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In vivo efficacy of PF1022A and nicotinic acetylcholine receptor agonists alone and in combination against Nippostrongylus brasiliensis

Published online by Cambridge University Press:  07 June 2013

DANIEL KULKE ,
JÜRGEN KRÜCKEN ,
ACHIM HARDER ,
RALPH KREBBER ,
KRISTINE FRAATZ ,
HEINZ MEHLHORN  and
GEORG VON SAMSON-HIMMELSTJERNA
DANIEL KULKE*
Affiliation:
Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany Global Drug Discovery – Animal Health – Parasiticides, Bayer HealthCare, Leverkusen, Germany
JÜRGEN KRÜCKEN
Affiliation:
Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany
ACHIM HARDER
Affiliation:
Department for Biology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
RALPH KREBBER
Affiliation:
Research and Development – Development – Human Safety – Residue Analysis, Bayer CropScience AG, Monheim am Rhein, Germany
KRISTINE FRAATZ
Affiliation:
Global Drug Discovery – Animal Health – Department for Pharmacokinetics and Safety, Bayer HealthCare, Leverkusen, Germany
HEINZ MEHLHORN
Affiliation:
Institute for Zoomorphology, Cytology and Parasitology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
GEORG VON SAMSON-HIMMELSTJERNA
Affiliation:
Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany
*
*Corresponding author. Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Königsweg 67, 14163 Berlin, Germany. E-mail: daniel.kulke@fu-berlin.de
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Summary

The cyclooctadepsipeptide PF1022A and the aminophenylamidines amidantel, deacylated amidantel (dAMD) and tribendimidine were tested as examples for drug classes potentially interesting for development as anthelmintics against human helminthiases. These compounds and levamisole were tested alone and in combination to determine their efficacy against the rat hookworm Nippostrongylus brasiliensis. After three oral treatments, intestinal worms were counted. Drug effects on parasite morphology were studied using scanning electron microscopy (SEM). Plasma pharmacokinetics were determined for tribendimidine and dAMD. All drugs reduced worm burden in a dose-dependent manner, however amidantel was significantly less active than the other aminophenylamidines. Combinations of tribendimidine and dAMD with levamisole or PF1022A at suboptimal doses revealed additive effects. While PF1022A caused virtually no changes in morphology, levamisole, dAMD and tribendimidine caused severe contraction, particularly in the hind body region. Worms exposed to combinations of PF1022A and aminophenylamidines were indistinguishable from worms exposed only to aminophenylamidines. After oral treatment with tribendimidine, only the active metabolite dAMD was detectable in plasma and concentrations were not significantly different for oral treatment with dAMD. The results support further evaluation of cyclooctadepsipeptides alone and in combination with cholinergic drugs to improve efficacy. Combining these with registered drugs may help to prevent development of resistance.

Keywords

PF1022Atribendimidineamidanteldeacylated amidantelNippostrongylus brasiliensisanthelminticshookwormscyclooctadepsipeptidesaminophenylamidines
Type
Research Article
Information
Parasitology , Volume 140 , Issue 10 , September 2013 , pp. 1252 - 1265
Copyright
Copyright © Cambridge University Press 2013 

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