Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs

Artemether (AM) is an antimalarial drug derived from artemisinin (Qinghaosu ), an extract of the herb Artemisia annua L,., sweet wormwood. Its antipara sitic effect is that of a schizontocide and is explained by rapid uptake by parasitized erythrocytes and interaction with a component of hemoglobin de gradation resulting in formation of free radicals. It has been shown to exh ibit a high clinical cure rate. Previous animal safety studies with Qinghao su derivatives revealed dose-dependent neurotoxicity with movement disturba nces and neuropathic changes in the hindbrain of intramuscularly treated do gs, rats and monkeys. Such effects have not been seen in man. The objective of our present studies was to compare the effects of high levels of AM adm inistered to dogs p.o. versus i.m. In a pilot study 20 mg/kg/day of AM was given i.m. to groups of 3 male Beagle dogs for 5 and 30 days, respectively. Clinical signs of neurotoxicity were noted in some individual dogs from te st day 23 on. One dog had to be sacrificed pre-term. Hematologic findings i ndicated a hypochromic, microcytic anemia. Microscopic examination demonstr ated neuropathic changes only at 30 days, but not at 5 days. The animals ha d neuronal and secondary axonal damage, most prominent in the cerebellar ro of, pontine and vestibular nuclei, and in the raphe/paralemniscal region. T he affected neurons showed loss of Nissl substance, cytoplasmic eosinophili a, shrinkage of the nucleus and in advanced stages scavenging by microglia. In a subsequent experiment, AM was administered to groups of 4 male and 4 female dogs, respectively, at 8 daily doses of 0, 20, 40 and 80 mg/kg i.m., or 0, 50, 150 and 600 mg/kg p.o. Neurologic signs were seen at high i.m. d oses only. In most animals they were inconspicuous and consisted of reduced activity with convulsions seen in single dogs shortly before death. Neuron al damage occurred in all animals at 40 and 80 mg/kg following i.m. treatme nt. At 20 mg/kg minimal effects occurred in 5/8 dogs only, indicating that this level was close to tolerated exposure. No comparable lesions were obse rved after oral administration. Both i.m. and p.o. exposure at high dose le vels was associated with a prolongation of mean QT interval of EGG, suggest ing slowing of repolarization of the myocardium. Individual data indicated that in 1 of 4 females at 80 mg/kg i.m. this prolongation was above the 25% level considered as threshold for concern. After intramuscular administrat ion pharmacokinetics indicated peak plasma levels of AM at 2 to 4 hours pos tdose, slow elimination and a tendency to accumulate after repeated adminis tration. Only low levels of the major metabolite, dihydroartemisinin (DHA), were found. AM levels in the cerebrospinal fluid (CSF) were < 10 % of plas ma levels. After oral administration AM concentrations were consider ably l ower than after i.m. administration. The concentration of DHA was high on d ay 1 but almost nil on day 7 indicating its fast inactivation in dogs. Two hours after the 8(th) oral administration neither AM nor DHA was detected i n CSF which may explain the absence of neurotoxicity in dogs after oral adm inistration of AM.