以度鲁特韦为基础药物的抗HIV-1体外药效学研究  

The in vitro HAART pharmacodynamics study with dolutegravir as the “anchor”

作　　者：郭家梅 郭颖 

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,新药作用机制研究与药效评价北京市重点实验室,北京100050

出　　处：《药学学报》2015年第1期50-58,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81273561);传染病“十二五”重大专项资助项目(2013ZX10004601);中央级公益性科研院所基本科研业务费专项资助项目(2013ZD06)

摘　　要：本文以研究度鲁特韦(dolutegravir,DTG)为基础药物抗HIV-1体外药效学为目的,以野生HIV-1、核苷类逆转录酶抑制剂耐药HIV-1(HIV-1RT-D67N,K70R,T215F)及整合酶抑制剂耐药HIV-1(HIV-1IN-G140S,Q148H)重组病毒模型为代表,首先比较了整合酶抑制剂与非核苷类逆转录酶抑制剂作为基础药物联合用药的体外药效学;本研究还比较了度鲁特韦和雷特格韦(raltegravir,RAL)分别与两个核苷类逆转录酶抑制剂联合用药的体外药效学。结果显示,以整合酶抑制剂DTG为基础药物抑制野生HIV-1的药效优于非核苷类逆转录酶抑制剂,与RAL效果相当;以DTG为基础药物对核苷类逆转录酶抑制剂耐药病毒(HIV-1RT-D67N,K70R,T215F)的药效与依法韦伦(efavirenz,EFV)和奈韦拉平(nevirapine,NVP)相近;对整合酶抑制剂耐药病毒(HIV-1IN-G140S,Q148H)的药效优于RAL。本研究明确了DTG联合用药的体外药效学,研究结果为临床选择药物提供了实验数据。This study is to evaluate the HAART pharmacodynamics with dolutegravir as the ＂anchor＂ in vitro. A nucleoside reverse transcriptase inhibitors （NRTIs） resistant recombinant virus model （VSVG/ HIV-lRT-D67N,K70g,T215F） and an integrase inhibitors （INIs） resistant recombinant virus model （VSVG/ HIV-11N-G140S,Q148n） were constructed and established. The anti-viral pharmacodynamics was evaluated with drug combinations including two NRTIs along with one INI or one NNRTI. The results showed that the combination with an INI gave a stronger synergism on wild type HIV-1 replication comparing to that with an NNRTI. Comparing the two INIs as the ＂anchor＂ for HAART, DTG exhibited an equivalent CI to that of RAL on wild type HIV-1 replication; but a greater synergy than RAL on 1NI-resistant HIV-1 replication. Besides of the pharmaeodynamics results of DTG-based drug combination, the results may contribute to clinical antiviral therapy.

关 键 词：HIV-1 度鲁特韦 联合用药 药物协同作用 

分 类 号：R962[医药卫生—药理学]