COMPARATIVE IN-VITRO EFFECTS OF CLOSANTEL AND SELECTED BETA-KETOAMIDEANTHELMINTICS ON A GASTROINTESTINAL NEMATODE AND VERTEBRATE LIVER-CELLS

PNU-87407 and PrNU-88509, beta-ketoamide anthelmintics that are struct urally related to each other and to the salicylanilide anthelmintic cl osantel, 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, H aemonchus contortus, and in a vertebrate liver cell line and mitochond ria, PNU-87407 and PNU-88509 both exhibited functional cross-resistanc e with closantel in larval migration assays using closantel-resistant and -sensitive isolates of H, contortus. Each compound reduced motilit y and,ATP levels in cultured adult H. contortus in a concentration- an d time-dependent manner: however, motility was reduced more rapidly by PNU-88509, and ATP levels were reduced by lower concentrations of clo santel than the beta-ketoamides. Tension recordings from segments of a dult H, contortus showed that PNU-88509 induces spastic paralysis, whi le PNU-87407 and closantel induce flaccid paralysis of the somatic mus culature. Marked differences in the actions of these compounds were al so observed in the mammalian preparations. In Chang liver cells, ATP l evels were reduced after 3 h exposures to greater than or equal to 0.2 5 mu M PNU-87407 1 mu M closantel or 10 mu 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 an d 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 mu M respectively.