作者: Zhou, Zan ; Zhu, Qing ; Zhou, Hu ; Yang, Renchi ; Dai, Xinyue ; Zhang, Lei ; Wang, Xiaomin ; Fu, Rongfeng ; Liu, Wei ; Xue, Feng ; Ding, Bingjie ; Yu, Jiaojiao ; Li, Mengjuan ; Sun, Ting ; Ju, Mankai ; Wu, Quanrui ; Chen, Yunfei ; Liu, Xiaofan

BACKGROUNDBleeding episodes in hemophiliacs with inhibitors are difficult to control. Staidson protein-0601 (STSP-0601), a specific factor (F)X activator purified from the venom of Daboia russelii siamensis, has been developed.OBJECTIVESWe aimed to investigate the efficacy and safety of STSP-0601 in preclinical and clinical studies.METHODSIn vitro and in vivo preclinical studies were performed. A phase 1, first-in-human, multicenter, and open-label trial was conducted. The clinical study was divided into parts A and B. Hemophiliacs with inhibitors were eligible for this study. Patients received a single intravenous injection of STSP-0601 (0.01 U/kg, 0.04 U/kg, 0.08 U/kg, 0.16 U/kg, 0.32 U/kg, or 0.48 U/kg) in part A or a maximum of 6 4-hourly injections (0.16 U/kg) in part B. The primary endpoint for each part was the number of adverse events (AEs) from baseline to 168 hours after administration. This study was registered at clinicaltrials.gov (NCT-04747964 and NCT-05027230).RESULTSPreclinical studies showed that STSP-0601 could specifically activate FX in a dose-dependent manner. In the clinical study, 16 patients in part A and 7 patients in part B were enrolled. Eight (22.2%) AEs in part A and 18 (75.0%) AEs in part B were reported to be related to STSP-0601. Neither severe AEs nor dose-limiting toxicity events were reported. There were no thromboembolic event. The antidrug antibody of STSP-0601 was not detected.CONCLUSIONPreclinical and clinical studies showed that STSP-0601 had a good ability to activate FX and had a good safety profile. STSP-0601 could be used as a hemostatic treatment in hemophiliacs with inhibitors.

2021-01-01·Blood Coagulation & Fibrinolysis4区 · 医学

Microkinetic coagulation assays for human and zebrafish plasma

4区 · 医学

Article

作者: Iyer, Neha ; Jagadeeswaran, Pudur

Coagulation assays, prothrombin time (PT), and partial thromboplastin time (PTT) are tests to measure the clotting ability of plasma and used in evaluating patients suffering from bleeding disorders. These assays require 100 μl of human plasma. In zebrafish, dilute plasma with exogenously added human fibrinogen was used. Our objective is to create a microkinetic coagulation assay for human and zebrafish plasmas using 1 μl plasma under conditions similar to PT and PTTs. Here, we developed an assay using the Take3 plate with wells holding up to 6 μl, which can be loaded in a microplate reader for measuring the absorbance of fibrin formation. In this assay, we used 1 μl of citrated zebrafish or human plasma followed by the addition of either thromboplastin or Dade ACTIN or factor X activator from Russell viper venom as an activating agent and CaCl2. We found 4 or 3 μl of the final volume of reaction was optimal. Our results showed both zebrafish and human plasmas yielded kinetic PT, kinetic PTT, and kinetic Russel's viper venom time curves similar to previously established curves using dilute plasma. This kinetic coagulation was inhibited by heparin and was reduced significantly in coagulation factor deficient plasmas. These results validated our microkinetic coagulation assays. Moreover, we derived clotting times from these kinetic curves, which were identical to human PT, PTT, and Russel's viper venom time. In conclusion, we established a microkinetic assay that could measure blood coagulation activity in models like zebrafish and human blood samples obtained from a finger prick in adults or heel prick in infants.

2018-08-01·Drug Metabolism and Disposition2区 · 医学

Regulation of Cytosolic Sulfotransferases in Models of Human Hepatocyte Development

2区 · 医学

Article

作者: Fang, Hailin ; Barrett, Kathleen G ; Guzman-Lepe, Jorge ; Kocarek, Thomas A ; Dubaisi, Sarah ; Runge-Morris, Melissa ; Soto-Gutierrez, Alejandro

Cytosolic sulfotransferases (SULTs) are expressed during early life and therefore metabolize endogenous and xenobiotic chemicals during development. Little is currently known about the regulation of individual SULTs in the developing human liver. We characterized SULT expression in primary cultures of human fetal hepatocytes and the HepaRG model of liver cell differentiation. SULT1A1 (transcript variants 1-4), SULT1C2, SULT1C4, SULT1E1, and SULT2A1 were the most abundant transcripts in human fetal hepatocytes. In HepaRG cells, SULT1B1, SULT1C2/3/4, and SULT1E1 mRNA levels increased during the transition from proliferation to confluency and then decreased as the cells underwent further differentiation. By contrast, SULT2A1 mRNA levels increased during differentiation, whereas SULT1A1 and SULT2B1 mRNA levels remained relatively constant. The temporal patterns of SULT1C2, SULT1E1, and SULT2A1 protein content were consistent with those observed at the mRNA level. To identify regulators of SULT expression, cultured fetal hepatocytes and HepaRG cells were treated with a panel of lipid- and xenobiotic-sensing receptor activators. The following effects were observed in both fetal hepatocytes and HepaRG cells: 1) liver X receptor activator treatment increased SULT1A1 transcript variant 5 levels; 2) vitamin D receptor activator treatment increased SULT1C2 and SULT2B1 mRNA levels; and 3) farnesoid X receptor activator treatment decreased SULT2A1 expression. Activators of aryl hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, and peroxisome proliferator-activated receptors produced additional gene-dependent effects on SULT expression in HepaRG cells. These findings suggest that SULT-regulating chemicals have the potential to modulate physiologic processes and susceptibility to xenobiotic stressors in the developing human liver.

100 项与凝血X因子激活酶 (上海复星医药集团) 相关的药物交易

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