Hochschulschrift:
Zugl.: Hannover, Tierärztl. Hochsch., Inst. für Pathologie, Diss., 2009
Anmerkungen:
Beschreibung:
Malaria, Artemether, Chromatolyse. - Artemisinin compounds are now used as first-line antimalarial drugs but converse information is available regarding animal and human toxicity. The aim of this study was a morphological evaluation of brains and ears of dogs after administration of multiple-doses of artemether or artemether-lumefantrine for three and eight-days in two various modes of application (i. m. or orally). Dogs treated with high-doses (40 mg/kg b. w.) of artemether for eight days intramuscularly displayed significantly more neuropathological changes in the brain stem with various degrees of severity compared to all other experimental groups of animals. The alterations in the brain occurred in a dose- and time-related and non-specific manner. The lesions included neuronal degeneration characterized by central chromatolysis, total chromatolysis, swelling and rounding of neurons, increased granular eosinophilic cytoplasm, vacuolization of cytoplasm and neuronal necrosis characterized by karyopyknosis, karyorrhexis and karyolysis. In addition, axonal damage in form of spheroid formation, and mild inflammatory changes were present. Reactive lesions were characterized by gliosis located in areas with neuronal damage. Occasionally mild inflammatory infiltrations were observed. The pathogenesis of neurotoxicity is not well understood, but appears to be closely related to a sustained level of the circulating drug (prolonged exposure time) or a metabolite. Laboratory research on this topic has decreased in recent years, even as major questions regarding to neurotoxicity remained to be addressed. If effective pharmacovigilance is to be maintained with the continued increase in the use of artemisinins, it is particularly important that progress is made in these areas. Although neurotoxicity in animal studies has been documented fairly well, the artemisinins have been increasingly deployed in the global fight against falciparum malaria in humans, even though it cannot be completely ruled out that the artemisinin derivatives have a potential neurotoxic effect in humans.