关键词: 新药, 心脏毒性, 体外, 检测方法

Abstract: OBJECTIVE: To develop a human cardiomyocyte model for cardiotoxicity drug evaluation, and to evaluate its potential for screening new cardiotoxicity drugs. METHODS: Human cardiomyocytes in cultures were treated with tamoxifen (0.33, 1, 3 μmol/mL) and haloperidol (0.11, 0.33, 1 μmol/mL) for 48 h. At 1, 2, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 h after the initiation of treatments realtime cell analyses and highcontent cell imaging technology were used to monitor changes of cardiac myocyte pulse frequency, amplitude, regularity and mitochondrial membrane potential before and after administration. The data were used to evaluate the usefulness of this model as an in vitro cardiotoxicity assay. RESULTS: After tamoxifen and haloperidol were co-incubated with human cardiomyocytes, the FPD and systolic frequencies reduced to 0 after 3 h treatment with 3μmol/mL tamoxifen but recovered after 18 h treatment. Results from the other treatment concentrations were similar to those in the control group. Both FPD and systolic frequency of cardiomyocytes were concentration-dependent on fluperidol. The higher the concentrations, the higher were the values of FPD (Max), and the smaller were the values of systolic frequency. After 24 h, complete fluid exchange was conducted and all cardiomyocytes treated with different concentrations recovered. CONCLUSION: Our data suggest that human cardiomyocytes can be used to establish a feasible model for evaluating cardiotoxicity in vitro. In addition, real-time cell analysis and high-content cell imaging can be used to evaluate cardiotoxicity of drugs.

Key words: new drugs, cardiotoxicity, in vitro, test method