Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria.
Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria.
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DOI：
10.1086/503423
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发表时间：
2006-06-01
期刊：
影响因子：
--
通讯作者：
Nosten F
中科院分区：
文献类型：
--
作者：
Price RN;Uhlemann AC;van Vugt M;Brockman A;Hutagalung R;Nair S;Nash D;Singhasivanon P;Anderson TJ;Krishna S;White NJ;Nosten F
我们的研究探讨了宿主，药代动力学和寄生虫学因素在确定治疗反应蒿甲醚-本芴醇（AL）的相对贡献。在泰国西北边境，患有单纯性恶性疟原虫疟疾的患者参加了AL治疗（4或6剂方案）的前瞻性研究，并随访42天。血浆苯芴醇浓度测定高效液相色谱法，疟原虫pfmdr 1拷贝数进行定量使用实时聚合酶链反应（PCR），并在体外药物敏感性进行了测试。所有治疗均产生快速临床反应，且耐受性良好。第42天，4剂方案的PCR校正失败率为13%（95%置信区间[CI]，9.6%-17%），6剂方案的失败率为3.2%（95% CI，1.8%-4.6%）。pfmdr 1拷贝数增加与本芴醇抑制浓度增加2倍（95%CI，1.8-2.4倍）相关50（P = 0.001），完成4剂方案后治疗失败风险的校正风险比为4.0（95%CI，1.4-11; P = 0.008），而不是6剂方案。在第7天本芴醇水平低于175 ng/mL的患者更有可能在第42天复发（校正的风险比，17; 95% CI，5.5-53），允许预测治疗失败，灵敏度为75%，特异性为84%。6次给药方案确保91%的治疗患者达到治疗水平。本芴醇血药浓度曲线是蒿甲醚-本芴醇疗效的主要决定因素。pfmdr 1的扩增决定了本芴醇的敏感性，因此，当血浆本芴醇水平低于治疗水平时，决定了治疗反应。
Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%–17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%–4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8–2.4-fold) increase in lumefantrine inhibitory concentration50 (P = .001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4–11; P = .008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5–53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.
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影响因子：
1.5
作者：
Duraisingh, MT;Jones, P;Warhurst, DC
通讯作者：
Warhurst, DC
DOI：
10.1016/s0924-8579(99)00070-9
发表时间：
1999-07-01
影响因子：
10.8
作者：
van Agtmael, M;Bouchaud, O;Mull, R
通讯作者：
Mull, R
影响因子：
4.9
作者：
Price, RN;Cassar, C;Krishna, S
通讯作者：
Krishna, S
影响因子：
168.9
作者：
Mutabingwa, TK;Anthony, D;Whitty, CJM
通讯作者：
Whitty, CJM
DOI：
10.4269/ajtmh.1999.60.936
发表时间：
1999-06-01
影响因子：
3.3
作者：
van Vugt, M;Wilairatana, P;Looareesuwan, S
通讯作者：
Looareesuwan, S