Efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.

<h4>Background</h4>The genus Trichuris includes parasites of major relevance in veterinary and human medicine. Despite serious economic losses and enormous impact on public health, treatment options against whipworms are very limited. Additionally, there is an obvious lack of appropriate...

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Autores principales:	Daniel Kulke, Jürgen Krücken, Achim Harder, Georg von Samson-Himmelstjerna
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/aa7e615f461446c9b546ada612424e21
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spelling	oai:doaj.org-article:aa7e615f461446c9b546ada612424e212021-11-18T09:16:22ZEfficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.1935-27271935-273510.1371/journal.pntd.0002698https://doaj.org/article/aa7e615f461446c9b546ada612424e212014-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24587460/?tool=EBIhttps://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735<h4>Background</h4>The genus Trichuris includes parasites of major relevance in veterinary and human medicine. Despite serious economic losses and enormous impact on public health, treatment options against whipworms are very limited. Additionally, there is an obvious lack of appropriately characterized experimental infection models. Therefore, a detailed parasitological characterization of a Trichuris muris isolate was performed in C57BL/10 mice. Subsequently, the in vivo efficacies of the aminophenylamidines amidantel, deacylated amidantel (dAMD) and tribendimidine as well as the cyclooctadepsipeptides emodepside and in particular PF1022A were analyzed. This was performed using various administration routes and treatment schemes targeting histotropic and further developed larval as well as immature and mature adult stages.<h4>Methodology/principal findings</h4>Duration of prepatent period, time-dependent localization of larvae during period of prepatency as well as the duration of patency of the infection were determined before drugs were tested in the characterized trichurosis model. Amidantel showed no effect against mature adult T. muris. Tribendimidine showed significantly higher potency than dAMD after oral treatments (ED50 values of 6.5 vs. 15.1 mg/kg). However, the opposite was found for intraperitoneal treatments (ED50 values of 15.3 vs. 8.3 mg/kg). When emodepside and PF1022A were compared, the latter was significantly less effective against mature adults following intraperitoneal (ED50 values of 6.1 vs. 55.7 mg/kg) or subcutaneous (ED50 values of 15.2 vs. 225.7 mg/kg) administration. Only minimal differences were observed following oral administration (ED50 values of 2.7 vs. 5.2 mg/kg). Triple and most single oral doses with moderate to high dosages of PF1022A showed complete efficacy against histotropic second stage larvae (3 × 100 mg/kg or 1 × 250 mg/kg), further developed larvae (3 × 10 mg/kg or 1 × 100 mg/kg) and immature adults (3 × 10 mg/kg or 1×100 mg/kg). Histotropic first stage larvae were only eliminated after three doses of PF1022A (3 × 100 mg/kg) but not after a single dose.<h4>Conclusions/significance</h4>These results indicate that the cyclooctadepsipeptides are a drug class with promising candidates for further evaluation for the treatment of trichurosis of humans and livestock animals in single dose regimens.Daniel KulkeJürgen KrückenAchim HarderGeorg von Samson-HimmelstjernaPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 8, Iss 2, p e2698 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Daniel Kulke Jürgen Krücken Achim Harder Georg von Samson-Himmelstjerna Efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.
description	<h4>Background</h4>The genus Trichuris includes parasites of major relevance in veterinary and human medicine. Despite serious economic losses and enormous impact on public health, treatment options against whipworms are very limited. Additionally, there is an obvious lack of appropriately characterized experimental infection models. Therefore, a detailed parasitological characterization of a Trichuris muris isolate was performed in C57BL/10 mice. Subsequently, the in vivo efficacies of the aminophenylamidines amidantel, deacylated amidantel (dAMD) and tribendimidine as well as the cyclooctadepsipeptides emodepside and in particular PF1022A were analyzed. This was performed using various administration routes and treatment schemes targeting histotropic and further developed larval as well as immature and mature adult stages.<h4>Methodology/principal findings</h4>Duration of prepatent period, time-dependent localization of larvae during period of prepatency as well as the duration of patency of the infection were determined before drugs were tested in the characterized trichurosis model. Amidantel showed no effect against mature adult T. muris. Tribendimidine showed significantly higher potency than dAMD after oral treatments (ED50 values of 6.5 vs. 15.1 mg/kg). However, the opposite was found for intraperitoneal treatments (ED50 values of 15.3 vs. 8.3 mg/kg). When emodepside and PF1022A were compared, the latter was significantly less effective against mature adults following intraperitoneal (ED50 values of 6.1 vs. 55.7 mg/kg) or subcutaneous (ED50 values of 15.2 vs. 225.7 mg/kg) administration. Only minimal differences were observed following oral administration (ED50 values of 2.7 vs. 5.2 mg/kg). Triple and most single oral doses with moderate to high dosages of PF1022A showed complete efficacy against histotropic second stage larvae (3 × 100 mg/kg or 1 × 250 mg/kg), further developed larvae (3 × 10 mg/kg or 1 × 100 mg/kg) and immature adults (3 × 10 mg/kg or 1×100 mg/kg). Histotropic first stage larvae were only eliminated after three doses of PF1022A (3 × 100 mg/kg) but not after a single dose.<h4>Conclusions/significance</h4>These results indicate that the cyclooctadepsipeptides are a drug class with promising candidates for further evaluation for the treatment of trichurosis of humans and livestock animals in single dose regimens.
format	article
author	Daniel Kulke Jürgen Krücken Achim Harder Georg von Samson-Himmelstjerna
author_facet	Daniel Kulke Jürgen Krücken Achim Harder Georg von Samson-Himmelstjerna
author_sort	Daniel Kulke
title	Efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.
title_short	Efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.
title_full	Efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.
title_fullStr	Efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.
title_full_unstemmed	Efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.
title_sort	efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/aa7e615f461446c9b546ada612424e21
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Efficacy of cyclooctadepsipeptides and aminophenylamidines against larval, immature and mature adult stages of a parasitologically characterized trichurosis model in mice.

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