Neurotoxicity Assessment of Artemether in Juvenile Rats

Beckman, David A.; Youreneff, Maureen; Butt, Mark T.

doi:10.1002/bdrb.21054

Cited by 6 publications

(5 citation statements)

References 14 publications

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“…ATM doses used in the present work were based on a previous study (Beckman et al 2013), that reported neurotoxicity in juvenile rats by different protocols using doses from 20 to 200 mg kg −1 day −1 for 7 days, by the oral route. They showed that doses higher than 30 mg kg −1 day −1 increased mortality, renal necrosis and brain haemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Reduced cardiotoxicity and increased oral efficacy of artemether polymeric nanocapsules in Plasmodium berghei-infected mice

et al. 2017

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Artemether (ATM) cardiotoxicity, its short half-life and low oral bioavailability are the major limiting factors for its use to treat malaria. The purposes of this work were to study free-ATM and ATM-loaded poly-ε-caprolactone nanocapules (ATM-NC) cardiotoxicity and oral efficacy on Plasmodium berghei-infected mice. ATM-NC was obtained by interfacial polymer deposition and ATM was associated with polymeric NC oily core. For cardiotoxicity evaluation, male black C57BL6 uninfected or P. berghei-infected mice received, by oral route twice daily/4 days, vehicle (sorbitol/carboxymethylcellulose), blank-NC, free-ATM or ATM-NC at doses 40, 80 or 120 mg kg-1. Electrocardiogram (ECG) lead II signal was obtained before and after treatment. For ATM efficacy evaluation, female P. berghei-infected mice were treated the same way. ATM-NC improved antimalarial in vivo efficacy and reduced mice mortality. Free-ATM induced significantly QT and QTc intervals prolongation. ATM-NC (120 mg kg-1) given to uninfected mice reduced QT and QTc intervals prolongation 34 and 30%, respectively, compared with free-ATM. ATM-NC given to infected mice also reduced QT and QTc intervals prolongation, 28 and 27%, respectively. For the first time, the study showed a nanocarrier reducing cardiotoxicity of ATM given by oral route and it was more effective against P. berghei than free-ATM as monotherapy.

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Section: Discussionmentioning

confidence: 99%

Reduced cardiotoxicity and increased oral efficacy of artemether polymeric nanocapsules in Plasmodium berghei-infected mice

et al. 2017

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“…Although artemisinins have been known to cause neurotoxic effects in animals [ 18 - 20 ], there is no conclusive evidence of neurotoxic effects in adults or children [ 4 , 21 ]. Further, neurotoxicity has not been observed after oral artemether administration [ 22 ], suggesting that it is the total exposure over an extended period that leads to this toxicity, which can occur with intramuscular administration because of its slow continuous absorption without first pass effect. However, it was not possible to calculate reliable AUC in infants in this study because of the limitations in both the number and total volume of blood samples obtained from this population.…”

Section: Discussionmentioning

confidence: 99%

“…Higher exposures (C max and AUC) and greater systemic toxicity with decreasing age of rat pups after artemether oral administration were reported [ 22 ]. Greater systemic toxicity was observed in the younger animals (mortality in seven to 13-day-old pups started at 30 mg/kg/day dose but no mortality in older pups was observed at this dose).…”

Section: Discussionmentioning

confidence: 99%

Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®)

Tiono

Tinto²,

Alao

et al. 2015

Malar J

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BackgroundArtemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg.MethodsThis multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up).ResultsA total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg.ConclusionsA three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown.Trial RegistrationClinicaltrials.gov NCT01619878.

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“…It is not recommended to use ACTs during the first trimester due to side effects observed in preclinical models [24]. Currently, sulfadoxine-pyrimethamine is used in pregnant women as an intermittent preventive treatment to reduce infections and improve pregnancy outcomes.…”

Section: Pharmacological Approachesmentioning

confidence: 99%

Alternatives to currently used antimalarial drugs: in search of a magic bullet

Bhagavathula

Elnour²,

Shehab

2016

Infect Dis Poverty

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Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically. However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data.To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners’ collaboration. However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date.We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules. We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies. Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women. Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads. Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy. AQ-13 induced electrocardiac events, which led to prolonged QTc intervals. Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity. Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children.At this stage, we are unable to identify a single magic bullet against malaria. Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission. Newer medicines have also raised concerns in terms of efficacy and safety. Overall, more evidence is needed to effectively reduce the current malaria burden. Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s40249-016-0196-8) contains supplementary material, which is available to authorized users.

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Neurotoxicity Assessment of Artemether in Juvenile Rats

Abstract: As in the adult rat, oral administration of artemether in the juvenile rat is not associated with the neurotoxicity produced by intramuscular administration.

Cited by 6 publications

References 14 publications

Reduced cardiotoxicity and increased oral efficacy of artemether polymeric nanocapsules in Plasmodium berghei-infected mice

Reduced cardiotoxicity and increased oral efficacy of artemether polymeric nanocapsules in Plasmodium berghei-infected mice

Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®)

Alternatives to currently used antimalarial drugs: in search of a magic bullet

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