Potential therapies directed at disease mechanisms

In tropical countries many hospital deaths from falciparum malaria happen before anti-malarial drugs have had time to kill the parasites. Two approaches could help rectify this - addressing public-health problems resulting in delayed presentation, and identifying the physiological processes and molecular pathways that lead to these early deaths, with a view to developing evidence-based adjunct therapies.

Therapies being explored in sepsis, and based on disease pathogenesis data common to sepsis and malaria, may prove to be transferable from either of these diseases to the other. As noted above, circulating levels of a late-appearing inflammatory cytokine, HMGB1, are increased in falciparum malaria [41] as well as in sepsis. Results from animal models on the role of HMGB1, although untested in humans, have inspired enthusiasm for inhibition of this molecule as a potential intervention for human sepsis. For instance, anti-HMGBl antibodies provided dose-dependent protection [37] and reduced mortality [195] against experimental sepsis in mice. Late administration of ethyl pyruvate, which inhibits HMGB1 release from macrophages, also conferred protection against endotoxaemia in mice [196].

Treatments directed towards critical downstream consequences of malaria infection and inflammation, such as those intended to limit acidosis, are also a focus of investigation. One current approach is to identify which acute malaria patients most benefit from early volume expansion [197]. Controlling lactic acidosis via sodium dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenate kinase (maintaining pyruvate dehydrogenase in its active form), is also being examined. DCA reduced lactate levels in acute malaria patients [198], although the study was unable to determine whether treatment improved outcome. An earlier large sepsis study also demonstrated that DCA reduced lactate, but again with no improvement in outcome [126]. As outlined in the section 'Is hyperlactataemia a cause or marker of the acidosis of malaria?', some researchers argue, in view of the strong ion difference contributing to acidosis and the postulated mitochon-drial dysfunction during acute malaria infection, that lactate reduction per se may have limited impact on prognosis.

Other adjunct therapies are also being examined. Improving RBC deformability provides one potential therapeutic approach. In vitro studies with ^-acetylcysteine (NAC), reported to scavenge free radicals, showed improvement in red cell deformability through in vitro studies [199]. Unfortunately, an initial in vivo trial of NAC in malaria patients had no effect on mortality [200]. Blocking endothelial activation is also a focus of research, with initial in vitro studies providing some encouraging results [201].

In conclusion, continuing to identify the host responses to malaria infection that lead to disease is providing insights into novel molecular mechanisms. This information is beginning to guide the design of much needed additional therapies against this disease. There is little doubt that poor oxygen supply through vascular occlusion or anaemia could contribute to the body relying on excessive glycolysis to generate energy, resulting in hyperlactataemia, hypoglycaemia, and metabolic acidosis, and altered consciousness. However, inflammatory cytokines control these changes, as well as inhibit the capacity of mitochondria to use oxygen. Thus, as described

Figure 1. The wide-ranging influences of inflammatory cytokines in severe malaria.

throughout this review, inflammatory cytokines are likely to have various pivotal roles across the multiple pathological processes involved in malarial disease (Fig. 1).

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