First-in-human trial of SAR107375E, a novel small molecule anticoagulant with dual inhibition of factor Xa and factor IIa.

BACKGROUND: SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects. METHODS: In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events were recorded to evaluate safety. RESULTS: In plasma, from the 0.5 to 20.0 mg dose group, t1/2 is 1.51-4.00 h, Cmax is 59.05-1360 ug/L, and AUC0-t is 25.01-528.45 h*ug/L. And it shows dose proportionality in the 5.0-20.0 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study. CONCLUSION: SAR107375E exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn, identifier is CTR20211082.

Zebrafish model for assessing induced organ toxicity by Strychnos nux-vomica.

OBJECTIVE: To assess the acute organ toxicity of Strychnos nux-vomica with zebrafish model visually. METHODS: To assess acute toxicity, we initially determined the lethal concentration after Strychnos nux-vomica treatment for 24 h. Zebrafish was treated with five concentrations ≦ LC10 for 24 h, and the effects of Strychnos nux-vomica on morphology, function of heart, central nervous system, liver, kidney and organ-specific cell death were assessed. Next, we assessed the reversibility of toxic effect. RESULTS: Strychnos nux-vomica has an effect on the different organs of zebrafish, including heart, central nervous system, liver, and kidney, and cadiotoxicity induced by Strychnos nux-vomica was reversible to some extent. CONCLUSION: Zebrafish model is suitable for confirming the toxic target organs for Chinese traditional medicine.

Effect of artificial musk aqueous extract on the expressions of inflammatory mediators released from lipopolysaccharide-stimulated RAW264.7 cells.

OBJECTIVE: To identify the anti-inflammatory effects of artificial musk aqueous extract(AME)on lipopolysaccharide-stimulated cytokines secreted or released by RAW264.7 cells. METHODS: Cytokines including interleukin(IL)-6,IL-10,and tumor necrosis factor Α were determined using cytokine enzyme-linked immunosorbent assay kits. RESULT: Compared with model group,the levels of major cytokines such as tumor necrosis factor Α,IL-6,and IL-10 significantly decreased in different AME groups in a dose-dependent manner. CONCLUSION: In lipopolysaccharide-stimulated RAW264.7 macrophages,AME can remarkably inhibit the release of inflammatory cytokines and thus exerts its anti-inflammatory effects.

Detection of artificial musk in Xihuangwan by gas chromatography-mass spectrometery.

OBJECTIVE: To control the quality of Xihuangwan by improving the qualitative detection of artificial musk inside this pill. METHOD: The qualitative detection of artificial musk was carried out by gas chromatography-mass spectrometery(GC-MS). RESULT: The established GC-MS successfully detected artificial musk in Xihuangwan. CONCLUSION: GC-MS is reliable,accurate,and practical in the identification of artificial must inside Xihuangwan.

Determination of the contents of five heavy metals in artificial musk.

OBJECTIVE: To evaluate the safety of artificial musk by determining its content of five hazard heavy metals. METHOD: The contents of Pb, Cd,As,Hg,and Cu in artificial musk were detected using inductively coupled plasma-mass spectrometry. RESULT: The contents of Pb,Cd,As,Hg,and Cu was less than 0.35,0.05,0.30,0.20,and 4.50 mg/kg in artificial musk. CONCLUSION: Artificial musk has low contents of heavy metals and therefore meets the safety and quality requirments.