药物相互作用改变了剂量效应关系,可能会降低疗效或增加毒性,是临床应用中合并用药治疗时重要的考虑因素。预测具有临床意义的药物相互作用是药物研发过程中获益风险评估的重要环节。本文概述了药物研发过程中药物相互作用研究的目的和意义,体内和体外研究的主要内容;梳理分析了2020年国家药品监督管理局(National Medical Products Administration, NMPA)和美国食品药品监督管理局(Food and Drug Administration, FDA)批准上市的新药药物相互作用研究情况,旨在为我国药物研发过程中药物相互作用研究及其监管审评提供参考。 相似文献
The traction motor is the power source of the locomotive. If the surface waviness occurs on the races of the motor bearing, it will cause abnormal vibration and noise, accelerate fatigue and wear, and seriously affect the stability and safety of the traction power transmission. In this paper, an excitation model coupling the time-varying displacement and contact stiffness excitations is adopted to investigate the effect of the surface waviness of the motor bearing on the traction motor under the excitation from the locomotive-track coupled system. The detailed mechanical power transmission path and the internal/external excitations (e.g., wheel–rail interaction, gear mesh, and internal interactions of the rolling bearing) of the locomotive are comprehensively considered to provide accurate dynamic loads for the traction motor. Effects of the wavenumber and amplitude of the surface waviness on the traction motor and its neighbor components of the locomotive are investigated. The results indicate that controlling the amplitude of the waviness and avoiding the wavenumber being an integer multiple of the number of the rollers are helpful for reducing the abnormal vibration and noise of the traction motor.
Spinal muscular atrophy (SMA) is an autosomal recessive hereditary neuromuscular disease. Exon 7 and 8 of survival of motor neuron 1 (SMN1) gene or only exon 7 homology deletion leads to the failure to produce a full-length SMN gene. The copy number of SMN2 gene with high homology of SMN1 affects the degree of disease and was the target gene for targeting therapy, in which splicing silencer in intron 7 was the key to suppress the inclusion of exon 7. In this study, we projected to use CRISPR/Case 9 for the targeted editing of intronic-splicing silencer (ISS) sequence to promote the inclusion of SMN2 exon 7 and increase the production of SMN2 full-length (FL) gene expression. It happens that there was a protospacer adjacent motif (PAM) at one end of the ISS sequence according to the design of sgRNA. The recombinant vector of sgRNA HSMN2 CRISPR/Case 9 was constructed and transfected into HEK293 cells. Sequencing results showed that the ISS sequence could be edited accurately and targeting in the predicted direction, in which deleting small fragments, inserting small amounts and mutation. Quantitative analysis of RT-PCR products by restriction enzyme of DdeI digestion showed that the FL of SMN2 increased by 8% (P < 0.05). In the primary cultured chondrocytes of SMA mice, in which sgRNA HSMN2 CRISPR/Case9 recombinant vector transfection could increase the SMN2 FL gene by 23% (P < 0.05) and significantly improve SMN protein levels (P < 0.05). CRISPR/Case 9 is an effective tool for gene editing and therapy of hereditary diseases, but it is rarely reported in the treatment of SMA diseases. This study shows that CRISPR/Case 9 was first used for the precision target of ISS sequence editing, which can effectively promote the production of SMN2 FL gene expressions, in which there was an important clinical reference value. 相似文献