Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0024530 (malaria)
44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chlorpromazine has previously been shown to trigger suicidal erythrocyte death or eryptosis, which is characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage. Premature suicidal death of infected erythrocytes is in turn considered to delay development of parasitemia and thus favourably influence the clinical course of malaria. The present experiments have been performed to explore whether chlorpromazine influences in vitro parasite growth and eryptosis of Plasmodium falciparum infected human erythrocytes and in vivo parasitemia and survival of P. berghei infected mice. Phosphatidylserine was estimated from annexin V binding and cell volume from forward scatter in FACS analysis. In vitro infection of human erythrocytes increased annexin binding and decreased forward scatter, effects augmented in the presence of chlorpromazine (>or=10 microM). Chlorpromazine did not significantly alter intraerythrocytic DNA/RNA content but significantly (>or=1 microM) decreased in vitro parasitemia. In chlorpromazine treated mice erythrocytes were more rapidly cleared from circulating blood than in nontreated mice. Parasitemia in P. berghei infected mice was significantly decreased (from 50 % to 28 % of circulating erythrocytes 22 days after infection) and mouse survival significantly enhanced (from 0 % to 80 % 30 days after infection) by addition of 1 mM chlorpromazine to the drinking water from the first day of infection. In conclusion, chlorpromazine favourably influences the course of malaria, an effect at least partially due to stimulation of suicidal erythrocyte death.
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PMID:Influence of chlorpromazine on eryptosis, parasitemia and survival of Plasmodium berghe infected mice. 1876 53

Parasitemia patterns, survival and cytokine levels of Plasmodium berghei NK65-infected BALB/c mice, treated orally with the alkaloidal mixture of febrifugine and isofebrifugine at a dose of 1 mg/kg twice a day for 4 consecutive days were monitored. Whereas the untreated mice showed a progressive increase in parasitemia and ultimate death, the alkaloid mixture-treated group showed a transient suppression of parasitemia during the course of treatment. However, the parasitemia increased on discontinuation of treatment, leading to earlier death of mice in the treated group than in the infected but untreated controls. Mice in the infected but untreated group displayed a significant elevation in serum IFN-gammay levels during the first week post-infection (pI) and from Day 14 pI, relative to the levels in the uninfected controls. In contrast, although mice in the alkaloid mixture-treated group displayed no significant elevation in serum IFN-gamma levels during the first week pI, they showed considerable levels on Day 14 pI. There were no significant differences in serum IL-4 levels among the groups. The titers of the parasite-specific IgG1, IgG2a, IgG2b and IgG3 were significantly elevated from Day 11 pI in both the treated and untreated groups. There was a significant difference in survival duration between the IFN-gamma-/- mutant and BALB/c mice. IFN-gamma-/- mutant mice showed a decrease in parasitemia levels while receiving medication, which was significantly lower than those of the treated BALB/c mice. The results of the present study suggest that although IFN-gamma is significant for protective immunity in mice with malaria infection, it may play an adverse role post-medication, causing earlier mortality of treated BALB/c mice.
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PMID:Possible involvement of IFN-gamma in early mortality of Plasmodium berghei NK65-infected BALB/c mice after febrifugine treatment. 1906 81

Plasmodia express a sphingomyelinase, which is apparently required for their development. On the other hand, the sphingomyelinase product ceramide has previously been shown to delay parasite development. Moreover, ceramide triggers suicidal erythrocyte death or eryptosis, characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage. Accelerated eryptosis of infected erythrocytes is considered to clear infected erythrocytes from circulating blood and, thus, to favourably influence the clinical course of malaria. The present experiments explored whether the sphingomyelinase inhibitor amitriptyline or genetic knockout of host acid sphingomyelinase influence in vitro parasite growth, eryptosis of Plasmodium falciparum-infected human erythrocytes, in vivo parasitemia and survival of P. berghei-infected mice. Phosphatidylserine exposure was determined by annexin V-binding and cell volume by forward scatter in FACS analysis. In vitro infection of human erythrocytes increased annexin- binding, an effect blunted in the presence of amitriptyline (>or=50 microM). Amitriptyline did not significantly alter intraerythrocytic parasite development but significantly (>or= 1 microM) delayed the increase in parasitemia in vitro. Most importantly, amitriptyline treatment (1 mM in drinking water) resulted in a significant delay of parasitemia and death of infected mice. However, upon infection, ceramide formation was stimulated in both, acid sphingomyelinase knockout mice (Smpd1(-/-)) and their wild type littermates (Smpd1(+/+)). Parasitemia following P. berghei infection was significantly lower in Smpd1(-/-) than in Smpd1(+/+) mice but did not significantly extend the life span of infected animals. In conclusion, mammalian and parasite sphingomyelinase contribute to ceramide formation during malaria, whereby the parasite sphingomyelinase ultimately determines the course of the infection. Amitriptyline presumably blocks both sphingomyelinases and, thus, its use might be a novel strategy to treat malaria.
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PMID:Influence of amitriptyline on eryptosis, parasitemia and survival of Plasmodium berghei-infected mice. 1908 22

Plasmodium juxtanucleare is one of the agents that cause chicken malaria. High parasitemia causes anemia, diarrhea and weight loss that leads to death. This parasite is spread through the tropics and little is known about the physiological changes caused by P. juxtanucleare infections in chickens. The aim of this work was to determine hematological changes in chickens experimentally infected with this parasite. No weight or temperature differences between infected and control groups were detected. Low parasitemia was observed reaching a peak after 15 days; trophozoits was the most observed form, followed by schizonts detected on day 12 and gametocytes on day 27. Infected thrombocytes and thrombocytes with pyknotic nuclei and retracted cytoplasm were observed along the experimental infection. No changes were observed on the erythrocyte values. However, a reduction of thrombocyte number and an increase of total leukocyte and basophil numbers, all significant, were detected in infected chickens. Parasitemia was probably kept low by general immunological activation. These results suggest that classical hematology can monitor physiological changes caused by P. juxtanucleare infections in chickens.
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PMID:Hematological changes of chickens experimentally infected with Plasmodium (Bennettinia) juxtanucleare. 1934 20

Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-gamma, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum-infected RBC (iRBC) Ag, 28 and 90 days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-gamma cultured ELISPOT, were low and unstable over time, despite CD4(+) T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-beta, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-gamma measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed.
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PMID:Multiple functions of human T cells generated by experimental malaria challenge. 1965 96

A new fixed-dose combination of artesunate (AS) plus amodiaquine (AQ) (TRIMALACT) was recently developed for the treatment of uncomplicated falciparum malaria. The originality of this combination lies in its galenic formulation which consists of a three-layer tablet with two layers containing each of the active ingredients, i.e. AS and AQ, and these are separated by a middle layer containing an antioxidant compound. To evaluate the efficacy and tolerability of this combination, adults with uncomplicated malaria received three administrations of two tablets (100:300 mg AS/AQ) in a 24-h interval, in Democratic Republic of Congo. Parasitemia and fever were measured and the plasma levels of parent compounds and metabolites [dihydroartemisinin (DHA) and monodesethylamodiaquine (MdAQ)] were determined by high-performance liquid chromatography. In addition, we determined the prevalence of molecular markers of resistance to chloroquine (CQ) and sulfadoxine/pyrimethamine (SP). The AS/AQ combination TRIMALACT demonstrated a good efficacy resulting in an excellent clinical and parasitological response rate of 100% after correction for PCR results. Treatment regimen was well tolerated. The main disposition parameters to AS+AQ were: for DHA, AUC = 632 +/- 475 ng h/ml and Cmax = 432 +/- 325 ng/ml, and for MdAQ = 14268 +/- 4114 ng h/ml and Cmax = 336 +/- 225 ng/ml (mean +/- standard deviation). Parasite genotyping show high frequencies of molecular SP- and CQ-resistance markers with more 80% of the samples showing more than three mutations linked to SP resistance and 93.48% carrying parasite with the CQ-resistant haplotype. This study shows that the AS/AQ combination TRIMALACT is safe and effective in the treatment of highly drug-resistant falciparum malaria.
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PMID:Pharmacokinetics and pharmacodynamics of a new ACT formulation: Artesunate/Amodiaquine (TRIMALACT) following oral administration in African malaria patients. 2016 28

We examined the cross-sectional relationships between malaria parasitemia and CD4 T cell count and viral load among human immunodeficiency virus (HIV)-infected pregnant women. We then followed women to investigate whether or not baseline parasitemia predicted CD4 T cell counts or viral loads > 90 days post-baseline or predicted time to HIV disease stage 3 or 4 or acquired immune deficiency syndrome (AIDS)-related death (ARD). Parasitemia level was nonlinearly associated with viral load at baseline and among measurements taken > 90 days post-baseline; women with low baseline parasitemia, versus none, had higher viral loads at both time points. Any baseline parasitemia predicted an increased rate of ARD among women with baseline CD4 T cell counts > or = 500 cells/microL (ratio rate [RR] = 2.6; 95% confidence interval [CI] = 1.1-6.0; P test for heterogeneity = 0.05). Further study is warranted to determine whether or not parasitemia is especially detrimental to individuals with lower levels of immunosuppression or chronic low parasitemia.
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PMID:Malaria parasitemia and CD4 T cell count, viral load, and adverse HIV outcomes among HIV-infected pregnant women in Tanzania. 2034 98

Malaria transmission is high and perennial in south-east Nigeria and is associated with a high burden of morbidity and mortality in children under 5 years and pregnant women. It is associated with maternal anemia, placental infection, intrauterine growth retardation and low birth weight. To evaluate the status of malaria in pregnancy in Cross River State, Nigeria, we assessed the prevalence rates of maternal, cord and placental malaria parasitemia in the dry and rainy seasons for 626 consecutively recruited pregnant women who delivered at two rural and two urban health facilities. Demographic data were obtained at delivery and maternal, placental and cord blood samples were collected and examined for malaria parasites by light microscopy. Of the mother and infant pairs, 120 (19.2%), 69 (14.7%) and 62 (13.5%), respectively, had positive maternal, placental and cord blood parasitemia. Parasitemia rates in the rainy season were higher than in the dry season (p < 0.05). There were no significant differences in maternal, placental and cord parasitemia between urban and rural areas. The prevalence rates of parasitemia at delivery indicate high malaria transmission and poor control during pregnancy.
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PMID:Patterns of cord, placental and post-delivery maternal malaria parasitemia. 2052 11

Plasmodium infection causes major losses to animal and human populations. The characterization of experimental malaria models is needed for a better understanding of disease mechanisms and the development of new treatment protocols. Chickens infected with Plasmodium gallinaceum constitute an adequate malaria model due to the phylogenetic proximity of this parasite to human Plasmodium as well as similarities in disease manifestation, such as cerebral malaria. The aim of the present study was to further characterize the experimental chicken model with an emphasis on clinical manifestations, cerebral histology and nitric oxide (NO) produced by macrophages. The results revealed that mortality was correlated to higher parasitemia. Parasitemia was positively correlated to temperature and negatively correlated to haematocrit value. Brain histology of infected birds revealed inflammatory infiltrates and blocked microvasculature. Macrophages derived from blood monocytes produced NO after activation, with a higher production positively correlated to parasitemia. These results characterize histological aspects of chicken brain malaria and demonstrate the activation of the innate immune system caused by the infection in chickens.
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PMID:Pathogenic action of Plasmodium gallinaceum in chickens: brain histology and nitric oxide production by blood monocyte-derived macrophages. 2053 66

Eryptosis, the suicidal death of erythrocytes, is characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage. Triggers of eryptosis include anandamide. Enhanced eryptosis of infected human erythrocytes is expected to delay the development of parasitaemia during infection with Plasmodium, the parasite causing malaria. The present experiments aimed to test, whether anandamide influences eryptosis, parasite growth and/or host survival during in vitro or in vivo infection with Plasmodia. Human erythrocytes were infected in vitro with P. falciparum, and mice in vivo with P. berghei. Parasitemia was determined with Syto16. Phosphatidylserine-exposing erythrocytes were identified by analysing annexin V-binding in FACS analysis. In vitro infection of human erythrocytes was followed by a significant increase in annexin V-binding, an effect slightly enhanced by anandamide (> or = 50 microM), which significantly reduced intraerythrocytic DNA/RNA content and in vitro parasitaemia. In vivo administration of anandamide (5 mg/kg b.w. subcutaneously) blunted the parasitaemia (from 36.9% to 24.2% of circulating erythrocytes 21 days after infection) and significantly enhanced the survival of P. berghei-infected mice (from 0% to 67% 26 days after infection). The percentage of phosphatidylserine-exposing erythrocytes was significantly increased in anandamide-treated infected mice compared to non-treated infected mice. In conclusion, anandamide stimulated eryptosis of infected erythrocytes thus counteracting parasitaemia and a lethal course of the disease.
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PMID:Effect of anandamide in Plasmodium Berghei-infected mice. 2079 20


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