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Neurotoxicity assessment of artemether in juvenile rats

Beckman, David and Youreneff, Maureen and Butt, Mark (2013) Neurotoxicity assessment of artemether in juvenile rats. Birth Defects Research Part B: Developmental and Reproductive Toxicology, 98 (2). pp. 183-199. ISSN 1542-9741

Abstract

BACKGROUND: Oral administration of artemether in combination with lumefantrine is approved for the treatment of malaria in adults and children. In adult animals, artemether can produce neurotoxicity with intramuscular, but not oral, administration. Herein, the potential of orally administered artemether to produce neurotoxicity in juvenile rats is investigated. METHODS: In the first study, the toxicity of artemether was evaluated in juvenile rats dosed with 0, 10, 30 and 100 m/k/d on post partum days (ppd) 7-21. In-life, clinical pathology, anatomic pathology, functional, and toxicokinetics evaluations were performed. The second study focused on neurotoxicity during different dosing intervals, with doses of 0, 30, and 80 m/k/d on ppd 7-13, and doses of 0, 30, and 120 m/k/d on ppd 14-21, 22-28, and 29-36. For each dosing interval, in-life, extensive histology, toxicokinetics, and functional evaluations were performed. In the third study, toxicokinetics evaluations in the adult were conducted at 20 and 200 m/k/d. RESULTS: The first study demonstrated increased mortality, renal necrosis, and brain hemorrhage at ≥ 30 m/k/d with no chronic effects in surviving animals. In the second study, increased mortality, body weight effects, and a trend towards increased exposure were observed in the ppd 14 and younger animals. Neither specific neurotoxicity nor chronic effects were seen. The toxicokinetic study in adults revealed a trend towards lower exposures as compared to those in the younger juvenile rats. CONCLUSIONS: As in the adult rat, oral administration of artemether in the juvenile rat is not associated with the neurotoxicity produced by intramuscular administration.

Item Type: Article
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Keywords: artemether; juvenile toxicity; neurotoxicity; rat
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8554

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