Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
Lancet. 2015 Feb 26;385 Suppl 1:S80. doi: 10.1016/S0140-6736(15)60395-6.
In Bihar state, India, the cure rate of antimonial compounds (eg, sodium stibogluconate) in the treatment of visceral leishmaniasis (VL) has fallen from more than 85% to less than 50%. This reduction has been attributed to long-term, widespread misuse of antimonial drugs within the Indian private health-care system. We aimed to test the hypothesis that exposure to arsenic in drinking water in this region has resulted in antimony-resistant Leishmania parasites.
L donovani parasites were serially passaged in mice exposed to environmentally relevant concentrations of arsenic in drinking water. Arsenic concentrations in murine organs were quantified and the sensitivity of L donovani to sodium stibogluconate assessed at each passage. A retrospective field study on a cohort of antimony-treated patients with VL was performed in an arsenic-contaminated area of Bihar to assess risk of treatment failure and death in people exposed to arsenic.
Arsenic accumulation in organs of exposed mice was proportional to exposure level. After five passages, isolated parasites were refractory to sodium stibogluconate in in-vitro drug sensitivity assays. Treatment of arsenic exposed, infected mice with this drug confirmed that these parasites retained resistance in vivo. In the field work study, 110 patients with VL treated with sodium stibogluconate, failure rate was 59%. Patients using well water with high mean arsenic concentrations had a higher risk of treatment failure than patients using wells with arsenic levels of less than 10 μg/L (odds ratio 1·78, 95% CI 0·7-4·6, p=0·23). 21 patients died, 16 directly as a result of their disease. Mean arsenic concentrations of more than 10 μg/L increased the risk of all-cause and VL-related mortality (hazard ratio 3·27, 95% CI 1·4-8·1, and 2·65, 0·96-7·65, respectively).
These data suggest that arsenic contamination might have contributed to the development of antimonial resistance in Leishmania parasites in Bihar. Our epidemiological study was underpowered and retrospective in nature, so firm conclusions cannot be made. Further research into the associations between arsenic exposure and antimonial treatment failure and death in the leishmaniases is warranted.
Wellcome Trust.
在印度比哈尔邦，抗锑化合物（如葡萄糖酸锑钠）治疗内脏利什曼病（VL）的治愈率已从 85%以上降至 50%以下。这种下降归因于印度私营医疗保健系统中长期、广泛滥用抗锑药物。我们旨在检验以下假设，即该地区饮用水中的砷暴露导致了对锑具有抗性的利什曼原虫寄生虫。
在暴露于环境相关浓度砷的饮用水中的小鼠中连续传代 L. donovani 寄生虫。定量测定小鼠器官中的砷浓度，并在每次传代时评估 L. donovani 对葡萄糖酸锑钠的敏感性。在比哈尔邦一个砷污染地区对接受锑治疗的 VL 患者进行了回顾性队列研究，以评估接触砷的人群治疗失败和死亡的风险。
暴露小鼠器官中的砷积累与暴露水平成正比。经过五次传代后，分离出的寄生虫在体外药物敏感性测定中对葡萄糖酸锑钠产生抗药性。用该药治疗暴露于砷并感染的小鼠证实，这些寄生虫在体内仍保持耐药性。在现场工作研究中，110 名接受葡萄糖酸锑钠治疗的 VL 患者的治疗失败率为 59%。使用高平均砷浓度井水的患者比使用砷含量低于 10μg/L 的水井的患者更有可能治疗失败（比值比 1.78，95%置信区间 0.7-4.6，p=0.23）。21 名患者死亡，其中 16 名直接死于疾病。超过 10μg/L 的平均砷浓度增加了全因和 VL 相关死亡率的风险（风险比 3.27，95%置信区间 1.4-8.1 和 2.65，95%置信区间 0.96-7.65）。
这些数据表明，砷污染可能导致比哈尔邦利什曼原虫寄生虫对锑的耐药性发展。我们的流行病学研究在性质上存在权力不足和回顾性，因此无法得出确定的结论。有必要进一步研究砷暴露与利什曼病抗锑治疗失败和死亡之间的关联。
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