Single- and two-species tests to study effects of the anthelmintics ivermectin and morantel and the coccidiostatic monensin on soil invertebrates.

Soil invertebrates in arable land are potentially exposed to veterinary medicines excreted by husbandry. The toxicity of three widely used pharmaceuticals was therefore investigated with the use of common soil invertebrates exposed in the laboratory in single- or two-species test system. The anthelmintic morantel did not cause significant mortality to either Folsomia fimetaria or Enchytraeus crypticus even at the highest tested concentration of 900 mg kg(-1) dry soil. The coccidiostatic monensin affected the reproduction of F. fimetaria and E. crypticus with soil concentrations estimated to cause a 10% effect at values of approximately 109 and 71.8 mg kg(-1) dry soil, respectively, but caused no mortality to adult. The anthelmintic ivermectin did not affect the survival of adult Hypoaspis aculeifer. Reproduction of H. aculeifer declined approximately 45% in response to ivermectin exposure of 5 mg kg(-1) dry soil. Ivermectin was highly toxic to F. fimetaria and affected the survival of adults with soil concentrations estimated to cause a 50% mortality at values of 5.3 mg kg(-1) dry soil in the single-species test system and 0.14 mg kg(-1) dry soil in the two-species test system. Reproduction of F. fimetaria was reduced by ivermectin with 10% effective concentration at 0.19 mg kg(-1) dry soil in the single-species test system and 0.02 mg kg(-1) dry soil in two-species test system. It was shown that species interactions may influence the response of test organisms to toxic substances. The data from this study and previously published data showed that, whereas ivermectin is likely to pose a risk to soil-dwelling invertebrates, adverse effects of morantel and monensin are unlikely to occur as a result of residue excretion from treated farm animals.

Membrane-water partitioning, membrane permeability, and baseline toxicity of the parasiticides ivermectin, albendazole, and morantel.

A comparative hazard assessment of the antiparasitics ivermectin, albendazole, and morantel was performed, with a particular focus on bioavailability and uptake into biological membranes. The experimentally determined liposome-water distribution ratio at pH 7 (D(lipw) (pH 7)) of the positively charged morantel was 100 L/kg lipid. The D(lipw) (pH 7) of albendazole was 3,000 L/kg lipid. The membrane permeability determined with the parallel artificial membrane permeability assay was consistent with predictions from a quantitative structure-activity relationship (QSAR) for morantel but 14-fold lower than predicted for albendazole, which can be rationalized because neutral albendazole is, in fact, zwitterionic and the large dipole moment hinders permeation through hydrophobic membranes. An unusually large molecule, ivermectin was suspected to show decreased bioaccumulation because of its bulkiness, but experimental determination of solubility showed that it was 40-fold less soluble than expected from a QSAR between solubility and the octanol-water partition coefficient. In contrast, its membrane permeability appeared to be typical for a compound of the given hydrophobicity, but it was not possible to determine the membrane-water partition coefficient because of its low solubility and high affinity to the dialysis membrane of the experimental device. The D(lipw) (pH 7) for ivermectin of 2,700 L/kg lipid was calculated with a QSAR model. Morantel and albendazole were baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri and a test for inhibition of photosynthesis in green algae. Only ivermectin exhibited a specific effect toward algae, but the excess toxicity was not very pronounced and might be biased by the uncertainty of the estimated hydrophobicity descriptor. Overall, we did not find any unexpected effect on nontarget endpoints.

Fumarate reductase: a target for therapeutic intervention against Helicobacter pylori.

The potential of fumarate reductase as a therapeutic target against the human pathogen Helicobacter pylori was investigated by studying the cytotoxicity of morantel, oxantel, and thiabendazole, known to inhibit the enzyme in parasitic worms. Nuclear magnetic resonance spectroscopy was employed to investigate the effects of the inhibitors on the fumarate reductase activity of laboratory-adapted and wild-type bacterial strains. Production of succinate from fumarate in H. pylori cells was inhibited by morantel, oxantel, and thiabendazole. Cell growth and viability techniques were used to examine the bacteriostatic and bactericidal effects of the three anthelmintics. Each of the antiparasites arrested growth and produced cell death in liquid cultures, although the minimal inhibitory and bactericidal concentrations of these compounds are such that they would not be of therapeutic use. The strength of the effects as measured by minimal inhibitory and bactericidal concentrations was oxantel > thiabendazole > morantel. The findings suggested that fumarate reductase is an essential component of the metabolism of H. pylori and as such constitutes a possible target for therapeutic intervention in the treatment of the bacterium.