Transarterial chemoembolization (TACE) has been widely introduced to treat hepatocellular carcinoma (HCC) especially for unresectable patients for decades. However, TACE evokes an angiogenic response due to the secretion of vascular endothelial growth factor (VEGF), resulting in the formation of new blood vessels and eventually tumor recurrence. Thus, we aimed to develop regorafenib (REGO)-loaded poly (lactide-co-glycolide) (PLGA) microspheres that enabled localized and sustained drug delivery to limit proangiogenic responses following TACE in HCC treatment. REGO-loaded PLGA microspheres were prepared using the emulsion-solvent evaporation/extraction method, in which DMF was selected as an organic phase co-solvent. Accordingly, we optimized the proportion of DMF, which the optimal ratio to DCM was 1:9 (v/v). After preparation, the microspheres provided high drug loading capacity of 28.6%, high loading efficiency of 91.5%, and the average particle size of 149 µm for TACE. IR spectra and XRD were applied to confirming sufficient REGO entrapment. The in vitro release profiles demonstrated sustained drug release of microspheres for more than 30 d To confirm the role of REGO-loaded microspheres in TACE, the cell cytotoxic activity on HepG2 cells and anti-angiogenic effects in HUVECs Tube-formation assay were studied in combination with miriplatin. Moreover, the microspheres indicated the potential of antagonizing miriplatin resistance of HepG2 cells in vitro. Pharmacokinetics preliminary studies exhibited that REGO could be sustainably released from microspheres for more than 30 d after TACE in vivo. In vivo anti-tumor efficacy was further determined in HepG2 xenograft tumor mouse model, demonstrating that REGO microspheres could improve the antitumor efficacy of miriplatin remarkably compared with miriplatin monotherapy. In conclusion, the obtained REGO microspheres demonstrated promising therapeutic effects against HCC when combined with TACE.
Background . Abelmoschus manihot (L.) Medic flower is a medicinal plant for the treatment of diseases in China. The present study was carried out to scientifically validate the gastroprotective activity and clarify the possible mechanism of the total flavones from Abelmoschus manihot (L.) Medic flowers (TFA). Methods . Gastric ulcer was induced in mice by oral administration of ethanol. The gastroprotective activity of TFA was evaluated by the gastric ulcer index and histological examinations. The gastric tissue was collected in the form of homogenate. The level of malondialdehyde (MDA) and glutathione (GSH), the activity of superoxide dismutase (SOD), and protein content were measured. Western blotting for the expression of Bax, Bcl‐2, TNF‐ α , and NF‐ κ B(p65) was also carried out. The effect of TFA was compared with that of standard antiulcer drug omeprazole (100 mg/kg). Results . This gastroprotective effect of TFA could be attributed to the increase in the activity of SOD and GSH and decrease in the levels of MDA and also decrease in the levels of Bax, TNF‐ α , and NF‐ κ B(p65) expressions and increase in the Bcl‐2 expression level. Conclusion . The findings of this study demonstrated that TFA could significantly attenuate ethanol‐induced gastric injury via antioxidative, anti‐inflammatory, and antiapoptotic effects.
Background: HY-021068 [4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoate], developed by Hefei Industrial Pharmaceutical Institute Co., Ltd. (Anhui, China), is a potential thromboxane synthetase inhibitor under development as an anti-platelet agent for the treatment of stroke. A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the PK of HY-021068 and its platelet aggregation inhibitory effect in beagle dogs. Method: Beagle dogs received single oral administration of 2.5 mg/kg HY-021068 or consecutively oral administration of 5 mg/kg HY-021068 once daily for 7 days. The plasma concentration of HY-021068 and the platelet aggregation rate (PAR) were determined by liquid chromatography tandem-mass spectrometry (LC‐MS/MS) assay and a photometric method, respectively. The PK/PD data was sequentially fitted by Phoenix NLME. The PK/PD parameters of HY-021068 in beagle dogs were estimated by 2.5 and 5 mg/kg dosing on the 1st day, and then used to simulate the PAR of HY-021068 on the 7th day after 5 mg/kg dosing daily. Result: A one-compartment model with saturable Michaelis-Menten elimination was best fitted to the PK of HY-021068. A mechanistic PD model based on irreversible inhibition of thromboxane synthetase was constructed to describe the relationship between plasma concentration of HY-021068 and PAR. Diagnostic plots showed no obvious bias. Visual predictive check confirmed the stability and reliability of the model. Most of PK/PD observed data on the 7th day after 5 mg/kg dosing fell in the 90% prediction interval. Conclusion: We established a semi-mechanistic PK/PD model for characterizing the PK of HY-021068 and its anti-platelet effect in beagle dogs. The model can be used to predict the concentration and PAR under different dosage regimen of HY-021068, and might be served as a reference for dose design in the future clinical studies.
Background and Objective: Inhibition of thrombosis and platelet aggregation through a thromboxane synthetase inhibitor proved to be an effective and promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) patients. This phase I study evaluated the safety, tolerability and pharmacokinetics of sodium pyragrel, a novel thromboxane A2 synthetase inhibitor, in healthy volunteers. Methods: A total of 84 healthy Chinese volunteers were enrolled in the study and randomized into one of five dosing regimens of intravenous pyragrel, which were single ascending dose (30 to 300 mg), multiple doses [pyragrel 180 mg once daily on Day 1 and Day 6, twice daily from Day 2 to Day 5)], 3×3 Latin square crossover (60, 120, 240 mg) and a continuous dose (360 mg in 24 h), respectively. Plasma concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Results: The maximum plasma concentrations of pyragrel were essentially reached at the end of the 3 h infusion. The pharmacokinetic process of pyragrel and two main metabolites (BBS and BJS) is linear over the 30-300 mg dose range, with no significant accumulation on multiple doses. The urinary excretion of pyragrel accounted for more than 70% of the total drug amount. Preliminary pharmacodynamic results demonstrated that the production of urinary 11-D-HTXB2 was time- and dose-dependently inhibit by single i.v. dose of pyragrel. Conclusions: Pyragrel was well tolerated after single ascending doses up to 300 mg, multiple doses of 180 mg and continuous administration of 360 mg within 24 h. No drug-related, serious adverse drug reactions occurred during the five-part study. The most common pyragrel-related adverse events (AEs) were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low incidence rate and seemed to be dose independent. Given the acceptable safety and appropriate pharmacokinetic properties of sodium pyragrel proven in this study, continued clinical development is warranted. The study was registered at http://www.chictr.org.cn (ChiCTR-IID-16010159).
Pyragrel, a new anticoagulant drug, is derived from the molecular combination of ligustrazine and ferulic acid. Pyragrel showed significant inhibitory activity against platelet aggregation induced by adenosine diphosphate (ADP), and had been approved for a phase I clinical trial by CFDA. To characterize the metabolites of Pyragrel in human urine after intravenous administration, a reliable online solid-phase extraction couple with high performance liquid chromatography tandem mass spectrometry (online SPE-HPLC-MSn) method was conceived and applied. Five metabolites were detected and tentatively identified, which suggested that the major metabolic pathways of Pyragrel in human were double-bond reduction, double-bond oxidation, and then followed by glucuronide conjugation. Two main metabolites were then prepared using β-glucuronide hydrolysis and macroporous resin purification approach followed by preparative high-performance liquid chromatography (PHPLC) method, with their structures confirmed on the basis of nuclear magnetic resonance (NMR) data. This study provided information for the further study of the metabolism and excretion of Pyragrel.
HY072808 is a novel phosphodiesterase 4 inhibitor currently under clinical development to treat atopic dermatitis. The first step is to address the pharmacokinetics and safety after topical administration of HY072808 ointments in healthy humans. In this study, we developed a highly sensitive liquid chromatography-tandem mass spectrometry method to determine plasma HY072808 and its active metabolite, ZZ24, in tiny amounts. The plasma samples were prepared using a simple liquid-liquid extraction method. Liquid chromatographic separation was achieved by gradient elution. The MS/MS quantification was performed in positive ion mode via multiple reaction monitoring. The method showed satisfactory linearity from 10 to 4,000 pg/ml for HY072808 and ZZ24. There was no significant interference from blank plasma. The method was validated for accuracy and precision, matrix effect and extraction recovery, dilution integrity, injection carryover and stability according to the related guidelines of the regulatory authorities. The HY072808 and ZZ24 concentrations in human plasma from a clinical trial were determined using this method. In conclusion, the validated method was robust and could be utilized to support the clinical development of HY072808.
Sinomenine (SIN), a natural product, has been used to treat rheumatoid arthritis (RA) in China for thousands of years. SIN has been developed for the treatment of RA by way of tablets and injections, but both dosage forms have been associated with severe adverse reactions. Making SIN into liposomes-in-hydrogel biomaterials for external use has a good slow-release effect and can play an important role in avoiding the first-pass effect, gastrointestinal reaction, and increasing the local action time of drugs. SIN-loaded liposomes were formed by the thin-film dispersion method, then SIN-loaded liposomes-in-hydrogels were prepared by combining the SIN-L with hyaluronic acid (HA) hydrogels. In this paper, the basic characteristics, In vitro and Ex vivo release, and antioxidant activity of SIN-loaded liposomes-in-hydrogels were studied. The results showed that SIN-loaded liposomes-in-hydrogels have good sustained-release and antioxidant effects, and the preparation is expected to be a good biomaterial.
To investigate the protective effect and mechanism of liquiritin (LIQ) on cardiomyocyte hypertrophy induced by angiotensin II (Ang II).H9c2 cells were pretreated with LIQ before and after Ang II treatment. CCK8 assay was performed to evaluate cell viability. The cell surface area was measured by phalloidin staining. The mRNA expression of atrial and B-type natriuretic peptides (ANP and BNP, respectively) and β-myosin heavy chain (β-MHC) was determined by quantitative reverse transcription-polymerase chain reaction (RT-qPCR); the protein levels of arginyltransferase 1 (ATE1), transforming growth factor beta-activated kinase 1 (TAK1), phos-TAK1, c-Jun N-terminal kinases1/2 (JNK1/2), and phos-JNK1/2 were determined by Western blotting. After constructing the ATE1 overexpression cell models with the pcDNA3.1/ATE1, the abovementioned indicators were tested using the introduced methods.LIQ at a concentration of ≤30 μM was not cytotoxic to H9c2 cells before exposure to Ang II. The protective effect of LIQ was best observed at 30 μM after Ang II treatment. Phalloidin staining and RT-qPCR results indicated that the deposition of Ang II increased the cell surface area and levels of ANP, BNP, and β-MHC. On the other hand, Western blotting results showed that Ang II increased the ATE1 protein levels and TAK1 and JNK1/2 phosphorylation, which were significantly alleviated after LIQ treatment. LIQ also directly inhibited the ATE1 overexpression in H9c2 cells transfected with pcDNA3.1/ATE1 and further inhibited TAK1 and JNK1/2 phosphorylation.LIQ can attenuate Ang II-induced cardiomyocyte hypertrophy by regulating the ATE1/TAK1-JNK1/2 pathway.
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