Department of Microbiology and Molecular Genetics, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University of Jerusalem (HU)-Hadassah Medical School (HMS), Jerusalem, Israel.
Macromolecular Chemistry II, University of Bayreuth, Universitätsstrasse 30, Bayreuth, Germany.
Parasit Vectors. 2017 Mar 1;10(1):117. doi: 10.1186/s13071-017-2018-7.
Cerebral malaria (CM) is a leading cause of malarial mortality resulting from infection by Plasmodium falciparum. Treatment commonly involves adjunctive care and injections or transfusion of artemisinins. All artemisinins that are in current use are metabolized to dihydroxyartemisinin (DHA), to which there is already some parasite resistance. We used artemisone, a derivative that does not convert to DHA, has improved pharmacokinetics and anti-plasmodial activity and is also anti-inflammatory (an advantage given the immunopathological nature of CM).
We examined controlled artemisone release from biodegradable polymers in a mouse CM model. This would improve treatment by exposing the parasites for a longer period to a non-toxic drug concentration, high enough to eliminate the pathogen and prevent CM. The preparations were inserted into mice as prophylaxis, early or late treatment in the disease course.
The most efficient formulation was a rigid polymer, containing 80 mg/kg artemisone, which cured all of the mice when used as early treatment and 60% of the mice when used as a very late treatment (at which stage all control mice would die of CM within 24 h). In those mice that were not completely cured, relapse followed a latent period of more than seven days. Prophylactic treatment four days prior to the infection prevented CM. We also measured the amount of artemisone released from the rigid polymers using a bioassay with cultured P. falciparum. Significant amounts of artemisone were released throughout at least ten days, in line with the in vivo prophylactic results.
Overall, we demonstrate, as a proof-of-concept, a controlled-sustained release system of artemisone for treatment of CM. Mice were cured or if treated at a very late stage of the disease, depicted a delay of a week before death. This delay would enable a considerable time window for exact diagnosis and appropriate additional treatment. Identical methods could be used for other parasites that are sensitive to artemisinins (e.g. Toxoplasma gondii and Neospora caninum).
脑型疟疾（CM）是由恶性疟原虫感染引起的疟疾死亡的主要原因。治疗通常包括辅助治疗和注射或输血青蒿素类药物。目前使用的所有青蒿素类药物都会代谢为双氢青蒿素（DHA），而寄生虫已经对 DHA 产生了一定的耐药性。我们使用了青蒿琥酯，一种不会转化为 DHA 的衍生物，它具有更好的药代动力学和抗疟原虫活性，同时也具有抗炎作用（鉴于 CM 的免疫病理性质，这是一个优势）。
我们在小鼠 CM 模型中研究了可生物降解聚合物中青蒿琥酯的控制释放。这将通过使寄生虫更长时间暴露于无毒药物浓度来改善治疗效果，该浓度足以消除病原体并预防 CM。这些制剂被插入到小鼠体内，作为预防、疾病早期或晚期治疗。
最有效的制剂是一种刚性聚合物，其中含有 80mg/kg 的青蒿琥酯，早期治疗时，所有小鼠均被治愈，晚期治疗（此时所有对照小鼠将在 24 小时内死于 CM）时 60%的小鼠被治愈。在那些未完全治愈的小鼠中，复发潜伏期超过七天。在感染前四天进行预防性治疗可预防 CM。我们还使用培养的恶性疟原虫进行生物测定测量了从刚性聚合物中释放的青蒿琥酯的量。在至少 10 天内释放了大量的青蒿琥酯，与体内预防性结果一致。
总的来说，我们证明了一种青蒿琥酯的控释系统可以作为治疗 CM 的概念验证。如果小鼠被治愈，或者在疾病的晚期进行治疗，则在死亡前会延迟一周。这将为准确诊断和适当的附加治疗提供一个相当长的时间窗口。相同的方法可用于其他对青蒿素敏感的寄生虫（例如刚地弓形虫和新生隐球菌）。
