A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Thuma, Philip E.; Bhat, Ganapati; Mabeza, George; Osborne, C.; Biemba, Godfrey; Shakankale, G. M.; Peeters, Pierre; Oosterhuis, B.; Lugt, C.; Gordeuk, VR

doi:10.4269/ajtmh.2000.62.524

Cited by 24 publications

(23 citation statements)

References 27 publications

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“…9,58 The results contributed to a low therapeutic potential of intramuscular AE when compared with oral DQHS, oral and intravenous artesunate (AS), intramuscular AM, and even intramuscular ␣/␤-AE formulated with peanut oil in humans. 9,[59][60][61] Although far fewer undesirable side effects were reported in these trials, the lower efficacy limited the use of the drug in patients infected with P. falciparum malarias. Previous PK data demonstrated that the AM plasma concentration was more than three-fold higher than that of AE in rats at a same dose level and with the same sesame oil formulation.…”

Section: Resultsmentioning

confidence: 99%

“…20 It may be that AM has a less lipophilic property than AE that favors absorption from muscle. Better efficacy of ␣/␤-AE was found in a peanut oil formulation in India, [59][60][61] suggesting that peanut oil may also facilitate better absorption of this drug in humans. Therefore, further investigation on new intramuscular formulations needs to be done to increase efficacy and decrease toxicity of the oil-soluble antimalarial drug AE.…”

Section: Resultsmentioning

confidence: 99%

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Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents.

Mog²,

Z³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. The neurotoxicity of ␤-arteether (AE) is related to drug accumulation in blood due to slow and prolonged absorption from the intramuscular injection sites. In this efficacy and toxicity study of AE, the traditional sesame oil vehicle was replaced with cremophore to decrease the accumulation and toxicity of AE. Dihydroartemisinin (DQHS), a more toxic and active metabolite of AE, was also analyzed. When administered at a daily dosage of 25 mg/kg for seven days, blood accumulation of AE with sesame oil (AESO) was used had a 7.5-fold higher area under the curve (AUC) (on last versus first day dosing), while AE with cremophore (AECM) had only a 1.8-fold higher AUC. Although the accumulation of AECM was greatly reduced, its total exposure level (46.29 g и h/ml) was 2.7-fold higher than with AESO (16.92 gиh/ml) due to a higher bioavailability of AECM (74.5%) compared with AESO (20.3%). Total exposure time (calculated at over the minimal detected neurotoxicity level of 41.32 ng/ml) of AECM was 103 hours during the whole treatment period (192 hours), which was more than one-third (37%) less than with AESO (162 hours). Similar pharmacokinetic results were also shown with the active metabolite, DQHS. Anorexia and gastrointestinal toxicity with AESO were significantly more severe than with AECM (P < 0.001). Histopathologic examination of the brain demonstrated neurotoxic changes; the AESO rat group was significantly more severe than the AECM rat group. The brain injury scores with AECM were mild to moderate (2.3-3.0), and with AESO they were moderate to severe (3.0-4.7) on day 7 and day 10, respectively. In addition, the results of a 50% cure dose (CD 50 ) against Plasmodium berghei in mice were 34.1 mg/kg for AESO and 14.2 mg/kg for AECM, indicating a significant higher efficacy was found in the AECM animals. Toxicity and efficacy of DQHS were also dependent on its exposure time and level, which was the same as its parent drug (AE). In conclusion, following the seven-day treatment in rats, AE and DQHS exposure time and level varied based on the vehicle used. The extension of drug exposure time and the low peak level of AE and DQHS were more associated with severe neurotoxicity and lower antimalarial efficacy, whereas the high level and short exposure time of AE and DQHS resulted in higher efficacy and milder toxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents.

Mog²,

Z³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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“…The trials examined mortality, clinical outcomes (fever clearance time, coma recovery time, neurological sequelae), parasite clearance and some side effects. (Table II) was low for three trials (11,12,14), moderate for another three (8,10,17) and high for four trials (9,13,15,16). Only one trial(11) provided a sample size calculation.…”

Section: Current Best Evidencementioning

confidence: 96%

“…Table I summarizes the trial characteristics. Two trials compared quinine with artesunate (8,9), six with artemether(10-15), and two with arteether (16,17). Four trials recruited only participants with cerebral malaria (10,11,13,14).…”

Section: Current Best Evidencementioning

confidence: 98%

Artemisinin derivatives Versus quinine for severe malaria in children: A systematic review and meta-analysis

Mathew

2010

Indian Pediatr

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“…3 days) [14,[19][20][21] . ␤ AE formulated in sesame oil by the WHO [31,32] for higher-dose injections (total dose: 576-768 mg, i.m., in 5 days) has been reported to produce much lower cure rates [33,34] . AE ( ␣ / ␤ ) has been claimed to exhibit synergistic action [35,36] .…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Novel Oral Formulations of α/β Arteether against Multidrug-Resistant Malaria in Mice

Tripathi

Khanna²,

Dwivedi³

2010

Chemotherapy

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Background: α/β arteether (AE), an effective artemisinin derivative, was developed as intramuscular injection for multidrug-resistant (MDR) and severe falciparum malaria, but intramuscular treatment has its own limitations and cannot be given to patients in rural areas where proper hospital facilities are not available and people are reluctant to take injections. Due to widespread occurrence of MDR strains of Plasmodiumfalciparum, an oral AE formulation is urgently needed to cure the malaria patients. Methods: Several AE formulations were prepared and tested orally in Swiss mice infected with MDR P. yoelii nigeriensis at a dose of 50 mg/kg/day for 5 days. The comparative antimalarial efficacy of eight different AE formulations was assessed at different time intervals in treated and control animals. Results: Three new AE formulations, namely AE F-2, F-10B and F-14, were found to have 100% curative antimalarial activity in an experimental model, as shown by survival of treated animals beyond 28 days, with no recrudescence of parasitemia being recorded. Another two formulations, AE F-8 and F-9B, produced 96–97% cure. Conclusion: Five α/β AE formulations (F-2, F-10B, F-8, F-9B and F-14) can be considered potential candidates for further drug development. AE F-14, a solid dosage form of AE prepared by completely removing oil and incorporating 0.2% cholesterol, is a new promising lead, even in pediatric malaria, which can reduce the neurotoxic potential of AE and other artemisinin derivatives.

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A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Cited by 24 publications

References 27 publications

Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents.

Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents.

Artemisinin derivatives Versus quinine for severe malaria in children: A systematic review and meta-analysis

Efficacy of Novel Oral Formulations of α/β Arteether against Multidrug-Resistant Malaria in Mice

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