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 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.
Petras
J M
JM
Division of Neurosciences, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Young
G D
GD
Bauman
R A
RA
Kyle
D E
DE
Gettayacamin
M
M
Webster
H K
HK
Corcoran
K D
KD
Peggins
J O
JO
Vane
M A
MA
Brewer
T G
TG
D000818:Animals; D000962:Antimalarials / Q000633:toxicity*; D037621:Artemisinins; D001930:Brain Injuries / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping; D002531:Cerebellum / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008253:Macaca mulatta; D016779:Malaria, Cerebral / Q000188:drug therapy; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D012154:Reticular Formation / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D012717:Sesquiterpenes / Q000633:toxicity*
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C055141:artemotil