Artemisinin Neurotoxicity: Neuropathology in Rats and Mechanistic Studies in Vitro

Kamchonwongpaisan, Sumalee; McKeever, Paul E.; Hossler, Paul A.; Ziffer, Herman; Meshnick, Steven R.

doi:10.4269/ajtmh.1997.56.7

Cited by 93 publications

(60 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The neurotoxicity reported in rodents, dogs, and monkeys has occurred with high doses. 2,[4][5][6]14 In this series of mice, the cumulative dose causing clinical neurotoxicity in 50% of animals FIGURE 6. Correlation between clinical severity scores and neuropathic severity scores in mice receiving intramuscular artemether (25−100 mg/kg/day for 28 days).…”

Section: Discussionmentioning

confidence: 87%

“…[3][4][5][6][7][8][9] Neurotoxicity was dose-dependent and occurred after exposure of doses more than 25 mg/kg per day for 28 consecutive days. Although compared with the other species tested, the mouse appears to be relatively resistant to the neurotoxic effects of artemether, these results are in accordance with those of the studies of Genovese and others, 8,14 who did not observe any neurologic changes in rats receiving doses lower than 25 mg/ kg artemether for seven days.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Nontprasert¹,

Pukrittayakamee²,

Dondorp³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Intramuscular administration of high doses of artemether and arteether to experimental mammals produces selective damage to brain stem centers involved predominantly in auditory processing and vestibular reflexes. The relationship between clinical signs of neurotoxicity and neuropathologic toxicity was studied in the mouse. Intramuscular artemether (50−100 mg/kg/day for 28 days) caused dose-dependent neuropathologic damage to the brain stem. There was no pathologic evidence of neuronal death in mice receiving either oral artemether, or oral or intramuscular artesunate, in doses up to 300 mg/kg/day. The neurons in the lower brain stem trapezoid nucleus, the gigantocellular reticular nucleus, and the inferior cerebellar peduncle were the most sensitive to the toxic effects of artemether. All mice with neuropathologic changes also showed behavioral changes, whereas in some mice with gait disturbance, no corresponding histopathologic damage could be detected. Thus clinical assessment was a sensitive measure of neurotoxicity. There may be a reversible component to artemether neurotoxicity.

show abstract

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Nontprasert¹,

Pukrittayakamee²,

Dondorp³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

show abstract

“…Also reported were allergic reactions [8] , haemolysis [9] and mild hearing loss [10] . In animal studies side effects documented include neurotoxicity [11,12] and contragestational effects in animals [4,13] . The fact that artemisinin anti-malarials originated from a Chinese herb and did not undergo extensive rigors of orthodox drug development, calls for continuous animal toxicity studies on these drugs [14] .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Toxic Effects of Dihydroartemisinin on the Vital Organs of Wistar Albino Rats

Utoh-nedosa¹,

Akah²,

Okoye³

et al. 2009

American J. of Pharmacology and Toxicology

View full text Add to dashboard Cite

Problem statement:The current surge in the use of Artemisinin based Combination Therapy (ACT) in the treatment of falciparium resistant malaria in the tropics and the potentials of Dihydroartemisinin (DHA), a member of the artemisinin family, to produce toxic effect in the vital organs (such as the liver, heart, lungs, intestine, spleen kidney and blood cells) necessitated this research. Approach: Rats were treated once orally with DHA (2 mg kg −1 ) on day 1 and then (1 mg kg −1 ) on day 2-5 and the treatment was repeated 7 days after the first treatment. The animals were sacrificed 24 h after the second treatment for toxicity studies on the vital organs and liver enzymes activity tests: Serum Alanine amino Transferase (ALT), Serum Aspartate amino Transferase (AST) and serum Alkaline Phosphatase (ALP) tests. Results: Results indicated that dihydroartemisinin significantly (p<0.05) elevated the Packed Cell Volume (PCV), the total White Cell Count (WBC), the percentage neutrophil count (NC) and the percentage Lymphocyte Count (LC). DHA did not affect the serum levels of ALT, AST and ALP, as all the values fell within the normal laboratory range. Histopathological studies revealed no evidence of toxicities in the heart, liver, lungs, intestine, spleen and kidney. The DHA treated and control rats exhibited 75.87 and 29.76% increase in the mean body weight respectively at the end of the second treatment. Conclusion/Recommendations: Oral DHA had no deleterious effects on the hematological parameters, did not alter the values of serum liver enzymes and is devoid of obvious toxic effects on vital organs at the doses tested, while the effects on the WBC also suggested potentials of immunomodulatory effects.

show abstract

“…These centers are concerned predominantly with the auditory and vestibular relays. [3][4][5][6][7] In a mouse model of neurotoxicity, we have shown recently that parenteral artesunate, a water-soluble derivative of dihydroartemisinin, is significantly less neurotoxic than intramuscular artemether. 8 Since both artesunate and artemether are metabolized in vivo back to the parent dihydroartemisinin, and as this is the most neurotoxic of all the compounds in cell culture systems, 9 these data suggested that pharmacokinetic rather than pharmacodynamic factors may be the more important in determining neurotoxic potential.…”

Section: Introductionmentioning

confidence: 99%

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Nontprasert¹,

Pukrittayakamee²,

Nosten‐Bertrand³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED 50 ), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether Ͼ 100 mg/ kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P ϭ 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED 50 ϭ 150 mg/kg/day (P ϭ 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential.

show abstract

Artemisinin Neurotoxicity: Neuropathology in Rats and Mechanistic Studies in Vitro

Cited by 93 publications

References 0 publications

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Evaluation of the Toxic Effects of Dihydroartemisinin on the Vital Organs of Wistar Albino Rats

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Contact Info

Product

Resources

About