<xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>), encompassing a total of 378 participants, evaluated homocysteine (Hcy) concentration. Among these, two studies (<xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>) observed a decreasing trend in Hcy concentration (<italic>p</italic> &#x003c; 0.05). Two studies (<xref ref-type="bibr" rid="B47">Qian et al., 2017</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>) demonstrated statistically significant differences in Hcy concentration between groups (<italic>p</italic> &#x003c; 0.01). The consolidated results indicate that NBP effectively reduced the Hcy concentration. MD &#x003D; &#x2212;3.97, 95% CI: &#x2212;4.39 &#x223c; &#x2212;3.55 (<italic>p</italic> &#x003D; 0.00). Q (3) &#x003D; 1.15 (<italic>p</italic> &#x003D; 0.76), I<sup>2</sup> &#x003D; 0.00%, as illustrated in <xref ref-type="fig" rid="F11">Figure 11</xref>.</p>
<fig id="F11" position="float">
<label>FIGURE 11</label>
<caption>
<p>Meta-analysis of Hcy concentration.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g011.tif"/>
</fig>
</sec>
<sec id="s3-4-8">
<title>3.4.8 SP concentration</title>
<p>Four studies (<xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>), encompassing a total of 358 participants, evaluated SP concentration. Among these, two studies (<xref ref-type="bibr" rid="B28">Jia et al., 2017</xref>; <xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>) reported a rising trend in SP concentration, and there is a statistical difference (<italic>p</italic> &#x003c; 0.05). Otherwise, two studies (<xref ref-type="bibr" rid="B19">Han et al., 2021</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>) demonstrated statistically significant differences in SP concentration between groups (<italic>p</italic> &#x003c; 0.01). The aggregated data reveal that NBP effectively increased SP concentration. MD &#x003D; 3.63, 95% CI: 2.95&#x2013;4.31 (<italic>p</italic> &#x003D; 0.00). Q (3) &#x003D; 1.30 (<italic>p</italic> &#x003D; 0.73), I<sup>2</sup> &#x003D; 0.00%, as depicted in <xref ref-type="fig" rid="F12">Figure 12</xref>.</p>
<fig id="F12" position="float">
<label>FIGURE 12</label>
<caption>
<p>Meta-analysis of SP concentration.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g012.tif"/>
</fig>
</sec>
<sec id="s3-4-9">
<title>3.4.9 Sensitivity analysis (NIHSS, ADL score, hemodynamic indexes)</title>
<p>A Galbraith map was utilized for sensitivity analysis to identify the sources of high heterogeneity in the NIHSS score. This analysis revealed that two studies (<xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>) fell outside the 95% CI, suggesting they might be anomalies contributing to the heterogeneity, as depicted in <xref ref-type="fig" rid="F13">Figure 13A</xref>. Excluding two studies (<xref ref-type="bibr" rid="B18">Guo and Liao, 2022</xref>; <xref ref-type="bibr" rid="B11">fang and yixin, 2021</xref>) from the analysis, the NIHSS score remained statistically significant (SMD &#x003D; &#x2212;1.29, 95% CI -1.72 to &#x2212;0.85; <italic>p</italic> &#x003c; 0.0001), and heterogeneity was notably reduced (<italic>p</italic> &#x003D; 0.000; I<sup>2</sup> &#x003D; 88%). In the ADL score heterogeneity analysis, the study (<xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>) was identified as not within the 95% CI, potentially indicating a source of heterogeneity, as shown in <xref ref-type="fig" rid="F13">Figure 13B</xref>. Removal of study (<xref ref-type="bibr" rid="B56">Shi and Chen, 2022</xref>) maintained the statistical significance of the ADL score (MD &#x003D; 15.03, 95% CI 14.02 to 16.04; <italic>p</italic> &#x003c; 0.0001), with a significant reduction in heterogeneity (<italic>p</italic> &#x003D; 0.34; I<sup>2</sup> &#x003D; 12%). Sensitivity analysis of mean blood flow, as illustrated in <xref ref-type="fig" rid="F13">Figure 13C</xref>, did not reveal specific sources of heterogeneity. Regarding mean blood flow velocity, sensitivity analysis indicated that the statistical significance persisted even after the exclusion of study (<xref ref-type="bibr" rid="B19">Han et al., 2021</xref>) (SMD &#x003D; 1.37, 95% CI 1.10 to 1.64; <italic>p</italic> &#x003c; 0.0001), with a substantial reduction in heterogeneity (<italic>p</italic> &#x003D; 0.27, I<sup>2</sup> &#x003D; 23%), as shown in <xref ref-type="fig" rid="F13">Figure 13D</xref>.</p>
<fig id="F13" position="float">
<label>FIGURE 13</label>
<caption>
<p>
<bold>(A)</bold> NIHSS score, <bold>(B)</bold> ADL score, <bold>(C)</bold> MCBF, <bold>(D)</bold> MBFV.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g013.tif"/>
</fig>
</sec>
</sec>
<sec id="s3-5">
<title>3.5 Meta-regression analysis</title>
<p>The results of meta-analysis of clinical efficacy showed that the effect size was not significantly correlated with age, gender, and drug dosage form (<italic>p</italic> &#x003e; 0.05).</p>
</sec>
<sec id="s3-6">
<title>3.6 Publication bias</title>
<p>Given the requirement of a minimum of 10 original studies for funnel plot analysis, this approach was applied exclusively to clinical efficacy rates. Subsequently, an Egger test was conducted, revealing a statistically significant difference (<italic>p</italic> &#x003c; 0.01), indicating publication bias in clinical remission rates. To address this, a &#x201c;trim and filling&#x201d; method was employed to estimate the adjusted combined effect size for publication bias. The adjusted combined effect size was found to remain statistically significant (<italic>p</italic> &#x003c; 0.01), aligning with the unadjusted findings. In conclusion, the publication bias in clinical efficiency rates was minimal, and the results were robust, as evidenced in <xref ref-type="fig" rid="F14">Figures 14A, B</xref>.</p>
<fig id="F14" position="float">
<label>FIGURE 14</label>
<caption>
<p>
<bold>(A)</bold> Funnel plot of clinical efficacy, <bold>(B)</bold> Trim and filling figure of meta-analysis of clinical efficiency.</p>
</caption>
<graphic xlink:href="fphar-15-1360932-g014.tif"/>
</fig>
</sec>
</sec>
<sec id="s4" sec-type="discussion">
<title>4 Discussion</title>
<sec id="s4-1">
<title>4.1 Findings analysis</title>
<p>To our knowledge, this is the inaugural systematic review and meta-analysis investigating the clinical efficacy and outcomes of NBP in cerebral hemorrhage patients. The findings indicate that NBP markedly enhances clinical efficacy, cerebral blood flow, and velocity, facilitates neurological function recovery, ameliorates symptoms of cerebral edema, and attenuates the inflammatory response. Furthermore, the use of NBP in treating cerebral hemorrhage was not associated with significant adverse reactions. Consequently, NBP can be considered a viable therapeutic option for cerebral hemorrhage treatment.</p>
<p>This study reveals that NBP enhances clinical efficacy in patients with cerebral hemorrhage, contributing to reductions in both the NIHSS score and the ADL score. Furthermore, NBP was found to promote neurological recovery and elicit a greater clinical response than conventional treatment. These findings align with the experimental results reported by Zhao et al. (<xref ref-type="bibr" rid="B71">Zhao et al., 2017</xref>), which indicated that continuous NBP administration for 21 days post-traumatic brain injury (TBI) significantly improved sensorimotor recovery in adult male mice. Our meta-analysis corroborates the ability of NBP to notably improve patient living capabilities. Correspondingly, Lv et al. (<xref ref-type="bibr" rid="B39">Lv et al., 2021</xref>) reported that a combination of NBP with modified mandatory exercise therapy markedly enhanced daily living abilities in patients with cerebral hemorrhage, echoing our observations.</p>
<p>NBP has been effective in alleviating symptoms of cerebral hemorrhage by reducing Hcy concentrations. Multiple studies have identified Hcy as a biomarker for predicting cerebral hemorrhage, categorizing it as an independent predictor (<xref ref-type="bibr" rid="B70">Zhang et al., 2022</xref>). Consequently, Hcy was chosen as one of the main indicators in this study. Xu et al. reported that Hcy levels can be instrumental in assessing the progression and prognosis of cerebral hemorrhage. Their research indicated that higher serum Hcy concentrations in patients are associated with larger cerebral hemorrhage volumes, which is crucial for timely assessment of the condition&#x2019;s progression and prognosis (<xref ref-type="bibr" rid="B67">Xu et al., 2022</xref>). In this studies, a positive correlation was found between Hcy concentration and the severity of cerebral hemorrhage. Our findings confirm that NBP significantly reduces Hcy concentrations.</p>
<p>SP, a neuropeptide of the tachykinin family, is widely distributed in the central and peripheral nervous systems, respiratory system, and intestinal tract. It exhibits proinflammatory effects upon binding to its receptors. In cerebral hemorrhage patients, SP may play a key role in hematoma enlargement, perihematoma edema, and neuroinflammatory responses (<xref ref-type="bibr" rid="B38">Lorente et al., 2020</xref>; <xref ref-type="bibr" rid="B60">Wang et al., 2020</xref>). Animal model studies have shown that inflammation can lead to neuronal death, blood-brain barrier disruption, and neurological deficits post-ICH in rats (<xref ref-type="bibr" rid="B72">Zhu et al., 2018</xref>; <xref ref-type="bibr" rid="B6">Chen S. et al., 2022b</xref>). Our results indicated that NBP significantly increases SP concentration. Potentially by blocking SP&#x2019;s binding to its receptor, thus reducing inflammation and edema in brain tissue. The rise in peripheral SP level might be a feedback regulation after the inhibition of the SP receptor, consistent with the conclusions of Wang et al. (<xref ref-type="bibr" rid="B61">Wang haibo et al., 2021b</xref>). However, the specific mechanism requires further exploration.</p>
<p>Perihematoma edema is a principal contributor to the high morbidity and mortality associated with intracranial hemorrhage. The edema volume often surpasses that of the original hematoma, potentially increasing intracranial pressure or leading to hydrocephalus, thereby causing neurological deterioration and even death (<xref ref-type="bibr" rid="B41">Mehdiratta et al., 2008</xref>). Persistent or expanding edema can further impede cerebral blood supply, disrupt the intracellular environment of nerve cells, and exacerbate nerve cell damage (<xref ref-type="bibr" rid="B17">Gong et al., 2015</xref>; <xref ref-type="bibr" rid="B63">Wang et al., 2016</xref>). Animal experimental studies have demonstrated that NBP significantly enhances neurological function and mitigates symptoms of cerebral edema in rats experiencing cerebral hemorrhage (<xref ref-type="bibr" rid="B23">Huang et al., 2021</xref>). These findings are consistent with our own observations.</p>
<p>The monitoring and regulation of hemodynamic parameters are critical in cerebral hemorrhage management (<xref ref-type="bibr" rid="B30">Jurgen et al., 2021</xref>). Cerebral vasospasm, commonly observed in subarachnoid hemorrhage patients, is intricately linked to the reduction in blood flow velocity and volume, potentially impairing the body&#x2019;s capacity for autoregulation of these parameters. Experimental studies have indicated that alterations in cerebral blood flow (CBF) correlate with the capacity for oxygen delivery. Cerebral hypoperfusion and inadequate oxygen delivery can result in brain tissue injury (<xref ref-type="bibr" rid="B46">Prunell et al., 2004</xref>; <xref ref-type="bibr" rid="B42">Muench et al., 2007</xref>). Lennihan L et al. demonstrated that increasing CBF and enhancing microcirculation can mitigate brain tissue damage (<xref ref-type="bibr" rid="B32">Lennihan et al., 2000</xref>; <xref ref-type="bibr" rid="B50">Qiu et al., 2019</xref>). The meta-analysis results of this study suggest that NBP may enhance cerebral blood flow and velocity, which could be a key mechanism in restoring cerebral nerve function deficits. However, due to limited sample sizes, extensive evidence is still required for confirmation. Our meta-analysis observed that the improvement in cerebral hemorrhage adverse effects by NBP was marginally lower than that reported in the retrospective study by Lv et al. (<xref ref-type="bibr" rid="B39">Lv et al., 2021</xref>). In this study, the improvement in adverse effects was less pronounced with NBP, but did not exacerbate the adverse effects.</p>
</sec>
<sec id="s4-2">
<title>4.2 Limitations</title>
<p>This study acknowledges five limitations in the evidence presented. Firstly, the majority of the included studies originated from China, with all cases involving Chinese patients, introducing potential regional publication bias. Further international clinical trials are warranted. Secondly, the assessment of evidence quality revealed that only seven studies in the meta-analysis reported random sequence generation, and none implemented blinding for subjects and clinicians or reported on it. This aspect necessitates optimization in clinical trial design and may significantly impact the quality of the literature. Thirdly, due to publication bias in clinical response rates, the &#x201c;trim and filling&#x201d; method was employed to estimate the adjusted combined effect size. However, this approach, based on the principle of symmetry and the inclusion of hypothetical small-sample studies, warrants cautious interpretation of clinical response rate results. Importantly, the interventions in the control groups of the included studies were all conventional Western medical treatments viewed as placebo therapy was not involved in the control groups and most of the studies did not have a follow-up period, which may expensively result in a waste of research Finally, while efforts were made to encompass a comprehensive range of studies, the exclusion of grey literature might have led to the omission of crucial literature.</p>
<p>This review process is subject to two main limitations. Firstly, the scope of our study predominantly focused on evaluating the clinical efficacy, neurological function, quality of life, and blood indices of NBP in cerebral hemorrhage patients. It did not extensively delve into the occurrence of adverse events linked to the prognosis of cerebral hemorrhage. This limitation stems from the absence of clinical trials concerning NBP that investigate prognosis-related adverse outcomes. Secondly, the studies incorporated in our analysis were characterized by small sample sizes. Future research should encompass a substantial number of multi-center, randomized, double-blind controlled trials with larger samples to substantiate the efficacy of NBP and elucidate its specific biomolecular mechanisms.</p>
</sec>
</sec>
<sec id="s5" sec-type="conclusion">
<title>5 Conclusion</title>
<p>In conclusion, our study demonstrates that NBP effectively enhances clinical response rates, neurological function, and quality of life, while reducing cerebral blood flow and velocity in cerebral hemorrhage patients. Additionally, NBP exhibits minimal side effects and may ameliorate brain injury and clinical symptoms by diminishing inflammatory responses and Hcy concentrations. This review substantiates that timely administration of NBP can improve clinical symptoms in the cerebral hemorrhage population. The findings aim to shed light on NBP&#x2019;s potential targets in treating cerebral hemorrhage and provide valuable insights for clinicians, medical institutions, and intervention strategists dealing with cerebral hemorrhage.</p>
</sec>
</body>
<back>
<sec id="s6" sec-type="data-availability">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.</p>
</sec>
<sec id="s7">
<title>Author contributions</title>
<p>YM: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Software, Visualization, Writing&#x2013;original draft, Validation. CG: Data curation, Formal Analysis, Investigation, Methodology, Software, Validation, Visualization, Writing&#x2013;original draft. YW: Data curation, Formal Analysis, Investigation, Methodology, Software, Validation, Visualization, Writing&#x2013;original draft. XL: Conceptualization, Supervision, Writing&#x2013;original draft, Writing&#x2013;review and editing.</p>
</sec>
<sec id="s8" sec-type="funding-information">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The study were supported by the Science and Technology Innovation project of China Academy of Chinese Medical Sciences (grant number. CI 2021A05407).</p>
</sec>
<sec id="s9" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s10" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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