Manion D J, Vibhagool A, Chou T C, Kaplan J, Caliendo A, Hirsch M S
Infectious Disease Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Antivir Ther. 1996 Dec;1(4):237-45.
Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality for immunocompromised hosts. We sought to determine the in vitro susceptibility of HCMV reference laboratory strains, clinical isolates and strains with known resistance to currently available anticytomegaloviral drugs to two-drug combinations of the following compounds: ganciclovir, foscarnet, cidofovir and its cyclic congener, cyclic HPMPC (cHPMPC), and lobucavir. Cytotoxicity was determined by Trypan Blue exclusion of cells exposed both when proliferating (non-confluent) and once confluent. Antiviral effect was determined by a plaque-reduction assay in MRC-5 human embryonic lung cells. Drug interactions were determined by median-dose effect analysis with the combination index calculated at 50, 75, 90 and 95% inhibitory concentrations. No drug, either alone or in combination, reached a 50% cytotoxicity concentration in the dose ranges tested. Overall, 252/280 (90.0%) of the two-drug combinations demonstrated additive or synergistic interactive effects towards the panel of HCMV isolates tested. No combination demonstrated antagonism at all inhibitory concentrations to more than one isolate. Interestingly, the clinical isolate tested demonstrated the highest frequency of antagonistic combinations (3/10), as well as marked differences from pan-susceptible laboratory strains. The combinations of ganciclovir + foscarnet and cHPMPC + foscarnet demonstrated additive to synergistic effects against all isolates tested. In vitro combination drug studies could help in the rational choice of therapeutic regimens for use in clinical trials, potentially resulting in decreased toxicity, increased efficacy and delayed onset of drug resistance.
人巨细胞病毒（HCMV）是免疫功能低下宿主发病和死亡的主要原因。我们试图确定HCMV参考实验室菌株、临床分离株以及对现有抗巨细胞病毒药物已知耐药的菌株对以下化合物的两药组合的体外敏感性：更昔洛韦、膦甲酸钠、西多福韦及其环状类似物环状HPMPC（cHPMPC）和洛布卡韦。细胞毒性通过锥虫蓝排斥法测定，该方法用于检测增殖期（未汇合）和汇合后的细胞。抗病毒效果通过在MRC-5人胚肺细胞中进行的蚀斑减少试验来确定。药物相互作用通过中位剂量效应分析确定，并在50%、75%、90%和95%抑制浓度下计算组合指数。在所测试的剂量范围内，单独或联合使用的任何药物均未达到50%细胞毒性浓度。总体而言，252/280（90.0%）的两药组合对所测试的HCMV分离株显示出相加或协同的相互作用效应。没有一种组合在所有抑制浓度下对超过一种分离株表现出拮抗作用。有趣的是，所测试的临床分离株表现出最高频率的拮抗组合（3/10），并且与全敏感的实验室菌株有明显差异。更昔洛韦+膦甲酸钠和cHPMPC+膦甲酸钠的组合对所有测试分离株均显示出相加至协同效应。体外联合药物研究有助于合理选择用于临床试验的治疗方案，可能会降低毒性、提高疗效并延缓耐药性的出现。
