A Trial of Artemether or Quinine in Children with Cerebral Malaria

Hensbroek, Michaël Boele van; Onyiorah, E.; Jaffar, Shabbar; Schneider, G.; Palmer, Ayo; Frenkel, Joost; Enwere, Godwin; Forck, S.; Nusmeijer, A.; Bennett, S.C.J.; Greenwood, Brian; Kwiatkowski, Dominic P.

doi:10.1056/nejm199607113350201

Cited by 232 publications

(157 citation statements)

References 14 publications

(14 reference statements)

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“…For example, there was a large difference in FCTs reported in two large recent studies in Vietnam and in The Gambia that used artemether (with median values of 127 and 30 hr, respectively). 11,14 A further important endpoint used in malaria studies is mortality, but this is so low in the unit where this study was conducted (4% in the present study) that a very large study would be required. However, the time course for clinical improvement was encouragingly short and is reassuring that the antibody is not prolonging the natural history of the infection.…”

Section: Discussionmentioning

confidence: 94%

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Looareesuwan

Sjostrom²,

Krudsood³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-␣ (TNF-␣) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-␣ (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-␥ (IFN-␥) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1␤ levels. Antibody treatment reduced IFN-␥ concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-␣ was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination halflife of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.

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Section: Discussionmentioning

confidence: 94%

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Looareesuwan

Sjostrom²,

Krudsood³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…28 This raised some concern about a possible neurotoxic effect of artemether, but this was not confirmed in other studies. 29,30 Extensive clinical studies that included detailed neurologic testing and specific evaluation of auditory-evoked potentials have also reported no evidence for neurotoxic side effects of artemether. 31,32 Currently, the artemisinin drugs have been used in more than two million people with malaria, of whom more than ten thousand have been included in carefully monitored clinical trials, and no direct evidence for a clinically relevant neurotoxic effect in humans has been reported.…”

Section: Discussionmentioning

confidence: 99%

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Nontprasert¹,

Pukrittayakamee²,

Dondorp³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. Intramuscular administration of high doses of artemether and arteether to experimental mammals produces selective damage to brain stem centers involved predominantly in auditory processing and vestibular reflexes. The relationship between clinical signs of neurotoxicity and neuropathologic toxicity was studied in the mouse. Intramuscular artemether (50−100 mg/kg/day for 28 days) caused dose-dependent neuropathologic damage to the brain stem. There was no pathologic evidence of neuronal death in mice receiving either oral artemether, or oral or intramuscular artesunate, in doses up to 300 mg/kg/day. The neurons in the lower brain stem trapezoid nucleus, the gigantocellular reticular nucleus, and the inferior cerebellar peduncle were the most sensitive to the toxic effects of artemether. All mice with neuropathologic changes also showed behavioral changes, whereas in some mice with gait disturbance, no corresponding histopathologic damage could be detected. Thus clinical assessment was a sensitive measure of neurotoxicity. There may be a reversible component to artemether neurotoxicity.

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“…An artemisinin derivative, dihydroartemisinin (DHA), is more water-soluble and currently considered the most effective drug in treating cerebral malaria (21,22). DHA has also demonstrated strong anti-tumor activity (23).…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin transiently activates the JNK/SAPK signaling pathway in endothelial cells

et al. 2016

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Abstract. Artemisinin and its derivatives are well-known anti-malaria drugs and in the early stages of research for cancer treatment. Dihydroartemisinin (DHA), a more water-soluble derivative of artemisinin, has demonstrated strong anti-angiogenic activity. The purpose of the present study was to investigate the underlying molecular mechanisms of the effect of DHA on angiogenesis. Human umbilical vein endothelial cells (HUVECs) treated with DHA were examined for apoptosis and activation of the c-Jun N-terminal kinase (JNK) signaling pathway, one of the major mitogen-activated protein kinase cascades. It was observed that 20 µM DHA induces transient activation of JNK in HUVECs. DHA also elevates the expression of cyclooxygenase-2 and matrix metalloproteinase-13, which is abolished by treatment with the JNK inhibitor SP600125. Although DHA persistently increases inhibitor of κB-α protein and thus inhibits nuclear factor-κB signaling, it does not affect apoptosis or caspase 3/9 activities in HUVECs. The present study provides key information for understanding the effects of DHA on endothelial cells, which is required for investigating its potential for clinic application as a chemotherapeutic agent.

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A Trial of Artemether or Quinine in Children with Cerebral Malaria

Abstract: Artemether is as effective as quinine in the treatment of cerebral malaria in children.

Cited by 232 publications

References 14 publications

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Dihydroartemisinin transiently activates the JNK/SAPK signaling pathway in endothelial cells

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