Physiologically based pharmacokinetic modeling of apixaban to predict exposure in populations with hepatic and renal impairment and elderly populations.

BACKGROUND: Apixaban is a factor Xa inhibitor with a limited therapeutic index that belongs to the family of oral direct anticoagulants. The pharmacokinetic (PK) behavior of apixaban may be altered in elderly populations and populations with renal or hepatic impairment, necessitating dosage adjustments. METHODS: This study was conducted to examine how the physiologically based pharmacokinetic (PBPK) model describes the PKs of apixaban in adult and elderly populations and to determine the PKs of apixaban in elderly populations with renal and hepatic impairment. After PBPK models were constructed using the reported physicochemical properties of apixaban and clinical data, they were validated using data from clinical studies involving various dose ranges. Comparing predicted and observed blood concentration data and PK parameters was utilized to evaluate the model's fit performance. RESULTS: Doses should be reduced to approximately 70% of the healthy adult population for the healthy elderly population to achieve the same PK exposure; approximately 88%, 71%, and 89% of that for the elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 96%, 81%, and 58% of that for the Child Pugh-A, Child Pugh-B, and Child Pugh-C hepatic impairment elderly populations, respectively to achieve the same PK exposure. CONCLUSION: The findings indicate that the renal and hepatic function might be considered for apixaban therapy in Chinese elderly patients and the PBPK model can be used to optimize dosage regimens for specific populations.

Influencing factors of stroke in patients with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and disability within this patient demographic. Presently, numerous studies have been conducted to investigate the underlying causes of stroke in individuals with T2DM, yet the findings exhibit inconsistencies. OBJECTIVE: This paper aims to consolidate and summarize the available evidence concerning the influential factors contributing to stroke among patients diagnosed with T2DM. METHODS: We conducted a comprehensive search across multiple databases, including Cochrane Library, PubMed, Web Of Science, Embase, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Weipu up to August 2023. Google Scholar was also searched to retrieve gray literature. We calculated odds ratios (OR) and 95% confidence intervals (CI) using Stata software. RESULTS: Our analysis encompassed 43 observational studies, exploring factors across sociodemographic, biochemical, complications, and hypoglycemic agent categories. The findings identified several risk factors for stroke in patients with T2DM: age, gender, T2DM duration, hypertension, body-mass index (BMI), smoking, Glycated hemoglobin (HbA1c), estimated Glomerular Filtration Rate (eGFR), albuminuria, Triglycerides (TG), Low density lipoprotein cholesterol (LDL-C), Coronary heart disease (CHD), Atrial fibrillation (AF), diabetic retinopathy (DR), Peripheral vascular disease (PVD), and carotid plaque. Conversely, exercise, High density lipoprotein cholesterol (HDL-C), metformin (MET), pioglitazone, and metformin combination therapy emerged as protective factors. CONCLUSION: This study underscores the multitude of influencing factors contributing to stroke in people with T2DM patients, among which the microvascular complications of T2DM play an most important role. Therefore, we emphasize the importance of screening for microvascular complications in patients with T2DM. However, due to limitations arising from the number of articles reviewed, there remain areas where clarity is lacking. Further research efforts are warranted to expand upon and reinforce our current findings.

Upregulation of miRNA-1228-3p alleviates TGF-ß-induced fibrosis in renal tubular epithelial cells.

BACKGROUND: Chronic kidney disease (CKD) has become a major public health issue, which can lead to renal fibrosis regardless of the initial injury. It has been previously reported that miRNA-1228-3p was correlate with the progression of kidney fibrosis. However, the mechanism by which miRNA-1228-3p regulates renal fibrosis remains unclear. METHODS: Renal tubular epithelial cells (HK-2) were treated with TGF-ß1 (10 ng/ml) in an in vitro model of renal fibrosis. Gene and protein expressions in HK-2 cells were measured by Western-blot and RT-qPCR, respectively. The relation between miRNA-1228-3p and its target gene was investigated by dual luciferase report analysis. RESULTS: Upregulation of miRNA-1228-3p significantly inhibited TGF-ß1-induced fibrosis of HK-2 cells in vitro by targeting GDF11. In addition, miRNA-1228-3p exhibited anti-fibrosis effect through inhibition of the smad2/smad4 signaling pathway. CONCLUSION: Upregulation of miRNA-1228-3p markedly inhibited the progression of renal fibrosis in vitro, indicating that miRNA-1228-3p may serve as a potential novel target for the treatment of renal fibrosis.