Arteether: Risks of Two-Week Administration in Macaca mulatta

Jm, Petras; Kyle, Dennis E.; Gettayacamin, Montip; Gd, Young; Ra, Bauman; Hk, Webster; Kd, Corcoran; Jo, Peggins; Ma, Vane; Tg, Brewer

doi:10.4269/ajtmh.1997.56.390

Cited by 70 publications

(63 citation statements)

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“…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

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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.

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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

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“…Accordingly, the half life of AE was significantly prolonged from the first dosing day to the last dosing day after intramuscular AE administrations. The monkey showed moderate neurotoxicity after this intramuscular AE dosing regimen (Petras et al, 1997(Petras et al, , 2000.…”

Section: Half Lives Of Arts In Monkeysmentioning

confidence: 96%

“…Based on the minimal injury observed to the neuronal tissues in the monkeys treated with 8 mg/kg daily for 14 days, it was possible to correctly identify 193.8 ng/ml as the LONEL (Li & Hickman, 2011). The neurotoxic exposure period of AE was calculated as 307.4 hr in this study following daily intramuscular injection of 16 mg/kg for 14 days in monkeys with moderate neurotoxicity (Petras et al, 1997 and (Table 2). This calculation was based on the estimated exposure time of AE above the LONEL concentration (193.8 ng/ml).…”

Section: Exposure Time With Neurotoxic Effects Of Ae In Rhesus Monkeysmentioning

confidence: 96%

“…Since AE-induced brainstem neuropathology in rhesus monkeys occurred at a minimal dose of 8 mg/kg dosed daily for 14 days (Petras et al, 1997(Petras et al, , 2000, the LONEL of AE was estimated to be 193.8 ng/ml. This estimate is based on our TK analysis conducted by dosing monkeys with AE at 16 mg/kg dosed daily for 14 days which should, based on a number of repeat dosing studies, result in evidence of AE-induced neurotoxicity (Petras et al, 1997;Li et al, 2006bLi et al, , 2007a.…”

Section: Neurotoxicity Induced By Intramuscular Ae In Monkeysmentioning

confidence: 99%

“…This estimate is based on our TK analysis conducted by dosing monkeys with AE at 16 mg/kg dosed daily for 14 days which should, based on a number of repeat dosing studies, result in evidence of AE-induced neurotoxicity (Petras et al, 1997;Li et al, 2006bLi et al, , 2007a. By conducting TK simulations of 14 repeated AE treatments of monkeys dosed intramuscularly at 8 mg/kg, a neurotoxic exposure time of 179.5 hr in plasma was calculated as the minimum time spent above the LONEL (193.8 ng/ml) required to induce pathological neurotoxicity (Figure 2, bottom).…”

Section: Neurotoxicity Induced By Intramuscular Ae In Monkeysmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetic (PK) and Pharmacodynamic Profiles of Artemisinin Derivatives Influence Drug Neurotoxicity in Animals

Li¹,

Hickman²

2012

Readings in Advanced Pharmacokinetics - Theory, Methods and Applications

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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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Arteether: Risks of Two-Week Administration in Macaca mulatta

Cited by 70 publications

References 0 publications

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Pharmacokinetic (PK) and Pharmacodynamic Profiles of Artemisinin Derivatives Influence Drug Neurotoxicity in Animals

Antimalarial Agents

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