Evidence for in vitro and in vivo activity of the antimalarial pyronaridine against Schistosoma

TY - JOUR

T1 - Evidence for in vitro and in vivo activity of the antimalarial pyronaridine against Schistosoma

AU - Koehne, Erik

AU - Zander, Nina

AU - Rodi, Miriam

AU - Held, Jana

AU - Hoffmann, Wolfgang

AU - Zoleko-Manego, Rella

AU - Ramharter, Michael

AU - Mombo-Ngoma, Ghyslain

AU - Kremsner, Peter G

AU - Kreidenweiss, Andrea

PY - 2021/6

Y1 - 2021/6

N2 - BACKGROUND: 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.RESULTS: 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.CONCLUSION: 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.TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03201770.

AB - BACKGROUND: 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.RESULTS: 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.CONCLUSION: 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.TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03201770.

KW - Animals

KW - Antimalarials/pharmacology

KW - Antiprotozoal Agents/pharmacology

KW - Artesunate/pharmacology

KW - Child

KW - Drug Combinations

KW - Gabon

KW - Humans

KW - Larva/drug effects

KW - Methylene Blue/pharmacology

KW - Mice

KW - Naphthyridines/pharmacology

KW - Schistosoma haematobium/drug effects

KW - Schistosoma mansoni/drug effects

KW - Schistosomiasis haematobia/drug therapy

KW - Schistosomiasis mansoni/drug therapy

U2 - 10.1371/journal.pntd.0009511

DO - 10.1371/journal.pntd.0009511

M3 - SCORING: Journal article

C2 - 34166393

VL - 15

JO - PLOS NEGLECT TROP D

JF - PLOS NEGLECT TROP D

SN - 1935-2735

IS - 6

M1 - e0009511

ER -