title: In vivo efficacy of PF1022A and nicotinic acetylcholine receptor agonists alone and in combination against Nippostrongylus brasiliensis.
abstract: 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.
authors.affiliation: Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kulke
authors.affiliation: Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krücken
authors.affiliation: Department for Biology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Harder
authors.affiliation: Research and Development - Development - Human Safety - Residue Analysis, Bayer CropScience AG, Monheim am Rhein, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Krebber
authors.affiliation: Global Drug Discovery - Animal Health - Department for Pharmacokinetics and Safety, Bayer HealthCare, Leverkusen, Germany.
authors.forename: Kristine
authors.initials: K
authors.lastname: Fraatz
authors.affiliation: Institute for Zoomorphology, Cytology and Parasitology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Mehlhorn
authors.affiliation: Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: VON Samson-Himmelstjerna
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D047630:Depsipeptides / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006373:Helminthiasis / Q000188:drug therapy*; D008855:Microscopy, Electron, Scanning; D009559:Nippostrongylus / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D000871:Anthelmintics; D047630:Depsipeptides; C075544:PF 1022A