Safety of Epoietin Beta-Quinine Drug Combination in Children With Cerebral Malaria in Mali

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´╗┐Safety of Epoietin Beta-Quinine Drug Combination in Children With Cerebral Malaria in Mali

Abstract and Background

Abstract


Background: Cerebral malaria carries an unacceptable case fatality rate in children despite timely and adequate chemotherapy. To improve the survival rate, adjunctive therapies previously tested mainly focused on the modulation of the inflammatory response, without definitive effect in humans. In this context, a new adjunctive strategy using a neuroprotective drug: erythropoietin (epoietin-beta, Epo) was proposed.
Methods: An open-labelled study including cerebral malaria children (Blantyre coma score below 3) was conducted in Mali. The objective was to assess the short-term safety (seven days) of erythropoietin at high doses (1,500 U/kg/day during three days) combined to quinine.
Results: 35 patients with unrousable coma were included in the study. None of expected side effects of erythropoietin were observed during the seven days follow-up. No significant increase in the case fatality rate (7/35 patients) was observed compared to other studies with mortality rates ranging from 16 to 22% in similar endemic areas.
Conclusion: These data provide the first evidence of the short-term safety of erythropoietin at high doses combined to quinine. A multicentre study is needed to assess the potential of Epo as an adjunctive therapy to increase the survival during cerebral malaria.

Background


Malaria is one of the most common life-threatening diseases in sub-Sahara Africa with a dramatic impact on public health: more than one million deaths each year. Cerebral malaria (CM) carries unacceptable case fatality rate in children despite timely and adequate chemotherapy. The SEAQUAMAT group provided the first evidence of artesunate superiority (mortality rate: 15%) compared to quinine (mortality rate: 22%) during severe falciparum malaria in adults. However, available artemisinin-based combination therapy (ACT) is not associated with a complete recovery in case of severe malaria, suggesting a potential role for adjunctive therapies in the early phase of the disease. Most adjunctive therapies tested in human cerebral malaria were focussed on the modulation of the inflammatory response. However, none of the trial using adjunctive therapies from data obtained in animal models provides an increase in survival or an improvement of patient outcome. It was highlighted that most of these studies were underpowered. In some cases, these adjunctive drugs were responsible for deleterious effects and trials were suspended. A new opportunity was opened when the beneficial effect of neuro-protective drugs, including erythropoietin (epoietin-beta, Epo), was demonstrated both in animals and humans during stroke. The neuro-protective effect is mediated through the inhibition of cell death in the ischemic penumbra surroundings the tissue injury. There is now a growing evidence for this concept of cell protection during acute ischemic diseases.

Epo has recently been considered in a new light as a tissue-protective cytokine. Its neuro-protective properties have attracted considerable attention: Epo and its receptor (EpoR) are part of a highly potent endogenous neuro-protective system in the brain. Similar to the mechanism of action shown for cells in the haematopoietic system, Epo acts on cells of the nervous system via binding to its specific receptor EpoR. Dimerizing of EpoR leads to autophosphorylation of the receptor associated Janus tyrosine kinase 2 and activation of distal signal transduction cascade: phosphatidylinositol-3-kinase (PI3-K), akt protein kinase, RAS mitogen-activated protein kinases, signal transducers and activators of transcription-5 (STAT-5) and NF-kB-dependant transcription. The underlying mechanisms are hypothesized to be multifactorial. Epo may antagonize the cytotoxic effect of glutamate, increase expression of antioxidant enzymes, reduce nitric oxide mediated formation of radicals, normalize cerebral blood flow, influence neurotransmitter release and promote neuroangiogenesis. All these mechanisms are contributing to attenuation of apoptosis and reduction of brain inflammation.

The effect of neuro-protective therapies was not previously investigated during malaria in humans, although the manifestations of cerebral malaria partly share features with neurological stroke, neuron damage related to ischaemia-reperfusion stress or acute non-specific neurological disorders. From experimental malaria, it was speculated that the progression from cerebral malaria to death could be counteracted by Epo high doses at the onset of clinical phase of the disease.

While the safety of Epo in chronic diseases is known, using high doses for a short period of time is a major issue to be addressed in severe cerebral malaria patients. Indeed, in September 2008, FDA has been made aware of preliminary safety concerns from a clinical trial conducted in Germany investigating the use of epoietin-alfa high doses (40,000 units daily for three days) to treat acute ischemic stroke, while investigators considered this as premature alert. Early in 2009 another clinical trial using epoietin-alfa high doses (1,000 unit/kg/day for seven days) in extremely premature infants to prevent/attenuate brain injury was also FDA hold. In both cases, epoeitin-alfa was used and FDA did not communicate their final conclusions and recommendations to the public. The in vivo/in vitro bioactivity ratio is more than 20% higher for epoietin-beta than for epoietin-alpha, because epoietin-beta is less sialylated than epoietin-alpha. Desialylation of Epo is known to reduce the plasma survival of Epo and the biological effect and to increase the affinity of Epo for its receptors. To obtain the appearance of exogenous Epo in the cerebrospinal fluid and the neuro-protective effect, Epo doses higher than those used for anaemia treatment are needed.

To document the safety of epoietin-beta high doses (1500 U/Kg) at day 7 post-admission, combined to quinine, the local recommended drug for cerebral malaria, a clinical trial in Bamako (Mali) including children admitted with highly critical stage cerebral malaria (Blantyre coma score <3) was conducted. The safety was defined as the lack of severe adverse effects attributable to Epo.

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