{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:31:08Z","timestamp":1786516268368,"version":"build-2736575974"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Acute ischemic stroke (AIS) remains a leading cause of death and disability in China. Most AIS patients are ineligible for reperfusion therapies owing to the narrow therapeutic time window and risk of bleeding complications. Xingnaojing injection (XNJI) is the only traditional Chinese medicine injection that is formally approved for prehospital stroke care. Nevertheless, high-quality real-world evidence regarding its effectiveness and safety for early use within 24\u00a0h after stroke onset remains scarce. Therefore, this prospective study aimed to explore the correlations between early XNJI administration within 24\u00a0h of symptom onset and clinical outcomes in AIS patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This is a multicenter prospective observational cohort study. In total, 512 AIS patients were enrolled from 10 tertiary hospitals in Beijing and were grouped according to whether XNJI was initiated within 24\u00a0h of symptom onset, split into an exposed group (XNJI combined with standard care, n = 208) and a non-exposed group (standard care alone, n = 304). The primary endpoint was early neurological deterioration (END), defined as a \u22652-point elevation in NIHSS score within 72\u00a0h post-onset. Inverse probability weighting (IPW) was used to balance baseline covariates. Following IPW adjustment, we further adjusted models for time-updated in-hospital and post-discharge concomitant treatment covariates to partially attenuate dynamic confounding during follow-up.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In the IPW-adjusted models, early XNJI administration within 24\u00a0h after the onset of AIS was associated with a reduced risk of END (adjusted odds ratio [aOR] = 0.46, 95% CI: 0.25\u20130.88; P = 0.018; E-value = 3.73). After adjustment, longitudinal analyses revealed significant time-by-group interactions for neurological function, functional independence and independent ADL (all P &amp;lt; 0.05), while the overall between-group main effects were non-significant (all P &amp;gt; 0.05). The two groups exhibited divergent recovery trajectories: patients receiving XNJI showed a correlative trend of more rapid improvement in neurological function at Days 3 and 10 (adjusted \u03b2 ranged from \u22120.97 to \u22120.82; all P &amp;lt; 0.05). The XNJI group was also correlated with higher odds of achieving functional independence (modified Rankin Scale [mRS]\u22642) at 1, 2, and 3 months (aOR range: 2.18\u20132.25; all P &amp;lt; 0.05) and independent activities of daily living (ADL) (Barthel Index [BI]\u226590) at 2 and 3 months (aOR range: 1.49\u20131.62; all P &amp;lt; 0.05). Additionally, XNJI administration was also correlated with a reduced risk of abnormalities in neutrophil percentage (NE%) and D-dimer (all P &amp;lt; 0.05). No significant correlations were observed between XNJI use and in-hospital mortality, systolic blood-pressure (SBP) variation, or the risk of hepatorenal dysfunction (all P &amp;gt; 0.05).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This real-world observational cohort study showed that early XNJI administration within 24 h of AIS onset reduced the risk of END. Patients receiving early XNJI intervention achieved faster recovery in acute neurological function and long-term functional outcomes; however, no sustained overall therapeutic benefit was observed across all follow-up periods compared with standard stroke care alone. No significant associations were observed between XNJI and elevated risks of in-hospital mortality, SBP fluctuation or hepatorenal dysfunction. The present study only reveals observational associations, and its definite clinical efficacy and safety remain to be further verified in subsequent Randomized Controlled Trials (RCTs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>ClinicalTrials.gov<\/jats:ext-link>\n                      , identifier NCT04275349.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1697607","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:56:34Z","timestamp":1786514194000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Effectiveness and safety of xingnaojing injection within 24 hours for acute ischemic stroke: a multicenter prospective cohort study (TRACE)"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuanyuan","family":"Chen","sequence":"first","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahe","family":"Qi","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyao","family":"Che","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zangwei","family":"Chang","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dixiang","family":"Zhong","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Hao","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Guo","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingbo","family":"Kong","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1159\/000076161","article-title":"Progressing stroke: towards an internationally agreed definition","volume":"17","author":"Birschel","year":"2004","journal-title":"Cerebrovasc. Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"312","DOI":"10.11656\/j.issn.1672-1519.2015.05.15","article-title":"Post-marketing safety re-evaluation of xingnaojing injection","volume":"32","author":"Chen","year":"2015","journal-title":"Tianjin J. Tradit. Chin. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"120","DOI":"10.16808\/j.cnki.issn1003-7705.2017.12.058","article-title":"Meta-analysis of clinical efficacy of xingnaojing injection in the treatment of ischemic stroke","volume":"33","author":"Chen","year":"2017","journal-title":"Hunan J. Tradit. Chin. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"590","DOI":"10.3969\/j.issn.1004-745X.2021.04.007","article-title":"Clinical efficacy of xingnaojing injection combined with alteplase in the treatment of acute ischemic stroke: a meta-analysis","volume":"30","author":"Cheng","year":"2021","journal-title":"Chin. J. Emerg. Tradit. Chin. Med."},{"key":"B5","article-title":"National Drug Standard WS3-B-3353-98-2003: Xingnaojing Injection [Standard]","year":"2003"},{"key":"B6","unstructured":"Notice on revising the instructions of xingnaojing injection\n          \n          \n          2015"},{"key":"B7","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3877\/cma.j.issn.2095-9133.2019.02.001","article-title":"Expert consensus on clinical application of xingnaojing injection in the treatment of acute critical diseases (conditions)","year":"2019","journal-title":"Chin. J. Hyg. Rescue (Electron. Ed.)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"666","DOI":"10.3760\/cma.j.issn.1006\u20137876.2018.004","article-title":"Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018","volume":"51","year":"2018","journal-title":"Chin. J. Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"S31","DOI":"10.4103\/sja.SJA_543_18","article-title":"The STROBE guidelines","volume":"13","author":"Cuschieri","year":"2019","journal-title":"Saudi J. Anaesth."},{"key":"B10","doi-asserted-by":"publisher","first-page":"215","DOI":"10.13422\/j.cnki.syfjx.2010.12.053","article-title":"Research progress on clinical application of angong niuhuangwan and its derivative prescription","volume":"16","author":"Deng","year":"2010","journal-title":"Chin. J. Exp. Tradit. Med. Formulae."},{"key":"B11","doi-asserted-by":"publisher","first-page":"633","DOI":"10.3969\/j.issn.1674-2257.2021.05.020","article-title":"Clinical effect of xingnaojing injection combined with intravenous thrombolysis with alteplase for acute ischemic stroke","volume":"16","author":"Dong","year":"2021","journal-title":"J. Chengdu Med. Coll."},{"key":"B12","volume-title":"Screening of Effective Administration Route of Xingnaojing Against Stroke Based on Pharmacodynamics and Pharmacokinetics","author":"Duan","year":"2021"},{"key":"B13","doi-asserted-by":"publisher","first-page":"96","DOI":"10.13422\/j.cnki.syfjx.2012.08.045","article-title":"Simultaneous determination of muscone, borneol, camphor and isoborneol in xingnaojing injection by GC","volume":"18","author":"Fang","year":"2012","journal-title":"Chin. J. Exp. Tradit. Med. Formulae."},{"key":"B14","doi-asserted-by":"publisher","first-page":"193","DOI":"10.3760\/cma.j.issn.2095-4352.2018.03.001","article-title":"Expert consensus of Chinese and Western medicine emergency treatment for acute ischemic stroke in China","volume":"30","author":"Fang","year":"2018","journal-title":"Chin. Crit. Care Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/S1474\u20134422(24)00369\u20137","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990\u20132021: a systematic analysis for the global burden of disease study 2021","volume":"23","author":"Abate","year":"2024","journal-title":"Lancet Neurol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e9068","DOI":"10.1097\/MD.0000000000009068","article-title":"Early neurological deterioration during the acute phase as a predictor of long-term outcome after first-ever ischemic stroke","volume":"96","author":"Geng","year":"2017","journal-title":"Medicine"},{"key":"B17","doi-asserted-by":"publisher","first-page":"206","DOI":"10.3969\/j.issn.1006\u20135725.2022.02.015","article-title":"Systematic review of efficacy and safety of xingnaojing injection combined with alteplase for ischemic stroke","volume":"38","author":"Guo","year":"2022","journal-title":"J. Pract. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"774","DOI":"10.13699\/j.cnki.1001-6821.2017.09.002","article-title":"Clinical trial of xingnaojing combined with atorvastatin calcium in acute cerebral hemorrhage","volume":"33","author":"He","year":"2017","journal-title":"Chin. J. Clin. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"953205","DOI":"10.3389\/fphar.2022.953205","article-title":"Best practice in the chemical characterisation of extracts used in pharmacological and toxicological research-The ConPhyMP-Guidelines","volume":"13","author":"Heinrich","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"219","DOI":"10.19845\/j.cnki.zfysjjbzz.2026.0038","article-title":"Efficacy and safety of xingnaojing as an adjuvant therapy for thrombolysis in the treatment of acute ischemic stroke: a meta-analysis","volume":"43","author":"Hu","year":"2026","journal-title":"J. Apoplexy Nerv. Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.13463\/j.cnki.jlzyy.2020.09.023","article-title":"Effect on local cerebral blood flow, cerebral edema, the levels of MMP and NSE in patients with acute cerebral infarction by using xingnaojing injection","volume":"40","author":"Jia","year":"2020","journal-title":"Jilin J. Tradit. Chin. Med."},{"key":"B22","volume-title":"Risk Factors and Prediction Models for Early Neurological Deterioration in Acute Ischemic Stroke","author":"Lai","year":"2017"},{"key":"B23","volume-title":"Study on the Compatible Stability of Xingnaojing Injection and the Pharmacokinetics of Combined with Edaravone Injection in Rats","author":"Liang","year":"2020"},{"key":"B24","volume-title":"Mechanism of Xingnaojing Injection in the Treatment of Ischemic Stroke Based on Gut Microecology","author":"Liu","year":"2022"},{"key":"B25","first-page":"2686","article-title":"Establishment of the guidelines for assigned xingnaojing injection of medical insurance in beijing","volume":"21","author":"Liu","year":"2010","journal-title":"China Pharm."},{"key":"B26","doi-asserted-by":"publisher","first-page":"574","DOI":"10.14009\/j.issn.1672-2124.2024.05.015","article-title":"Meta-analysis on the effects of xingnaojing injection on inflammatory factors in patients with stroke","volume":"24","author":"Liu","year":"2024","journal-title":"Eval. Anal. Drug Use Hosp. China"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1177\/17474930251344450","article-title":"Nationwide analysis of routine clinical practices in the management of acute ischemic stroke in China","volume":"20","author":"Liu","year":"2025","journal-title":"Int. J. Stroke."},{"key":"B28","doi-asserted-by":"publisher","first-page":"336","DOI":"10.4103\/aian.AIAN_323_18","article-title":"The risk of symptomatic intracranial hemorrhage after thrombolysis for acute stroke: current concepts and perspectives","volume":"22","author":"Modrego","year":"2019","journal-title":"Ann. Indian Acad. Neurol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3191","DOI":"10.1161\/STROKEAHA.120.032966","article-title":"Different predictive factors for early neurological deterioration based on the location of single subcortical infarction: early prognosis in single subcortical infarction","volume":"52","author":"Nam","year":"2021","journal-title":"Stroke"},{"key":"B30","doi-asserted-by":"publisher","first-page":"210851","DOI":"10.1155\/2014\/210851","article-title":"Systematic review and meta-analysis of randomized controlled trials of xingnaojing treatment for stroke","volume":"2014","author":"Peng","year":"2014","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B31","volume-title":"Drug Standard of Ministry of Public Health of China - The 17th Volume of Chinese Patent Drugs","year":"1998"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3042","DOI":"10.11842\/wst.20181223004","article-title":"Research progress on the pharmacological effects of musk ketone","volume":"22","author":"Qi","year":"2020","journal-title":"World Sci. Technol. Mod. Tradit. Chin. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.19540\/j.cnki.cjcmm.20180115.011","article-title":"Explore compatibility mechanism of xingnaojing injection in treating cerebral infarction based on network pharmacology","volume":"43","author":"Song","year":"2018","journal-title":"China J. Chin. Mater. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"104586","DOI":"10.1016\/j.ijmedinf.2021.104586","article-title":"A risk score for prediction of symptomatic intracerebral haemorrhage following thrombolysis","volume":"156","author":"Soni","year":"2021","journal-title":"Int. J. Med. Inf."},{"key":"B35","doi-asserted-by":"publisher","first-page":"947","DOI":"10.3969\/j.issn.1006-7795.2025.06.001","article-title":"Brief report on stroke prevention and treatment in China, 2024","volume":"46","author":"Ji","year":"2025","journal-title":"J. Cap. Med. Univ."},{"key":"B36","doi-asserted-by":"publisher","first-page":"15","DOI":"10.15900\/j.cnki.zylf1995.2015.01.005","article-title":"Analysis of 62 cases on adverse drug reactions of xingnaojing injection","volume":"21","author":"Tang","year":"2015","journal-title":"Chin. J. Drug Abuse Prev. Treat."},{"key":"B37","doi-asserted-by":"publisher","first-page":"238","DOI":"10.16150\/j.1671-2870.2023.03.06","article-title":"Interpretation on the report of global stroke data 2022","volume":"22","author":"Tang","year":"2023","journal-title":"J. Diagn. Concepts Pract."},{"key":"B38","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1136\/pgmj.2007.066118","article-title":"Early neurological deterioration in acute ischaemic stroke: predictors, mechanisms and management","volume":"84","author":"Thanvi","year":"2008","journal-title":"Postgrad. Med. J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"659408","DOI":"10.3389\/fphar.2021.659408","article-title":"Chinese herbal medicine xingnaojing injection for acute ischemic stroke: an overview of systematic reviews and meta-analyses","volume":"12","author":"Tian","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2972","DOI":"10.19540\/j.cnki.cjcmm.20210326.503","article-title":"Overview of systematic reviews\/meta-analysis of xingnaojing injection in treatment of cerebral ischaemic stroke","volume":"46","author":"Wang","year":"2021","journal-title":"China J. Chin. Mater. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"839305","DOI":"10.3389\/fphar.2022.839305","article-title":"Efficacy and safety of xingnaojing injection for emergency treatment of acute ischemic stroke: a systematic review and meta-analysis","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"52","DOI":"10.13457\/j.cnki.jncm.2020.09.015","article-title":"A study of effect of xingnaojing injection on recovery of neurological function in patients with acute ischemic stroke and its anti-inflammatory effect","volume":"52","author":"Wu","year":"2020","journal-title":"J. New Chin. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"175","DOI":"10.16121\/j.cnki.cn45-1347\/r.2024.02.13","article-title":"Research progress on risk factors related to early neurological deterioration in acute cerebral infarction","volume":"19","author":"Xie","year":"2024","journal-title":"Intern. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1640","DOI":"10.4268\/cjcmm20160912","article-title":"HPLC specific chromatograms of xingnaojing injection","volume":"41","author":"Yang","year":"2016","journal-title":"Chin. J. Chin. Mater. Med."},{"key":"B45","first-page":"13","article-title":"Meta-analysis of the efficacy and safety of xingnaojing injection compared with usual care alone in the treatment of acute ischemic stroke","volume":"21","author":"Zha","year":"2023","journal-title":"J. China Prescr. Drug"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.3760\/j.issn.1673-4777.2020.09.029","article-title":"Analysis of adverse drug reaction in clinical application induced by xingnaojing injection in beijing from 2015 to 2019","volume":"15","author":"Zhang","year":"2020","journal-title":"China Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.14009\/j.issn.1672-2124.2021.11.019","article-title":"Rapid health technology assessment of xingnaojing injection in the treatment of stroke","volume":"21","author":"Zhang","year":"2021","journal-title":"Eval. Anal. Drug Use Hosp. China"},{"key":"B48","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1093\/jpp\/rgaa028","article-title":"l-Borneol ameliorates cerebral ischaemia by downregulating the mitochondrial calcium uniporter-induced apoptosis cascade in pMCAO rats","volume":"73","author":"Zhang","year":"2021","journal-title":"J. Pharm. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"80","DOI":"10.3969\/j.issn.1672-3384.2025.10.013","article-title":"Meta-analysis of intracranial blood flow velocity and safety of xingnaojing combined with alteplase in the treatment of acute ischemic stroke","volume":"23","author":"Zhao","year":"2025","journal-title":"Clin. Med. J."},{"key":"B50","doi-asserted-by":"publisher","first-page":"31","DOI":"10.3969\/j.issn.1673-1492.2026.06.009","article-title":"Blood pressure fluctuation pattern in acute stage of cerebral infarction and early neurological deterioration","volume":"42","author":"Zhou","year":"2026","journal-title":"J. Hebei North Univ. Nat. Sci. Ed."},{"key":"B51","doi-asserted-by":"publisher","first-page":"683","DOI":"10.19803\/j.1672-8629.2014.11.012","article-title":"Literature analysis of 30 adverse drug reaction\/event cases induced by xingnaojing injection","volume":"11","author":"Zou","year":"2014","journal-title":"Chin. J. Pharmacovigil."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1697607\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:57:00Z","timestamp":1786514220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1697607\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":51,"alternative-id":["10.3389\/fphar.2026.1697607"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1697607","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"article-number":"1697607"}}