Understanding the pharmacokinetic/pharmacodynamic (PK/PD)-relationship of a drug candidate is key to determine effective, yet safe treatment regimens for patients. However, current testing strategies are inefficient in characterizing responses to fluctuating drug concentrations during multi-day treatment cycles. Methods based on animal models are resource-intensive and require time, while traditional cell-culturing methods usually do not provide temporally-resolved information on the effects of -like drug exposure scenarios. To address this issue, we developed a microfluidic system to 1) culture arrays of three-dimensional spheroids to 2) apply specific dynamic drug exposure profiles, and to 3) analyze spheroid growth and the invoked drug effects in 3D by means of 2-photon microscopy at tissue and single-cell level. Spheroids of fluorescently-labeled T-47D breast cancer cells were monitored under perfusion-culture conditions at short time intervals over three days and exposed to either three 24 h-PK-cycles or a dose-matched constant concentration of the phosphatidylinositol 3-kinase inhibitor BYL719. While the overall efficacy of the two treatment regimens was similar, spheroids exposed to the PK profile displayed cycle-dependent oscillations between regression and regrowth. Spheroids treated with a constant BYL719 concentration regressed at a steady, albeit slower rate. At a single-cell level, the cell density in BYL719-treated spheroids oscillated in a concentration-dependent manner. Our system represents a versatile tool for in-depth preclinical characterization of PK/PD parameters, as it enables an evaluation of drug efficacy and/or toxicity under realistic exposure conditions.
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http://dx.doi.org/10.3389/fphar.2021.785851 | DOI Listing |
JAMA Health Forum
January 2025
Department of Population Health Sciences, Weill Cornell Medical College, New York, New York.
Importance: The prevalence of pharmacies owned by integrated insurers and pharmacy benefit managers (PBMs), or insurer-PBMs, is of growing regulatory concern. However, little is known about the role of these pharmacies in Medicare, in which pharmacy network protections may influence market dynamics.
Objective: To evaluate the prevalence of insurer-PBM-owned pharmacies and the extent to which insurer-PBMs steer patients to pharmacies they own in Medicare.
JAMA Health Forum
January 2025
Department of Health Systems, Management, and Policy, University of Colorado Cancer Center, Aurora.
Importance: Medicare Advantage (MA) plans are designed to incentivize the use of less expensive drugs through capitated payments, formulary control, and preauthorizations for certain drugs. These conditions may reduce spending on high-cost therapies for conditions such as cancer, a condition that is among the most expensive to treat.
Objective: To determine whether patients insured by MA plans receive less high-cost drugs than those insured by traditional Medicare (TM).
Invest Ophthalmol Vis Sci
January 2025
Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, United States.
Purpose: Sulfur mustard gas (SM) exposure to eyes causes multiple corneal injuries including stromal cell loss in vivo. However, mechanisms mediating stromal cell loss/death remains elusive. This study sought to test the novel hypothesis that SM-induced toxicity to human corneal stromal fibroblasts involves ferroptosis mechanism via p38 MAPK signaling.
View Article and Find Full Text PDFVet Med Sci
January 2025
Department of Medical Biology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey.
Background: Chemotherapy drugs may lead to hepatic injury, which is considered one of the limitations of these drugs.
Objectives: The aim of this study was to evaluate the effect of quercetin (QUE) on M1/M2 macrophage polarization and hepatoprotective effect in cyclophosphamide (CTX)-induced liver toxicity.
Methods: Twenty-four mice were divided into four groups (Control, QUE, CTX, CTX + QUE).
Cancer Med
January 2025
Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong SAR, China.
Purpose: Recent research (Li et al. 2021) suggests an upregulated expression and activation of H1 receptors on macrophages in the tumor microenvironment, and concomitant H1-antihistamine use is associated with improved overall survival in patients with lung and skin cancers receiving immunotherapy. Therefore, we retrospectively evaluated the impacts of H1-antihistamine use in cancer patients during immunotherapy.
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