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The plant-based immunomodulator curcumin as a potential candidate for the development of an adjunctive therapy for cerebral malaria
Mimche Patrice N,Taramelli Donatella,Vivas Livia
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-s1-s10
Abstract: The clinical manifestations of cerebral malaria (CM) are well correlated with underlying major pathophysiological events occurring during an acute malaria infection, the most important of which, is the adherence of parasitized erythrocytes to endothelial cells ultimately leading to sequestration and obstruction of brain capillaries. The consequent reduction in blood flow, leads to cerebral hypoxia, localized inflammation and release of neurotoxic molecules and inflammatory cytokines by the endothelium. The pharmacological regulation of these immunopathological processes by immunomodulatory molecules may potentially benefit the management of this severe complication. Adjunctive therapy of CM patients with an appropriate immunomodulatory compound possessing even moderate anti-malarial activity with the capacity to down regulate excess production of proinflammatory cytokines and expression of adhesion molecules, could potentially reverse cytoadherence, improve survival and prevent neurological sequelae. Current major drug discovery programmes are mainly focused on novel parasite targets and mechanisms of action. However, the discovery of compounds targeting the host remains a largely unexplored but attractive area of drug discovery research for the treatment of CM. This review discusses the properties of the plant immune-modifier curcumin and its potential as an adjunctive therapy for the management of this complication.
PPARγ Agonists Improve Survival and Neurocognitive Outcomes in Experimental Cerebral Malaria and Induce Neuroprotective Pathways in Human Malaria  [PDF]
Lena Serghides ,Chloe R. McDonald equal contributor,Ziyue Lu equal contributor,Miriam Friedel,Cheryl Cui,Keith T. Ho,Howard T. J. Mount,John G. Sled,Kevin C. Kain
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003980
Abstract: Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM.
Inhaled nitric oxide for the adjunctive therapy of severe malaria: Protocol for a randomized controlled trial
Michael Hawkes, Robert O Opoka, Sophie Namasopo, Christopher Miller, Kevin E Thorpe, James V Lavery, Andrea L Conroy, W Conrad Liles, Chandy C John, Kevin C Kain
Trials , 2011, DOI: 10.1186/1745-6215-12-176
Abstract: This prospective, parallel arm, randomized, placebo-controlled, blinded clinical trial compares adjunctive continuous inhaled nitric oxide at 80 ppm to placebo (both arms receiving standard anti-malarial therapy), among Ugandan children aged 1-10 years of age with severe malaria. The primary endpoint is the longitudinal change in Ang-2, an objective and quantitative biomarker of malaria severity, which will be analysed using a mixed-effects linear model. Secondary endpoints include mortality, recovery time, parasite clearance and neurocognitive sequelae.Noteworthy aspects of this trial design include its efficient sample size supported by a computer simulation study to evaluate statistical power, meticulous attention to complex ethical issues in a cross-cultural setting, and innovative strategies for safety monitoring and blinding to treatment allocation in a resource-constrained setting in sub-Saharan Africa.ClinicalTrials.gov Identifier: NCT01255215Malaria is the leading parasitic cause of morbidity and mortality worldwide, causing an estimated 240 million clinical cases and 800,000 deaths annually [1]. Children in sub-Saharan Africa bear the greatest burden of disease, where one in every five childhood deaths is due to malaria and 25% of survivors of cerebral malaria develop long-term neurocognitive impairment [1,2]. Despite the use of highly effective anti-malarial medications, 10-30% patients with severe malaria will die [3-5], underscoring the need for adjunctive therapies that can be applied in endemic areas. To date, effective adjunctive treatments have been elusive despite numerous clinical trials [6]. New therapies, appropriate for use in endemic areas, are therefore urgently needed to address the unacceptably high residual mortality associated with severe malaria in pediatric populations.NO is a gaseous, lipid-soluble free radical that is produced in vivo by the enzymatic conversion of L-arginine and molecular oxygen to L-citrulline by members of the nitr
Safety of epoietin beta-quinine drug combination in children with cerebral malaria in Mali
Stéphane Picot, Anne-Lise Bienvenu, Salimata Konate, Sibiri Sissoko, Abdoulaye Barry, Elisabeth Diarra, Karidiatou Bamba, Abdoulaye Djimdé, Ogobara K Doumbo
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-169
Abstract: 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.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.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.ClinicalTrials.gov ID: NCT00697164Malaria 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 [1]. 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 [2]. 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 [3-5]. It was highlighted that most of these studies were underpowered [6]. In some cases, these adjunctive drugs were responsible for deleterious effect
Inhaled Nitric Oxide Reduces Endothelial Activation and Parasite Accumulation in the Brain, and Enhances Survival in Experimental Cerebral Malaria  [PDF]
Lena Serghides,Hani Kim,Ziyue Lu,Dylan C. Kain,Chris Miller,Roland C. Francis,W. Conrad Liles,Warren M. Zapol,Kevin C. Kain
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0027714
Abstract: The host immune response contributes to the onset and progression of severe malaria syndromes, such as cerebral malaria. Adjunctive immunomodulatory strategies for severe malaria may improve clinical outcome beyond that achievable with artemisinin-based therapy alone. Here, we report that prophylaxis with inhaled nitric oxide significantly reduced systemic inflammation (lower TNF, IFNγ and MCP-1 in peripheral blood) and endothelial activation (decreased sICAM-1 and vWF, and increased angiopoeitin-1 levels in peripheral blood) in an experimental cerebral malaria model. Mice that received inhaled nitric oxide starting prior to infection had reduced parasitized erythrocyte accumulation in the brain, decreased brain expression of ICAM-1, and preserved vascular integrity compared to control mice.
Pentoxifylline as an adjunct therapy in children with cerebral malaria
Bertrand Lell, Carsten K?hler, Betty Wamola, Christopher HO Olola, Esther Kivaya, Gilbert Kokwaro, David Wypij, Sadik Mithwani, Terrie E Taylor, Peter G Kremsner, Charles RJC Newton
Malaria Journal , 2010, DOI: 10.1186/1475-2875-9-368
Abstract: Ten children admitted to the high dependency unit of the Kilifi District Hospital in Kenya with cerebral malaria (Blantyre coma score of 2 or less) received quinine plus a continuous infusion of 10 mg/kg/24 hours PTX for 72 hours. Five children were recruited as controls and received normal saline instead of PTX. Plasma samples were taken for PTX and tumour necrosis factor (TNF) levels. Blantyre Coma Score, parasitemia, hematology and vital signs were assessed 4 hourly.One child (20%) in the control group died, compared to four children (40%) in the PTX group. This difference was not significant (p = 0.60). Laboratory parameters and clinical data were comparable between groups. TNF levels were lower in children receiving PTX.The small sample size does not permit definitive conclusions, but the mortality rate was unexpectedly high in the PTX group.The mortality of severe falciparum malaria in children admitted to African hospitals has not decreased significantly in recent decades despite the introduction of new anti-malarial drugs, including the rapidly acting artemisinins. Disruption of the pathogenic mechanisms may improve the outcome.The pathogenesis of severe malaria is unclear and several different processes may be responsible. Enhanced production of the cytokine tumour necrosis factor (TNF), induction of nitric oxide, cytoadherence and sequestration, rosetting (the aggregation of parasitized and non-parasitized red blood cells), and decreased red blood cell (RBC) deformability are thought to contribute to the pathogenesis of severe malaria [1,2].Pentoxifylline (PTX), a methylxanthine, which acts as a phosphodiesterase inhibitor, has effects on many of these processes. It was initially developed to increase RBC deformability and enhance blood flow in the microvasculature. It leads to an overall improvement in haemorheological characteristics such as RBC deformability, blood viscosity, platelet aggregation, and plasma fibrinogen concentration [3]. It may be parti
Pharmacologic Inhibition of CXCL10 in Combination with Anti-malarial Therapy Eliminates Mortality Associated with Murine Model of Cerebral Malaria  [PDF]
Nana O. Wilson, Wesley Solomon, Leonard Anderson, John Patrickson, Sidney Pitts, Vincent Bond, Mingli Liu, Jonathan K. Stiles
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060898
Abstract: Despite appropriate anti-malarial treatment, cerebral malaria (CM)-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM) mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs) and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection) and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10) and increasing angiogenic factor (VEGF) production. Treatment with a combination of atorvastatin and artemether improved survival (100%) when compared with artemether monotherapy (70%), p<0.05. Thus, adjunctively reducing CXCL10 levels and inflammation by atorvastatin treatment during anti-malarial therapy may represent a novel approach to treating CM patients.
Mannitol as adjunct therapy for childhood cerebral malaria in Uganda: A randomized clinical trial
Beatrice Namutangula, Grace Ndeezi, Justus S Byarugaba, James K Tumwine
Malaria Journal , 2007, DOI: 10.1186/1475-2875-6-138
Abstract: This randomized double-blind placebo controlled clinical trial was carried out at the Emergency Paediatric ward of Mulago Hospital, Uganda's national referral and teaching hospital. One hundred and fifty six children aged 6 to 60 months with cerebral malaria were randomized to either one dose of mannitol 1 g/kg or placebo, in addition to intravenous quinine. Main outcome measures included coma recovery time; time to sit unsupported, begin oral intake; duration of hospitalization; death and adverse effects.Time to regain consciousness (p = 0.11), sit unsupported (p = 0.81), time to start oral intake (p = 0.13) and total coma duration (p = 0.07) were similar in both groups. There was no significant difference in the mortality between the placebo (13/80 or 16.3%) and mannitol (10/76 or 13.2%) groups: RR = 1.2 (CI 0.5–2.7). No adverse effects were observed after administration of mannitol.Mannitol had no significant impact on clinical outcome of cerebral malaria. It is difficult to recommend intravenous mannitol as adjunct therapy for childhood cerebral malaria.ClinicalTrials.gov ID: NCT00113854Cerebral malaria is one of the most severe and life threatening complications of Plasmodium falciparum infection accounting for high mortality [1-3]. Several studies have shown evidence of raised intracranial pressure in children with cerebral malaria and this may be associated with poor outcome[4,5].Mannitol, an osmotic diuretic lowers intracranial pressure by creating an osmotic gradient that draws water from brain parenchyma into the brain capillaries. It also slows production of cerebral spinal fluid, which further reduces intracranial pressure [6]. Although recommended and used to treat post-traumatic comatose patients[6,7] it is not yet recommended in cerebral malaria due to lack of conclusive evidence. No randomized or quasi-randomized controlled trials support or refute the use of mannitol as adjunct treatment for cerebral malaria. A randomized trial was performed to dete
Hydroxyethyl starch 130/0.4 and sodium chloride injection as adjunctive therapy in patients with cerebral hypoperfusion  [cached]
Han Junliang,Yang Fang,Jiang Wenrui,Zhang Guangyun
BMC Neurology , 2012, DOI: 10.1186/1471-2377-12-127
Abstract: Background Both severe stenosis and completed occlusion in internal carotid artery or its distal branches have been considered the main reasons of cerebral hypoperfusion, which contributes to the washout disturbances of embolism in low perfusion territories distal to stenosis. An aggravated hypoperfusion state in certain brain region may induce ischemic stroke and further cognitive decline. However, the effective medication for cerebral hypoperfusion is largely unsettled. Methods/design By using computed tomography perfusion (CTP) imaging, the trial will evaluate the effectiveness, safety and tolerability of hydroxyethyl starch (HES) 130/0.4 for patients with extra-/intra-cranial artery stenosis and cerebral hypoperfusion. From 5 neurological inpatient wards, 300 patients will be randomly recruited for administered routine medications plus intravascular volume therapies using the equal volume of HES 130/0.4 or 0.9% sodium chloride solution. Cerebral hypoperfusion state after 7-day intervention is the primary outcome measure. The secondary outcome measures includes, impaired renal function, abnormal heart function, hematological changes, neurological dysfunctions and cerebrovascular events in peri-intervention period and/or 3-month follow-up. The sample size will allow the detection of a two-sided 5% significance level between groups in the endpoint with a power of 80%. Discussion The trial would provide important efficacy and safety data on the intravascular administration of HES 130/0.4 in patients with unilateral cerebral hypoperfusion. The effects on kidney function, heart function, coagulation, neurological function and cerebralvascular events will be assessed. Trial registration ClinicalTrials.gov (Identifier: NCT01192581)
Cognitive Dysfunction Is Sustained after Rescue Therapy in Experimental Cerebral Malaria, and Is Reduced by Additive Antioxidant Therapy  [PDF]
Patricia A. Reis,Clarissa M. Comim,Fernanda Hermani,Bruno Silva,Tatiana Barichello,Aline C. Portella,Flavia C. A. Gomes,Ive M. Sab,Valber S. Frutuoso,Marcus F. Oliveira,Patricia T. Bozza,Fernando A. Bozza,Felipe Dal-Pizzol,Guy A. Zimmerman,Jo?o Quevedo,Hugo C. Castro-Faria-Neto
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000963
Abstract: Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.
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