Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial

Mwanga-Amumpaire, Juliet; Carroll, Ryan W.; Baudin, Elisabeth; Kemigisha, Elisabeth; Nampijja, Dorah; Mworozi, Kenneth; Santorino, Data; Nyehangane, Dan; Nathan, Daniel I.; Beaudrap, Pierre De; Étard, Jean-François; Feelisch, Martin; Fernandez, Bernadette; Berssenbrugge, Annie; Bangsberg, David R.; Bloch, Kenneth D.; Boum, Yap; Zapol, Warren M.

doi:10.1093/ofid/ofv111

Cited by 28 publications

(24 citation statements)

References 38 publications

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“…Various attempts to improve NO bioavailability have included the use of L-arginine, a precursor for NO synthesis (16), and inhaled NO (23,24). However, despite initial enthusiasm (24), inhaled NO failed to reduce markers of endothelial activation in either a randomized placebocontrolled trial (25) or an open-label trial (26), presumably reflecting the inability of this modality to deliver NO bioactivity to relevant microvascular beds and immune targets.…”

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confidence: 99%

S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

et al. 2017

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Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with Plasmodium berghei ANKA had significantly delayed mortality compared to WT animals (P Ͻ 0.0001), despite higher parasite burdens (P Ͻ 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; P Ͻ 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4 ϩ and CD8 ϩ T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following P. berghei ANKA infection compared to those receiving KO bone barrow (P Ͻ 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.

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confidence: 99%

S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

et al. 2017

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“…The second study compared 46 children receiving iNO at 80 ppm with 46 children in the placebo group, with similar results. Plasma levels of Ang-2 and inflammatory cytokines remained similar between groups, and there was no difference in mortality (19). Treatment with iNO resulted in increased levels of plasma nitrate, and methemoglobinemia developed, but without sequelae.…”

Section: Nitric Oxidementioning

confidence: 80%

“…Given that iNO is used in the treatment of other diseases, with a well-established safety profile and low cost, along with positive results in animal models, it is an attractive option for clinical tests in malaria patients. Based on these advantages, two randomized phase II clinical trials in patients with severe malaria have been recently reported in Uganda (18,19,75). The first study compared 88 children who received iNO at 80 ppm with 92 children who received placebo (all subjects received artesunate i.v.)…”

Section: Nitric Oxidementioning

confidence: 99%

“…Nevertheless, the use of gaseous therapy for malaria is incipient. At the moment, only two phase II clinical trials have been completed, both examining the effect of NO administration for children with severe malaria (18,19). Nevertheless, some in vitro and in vivo studies-using the experimental cerebral malaria (ECM) murine model-have shed light on the topic and opened perspectives for adjunctive therapies in malaria.…”

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Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

et al. 2016

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cOver 200 million people worldwide suffer from malaria every year, a disease that causes 584,000 deaths annually. In recent years, significant improvements have been achieved on the treatment of severe malaria, with intravenous artesunate proving superior to quinine. However, mortality remains high, at 8% in children and 15% in adults in clinical trials, and even worse in the case of cerebral malaria (18% and 30%, respectively). Moreover, some individuals who do not succumb to severe malaria present longterm cognitive deficits. These observations indicate that strategies focused only on parasite killing fail to prevent neurological complications and deaths associated with severe malaria, possibly because clinical complications are associated in part with a cerebrovascular dysfunction. Consequently, different adjunctive therapies aimed at modulating malaria pathophysiological processes are currently being tested. However, none of these therapies has shown unequivocal evidence in improving patient clinical status. Recently, key studies have shown that gaseous therapies based mainly on nitric oxide (NO), carbon monoxide (CO), and hyperbaric (pressurized) oxygen (HBO) alter vascular endothelium dysfunction and modulate the host immune response to infection. Considering gaseous administration as a promising adjunctive treatment against severe malaria cases, we review here the pathophysiological mechanisms and the immunological aspects of such therapies. Malaria exerts a heavy burden over human populations, with an estimated 124 to 283 million cases and 584,000 deaths in 2013 (1). Currently, intravenous (i.v.) artesunate is the treatment of choice in severe malaria cases in children and adults (2, 3). However, despite the efficacy of intravenous artesunate, mortality from severe malaria in general and from cerebral malaria (CM) in particular remains high, at 18% for African children and 30% for adults in Southeast Asia (2, 3). In addition, 11% of children who survive CM show severe neurological deficits, and up to 25% can maintain long-term cognitive deficits (4-8). Therefore, strategies focusing only on parasite killing may not be sufficient to prevent neurological complications and deaths related to severe malaria. Accordingly, adjunctive therapies-defined as therapies administered in combination with antiparasitic drugs that modify pathophysiological processes caused by malaria-are being sought in order to mitigate complications caused by severe malaria (9). Considering the fact that currently administered antimalarial drugs often take 12 to 18 h to kill parasites, adjunctive therapies could reduce the risk of neurocognitive sequelae and mortality, particularly in patients with CM (10).Different adjunctive therapies have been or are being tested, including treatments aimed at modulation of the immune response to infection (dexamethasone, intravenous immunoglobulin), reduction of iron burden, reduction of oxidative stress, modulation of the prothrombotic state, and reduction of parasitemia (blood transfusion), amon...

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“…1 They are also made with universities in countries where we implement research activities, such as Mbarara University of Science and Technology (MUST), and with international universities, including Harvard University, with whom Epicentre ran a clinical trial to improve the management of the treatment of children with severe malaria in Uganda (Mwanga-Amumpaire et al 2015). In some cases partnerships with private and/or nongovernmental organisations are formed.…”

Section: Introductionmentioning

confidence: 99%

Is Africa part of the partnership?

Boum¹

2018

MAT

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This essay presents an African perspective on medical research partnerships done in Africa. While African institutions have a long history of establishing research partnerships with Western institutions it is important to assess how they have been contributing to this relationship. After describing how partnerships are established and how they currently function for many institutions, I discuss how mutual and antagonistic interests can affect those global health relationships that finish in 'divorce'. I end with defining the place of Africa in its partnerships with Western institutions in medical research, and argue for a new mind-set that would bolster African ownership and funding of research done in Africa.

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Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial

Abstract: Treatment with inhaled nitric oxide as an adjuvant therapy for pediatric patients with cerebral malaria for 48 hours did not result in a significant difference in plasma Angiopoietin-1 levels when compared with placebo in a phase II open-label clinical trial.

Cited by 28 publications

References 38 publications

S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

Is Africa part of the partnership?

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