Expert Opinion on Drug Delivery最新文献

{"title":"The importance of dissolution for orally inhaled drug products: pharmaceutical, regulatory, and clinical considerations.","authors":"Karin Somby, Martin Hingle, Ivana Tomic, Ben Forbes","doi":"10.1080/17425247.2023.2205636","DOIUrl":"10.1080/17425247.2023.2205636","url":null,"abstract":"Almost all current orally inhaled drug products (OIDPs) are for the treatment of respiratory diseases, and many have been designed using molecular or formulation strategies to retain drug in the lungs. After deposition in the lungs, the rate at which aerosol particles release drug into the lung lining fluid is a determinant of local bioavailability for drugs with poor solubility. Slow dissolution provides an absorption rate-limiting mechanism for prolonging lung exposure to an inhaled drug and extending the duration of pharmacodynamic effects. Historically, the Inhalation Ad Hoc Advisory Panel of the United States (US) Pharmacopoeia (2008) considered that there was an absence of ‘compelling evidence that dissolution testing is kinetically important for currently approved inhaled drug products’; a conclusion supported in 2012 by an IPAC-RS Dissolution Working Group [1]. Paradoxically, there has since been an intensification of interest in dissolution testing for OIDPs, driven at least in part by the US Food and Drug Administration sponsorship of research in this area [2,3]. More recently, solubility has been proposed as a key attribute of the drug substance and dissolution as a key attribute of the drug product under the foundational principles of an inhaled biopharmaceuticals classification system (iBCS) [4]. This brings closer the prospect of dissolution being recognized formally as a critical quality attribute for certain classes of OIDP and that in vitro dissolution methods will be required to characterize OIDPs in a way that is biorelevant, predictive, and can be used with confidence by medicine developers and regulators. Developing a biorelevant dissolution assay for OIDPs is challenging in practice, requiring collection of a relevant aerosol fraction, a dissolution apparatus, and dissolution medium that replicate the key determinants of dissolution in the lungs and methods for data analysis and interpretation. This article summarizes briefly recent developments in dissolution testing with a focus on pharmaceutical, regulatory, and clinical relevance (Figure 1).","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1033-1036"},"PeriodicalIF":6.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9384892","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":"Oral delivery of biomacromolecules by overcoming biological barriers in the gastrointestinal tract: an update.","authors":"Shiyun Liu,&nbsp;Xiangce Wen,&nbsp;Xin Zhang,&nbsp;Shirui Mao","doi":"10.1080/17425247.2023.2231343","DOIUrl":"10.1080/17425247.2023.2231343","url":null,"abstract":"<p><strong>Introduction: </strong>Biomacromolecules have proven to be an attractive choice for treating diseases due to their properties of strong specificity, high efficiency, and low toxicity. Besides greatly improving the patient's complaint, oral delivery of macromolecules also complies with hormone physiological secretion, which has become one of the most innovative fields of research in recent years.</p><p><strong>Areas covered: </strong>Oral delivery biological barriers for biomacromolecule, transport mechanisms, and various administration strategies were discussed in this review, including absorption enhancers, targeting nanoparticles, mucoadhesion nanoparticles, mucus penetration nanoparticles, and intelligent bionic drug delivery systems.</p><p><strong>Expert opinion: </strong>The oral delivery of biomacromolecules has important clinical implications; however, these are still facing the challenges of low bioavailability due to certain barriers. Various promising technologies have been developed to overcome the barriers and improve the therapeutic effect of oral biomacromolecules. By considering safety and efficacy comprehensively, the development of intelligent nanoparticles based on the GIT environment has demonstrated some promise in overcoming these barriers; however, a more comprehensive understanding of the oral fate of oral biomacromolecules is still required.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1333-1347"},"PeriodicalIF":6.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10150226","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":"Continuous subcutaneous levodopa-carbidopa for the treatment of advanced Parkinson's disease: is it an improvement on other delivery?","authors":"Sheila A Doggrell","doi":"10.1080/17425247.2023.2253146","DOIUrl":"10.1080/17425247.2023.2253146","url":null,"abstract":"<p><strong>Introduction: </strong>Parkinson's disease (PD) is the second most common neurodegenerative disease and is growing in prevalence and disability. The standard treatment for PD is oral levo-dopa (LD) with carbidopa (CD). As PD progresses, despite higher doses of LD/CD, plasma levels of LD fluctuate, and may be associated with motor fluctuations and dyskinesia.</p><p><strong>Areas covered: </strong>The development of two new subcutaneous preparations of LD/CD (ND0612 and ABBV-951) for the treatment of motor fluctuations in PD is described in detail. Both reduce motor fluctuations and dyskinesia with minor infusion site adverse events. A third subcutaneous preparation, DIZ102, is in early-stage development.</p><p><strong>Expert opinion: </strong>The premise for using continuous release LD in advanced PD is that steady state levels of LD will prevent motor fluctuations/dyskinesia, but this is not the whole story, and will limit the benefits of subcutaneous continuous release LD. With its present pump system ND0612 cannot be used as monotherapy, whereas ABBV-951 can be. Having to combine with oral LD/CD will complicate the use of ND0612. Both ND0612 and ABBV-951 only cause modest reductions in OFF time. It is not clear whether these subcutaneous preparations will have more benefits than the intestinal gel, which also reduces OFF time and dyskinesia.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1189-1199"},"PeriodicalIF":6.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10251463","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":"Receptor-mediated transcytosis of macromolecules across the blood-brain barrier.","authors":"Habib Baghirov","doi":"10.1080/17425247.2023.2255138","DOIUrl":"10.1080/17425247.2023.2255138","url":null,"abstract":"<p><strong>Introduction: </strong>The blood-brain barrier (BBB) restricts brain access of virtually all macromolecules. Receptor-mediated transcytosis (RMT) is one strategy toward their brain delivery. In this strategy, targeting ligands conjugated to therapeutic payload or decorating particles containing the payload interact with targets on brain capillary endothelial cells (BCEC), triggering internalization, trafficking, and release from BCEC.</p><p><strong>Areas covered: </strong>RMT at the BBB has leveraged multiple formats of macromolecules and large particles. Interactions between those and BCEC have been studied primarily using antibodies, with findings applicable to the design of larger particles. BBB-penetrant constructs have also been identified in screening campaigns and directed evolution, and subsequently found to interact with RMT targets. In addition, BCEC targeted by constructs incorporating genomic payload can be made to produce therapeutic proteins.</p><p><strong>Expert opinion: </strong>While targeting may not be strictly necessary to reach a therapeutic effect for all macromolecules, it can improve a molecule's BBB transport, exposing it to the entire brain parenchyma and enhancing its effect. Constructs with better BCEC transcytosis may be designed rationally, leveraging knowledge about BCEC trafficking, and found in screening campaigns, where this knowledge can reduce the search space and improve iterative refinement. Identification of new targets may also help generate BBB-crossing constructs.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1699-1711"},"PeriodicalIF":6.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10229954","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":"Nose to brain delivery of naringin-loaded chitosan nanoparticles for potential use in oxaliplatin-induced chemobrain in rats: impact on oxidative stress, cGAS/STING and HMGB1/RAGE/TLR2/MYD88 inflammatory axes.","authors":"Diana M F Hanna, John Youshia, Sarah Farid Fahmy, Mina Y George","doi":"10.1080/17425247.2023.2228685","DOIUrl":"10.1080/17425247.2023.2228685","url":null,"abstract":"<p><strong>Objectives: </strong>Oxaliplatin induces chemobrain in cancer patients/survivors. Nutraceutical naringin has antioxidant and anti-inflammatory properties with low oral bioavailability. Our aim was to formulate naringin in chitosan nanoparticles for nose to brain delivery and assess its neuroprotective effect against oxaliplatin-induced chemobrain in rats.</p><p><strong>Methods: </strong>Naringin chitosan nanoparticles were prepared by ionic gelation. Rats were administered oral naringin (80 mg/kg), intranasal naringin (0.3 mg/kg) or intranasal naringin-loaded chitosan nanoparticles (0.3 mg/kg). Naringin's neuroprotective efficacy was assessed based on behavioral tests, histopathology, and measuring oxidative stress and inflammatory markers.</p><p><strong>Results: </strong>Selected nanoparticles formulation showed drug loading of 5%, size of 150 nm and were cationic. Intranasal naringin administration enhanced memory function, inhibited hippocampal acetylcholinesterase activity, and corrected oxaliplatin-induced histological changes. Moreover, it reduced malondialdehyde and elevated reduced glutathione hippocampal levels. Furthermore, it decreased levels of inflammatory markers: NF-kB and TNF-α by 1.25-fold. Upstream to this inflammatory status, intranasal naringin downregulated the hippocampal protein levels of two pathways: cGAS/STING and HMGB1/RAGE/TLR2/MYD88.</p><p><strong>Conclusion: </strong>Intranasal naringin-loaded chitosan nanoparticles showed superior amelioration of oxaliplatin-induced chemobrain in rats at a dose 267-fold lower to that administered orally. The potential involvement of cGAS/STING and HMGB1/RAGE/TLR2/MYD88 pathways in the mechanistic process of either oxaliplatin-induced chemobrain or naringin-mediated neuroprotection was evidenced.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1859-1873"},"PeriodicalIF":6.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10125287","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":"Oral administration of M13-loaded nanoliposomes is safe and effective to treat colitis-associated cancer in mice.","authors":"Dingpei Long, Zahra Alghoul, Junsik Sung, Chunhua Yang, Didier Merlin","doi":"10.1080/17425247.2023.2231345","DOIUrl":"10.1080/17425247.2023.2231345","url":null,"abstract":"<p><strong>Objective: </strong>Colitis-associated cancer (CAC) treatment lacks effective small-molecule drugs and efficient targeted delivery systems. Here, we loaded M13 (an anti-cancer drug candidate) to colon-targeting ginger-derived nanoliposomes (NL) and investigated if orally administered M13-NL could enhance the anticancer effects of M13 in CAC mouse models.</p><p><strong>Methods: </strong>The biopharmaceutical properties of M13 were assessed by physicochemical characterizations. The in vitro immunotoxicity of M13 was assessed against PBMCs using FACS and the mutagenic potential of M13 was evaluated by the Ames assay. The in vitro efficacy of M13 was tested in 2D- and 3D-cultured cancerous intestinal cells. AOM/DSS-induced CAC mice were used to evaluate the therapeutic effects of free M13 or M13-NL on CAC in vivo.</p><p><strong>Results: </strong>M13 has beneficial physiochemical properties, including high stability, and no apparent immunotoxicity or mutagenic potential in vitro. M13 is effective against the growth of 2D- and 3D-cultured cancerous intestinal cells in vitro. The in vivo safety and efficacy of M13 were significantly improved by using NL for drug delivery (<i>p</i> < 0.001). Oral administration of M13-NL exhibited excellent therapeutic effects in AOM/DSS-induced CAC mice.</p><p><strong>Conclusion: </strong>M13-NL is a promising oral drug formulation for CAC treatment.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1443-1462"},"PeriodicalIF":5.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10810011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10095905","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":"Delivering monoclonal antibodies via inhalation: a systematic review of clinical trials in asthma and COPD.","authors":"Rossella Laitano, Luigino Calzetta, Francesco Cavalli, Mario Cazzola, Paola Rogliani","doi":"10.1080/17425247.2023.2228681","DOIUrl":"10.1080/17425247.2023.2228681","url":null,"abstract":"<p><strong>Introduction: </strong>Advances in understanding the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD) led to investigation of biologic drugs targeting specific inflammatory pathways. No biologics are licensed for COPD while all the approved monoclonal antibodies (mAbs) for severe asthma treatment are systemically administered. Systemic administration is associated with low target tissue exposure and risk of systemic adverse events. Thus, delivering mAbs via inhalation may be an attractive approach for asthma and COPD treatment due to direct targeting of the airways.</p><p><strong>Areas covered: </strong>This systematic review of randomized control trials (RCTs) evaluated the potential role of delivering mAbs via inhalation in asthma and COPD treatment. Five RCTs were deemed eligible for a qualitative analysis.</p><p><strong>Expert opinion: </strong>Compared to systemic administration, delivering mAbs via inhalation is associated with rapid onset of action, greater efficacy at lower doses, minimal systemic exposure, and lower risk of adverse events. Although some of the inhaled mAbs included in this study showed a certain level of efficacy and safety in asthmatic patients, delivering mAbs via inhalation is still challenging and controversial. Further adequately powered and well-designed RCTs are needed to assess the potential role of inhaled mAbs in the treatment of asthma and COPD.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1041-1054"},"PeriodicalIF":5.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10062840","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":"Targeting the gut microbiome to control drug pharmacomicrobiomics: the next frontier in oral drug delivery.","authors":"Srinivas Kamath,&nbsp;Andrea M Stringer,&nbsp;Clive A Prestidge,&nbsp;Paul Joyce","doi":"10.1080/17425247.2023.2233900","DOIUrl":"10.1080/17425247.2023.2233900","url":null,"abstract":"<p><strong>Introduction: </strong>The trillions of microorganisms that comprise the gut microbiome form dynamic bidirectional interactions with orally administered drugs and host health. These relationships can alter all aspects of drug pharmacokinetics and pharmacodynamics (PK/PD); thus, there is a desire to control these interactions to maximize therapeutic efficacy. Attempts to modulate drug-gut microbiome interactions have spurred advancements within the field of 'pharmacomicrobiomics' and are poised to become the next frontier of oral drug delivery.</p><p><strong>Areas covered: </strong>This review details the bidirectional interactions that exist between oral drugs and the gut microbiome, with clinically relevant case examples outlining a clear motive for controlling pharmacomicrobiomic interactions. Specific focus is attributed to novel and advanced strategies that have demonstrated success in mediating drug-gut microbiome interactions.</p><p><strong>Expert opinion: </strong>Co-administration of gut-active supplements (e.g. pro- and pre-biotics), innovative drug delivery vehicles, and strategic polypharmacy serve as the most promising and clinically viable approaches for controlling pharmacomicrobiomic interactions. Targeting the gut microbiome through these strategies presents new opportunities for improving therapeutic efficacy by precisely mediating PK/PD, while mitigating metabolic disturbances caused by drug-induced gut dysbiosis. However, successfully translating preclinical potential into clinical outcomes relies on overcoming key challenges related to interindividual variability in microbiome composition and study design parameters.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1315-1331"},"PeriodicalIF":6.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9761673","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":"Challenges and opportunities in delivering oral peptides and proteins.","authors":"Haisheng Peng, Jiahe Wang, Jiayu Chen, Yanbo Peng, Xiaoxian Wang, Ying Chen, David L Kaplan, Qun Wang","doi":"10.1080/17425247.2023.2237408","DOIUrl":"10.1080/17425247.2023.2237408","url":null,"abstract":"<p><strong>Introduction: </strong>Rapid advances in bioengineering enable the use of complex proteins as therapeutic agents to treat diseases. Compared with conventional small molecule drugs, proteins have multiple advantages, including high bioactivity and specificity with low toxicity. Developing oral dosage forms with active proteins is a route to improve patient compliance and significantly reduce production costs. However, the gastrointestinal environment remains a challenge to this delivery path due to enzymatic degradation, low permeability, and weak absorption, leading to reduced delivery efficiency and poor clinical outcomes.</p><p><strong>Areas covered: </strong>This review describes the barriers to oral delivery of peptides and complex proteins, current oral delivery strategies utilized and the opportunities and challenges ahead to try and circumvent these barriers. Oral protein drugs on the market and clinical trials provide insights and approaches for advancing delivery strategies.</p><p><strong>Expert opinion: </strong>Although most current studies on oral protein delivery rely on <i>in vitro</i> and <i>in vivo</i> animal data, the safety and limitations of the approach in humans remain uncertain. The shortage of clinical data limits the development of new or alternative strategies. Therefore, designing appropriate oral delivery strategies remains a significant challenge and requires new ideas, innovative design strategies and novel model systems.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":" ","pages":"1349-1369"},"PeriodicalIF":6.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10990675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826380","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":"Enzyme/pH dual stimuli-responsive nanoplatform co-deliver disulfiram and doxorubicin for effective treatment of breast cancer lung metastasis.","authors":"Peifu Xiao,&nbsp;Xiaoguang Tao,&nbsp;Hanxun Wang,&nbsp;Hongbing Liu,&nbsp;Yupeng Feng,&nbsp;Yueqi Zhu,&nbsp;Zhengzhen Jiang,&nbsp;Tian Yin,&nbsp;Yu Zhang,&nbsp;Haibing He,&nbsp;Jingxin Gou,&nbsp;Xing Tang","doi":"10.1080/17425247.2023.2237888","DOIUrl":"10.1080/17425247.2023.2237888","url":null,"abstract":"<p><strong>Objectives: </strong>Metastasis is still one of the main obstacles in the treatment of breast cancer. This study aimed to develop disulfiram (DSF) and doxorubicin (DOX) co-loaded nanoparticles (DSF-DOX NPs) with enzyme/pH dual stimuli-responsive characteristics to inhibit breast cancer metastasis.</p><p><strong>Methods: </strong>DSF-DOX NPs were prepared using the amphiphilic poly(ε-caprolactone)-b-poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer by a classical dialysis method. In vitro release tests, in vitro cytotoxicity assay, and anti-metastasis studies were conducted to evaluate pH/enzyme sensitivity and therapeutic effect of DSF-DOX NPs.</p><p><strong>Results: </strong>The specific pH and enzyme stimuli-responsiveness of DSF-DO NPs can be attributed to the transformation of secondary structure and the degradation of amide bonds in the PGlu segment, respectively. This accelerated drug release significantly increased the cytotoxicity to 4T1 cells. Compared with the control group, the DSF-DOX NPs showed a strong inhibition of in vitro metastasis with a wound healing rate of 36.50% and a migration rate of 18.39%. Impressively, in vivo anti-metastasis results indicated that the metastasis of 4T1 cells was almost completely suppressed by DSF-DOX NPs.</p><p><strong>Conclusion: </strong>DSF-DOX NPs with controllable tumor site delivery of DOX and DSF were a prospectively potential strategy for metastatic breast cancer treatment.</p>","PeriodicalId":12229,"journal":{"name":"Expert Opinion on Drug Delivery","volume":"20 7","pages":"1015-1031"},"PeriodicalIF":6.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10364844","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}