| Autor: |
Brewer TG; Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, DC 20307-5100., Peggins JO, Grate SJ, Petras JM, Levine BS, Weina PJ, Swearengen J, Heiffer MH, Schuster BG |
| Jazyk: |
angličtina |
| Zdroj: |
Transactions of the Royal Society of Tropical Medicine and Hygiene [Trans R Soc Trop Med Hyg] 1994 Jun; Vol. 88 Suppl 1, pp. S33-6. |
| DOI: |
10.1016/0035-9203(94)90469-3 |
| Abstrakt: |
Several artemisinin (qinghaosu) derivatives have been developed and are in use as antimalarial drugs but scant animal or human toxicity data are available. We noted a progressive syndrome of clinical neurological defects with cardio-respiratory collapse and death in 5/6 dogs dosed daily for 8 d with intramuscular arteether (AE) at 20 mg/kg/d in a pharmacokinetic study. Neurological findings included gait disturbances, loss of spinal reflexes, pain response reflexes and prominent loss of brain-stem and eye reflexes. Electrocardiography showed prolongation of the QT interval corrected for rate (QTc). Prominent neuropathic lesions were sharply limited to the pons and medulla. Neurological injury, graded by a pathologist 'blinded' to dose group, showed a dose-related region-specific injury which was most pronounced in the pons and medulla in all animals. Rats treated with AE and artemether (AM) at 12.5 to 50 mg/kg/d for 28 d confirmed clinical neurological abnormalities with high doses (> 25 mg/kg/d) after 6-14 d. Neuropathological examination of rat brain sections at 5 levels from the rostral cerebrum to the caudal medulla showed a dose-related pattern of injury characterized by hyalinized neuron cell bodies and loss of Nissl substance; changes congruent with those noted in dogs. No significant difference was noted in the extent, type, or distribution of lesions in the brains of rats treated with equivalent doses of AE or AM.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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