A Controlled Trial of Artemether or Quinine in Vietnamese Adults with Severe Falciparum Malaria

Hien, Tran Tinh; Day, Nicholas P. J.; Phu, Nguyen Hoan; Hoang, Nguyen Thi; Chau, Tran Thi Hong; Loc, Pham Phu; Sinh, Dinh Xuan; Chuong, Ly Van; Vinh, Ha; Waller, Deborah; Peto, Timothy E. A.; White, Nicholas J.

doi:10.1056/nejm199607113350202

Cited by 371 publications

(275 citation statements)

References 17 publications

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“…Seven had cerebral malaria and recovered consciousness in 26-69 hr, which is similar to values observed in an earlier study in which quinine was used (mean Ϯ SEM ϭ 47.4 Ϯ 3.2 hr) 2 and in a recent large Vietnamese study of adults (median ϭ 66 hr, range ϭ 0-828 hr). 12 The initial parasite counts include some very high values (8 more than 400,000/l) but were again in the same range observed in previous studies. Treatment with intravenous artesunate resulted in parasite clearance in 29-86 hr and combined with the longer-acting mefloquine prevented any reoccurrence of parasitemia.…”

Section: Discussionsupporting

confidence: 85%

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: Discussionsupporting

confidence: 85%

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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“…In the early Chinese studies, neutropenia was reported, 17 but no significant changes in leukocyte counts were noted this study. Hemoglobinuria had been reported in previous studies with artemether and artesunate 24,25 and occurred in three patients in this study. All had high parasite counts (104,000-790,000/l).…”

Section: Discussionsupporting

confidence: 82%

Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.

Price

Vugt²,

Phaipun³

et al. 1999

Am J Trop Med Hyg

235

124

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Abstract. In prospective studies of acute uncomplicated, multidrug-resistant falciparum malaria on the western border of Thailand, the oral artemisinin derivatives were used alone in the treatment of 836 patients (artesunate 630, artemether 206), were combined with mefloquine (15-25 mg base/kg) in 2,826 patients, and mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine plus an artemisinin derivative were associated with more side effects than those with an artemisinin derivative alone; acute nausea (31% versus 16%), vomiting (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P Ͻ 0.001). Oral artesunate and artemether alone were very well tolerated. There was no difference in the incidence of possible adverse effects between the two drugs, and no evidence that either derivative caused allergic reactions, neurologic or psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater fever occurred in three patients treated with mefloquine plus artesunate regimens. Oral artesunate and artemether are safe and well tolerated antimalarial drugs.

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“…The patients were part of a large double-blind trial of artemether versus quinine for the treatment of severe malaria in Viet Nam. 13 Two groups were defined prospectively, CM (n ϭ 28) and non-CM (n ϭ 26). CM was defined according to established World Health Organization guidelines as a Glasgow Coma score of 11 or less during the episode of severe malaria, 14 other causes of unconsciousness having been excluded, (eg, hypoglycemia, meningitis, or other encephalopathy) by clinical, biochemical, and cerebrospinal fluid (CSF) examination.…”

Section: Case Selectionmentioning

confidence: 99%

Axonal Injury in Cerebral Malaria

Medana¹,

Day²,

Hien³

et al. 2002

The American Journal of Pathology

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157

130

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Impairment of consciousness and other signs of cerebral dysfunction are common complications of severe Plasmodium falciparum malaria. Although the majority of patients make a complete recovery a significant minority, particularly children, have sequelae. The pathological process by which P. falciparum malaria induces severe but usually reversible neurological complications has not been elucidated. Impairment of transport within nerve fibers could induce neurological dysfunction and may have the potential either to resolve or to progress to irreversible damage. ␤-amyloid precursor protein (␤-APP) immunocytochemistry, quantified using digital image analysis, was used to detect defects in axonal transport in brain sections from 54 Vietnamese cases with P. falciparum malaria. The frequency and extent of ␤-APP staining were more severe in patients with cerebral malaria than in those with no clinical cerebral involvement. ␤-APP staining was often associated with hemorrhages and areas of demyelination, suggesting that multiple processes may be involved in neuronal injury. The age of focal axonal damage, as determined by the extent of the associated microglial response, varied considerably within tissue sections from individual patients. These findings suggest that axons are vulnerable to a broad range of cerebral insults that occur during P. falciparum malaria infection. Disruption in axonal transport may represent a final common pathway leading to neurological dysfunction in cerebral malaria. Cerebral malaria (CM) is a diffuse, potentially reversible, encephalopathy, caused by infection with the protozoan parasite Plasmodium falciparum. CM presents clinically with convulsions and coma, and carries 15 to 20% mortality. The malaria parasite invades and develops within erythrocytes that sequester in the cerebral microvasculature and other vital organs by adhesion to specific endothelial receptors. 1,2 The pathophysiological consequences of severe malaria infection have not been satisfactorily resolved. In particular it is not known how parasitized red blood cells, which remain within the vascular space, influence parenchymal brain function to induce coma and death. Histopathological studies reveal a variety of neurological abnormalities including chromatolysis, neuronophagia, and decreased glial cell numbers. [2][3][4][5]

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A Controlled Trial of Artemether or Quinine in Vietnamese Adults with Severe Falciparum Malaria

Abstract: Artemether is a satisfactory alternative to quinine for the treatment of severe malaria in adults.

Cited by 371 publications

References 17 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.

Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.

Axonal Injury in Cerebral Malaria

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