Drug Design, Development and Therapy最新文献

{"title":"Feasibility of Closed-Loop TCI Based on New EEG Baseline in the Presence of Low Dose of Esketamine: A Randomized Controlled Equivalence Trial.","authors":"Xiaoshan Li, Shengchao Li, Chanyan Xu, Huan He, Weidong Shao, Shuteng Zhan, Bo Xu","doi":"10.2147/DDDT.S508264","DOIUrl":"10.2147/DDDT.S508264","url":null,"abstract":"<p><strong>Objective: </strong>This research aimed to quantify the impact of low dose of esketamine on BIS and validate the feasibility of closed-loop TCI system based on the new BIS baseline with low dose of esketamine.</p><p><strong>Methods: </strong>This study consisted of two phases. The first phase was to quantify the impact of a low dose of esketamine (0.2mg kg^-1 bolus, 5μg kg^-1 min^-1 infusion for 30min) on BIS and establish a new BIS baseline for propofol-remifentanil general anesthesia. The second phase was used to validate the feasibility of closed-loop TCI system based on the new BIS baseline. One hundred and eleven patients were randomly and equally assigned to three groups (group A: adjusted group, group N: non-adjusted group and group C: control group). After administering a low dose of esketamine, group A adjusted drug dosage based on new BIS baseline, while group N based on the original BIS baseline of 50, group C adjusted drug doses based on the original baseline of 50 without esketamine. Main outcome was controller performance (% time within±10units of the BIS setpoint). Secondary outcomes were drug consumption, occurrence of adverse events such as intraoperative awareness, treatment of hemodynamic changes and postoperative recovery quality.</p><p><strong>Results: </strong>In the first phase, after administering a low dose of esketamine, the BIS increased from 49.9±4.5 to 59.6±6.0, <i>p</i><0.01. In the second phase, the controller performance in group A and N were within the range of high-performance systems, and both were equivalent with control group. Group A showed lower consumption of propofol compared to control group (5.58±1.12 vs 6.69±1.36 (mg·kg^-1·h^-1), <i>p</i><0.05). There was no difference in adverse events such as intraoperative awareness, recovery assessment and postoperative VAS, PONV and shivering, QoR-15 assessment after adjusting the BIS baseline.</p><p><strong>Conclusion: </strong>It is feasible to operate the closed-loop TCI system based on the adjusted BIS baseline in the presence of low dose of esketamine.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3237-3252"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995645","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":"Optimal Effect-Site Concentration of Propofol for Hemodynamic Stability During Intubation with Dexmedetomidine: A Randomized Controlled Study.","authors":"Huayuan Gao, Junmei Wu, Youwen Chen, Chengyu Wang, Minmin Yao, Yan Yang, Changhong Miao, Chao Liang","doi":"10.2147/DDDT.S508736","DOIUrl":"https://doi.org/10.2147/DDDT.S508736","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to determine the 95% effective concentration (EC₉₅) of propofol via target-controlled infusion (TCI) for endotracheal intubation at three different doses of dexmedetomidine.</p><p><strong>Methods: </strong>One hundred and eighty patients aged 18-60 and classified as American Society of Anesthesiologists (ASA) class I-II were enrolled to undergo general anesthesia. Patients were randomly assigned to one of the three groups (A, B, or C), receiving three different doses of dexmedetomidine (0.6, 0.8, or 1 μg/kg) infused over 10 min. Anesthesia was then induced with propofol TCI, followed by rocuronium. The biased coin design method was used to calculate the EC₉₅ of propofol for successful intubation. The primary outcome endpoint was the EC₉₅ of propofol for successful endotracheal intubation at each dexmedetomidine dose.</p><p><strong>Results: </strong>Sixty patients in each group completed the trial. The time from propofol administration to intubation in group C (132.5 ± 10.7 s) was significantly shorter compared to group A (140.2 ± 14.4 s, <i>P</i><0.0001) and group B (142.6 ± 13.2 s, <i>P</i>=0.0037). Both the EC₉₅ and the average total dose of propofol in group B [14.6 (10.8, 14.8) μg/mL and 3.6 ± 1.1 mg/kg] and C [12.7 (11.5, 12.8) μg/mL and 2.8 ± 1.0 mg/kg] were lower than those in group A [14.9 (4.5, 15.0) μg/mL and 3.8 ± 0.9 mg/kg] (<i>P</i><0.001). The incidence of hypotension and bradycardia during induction was low in each group.</p><p><strong>Conclusion: </strong>The EC₉₅ of propofol for endotracheal intubation across three different background doses of dexmedetomidine was determined. We suggest administering 1.0 μg/kg dexmedetomidine and then the EC₉₅ of propofol for successful endotracheal intubation was 12.7 μg/mL.</p><p><strong>Registration: </strong>Chinese Clinical Trial Registry; Registration number: ChiCTR2400089952, URL:https://www.chictr.org.cn/showproj.html?proj=221236.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3129-3138"},"PeriodicalIF":4.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990350","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":"The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Subcutaneous Administration of a Novel Anti-NGF Monoclonal Antibody (AK115) in Healthy Participants: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase I Clinical Trial.","authors":"Juan Zhang, Yu-Xin Fan, Yu Huang, Runfang Guan, Ruixia Li, Shuxian Long, Mei Yang, Binge Yu, Guo Qin Wang, Peng Chen, Xia Gong, Baiyong Li, Michelle Xia, Jianchang He","doi":"10.2147/DDDT.S500902","DOIUrl":"10.2147/DDDT.S500902","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of a novel anti-nerve growth factor (NGF) monoclonal antibody (mAb) (AK115) in healthy Chinese participants.</p><p><strong>Methods: </strong>A randomized, double-blind, placebo-controlled, dose-escalation phase I clinical study was conducted as follows: eligible participants were divided into 6 dose groups, among which 0.5 mg group was administrated with AK115 injection and the remaining 5 groups were randomly assigned to AK115 injection or accompanying placebo at a ratio of 3:1. Adverse events (AEs), PKs, PDs, and anti-drug antibodies (ADAs)/neutralizing antibody were monitored throughout the study.</p><p><strong>Results: </strong>A total of 42 participants completed the study. Twenty-seven (64.3%) participants occurred treatment emergent AEs (TEAEs), and 2 (4.80%) participants experienced treatment-related TEAEs. The TEAEs among the different dose groups were comparable. No significant differences were observed between the combined AK115 and the placebo group. It was demonstrated that the median T_max was 4.50-14.0 days, the mean C_max and AUC_0-t of different doses groups were 30.8-5500 ng/mL and 792~181010 Day*ng/mL, respectively. The elimination half-life (t_1/2) did not differ among the different dose groups and was calculated to be 7.60-17.7 days. In addition, the total NGF concentration and percentage change from baseline increased with an increase in the AK115 dose. No ADA positivity was detected in the healthy participants.</p><p><strong>Conclusion: </strong>The favorable safety and tolerability of AK115 in healthy Chinese participants, as well as the predictable PK and PD profiles, will provide sufficient support for future dose exploration studies of AK115 in patients with analgesia.</p><p><strong>Trial registration: </strong>This study was registered in the Chinese Clinical Trial Registry (CTR20220431) and the official website of the US Department of Health and Human Services, National Institutes of Health, with Clinical Trials. gov (NCT05286970) on March 2022.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3225-3235"},"PeriodicalIF":4.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964275","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":"Model-Informed Precision Dosing of Levamlodipine Besylate in Smoking Patients.","authors":"Guoxing Li, Ying Guan, YingYing Yang, Qiulin Xiang, Song Chen, Jiaqi Shao, Yue Chen, Xian Yu","doi":"10.2147/DDDT.S501762","DOIUrl":"https://doi.org/10.2147/DDDT.S501762","url":null,"abstract":"<p><strong>Object: </strong>To quantitatively investigate the influence of various factors, including nicotine, demographics, biochemical index, and genetic polymorphisms of PAHs and drug metabolising enzymes, on the steady-state trough concentrations of levamlodipine besylate and its therapeutic effects in smokers. Using models to promote rational and accurate medication dosing in smoking patients when administered as initial monotherapy.</p><p><strong>Methods: </strong>A prospective study (NCT05126381) enrolled 43 patients receiving levamlodipine monotherapy. Pop PK/PD model of levamlodipine besylate was established to investigate the effects of nicotine concentration, demographics (age, sex, height, weight, BMI), biochemical index (ALT, AST, ALB, UA, eGFR), and the genetic polymorphisms (rs4646903, rs1048943, rs762551, rs12459249, rs776746, rs2740574) on the patients' steady state trough concentrations and the antihypertensive efficacy (ΔSBP) of levamlodipine besylate after dosing.</p><p><strong>Results: </strong>The Pop PK/PD model was conducted using the study data of 43 patients. One-compartment model was used to describe the PK characteristics, and the direct effect model was used to describe the antihypertensive effect of levamlodipine besylate. The final Pop PK/PD model showed that the typical value of V = 3521L, CL = 62.6L·h^-1, E₀ = 168mmHg, I_max = 31mmHg, IC₅₀ = 1.71ng·mL^-1; eGFR and UA were found in the model had significant effect on the CL of levamlodipine besylate.</p><p><strong>Conclusion: </strong>Patients with lower eGFR and UA levels exhibited lower CL levels, higher dosages may be considered for initial monotherapy in such patients. The current study tentatively do not show that nicotine concentration and PAHs metabolizing enzymes have significant effect on PK and PD in patients taking the drug. More data may be needed in the future to refine the effects of the above covariates on the PK and PD parameters of the levamlodipine besylate.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3193-3207"},"PeriodicalIF":4.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978487","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":"Study of the Chemical Composition and Anti-Inflammatory Mechanism of Shiyiwei Golden Pill Based on UPLC-Q-TOF/MS and Network Pharmacology.","authors":"Cong Han, Jing Chen, Chuanlin Shen, Qiuxia Liang, Ying An, Chaoyi Zhou, Kechun Liu, Qing Xia, Qiuxia He, Huazheng Zhang","doi":"10.2147/DDDT.S505880","DOIUrl":"https://doi.org/10.2147/DDDT.S505880","url":null,"abstract":"<p><strong>Purpose: </strong>Shiyiwei Golden Pill (SYW) is a classic traditional prescription used to treat mKhris-pa according to the theory of Tibetan medicine. At present, SYW is widely used to treat cholecystitis in Tibetan areas. However, the chemical constituents and anti-inflammatory mechanisms are still largely undiscovered. This study aimed to investigate the chemical composition and anti-inflammatory effects of SYW, as well as its potential mechanisms.</p><p><strong>Methods: </strong>The components of SYW were identified using ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The anti-inflammatory effects of SYW were determined on zebrafish and RAW264.7 cell inflammation models. Additionally, we predicted the targets and pathways of SYW to confirm its anti-inflammatory effects using network pharmacology approaches. Finally, a quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression of genes associated with anti-inflammatory pathways.</p><p><strong>Results: </strong>We identified 94 compounds in SYW, mainly alkaloids, phenols, and flavonoids. SYW inhibited inflammatory cell proliferation and migration in the three zebrafish inflammation models. In the RAW264.7 cell model, SYW suppressed the levels of NO and pro-inflammatory cytokines. In addition, network pharmacology analysis revealed that ALB, IL6, TNF, AKT1, and EGFR were identified as the potential key targets of SYW. KEGG enrichment and qRT-PCR analysis showed that PI3K/Akt/FoxO signaling pathway was involved in the anti-inflammatory effects of SYW.</p><p><strong>Conclusion: </strong>Herein, we identified 94 chemical constituents of SYW and demonstrated that SYW exerts anti-inflammatory effects by regulating the PI3K/Akt/FoxO signaling pathway.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3159-3177"},"PeriodicalIF":4.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984675","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":"Study on the Protective Effect of Methyl Rosmarinate on Hypoxic Mice and Their Erythrocytes.","authors":"Qianwen Guo, Ziyue Yin, Rong Wang, Yuemei Sun, Anpeng Zhao, Wanteng Yao, Wenbin Li","doi":"10.2147/DDDT.S493866","DOIUrl":"https://doi.org/10.2147/DDDT.S493866","url":null,"abstract":"<p><strong>Objective: </strong>We have previously identified methyl rosmarinic (MR) acid as a 2.3-bisphosphoglycerate mutase (BPGM) activator. The present study aimed to verify the protective effect of MR on plateau field hypoxia mice and the mechanism of increased oxygen release capacity of erythrocytes in vivo.</p><p><strong>Methods: </strong>The anti-hypoxic effect of MR was investigated in a plateau field environment in Specific Pathogen Free -grade healthy BALB/c mice, male and female, and the effect of different doses of MR on the survival time of mice in confined space was investigated in an atmospheric pressure confinement hypoxia experiment, plasma inflammatory markers, oxidative stress indices of myocardial, brain, lung and liver tissues, as well as the histopathological damage and hypoxia in each experimental group were measured by HE staining and hypoxia probe method. Finally, the effects of MR administration to mice on the energy metabolic pathways and metabolites of erythrocytes in vivo were investigated.</p><p><strong>Results: </strong>After acute plateau entry in mice, the energy metabolic pathway of erythrocytes shifted to the glycolytic pathway as the duration of hypoxia increased. The administration of MR to hypoxic mice further activated Bisphosphoglycerate mutase (BPGM) and increased the levels of glyceraldehyde-3-phosphate and 2.3-bisphosphoglycerate (2,3-BPG), as well as further shifted glucose to the glycolytic pathway and further enhanced the activity of rate-limiting enzymes in the glycolytic pathway.</p><p><strong>Conclusions: </strong>MR activates BPGM in erythrocytes to produce more 2, 3-BPG from the glycolytic branch, thus exerting a protective effect against injury in hypoxic mice in the highland field.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3179-3192"},"PeriodicalIF":4.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997611","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":"Therapeutic Challenges of Diabetes Mellitus-Related Erectile Dysfunction and The Potential Therapeutic Role of Medicinal Plants: A Narrative Review.","authors":"Hao Wang, Hongyuan Chang, Di Sun, Anmin Wang, Bin Yan, Eric Chung","doi":"10.2147/DDDT.S515403","DOIUrl":"https://doi.org/10.2147/DDDT.S515403","url":null,"abstract":"<p><p>Erectile dysfunction (ED) is a common male sexual dysfunction and can be induced by diabetes mellitus (DM). Diabetes mellitus-induced erectile dysfunction (DMED) affects various aspects of the patient's quality of life, mental well-being, and relationship dynamics. Given the increasing incidence of DM worldwide, the incidence of DMED is expected to increase accordingly. There are more challenges to treat DMED compared to non-DMED. The efficacy of oral phosphodiesterase-5 inhibitors is often ineffective in DMED and there is a need to search for effective drugs. Medicinal plants such as Eucommia ulmoides Oliv. Leaf, Cordycep militaris have been used in treating DMED in some experiments. And some ingredients from the medicinal plants such as Icariside II, Panax notoginseng Saponins have also shown to be beneficial in improving erectile function in animal models of DMED. These medicinal plants and ingredients may act by regulating hormone levels, ameliorating oxidative damage, and promoting NO/cGMP. We summarize the challenges in treating DMED due to related complicated pathogenesis and limited therapeutic options, while particularly highlight the role of the medicinal plants and their ingredients in DMED.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3209-3223"},"PeriodicalIF":4.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971055","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":"Development and Validation of a Population Pharmacokinetics Model of Perampanel for Pediatric Epilepsy Patients for Optimized Dosing.","authors":"Lingyan Yu, Fengqian Mao, Shunan Chen, Jieqiong Liu, Jiayu Xiao, Meng Chen, Huan Luo, Zhenwei Yu, Haibin Dai","doi":"10.2147/DDDT.S499085","DOIUrl":"https://doi.org/10.2147/DDDT.S499085","url":null,"abstract":"<p><strong>Background: </strong>Perampanel exhibits substantial interindividual variability, and pharmacokinetic data in pediatric patients are scarce. The aim of this study was to develop a population pharmacokinetic (PPK) model to optimize the dosing of perampanel in children with epilepsy.</p><p><strong>Methods: </strong>The PPK model was developed via a nonlinear mixed-effects modeling approach, utilizing a dataset comprising 454 plasma concentrations of perampanel obtained from 151 pediatric patients with epilepsy, 120 (79.5%) of whom were aged < 12 years. Goodness-of-fit plots and bootstrap analysis were employed to evaluate the final model. Monte Carlo simulations were utilized to suggest perampanel dosing strategies using a reference plasma concentration range of 100-1000 ng/mL.</p><p><strong>Results: </strong>In the final PPK models of perampanel, linear centralized age, coadministration of oxcarbazepine (OXC), carbamazepine (CBZ), and valproic acid (VPA) were covariates of clearance (CL/F), and log-transformed body weight was a covariate of the apparent distribution volume (V). The CL/F was estimated via the formula CL/F=0.177*((age+10)/8.8)^1.31*1.51^OXC*0.745^VPA*1.88^CBZ. The relative standard errors (RSEs) for each fixed effect parameter were 15.2%, 14.2%, 12.0%, 7.92%, and 16.3%, respectively. The V was estimated via the formula V=227*LGBW with an RSE of 14.1%. The model demonstrated good robustness according to goodness-of-fit plots and bootstrap analysis. The simulation analysis resulted in a dosing regimen stratified by covariates.</p><p><strong>Conclusion: </strong>A reliable perampanel PPK model for pediatric patients was successfully developed. This result could be helpful for dosing optimization in pediatric patients receiving perampanel, especially those aged under 12 years.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3119-3128"},"PeriodicalIF":4.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981792","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":"Exploring the Therapeutic Mechanism of Jianpi Zhidong Decoction on Tourette Syndrome Based on Proteomics and Network Pharmacology.","authors":"Ning Zhang, Hongxian Zhang, Jianning Guo, Yaluan Ma, Xue Bai, Ning Ma, Xiaoxiao Ji, Yanli Meng, Huifang Li, Tananan Sangwanit, Yixin Shi, Jing Zhao, Xiang Li, Jingyuan Lin, Xia Cui","doi":"10.2147/DDDT.S505173","DOIUrl":"https://doi.org/10.2147/DDDT.S505173","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the pharmacological effects of Jianpi Zhidong Decoction (JPZDD) on Tourette Syndrome (TS) using proteomics and network pharmacology.</p><p><strong>Materials and methods: </strong>Chemical components of JPZDD were identified via UPLC-MS/MS. Chronic restraint stress TS model was established by intraperitoneal injection of iminodipropionitrile (IDPN) for 1 week with restraint stress for 3 weeks. Sixty male SD rats were divided into control, model, Tiapride (Tia), and JPZDD groups. After the intervention of 28 days, behavioral tests, Nissl staining, Western blot, immunofluorescence, colorimetry, and ELISA were performed to evaluate the pharmacological effects of JPZDD. Proteomics and network pharmacology predicted targets, validated by Western blot.</p><p><strong>Results: </strong>JPZDD alleviated stereotypic behaviors, hippocampal pathology, and modulated glucose metabolites (GLU, pyruvate, lactate, ATP). It downregulated GLUT1, GLUT3, HK2, and LDHA levels while upregulating PDHA level. Besides, JPZDD balanced M1/M2 microglial phenotypes, reducing IL-1β and IL-6 and increasing IL-4 and IL-10. UPLC-MS/MS identified 44 active ingredients and 123 targets; proteomics revealed 28 differentially expressed proteins. GO/KEGG analysis implicated that the PI3K/AKT/mTOR pathway may be the molecular target. JPZDD inhibited PI3K, AKT, and mTOR phosphorylation.</p><p><strong>Conclusion: </strong>JPZDD (16 g·kg⁻¹·d⁻¹) alleviates motor tics, modulates microglial activation and glucose metabolism, and downregulates the PI3K/AKT/mTOR pathway, providing a mechanistic basis for its therapeutic role in TS.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3139-3158"},"PeriodicalIF":4.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971070","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":"Recombinant Hydrophobic Polypeptide MBAY Loaded Into SPION-Exosome Realizes Sustained-Release to Improve Type 2 Diabetes Mellitus.","authors":"Xinyu Zong, Shangying Xiao, Haishan Xia, Dan Guo, Jiaping Wu, Manjiao Zhuang, Lei Rao","doi":"10.2147/DDDT.S499641","DOIUrl":"https://doi.org/10.2147/DDDT.S499641","url":null,"abstract":"<p><strong>Background: </strong>BAY55-9837, a potential therapeutic peptide for the treatment of type 2 diabetes mellitus (T2DM), can induce glucose (GLC)-dependent insulin secretion. Our previous study has demonstrated that the use of superparamagnetic iron oxide nanoparticle-decorated exosome (exosome-SPION) and external magnetic force (MF) enables BAY 55-9837 to target pancreatic islets. However, the initial burst release of BAY 55-9837 loaded within exosome-SPION shortens its in vivo half-life and consequently reduces the frequency of GLC responsiveness. Therefore, in our study, the transmembrane hydrophobic structure of the exosome signature protein CD81 was fused with BAY 55-9837 to obtain MBAY with sustained-release capability.</p><p><strong>Methods: </strong>MBAY was fabricated via genetic engineering, and the dissociation constant (Kd) was determined to assess its affinity for vasoactive intestinal peptide receptor type 2 (VPACII). Subsequently, MABY was incorporated into exosomes through electroporation to obtain MBAY-exosome, and SPOIN was adorned on MBAY-exosome by means of the self-assembly of transferrin (Tf) and the transferrin receptor (TfR). The in vitro release profile and in vivo pharmacokinetic profile of MBAY-Exosome-SPION were detected using high-performance liquid chromatography (HPLC). The L9(3⁴) orthogonal design approach was utilized to optimize the drug administration mode in vivo. The therapeutic effect of MBAY-exosome-SPIONs/MF on T2DM was assessed both in vitro and in vivo.</p><p><strong>Results: </strong>In vitro studies showed that the release rate of MBAY from exosome-SPION was slower compared with BAY 55-9837. Meanwhile, MBAY still maintained high affinity and selectivity for VPAC II and MBAY-exosome-SPIONs/MF could effectively promote insulin secretion in response to elevated GLC as BAY-exosome-SPIONs/MF. In vivo studies indicated that MBAY-exosome-SPIONs had a prolonged half-life and improved pharmacokinetic parameters compared to BAY-exosome-SPIONs, which further alleviated the symptoms of T2DM model mice.</p><p><strong>Conclusion: </strong>Thus, the reconstructed MBAY loaded in SPION-exosome realized sustained-release and exosomes-SPIONS achieved pancreatic targeting which led to ideal therapeutic effect in T2DM mice.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3103-3118"},"PeriodicalIF":4.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986574","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}