Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial

Hawkes, Michael; Conroy, Andrea L.; Opoka, Robert O.; Hermann, Laura; Thorpe, Kevin E.; McDonald, Chloë R.; Kim, Hani; Higgins, Sarah J.; Namasopo, Sophie; John, Chandy C.; Miller, Chris; Liles, W. Conrad; Kain, Kevin C.

doi:10.1186/s12936-015-0946-2

Cited by 55 publications

(69 citation statements)

References 29 publications

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“…A clinical trial in pediatric malaria showed that inhaled nitric oxide did not affect biomarkers of severe disease. 91 More recently, the role of NO in severe malaria has also implicated the angiogenic factor Ang-2 which is stored in Weibel-Palade bodies (WPB) in endothelial cells and secreted in conjunction with von Willebrand Factor. 92 The decreased vascular NO bioavailability found in severe malaria is proposed to increase exocytosis of WPB with a resultant increase in Ang-2 release.…”

Section: Host Inflammatory Mediatorsmentioning

confidence: 99%

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Gillrie

2016

Tissue Barriers

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Plasmodial species are protozoan parasites that infect erythrocytes. As such, they are in close contact with microvascular endothelium for most of the life cycle in the mammalian host. The hostparasite interactions of this stage of the infection are responsible for the clinical manifestations of the disease that range from a mild febrile illness to severe and frequently fatal syndromes such as cerebral malaria and multi-organ failure. Plasmodium falciparum, the causative agent of the most severe form of malaria, is particularly predisposed to modulating endothelial function through either direct adhesion to endothelial receptor molecules, or by releasing potent host and parasite products that can stimulate endothelial activation and/or disrupt barrier function. In this review, we provide a critical analysis of the current clinical and laboratory evidence for endothelial dysfunction during severe P. falciparum malaria. Future investigations using state-of-the-art technologies such as mass cytometry and organs-on-chips to further delineate parasite-endothelial cell interactions are also discussed.

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Section: Host Inflammatory Mediatorsmentioning

confidence: 99%

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Gillrie

2016

Tissue Barriers

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“…The study was conducted according to Declaration of Helsinki and International Council for Harmonisation guidelines on Good Clinical Practice. Serum samples were collected from children presenting to the Jinja Regional Pediatric Referral Hospital who met World Health Organization criteria for CM (26). Sera were collected at admission and stored at -80°C until use.…”

Section: Patient Samplesmentioning

confidence: 99%

miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria

Barker

Kim

et al. 2017

Mol Med

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miR-155 has been shown to participate in host response to infection and neuroinflammation via negative regulation of blood-brain barrier (BBB) integrity and T cell function. We hypothesized that miR-155 may contribute to the pathogenesis of cerebral malaria (CM). To test this hypothesis, we used a genetic approach to modulate miR-155 expression in an experimental model of cerebral malaria (ECM). In addition, an engineered endothelialized microvessel system and serum samples from Ugandan children with CM were used to examine anti-miR-155 as a potential adjunctive therapeutic for severe malaria. Despite higher parasitemia, survival was significantly improved in miR-155 -/-mice versus wild-type littermate mice in ECM. Improved survival was associated with preservation of BBB integrity and reduced endothelial activation, despite increased levels of proinflammatory cytokines. Pretreatment with antagomir-155 reduced vascular leak induced by human CM sera in an ex vivo endothelial microvessel model. These data provide evidence supporting a mechanistic role for miR-155 in host response to malaria via regulation of endothelial activation, microvascular leak and BBB dysfunction in CM.

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“…The first study compared 88 children who received iNO at 80 ppm with 92 children who received placebo (all subjects received artesunate i.v.) and showed that iNO failed to reduce angiopoietin-2 (Ang-2; a marker of endothelial dysfunction) levels and had no effect on mortality (18). Methemoglobinemia did develop in 25% of children in the treated group, but without sequelae.…”

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.…”

mentioning

confidence: 99%

“…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.)…”

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confidence: 99%

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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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Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial

Cited by 55 publications

References 29 publications

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

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