{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T23:52:21Z","timestamp":1787097141982,"version":"build-2736575974"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"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>Introduction<\/jats:title>\n                    <jats:p>Phosphodiesterase-4 (PDE4) inhibitors, including apremilast, crisaborole and roflumilast, are widely prescribed for chronic inflammatory diseases. However, sex-specific safety profiles of these agents in routine clinical practice remain poorly characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a retrospective pharmacovigilance study using the US Food and Drug Administration Adverse Event Reporting System (FAERS) from Q1-2004 to Q1-2025. Data cleaning and deduplication were performed following the FDA Guidance for Industry: Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (FDA, 2005). Specifically, deduplication was executed by retaining only the most recent FDA_DT for each unique CASEID, and demographic (DEMO), drug (DRUG), and reaction (REAC) files were merged. Reports listing apremilast, crisaborole, or roflumilast as primary suspect drugs formed three target cohorts. Disproportionality analyses were performed using reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN, information component), and multi-item gamma Poisson shrinker (MGPS, empirical Bayes geometric mean). Positive signals required meeting all four algorithmic thresholds. Signals were summarised at Preferred Term (PT) and System Organ Class (SOC) levels, stratified by sex, and visualised with volcano plots, forest plots, and SOC-level heatmaps. Time-to-onset (TTO) was calculated as the interval between treatment start and event onset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 127,516 Apremilast, 7,562 Crisaborole, and 2,142 Roflumilast reports were included. Clear sex-specific disproportionality patterns emerged across the three agents. For Apremilast, females exhibited higher reporting of dizziness, palpitations, and infection-related adverse events, whereas Crisaborole showed a modest male predominance for \u201cproduct use issue,\u201d and Roflumilast demonstrated male-skewed signals, particularly for malignancy- and metabolism-related events. System Organ Class (SOC) analyses further revealed distinct organ-system involvement for each agent. Time-to-onset profiles showed substantially delayed onset for Apremilast compared with the more immediate onset observed for Crisaborole and Roflumilast. The median TTO (IQR) was 24 (7\u201386) days for Apremilast, 4 (1\u201315) days for Crisaborole, and 42 (14\u2013128) days for Roflumilast.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion\/Conclusion<\/jats:title>\n                    <jats:p>This large-scale real-world analysis reveals pronounced sex-specific and drug-specific heterogeneity in the safety profiles of PDE4 inhibitors. These findings highlight the need for sex-stratified risk communication, individualized monitoring strategies, and further mechanistic investigations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1761303","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:33:18Z","timestamp":1774935198000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Sex-specific adverse event profiles of PDE4 inhibitors: a comparative big-data pharmacovigilance study of apremilast, crisaborole, and roflumilast in FAERS (2004\u20132025)"],"prefix":"10.3389","volume":"17","author":[{"given":"Baiqing","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Surgery, Tongji Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaorui","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Tongji Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yirou","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Tongji Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Tongji Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Tongji Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"B1","volume-title":"Otezla (apremilast) tablets prescribing information","year":"2014"},{"key":"B2","volume-title":"Daliresp (roflumilast) tablets prescribing information","year":"2011"},{"key":"B3","volume-title":"Eucrisa (crisaborole) ointment prescribing information","year":"2016"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3285","DOI":"10.1007\/s00210-025-04721-8","article-title":"Biological sex differences in pharmacokinetics and adverse drug reactions","volume":"399","author":"Aljohmani","year":"2025","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1038\/sj.jcbfm.9600122","article-title":"Altered functional connectivity related to white matter changes inside the working memory network at the very early stage of MS","volume":"25","author":"Au Duong","year":"2005","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"B6","doi-asserted-by":"publisher","first-page":"623","DOI":"10.2165\/00002018-200730070-00011","article-title":"Bayesian confidence propagation neural network","volume":"30","author":"Bate","year":"2007","journal-title":"Drug Saf."},{"key":"B7","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/1465-9921-13-59","article-title":"The effect of budesonide\/formoterol maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever use: an exploratory analysis of two randomised, controlled studies with comparisons to standard therapy","volume":"13","author":"Buhl","year":"2012","journal-title":"Respir. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nrn1909","article-title":"Why sex matters for neuroscience","volume":"7","author":"Cahill","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"4657","DOI":"10.1007\/s00210-024-02971-6","article-title":"Efficacy and safety of Ruxolitinib, Crisaborole, and Tapinarof for mild-to-moderate atopic dermatitis: a Bayesian network analysis of RCTs","volume":"397","author":"Cao","year":"2024","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"100618","DOI":"10.1016\/j.ynstr.2024.100618","article-title":"The role of brain serotonin signaling in excessive alcohol consumption and withdrawal: a call for more research in females","volume":"30","author":"Castle","year":"2024","journal-title":"Neurobiol. Stress"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.21037\/jtd.2019.04.49","article-title":"Efficacy and safety profile of roflumilast in a real-world experience","volume":"11","author":"Cilli","year":"2019","journal-title":"J. Thorac. Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"4964","DOI":"10.3390\/molecules27154964","article-title":"An overview of PDE4 inhibitors in clinical trials: 2010 to early 2022","volume":"27","author":"Crocetti","year":"2022","journal-title":"Molecules"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2025.2597341","article-title":"Pharmacokinetics and pharmacodynamics: making clinical sense of sex differences in psychopharmacology","author":"Dalla","year":"2025","journal-title":"Expert Opin. Drug Metab. Toxicol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1111\/bcp.13923","article-title":"Sex differences in adverse drug reactions reported to the National pharmacovigilance centre in the Netherlands: an explorative observational study","volume":"85","author":"de Vries","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/j.jaad.2017.06.010","article-title":"Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis","volume":"77","author":"Eichenfield","year":"2017","journal-title":"J. Am. Acad. Dermatol"},{"key":"B16","volume-title":"Evaluation of sex differences in clinical investigations silver spring, MD","year":"2013"},{"key":"B17","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/S0140-6736(07)61383-X","article-title":"From COPD to chronic systemic inflammatory syndrome?","volume":"370","author":"Fabbri","year":"2007","journal-title":"Lancet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3389\/fphar.2024.1407871","article-title":"PDE4 inhibitors: potential protective effects in inflammation and vascular diseases","author":"Fan","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1007\/s40264-024-01433-5","article-title":"Comparators in pharmacovigilance: a quasi-quantification bias analysis","volume":"47","author":"Gravel","year":"2024","journal-title":"Drug Saf."},{"key":"B20","doi-asserted-by":"publisher","first-page":"100639","DOI":"10.1016\/j.lanepe.2023.100639","article-title":"Efficacy and safety of oral roflumilast for moderate-to-severe psoriasis-a randomized controlled trial (PSORRO)","volume":"30","author":"Gyldenl\u00f8ve","year":"2023","journal-title":"Lancet Reg. Health Eur."},{"key":"B21","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.jaad.2024.02.036","article-title":"Effects of oral roflumilast therapy on body weight and cardiometabolic parameters in patients with psoriasis - results from a randomized controlled trial (PSORRO)","volume":"91","author":"Gyldenl\u00f8ve","year":"2024","journal-title":"J. Am. Acad. Dermatol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"100005","DOI":"10.1016\/j.ailsci.2021.100005","article-title":"Signal detection in pharmacovigilance: a review of informatics-driven approaches for the discovery of drug-drug interaction signals in different data sources","volume":"1","author":"Ibrahim","year":"2021","journal-title":"Artif. Intell. Life Sci."},{"key":"B23","first-page":"390","article-title":"Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis","volume":"15","author":"Jarnagin","year":"2016","journal-title":"J. Drugs Dermatol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1186\/s13075-019-1901-3","article-title":"Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1-3 pooled analysis","volume":"21","author":"Kavanaugh","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"B25","doi-asserted-by":"publisher","first-page":"518345","DOI":"10.3389\/fphar.2021.518345","article-title":"Phosphodiesterase-4 inhibitors for Non-COPD respiratory diseases","volume":"12","author":"Kawamatawong","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1593989","DOI":"10.3389\/fphar.2025.1593989","article-title":"Comparison of safety of lecanemab and aducanumab: a real-world disproportionality analysis using the FDA adverse event reporting system","volume":"16","author":"Kong","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1186\/1741-7015-11-96","article-title":"Phosphodiesterase 4-targeted treatments for autoimmune diseases","volume":"11","author":"Kumar","year":"2013","journal-title":"BMC Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.therap.2022.10.002","article-title":"Sex differences in adverse drug reactions: are women more impacted?","volume":"78","author":"Lacroix","year":"2022","journal-title":"Therapie"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1682259","DOI":"10.3389\/fphar.2025.1682259","article-title":"Pharmacovigilance study of the frequency of gastrointestinal ulceration reports associated with immune checkpoint inhibitors: insights from the FDA adverse event reporting system","volume":"16","author":"Lei","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.3389\/fphar.2018.01048","article-title":"Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases","volume":"9","author":"Li","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"20420986231200746","DOI":"10.1177\/20420986231200746","article-title":"Opportunities and challenges of pharmacovigilance in special populations: a narrative review of the literature","volume":"14","author":"Li","year":"2023","journal-title":"Ther. Adv. Drug Saf."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1672343","DOI":"10.3389\/fimmu.2025.1672343","article-title":"Risk of pulmonary fungal infections associated with biologics: a FAERS database disproportionality analysis","volume":"16","author":"Li","year":"2025","journal-title":"Front. Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4280","DOI":"10.3390\/jcm11154280","article-title":"Sex\/Gender- and age-related differences in \u03b2-Adrenergic receptor signaling in cardiovascular diseases","volume":"11","author":"Liccardo","year":"2022","journal-title":"J. Clin. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"50","DOI":"10.18773\/austprescr.2018.010","article-title":"Pharmacovigilance and expedited drug approvals","volume":"41","author":"Linger","year":"2018","journal-title":"Aust. Prescr."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1485190","DOI":"10.3389\/fphar.2024.1485190","article-title":"A real-world pharmacovigilance analysis of adverse events associated with irbesartan using the FAERS and JADER databases","volume":"15","author":"Liu","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.canlet.2020.07.030","article-title":"Sex differences in health and disease: a review of biological sex differences relevant to cancer with a spotlight on glioma","volume":"498","author":"Massey","year":"2020","journal-title":"Cancer Lett."},{"key":"B38","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1002\/acr2.11156","article-title":"Long-Term safety and tolerability of apremilast Versus placebo in psoriatic arthritis: a pooled safety analysis of three phase III, randomized, controlled trials","volume":"2","author":"Mease","year":"2020","journal-title":"ACR Open Rheumatol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1007\/s40257-023-00783-7","article-title":"Apremilast long-term safety up to 5 years from 15 pooled randomized, placebo-controlled studies of psoriasis, psoriatic arthritis, and beh\u00e7et's syndrome","volume":"24","author":"Mease","year":"2023","journal-title":"Am. J. Clin. Dermatol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1289259","DOI":"10.3389\/fmed.2024.1289259","article-title":"Sex-differences in COPD: from biological mechanisms to therapeutic considerations","volume":"11","author":"Milne","year":"2024","journal-title":"Front. Med. (Lausanne)"},{"key":"B41","volume-title":"NIH policy on sex as a biological variable (SABV)","year":"2025"},{"key":"B42","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.jaad.2016.05.046","article-title":"Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults","volume":"75","author":"Paller","year":"2016","journal-title":"J. Am. Acad. Dermatol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.jaad.2015.03.049","article-title":"Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and safety trial evaluating the effects of apremilast in psoriasis [ESTEEM] 1)","volume":"73","author":"Papp","year":"2015","journal-title":"J. Am. Acad. Dermatol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1111\/bjd.14164","article-title":"Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2)","volume":"173","author":"Paul","year":"2015","journal-title":"Br. J. Dermatol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2835","DOI":"10.2147\/CCID.S544845","article-title":"Risk factors for drug-induced acute generalized exanthematous Pustulosis(AGEP) from 2004 to 2024: a real-world study based on the FAERS","volume":"18","author":"Que","year":"2025","journal-title":"Clin. Cosmet. Investig. Dermatol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"713391","DOI":"10.3389\/fneur.2021.713391","article-title":"Decreased autonomic reactivity and psychiatric comorbidities in neurological patients with medically unexplained sensory symptoms: a case-control study","volume":"12","author":"Ruschil","year":"2021","journal-title":"Front. Neurol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1096366","DOI":"10.3389\/fphar.2023.1096366","article-title":"A systematic review on sex differences in adverse drug reactions related to psychotropic, cardiovascular, and analgesic medications","volume":"14","author":"Shan","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1126\/science.adx4381","article-title":"Sex differences in tissue-specific immunity and immunology","volume":"389","author":"Sharma","year":"2025","journal-title":"Science."},{"key":"B49","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13293-022-00422-6","article-title":"Shedding light on biological sex differences and microbiota\u2013gut\u2013brain axis: a comprehensive review of its roles in neuropsychiatric disorders","volume":"13","author":"Shobeiri","year":"2022","journal-title":"Biol. Sex. Differ."},{"key":"B50","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1016\/j.jaad.2023.12.048","article-title":"Efficacy and safety of crisaborole ointment, 2%, in participants aged \u226545 years with stasis dermatitis: results from a fully decentralized, randomized, proof-of-concept phase 2a study","volume":"90","author":"Silverberg","year":"2024","journal-title":"J. Am. Acad. Dermatol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1397291","DOI":"10.3389\/fphar.2024.1397291","article-title":"Sex and gender differences and pharmacovigilance: a knot still to be untied","volume":"15","author":"Sportiello","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/sj.clpt.6100032","article-title":"Clinical pharmacology: the science of therapeutics","volume":"81","author":"Waldman","year":"2007","journal-title":"Clin. Pharmacol. & Ther."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1559447","DOI":"10.3389\/fphar.2025.1559447","article-title":"A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for lecanemab","volume":"16","author":"Yan","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"100192","DOI":"10.1016\/j.crphar.2024.100192","article-title":"The relationship between gender and pharmacology","volume":"7","author":"Younes","year":"2024","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"B55","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1136\/thoraxjnl-2013-204155","article-title":"Benefits and harms of roflumilast in moderate to severe COPD","volume":"69","author":"Yu","year":"2013","journal-title":"Thorax"},{"key":"B56","doi-asserted-by":"publisher","first-page":"853","DOI":"10.2217\/imt-2016-0023","article-title":"Crisaborole and its potential role in treating atopic dermatitis: overview of early clinical studies","volume":"8","author":"Zane","year":"2016","journal-title":"Immunotherapy"},{"key":"B57","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1111\/bjd.12387","article-title":"Meta\u2010analysis of the association between psoriasis and human leucocyte antigen\u2010B","volume":"169","author":"Zhao","year":"2013","journal-title":"Br. J. Dermatology"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1333662","DOI":"10.3389\/fphar.2024.1333662","article-title":"A real-world disproportionality analysis of everolimus: data mining of the public version of FDA adverse event reporting system","volume":"15","author":"Zhao","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"38170","DOI":"10.1038\/s41598-025-22083-2","article-title":"Disproportionality analysis comparing safety profiles of sonidegib and vismodegib based on the FAERS database","volume":"15","author":"Zheng","year":"2025","journal-title":"Sci. Rep."},{"key":"B60","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13293-020-00308-5","article-title":"Sex differences in pharmacokinetics predict adverse drug reactions in women","volume":"11","author":"Zucker","year":"2020","journal-title":"Biol. Sex. Differ."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1761303\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:33:20Z","timestamp":1774935200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1761303\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":60,"alternative-id":["10.3389\/fphar.2026.1761303"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1761303","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]},"article-number":"1761303"}}