Fatal Neurotoxicity of Arteether and Artemether

Brewer, Thomas G.; Grate, Stephen J.; Peggins, James O.; Weina, Peter J.; Petras, J.M.; Levine, Barry; Heiffer, Melvin H.; Schuster, Brian G.

doi:10.4269/ajtmh.1994.51.251

Cited by 258 publications

(166 citation statements)

References 0 publications

Supporting

Mentioning

148

Contrasting

Unclassified

Order By: Relevance

“…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

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

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

“…2 However, animal studies have raised concerns about the potential neurotoxicity of some of the artemisinin derivatives. [3][4][5][6][7][8] These studies showed that rodents, dogs, and monkeys treated with intramuscular arteether or artemether (the 2 oil-soluble derivatives) develop dose-dependent damage to certain brain stem nuclei. Neurologic findings included gait disturbance, loss of spinal, brain stem, and pain responses, and, eventually, death.…”

mentioning

confidence: 99%

A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria.

Vugt¹,

Angus²,

Price³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. The artemisinin derivatives are now used widely in areas with multidrug-resistant Plasmodium falciparum malaria such as Southeast Asia, but concerns remain over their potential for neurotoxicity. Mice, rats, dogs, and monkeys treated with high doses of intramuscular artemether or arteether develop an unusual pattern of focal damage to brain stem nuclei (particularly those involved in auditory processing). To investigate whether a similar toxic effect occurs in patients treated with these compounds, clinical neurologic evaluation, audiometry and early latency auditory evoked responses were measured in a single-blind comparison of 79 patients who had been treated with Ն2 courses of oral artemether or artesunate within the previous 3 years, and 79 age-and sex-matched controls living in a malaria-endemic area on the northwestern border of Thailand. There were no consistent differences in any of these test results between the cases and controls. This study failed to detect any evidence of significant neurotoxicity in patients treated previously with oral artemether or artesunate for acute malaria.Artemisinin derivatives are now used widely for the treatment of Plasmodium falciparum malaria in Southeast Asia. On the western border of Thailand where P. falciparum has developed resistance to nearly all antimalarials, the combination of mefloquine and artesunate was introduced in 1994 as a first-line treatment. 1 More than 3,000 patients with uncomplicated falciparum malaria have been recruited subsequently in prospective studies to optimize antimalarial treatment. Detailed prospective follow-up of these patients, including simple neurologic examinations, has failed to identify any serious adverse effects associated with the 2 most widely used compounds, oral artesunate or artemether. 2 However, animal studies have raised concerns about the potential neurotoxicity of some of the artemisinin derivatives. [3][4][5][6][7][8] These studies showed that rodents, dogs, and monkeys treated with intramuscular arteether or artemether (the 2 oil-soluble derivatives) develop dose-dependent damage to certain brain stem nuclei. Neurologic findings included gait disturbance, loss of spinal, brain stem, and pain responses, and, eventually, death. Pathologic changes in these experimental animals were found even in the absence of any detectable neurobehavioural symptoms. 4,5 The neuropathologic lesions were unusual in that they were confined to the neuronal cells of certain brain stem nuclei, whereas adjacent nuclei were often unaffected. The nuclei affected included those in the auditory relay. 6,7 Despite the lack of reported toxicity in extensive clinical studies to date, 2,9 it remains possible that the artemisinin compounds produce a similar pattern of neurotoxicity in humans. To assess possible toxic effects on the brain stem in patients treated with repeated courses of artemether or artesunate, brain stem auditory evoked responses (BAERs) were measured in a case-control study. These have been used 10 to detect neurotoxici...

show abstract

Fatal Neurotoxicity of Arteether and Artemether

Cited by 258 publications

References 0 publications

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

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

A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria.

Contact Info

Product

Resources

About