European Journal of Pharmaceutics and Biopharmaceutics最新文献

{"title":"Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency","authors":"","doi":"10.1016/j.ejpb.2024.114429","DOIUrl":"10.1016/j.ejpb.2024.114429","url":null,"abstract":"<div><h3>Background</h3><p>sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child’s needs, as the splitting of the tablet into smaller portions or its dilution in water. It’s essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients.</p></div><div><h3>Materials and methods</h3><p>we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD.</p></div><div><h3>Results</h3><p>we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance.</p></div><div><h3>Conclusions</h3><p>in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888807","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":"Cationic pH-sensitive liposome-based subunit tuberculosis vaccine induces protection in mice challenged with Mycobacterium tuberculosis","authors":"","doi":"10.1016/j.ejpb.2024.114437","DOIUrl":"10.1016/j.ejpb.2024.114437","url":null,"abstract":"<div><p>Tuberculosis (TB) has been and still is a global emergency for centuries. Prevention of disease through vaccination would have a major impact on disease prevalence, but the only available current vaccine, BCG, has insufficient impact. In this article, a novel subunit vaccine against TB was developed, using the Ag85B-ESAT6-Rv2034 fusion antigen, two adjuvants – CpG and MPLA, and a cationic pH-sensitive liposome as a delivery system, representing a new TB vaccine delivery strategy not previously reported for TB.</p><p><em>In vitro</em> in human dendritic cells (DCs), the adjuvanted formulation induced a significant increase in the production of (innate) cytokines and chemokines compared to the liposome without additional adjuvants. <em>In vivo</em>, the new vaccine administrated subcutaneously significantly reduced <em>Mycobacterium tuberculosis</em> (Mtb) bacterial load in the lungs and spleens of mice, significantly outperforming results from mice vaccinated with the antigen mixed with adjuvants without liposomes. In-depth analysis underpinned the vaccine’s effectiveness in terms of its capacity to induce polyfunctional CD4⁺ and CD8⁺ T-cell responses, both considered essential for controlling Mtb infection. Also noteworthy was the differential abundance of various CD69⁺ B-cell subpopulations, which included IL17-A-producing B-cells. The vaccine stimulated robust antigen-specific antibody titers, further extending its potential as a novel protective agent against TB.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002637/pdfft?md5=1a1aa331630a54c5190dd72437be78fc&pid=1-s2.0-S0939641124002637-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912304","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":"Rationalisation of the purification process for a phage active pharmaceutical ingredient","authors":"","doi":"10.1016/j.ejpb.2024.114438","DOIUrl":"10.1016/j.ejpb.2024.114438","url":null,"abstract":"<div><p>The resurgence of phage therapy, once abandoned in the early 20th century in part due to issues related to the purification process and stability, is spurred by the global threat of antibiotic resistance. Engineering advances have enabled more precise separation unit operations, improving overall purification efficiency. The present review discusses the physicochemical properties of impurities commonly found in a phage lysate, e.g., contaminants, phage-related impurities, and propagation-related impurities. Differences in phages and bacterial impurities properties are leveraged to elaborate a four-step phage purification process: clarification, capture and concentration, subsequent purification and polishing. Ultimately, a framework for rationalising the development of a purification process is proposed, considering three operational characteristics, i.e., scalability, transferability to various phages and duration. This guide facilitates the preselection of a sequence of unit operations, which can then be confronted with the expected impurities to validate the theoretical capacity of the process to purify the phage lysate.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002649/pdfft?md5=c735cdb388314a96724b855a75e9e09a&pid=1-s2.0-S0939641124002649-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901394","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":"Dissolution profiles of BCS class II drugs generated by the gastrointestinal simulator alpha has an edge over the compendial USP II method","authors":"","doi":"10.1016/j.ejpb.2024.114436","DOIUrl":"10.1016/j.ejpb.2024.114436","url":null,"abstract":"<div><p>The poor water solubility of orally administered drugs leads to low dissolution in the GI tract, resulting to low oral bioavailability. Traditionally, in vitro dissolution testing using the compendial dissolution apparatuses I and II has been the gold-standard method for evaluating drug dissolution and assuring drug quality. However, these methods don’t accurately represent the complex physiologies of the GI tract, making it difficult to predict in vivo behavior of these drugs. In this study, the in vivo predictive method, gastrointestinal simulator alpha (GIS-α), was used to study the dissolution profiles of commercially available BCS Class II drugs, danazol, fenofibrate, celecoxib, and ritonavir. This biorelevant transfer method utilizes multiple compartments alongside peristaltic pumps, to effectively model the transfer of material in the GI tract. In all cases, the GIS-α with biorelevant buffers gave superior dissolution profiles. In silico modeling using GastroPlus^TM yielded better prediction when utilizing the results from the GIS-α as input compared to the dissolution profiles obtained from the USP II apparatus. This gives the GIS-α an edge over compendial methods in generating drug dissolution profiles and is especially useful in the early stages of drug and formulation development. This information gives insight into the dissolution behavior and potential absorption patterns of these drugs which can be crucial for formulation development, as it allows for the optimization of drug delivery systems to enhance solubility, dissolution, and ultimately, bioavailability.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901393","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":"Investigating experimental vs. Predicted pKa values for PET radiotracer","authors":"","doi":"10.1016/j.ejpb.2024.114430","DOIUrl":"10.1016/j.ejpb.2024.114430","url":null,"abstract":"<div><p>The prediction of central nervous system (CNS) active pharmaceuticals and radiopharmaceuticals has experienced a boost by the introduction of computational approaches, like blood–brain barrier (BBB) score or CNS multiparameter optimization values. These rely heavily on calculated pK_a values and other physicochemical parameters. Despite the inclusion of various physicochemical parameters in online data banks, pK_a values are often missing and published experimental pK_a values are limited especially for radiopharmaceuticals. This comparative study investigated the discrepancies between predicted and experimental pK_a values and their impact on CNS activity prediction scores. The pK_a values of 46 substances, including therapeutic drugs and PET imaging radiopharmaceuticals, were measured by means of potentiometry and spectrophotometry. Experimentally obtained pK_a values were compared with <em>in silico</em> predictions (Chemicalize/Marvin). The results demonstrate a considerable discrepancy between experimental and <em>in silico</em> values, with linear regression analysis showing intermediate correlation (R²_(Marvin) = 0.88, R²_{(Chemicalize)} = 0.82). This indicates that if one requires an accurate pK_a value, it is essential to experimentally assess it. This underscores the importance of experimentally determining pK_a values for accurate drug design and optimization. The study’s data provide a valuable library of reliable experimental pK_a values for therapeutic drugs and radiopharmaceuticals, aiding researchers in the field.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S093964112400256X/pdfft?md5=9520f0e4ca8c940dfd6bd6ed92e620c2&pid=1-s2.0-S093964112400256X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893211","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":"Improved therapeutic index of the liposomal docetaxel-glutathione prepared by active click loading","authors":"","doi":"10.1016/j.ejpb.2024.114435","DOIUrl":"10.1016/j.ejpb.2024.114435","url":null,"abstract":"<div><p>The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (∼95 %) and loading capacity (∼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (∼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors &gt; 500 mm³ could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893210","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":"Therapeutic targeting of siRNA/anti-cancer drug delivery system for non-melanoma skin cancer. Part I: Development and gene silencing of JAK1siRNA/5-FU loaded liposome nanocomplexes","authors":"","doi":"10.1016/j.ejpb.2024.114432","DOIUrl":"10.1016/j.ejpb.2024.114432","url":null,"abstract":"<div><p>Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, <em>in vitro</em> drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120 nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72 h showed cell viability above 80 % at concentrations up to 8.5 × 10¹ µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5 µM and above (p &lt; 0.05) after 24 h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene <em>in vitro</em>, reducing its expression by 50 %. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37 % reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888810","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":"Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1G93A mouse model of amyotrophic lateral sclerosis following oral administration","authors":"","doi":"10.1016/j.ejpb.2024.114434","DOIUrl":"10.1016/j.ejpb.2024.114434","url":null,"abstract":"<div><p>Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114–120 male and female SOD1^G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the <em>ex vivo</em> intestinal permeability of caffeine were assessed. The area under the plasma concentration–time curves (AUC_plasma) of digoxin and sulfasalazine were not significantly different between SOD1^G93A and WT mice for both sexes. However, the AUC_plasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1^G93A compared to WT mice, which was associated with lower AUC_brain (female: 0.76-fold, male: 0.80-fold) and AUC_{spinal cord} (female: 0.81-fold, male: 0.82-fold). The AUC_stomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1^G93A compared to WT mice, suggesting reduced gastric emptying in SOD1^G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and <em>ex vivo</em> intestinal permeability of caffeine (0.52-fold) in male SOD1^G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1^G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002601/pdfft?md5=e2cf0e874064372a6370d29ef3f4efa3&pid=1-s2.0-S0939641124002601-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888809","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":"Investigation of keratolytic impact of synthetic bolalipids on skin penetration of a model hydrophilic permeant","authors":"","doi":"10.1016/j.ejpb.2024.114433","DOIUrl":"10.1016/j.ejpb.2024.114433","url":null,"abstract":"<div><p>Synthetic single-chain bolalipids (SSCBs) are novel excipients in drug delivery, with potential as stabilizers or solubilizers. However, their impact on skin barrier function has not been comprehensively studied. Therefore, two SSCBs (PC-C24-PC and PC-C32-PC) were studied in aqueous systems for their impact on penetration of a model permeant into porcine skin. Concentrations of 0.05 – 5 % w/w were tested; PC-C24-PC formulations were low-viscosity liquids while PC-C32-PC formed viscous dispersions to gels at room temperature. Formulations were compared for their ability to enhance sodium fluorescein penetration (SF, 0.1 % w/w) into skin via tape stripping. Using NIR-densitometry, the effect of SSCB formulations on corneocyte cohesion was evaluated. Data were compared with phospholipid mixture Lipoid S-75, sodium dodecyl sulfate (SDS), and polyethylene glycol 12-hydroxystearate (PEG-HS), and distilled water as negative control. Contrary to the hypothesis, both SSCBs failed to increase SF penetration into the stratum corneum, but rather showed a significant decrease in penetration depth compared to water. Both SSCBs exhibited a keratolytic effect at 5 % w/w, leading to substantial removal of proteins from the skin surface. Consequently, SSCBs may not enhance penetration of hydrophilic drugs into skin, but could be used as keratolytic agents.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002595/pdfft?md5=d30fb352ac7df7ebaf8fb0d55041104d&pid=1-s2.0-S0939641124002595-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888808","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":"Directional freezing and thawing of biologics in drug substance bottles","authors":"","doi":"10.1016/j.ejpb.2024.114427","DOIUrl":"10.1016/j.ejpb.2024.114427","url":null,"abstract":"<div><p>Biological drug substance (DS) is typically stored frozen to increase stability. However, freezing and thawing (F/T) of DS can impact product quality and therefore F/T processes need to be controlled. Because active F/T systems for DS bottles are lacking, freezing is often performed uncontrolled in conventional freezers, and thawing at ambient temperature or using water baths.</p><p>In this study, we evaluated a novel device for F/T of DS in bottles, which can be operated in conventional freezers, generating a directed air stream around bottles. We characterized the F/T geometry and process performance in comparison to passive F/T using temperature mapping and analysis of concentration gradients. The device was able to better control the F/T process by inducing directional bottom-up F/T. As a result, it reduced cryo-concentration during freezing as well as ice mound formation. However, freezing with the device was dependent on freezer performance, i.e. prolonged process times in a highly loaded freezer were accompanied by increased cryo-concentrations. Thawing was faster compared to without the device, but had no impact on concentration gradients and was slower compared to thawing in a water bath.</p><p>High-performance freezers might be required to fully exploit the potential of directional freezing with this device and allow F/T process harmonization and scaling across sites.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002534/pdfft?md5=c285bfef17e8e9fbdc617a851090fde8&pid=1-s2.0-S0939641124002534-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878581","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}