scholarly journals Asymmetric Dimethylarginine in Adult Falciparum Malaria: Relationships With Disease Severity, Antimalarial Treatment, Hemolysis, and Inflammation

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Bridget E. Barber ◽  
Timothy William ◽  
Matthew J. Grigg ◽  
Uma Parameswaran ◽  
Kim A. Piera ◽  
...  
Keyword(s):  
Falciparum Malaria ◽  
Asymmetric Dimethylarginine ◽  
Interleukin 10 ◽  
Antimalarial Treatment ◽  
Factors Associated ◽  
Plasma Adma ◽  
No Bioavailability ◽  
Baseline Levels ◽  
Endothelial Nitric Oxide ◽  
Severe Falciparum Malaria

Abstract Background.  Endothelial nitric oxide (NO) bioavailability is impaired in severe falciparum malaria (SM). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (NOS), contributes to endothelial dysfunction and is associated with mortality in adults with falciparum malaria. However, factors associated with ADMA in malaria, including the NOS-substrate l-arginine, hemolysis, and antimalarial treatment, are not well understood. Methods.  In a prospective observational study of Malaysian adults with SM (N = 22) and non-SM (NSM; N = 124) and healthy controls (HCs), we investigated factors associated with plasma ADMA including the effects of antimalarial treatment. Results.  Compared with HCs, ADMA levels were lower in NSM (0.488 µM vs 0.540 µM, P = .001) and in the subset of SM patients enrolled before commencing treatment (0.453 µM [N = 5], P = .068), but levels were higher in SM patients enrolled after commencing antimalarial treatment (0.610 µM [N = 17], P = .026). In SM and NSM, ADMA levels increased significantly to above-baseline levels by day 3. Baseline ADMA was correlated with arginine and cell-free hemoglobin in SM and NSM and inversely correlated with interleukin-10 in NSM. Arginine and the arginine/ADMA ratio (reflective of arginine bioavailability) were lower in SM and NSM compared with HCs, and the arginine/ADMA ratio was lower in SM compared with NSM. Conclusions.  Pretreatment ADMA concentrations and l-arginine bioavailability are reduced in SM and NSM. Asymmetric dimethylarginine increases to above-baseline levels after commencement of antimalarial treatment. Arginine, hemolysis, and posttreatment inflammation all likely contribute to ADMA regulation, with ADMA likely contributing to the reduced NO bioavailability in SM.

scholarly journals Relationship of Cell‐Free Hemoglobin to Impaired Endothelial Nitric Oxide Bioavailability and Perfusion in Severe Falciparum Malaria

2009 ◽  
Vol 200 (10) ◽  
pp. 1522-1529 ◽  
Author(s):  
Tsin W. Yeo ◽  
Daniel A. Lampah ◽  
Emiliana Tjitra ◽  
Retno Gitawati ◽  
Enny Kenangalem ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Falciparum Malaria ◽  
Free Hemoglobin ◽  
Relationship Of ◽  
Endothelial Nitric Oxide ◽  
Severe Falciparum Malaria ◽  
Nitric Oxide Bioavailability

scholarly journals Impaired nitric oxide bioavailability and l-arginine–reversible endothelial dysfunction in adults with falciparum malaria

2007 ◽  
Vol 204 (11) ◽  
pp. 2693-2704 ◽  
Author(s):  
Tsin W. Yeo ◽  
Daniel A. Lampah ◽  
Retno Gitawati ◽  
Emiliana Tjitra ◽  
Enny Kenangalem ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Falciparum Malaria ◽  
Reactive Hyperemia ◽  
Severe Disease ◽  
Microvascular Endothelium ◽  
Tissue Ischemia ◽  
Exhaled No ◽  
No Bioavailability ◽  
Severe Falciparum Malaria

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia–peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33–1.47) than in MSM (1.82; 95% CI = 1.7–2.02) and controls (1.93; 95% CI = 1.8–2.06; P < 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6–34; P = 0.006) and exhaled NO by 55% (95% CI = 32–73; P < 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.

Decreased NO Bioavailability Leading to Endothelial Dysfunction in Children with ALL Results From Increased eNOS Inhibiting by Asymmetrical Dimethylarginine and May Be Associated with Increased Mortality

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5318-5318
Author(s):  
Julita Porwolik ◽  
Ewa Niedzielska ◽  
Adrian Doroszko ◽  
Alicja Piasecka-Grzeszek ◽  
Urszula Solska ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Conflicts Of Interest ◽  
Control Group ◽  
Healthy Children ◽  
Asymmetrical Dimethylarginine ◽  
Plasma Adma ◽  
No Bioavailability ◽  
Endothelial Nitric Oxide

Abstract Abstract 5318 Background Endothelial dysfunction worsens the prognosis in numerous severe diseases. Impaired vascular reactivity, increased procoagulative and proinflammatory action are commonly observed when the nitric oxide bioavailability is limited. Asymmetrical dimethylarginine (ADMA) is a competive inhibitor of the endothelial nitric oxide synthase (eNOS). ADMA is produced during proteolysis of methylated proteins, especially histones. The aim this study was to determine if ADMA may play important role in pathogenesis of endothelial dysfunction in children with ALL. Material and Methods N=14 children at age of 4–18 years with ALL treated with the ALLIC protocol were investigated. Plasma levels of the NO pathway metabolites (L-Arginine, ADMA) were analyzed at baseline, then during the 33rd and 78th day of protocol. The control group constituted of N=14, age-matched healthy children. Results Plasma ADMA levels were significantly higher in children with ALL at baseline as compared to the control group (1.92±0.42 vs. 0.56±0.1 ng/ml, p<0.05), and were significantly decreasing to 0.63±0.15ng/ml, p<0.05 following the steroid therapy. During the 78th day the ADMA levels were maintained at similar levels as compared to the 33rd day. Opposite trends were observed with the L-Arginine levels and the L-Arg/ADMA ratio reflecting the NO synthesis. L-Arg and L-Arg/ADMA ratio were significantly lower in children with ALL at baseline vs. control group (41.65±4.12vs.52.4±2.31pg/ml and 28.7±6.61vs.83.41±14.13, respectively, p<0.05). Moreover, the L-Arg/ADMA ratio at the 78th day was significantly higer in cases treated unsuccesfully in comparison with those who survived (88.1±21.3vs.43.0±10.2, p<0.05). Conclusions Decreased NO bioavailability in children with ALL at baseline results from the eNOS inhibiting by ADMA and may be associated with increased mortality. Disclosures: No relevant conflicts of interest to declare.

scholarly journals ADMA and hyperhomocysteinemia

2005 ◽  
Vol 10 (2_suppl) ◽  
pp. S27-S33 ◽  
Author(s):  
Sanjana Dayal ◽  
Steven R Lentz
Keyword(s):  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Asymmetric Dimethylarginine ◽  
Strong Association ◽  
Dimethylarginine Dimethylaminohydrolase ◽  
Plasma Adma ◽  
Total Homocysteine ◽  
No Bioavailability ◽  
Plasma Total Homocysteine

Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. Like many other cardiovascular risk factors, hyperhomocysteinemia produces endothelial dysfunction due to impaired bioavailability of endothelium-derived nitric oxide (NO). The molecular mechanisms responsible for decreased NO bioavailability in hyperhomocysteinemia are incompletely understood, but emerging evidence suggests that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may be a key mediator. Homocysteine is produced during the synthesis of ADMA and can alter ADMA metabolism by inhibiting dimethylarginine dimethylaminohydrolase (DDAH). Several animal and clinical studies have demonstrated a strong association between plasma total homocysteine, plasma ADMA, and endothelial dysfunction. These observations suggest a model in which elevation of ADMA may be a unifying mechanism for endothelial dysfunction during hyper-homocysteinemia. The recent development of transgenic mice with altered ADMA metabolism should provide further mechanistic insights into the role of ADMA in hyperhomocysteinemia.

scholarly journals Increased Asymmetric Dimethylarginine in Severe Falciparum Malaria: Association with Impaired Nitric Oxide Bioavailability and Fatal Outcome

2010 ◽  
Vol 6 (4) ◽  
pp. e1000868 ◽  
Author(s):  
Tsin W. Yeo ◽  
Daniel A. Lampah ◽  
Emiliana Tjitra ◽  
Retno Gitawati ◽  
Christabelle J. Darcy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Falciparum Malaria ◽  
Asymmetric Dimethylarginine ◽  
Fatal Outcome ◽  
Severe Falciparum Malaria ◽  
Nitric Oxide Bioavailability

scholarly journals Identifying prognostic factors of severe metabolic acidosis and uraemia in African children with severe falciparum malaria: a secondary analysis of a randomized trial

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Grace Mzumara ◽  
Stije Leopold ◽  
Kevin Marsh ◽  
Arjen Dondorp ◽  
Eric O. Ohuma ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Metabolic Acidosis ◽  
Falciparum Malaria ◽  
Model Building ◽  
Statistical Significance ◽  
Severe Metabolic Acidosis ◽  
African Countries ◽  
Prognostic Features ◽  
African Children ◽  
Severe Falciparum Malaria

Abstract Background Severe metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings. Methods A retrospective analysis of the ‘Artesunate versus quinine in the treatment of severe falciparum malaria in African children’ (AQUAMAT) trial was conducted to identify clinical features of severe metabolic acidosis and uraemia in 5425 children from nine African countries. Separate models were fitted for uraemia and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis and uraemia. Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model performance was assessed through calibration, discrimination, and internal validation with bootstrapping. Results There were 2296 children identified with severe metabolic acidosis and 1110 with uraemia. Prognostic features of severe metabolic acidosis among them were deep breathing (OR: 3.94, CI 2.51–6.2), hypoglycaemia (OR: 5.16, CI 2.74–9.75), coma (OR: 1.72 CI 1.17–2.51), respiratory distress (OR: 1.46, CI 1.02–2.1) and prostration (OR: 1.88 CI 1.35–2.59). Features associated with uraemia were coma (3.18, CI 2.36–4.27), Prostration (OR: 1.78 CI 1.37–2.30), decompensated shock (OR: 1.89, CI 1.31–2.74), black water fever (CI 1.58. CI 1.09–2.27), jaundice (OR: 3.46 CI 2.21–5.43), severe anaemia (OR: 1.77, CI 1.36–2.29) and hypoglycaemia (OR: 2.77, CI 2.22–3.46) Conclusion Clinical and laboratory parameters representing contributors and consequences of severe metabolic acidosis and uraemia were independently associated with these outcomes. The model can be useful for identifying patients at high risk of these complications where laboratory assessments are not routinely available.

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