Safety assessment of peroxide antimalarials: clinical and chemical perspectives

Park, B. Kevin; O’Neill, Paul M.; Maggs, James L.; Pirmohamed, Munir

doi:10.1046/j.1365-2125.1998.00838.x

Cited by 46 publications

(39 citation statements)

References 52 publications

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“…These studies also show that the ART drug half-life is due to the accumulation of ART drugs in the plasma following multiple doses of AE and AM administered intramuscularly and AL administered orally. In accordance with the published literatures and our research experience, ARTs (QHS, AS, AM, and DHA) elicit auto-induction of a drug metabolism pathway during multiple oral treatments in malaria patients and healthy subjects (van Agtmael et al, 1999;Ashton et al, 1996 and1998;Khanh et al, 1999: Li et al, 2004Park et al, 1998). The C max and AUC values of these patients were markedly reduced from one-third to one-seventh on the last dose day compared with the first dosing day.…”

Section: Blood Accumulation Of Arts Leads To Prolonged Half-livessupporting

confidence: 64%

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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Section: Blood Accumulation Of Arts Leads To Prolonged Half-livessupporting

confidence: 64%

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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“…Briefly, the number of chromatolytic neurons is higher with the more severe or higher grades. A score of 0 (normal or no neurons affected), 1 (1-2 neurons affected/target nucleus), 2 (3-4), 3 (5-10), 4 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20), and 5 (Ն 21) was assigned to each rat case based on the slide set examined. Each brain stem section evaluated had two bilateral target nuclei; scoring was averaged from all nuclei counted.…”

Section: Methodsmentioning

confidence: 99%

“…The decrease in drug exposure levels during treatment was not malaria disease-related, since the artemisinin drug pharmacokinetics (PK) on the first day was similar to those reported in healthy subjects. [13][14][15][16][17][18] One possible explanation for the decrease in plasma concentration-time during treatment is an increase in metabolic capacity due to autoinduction of hepatic drug-metabolizing enzymes. 17 In the neurotoxic experiments with AM and AE, an anorectic toxicity was always concomitant in the animals.…”

Section: Introductionmentioning

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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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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“…1) that are currently deployed in the frontline combination treatments for drug-resistant malaria because of their rapid clearance of parasites and high tolerability in humans (1,2). Despite the widespread use of artemisinin-based compounds (ARTs) 2 (2), there have been persistent reports of neurotoxicity and embryotoxicity in cross-species animal studies, although this hazard has not translated to clinical use (2)(3)(4)(5). It is currently perceived that the benefits of these drugs in treating malaria outweigh the risks when administered in the second and third trimesters of pregnancy; however, the World Health Organization have contraindicated the use of ARTs during the first trimester (6).…”

mentioning

confidence: 99%

The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials

Mercer

Copple

Maggs

et al. 2011

Journal of Biological Chemistry

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144

128

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Safety assessment of peroxide antimalarials: clinical and chemical perspectives

Cited by 46 publications

References 52 publications

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

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

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

The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials

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