[POST-ARTEMISININ DELAYED HEMOLYSIS AFTER TREATMENT OF MALARIA].

INTRODUCTION: Falciparum malaria is highly endemic in sub-Saharan Africa. The disease is caused by the intra-cellular parasite Plasmodium within erythrocytes. The recommended treatment is artemisinin-based combination which is efficient and safe. In some patients, artemisinin can cause hemolysis weeks after treatment, presenting with severe anemia. Most of the published cases were following intravenous treatment. We present a case of a falciparum malaria patient with hemolysis and severe anemia two weeks after oral treatment with artemisinin-based combination therapy.

Prospective observational study to evaluate the clinical and biological safety profile of pyronaridine-artesunate in a rural health district in Burkina Faso.

The assessment in real-life conditions of the safety and efficacy of new antimalarial drugs is of greatest interest. This study aimed to monitor and evaluate both clinical and biological safety of pyronaridine-artesunate (PA) in real-life conditions in Burkina Faso's health system. This was a single-arm, open-label study, where patients attending Nanoro health facilities with uncomplicated malaria were consented to be part of a cohort event monitoring (CEM). At inclusion (day-0), PA was administered orally once a day for 3 days. Patients spontaneous reported any clinical adverse events (AEs) occurring within 28 days following the treatment. Additionally, the study focused on AEs of special interest (AESI), namely clinical signs related to hepatotoxicity and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). A nested subset of patients with blood sample collection at day-0 and day-7 were monitored to investigate the effect of PA on biochemistry parameters. From September 2017 to October 2018, 2786 patients were treated with PA. About 97.8% (2720/2786) of patients did not report any AE. The most commonly reported events were respiratory, thoracic, and mediastinal disorders (8.3 per 1000), infections and infestations (7.9 per 1000), and gastrointestinal disorders (7.2 per 1000). No clinical or biological hepatotoxicity event related to PA was reported during the follow-up. Changes in biochemistry parameters remained within laboratory reference ranges. The study showed that PA is a well-tolerated drug and should be considered as a good option by malaria control programs in countries where existing first-line antimalarial drugs are continuously threatened by the emergence of drug resistance.

Open Clinical Trial of Sambiloto (Andrographis paniculata) Ethanolic Extract Capsules in Treatment of Malaria Patients in Batubara District, Indonesia.

Introduction: Malaria infection is still a public health problem in Indonesia. One of the problems in combating malaria in Indonesia is the limited kind of antimalarial drugs provided by the government. Sambiloto (Andrographis paniculata) extract has been shown to have antimalarial activity in human clinical trials. Aim: To assess the ability of a single A. paniculata ethanolic extract capsule to treat malaria in humans caused by Plasmodium falciparum or P. vivax alone or mixed infections of both. Methods: An open clinical trial was conducted in Batubara District, Sumatra Utara Province, Indonesia, a malaria-endemic area. Sixty-nine malaria patients found in the field were diagnosed microscopically as malaria vivax, malaria falciparum, and mixed infections uncomplicated malaria with 12 years old and above. Previously all patients signed informed consent. All patients have been treated with A. paniculata ethanolic extract capsules 250 mg thrice a day for five days. Parasite density was calculated from D0, D1, D2, D3, D7, D14, and D28. Results: The efficacy of A . paniculata ethanolic extract capsules 250 mg thrice a day for five days against malaria vivax, malaria falciparum, and mixed malaria patients was 94.2%. There are no side effects were found during treatment. Conclusion: A. paniculata ethanolic extract can be used as an alternative antimalarial candidate derived from native Indonesian medicinal plants or as an adjunct in standard treatment for malaria.

Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination.

BACKGROUND: Development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage Plasmodium falciparum. METHODS: We undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the P. falciparum reticulocyte-binding protein homolog 5 (RH5), formulated in AS01B adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145. FINDINGS: The RH5.1/AS01B formulation was administered using a range of RH5.1 protein vaccine doses (2, 10, and 50 µg) and was found to be safe and well tolerated. A regimen using a delayed and fractional third dose, in contrast to three doses given at monthly intervals, led to significantly improved antibody response longevity over ∼2 years of follow-up. Following primary and secondary CHMI of vaccinees with blood-stage P. falciparum, a significant reduction in parasite growth rate was observed, defining a milestone for the blood-stage malaria vaccine field. We show that growth inhibition activity measured in vitro using purified immunoglobulin G (IgG) antibody strongly correlates with in vivo reduction of the parasite growth rate and also identify other antibody feature sets by systems serology, including the plasma anti-RH5 IgA1 response, that are associated with challenge outcome. CONCLUSIONS: Our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease. FUNDING: This study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC.

Malaria after chemotherapy for hematological malignancies.

The treatment of cancer, whether a solid tumor or a malignant hemopathy, is accompanied by bouts of infection, the severity and prognosis of which are often correlated to the patient's immune status. In Gabon, where the transmission of Plasmodium falciparum malaria is perennial, the prevalence - around 36% in Libreville - increases in older children and adults. Few authors have described the involvement of this parasite during fever after chemotherapy for hematological malignancies. This work reports three cases of malaria including two severe and one with neutropenia occurring in patients treated for hematological neoplasms.

Methanol extracts of Fagara zanthoxyloides leaves possess antimalarial effects and normalizes haematological and biochemical status of Plasmodium berghei-passaged mice.

Context: The resistance of Plasmodium species to many available antimalarials calls for a continuous search for newer antimalarial agents. One possible source of new antimalarials is from natural sources such as Fagara zanthoxyloides Lam (Rutaceae), a medicinal plant used traditionally for treating malaria in South-Eastern Nigeria, Uganda and Asia. Objectives: To investigate the application of methanol extracts of F. zanthoxyloides in combating malaria infection and its associated disorders. Materials and methods: Methanol extracts of F. zanthoxyloides leaves (MEFZ) were evaluated for in vivo antimalarial activity. MEFZ at doses of 200, 400, and 600 mg/kg/d were administered orally for 4 consecutive days (days 0-4) to P. berghei-infected mice. The possible ameliorative effects of MEFZ on malaria-associated organ malfunctions were also assessed. Results: At 200, 400 and 600 mg/kg b.w., respectively, MEFZ produced 82.37% and 68.39%, 84.84%, and 90.75%, 95.95% and 92.67% chemosuppression and inhibition of P. berghei, respectively, comparable to 98.67% and 97.29% by combisunate, a standard antimalarial. The IC50 of MEFZ was estimated to be 235.23 mg/kg b.w. Similarly, treatment of parasitized mice with MEFZ significantly restored the malaria-modified haematological and biochemical status of the parasitized-MEFZ-treated mice compared with parasitized-untreated mice. MEFZ was tolerable up to 5000 mg/kg b.w dose; hence, the LD50 is above 5000 mg/kg b.w. Discussion and conclusions: The results of this curative assay demonstrated that MEFZ has antimalarial effects and normalized haematological and biochemical aberrations generated by malaria. The isolation of the antimalarial principles in MEFZ is warranted; they could be lead molecules for the development of new antimalarials.

Oral iron supplements for children in malaria-endemic areas.

BACKGROUND: Iron-deficiency anaemia is common during childhood. Iron administration has been claimed to increase the risk of malaria. OBJECTIVES: To evaluate the effects and safety of iron supplementation, with or without folic acid, in children living in areas with hyperendemic or holoendemic malaria transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library, MEDLINE (up to August 2015) and LILACS (up to February 2015). We also checked the metaRegister of Controlled Trials (mRCT) and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2015. We contacted the primary investigators of all included trials, ongoing trials, and those awaiting assessment to ask for unpublished data and further trials. We scanned references of included trials, pertinent reviews, and previous meta-analyses for additional references. SELECTION CRITERIA: We included individually randomized controlled trials (RCTs) and cluster RCTs conducted in hyperendemic and holoendemic malaria regions or that reported on any malaria-related outcomes that included children younger than 18 years of age. We included trials that compared orally administered iron, iron with folic acid, and iron with antimalarial treatment versus placebo or no treatment. We included trials of iron supplementation or fortification interventions if they provided at least 80% of the Recommended Dietary Allowance (RDA) for prevention of anaemia by age. Antihelminthics could be administered to either group, and micronutrients had to be administered equally to both groups. DATA COLLECTION AND ANALYSIS: The primary outcomes were clinical malaria, severe malaria, and death from any cause. We assessed the risk of bias in included trials with domain-based evaluation and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We performed a fixed-effect meta-analysis for all outcomes and random-effects meta-analysis for hematological outcomes, and adjusted analyses for cluster RCTs. We based the subgroup analyses for anaemia at baseline, age, and malaria prevention or management services on trial-level data. MAIN RESULTS: Thirty-five trials (31,955 children) met the inclusion criteria. Overall, iron does not cause an excess of clinical malaria (risk ratio (RR) 0.93, 95% confidence intervals (CI) 0.87 to 1.00; 14 trials, 7168 children, high quality evidence). Iron probably does not cause an excess of clinical malaria in both populations where anaemia is common and those in which anaemia is uncommon. In areas where there are prevention and management services for malaria, iron (with or without folic acid) may reduce clinical malaria (RR 0.91, 95% CI 0.84 to 0.97; seven trials, 5586 participants, low quality evidence), while in areas where such services are unavailable, iron (with or without folic acid) may increase the incidence of malaria, although the lower CIs indicate no difference (RR 1.16, 95% CI 1.02 to 1.31; nine trials, 19,086 participants, low quality evidence). Iron supplementation does not cause an excess of severe malaria (RR 0.90, 95% CI 0.81 to 0.98; 6 trials, 3421 children, high quality evidence). We did not observe any differences for deaths (control event rate 1%, low quality evidence). Iron and antimalarial treatment reduced clinical malaria (RR 0.54, 95% CI 0.43 to 0.67; three trials, 728 children, high quality evidence). Overall, iron resulted in fewer anaemic children at follow up, and the end average change in haemoglobin from base line was higher with iron. AUTHORS' CONCLUSIONS: Iron treatment does not increase the risk of clinical malaria when regular malaria prevention or management services are provided. Where resources are limited, iron can be administered without screening for anaemia or for iron deficiency, as long as malaria prevention or management services are provided efficiently.

Iron and malaria interactions: research needs from basic science to global policy.

The resurgence in interest and concern regarding the potentially malign interactions between iron administration and malaria infections, especially in young children and pregnant women, has generated a research agenda that is both broad and deep. This paper highlights some of the key questions under 5 headings: basic science; clinical science and epidemiology; technological developments; country level planning; and global policy. At a time of unparalleled progress in basic science, which is illuminating the mechanisms by which iron interacts with infectious organisms, it is concluded that there are good medium-term prospects for achieving policy breakthroughs based on a secure foundation of disease-nutrient interactions. However, it is also stressed that there is much that can be done in the interim, especially in relation to health systems and implementation research that can empower systems to integrate iron interventions with programs for malaria prevention, surveillance, and treatment.

Oral iron supplements for children in malaria-endemic areas.

BACKGROUND: Iron-deficiency anaemia is common during childhood. Iron supplementation has been claimed to increase the risk of malaria. OBJECTIVES: To assess the effect of iron on malaria and deaths. SEARCH STRATEGY: We searched The Cochrane Library, PUBMED, MEDLINE, LILACS; and trial registry databases, all up to June 2011. We scanned references of included trials. SELECTION CRITERIA: Individually and cluster randomized controlled trials conducted in hypoendemic to holoendemic malaria regions and including children below 18 years of age. We included trials comparing orally administered iron, iron with antimalarial treatment, or iron with folic acid versus placebo or no treatment. Iron fortification was excluded. Antihelminthics could be administered to either group. Additional micronutrients had to be administered equally to both groups. DATA COLLECTION AND ANALYSIS: The primary outcomes were clinical (symptomatic) malaria, severe malaria, and death. Two authors independently selected the studies and extracted the data. We assessed heterogeneity and conducted subgroup analyses by the presence of anaemia at baseline, age, and malaria endemicity. We assessed risk of bias using domain-based evaluation. We performed a fixed-effect meta-analysis for all outcomes and random-effects meta-analysis for hematological outcomes. We adjusted analyses for cluster randomized trials. MAIN RESULTS: Seventy-one trials (45,353 children) were included. For clinical malaria, no significant difference between iron alone and placebo was detected, (risk ratio (RR) 0.99, 95% confidence intervals (CI) 0.90 to 1.09, 13 trials). The results were similar in the subgroups of non-anaemic children and children below 2 years of age. There was no significant difference in deaths in hyper- and holoendemic areas, risk difference +1.93 per 1000 children (95% CI -1.78 to 5.64, 13 trials, 17,898 children). Iron administered for treatment of anaemia resulted in a larger increase in haemoglobin than iron given for prevention, and the benefit was similar in hyper- or holoendemic and lower endemicity settings. Iron and folic acid supplementation resulted in mixed results for severe malaria. Overall, the risk for clinical malaria was higher with iron or with iron plus folic acid in trials where services did not provide for malaria surveillance and treatment. Iron with antimalarial treatment significantly reduced malaria. Iron supplementation during an acute attack of malaria did not increase the risk for parasitological failure, (RR 0.96, 95% CI 0.74 to 1.24, three trials) or deaths. AUTHORS' CONCLUSIONS: Iron alone or with antimalaria treatment does not increase the risk of clinical malaria or death when regular malaria surveillance and treatment services are provided. There is no need to screen for anaemia prior to iron supplementation.

Do post-disaster public health interventions impede malaria eradication?

In this paper, we hypothesise that public health interventions aimed at controlling post-disaster malaria epidemics may in fact impede malaria eradication efforts in the longer term. A major factor hampering malaria eradication efforts is the development of resistance to antimalarial drugs in the Plasmodium parasite. Following natural disasters such as flooding, public health responses includes a massive influx of antimalarial drugs that may facilitate the development of resistance. Resistance is common in areas with frequent natural disasters, and if such an association could be shown to be generalisable and causative, there may be direct implications for the way that future disaster-related malaria risks are managed. Because the frequency and severity of climate-associated disasters is likely to increase with global warming, it is timely to study the possibility that well intentioned public health action may in fact exacerbate the disease burden from the very parasites that it sets out to control.

Oral iron supplementation for preventing or treating anaemia among children in malaria-endemic areas.

BACKGROUND: Iron-deficiency anaemia is common during childhood. Iron supplementation has been claimed to increase the risk of malaria. OBJECTIVES: To assess the effect of iron on malaria and deaths. SEARCH STRATEGY: We searched The Cochrane Library (2009, issue 1); MEDLINE; EMBASE; LILACS and metaRegister of Controlled Trials, all up to March 2009. We scanned references of included trials. SELECTION CRITERIA: Individually and cluster-randomized controlled trials conducted in hypoendemic to holoendemic malaria regions and including children < 18 years. We included trials comparing orally administered iron with or without folic acid vs. placebo or no treatment. Iron fortification was excluded. Antimalarials and/or antiparasitics could be administered to either group. Additional micronutrients could only be administered equally to both groups. DATA COLLECTION AND ANALYSIS: The primary outcomes were malaria-related events and deaths. Secondary outcomes included haemoglobin, anaemia, other infections, growth, hospitalizations, and clinic visits. We assessed risk of bias using domain-based evaluation. Two authors independently selected studies and extracted data. We contacted authors for missing data. We assessed heterogeneity. We performed fixed-effect meta-analysis and presented random-effects results when heterogeneity was present. We present pooled risk ratios (RR) with 95% confidence intervals (CIs). We used adjusted analyses for cluster-randomized trials. MAIN RESULTS: Sixty-eight trials (42,981 children) fulfilled the inclusion criteria. Iron supplementation did not increase the risk of clinical malaria (RR 1.00, 95% CI 0.88 to 1.13; 22,724 children, 14 trials, random-effects model). The risk was similar among children who were non-anaemic at baseline (RR 0.96, 95% CI 0.85 to 1.09). An increased risk of malaria with iron was observed in trials that did not provide malaria surveillance and treatment. The risk of malaria parasitaemia was higher with iron (RR 1.13, 95% CI 1.01 to 1.26), but there was no difference in adequately concealed trials. Iron + antimalarial was protective for malaria (four trials). Iron did not increase the risk of parasitological failure when given during malaria (three trials). There was no increased risk of death across all trials comparing iron versus placebo (RR 1.11, 95% CI 0.91 to 1.36; 21,272 children, 12 trials). Iron supplementation increased haemoglobin, with significant heterogeneity, and malaria endemicity did not affect this effect. Growth and other infections were mostly not affected by iron supplementation. AUTHORS' CONCLUSIONS: Iron does not increase the risk of clinical malaria or death, when regular malaria surveillance and treatment services are provided. There is no need to screen for anaemia prior to iron supplementation.

Derivados de 1, 4-di-N-óxido de quinoxalina y enfermedades olvidadas / Quinoxaline 1, 4-di-N-oxide derivatives and Neglected Diseases

Las enfermedades olvidadas son un grupo de enfermedades infecciosas médicamentediversas entre las que se encuentran tuberculosis, malaria, leishmaniasisy la enfermedad de Chagas, que afectan a millares de personas en todo el mundopero, principalmente, a la gente pobre en países en vías de desarrollo. Son un retopara la Salud Pública Internacional ya que no existen vacunas parar controlarlasy los medicamentos existentes para su tratamiento no son adecuados. La necesidadde buscar nuevas terapias económicamente accesibles para la población afectadaes cada vez más urgente y palpable, lo que ha dado lugar a la puesta en marchade nuevas iniciativas internacionales que buscan la erradicación de estas enfermedades.A lo largo de los años, nuestro grupo de investigación ha llevado a cabo eldiseño y la síntesis, mediante métodos sintéticos sencillos y de bajo coste, de diversos derivados de 1,4-di-N-óxido de quinoxalina con el objetivo de encontrarnuevos líderes para el tratamiento de algunas enfermedades olvidadas. Como resultadode varios proyectos de investigación, se han desarrollado nuevas estructurasactivas como agentes antituberculosos, antimaláricos, antichagas y, más recientemente,como agentes antileishmania. Este resumen presenta los resultadosmás importantes obtenidos en este campo, de los que se puede concluir que elnúcleo de 1,4-di-N-óxido de quinoxalina representa un posible avance en la búsquedade nuevos compuestos activos

Neglected diseases are diseases that affect thousands of people around theworld, but who do not have effective or suitable treatments. They are mainlyinfectious tropical diseases that fundamentally affect the poorest population; someexamples are tuberculosis, leishmaniasis, malaria and Chagas, which generate adevastating impact on humanity. This fact highlights the necessity to search fornew economically accessible therapies for the affected population. Throughout theyears our research group has carried out the design and synthesis of several quinoxaline1,4-di-N-oxide derivatives with the aim of finding new leaders for thetreatment of these types of diseases by means of simple, low cost synthetic methods.This work has resulted in the development of new active structures such asantitubercular, antimalarial and antichagas agents, and more recently, antileishmaniaagents. This summary displays the most important results obtained in thisfield, and it may be concluded that the quinoxaline 1,4-di-N-oxide nucleus representsa possible advance in the search of new active compounds

Testosterone signaling in T cells and macrophages.

This review summarizes data about non-genomic actions of testosterone on murine malaria, T cells and macrophages produced by our group during the last 15 years. In C57BL/10 mice, testosterone induces a lethal outcome of blood stage infections with Plasmodium chabaudi which normally takes a self-healing course controlled by genes of the H-2 complex and the non-H-2 background. This suppressive effect of testosterone is mediated neither via the classic intracellular androgen receptor (AR) response nor, after conversion of testosterone to estradiol, via the estrogen receptor. Testosterone acts non-genomically, i.e. through surface receptors, on murine T cells and macrophages, which becomes evident as a rapid rise in the intracellular free Ca(2+) concentration ([Ca(2+)](i)). In T cells, this rise reflects predominantly influx of extracellular Ca(2+), while it is predominantly due to release of Ca(2+) from intracellular Ca(2+)-stores in macrophages. The testosterone-induced rise in [Ca(2+)](i) of both macrophages and T cells is not inhibited by the AR-blocker cyproterone, and it is also inducible by the plasma membrane impermeable ligand testosterone-BSA. The surface receptors initiate a transcription-independent signaling pathway of testosterone. Currently, we are trying to isolate testosterone surface receptors and to investigate a possible cross-talk of non-genomic testosterone signaling with other genotropic signaling pathways.

Observacoes sobre o efeito de quinolonas na infeccao experimental de camundongos pelo Plasmodium berghei e sobre sua eventual utilidade terapeutica / Observations on the effect of quinolones in the experimental mice infection by Plasmodium berghei and its eventual therapeutic usefulness

Motivos de varias ordens e, sobretudo, a resistencia de plasmodios a medicamentos, tornam conveniente a procura de farmacos capazes de permitir adequado tratamento da malaria. Recentemente, algumas pesquisas clinicas e laboratoriais indicaram que quinolonas, hoje usadas assistencialmente para beneficiar pacientes acometidos por determinadas infeccoes bacterianas, possuem atividade antimalarica. Por isso, avaliamos a eventual acao do ciprofloxacino, do norfloxacino, do ofloxacino e do pefloxacino, administrados pela via oral, em camundongos experimentalmente parasitados pelo Plasmodium berghei. Levando em consideracao parasitemia e mortalidade, verificamos que, pelo menos de acordo com a metodologia empregada, essas drogas nao se mostram eficientes.

[Ultrasonographic changes in the gallbladder wall in non-gallbladder diseases]. / Alteraciones ultrasonográficas de la pared vesicular en patologías no vesiculares.

Alterations of the gallbladder wall is a well known sonographic sign of acute cholecystitis. But thickening of the gallbladder wall is also found in patients without intrinsic gallbladder disease. We present our experience on this regard in patients with cirrhosis, acute viral hepatitis, infectious mononucleosis, halothane hepatitis, fulminant hepatic failure, malaria due to plasmodium falciparum, heart failure, severe malnutrition due to gastric obstruction, septicemia, pyogenic hepatic abscess, amoebic hepatic abscess and in a 14 years old patient with fracture of the skull-acute anemia-shock. Most of these diseases affected the liver directly or indirectly. Knowledge of these alterations of the gallbladder wall in these circumstances are important in order to avoid a the erroneous diagnosis of acute cholecystitis.