Pharmaceutical Research最新文献_第8页

Accelerated Development of Pharmaceuticals Past, Present, and Future. 加速药品开发的过去、现在和未来。

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-08-06 DOI: 10.1007/s11095-024-03737-8

Stephen R Byrn

引用次数: 0

Evaluation of In Vitro Metabolism- and Transporter-Based Drug Interactions with Sunscreen Active Ingredients. 评估基于体外代谢和转运体的药物与防晒霜活性成分的相互作用。

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-07-24 DOI: 10.1007/s11095-024-03746-7

Mohammed Qusa, Hisham Qosa, Donna A Volpe

{"title":"Evaluation of In Vitro Metabolism- and Transporter-Based Drug Interactions with Sunscreen Active Ingredients.","authors":"Mohammed Qusa, Hisham Qosa, Donna A Volpe","doi":"10.1007/s11095-024-03746-7","DOIUrl":"10.1007/s11095-024-03746-7","url":null,"abstract":"Purpose: The aim of this study was to examine the ability of sunscreen active ingredients to inhibit in vitro drug metabolism via cytochrome P450 (CYP) enzymes and drug uptake transporters.Methods: Metabolism assays with human liver microsomes were conducted for CYP2C9, CYP2D6 and CYP3A4 using probe substrates warfarin, bufuralol and midazolam, respectively. Uptake transporter assays with transfected cell lines were conducted for OAT3, OCT2 and OATP1B1 with probe substrates estrone-3-sulfate, metformin and rosuvastatin, respectively. Six sunscreen active ingredients, avobenzone, enzacamene, oxybenzone, octinoxate, trolamine, and homosalate, were evaluated up to their aqueous solubility limits in the assays.Results: None of the sunscreen active ingredients inhibited CYP2D6 or CYP3A4 activities in the microsomes at concentration ranges up to tenfold higher than their known clinical total plasma levels. Only enzacamene, oxybenzone and trolamine were found to be inhibitory to CYP2C9 activity with IC50 values of 14.76, 22.46 and 154.7 µM, respectively. Avobenzone, enzacamene, homosalate and octinoxate were not inhibitory to the uptake transporters at the evaluated concentrations. Oxybenzone was inhibitory to OAT3 and OCT2 with IC50 values of 39.93 and 42.77 µM, respectively. Trolamine also inhibited uptake in OAT3 and OCT2 transfected cells with IC50 values of 448.1 and 1376 μM, respectively.Conclusions: Although enzacamene, oxybenzone and trolamine inhibited CYP2C9 and the renal transporters OAT3 and OCT2 in vitro, their IC50 values exceeded total plasma levels found in clinical studies. Therefore, it is unlikely that these sunscreen active ingredients in sunscreen products will inhibit the metabolism or transport of co-administered drugs in consumers.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1613-1620"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fluorinated PAMAM-Arginine Carrier Prodrugs for pH-Sensitive Sustained Ibuprofen Delivery. 氟化 PAMAM-精氨酸载体原药用于 pH 值敏感的布洛芬持续给药。

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-07-24 DOI: 10.1007/s11095-024-03747-6

Carola Romani, Mattia Sponchioni, Alessandro Volonterio

{"title":"Fluorinated PAMAM-Arginine Carrier Prodrugs for pH-Sensitive Sustained Ibuprofen Delivery.","authors":"Carola Romani, Mattia Sponchioni, Alessandro Volonterio","doi":"10.1007/s11095-024-03747-6","DOIUrl":"10.1007/s11095-024-03747-6","url":null,"abstract":"Objective: The development of an efficient, multifunctional drug delivery system overcoming different obstacles generally associated with drug formulations, including the poor accumulation of the active principle in the target site and its sustained release for prolonged time.Methods: Our study proposes the development of a fluorinated poly(amidoamine) (PAMAM) carrier prodrug combining drug release boosted in alkaline environments with a possible implementation in 19F MRI applications. In particular, we functionalized the terminal primary amines of PAMAM G2 and G4 through an ad hoc designed fluorinated ibuprofen-arginine Michael acceptor to obtain multifunctional ibuprofen-PAMAM-Arg conjugates.Results: These carriers demonstrated pH-dependent and sustained ibuprofen release for more than 5 days. This advantage was observed in both weak alkaline and physiological buffer solutions, allowing to overcome the limits associated to the burst release from similar fluorinated Arg-PAMAM dendrimers with ibuprofen physically encapsulated.Conclusion: These findings, coupled to the high biocompatibility of the system, suggest a potential synergistic biomedical application of our conjugates, serving as vehicles for drug delivery and as 19F magnetic resonance imaging contrast agents.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1725-1736"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comment on the article: In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model. 致编辑的信

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-07-13 DOI: 10.1007/s11095-024-03729-8

M J Giménez, L Aguilar, L Alou, D Sevillano

引用次数: 0

Development of a New Dry Powder Aerosol Synthetic Lung Surfactant Product for Neonatal Respiratory Distress Syndrome (RDS) - Part I: In Vitro Testing and Characterization. 开发治疗新生儿呼吸窘迫综合征 (RDS) 的新型干粉气雾剂合成肺表面活性剂产品--第一部分：体外测试和表征。

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-08-07 DOI: 10.1007/s11095-024-03740-z

Mohammad A M Momin, Dale Farkas, Michael Hindle, Felicia Hall, Robert M DiBlasi, Worth Longest

{"title":"Development of a New Dry Powder Aerosol Synthetic Lung Surfactant Product for Neonatal Respiratory Distress Syndrome (RDS) - Part I: In Vitro Testing and Characterization.","authors":"Mohammad A M Momin, Dale Farkas, Michael Hindle, Felicia Hall, Robert M DiBlasi, Worth Longest","doi":"10.1007/s11095-024-03740-z","DOIUrl":"10.1007/s11095-024-03740-z","url":null,"abstract":"Purpose: Improving the deep lung delivery of aerosol surfactant therapy (AST) with a dry powder formulation may enable significant reductions in dose while providing improved efficacy. The objective of Part I of this two-part study was to present the development of a new dry powder aerosol synthetic lung surfactant (SLS) product and to characterize performance based on aerosol formation and realistic in vitro airway testing leading to aerosol delivery recommendations for subsequent in vivo animal model experiments.Methods: A new micrometer-sized SLS excipient enhanced growth (EEG) dry powder formulation was produced via spray drying and aerosolized using a positive-pressure air-jet dry powder inhaler (DPI) intended for aerosol delivery directly to intubated infants with respiratory distress syndrome (RDS) or infant-size test animals.Results: The best-case design (D2) of the air-jet DPI was capable of high emitted dose (> 80% of loaded) and formed a < 2 µm mass median aerodynamic diameter (MMAD) aerosol, but was limited to ≤ 20 mg mass loadings. Testing with a realistic in vitro rabbit model indicated that over half of the loaded dose could penetrate into the lower lung regions. Using the characterization data, a dose delivery protocol was designed in which a 60 mg total loaded dose would be administered and deliver an approximate lung dose of 14.7-17.7 mg phospholipids/kg with a total aerosol delivery period < 5 min.Conclusions: A high-efficiency aerosol SLS product was designed and tested that may enable an order of magnitude reduction in administered phospholipid dose, and provide rapid aerosol administration to infants with RDS.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1703-1723"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tolterodine Tartrate Loaded Cationic Elastic Liposomes for Transdermal Delivery: In Vitro, Ex Vivo, and In Vivo Evaluations. 用于透皮给药的酒石酸托特罗定负载阳离子弹性脂质体：体外、体内和体内评估。

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-07-24 DOI: 10.1007/s11095-024-03741-y

Mohhammad Ramzan, Afzal Hussain, Tasneem Khan, Mohd Usman Mohd Siddique, Musarrat Husain Warsi

{"title":"Tolterodine Tartrate Loaded Cationic Elastic Liposomes for Transdermal Delivery: In Vitro, Ex Vivo, and In Vivo Evaluations.","authors":"Mohhammad Ramzan, Afzal Hussain, Tasneem Khan, Mohd Usman Mohd Siddique, Musarrat Husain Warsi","doi":"10.1007/s11095-024-03741-y","DOIUrl":"10.1007/s11095-024-03741-y","url":null,"abstract":"Objective: Tolterodine tartrate (TOTA) is a first-line therapy to treat overactive urinary bladder (OAB). Oral delivery causes high hepatic clearance, xerostomia, headache, constipation, and blurred vision. We addressed Hansen solubility parameter (HSP) and Design Expert oriented optimized cationic elastic liposomes for transdermal application.Methods: The experimental solubility was conducted in HSPiP predicted excipients to tailor formulations using surfactants, stearylamine, ethanol, and phosphatidylcholine (PC). These were evaluated for formulation characteristics. The optimized OTEL1 and OTEL1-G (gel) were compared against the drug solution (DS) and liposomes. In vitro and ex vivo studies were accomplished to investigate the insights into the mechanistic understanding of TOTA release and permeation ability. Finally, confocal laser scanning microscopy (CLSM) supported ex vivo results.Results: HSP values of TOTA were closely related to tween-80, stearylamine, and human's skin. The size (153 nm), %EE (87.6%), and PDI (0.25) values of OTEL1 were in good agreement to the predicted values (161 nm, 80.4%, and 0.31) with high desirability (0.963). Spherical and smooth OTEL1 (including OTEL1-G and liposomes) vesicles followed non-Fickian drug release as compared to DS (Fickian) as evidence with n > 0.5 (Korsmeyer and Peppas coefficient). OTEL1 (containing lipid and surfactant as 90 mg and 13.8 mg, respectively) exhibited 2.6 and 1.8-folds higher permeation flux than DS and liposomes, respectively. Biocompatible cationic OTEL1 was safe and non-hemolytic.Conclusions: OTEL1 was promised as a lead vesicular approach and an alternative to conventional oral therapy to treat OAB in children and advanced age patients.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1683-1702"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Impact of Annealing Methods on the Encapsulating Structure and Storage-Stability of Freeze-Dried Pellets of Probiotic Bacteria. 退火方法对冻干益生菌颗粒的封装结构和储存稳定性的影响

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-07-29 DOI: 10.1007/s11095-024-03751-w

Shuai Bai Palmkron, Björn Bergenståhl, Stephen Hall, Sebastian Håkansson, Marie Wahlgren, Emanuel Larsson, Anna Millqvist Fureby

{"title":"The Impact of Annealing Methods on the Encapsulating Structure and Storage-Stability of Freeze-Dried Pellets of Probiotic Bacteria.","authors":"Shuai Bai Palmkron, Björn Bergenståhl, Stephen Hall, Sebastian Håkansson, Marie Wahlgren, Emanuel Larsson, Anna Millqvist Fureby","doi":"10.1007/s11095-024-03751-w","DOIUrl":"10.1007/s11095-024-03751-w","url":null,"abstract":"Objective: This paper investigates the critical role of material thickness in freeze-dried pellets for enhancing the storage stability of encapsulated bacteria. Freeze dried material of varying thicknesses obtained from different annealing durations is quantified using Scanning Electron Microscopy (SEM) and X-ray microtomography (μCT), the material thickness is then correlated to the storage stability of the encapsulated cells.Methods: A formulation comprising of sucrose, maltodextrin, and probiotic cells is quenched in liquid nitrogen to form pellets. The pellets undergo different durations of annealing before undergoing freeze-drying. The material thickness is quantified using SEM and μCT. Storage stability in both oxygen-rich and oxygen-poor environments is evaluated by measuring CFU counts and correlated with the pellet structure.Results: The varying annealing protocols produce a range of material thicknesses, with more extensive annealing resulting in thicker materials. Storage stability exhibits a positive correlation with material thickness, indicating improved stability with thicker materials. Non-annealed pellets exhibit structural irregularities and inconsistent storage stability, highlighting the impracticality of avoiding annealing in the freeze-drying process.Conclusions: Extensive annealing not only enhances the storage stability of probiotic products but also provides greater control over the freeze-drying process, ensuring homogeneous and reproducible products. This study underscores the importance of material thickness in freeze-dried pellets for optimizing storage stability for probiotic formulations, and emphasize the necessity of annealing as a critical step in freeze-drying quenched pellets to achieve desired structural and stability outcomes.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1671-1682"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparison of Relative Activity versus Relative Expression Factors (RAF versus REF) in Predicting Glucuronidation Mediated Drug Clearance Using Recombinant UGTs. 使用重组 UGTs 预测葡萄糖醛酸化介导的药物清除率时相对活性与相对表达因子（RAF 与 REF）的比较。

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-08-06 DOI: 10.1007/s11095-024-03750-x

Sandhya Subash, Deepak Ahire, Mitesh Patel, Sahil Shaikh, Dilip Kumar Singh, Sujal Deshmukh, Bhagwat Prasad

{"title":"Comparison of Relative Activity versus Relative Expression Factors (RAF versus REF) in Predicting Glucuronidation Mediated Drug Clearance Using Recombinant UGTs.","authors":"Sandhya Subash, Deepak Ahire, Mitesh Patel, Sahil Shaikh, Dilip Kumar Singh, Sujal Deshmukh, Bhagwat Prasad","doi":"10.1007/s11095-024-03750-x","DOIUrl":"10.1007/s11095-024-03750-x","url":null,"abstract":"Purpose: Predicting the quantitative fraction of glucuronidation (fgluc) by individual UDP-glucuronosyltransferase enzymes (UGTs) is challenging due to the lack of selective inhibitors and inconsistent activity of recombinant UGT systems (rUGTs). Our study compares the relative expression versus activity factors (REF versus RAF) to predict fgluc based on rUGT data to human liver and intestinal microsomes (HLM and HIM).Methods: REF scalars were derived from a previous in-house proteomics study for eleven UGT enzymes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17), whereas RAF was calculated by measuring activities in rUGTs to microsomes of selective UGT probe substrates. Protein-normalized activity factor (pnAF) values were generated after correcting activity of individual UGTs to their corresponding protein abundance. The utility of REF and RAF in predicting fgluc was assessed for three UGT substrates-diclofenac, vorinostat, and raltegravir.Results: The REF values ranged from 0.02 to 1.75, RAF based on activity obtained in rUGTs to HLM/HIM were from 0.1 to 274. pnAF values were ~ 5 to 80-fold, except for UGT2B4 and UGT2B15, where pnAF was ~ 180 and > 1000, respectively. The results revealed confounding effect of differential specific activities (per pmol) of rUGTs in fgluc prediction.Conclusion: The data suggest that the activity of UGT enzymes was significantly lower when compared to their activity in microsomes at the same absolute protein amount (pmol). Collectively, results of this study demonstrate poor and variable specific activity of different rUGTs (per pmol protein), as determined by pnAF values, which should be considered in fgluc scaling.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1621-1630"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quality and Safety Considerations for Therapeutic Products Based on Extracellular Vesicles. 基于细胞外囊泡的治疗产品的质量和安全考虑因素。

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-08-07 DOI: 10.1007/s11095-024-03757-4

Yoshinobu Takakura, Rikinari Hanayama, Kazunari Akiyoshi, Shiroh Futaki, Kyoko Hida, Takanori Ichiki, Akiko Ishii-Watabe, Masahiko Kuroda, Kazushige Maki, Yasuo Miura, Yoshiaki Okada, Naohiro Seo, Toshihide Takeuchi, Teruhide Yamaguchi, Yusuke Yoshioka

{"title":"Quality and Safety Considerations for Therapeutic Products Based on Extracellular Vesicles.","authors":"Yoshinobu Takakura, Rikinari Hanayama, Kazunari Akiyoshi, Shiroh Futaki, Kyoko Hida, Takanori Ichiki, Akiko Ishii-Watabe, Masahiko Kuroda, Kazushige Maki, Yasuo Miura, Yoshiaki Okada, Naohiro Seo, Toshihide Takeuchi, Teruhide Yamaguchi, Yusuke Yoshioka","doi":"10.1007/s11095-024-03757-4","DOIUrl":"10.1007/s11095-024-03757-4","url":null,"abstract":"Extracellular vesicles (EVs) serve as an intrinsic system for delivering functional molecules within our body, playing significant roles in diverse physiological phenomena and diseases. Both native and engineered EVs are currently the subject of extensive research as promising therapeutics and drug delivery systems, primarily due to their remarkable attributes, such as targeting capabilities, biocompatibility, and low immunogenicity and mutagenicity. Nevertheless, their clinical application is still a long way off owing to multiple limitations. In this context, the Science Board of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has conducted a comprehensive assessment to identify the current issues related to the quality and safety of EV-based therapeutic products. Furthermore, we have presented several examples of the state-of-the-art methodologies employed in EV manufacturing, along with guidelines for critical processes, such as production, purification, characterization, quality evaluation and control, safety assessment, and clinical development and evaluation of EV-based therapeutics. These endeavors aim to facilitate the clinical application of EVs and pave the way for their transformative impact in healthcare.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1573-1594"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice. 丙泊酚对小鼠血脑屏障完整性的急性影响

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2024-08-01 Epub Date: 2024-07-24 DOI: 10.1007/s11095-024-03735-w

Ehsan Nozohouri, Yeseul Ahn, Sumaih Zoubi, Dhavalkumar Patel, Sabrina Rahman Archie, Khondker Ayesha Akter, Muhammad Bilal Siddique, Juyang Huang, Thomas J Abbruscato, Ulrich Bickel

{"title":"The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice.","authors":"Ehsan Nozohouri, Yeseul Ahn, Sumaih Zoubi, Dhavalkumar Patel, Sabrina Rahman Archie, Khondker Ayesha Akter, Muhammad Bilal Siddique, Juyang Huang, Thomas J Abbruscato, Ulrich Bickel","doi":"10.1007/s11095-024-03735-w","DOIUrl":"10.1007/s11095-024-03735-w","url":null,"abstract":"Purpose: We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABAA receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo.Methods: Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [13C12]sucrose as a permeability marker was injected as IV bolus 15 min after start of the infusions. Brain uptake clearance, Kin, of sucrose was calculated from the brain concentrations at 30 min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point.Results: The Kin value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7 µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma.Conclusions: Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1599-1611"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0