Comparative in vitro effects of closantel and selected β-ketoamide anthelmintics on a gastrointestinal nematode and vertebrate liver cells |
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| Authors: | JA BACON RG ULRICH JP DAVIS EM THOMAS SS JOHNSON GA CONDER NC SANGSTER JT ROTHWELL RO MCCRACKEN BH LEE MF CLOTHIER TG GEARY & DP THOMPSON |
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| Institution: | Investigative Toxicology Research, Pharmacia &Upjohn, Inc.,;Animal Health Discovery Research, Pharmacia &Upjohn, Inc. Kalamazoo, MI 49001, USA,;Department of Veterinary Pathology, University of Sydney, Sydney, Australia,;Department of Biology, Purdue University, Indianapolis, IN 46202 (deceased) |
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| Abstract: | PNU-87407 and PNU-88509, β-ketoamide anthelmintics that are structurally related to each other and to the salicylanilide anthelmintic closantel, exhibit different anthelmintic spectra and apparent toxicity in mammals. The basis for this differential pharmacology was examined in experiments that measured motility and adenosine triphosphate (ATP) levels in larval and adult stages of the gastrointestinal nematode, Haemonchus contortus , and in a vertebrate liver cell line and mitochondria. PNU-87407 and PNU-88509 both exhibited functional cross-resistance with closantel in larval migration assays using closantel-resistant and -sensitive isolates of H. contortus . Each compound reduced motility and ATP levels in cultured adult H. contortus in a concentration- and time-dependent manner; however, motility was reduced more rapidly by PNU-88509, and ATP levels were reduced by lower concentrations of closantel than the β-ketoamides. Tension recordings from segments of adult H. contortus showed that PNU-88509 induces spastic paralysis, while PNU-87407 and closantel induce flaccid paralysis of the somatic musculature. Marked differences in the actions of these compounds were also observed in the mammalian preparations. In Chang liver cells, ATP levels were reduced after 3 h exposures to  0.25 μ M PNU-87407, 1 μ M closantel or 10 μ M PNU-88509. Reductions in ATP caused by PNU-88509 were completely reversible, while the effects of closantel and PNU-87407 were irreversible. PNU-87407, closantel and PNU-88509 uncoupled oxidative phosphorylation in isolated rat liver mitochondria, inhibiting the respiratory control index (with glutamate or succinate as substrate) by 50% at concentrations of 0.14, 0.9 and 7.6 μ M , respectively. |
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