title: Subchronic toxicological study of two artemisinin derivatives in dogs.
abstract: The objective of our study was to profile and compare the systematic changes between orally administered artesunate and intramuscularly injected artemether at a low dose over a 3-month period (92 consecutive days) in dogs. Intramuscular administration of 6 mg kg-1 artemether induced a decreased red blood cell (RBC) count (anemia), concurrent extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. We also observed a prolonged QT interval and neuropathic changes in the central nervous system, which demonstrated the cortex and motor neuron vulnerability, but no behavioral changes. Following treatment with artesunate, we observed a decreased heart rate, which was most likely due to cardiac conduction system damage, as well as a deceased RBC count, extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. However, in contrast to treatment with artemether, neurotoxicity was not observed following treatment with artesunate. In addition, ultra-structural examination by transmission electron microscopy showed mitochondrial damage following treatment with artesunate. These findings demonstrated the spectrum of toxic changes that result upon treatment with artesunate and artemether and show that the prolonged administration of low doses of these derivatives result in diverse toxicity profiles.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Ji-ye
authors.initials: JY
authors.lastname: Yin
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: He-mei
authors.initials: HM
authors.lastname: Wang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Quan-jun
authors.initials: QJ
authors.lastname: Wang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Yan-sheng
authors.initials: YS
authors.lastname: Dong
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Han
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Yong-biao
authors.initials: YB
authors.lastname: Guan
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Ke-yong
authors.initials: KY
authors.lastname: Zhao
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Wen-sheng
authors.initials: WS
authors.lastname: Qu
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Xiao-xin
authors.initials: XX
authors.lastname: Gao
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Shu-fang
authors.initials: SF
authors.lastname: Jing
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Ri-gao
authors.initials: RG
authors.lastname: Ding
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000633:toxicity*; D000077332:Artesunate; D004285:Dogs; D004906:Erythrocyte Count; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D007273:Injections, Intramuscular; D008297:Male; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D018675:Toxicity Tests
chemical_list: D037621:Artemisinins; D000077332:Artesunate; D000077549:Artemether
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