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

Malaria poses a threat across several continents: Eurasia (Asia and parts o f Eastern Europe), Africa, Central and South America. Bradley (1991) estima tes human exposure at 2,073,000,000 with infection rates at 270,000,000, il lnesses at 110,000,000! and deaths at 1,000,000. Significant mortality rate s are: attributed to infection by the parasite Plasmodium falciparum, with an estimated 90% among African children. A worldwide effort is ongoing to c hemically and pharmacologically characterize a class of artemisinin compoun ds that might be promising antimalarial drugs. The U.S. Army is studying th e efficacy and toxicity of several artemisinin semi-synthetic compounds: ar temether, artemether, artelinic acid, and artesunate. The World Health Orga nization and the U.S. Army selected arteether for drug development and poss ible use in the emergency therapy of acute, severe malaria. Male Rhesus mon keys (Macaca mulatta) were administered different daily doses of arteether, or the vehicle alone (sesame oil), for a period of either 14 days, or 7 da ys. Neuropathological lesions were found in 14-day arteether treated monkey s in the precerebellar nuclei of the medulla oblongata, namely: (1) the lat eral reticular nuclei (subnuclei magnocellarus, parvicellularis, and subtri geminalis), (2) the paramedian reticular nuclei (subnuclei accessorius, dor salis, and ventralis), and the perihypoglossal nuclei (n. intercalatus of S taderini, n. of Roller, and n. prepositus hypoglossi). The data demonstrate that the simian medullary precerebellar nuclei have a high degree of vulne rability when arteether is given for 14 days at dose levels between 8 mg/kg per day and 24 mg/kg per day. The neurological consequences of this treatm ent regimen could profoundly impair posture, gait, and autonomic regulation , while eye movement disorders might also be anticipated.