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: Daniel Kulke, Jürgen Krücken, Achim Harder, Ralph Krebber, Kristine Fraatz, Heinz Mehlhorn, Georg VON Samson-Himmelstjerna
• Journal: Parasitology (Parasitology) Vol. 140 Issue 10 Pg. 1252-65 (Sep 2013) ISSN: 1469-8161 [Electronic] England
• PMID: 23742764 (Publication Type: Journal Article)

Chemical References

• Anthelmintics
• Depsipeptides
• PF 1022A

Topics

• Animals
• Anthelmintics (blood, pharmacology, therapeutic use)
• Depsipeptides (blood, pharmacology, therapeutic use)
• Drug Therapy, Combination
• Female
• Helminthiasis (drug therapy)
• Microscopy, Electron, Scanning
• Nippostrongylus (drug effects)
• Rats
• Rats, Wistar
• Treatment Outcome