keyword
https://read.qxmd.com/read/38543226/advancing-precision-medicine-a-review-of-innovative-in-silico-approaches-for-drug-development-clinical-pharmacology-and-personalized-healthcare
#1
REVIEW
Lara Marques, Bárbara Costa, Mariana Pereira, Abigail Silva, Joana Santos, Leonor Saldanha, Isabel Silva, Paulo Magalhães, Stephan Schmidt, Nuno Vale
The landscape of medical treatments is undergoing a transformative shift. Precision medicine has ushered in a revolutionary era in healthcare by individualizing diagnostics and treatments according to each patient's uniquely evolving health status. This groundbreaking method of tailoring disease prevention and treatment considers individual variations in genes, environments, and lifestyles. The goal of precision medicine is to target the "five rights": the right patient, the right drug, the right time, the right dose, and the right route...
February 27, 2024: Pharmaceutics
https://read.qxmd.com/read/38540783/in-silico-investigation-of-parkin-activating-mutations-using-simulations-and-network-modeling
#2
JOURNAL ARTICLE
Naeyma N Islam, Caleb A Weber, Matt Coban, Liam T Cocker, Fabienne C Fiesel, Wolfdieter Springer, Thomas R Caulfield
Complete loss-of-function mutations in the PRKN gene are a major cause of early-onset Parkinson's disease (PD). PRKN encodes the Parkin protein, an E3 ubiquitin ligase that works in conjunction with the ubiquitin kinase PINK1 in a distinct quality control pathway to tag damaged mitochondria for autophagic clearance, i.e., mitophagy. According to previous structural investigations, Parkin protein is typically kept in an inactive conformation via several intramolecular, auto-inhibitory interactions. Here, we performed molecular dynamics simulations (MDS) to provide insights into conformational changes occurring during the de-repression of Parkin and the gain of catalytic activity...
March 19, 2024: Biomolecules
https://read.qxmd.com/read/38537440/tanshinone-iia-induces-er-stress-and-jnk-activation-to-inhibit-tumor-growth-and-enhance-anti-pd-1-immunotherapy-in-non-small-cell-lung-cancer
#3
JOURNAL ARTICLE
Yi-Zhong Zhang, Huan-Ling Lai, Chen Huang, Ze-Bo Jiang, Hao-Xin Yan, Xuan-Run Wang, Chun Xie, Ju-Min Huang, Wen-Kang Ren, Jia-Xin Li, Zhi-Ran Zhai, Xiao-Jun Yao, Qi-Biao Wu, Elaine Lai-Han Leung
BACKGROUND: Non-small cell lung cancer (NSCLC) remains at the forefront of new cancer cases, and there is an urgent need to find new treatments or improve the efficacy of existing therapies. In addition to the application in the field of cerebrovascular diseases, recent studies have revealed that tanshinone IIA (Tan IIA) has anticancer activity in a variety of cancers. PURPOSE: To investigate the potential anticancer mechanism of Tan IIA and its impact on immunotherapy in NSCLC...
February 7, 2024: Phytomedicine
https://read.qxmd.com/read/38532525/quantitative-evaluation-of-trastuzumab-deruxtecan-pharmacokinetics-and-pharmacodynamics-in-mouse-models-of-varying-degrees-of-her2-expression
#4
JOURNAL ARTICLE
Christina Vasalou, Theresa A Proia, Laura Kazlauskas, Anna Przybyla, Matthew Sung, Srinivas Mamidi, Kim Maratea, Matthew Griffin, Rebecca Sargeant, Jelena Urosevic, Anton I Rosenbaum, Jiaqi Yuan, Krishna C Aluri, Diane Ramsden, Niresh Hariparsad, Rhys D O Jones, Jerome T Mettetal
Trastuzumab deruxtecan (T-DXd; DS-8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)-directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T-DXd was administered in tumor-bearing mice carrying NCI-N87, Capan-1, JIMT-1, and MDA-MB-468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T-DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response...
March 26, 2024: CPT: Pharmacometrics & Systems Pharmacology
https://read.qxmd.com/read/38529623/clinical-pharmacokinetics-and-pharmacodynamics-of-oral-systemic-nonbiologic-therapies-for-psoriasis-patients
#5
REVIEW
Justin M Eichinger, Divya M Shan, Jonathan D Greenzaid, Lisa Anakwenze, Steven R Feldman
INTRODUCTION: Psoriasis is a chronic inflammatory immune condition. Treatments for psoriasis vary with disease severity, ranging from topicals to systemic biologic agents. The pharmacokinetic (PK) and pharmacodynamic (PD) properties of these therapies establish drug efficacy, toxicity, and optimal dosing to ensure therapeutic drug levels are sustained and adverse effects are minimized. AREAS COVERED: A literature search was performed on PubMed, Google Scholar, and Ovid MEDLINE for PK and PD, efficacy, and safety data regarding oral systemic nonbiologic therapies utilized for moderate-to-severe plaque psoriasis...
March 26, 2024: Expert Opinion on Drug Metabolism & Toxicology
https://read.qxmd.com/read/38529546/metformin-suppresses-both-pd-l1-expression-in-cancer-cells-and-cancer-induced-pd-1-expression-in-immune-cells-to-promote-antitumor-immunity
#6
JOURNAL ARTICLE
Su Hwan Park, Juheon Lee, Hye Jin Yun, Seok-Ho Kim, Jong-Ho Lee
BACKGROUND: Metformin, a drug prescribed for patients with type 2 diabetes, has potential efficacy in enhancing antitumor immunity; however, the detailed underlying mechanisms remain to be elucidated. Therefore, we aimed to identify the inhibitory molecular mechanisms of metformin on programmed death ligand 1 (PD-L1) expression in cancer cells and programmed death 1 (PD-1) expression in immune cells. METHODS: We employed a luciferase reporter assay, quantitative real-time PCR, immunoblotting analysis, immunoprecipitation and ubiquitylation assays, and a natural killer (NK) cell-mediated tumor cell cytotoxicity assay...
March 26, 2024: Annals of Laboratory Medicine
https://read.qxmd.com/read/38529396/safety-tolerability-pharmacokinetics-and-pharmacokinetic-pharmacodynamic-modeling-of-cetagliptin-in-patients-with-type-2-diabetes-mellitus
#7
JOURNAL ARTICLE
Chen Zhou, Sufeng Zhou, Jie Wang, Lijun Xie, Zhanhui Lv, Yuqing Zhao, Lu Wang, Huan Luo, Daosheng Xie, Feng Shao
AIMS: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients. MATERIALS AND METHODS: 32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days...
2024: Frontiers in Endocrinology
https://read.qxmd.com/read/38529184/establishment-of-a-pharmacokinetics-and-pharmacodynamics-model-of-schisandra-lignans-against-hippocampal-neurotransmitters-in-ad-rats-based-on-microdi-alysis-liquid-chromatography-mass-spectrometry
#8
JOURNAL ARTICLE
Jinpeng Zhang, Xinyuan Cui, Shuo Zhao, Zenghui Chang, Junshuo Zhang, Yufeng Chen, Jiale Liu, Guohao Sun, Yiyuan Wang, Yuanyuan Liu
Objective: Our previous studies substantiated that the biological activity of Schisandra chinensis lignans during the treatment of Alzheimer's disease (AD) was mediated by neurotransmitter levels, and 15 of its active components were identified. However, the pharmacokinetic and pharmacodynamic relationship of Schisandra chinensis lignans has been less studied. The objective of this study was to investigate the relationship between the pharmacokinetics and pharmacodynamics of Schisandra chinensis lignans in the treatment of AD, and to establish a pharmacokinetic-pharmacodynamic (PK-PD) model...
2024: Frontiers in Pharmacology
https://read.qxmd.com/read/38528813/population-pharmacokinetic-pharmacodynamic-modeling-of-serum-biomarkers-as-predictors-of-tumor-dynamics-following-lenvatinib-treatment-in-patients-with-radioiodine-refractory-differentiated-thyroid-cancer-rr-dtc
#9
JOURNAL ARTICLE
Oneeb Majid, Seiichi Hayato, Sree Harsha Sreerama Reddy, Bojan Lalovic, Taro Hihara, Taisuke Hoshi, Yasuhiro Funahashi, Jagadeesh Aluri, Osamu Takenaka, Sanae Yasuda, Ziad Hussein
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor-α (PDGFRα), KIT, and RET that have been implicated in pathogenic angiogenesis, tumor growth, and cancer. The primary objective of this work was to evaluate, by establishing quantitative relationships, whether lenvatinib exposure and longitudinal serum biomarker data (VEGF, Ang-2, Tie-2, and FGF-23) are predictors for change in longitudinal tumor size which was assessed based on data from 558 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving either lenvatinib or placebo treatment...
March 26, 2024: CPT: Pharmacometrics & Systems Pharmacology
https://read.qxmd.com/read/38527692/hexavalent-chromium-exposure-activates-the-non-canonical-nuclear-factor-kappa-b-pathway-to-promote-immune-checkpoint-protein-programmed-death-ligand-1-expression-and-lung-carcinogenesis
#10
JOURNAL ARTICLE
Po-Shun Wang, Zulong Liu, Osama Sweef, Abdullah Farhan Saeed, Thomas Kluz, Max Costa, Kenneth R Shroyer, Kazuya Kondo, Zhishan Wang, Chengfeng Yang
Lung cancer is the leading cause of cancer-related death worldwide; however, the mechanism of lung carcinogenesis has not been clearly defined. Chronic exposure to hexavalent chromium [Cr(VI)], a common environmental and occupational pollutant, causes lung cancer, representing an important lung cancer etiology factor. The mechanism of how chronic Cr(VI) exposure causes lung cancer remains largely unknown. By using cell culture and mouse models and bioinformatics analyses of human lung cancer gene expression profiles, this study investigated the mechanism of Cr(VI)-induced lung carcinogenesis...
March 23, 2024: Cancer Letters
https://read.qxmd.com/read/38526820/an-integrated-strategy-to-evaluate-active-substances-of-astragali-radix-carthami-flos-combination-on-the-treatment-of-cerebral-ischemia-reperfusion-injury-based-on-tqsm-polypharmacokinetics-and-pharmacodynamics
#11
JOURNAL ARTICLE
Qiang Zeng, Chang Li, Shouchao Xu, Yu He
As a classic herb pair, Astragali Radix-Carthami Flos (AR-CF) has revealed good biological activity in the treatment of cerebral ischemia/reperfusion injury (CI/RI), which remained to be further clarified together with the underlying efficacy related compounds for material basis. In this study, the nine formulations were obtained by L9 (34) orthogonal array design of four active fractions (saponin and flavonoid extracted from AR, safflower yellow and safflower red extracted from CF). The concentrations of eleven components and the levels of four biochemical indicators in rat plasma were continuously detected after intragastric administration of nine formulations, respectively...
December 15, 2023: Journal of Food and Drug Analysis
https://read.qxmd.com/read/38526587/an-auxiliary-strategy-of-partial-least-squares-regression-in-pharmacokinetic-pharmacodynamic-studies-a-case-of-application-of-guhong-injection-in-myocardial-ischemia-reperfusion-rats
#12
JOURNAL ARTICLE
Hai-Yang Chen, Chang Li, Chong-Yu Shao, Yu-Jia Wu, Hai-Tong Wan, Yu He
Guhong injection (GHI) has been applied in the therapy of cardio-cerebrovascular disease in clinic, but there is no report about the pharmacokinetic/pharmacodynamic (PK/PD) research on GHI treating myocardial ischemia/reperfusion (MI/R) injury in rats. In this study, eight compounds of GHI in plasma, including N-acetyl-L-glutamine (NAG), chlorogenic acid (CGA), hydroxysafflor yellow A (HSYA), p-coumaric acid ( pCA), rutin, hyperoside, kaempferol-3-O-rutinoside, and kaempferol-3-O-glucoside, were quantified by LC-MS/MS...
March 15, 2024: Journal of Food and Drug Analysis
https://read.qxmd.com/read/38526051/updated-antimicrobial-dosing-recommendations-for-obese-patients
#13
REVIEW
Ana Castro-Balado, Iria Varela-Rey, Beatriz Mejuto, Cristina Mondelo-García, Irene Zarra-Ferro, Teresa Rodríguez-Jato, Anxo Fernández-Ferreiro
The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and pharmacodynamic (PD) alterations that can condition the correct exposure to antimicrobials if standard dosages are used. Inadequate dosing in obese patients can lead to toxicity or therapeutic failure. In recent years, additional antimicrobial PK/PD data, extended infusion strategies, and studies in critically ill patients have made it possible to obtain data to provide a better dosage in obese patients...
March 25, 2024: Antimicrobial Agents and Chemotherapy
https://read.qxmd.com/read/38524135/biomarkers-and-computational-models-for-predicting-efficacy-to-tumor-ici-immunotherapy
#14
REVIEW
Yurong Qin, Miaozhe Huo, Xingwu Liu, Shuai Cheng Li
Numerous studies have shown that immune checkpoint inhibitor (ICI) immunotherapy has great potential as a cancer treatment, leading to significant clinical improvements in numerous cases. However, it benefits a minority of patients, underscoring the importance of discovering reliable biomarkers that can be used to screen for potential beneficiaries and ultimately reduce the risk of overtreatment. Our comprehensive review focuses on the latest advancements in predictive biomarkers for ICI therapy, particularly emphasizing those that enhance the efficacy of programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors immunotherapies...
2024: Frontiers in Immunology
https://read.qxmd.com/read/38522579/cystatin-c-outperforms-creatinine-in-predicting-cefepime-clearance-in-pediatric-stem-cell-transplant-recipients
#15
JOURNAL ARTICLE
H Rhodes Hambrick, Lin Fei, Kathryn Pavia, Jennifer Kaplan, Tomoyuki Mizuno, Peter Tang, Erin Schuler, Stefanie Benoit, Sonya Tang Girdwood
BACKGROUND: Pediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage post-HSCT and requires dose adjustment based on kidney function. Since cefepime's anti-microbial efficacy is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC), it is important to assess kidney function accurately to ensure adequate concentrations. Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker...
March 22, 2024: Transplantation and cellular therapy
https://read.qxmd.com/read/38521069/nanodrug-bacteria-conjugates-mediated-oncogenic-collagen-depletion-enhances-immune-checkpoint-blockade-therapy-against-pancreatic-cancer
#16
JOURNAL ARTICLE
Zhaoting Li, Fanyi Mo, Kai Guo, Shuai Ren, Yixin Wang, Yu Chen, Patrick B Schwartz, Nathaniel Richmond, Fengyuan Liu, Sean M Ronnekleiv-Kelly, Quanyin Hu
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3β1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS: Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma...
March 21, 2024: Med
https://read.qxmd.com/read/38520701/pharmacokinetic-behaviour-and-pharmacokinetic-pharmacodynamic-integration-of-doxycycline-in-rainbow-trout-oncorhynchus-mykiss-after-intravascular-intramuscular-and-oral-administrations
#17
JOURNAL ARTICLE
Feray Altan, Orhan Corum, Duygu Durna Corum, Kamil Uney, Ertugrul Terzi, Soner Bilen, Adem Yavuz Sonmez, Muammer Elmas
OBJECTIVE: Doxycycline (DO) has been used in fish for a long time, but there are some factors that have not yet been clarified regarding its pharmacokinetic (PK) and pharmacodynamic (PD) properties. Therefore, the aim of this study was to investigate the PK and PK/PD targets of DO after 20 mg/kg intravascular (IV), intramuscular (IM) and oral (OR) gavage administration in rainbow trout (Oncorhynchus mykiss). METHODS: Plasma samples were collected at specific time points and subsequently analysed by HPLC-ultraviolet...
May 2024: Veterinary Medicine and Science
https://read.qxmd.com/read/38520083/pharmacokinetic-characteristics-of-florfenicol-in-green-sea-turtles-chelonia-mydas-and-hawksbill-sea-turtles-eretmochelys-imbricata-after-intramuscular-administration
#18
JOURNAL ARTICLE
Pandaree Sitthiangkool, Amnart Poapolathep, Thanaphan Chomcheun, Oranee Jongkolpath, Kraisiri Khidkhan, Narumol Klangkaew, Napasorn Phaochoosak, Mario Giorgi, Saranya Poapolathep
The pharmacokinetics of florfenicol (FFC) in green sea and hawksbill sea turtles were evaluated following intramuscular (i.m.) administration at two different dosages of 20 or 30 mg/kg body weight (b.w.). This study (longitudinal design) used 5 green sea and 5 hawksbill sea turtles for the two dosages. Blood samples were collected at assigned times up to 168 h. FFC plasma samples were analyzed using validated high-performance liquid chromatography equipped with diode array detection. The pharmacokinetic analysis was performed using a non-compartment approach...
March 22, 2024: Journal of Veterinary Pharmacology and Therapeutics
https://read.qxmd.com/read/38520004/cdkl1-potentiates-the-antitumor-efficacy-of-radioimmunotherapy-by-binding-to-transcription-factor-ybx1-and-blocking-pd-l1-expression-in-lung-cancer
#19
JOURNAL ARTICLE
Zixuan Li, Huichan Xue, Jinsong Li, Zhikun Zheng, Zhiwei Liu, Xiaorong Dong, Hongbo Wang, Jing Chen, Shuangbing Xu
BACKGROUND: The evasion of the immune response by tumor cells through programmed death-ligand 1 (PD-L1) has been identified as a factor contributing to resistance to radioimmunotherapy in lung cancer patients. However, the precise molecular mechanisms underlying the regulation of PD-L1 remain incompletely understood. This study aimed to investigate the role of cyclin-dependent kinase-like 1 (CDKL1) in the modulation of PD-L1 expression and the response to radioimmunotherapy in lung cancer...
March 22, 2024: Journal of Experimental & Clinical Cancer Research: CR
https://read.qxmd.com/read/38519814/evaluation-of-pharmacokinetic-and-pharmacodynamic-pk-pd-of-novel-fluorenylmethoxycarbonyl-phenylalanine-antimicrobial-agent
#20
JOURNAL ARTICLE
Avinash Y Gahane, Devesh Pratap Verma, Swagata Sarkar, Ashwani K Thakur
OBJECTIVE: To assess the pharmacokinetic profile, in-vivo toxicity, and efficacy of 9-Fluorenylmethoxycarbonyl-L-phenylalanine (Fmoc-F) as a potential antibacterial agent, with a focus on its suitability for clinical translation. METHODS: An RP-HPLC-based bio-analytical method was developed and qualified to quantify Fmoc-F levels in mouse plasma for pharmacokinetic analysis. Oral bioavailability was determined, and in-vivo toxicity was evaluated following intra-peritoneal administration...
March 22, 2024: Pharmaceutical Research
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