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Uncovering the impact of COVID-19-mediated bidirectional dysregulation of cytochrome P450 3A4 on systemic and pulmonary drug concentrations using physiologically based pharmacokinetic modeling.
Drug Metab Dispos
January 2025
Current affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Current affiliation: OneDrug Inc., Toronto, Ontario, Canada; Program in Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom. Electronic address:
Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized patients with COVID-19. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary cytochrome P450 (CYP) 3A4 affects drug concentrations, especially in the lung tissue, which is most affected by the disease. Herein, physiologically based pharmacokinetic modeling was used to demonstrate the differences in systemic and pulmonary concentrations of 4 respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19-CYP3A4 interactions at varying severity levels including outpatients, non-intensive care unit (ICU), and ICU patients.
View Article and Find Full Text PDFSevere pulmonary arterial hypertension and cardiogenic shock in acute systemic lupus erythematosus.
BMJ Case Rep
January 2025
Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia.
We describe a woman in her late 20s with newly diagnosed systemic lupus erythematosus (SLE), who presented with fulminant pulmonary arterial hypertension (PAH) requiring inotropic and extracorporeal support. She was established on triple pulmonary vasodilator therapy with concurrent aggressive immunosuppression; however, treatment was complicated by infection and diffuse alveolar haemorrhage, necessitating delays in immunosuppression and withdrawal of epoprostenol. Despite this, with ongoing suppression of her SLE, her pulmonary haemodynamics improved, with normal pressures on right heart catheterisation several months later allowing stepdown to sildenafil monotherapy.
View Article and Find Full Text PDFCombating sepsis-induced acute lung injury: PARP1 inhibition mediates oxidative stress mitigation and miR-135a-5p/SMAD5/Nanog axis drives regeneration.
Int Immunopharmacol
January 2025
Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India. Electronic address:
Purpose: The purpose of this study was to investigate the therapeutic potential of Poly (ADP-ribose) polymerase 1 (PARP1) inhibition combined with microRNA miR-135a-5p overexpression in sepsis-induced acute lung injury (ALI). Specifically, we aimed to elucidate combinatorial therapeutic potential of PARP1 inhibition in mitigating oxidative stress and inflammation across different models, simultaneously miR-135a-5p overexpression promoting regeneration through the SMAD5/Nanog axis.
Method: We used C57BL/6 mice to create Cecal Ligation Puncture (CLP) model of Sepsis-induced Acute Lung Injury.
Exploring the Causal Relationship Between Frailty and Chronic Obstructive Pulmonary Disease: Insights From Bidirectional Mendelian Randomization and Mediation Analysis.
Int J Chron Obstruct Pulmon Dis
January 2025
Department of Thoracic Surgery, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, Jiangsu, 215000, People's Republic of China.
Background: Observational studies have underscored a robust association between frailty and chronic obstructive pulmonary disease (COPD), yet the causality remains equivocal.
Methods: This study employed bidirectional two-sample Mendelian randomization (MR) analysis. Univariable MR investigated the causal relationship between frailty and COPD.
Urinary bioorthogonal reporters for the monitoring of the efficacy of chemotherapy for lung cancer and of associated kidney injury.
Nat Biomed Eng
January 2025
School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
The utility of urinary tests for the monitoring of the treatment efficacy and adverse events of anticancer therapies is constrained by the low concentration of relevant urinary biomarkers. Here we report, using mice with lung cancer and treated with chemotherapy, of a urinary fluorescence test for the concurrent monitoring of the levels of a tumour biomarker (cathepsin B) and of a biomarker of chemotherapy-induced kidney injury (N-acetyl-β-D-glucosaminidase). The test involves two intratracheally administered urinary reporters leveraging caged bioorthogonal click handles for the biomarker-dependent activation of 'clickability' and renal clearance, and the bioorthogonal click reaction of each renally cleared reporter with paired fluorescence indicators in the collected urine.
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