RÉSUMÉ
Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.
RÉSUMÉ
Objective To assess the acute toxicity of Cu2+, Cd2+, Hg2+ and Pb2+ to Oncomelania hupensis. Methods Cu2+, Cd2+, Hg2+ and Pb2+ solutions were prepared at five concentrations, and 10 snails were exposed to each concentration for 24, 48, 72 h and 96 h. Then, the inhibition of snail activity and snail death was observed, and the half maximal effective concentration (EC50) and median lethal concentrations (LC50) were estimated. Results The 24, 48, 72 h and 96 h EC50 values of Cu2+, Cd2+, Hg2+ and Pb2+ were 0.74, 0.56, 0.46, 0.37 mg/L, 4.79, 3.52, 1.70, 1.26 mg/L, 1.90, 1.49, 0.83, 0.76 mg/L and 21.40, 9.98, 7.90, 5.42 mg/L for snails, respectively. The 96 h LC50 values of Cu2+, Cd2+, Hg2+ and Pb2+ were 0.43, 2.96, 1.12 mg/L and 12.22 mg/L for snails, the safe concentrations were 0.004 3, 0.029 6, 0.011 2, 0.122 2 mg/L, respectively. Conclusion Cu2+ shows a high acute toxicity to snails, and Cd2+ and Hg2+ exhibit a moderate acute toxicity to snails, while Pb2+ is lowly toxic to snails.
RÉSUMÉ
A highly specific electrochemical biosensor based on T-Hg~(2+)-T structure for fast screening trace Hg~(2+) in complex animal drug matrix was constructed by cyclic voltammetry(CV) and differential pulse voltammetry(DPV). In the presence of Hg~(2+), it can be specifically binded to the T base of DNA sequence on the surface of modified gold electrode, which changes the conformation of DNA molecule and the electrochemical signal. The concentration ratio of EDC/NHS, the concentration ratio of FC-DNA and the reaction time of the biosensor were optimized by the index of sensitivity and reproducibility in CV. The results showed that the stability of the biosensor was good within 3 days(RSD≤1.3%), the difference between batches was low(RSD=4.7%), and the specificity of the biosensor was high in the presence of interfering ions(As~(3+), Cd~(2+), Cu~(2+), Pb~(2+), Zn~(2+) and Fe~(3+)). DPV results showed that the peak current signal value has a linear relationship with the lgC_((Hg)) over a concentration range from 0.1 nmol·L~(-1) to 1.0 μmol·L~(-1) with a detection limit of 0.066 nmol·L~(-1). Finally, the recovery rate tested in the matrix of animal medicine was satisfactory as 99.17%-101.3%, which can meet the needs of the determination of trace Hg~(2+) in the matrix of Bombyx Batryticatus, and provide a new idea for the rapid screening of trace heavy metals in the matrix of other types of complex traditional Chinese medicine.