Clinical Pharmacology & Therapeutics最新文献

{"title":"Leveraging Real-World Data to Address Potential Methadone Drug–Drug Interactions","authors":"Sarah A. Holstein","doi":"10.1002/cpt.3520","DOIUrl":"10.1002/cpt.3520","url":null,"abstract":"<p>As the sales of opioids rapidly increased in the United States at the turn of this century, so too did admissions for opioid abuse treatment and deaths due to opioid overdose.<span><sup>1</sup></span> The resulting opioid epidemic has devastated innumerable lives as well as strained an already struggling healthcare system. To combat this, a multi-faced approach has been implemented, including strategies to try to prevent inappropriate prescription of opioids in both the acute and chronic pain settings as well as employing pharmacological therapies to mitigate the consequences of opioid use disorders (OUD).<span><sup>2</sup></span> Currently, there are three agents approved as medications for OUD (MOUD), the opioid agonists methadone and buprenorphine as well as the opioid antagonist naltrexone. A retrospective comparative effectiveness study using deidentified claims data demonstrated that only methadone or buprenorphine use, but not other measures such as naltrexone, inpatient treatments, or non-intensive behavioral health initiatives, reduced overdose and opioid-related morbidity.<span><sup>3</sup></span></p><p>Despite the efficacy of MOUD, it was estimated that only 22% of the 2.5 million individuals in the United States who had past-year OUD in 2021 received MOUD.<span><sup>4</sup></span> This degree of undertreatment is in part due to the ongoing stigma associated with OUD as well as lack of sufficient knowledge regarding MOUD on the part of the healthcare enterprise. A recent scoping review focused on understanding healthcare workers’ knowledge and attitudes regarding outpatient use of methadone revealed key knowledge gaps as well as varying degrees of concern regarding the potential for misuse and skepticism regarding efficacy.<span><sup>5</sup></span> OUD is of course not unique to the United States and the stigma associated with OUD impacts management throughout the world. For example, a recent observational study conducted in France involving individuals with OUD revealed that approximately two-thirds of those surveyed had moderate to high levels of self-stigma and nearly one-half had experienced perceived stigma from a healthcare professional with respect to their OUD.<span><sup>6</sup></span> While it is critical that society address the stigma associated with OUD, it is also important that healthcare workers understand how to safely prescribe MOUD agents such as methadone.</p><p>One factor that may be contributing to healthcare workers hesitancy to prescribe methadone for OUD is the agent's complex pharmacology, characterized by high inter-individual variability, the potential for numerous drug–drug interactions and prolonged elimination half-life.<span><sup>7</sup></span> In 2006, the FDA issued a public health advisory regarding fatal overdoses involving methadone and noted that some of the overdoses may have been unintentional, possibly linked to prescribers being unfamiliar with methadone's pharmacological properties.<span><su","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 2","pages":"321-323"},"PeriodicalIF":6.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3520","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytokine Dynamics in Action: A Mechanistic Approach to Assess Interleukin 6 Related Therapeutic Protein-Drug-Disease Interactions.","authors":"Xian Pan, Katherine L Gill, Amita Pansari, Oliver Hatley, Liam Curry, Masoud Jamei, Iain Gardner","doi":"10.1002/cpt.3560","DOIUrl":"https://doi.org/10.1002/cpt.3560","url":null,"abstract":"<p><p>Understanding cytokine-related therapeutic protein-drug interactions (TP-DI) is crucial for effective medication management in conditions characterized by elevated inflammatory responses. Recent FDA and ICH guidelines highlight a systematic, risk-based approach for evaluating these interactions, emphasizing the need for a thorough mechanistic understanding of TP-DIs. This study integrates the physiologically based pharmacokinetic (PBPK) model for TP (specifically interleukin-6, IL-6) with small-molecule drug PBPK models to elucidate cytokine-related TP-DI mechanistically. The integrated model successfully predicted TP-DIs across a broad range of both constant and fluctuating IL-6 levels, as observed in patients with rheumatoid arthritis, Crohn's disease, HIV-infection, and those undergoing hip-surgery or bone marrow transplantation (all simulated AUC and Cmax ratios were within a twofold error of the observed data). Constant IL-6 levels that would be associated with mild, moderate, and strong inhibitory interactions were estimated. The time-course and extent of TP-DI potential were also assessed in cytokine storm triggered by SARS-CoV-2 infection (COVID-19) and T-cell engager therapies (blinatumomab, mosunetuzumab, and epcoritamab). Additionally, scenarios involving concurrent CYP enzyme suppression by IL-6 and induction by rifampicin were assessed for the magnitude of drug interaction. By providing a robust mechanistic framework for understanding cytokine-drug interactions and establishing reliable exposure-response relationships, this study enhances predictive accuracy and informs human dosing strategies. It demonstrates the potential of PBPK models to improve therapeutic decision making and patient care, particularly in inflammatory conditions.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Principled Pharmacoepidemiologic Research to Support Regulatory and Healthcare Decision Making: The Era of Real-World Evidence","authors":"Rohini K. Hernandez,&nbsp;Cathy W. Critchlow,&nbsp;Nancy Dreyer,&nbsp;Timothy L. Lash,&nbsp;Robert F. Reynolds,&nbsp;Henrik T. Sørensen,&nbsp;Jeff L. Lange,&nbsp;Nicolle M. Gatto,&nbsp;Rachel E. Sobel,&nbsp;Edward Chia-Cheng Lai,&nbsp;Marieke Schoonen,&nbsp;Jeffrey S. Brown,&nbsp;Jennifer B. Christian,&nbsp;M. Alan Brookhart,&nbsp;Brian D. Bradbury","doi":"10.1002/cpt.3563","DOIUrl":"10.1002/cpt.3563","url":null,"abstract":"<p>A compilation of factors over the past decade—including the availability of increasingly large and rich healthcare datasets, advanced technologies to extract unstructured information from health records and digital sources, advancement of principled study design and analytic methods to emulate clinical trials, and frameworks to support transparent study conduct—has ushered in a new era of real-world evidence (RWE). This review article describes the evolution of the RWE era, including pharmacoepidemiologic methods designed to support causal inferences regarding treatment effects, the role of regulators and other health authorities in establishing distributed real-world data networks enabling analytics at scale, and the many global guidance documents on principled methods of producing RWE. This article also highlights the growing opportunity for RWE to support decision making by regulators, health technology assessment groups, clinicians, patients, and other stakeholders and provides examples of influential RWE studies. RWE holds promise to address important questions that clinical trials typically do not answer about treatment benefits and risks, and to ultimately impact public health by helping to guide decision making across the healthcare ecosystem.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"927-937"},"PeriodicalIF":6.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Japan's Conditional/Time-Limited Early Approval System in Regenerative Medicine: A Case Study of Rise and Falls of Autologous Skeletal Myoblast Sheets.","authors":"Hayase Hakariya, Akihiko Ozaki, Yudai Kaneda, Tetsuya Tanimoto","doi":"10.1002/cpt.3562","DOIUrl":"https://doi.org/10.1002/cpt.3562","url":null,"abstract":"<p><p>Japan's conditional/time-limited early approval program, initiated in 2014, aimed to advance regenerative medicine by expediting market access. However, the withdrawal of autologous skeletal myoblast sheets (Heartsheet) due to ineffectiveness raises concerns about the balance between rapid approval and scientific integrity. While the program seeks to boost innovation, it risks endorsing costly, unclear treatments under national health care. This case highlights the need to refine regulatory approaches, ensuring clinical efficacy and fiscal responsibility in regenerative therapies.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating the Challenges of Cyclosporine as an Alternative to Rifampicin as an OATP1B Index Inhibitor.","authors":"Manthena V S Varma, Manoli Vourvahis","doi":"10.1002/cpt.3564","DOIUrl":"https://doi.org/10.1002/cpt.3564","url":null,"abstract":"<p><p>Rifampicin is a widely employed index inhibitor to assess the impact of organic anion transporting polypeptide 1B (OATP1B) inhibition on investigational drugs. The observation of nitrosamines in certain drug products, including rifampicin, has impacted the conduct of clinical drug-drug interaction (DDI) studies with rifampicin drug products. Cyclosporine is a recommended alternative to assess in vivo OATP1B activity; however, challenges exist in its use due to pharmacokinetic (PK) variability and non-selective inhibition of other drug disposition mechanisms.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esketamine Nasal Spray in Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials.","authors":"Zhibin Wang, Lili Jiang, Wenzhuang Ma, Xingyue Li, Qiushi Gao, Siyu Lian, Weiwei Yu","doi":"10.1002/cpt.3555","DOIUrl":"https://doi.org/10.1002/cpt.3555","url":null,"abstract":"<p><p>Despite being approved by the US FDA and the EU European Medicines Agency, the performance of esketamine nasal spray as an adjunctive therapy with an antidepressant in major depressive disorder is still controversial. Comprehensive retrieval in Embase, Pubmed, and Web of Science was conducted to identify randomized controlled trials comparing esketamine nasal spray versus control in major depressive disorder or treatment-resistant depression. The primary efficacy outcome was a reduction of the Montgomery-Asberg Depression Rating Scale, from baseline to Day 2 or Day 28 for patients with or without suicidal ideation, respectively. The long-term efficacy outcome was the relapse rate of patients who achieved stable remission. The certainty of evidence was assessed according to the Cochrane recommendation. Esketamine nasal spray was superior to placebo in reduction of Montgomery-Asberg Depression Rating Scale from baseline to Day 28 in patients without suicidal ideation (standardized mean difference: -0.24, 95% confidence interval: -0.38, -0.09, P = 0.001, I² = 24%), and on Day 2 in patients with suicidal ideation (standardized mean difference: -0.30, 95% confidence interval: -0.47, -0.12, P = 0.0008, I² = 0%). The long-term relapse rate was significantly lower in the esketamine nasal spray group than in the placebo/quetiapine group (risk ratio: RR: 0.60, 95% confidence interval: 0.45-0.80, I² = 0%). The rate of suicidal ideation was similar between the two groups. The certainty of evidence was graded as \"moderate\" or \"high\" in the abovementioned results. Esketamine nasal spray in conjunction with an antidepressant effectively controls short-term and long-term depressive symptoms in major depressive disorder and treatment-resistant depression, with a manageable trade-off between efficacy and safety.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microdose Cocktail Study Reveals the Activity and Key Influencing Factors of OATP1B, P-Gp, BCRP, and CYP3A in End-Stage Renal Disease Patients.","authors":"Weijie Kong, Yuejuan Pan, Yujie Wu, Yiyi Hu, Zhenbin Jiang, Xinkui Tian, Shuhong Bi, Song Wang, Feifei Feng, Yuyan Jin, Jiayu Li, Haiyan Li, Yue Wang, Hao Liang, Wen Tang, Dongyang Liu","doi":"10.1002/cpt.3546","DOIUrl":"https://doi.org/10.1002/cpt.3546","url":null,"abstract":"<p><p>OATP1B, P-gp, BCRP, and CYP3A are the most contributing drug-metabolizing enzymes or transporters (DMETs) for commonly prescribed medication. Their activities may change in end-stage renal disease (ESRD) patients with large inter-individual variabilities (IIVs), leading to altered substrate drug exposure and ultimately elevated safety risk. However, the changing extent and indictive influencing factors are not quantified so far. Here, a microdose cocktail regimen containing five sensitive substrate drugs (pitavastatin, dabigatran etexilate, rosuvastatin, midazolam, and atorvastatin) for these DMETs was administrated to Chinese healthy volunteers and ESRD patients. Drug pharmacokinetics profiles were determined, together with physiological, pharmacogenetic, and gut microbiome signature. Population pharmacokinetic and machine learning model were established to identify key influencing factors and quantify their contribution to drug exposure change. The exposure of pitavastatin, dabigatran, rosuvastatin, and atorvastatin increased to 1.8-, 3.1-, 1.1-, and 1.3-fold, respectively, whereas midazolam exposure decreased by 72% in ESRD patients. Notably, in addition to disease state, the relative abundance of genus Veillonella and Clostridium_XIVb were firstly identified as significant influencing factors for PTV and RSV apparent clearance, respectively, suggesting their indicative role for OATP and BCRP activity evaluation. Moreover, several genera were found to strongly associate with drug clearance and reduce unexplained IIVs. Accordingly, it was estimated that OATP1B and intestine P-gp activity decreased by 35-75% and 29-44%, respectively, whereas BCRP and CYP3A4 activity may upregulate to some extent. Our study provides a quantitative and mechanistic understanding of individual DMET activity and could support precision medicine of substrate drugs in ESRD patients.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidance for an Effective Approach to Integrated Evidence Planning in a Dynamic World","authors":"Jens Grueger,&nbsp;Vaidyanathan Srikant","doi":"10.1002/cpt.3556","DOIUrl":"10.1002/cpt.3556","url":null,"abstract":"<p>The value of a medicine is defined by its impact on patients, caregivers, health system, and society. A pharmaceutical company will generate evidence to demonstrate this value in various studies, including randomized clinical trials, non-interventional and observational studies, real-world data analyses, modeling, and simulation. The quality and strength of the evidence supporting a medicine's effectiveness, safety and product quality will drive decisions by healthcare system stakeholders for marketing authorization (regulatory authorities). Additional evidence of comparative clinical, humanistic, economic, and societal value of the medicine will be critical for reimbursement coverage by HTA (health technology assessment) bodies and payers, guideline inclusion by clinical societies, and ultimately the treatment decision between a patient and their healthcare provider (HCP). The purpose of this article is to provide practical guidance for an effective approach to evidence planning for pharmaceutical companies. In the first section, we give a brief overview of the requirements for evidence generation from the perspectives of healthcare system decision makers, key functions involved in evidence generation within a pharmaceutical company, and different archetypes of products. We then discuss how a company can implement effective integrated evidence planning across the lifecycle of a product. We also review how requirements are likely to evolve given recent changes in major healthcare system regulations, such as Centers for Medicare &amp; Medicaid Services (CMS) drug price negotiations in the US and EU HTA Regulation (HTAR) in Europe, and finally provide some practical recommendations of how to start implementing a new integrated evidence approach.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"920-926"},"PeriodicalIF":6.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Return of Clinically Actionable Pharmacogenetic Results From Molecular Tumor Board DNA Sequencing Data: Workflow and Estimated Costs","authors":"Hyunwoo Koo,&nbsp;Tayler B. Smith,&nbsp;John T. Callaghan,&nbsp;Wilberforce Osei,&nbsp;Steven M. Bray,&nbsp;Emma M. Tillman,&nbsp;Mya T. Tran,&nbsp;Christopher A. Fausel,&nbsp;Bryan P. Schneider,&nbsp;Tyler Shugg,&nbsp;Todd C. Skaar","doi":"10.1002/cpt.3545","DOIUrl":"10.1002/cpt.3545","url":null,"abstract":"<p>Pharmacogenetic testing can prevent severe toxicities from several oncology drug therapies; it also has the potential to improve the outcomes from supportive care drugs. Paired tumor and germline sequencing is increasingly common in oncology practice; these include sequencing of pharmacogenes, but the germline pharmacogenetic variants are rarely included in the clinical reports, despite many being clinically actionable. We established an informatics workflow to evaluate the clinical sequencing results for pharmacogenetic variants. We used the Aldy computational tool, which we have previously shown to determine the variant alleles in 14 pharmacogenes in clinical sequencing data with &gt;99% accuracy, to identify pharmacogenetic variants in the clinical whole exome sequencing from our molecular tumor board. Patients with genetic variants that are clinically actionable for their individual therapy programs, including both treatment and supportive care, are referred to a clinical pharmacogenetics testing laboratory for confirmation. Through an evaluation of our weekly informatics workflow, we determined it took approximately 3.25 hours to complete the analysis of the sequencing data from approximately 20 patients. Using a United States pharmacist's median salary, we estimated the incremental added cost of the process to be only ~$15 per patient. This adds only a minor increase to the patient's cost of testing and has the potential to improve the safety and efficacy of their treatment.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"1017-1020"},"PeriodicalIF":6.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Demonstration of Major Therapeutic Advantage From a Review of EU Conditional Marketing Authorizations in Oncology and Hematology","authors":"Florian Lasch,&nbsp;Joana R. B. Carvalho,&nbsp;Caroline Pothet","doi":"10.1002/cpt.3554","DOIUrl":"10.1002/cpt.3554","url":null,"abstract":"<p>In the EU, conditional marketing authorization is a pragmatic tool for early approval of a medicine that fulfills an unmet medical need. In the pharmaceutical legislation, an unmet medical need means that a condition lacks a satisfactory method for diagnosis, prevention, or treatment. If such satisfactory methods exist, the new medicinal product must hold a major therapeutic advantage for those affected, meaning that it must demonstrate an improvement in efficacy or safety over existing methods or, in exceptional cases, a major improvement in patient care. This review evaluates the approaches taken to justify a major therapeutic advantage in oncology and hematology products recommended for approval between 2006 and 2023. The review confirmed an increase in the number of conditional marketing authorizations over time. Out of a total of 65 CMAs, a satisfactory treatment method was available for 40 cases (61.5%), thereby requiring a demonstration of major therapeutic advantage to fulfill the unmet medical need requirement. Satisfactory treatments existed more often for the more recently approved medicinal products. Qualitative arguments and quantitative comparisons were common to demonstrate meaningful improvement in efficacy or safety. In the absence of head-to-head trials, indirect comparisons were often used. Most quantitative comparisons used naïve side-by-side comparisons, lacking adjustments for trial differences or quantification of uncertainty. Regulatory guidance on indirect comparisons and data requirements may be helpful to support applicants and assessors in making available promising medicines early that fulfill an unmet medical need and continue to meet rigorous efficacy and safety standards pending availability of comprehensive data post-approval.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"1098-1105"},"PeriodicalIF":6.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}