Institute of Tropical Medicine, University Hospital Tübingen, Tübingen, Germany.
Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.
PLoS Negl Trop Dis. 2021 Jun 24;15(6):e0009511. doi: 10.1371/journal.pntd.0009511. eCollection 2021 Jun.
Schistosomiasis is highly prevalent in Africa. Praziquantel is effective against adult schistosomes but leaves prepatent stages unaffected-which is a limit to patient management and elimination. Given the large-scale use of praziquantel, development of drug resistance by Schistosoma is feared. Antimalarials are promising drugs for alternative treatment strategies of Schistosoma infections. Development of drugs with activity against both malaria and schistosomiasis is particularly appealing as schistosome infections often occur concomitantly with malaria parasites in sub-Saharan Africa. Therefore, antiplasmodial compounds were progressively tested against Schistosoma in vitro, in mice, and in a clinical study.
Amongst 16 drugs and 1 control tested, pyronaridine, methylene blue and 5 other antimalarials were highly active in vitro against larval stage schistosomula with a 50% inhibitory concentration below 10 μM. Both drugs were lethal to ex vivo adult worms tested at 30 μM with methylene blue also active at 10 μM. Pyronaridine treatment of mice infected with S. mansoni at the prepatent stage reduced worm burden by 82% and cured 7 out of 12 animals, however in mice adult stages remained viable. In contrast, methylene blue inhibited adult worms by 60% but cure was not achieved. In an observational pilot trial in Gabon in children, the antimalarial drug combination pyronaridine-artesunate (Pyramax) reduced S. haematobium egg excretion from 10/10 ml urine to 0/10 ml urine, and 3 out of 4 children were cured.
Pyronaridine and methylene blue warrant further investigation as candidates for schistosomiasis treatment. Both compounds are approved for human use and evidence for their potential as antischistosomal compounds can be obtained directly from clinical testing. Particularly, pyronaridine-artesunate, already available as an antimalarial drug, calls for further clinical evaluation.
ClinicalTrials.gov Identifier NCT03201770.
血吸虫病在非洲高度流行。吡喹酮对成体血吸虫有效，但对未成熟阶段无效-这限制了对患者的管理和消除。鉴于吡喹酮的大规模使用，人们担心血吸虫会产生抗药性。抗疟药物是治疗血吸虫感染的替代治疗策略的有希望的药物。开发对疟疾和血吸虫病均有活性的药物特别有吸引力，因为在撒哈拉以南非洲，血吸虫感染通常与疟原虫同时发生。因此，抗疟化合物在体外、在小鼠体内和在临床研究中逐渐针对血吸虫进行了测试。
在所测试的 16 种药物和 1 种对照药物中，吡喃达酮、亚甲蓝和其他 5 种抗疟药物对幼虫期血吸虫有高度活性，半数抑制浓度低于 10 μM。两种药物在 30 μM 时对离体成虫均具有致死性，亚甲蓝在 10 μM 时也具有活性。吡喃达酮治疗感染曼氏血吸虫的未成熟期小鼠可使虫负荷减少 82%，并治愈 12 只动物中的 7 只，但成年期的老鼠仍存活。相比之下，亚甲蓝抑制成虫 60%，但未达到治愈效果。在加蓬的一项观察性试点试验中，抗疟药物组合吡喃达酮-青蒿琥酯（Pyramax）将 S. haematobium 的卵排量从 10/10 毫升尿液降低到 0/10 毫升尿液，4 名儿童中有 3 名治愈。
吡喃达酮和亚甲蓝值得进一步研究，作为治疗血吸虫病的候选药物。这两种化合物均已获准用于人类，并且可以直接从临床测试中获得它们作为抗血吸虫化合物的潜力的证据。特别是，吡喃达酮-青蒿琥酯，作为一种抗疟药物已经可用，需要进一步的临床评估。
ClinicalTrials.gov 标识符 NCT03201770。
