Arteether-induced brain injury in Macaca mulatta . I. The precerebellar nuclei: the lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei

Abstract

Malaria poses a threat across several continents: Eurasia (Asia and parts of Eastern Europe), Africa, Central and South America. Bradley (1991) estimates human exposure at 2,073,000,000 with infection rates at 270,000,000, illnesses at 110,000,000, and deaths at 1,000,000. Significant mortality rates are attributed to infection by the parasite Plasmodium falciparum, with an estimated 90% among African children. A worldwide effort is ongoing to chemically and pharmacologically characterize a class of artemisinin compounds that might be promising antimalarial drugs. The U.S. Army is studying the efficacy and toxicity of several artemisinin semi-synthetic compounds: arteether, artemether, artelinic acid, and artesunate. The World Health Organization and the U.S. Army selected arteether for drug development and possible use in the emergency therapy of acute, severe malaria. Male Rhesus monkeys (Macaca mulatta) were administered different daily doses of arteether, or the vehicle alone (sesame oil), for a period of either 14 days, or 7 days. Neuropathological lesions were found in 14-day arteether treated monkeys in the precerebellar nuclei of the medulla oblongata, namely: (1) the lateral reticular nuclei (subnuclei magnocellularis, parvicellularis, and subtrigeminalis), (2) the paramedian reticular nuclei (subnuclei accessorius, dorsalis, and ventralis), and the perihypoglossal nuclei (n. intercalatus of Staderini, n. of Roller, n. prepositus hypoglossi). The data demonstrate that the simina meduallry precerebellar nuclei have a high degree of vulnerability when arteether is given for 14 days at dose levels between 8mg/kg per day and 24 mg/kg per day. The neurological consequences of this treatment regimen could profoundly impair posture, gait, and autonomic regulation, while eye movement disorders might also be anticipated.

Neurotoxic Mode of Action of Artemisinin

“…Prominent neuropathic lesions were restricted primarily to the pons and medulla. In vivo toxicity studies with rats and monkeys also revealed neuropathies in the caudal brain stem (13,14,29,30).In humans treated with the artemisinin drugs, adverse affects directly ascribed to neurotoxicity have yet to be unambiguously demonstrated but may possibly be due to neurodegeneration (3.3% of the cases) (15,25,31,32,44).Recently, we described a new in vitro screening method using primary brain stem cell cultures from the rat (37). We demonstrated that the brain stem cells were selectively sensitive against artemisinin, in contrast to cells from other brain regions, such as the cortex.…”

Potential long-term toxicity of repeated orally administered doses of artemether in rats.

“…[4][5][6][7][8][9][10][11][12] However, there were 2 important differences in the design of these earlier experiments compared with the ones presented here. First, the previous studies quite closely followed the proposed malaria monotherapy regimen, with an artemisinin derivative administered daily for 7 consecutive days.…”

“…However, in rats, dogs, and rhesus monkeys, arteether and artemether have consistently shown symptomatic and pathological evidence of brainstem neurotoxicity after parenteral administration of high doses over several consecutive days. [4][5][6][7][8][9][10][11][12] There is accumulated evidence that neurotoxicity is dose dependent and host related, and evidence also suggests that neurotoxicity depends on the route of administration. 13 During the last 10 years, detailed in vivo studies consistently demonstrated that artemether also exhibits antischistosomal properties, with the young developmental stages being particularly susceptible.…”

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

“…Accordingly, the half life of AE was significantly prolonged from the first dosing day to the last dosing day after intramuscular AE administrations. The monkey showed moderate neurotoxicity after this intramuscular AE dosing regimen (Petras et al, 1997(Petras et al, , 2000.…”

“…Since AE-induced brainstem neuropathology in rhesus monkeys occurred at a minimal dose of 8 mg/kg dosed daily for 14 days (Petras et al, 1997(Petras et al, , 2000, the LONEL of AE was estimated to be 193.8 ng/ml. This estimate is based on our TK analysis conducted by dosing monkeys with AE at 16 mg/kg dosed daily for 14 days which should, based on a number of repeat dosing studies, result in evidence of AE-induced neurotoxicity (Petras et al, 1997;Li et al, 2006bLi et al, , 2007a.…”