Dose-Dependent Brainstem Neuropathology Following Repeated Arteether Administration in Rats

Genovese, Raymond F.; Newman, Donald B.; Li, Qigui; Peggins, James O.; Brewer, Thomas G.

doi:10.1016/s0361-9230(97)00339-0

Cited by 63 publications

(40 citation statements)

References 10 publications

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“…No neurologic abnormalities were observed following administration of 25 or 30 mg/ kg/day of parenteral arteether for 6 or 8 days to rats, but neurologic abnormalities were observed following administration of 50 mg/kg/day for 5-6 days. [3][4][5][6] High doses of arteether or artemether (20 mg/kg/day given intramuscularly for 8 days) are lethal in dogs, causing a progressive syndrome of clinical neurologic defects culminating in cardiorespiratory collapse. 6 Route of administration influences the toxicity: oral intermittent dosing of the same drugs is considerably less toxic.…”

Section: Discussionmentioning

confidence: 99%

“…The auditory evoked response tests the auditory pathway through its central connections and allows identification of the level at which abnormalities occur. Based on animal studies, [3][4][5][6][7][8] it was considered prospectively that the III to V latency would be the most likely to be affected by toxicity. There was no significant difference between cases and controls in IPLs I-V and III-V for both the right and left ears.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

“…They should be particularly useful when the auditory pathways or cochlea are involved specifically, as in the case of experimental artemisinin animal neurotoxicity. [3][4][5][6][7][8] …”

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confidence: 99%

“…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.…”

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confidence: 99%

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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

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…They should be particularly useful when the auditory pathways or cochlea are involved specifically, as in the case of experimental artemisinin animal neurotoxicity. [3][4][5][6][7][8] …”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

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Antimalarial Agents

Casteel¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Malaria continues to be a major global health problem and seems to be increasing in some parts of the world. By way of an introduction, relevant aspects of the disease, including incidence and resistance, and of the parasite and its biochemistry and genetics are presented. The chemotherapeutic agents now available to prevent and treat malaria are discussed individually. Some of these drugs have been in use for decades or even centuries, such as quinine, chloroquine, and primaquine. Other agents are of more recent origin including mefloquine, halofantrine, atovaquone, and the artemisinins. Chloroquine had been the drug of first resort for many years. It is inexpensive, well‐tolerated, and extremely effective where parasites remain sensitive. But the development of resistance to chloroquine has emphasized the need for new agents and strategies to treat malaria. New information on the genetic basis of chloroquine resistance and on the overall mechanism of action of chloroquine holds promise for advances in therapy. Another important tactic in dealing with infection by resistant parasites is the use of drug combinations. The combination of pyrimethamine and sulfadoxine has been very successful, but resistance is developing. Newer, highly effective combinations include atovaquone with proguanil, lumefantrine with artemether, and chlorproguanil with dapsone. The artemisinin group of compounds has made a powerful positive impact on malaria chemotherapy although their use in monotherapy is not recommended. Details of the mechanism of action of these drugs are becoming clearer. Knowledge about action should assist in addressing issues of possible toxicity. Great progress has been made in sequencing the genome of Plasmodium falciparum . New molecular targets have been identified as a result and efforts are underway to develop antimalarial agents based on these targets. Researchers around the world are also exploring natural products for yet another lead in antimalarial chemotherapy. “If we take as our standard of importance the greatest harm to the greatest number, then there is no question that malaria is the most important of all infectious diseases 1 .” “Ah, poor heart! he is so shaked of a burning quotidian tertian, that it is most lamentable to behold [2].”

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Drug-resistant Malaria

Loutfy¹,

Kain²

Reemergence of Established Pathogens in the 21st Century

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Dose-Dependent Brainstem Neuropathology Following Repeated Arteether Administration in Rats

Cited by 63 publications

References 10 publications

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

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

Antimalarial Agents

Drug-resistant Malaria

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