S. A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada.
Department of Pharmacology, Dartmouth Medical School, Hanover, NH, USA.
Malar J. 2017 Nov 14;16(1):463. doi: 10.1186/s12936-017-2109-0.
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection associated with high mortality and neurocognitive impairment in survivors. New anti-malarials and host-based adjunctive therapy may improve clinical outcome in CM. Synthetic oleanane triterpenoid (SO) compounds have shown efficacy in the treatment of diseases where inflammation and oxidative stress contribute to pathogenesis.
A derivative of the SO 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), CDDO-ethyl amide (CDDO-EA) was investigated for the treatment of severe malaria in a pre-clinical model. CDDO-EA was evaluated in vivo as a monotherapy as well as adjunctive therapy with parenteral artesunate in the Plasmodium berghei strain ANKA experimental cerebral malaria (ECM) model.
CDDO-EA alone improved outcome in ECM and, given as adjunctive therapy in combination with artesunate, it significantly improved outcome over artesunate alone (p = 0.009). Improved survival was associated with reduced inflammation, enhanced endothelial stability and blood-brain barrier integrity. Survival was improved even when administered late in the disease course after the onset of neurological symptoms.
These results indicate that SO are a new class of immunomodulatory drugs and support further studies investigating this class of agents as potential adjunctive therapy for severe malaria.
脑型疟疾（CM）是由恶性疟原虫感染引起的一种严重并发症，幸存者常伴有高死亡率和神经认知障碍。新型抗疟药物和宿主靶向辅助治疗可能改善 CM 的临床结局。合成齐墩果烷三萜（SO）化合物在炎症和氧化应激导致发病机制的疾病治疗中显示出疗效。
一种 SO 的衍生物 2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸乙酯（CDDO-EA）在临床前模型中被用于治疗严重疟疾。CDDO-EA 被评估为单一疗法以及与青蒿琥酯联合的辅助疗法，在伯氏疟原虫 ANKA 实验性脑型疟疾（ECM）模型中。
CDDO-EA 单独治疗可改善 ECM 的结局，并且作为辅助疗法与青蒿琥酯联合使用时，其疗效明显优于青蒿琥酯单一疗法（p=0.009）。改善的生存与炎症减少、内皮稳定性增强和血脑屏障完整性有关。即使在发病后神经系统症状出现后晚期开始治疗，也能提高生存率。
这些结果表明，SO 是一类新的免疫调节剂，支持进一步研究这类药物作为严重疟疾的潜在辅助治疗。
