Predicting bioequivalence and developing dissolution bioequivalence safe space in vitro for warfarin using a Physiologically-Based pharmacokinetic absorption model.

OBJECTIVE: Bioequivalence (BE) studies support the approval and clinical use of both new and generic drug products. Narrow therapeutic index (NTI) drugs have relatively high costs and low success rates of BE evaluation clinical trials as high-risk drugs. A physiologically-based pharmacokinetic (PBPK) model can be used to evaluate the BE of two preparations. METHODS: This study inputs the basic physical and chemical property parameters of warfarin sodium available at the present stage into GastroPlus™ software, and combined it with the Advanced Compartmental Absorption and Transit (ACAT™) model built into the software. The PBPK model of Chinese individuals taking 2.5 mg of warfarin sodium orally while fasted condition was developed using the disposal parameters calculated from the clinically measured PK data of the reference preparations. The model was tested using the PK data of other reference preparations and tested preparations from different domestic manufacturers. RESULTS: The results revealed that at least 30% of drugs are released in 30 min under a pH of 4.5 condition, and at least 80% are released in 30 min under a pH of 6.8 condition, which can be used as bioequivalent dissolution limits under fasted conditions. The risk of BE failure in the fed condition will be significantly reduced for the clinical study on the BE of warfarin sodium, which is a NTI drug if the fasted condition is bioequivalent. CONCLUSION: The results revealed that the PBPK models were successfully developed for 2.5 mg of warfarin sodium tablets in Chinese individuals. Developing a PBPK model for NTI drugs based on in vitro dissolution data in software is a promising method for BE evaluation, which can provide great help for developing new drugs and the clinical trial research of BE of generic drugs.

rFGF4 alleviates lipopolysaccharide-induced acute lung injury by inhibiting the TLR4/NF-κB signaling pathway.

Acute lung injury (ALI) is a serious and common clinical disease. Despite significant progress in ALI treatment, the morbidity and mortality rates remain high. However, no effective drug has been discovered for ALI. FGF4, a member of the FGF family, plays an important role in the regulation of various physiological and pathological processes. Therefore, in the present study, we aimed to study the protective effects of FGF4 against LPS-induced lung injury in vivo and in vitro. We found that rFGF4 treatment improved the lung W/D weight ratio, the survival rate, immune cell infiltration and protein concentrations in mice with LPS-induced ALI. Histological analysis revealed that rFGF4 significantly attenuated lung tissue injury and cell apoptosis. Furthermore, rFGF4 inhibited the activation of the TLR4/NF-κB signaling pathway and the production of pro-inflammatory mediators in LPS-injured lung tissues, murine alveolar macrophages (MH-S) and murine pulmonary epithelial (MLE-12) cells. The results of cell experiments further verified that rFGF4 inhibited the production of inflammatory mediators in MH-S cells and MLE-12 cells by regulating the TLR4/NF-κB signaling pathway. These results revealed that rFGF4 protected lung tissues and inhibited inflammatory mediators in mice with LPS-induced ALI by inhibiting the TLR4/NF-κB signaling pathway in MH-S and MLE-12 cells.

PPARγ Mediates the Anti-Epithelial-Mesenchymal Transition Effects of FGF1ΔHBS in Chronic Kidney Diseases via Inhibition of TGF-ß1/SMAD3 Signaling.

Podocytes are essential components of the glomerular basement membrane. Epithelial-mesenchymal-transition (EMT) in podocytes results in proteinuria. Fibroblast growth factor 1 (FGF1) protects renal function against diabetic nephropathy (DN). In the present study, we showed that treatment with an FGF1 variant with decreased mitogenic potency (FGF1ΔHBS) inhibited podocyte EMT, depletion, renal fibrosis, and preserved renal function in two nephropathy models. Mechanistic studies revealed that the inhibitory effects of FGF1ΔHBS podocyte EMT were mediated by decreased expression of transforming growth factor ß1 via upregulation of PPARγ. FGF1ΔHBS enhanced the interaction between PPARγ and SMAD3 and suppressed SMAD3 nuclei translocation. We found that the anti-EMT activities of FGF1ΔHBS were independent of glucose-lowering effects. These findings expand the potential uses of FGF1ΔHBS in the treatment of diseases associated with EMT.

FGF1ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression.

As a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and ß-oxidation in a 5' AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.