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

Abstract

Artemether (AM) is an antimalarial drug derived from artemisinin (Qinghaosu), an extract of the herb Artemisia annua L., sweet wormwood. Its antiparasitic effect is that of a schizontocide and is explained by rapid uptake by parasitized erythrocytes and interaction with a component of hemoglobin degradation resulting in formation of free radicals. It has been shown to exhibit a high clinical cure rate. Previous animal safety studies with Qinghaosu derivatives revealed dose-dependent neurotoxicity with movement disturbances and neuropathic changes in the hindbrain of intramuscularly treated dogs, 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 administered 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 test day 23 on. One dog had to be sacrificed pre-term. Hematologic findings indicated a hypochromic, microcytic anemia. Microscopic examination demonstrated neuropathic changes only at 30 days, but not at 5 days. The animals had neuronal and secondary axonal damage, most prominent in the cerebellar roof, pontine and vestibular nuclei, and in the raphe/paralemniscal region. The affected neurons showed loss of Nissl substance, cytoplasmic eosinophilia, 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. doses only. In most animals they were inconspicuous and consisted of reduced activity with convulsions seen in single dogs shortly before death. Neuronal damage occurred in all animals at 40 and 80 mg/kg following i.m. treatment. 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 observed after oral administration. Both i.m. and p.o. exposure at high dose levels was associated with a prolongation of mean QT interval of ECG, suggesting 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 administration pharmacokinetics indicated peak plasma levels of AM at 2 to 4 hours post-dose, slow elimination and a tendency to accumulate after repeated administration. Only low levels of the major metabolite, dihydroartemisinin (DHA), were found. AM levels in the cerebrospinal fluid (CSF) were < 10% of plasma levels. After oral administration AM concentrations were considerably lower than after i.m. administration. The concentration of DHA was high on day 1 but almost nil on day 7 indicating its fast inactivation in dogs. Two hours after the 8th oral administration neither AM nor DHA was detecte...

Pharmacokinetic (PK) and Pharmacodynamic Profiles of Artemisinin Derivatives Influence Drug Neurotoxicity in Animals

“…Similar accumulation results for AM were reported in dog plasma after daily intramuscular administration of 20, 40, and 80 mg/kg for 7 days (Classen et al, 1999). The PK profiles of AM dosed IM at 20 and 40 mg/kg in beagles is shown in Table 2.…”

“…Two hours after the eighth administration (on day 8), only low levels of AM (25, 60, and 71 ng/ml)were found in the cerebrospinal fluid (CSF) after dosing with 20, 40, and 80 mg/kg respectively. AM levels in the CSF were < 10% of the AM observed in the plasma concentration (Classen et al, 1999).…”

“…Similar results were found in animals treated IM with AM at 40 mg/kg daily for 7 days. The C max of AM (720 ng/ml) on day 7 was much higher than on day 1 (580 ng/ml), and the AUC (12.52 µg·h/ml) doubled on day 7 from the AUC observed on day 1 (6.70 µg·h/ml), indicating that the exposure concentration of AM had been increased (Classen et al, 1999).…”

“…In comparison to the dogs treated with intramuscular AE, the total AUCs observed in animals treated with AM dosed IM at 20 mg/kg (32.13 µg·h/ml) and 40 mg/kg (86.27 µg·h/ml) were significantly higher than the AUC observed after dosing with AE at 15 mg/kg (24.39 µg·h/ml) (Classen et al, 1999;Li et al, 1999a). The severity of neurotoxicity observed after dosing with intramuscular AM in dogs, however, was minimal in the 20 mg/kg group and moderate in the 40 mg/kg group.…”

“…We will outline the data that supports the hypothesis that drug accumulation with prolonged exposure time (half-life) demonstrated by PK profiling accompanies the neurological effects shown by Pharmacodynamic (PD) profiling. As will be shown, there is been shown to result in fatal neurotoxicity following intramuscular injection (Classen et al, 1999;Li et al, 2000). Table 1.…”