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Drug Metabolism and Disposition: the... Jun 2024Recently, we have proposed simple methodology to derive clearance and rate constant equations, independent of differential equations, based on Kirchhoff's Laws, a common...
Recently, we have proposed simple methodology to derive clearance and rate constant equations, independent of differential equations, based on Kirchhoff's Laws, a common methodology from physics used to describe rate-defining processes either in series or parallel. Our approach has been challenged in three recent publications, two published in this journal, but notably what is lacking is that none evaluate experimental pharmacokinetic data. As reviewed here, manuscripts from our laboratory have evaluated published experimental data, demonstrating that the Kirchhoff's Laws approach explains (1) why all of the experimental perfused liver clearance data appear to fit the equation that was previously believed to be the well-stirred model, (2) why linear pharmacokinetic systemic bioavailability determinations can be greater than 1, (3) why renal clearance can be a function of drug input processes, and (4) why statistically different bioavailability measures may be found for urinary excretion versus systemic concentration measurements. Our most recent paper demonstrates (5) how the universally accepted steady-state clearance approach utilized by the field for the past 50 years leads to unrealistic outcomes concerning the relationship between liver-to-blood and hepatic availability , highlighting the potential for errors in pharmacokinetic evaluations based on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, those that were previously adequately explained with present pharmacokinetic theory, and those that were not The publications that have attempted to rebut our position do not address unexplained experimental data, and we show here why their analyses are not valid. The Kirchhoff's Laws approach to deriving clearance equations for linear systems in parallel or in series, independent of differential equations, successfully describes published pharmacokinetic data that has previously been unexplained. Three recent publications claim to refute our proposed methodology; these publications only make theoretical arguments, do not evaluate experimental data; never demonstrate that the Kirchhoff methodology provides incorrect interpretations of experimental pharmacokinetic data, including statistically significant data not explained by present pharmacokinetic theory. We demonstrate why these analyses are invalid.
PubMed: 38942444
DOI: 10.1124/dmd.124.001735 -
Journal of Pharmaceutical Sciences Jun 2024This study aimed to investigate the impact of amorphous solubility and colloidal drug-rich droplets on drug absorption. The amorphous solubility of cilnidipine (CND) in...
This study aimed to investigate the impact of amorphous solubility and colloidal drug-rich droplets on drug absorption. The amorphous solubility of cilnidipine (CND) in AS-HF grade of hypromellose acetate succinate (HPMC-AS) solution was significantly reduced compared to that in non-polymer solution due to AS-HF partitioning into the CND-rich phase. In contrast, AS-LF grade of HPMC-AS has minimal effect on the amorphous solubility. The size of colloidal CND-rich droplets formed in the CND-supersaturated solution was less than 100 nm in the presence of AS-HF, while 200-450 nm in the presence of AS-LF. When the CND concentrations were near the amorphous solubility, CND membrane flux was reduced in the presence of AS-HF due to the decrease in the amorphous solubility of CND. However, the CND flux increased with the increase in CND-rich droplets, especially in the AS-HF solution. The size reduction of the CND-rich droplets led to their effective diffusion into the unstirred water layer, enhancing CND flux. In higher CND concentration regions, the CND flux became higher in the AS-HF solution than in the AS-LF solution. Thus, it is essential to elucidate the drug concentration-dependent impact of the colloidal drug-rich droplets on the drug absorption performance to optimize supersaturating formulations.
PubMed: 38942292
DOI: 10.1016/j.xphs.2024.06.017 -
Gene Jun 2024This study aimed to investigate placental microblood flow perfusion in fetal growth restriction (FGR) both pre- and post-delivery, and explore the influence of LINC00473...
This study aimed to investigate placental microblood flow perfusion in fetal growth restriction (FGR) both pre- and post-delivery, and explore the influence of LINC00473 and its downstream targets on FGR progression in trophoblast cells. Placental vascular distribution, placental vascular index (VI), CD34 expression, and histological changes were compared between control and FGR groups. FGR-related differentially expressed genes (DEGs) were analyzed and validated by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry (IHC) in placentae. In vitro experiments examined the regulatory relationships among LINC00473, miR-5189-5p, and StAR, followed by investigations into their impacts on cell proliferation and apoptosis. FGR placentae exhibited irregular shapes, uneven parenchymal echo, stromal dysplasia, ischemic infarction, and variable degrees of thickening in some cases. FGR samples showed less prominent mother vessel lakes, significantly lower VI, and decreased CD34 expression. Hematoxylin & eosin (H&E) staining revealed placental fibrosis, fibrin adhesion, infarction, and interstitial dysplasia in FGR. LINC00473, miR-5189-5p, and StAR were identified as DEG, with qPCR demonstrating a significant increase in LINC00473 and a decrease in miR-5189-5p in FGR, while both qPCR and IHC indicated a significant increase in StAR expression. LINC00473 served as an endogenous sponge against miR-5189-5p in human HTR-8/SV neo cells, and StAR expression was regulated by both LINC00473 and miR-5189-5p. Dysregulation of these genes affected cell proliferation and apoptosis. Pathological changes in the placenta are significant contributors to FGR, with placental microblood flow potentially serving as an indicator for monitoring its progression. LINC00473 and its downstream targets may modulate trophoblasts proliferation and apoptosis, thus influencing the onset of FGR, suggesting novel avenues for diagnosis and treatment.
PubMed: 38942180
DOI: 10.1016/j.gene.2024.148727 -
Biofabrication Jun 2024Human skin vasculature features a unique anatomy in close proximity to the skin appendages and acts as a gatekeeper for constitutive lymphocyte trafficking to the skin....
Human skin vasculature features a unique anatomy in close proximity to the skin appendages and acts as a gatekeeper for constitutive lymphocyte trafficking to the skin. Approximating such structural complexity and functionality in 3D skin models is an outstanding tissue engineering challenge. In this study, we leverage the capabilities of the digital-light-processing (DLP) bioprinting to generate an anatomically-relevant and miniaturized 3D skin-on-a-chip (3D-SoC) model in the size of a 6 mm punch biopsy. The 3D-SoC contains a perfusable vascular network resembling the superficial vascular plexus of the skin and closely surrounding bioengineered hair follicles. The perfusion capabilities of the 3D-SoC enables the circulation of immune cells, and high-resolution imaging of the immune cell-endothelial cell interactions, namely rolling, tethering and extravasation in real-time. Moreover, the vascular pattern in 3D-SoC captures the physiological range of shear rates found in cutaneous blood vessels and allows for studying the effect of shear rate on T cell trafficking. In 3D-SoC, as expected, in vitro-polarized T helper 1 (Th1) cells show a stronger attachment on the vasculature compared to naïve T cells. Both naïve and T cells exhibit higher retention in the low-shear zones in the early stages (< 5 min) of T cell attachment. Interestingly, at later stages T cell retention rate becomes independent of the shear rate. The attached Th1 cells further transmigrate from the vessel walls to the extracellular space and migrate toward the bioengineered hair follicles and interfollicular epidermis. When the epidermis is not present, Th1 cell migration toward the epidermis is significantly hindered, underscoring the role of epidermal signals on T cell infiltration. Our data validates the capabilities of 3D-SoC model to study the interactions between immune cells and skin vasculature in the context of epidermal signals. The biopsy-sized 3D-SoC model in this study represents a new level of anatomical and cellular complexity, and brings us a step closer to generating a truly functional human skin with its tissue-specific vasculature and appendages in the presence of circulating immune cells.
PubMed: 38941996
DOI: 10.1088/1758-5090/ad5d1a -
Phytomedicine : International Journal... Jun 2024Hypoxic pulmonary vascular remodeling (HPVR) is a key pathological feature of hypoxic pulmonary hypertension (HPH). Oxygen-sensitive potassium (K) channels in pulmonary...
BACKGROUND
Hypoxic pulmonary vascular remodeling (HPVR) is a key pathological feature of hypoxic pulmonary hypertension (HPH). Oxygen-sensitive potassium (K) channels in pulmonary artery smooth muscle cells (PASMCs) play a crucial role in HPVR. Luteolin (Lut) is a plant-derived flavonoid compound with variety of pharmacological actions. Our previous study found Lut alleviated HPVR in HPH rat.
PURPOSE
To elucidate the mechanism by which Lut mitigated HPVR, focusing on oxygen-sensitive voltage-dependent potassium channel 1.5 (Kv1.5).
METHODS
HPH rat model was established using hypobaric chamber to simulate 5000 m altitude. Isolated perfused/ventilated rat lung, isolated pulmonary arteriole ring was utilized to investigate the impact of Lut on K channels activity. Kv1.5 level in lung tissue and pulmonary arteriole of HPH rat was assessed. CyclinD1, CDK4, PCNA, Bax, Bcl-2, cleaved caspase-3 levels in lung tissue of HPH rat were tested. The effect of Lut on Kv1.5, cytoplasmic free calcium concentration ([Ca]), CyclinD1, CDK4, PCNA, Bax/Bcl-2 was examined in PASMCs under hypoxia, with DPO-1 as a Kv1.5 specific inhibitor. The binding affinity between Lut and Kv1.5 in PASMCs was detected by drug affinity responsive target stability (DARTS). The overexpression of KCNA5 gene (encoding Kv1.5) in HEK293T cells was utilized to confirm the interaction between Lut and Kv1.5. Furthermore, the impact of Lut on mitochondrial structure, SOD, GSH, GSH-Px, MDA and HIF-1α levels were evaluated in lung tissue of HPH rat and PASMCs under hypoxia.
RESULTS
Lut dilated pulmonary artery by directly activating Kv and Ca-activated K channels (K) in smooth muscle. Kv1.5 level in lung tissue and pulmonary arteriole of HPH rat was upregulated by Lut. Lut downregulated CyclinD1, CDK4, PCNA while upregulating Bax/Bcl-2/caspase-3 axis in lung tissue of HPH rat. Lut decreased [Ca], reduced CDK4, CyclinD1, PCNA, increased Bax/Bcl-2 ratio, in PASMCs under hypoxia, by upregulating Kv1.5. The binding affinity and the interaction between Lut and Kv1.5 was verified in PASMCs and in HEK293T cells. Lut also decreased [Ca] and inhibited proliferation via targeting Kv1.5 of HEK293T cells under hypoxia. Furthermore, Lut protected mitochondrial structure, increased SOD, GSH, GSH-Px, decreased MDA, in lung tissue of HPH rat. Lut downregulated HIF-1α level in both lung tissue of HPH rat and PASMCs under hypoxia.
CONCLUSION
Lut alleviated HPVR by promoting vasodilation of pulmonary artery, reducing cellular proliferation, and inducing apoptosis through upregulating of Kv1.5 in PASMCs.
PubMed: 38941817
DOI: 10.1016/j.phymed.2024.155840 -
Therapeutic Delivery Jun 2024The present study aimed to prepare and evaluate fexofenadine self-microemulsifying drug-delivery systems (SMEDDS) formulation and to determine and compare its...
The present study aimed to prepare and evaluate fexofenadine self-microemulsifying drug-delivery systems (SMEDDS) formulation and to determine and compare its intestinal permeability using single-pass intestinal perfusion (SPIP) technique. Fexofenadine-loaded SMEDDS were prepared and optimized. Droplet size, polydispersity index, zeta potential, drug release and intestinal permeability were evaluated. Optimized formulation consisted of 15% oil, 80% surfactant and 5% cosolvent. Droplet size and drug loading of optimized formulation was 13.77 nm and 60 mg/g and it has released 90% of its drug content. Intestinal permeability of fexofenadine was threefold enhanced in SMEDDS compared with free fexofenadine. The results of our study revealed that SMEDDS could be a promising tool for oral delivery of fexofenadine with enhanced dissolution rate and intestinal permeability.
PubMed: 38941109
DOI: 10.1080/20415990.2024.2363635 -
European Journal of Nuclear Medicine... Jun 2024Tumour perfusion is a nutrient-agnostic biomarker for cancer metabolic rate. Use of tumour perfusion for cancer growth assessment has been limited by complicated image...
PURPOSE
Tumour perfusion is a nutrient-agnostic biomarker for cancer metabolic rate. Use of tumour perfusion for cancer growth assessment has been limited by complicated image acquisition, image analysis and limited field-of-view scanners. Long axial field-of-view (LAFOV) PET scan using [O]HO, allows quantitative assessment of whole-body tumour perfusion. We created a tool for automated creation of quantitative parametric whole-body tumour perfusion images in metastatic cancer.
METHODS
Ten metastatic prostate cancer patients underwent dynamic LAFOV [O]HO PET (Siemens, Quadra) followed by [F]PSMA-1007 PET. Perfusion was measured as [O]HO K (mL/min/mL) with a single-tissue compartment model and an automatically captured cardiac image-derived input function. Parametric perfusion images were automatically calculated using the basis-function method with initial voxel-wise delay estimation and a leading-edge approach. Subsequently, perfusion of volumes-of-interest (VOI) can be directly extracted from the parametric images. We used a [F]PSMA-1007 SUV 4 fixed threshold for tumour delineation and transferred these VOIs to the perfusion map.
RESULTS
For 8 primary tumours, 64 lymph node metastases, and 85 bone metastases, median tumour perfusion were 0.19 (0.15-0.27) mL/min/mL, 0.16 (0.13-0.27) mL/min/mL, and 0.26 (0.21-0.39), respectively. The correlation between calculated perfusion from time-activity-curves and parametric images was excellent (r = 0.99, p < 0.0001).
CONCLUSION
LAFOV PET imaging using [O]HO enables truly quantitative parametric images of whole-body tumour perfusion, a potential biomarker for guiding personalized treatment and monitoring treatment response.
PubMed: 38940842
DOI: 10.1007/s00259-024-06799-3 -
Pediatric Cardiology Jun 2024Pediatric patients with coronary artery lesions (CALs) after Kawasaki disease (KD) may be complicated with myocardial ischemia. Although previous studies in adults have...
Pediatric patients with coronary artery lesions (CALs) after Kawasaki disease (KD) may be complicated with myocardial ischemia. Although previous studies in adults have proven the diagnostic value of Tc-MIBI myocardial perfusion imaging (MPI) for ischemic heart disease, its feasibility and accuracy in this pediatric population remain uncertain. In this retrospective study, we collected data of 177 pediatric patients (Age range: 6 months to 14 years) who had undergone MPI and coronary artery angiography (CAG) between July 2019 and February 2023. Using the positive result of CAG as the reference standard of myocardial ischemia, we compared the results of Tc-MIBI MPI with other non-invasive examinations, including cardiac magnetic resonance imaging (CMRI), echocardiogram, and comprehensive electrocardiogram-related examinations. All patients finished adenosine triphosphate stress MPI without major side effects. The sensitivity of MPI was 79.17%, which was greater than CMRI and echocardiogram (P < 0.05). The negative predictive value and the accuracy of MPI were 89.9% and 71.75%, indicating the advantages over others. Composite monitoring strategy of MPI and CMRI effectively improved the diagnostic performance (P < 0.001). In 4 cases diagnosed with myocardial ischemia by "MPI + CMRI," despite the absence of significant stenosis, multiple giant coronary artery aneurysms (GCAA) were all observed in CAG. Tc-MIBI MPI is the preferred non-invasive examination for detecting myocardial ischemia in pediatric patients with CAL after KD. When combined with CMRI, it can enhance diagnostic accuracy. Multiple GCAAs without stenosis may be an isolated risk factor of myocardial ischemia.
PubMed: 38940825
DOI: 10.1007/s00246-024-03545-2 -
Multimedia Manual of Cardiothoracic... Jun 2024Donor organ recovery techniques have improved with novel preservation solutions, implementation of advanced preservation systems and machine perfusion. However, surgical...
Donor organ recovery techniques have improved with novel preservation solutions, implementation of advanced preservation systems and machine perfusion. However, surgical techniques for organ procurement have not changed. In this video tutorial, we have outlined key steps in double lung en bloc organ recovery, including introduction of pulmonoplegia, pulmonectomy en bloc and separation of the two single-lung blocks.
Topics: Humans; Lung Transplantation; Tissue and Organ Procurement; Tissue and Organ Harvesting; Lung; Organ Preservation; Tissue Donors; Pneumonectomy
PubMed: 38940725
DOI: 10.1510/mmcts.2024.050 -
Journal of Clinical Ultrasound : JCU Jun 2024Twin reversed arterial perfusion (TRAP) sequence carries a high mortality risk to the "pump twin." Management involves disrupting blood flow to the acardiac mass. In...
Twin reversed arterial perfusion (TRAP) sequence carries a high mortality risk to the "pump twin." Management involves disrupting blood flow to the acardiac mass. In this case, the pregnant patient presented at 20 weeks 6 days with Stage IIb TRAP Sequence and underwent percutaneous ultrasound-guided microwave ablation (MWA) of the acardiac mass at 21 weeks 0 days. The probe traversed the thorax of the acardiac mass and ablated the confluence of the umbilical vessels. A healthy child was delivered at 33 weeks 5 days gestation. This report demonstrates the utility of MWA in TRAP sequence and describes a novel approach.
PubMed: 38940580
DOI: 10.1002/jcu.23754