Unité de Parasitologie, Département d'Infectiologie de Terrain, Institut de Recherche Biomédicale des Armées, Marseille, France.
Malar J. 2013 Aug 30;12:302. doi: 10.1186/1475-2875-12-302.
The medical care of malaria is a clinical emergency because it may develop into severe malaria, which has a high risk of complications and death. One of the major complications of Plasmodium falciparum infections is cerebral malaria (CM), which is responsible for at least 175,000 deaths worldwide each year and has long-term neurological sequelae. Moreover, treatment for CM is only partially effective. Statins are now known to have anti-inflammatory action, to attenuate sepsis and to have neuroprotective effects. In vitro, atorvastatin (AVA) has an anti-malarial activity and has improved the activity of quinine (QN), mefloquine (MQ), and dihydroartemisinin (DHA).
This study had two objectives. First, the ability of AVA to enhance DHA efficacy by improving the survival rate for CM and also decreasing signs of CM was evaluated in a murine model of experimental cerebral malaria (ECM), which was designed in C57BL6/N mice. Second, the inflammatory biomarkers were assessed at D6 and D10 in mice treated by DHA and in untreated mice in which clinical signs of CM appear rapidly and death occurs before D12. Both experiments were designed with seven days of treatment with 40 mg/kg AVA combined with five days of 3 mg/kg DHA administered intraperitoneally.
AVA in combination with DHA in a therapeutic scheme leads to a significant delay in mouse death, and it has an effect on the onset of CM symptoms and on the level of parasitaemia. Evaluation of the biomarkers highlights the significant difference between treated and control mice for five cytokines and chemokines (Eotaxin-CCL11, IL-13, LIX-CXCL5, MIP1b-CCL4 and MIP2) that are known to have a role in chemotaxis.
The combination of DHA and AVA seems to be effective as a therapeutic scheme for improving mouse survival but less effective for cytokine modulation, which is associated with protection against CM. These results call for clinical trials of AVA as an adjuvant with anti-malarial therapy, especially with artemisinin-based combination therapy, in CM treatment or prevention.
疟疾的医疗护理是一种临床急救，因为它可能发展为严重疟疾，严重疟疾有很高的并发症和死亡风险。恶性疟原虫感染的主要并发症之一是脑型疟疾（CM），每年导致全球至少 17.5 万人死亡，并存在长期神经后遗症。此外，CM 的治疗效果仅部分有效。目前已知他汀类药物具有抗炎作用，可减轻脓毒症并具有神经保护作用。在体外，阿托伐他汀（AVA）具有抗疟活性，并提高了奎宁（QN）、甲氟喹（MQ）和双氢青蒿素（DHA）的活性。
本研究有两个目的。首先，在 C57BL6/N 小鼠设计的实验性脑疟疾（ECM）小鼠模型中，评估 AVA 通过提高 CM 生存率和降低 CM 体征来增强 DHA 疗效的能力。其次，在 DHA 治疗的小鼠和快速出现 CM 临床症状并在 D12 之前死亡的未治疗小鼠中，评估 D6 和 D10 时的炎症生物标志物。两个实验均设计为用 40mg/kg AVA 联合腹腔内给予 3mg/kg DHA 进行 7 天的治疗。
在治疗方案中，AVA 与 DHA 联合使用可显著延迟小鼠死亡，并且对 CM 症状的发作和寄生虫血症水平有影响。对生物标志物的评估突出了治疗组和对照组小鼠之间的显著差异，其中五种细胞因子和趋化因子（Eotaxin-CCL11、IL-13、LIX-CXCL5、MIP1b-CCL4 和 MIP2）有显著差异，这些细胞因子和趋化因子已知在趋化作用中起作用。
DHA 和 AVA 的联合似乎是一种有效的治疗方案，可提高小鼠的生存率，但对细胞因子调节的效果较差，这与预防 CM 有关。这些结果呼吁进行临床试验，以评估 AVA 作为抗疟治疗的辅助药物，特别是在 CM 治疗或预防中与青蒿素为基础的联合疗法联合使用。
