RESUMO
In both humans and mice, natural killer (NK) cells are important lymphocytes of the innate immune system. They are often considered pro-inflammatory effector cells but may also have a regulatory or pro-resolving function by switching their cytokine profile towards the production of anti-inflammatory cytokines, including interleukin-10 (IL-10) and transforming growth factor-ß, and by killing pro-inflammatory immune cells. Here, the role of NK cells in the resolution of malaria lung pathology was studied. Malaria complications, such as malaria-associated acute respiratory distress syndrome (MA-ARDS), are often lethal despite the rapid and efficient killing of Plasmodium parasites with antimalarial drugs. Hence, studying the resolution and healing mechanisms involved in the recovery from these complications could be useful to develop adjunctive treatments. Treatment of Plasmodium berghei NK65-infected C57BL/6 mice with a combination of artesunate and chloroquine starting at the appearance of symptoms was used as a model to study the resolution of MA-ARDS. The role of NK cells was studied using anti-NK1.1 depletion antibodies and NK cell-deficient mice. Using both methods, NK cells were found to be dispensable in the development of MA-ARDS, as shown previously. In contrast, NK cells were crucial in the initiation of resolution upon antimalarial treatment, as survival was significantly decreased in the absence of NK cells. Considerably increased IL-10 expression by NK cells suggested an anti-inflammatory and pro-resolving phenotype. Despite the increase in Il10 expression in the NK cells, inhibition of the IL-10/IL-10R axis using anti-IL10R antibodies had no effect on the resolution for MA-ARDS, suggesting that the pro-resolving effect of NK cells cannot solely be attributed to their IL-10 production. In conclusion, NK cells contribute to the resolution of experimental MA-ARDS.
Assuntos
Antimaláricos , Modelos Animais de Doenças , Células Matadoras Naturais , Malária , Camundongos Endogâmicos C57BL , Plasmodium berghei , Síndrome do Desconforto Respiratório , Animais , Células Matadoras Naturais/imunologia , Antimaláricos/uso terapêutico , Camundongos , Malária/imunologia , Malária/tratamento farmacológico , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/etiologia , Plasmodium berghei/imunologia , Camundongos Knockout , Interleucina-10/metabolismo , Cloroquina/uso terapêutico , Cloroquina/farmacologia , Pulmão/imunologia , Pulmão/parasitologia , Artesunato/uso terapêutico , Artesunato/farmacologiaRESUMO
BACKGROUND: In most countries engaged on the last mile towards malaria elimination, residual transmission mainly persists among vulnerable populations represented by isolated and mobile (often cross-border) communities. These populations are sometimes involved in informal or even illegal activities. In regions with Plasmodium vivax transmission, the specific biology of this parasite poses additional difficulties related to the need for a radical treatment against hypnozoites to prevent relapses. Among hard-to-reach communities, case management, a pillar of elimination strategy, is deficient: acute malaria attacks often occur in remote areas, where there is limited access to care, and drugs acquired outside formal healthcare are often inadequately used for treatment, which typically does not include radical treatment against P. vivax. For these reasons, P. vivax circulation among these communities represents one of the main challenges for malaria elimination in many non-African countries. The objective of this article is to describe the protocol of the CUREMA study, which aims to meet the challenge of targeting malaria in hard-to-reach populations with a focus on P. vivax. RESULTS: CUREMA is a multi-centre, international public health intervention research project. The study population is represented by persons involved in artisanal and small-scale gold mining who are active and mobile in the Guiana Shield, deep inside the Amazon Forest. The CUREMA project includes a complex intervention composed of a package of actions: (1) health education activities; (2) targeted administration of treatment against P. vivax after screening against G6PD deficiency to asymptomatic persons considered at risk of silently carrying the parasite; (3) distribution of a self-testing and self-treatment kit (malakit) associated with user training for self-management of malaria symptoms occurring while in extreme isolation. These actions are offered by community health workers at settlements and neighbourhoods (often cross-border) that represent transit and logistic bases of gold miners. The study relies on hybrid design, aiming to evaluate both the effectiveness of the intervention on malaria transmission with a pre/post quasi-experimental design, and its implementation with a mixed methods approach. CONCLUSIONS: The purpose of this study is to experiment an intervention that addresses both Plasmodium falciparum and P. vivax malaria elimination in a mobile and isolated population and to produce results that can be transferred to many contexts facing the same challenges around the world.
Assuntos
Erradicação de Doenças , Malária Vivax , Humanos , Malária Vivax/prevenção & controle , Erradicação de Doenças/métodos , Erradicação de Doenças/estatística & dados numéricos , Masculino , Feminino , Antimaláricos/uso terapêutico , Adulto , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Criança , Plasmodium vivax/fisiologiaRESUMO
Maternal health remains a global priority, with particular emphasis on combating infectious diseases such as HIV and malaria during pregnancy. Despite significant progress in prevention and treatment efforts, both HIV and malaria continue to pose significant risks to maternal and fetal well-being, particularly in resource-limited settings. The prevention of mother-to-child transmission (PMTCT) programs for HIV and intermittent preventive treatment (IPTp) for malaria represent cornerstone strategies in mitigating the impact of these infections on pregnancy outcomes. PMTCT programs focus on early HIV diagnosis, antiretroviral therapy initiation, and promoting safe infant feeding practices to reduce the risk of mother-to-child transmission. Similarly, IPTp involves the administration of antimalarial medication to pregnant women in malaria-endemic regions to prevent maternal and fetal complications associated with malaria infection. Integration of HIV and malaria prevention and treatment services within existing maternal and child health programs is crucial for maximizing impact and minimizing healthcare system strain. Strengthening health systems, improving access to antenatal care services, and enhancing community engagement are essential components of comprehensive maternal health strategies. Furthermore, promoting awareness, education, and empowerment of pregnant women and communities are vital in fostering health-seeking behaviors and adherence to preventive measures against HIV and malaria. In conclusion, protecting maternal health from the dual threat of HIV and malaria requires a multifaceted approach that encompasses prevention, screening, treatment, and community engagement.
Assuntos
Infecções por HIV , Transmissão Vertical de Doenças Infecciosas , Malária , Complicações Infecciosas na Gravidez , Humanos , Gravidez , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Infecções por HIV/tratamento farmacológico , Malária/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Saúde Materna , Antimaláricos/uso terapêutico , Cuidado Pré-Natal/métodosRESUMO
Background: Plasmodium vivax malaria has been one of the most troublesome diseases in the Democratic People's Republic of Korea (DPRK). Given that a majority of malaria cases are concentrated near the demilitarized zone, concerted elimination efforts from both the Republic of Korea (ROK) and DPRK are essential for a malaria-free Korean Peninsula. This study assessed the impact of rapid diagnostic tests (RDTs) and tafenoquine on malaria incidence in DPRK. Methods: We patterned the current model structure from the previously developed Plasmodium vivax malaria dynamic transmission model for ROK. Model parameters were adjusted using demographic and climate data from malaria-risk areas in DPRK, and the model was calibrated to annual malaria incidences from 2014 to 2018 in DPRK, as reported by the World Health Organization. Subsequently, we estimated the preventable malaria cases over a decade after introducing RDTs and tafenoquine compared to using microscopy alone and primaquine, respectively. Sensitivity analysis was performed to account for uncertainty in model parameters. Results: When comparing RDTs to microscopy, a one-day reduction in diagnostic time due to the introduction of RDTs led to a reduction in malaria incidence by 26,235 cases (65.6%) over the next decade. With a two-day reduction, incidences decreased by 33,635 (84.1%). When comparing a single dose of tafenoquine with a 14-day primaquine regimen, the former prevented 1,222 (77.5%) relapse cases and 4,530 (11.3%) total cases over the years. Conclusion: The continuous and simultaneous implementation of RDTs and tafenoquine emerges as a potent strategy to considerably reduce malaria in DPRK.
Assuntos
Antimaláricos , Malária Vivax , Malária Vivax/epidemiologia , Malária Vivax/prevenção & controle , Humanos , Antimaláricos/uso terapêutico , Incidência , República Democrática Popular da Coreia/epidemiologia , Plasmodium vivax/efeitos dos fármacos , Aminoquinolinas/uso terapêutico , Testes Diagnósticos de Rotina/estatística & dados numéricos , Adulto , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Malaria in pregnancy (MiP) is a condition that can be prevented by using intermittent preventive treatment using Sulfadoxine-pyrimethamine. However, despite all the effort to reduce the consequences of MiP for the woman, the unborn child, and the neonate, the knowledge of Intermittent Preventive Treatment of Malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) is low in most malaria-endemic countries, including Ghana. Thus, the need to examine knowledge, and attitude of service users of intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine. METHODS: The study was a cross-sectional survey of two selected districts in the Volta Region of Ghana. The study participants were randomly selected from communities within Nkwanta North and North Tongu District. In all a total of 438 mothers who have delivered in the past 24 months were selected for the study. The women were interviewed using a structured questionnaire and the bivariate and multivariable logistic regression results presented in tables. RESULTS: The level of knowledge, and attitude were reported as 45.9% and 58.9% respectively. Knowledge of the service user is determined by the level of education of the women. The attitude of the service user is determined by making 4-7 visits during ANC, Gestational age at booking for ANC is 4-7 weeks, income level between 100 to 999, partner educational level above Middle/JHS/JSS, and age of a partner is above 40 years. CONCLUSION: The findings from the present studies highlighted important factor such as number of antenatal visits that affect both knowledge of services and attitude to use IPTp-SP. Therefore, a community-based health promotion programmes to help to increase knowledges and improved attitude on timely and regular antenatal attendance to promote the benefit of IPTp-SP should be encouraged.
Assuntos
Antimaláricos , Combinação de Medicamentos , Conhecimentos, Atitudes e Prática em Saúde , Malária , Complicações Parasitárias na Gravidez , Pirimetamina , Sulfadoxina , Humanos , Feminino , Gana/epidemiologia , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Gravidez , Adulto , Malária/prevenção & controle , Malária/tratamento farmacológico , Malária/epidemiologia , Antimaláricos/uso terapêutico , Estudos Transversais , Complicações Parasitárias na Gravidez/prevenção & controle , Complicações Parasitárias na Gravidez/tratamento farmacológico , Adulto Jovem , Adolescente , Inquéritos e QuestionáriosRESUMO
To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC50 550 nM; 3 96 h IC50 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC50 <40 nM; SI > 2500). Subsequent studies in mice with compound 1, which had the best microsomal stability of the compounds assessed (T1/2 >255 min), demonstrated rapid clearance and poor oral in vivo efficacy in a P. berghei murine malaria model. These data indicate that while N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements.
Assuntos
Antimaláricos , Oxidiazóis , Plasmodium falciparum , Oxidiazóis/química , Oxidiazóis/farmacologia , Oxidiazóis/síntese química , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/síntese química , Animais , Relação Estrutura-Atividade , Camundongos , Testes de Sensibilidade Parasitária , Estrutura Molecular , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Malária Falciparum/tratamento farmacológicoRESUMO
BACKGROUND: Malaria is a mosquito-transmitted disease that kills more than half a million people annually. The lack of effective malaria vaccines and recently increasing malaria cases urge innovative approaches to prevent malaria. Previously, we reported that the extract from the soil-dwelling fungus Purpureocillium lilacinum, a common fungus from the soil, reduced Plasmodium falciparum oocysts in Anopheles gambiae midguts after mosquitoes contacted the treated surface before feeding. METHODS: We used liquid chromatography to fraction fungal crude extract and tract the active fraction using a contact-wise approach and standard membrane feeding assays. The purified small molecules were analyzed using precise mass spectrometry and tandem mass spectrometry. RESULTS: We isolated four active small molecules from P. lilacinum and determined them as leucinostatin A, B, A2, and B2. Pre-exposure of mosquitoes via contact with very low-concentration leucinostatin A significantly reduced the number of oocysts. The half-maximal response or inhibition concentration (EC50) via pre-exposure was 0.7 mg/m2, similar to atovaquone but lower than other known antimalarials. The inhibitory effect of leucinostatin A against P. falciparum during intraerythrocytic development, gametogenesis, sporogonic development, and ookinete formation, with the exception of oocyst development, suggests that leucinostatins play a part during parasite invasion of new cells. CONCLUSIONS: Leucinostatins, secondary metabolites from P. lilacinum disrupt malaria development, particular transmission to mosquitoes by contact. The contact-wise malaria control as a nonconventional approach is highly needed in malaria-endemic areas.
Assuntos
Anopheles , Plasmodium falciparum , Animais , Anopheles/efeitos dos fármacos , Anopheles/parasitologia , Anopheles/microbiologia , Plasmodium falciparum/efeitos dos fármacos , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/parasitologia , Mosquitos Vetores/microbiologia , Hypocreales/química , Hypocreales/efeitos dos fármacos , Antimaláricos/farmacologia , Antimaláricos/química , Oocistos/efeitos dos fármacos , Malária Falciparum/transmissão , Malária Falciparum/prevenção & controle , Malária Falciparum/parasitologia , Cromatografia Líquida , Feminino , Peptídeos Catiônicos AntimicrobianosAssuntos
Antimaláricos , Malária , Complicações Parasitárias na Gravidez , Humanos , Gravidez , Feminino , Malária/prevenção & controle , Antimaláricos/uso terapêutico , Complicações Parasitárias na Gravidez/prevenção & controle , Disseminação de Informação/métodos , Complicações Infecciosas na Gravidez/prevenção & controleRESUMO
BACKGROUND: Severe malaria can cause respiratory symptoms, which may lead to malaria-acute lung injury (MA-ALI) due to inflammation and damage to the blood-gas barrier. Patients with severe malaria also often present thrombocytopenia, and the use of acetylsalicylic acid (ASA), a commonly used non-steroidal anti-inflammatory drug with immunomodulatory and antiplatelet effects, may pose a risk in regions where malaria is endemic. Thus, this study aimed to investigate the systemic impact of ASA and dihydroartemisinin (DHA) on ALI induced in mice by Plasmodium berghei NK65 (PbNK65). METHODS: C57BL/6 mice were randomly divided into control (C) and PbNK65 infected groups and were inoculated with uninfected or 104 infected erythrocytes, respectively. Then, the animals were treated with DHA (3 mg/kg) or vehicle (DMSO) at the 8-day post-infection (dpi) for 7 days and with ASA (100 mg/kg, single dose), and analyses were performed at 9 or 15 dpi. Lung mechanics were performed, and lungs were collected for oedema evaluation and histological analyses. RESULTS: PbNK65 infection led to lung oedema, as well as increased lung static elastance (Est, L), resistive (ΔP1, L) and viscoelastic (ΔP2, L) pressures, percentage of mononuclear cells, inflammatory infiltrate, hemorrhage, alveolar oedema, and alveolar thickening septum at 9 dpi. Mice that received DHA or DHA + ASA had an increase in Est, L, and CD36 expression on inflammatory monocytes and higher protein content on bronchoalveolar fluid (BALF). However, only the DHA-treated group presented a percentage of inflammatory monocytes similar to the control group and a decrease in ΔP1, L and ΔP2, L compared to Pb + DMSO. Also, combined treatment with DHA + ASA led to an impairment in diffuse alveolar damage score and lung function at 9 dpi. CONCLUSIONS: Therapy with ASA maintained lung morpho-functional impairment triggered by PbNK65 infection, leading to a large influx of inflammatory monocytes to the lung tissue. Based on its deleterious effects in experimental MA-ALI, ASA administration or its treatment maintenance might be carefully reconsidered and further investigated in human malaria cases.
Assuntos
Lesão Pulmonar Aguda , Antimaláricos , Artemisininas , Aspirina , Pulmão , Malária , Camundongos Endogâmicos C57BL , Plasmodium berghei , Animais , Artemisininas/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/parasitologia , Aspirina/farmacologia , Aspirina/administração & dosagem , Malária/tratamento farmacológico , Malária/complicações , Camundongos , Antimaláricos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Quimioterapia Combinada , Modelos Animais de Doenças , Masculino , Testes de Função RespiratóriaRESUMO
BACKGROUND: High-level resistance to sulfadoxine-pyrimethamine threatens the efficacy of WHO-recommended intermittent preventive treatment in pregnancy (IPTp) with single-dose sulfadoxine-pyrimethamine to prevent malaria. Monthly IPTp with dihydroartemisinin-piperaquine, a 3-day regimen, is an emerging alternative, but this regimen poses potential implementation and adherence challenges. We aimed to assess adherence to a multiday IPTp with dihydroartemisinin-piperaquine regimen and its delivery effectiveness in routine antenatal care settings in western Kenya. METHODS: We conducted a pragmatic, three-armed, open-label, cluster-randomised trial in antenatal clinics in 18 health-care facilities (six facilities per group) in Kisumu County and Homa Bay County in western Kenya. Clusters were facilities offering routine antenatal care services provided by trained Ministry of Health staff with 100 or more antenatal clinic attendances per month between July, 2018, and June, 2019. Private or mission hospitals, dispensaries, referral hospitals, and trial sites were excluded. Individuals in their first trimester, living with HIV, or who were not attending a scheduled antenatal clinic visit were excluded. The 18 antenatal clinics were grouped into matched triplets stratified by location and clinics in each matched triplet were randomly assigned to one of the three study groups (1:1:1). Masking was not possible. Two groups were given IPTp with dihydroartemisinin-piperaquine (one group with a targeted information transfer intervention and one group without any additional interventions) and one group was given the standard of care (ie, IPTp with sulfadoxine-pyrimethamine). The primary endpoint, adherence, was defined as the proportion of participants completing their most recent 3-day IPTp with dihydroartemisinin-piperaquine regimen. This completion was verified by pill counts during home visits no more than 2 days after participants' 3-day regimens ended. The secondary endpoint, delivery effectiveness, was defined as the proportion of participants who received the correct number of IPTp tablets and correctly repeated dosing instructions (ie, correctly recalled the instructions they received about self-administered dihydroartemisinin-piperaquine doses and the number of sulfadoxine-pyrimethamine tablets they had received) at their exit from the antenatal clinic. Individuals receiving treatment for malaria, visiting a clinic for registration only, or interviewed during IPTp drug stock-outs were excluded from analyses. We used generalised linear mixed models to compare endpoints among the IPTp with dihydroartemisinin-piperaquine groups. This trial was registered with ClinicalTrials.gov, NCT04160026, and is complete. FINDINGS: 15 facilities (five per group) completed the trial, with 1189 participants having exit interviews (377 in the IPTp with sulfadoxine-pyrimethamine group, 408 in the IPTp with dihydroartemisinin-piperaquine only group, and 404 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) and 586 participants having home visits (267 in the IPTp with dihydroartemisinin-piperaquine only group and 319 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) from Sept 8 to Dec 10, 2020. Relative to the IPTp with dihydroartemisinin-piperaquine only group, adherence was 16% higher in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group (266 [83%] of 319 participants vs 196 [73%] of 267 participants; adjusted relative risk [RR] 1·16, 95% CI 1·03-1·31; p=0·0140). Delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group was not significantly different from that in the IPTp with sulfadoxine-pyrimethamine group (352 [87%] of 403 participants vs 335 [89%] of 375 participants; adjusted RR 0·97, 95% CI 0·90-1·05; p=0·4810). However, delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine only group was significantly lower than in the IPTp with sulfadoxine-pyrimethamine group (300 [74%] of 404 participants vs 335 [89%] of 375 participants; 0·84, 0·75-0·95; p=0·0030). INTERPRETATION: Targeted information transfer interventions to health-care providers and pregnant individuals boost antenatal care delivery adherence to a multiday regimen with dihydroartemisinin-piperaquine. FUNDING: European and Developing Countries Clinical Trials Partnership 2, UK Joint Global Health Trials Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, National Institute for Health and Care Research, and Wellcome Trust; and Swedish International Development Cooperation Agency.
Assuntos
Antimaláricos , Artemisininas , Combinação de Medicamentos , Malária , Complicações Parasitárias na Gravidez , Pirimetamina , Quinolinas , Sulfadoxina , Humanos , Feminino , Gravidez , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Antimaláricos/administração & dosagem , Pirimetamina/uso terapêutico , Pirimetamina/administração & dosagem , Sulfadoxina/uso terapêutico , Sulfadoxina/administração & dosagem , Artemisininas/uso terapêutico , Artemisininas/administração & dosagem , Quênia , Adulto , Complicações Parasitárias na Gravidez/prevenção & controle , Complicações Parasitárias na Gravidez/tratamento farmacológico , Malária/prevenção & controle , Adulto Jovem , Adesão à Medicação/estatística & dados numéricos , Adolescente , Cuidado Pré-Natal/métodos , PiperazinasRESUMO
Background: Malaria remains a significant global health burden, with drug resistance posing a major challenge to its control. The emergence of resistance to antimalarial drugs represents a critical issue in malaria management, as it heightens the likelihood of morbidity and mortality associated with the disease. There is an urgent requirement for a novel candidate drug with a distinct mechanism of action. Aim: In light of the ongoing challenges in malaria management, particularly the emergence of drug resistance, this study aimed to investigate the efficacy of a novel combination therapy of borrelidin and fumagilin against Plasmodium berghei infection on Swiss Webster mice. The findings of this study could contribute to developing new and effective antimalarial treatments. Methods: This study employed a unique approach, using Swiss Webster mice aged 6-8 weeks and dividing them into five groups, each with five mice. The therapeutic efficacy of the combination treatment was evaluated through a comprehensive assessment of parasitemia levels, survival rates, and histological changes in the liver and spleen. This rigorous methodology ensures the reliability and validity of our findings. Results: The combination of borrelidin and fumagilin led to the lowest parasitemia at 5%, contrasting with the control group reaching 15%. Moreover, the combination group exhibited the highest inhibition rate of 69.6% on day nine post-infection. Histopathological alterations were limited to sinusoid dilation, hepatocyte ballooning, and the presence of hemozoin. Conclusion: These findings suggest that the combination of borrelidin and fumagilin holds promise as a potential antimalarial therapy.
Assuntos
Antimaláricos , Malária , Plasmodium berghei , Animais , Plasmodium berghei/efeitos dos fármacos , Camundongos , Malária/tratamento farmacológico , Malária/veterinária , Malária/parasitologia , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antimaláricos/administração & dosagem , Quimioterapia Combinada , Parasitemia/tratamento farmacológico , Feminino , Álcoois GraxosRESUMO
BACKGROUND: Azithromycin has been shown to be beneficial in preventing infectious diseases, including malaria, infectious diarrhoea and pneumonia. A cluster randomised control trial on azithromycin MDA in children in Niger, Malawi and Tanzania found a reduction in all-cause under-five (U5) mortality in communities who received azithromycin compared to placebo. However, the reduction was largest and statistically significant only in Niger. The purpose of this trial is to evaluate the impact of azithromycin plus intermittent preventive treatment in infants (IPTi), recently renamed by the World Health Organisation as perennial malaria chemoprevention (PMC), with sulfadoxine-pyrimethamine (SP) on all-cause mortality up to 18 months of age in children living in areas of high mortality burden through the Expanded Program on Immunisation (EPI) in Sierra Leone. METHODS: The Improving Care through Azithromycin Research for Infants in Africa (ICARIA) trial is a phase III two-arm, individually randomised, double-blinded, placebo-controlled trial administering oral AZI (20 mg/kg bodyweight) at three time points to children attending EPI visits in Sierra Leone. A total of 20,560 infants attending the first EPI contact at around 6 weeks of age are recruited and randomised to AZI or placebo in a 1:1 ratio. The second and third AZI/placebo doses are given at 9 and 15 months of age. The primary outcome of the trial is all-cause mortality rate at 18 months of age assessed through mortality surveillance. Other trial outcomes include the impact on antimicrobial resistance, and on the immune response to certain key routine EPI immunisations, the safety of the intervention, the prevalence of SP resistance markers and the feasibility, and acceptability of adding AZI to the EPI programme. DISCUSSION: The trial will provide the evidence needed to inform policy regarding the adoption and large-scale implementation of AZI in areas of high-mortality burden in sub-Saharan Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT04235816. Registered on 22 January 2020. Pan-African Clinical Trials Registry PACTR202004540256535. Registered on 14 April 2020.
Assuntos
Antimaláricos , Azitromicina , Mortalidade da Criança , Combinação de Medicamentos , Pirimetamina , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfadoxina , Humanos , Azitromicina/administração & dosagem , Azitromicina/uso terapêutico , Serra Leoa , Sulfadoxina/administração & dosagem , Sulfadoxina/uso terapêutico , Lactente , Método Duplo-Cego , Pirimetamina/administração & dosagem , Pirimetamina/uso terapêutico , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Administração Oral , Malária/prevenção & controle , Malária/mortalidade , Ensaios Clínicos Fase III como Assunto , Resultado do Tratamento , Feminino , Masculino , Esquema de Medicação , Fatores de TempoRESUMO
The focus of current studies was to fabricate dose flexible printlets of dapsone (DDS) for pediatric patients by selective laser sintering (SLS) 3D printing method, and evaluate its physicochemical, patient in-use stability, and pharmacokinetic attributes. Eight formulations were fabricated using Kollicoat® IR, Eudragit® L-100-55 and StarCap®as excipients and evaluated for hardness, disintegration, dissolution, amorphous phase by differential scanning calorimetry and X-ray powder diffraction, in-use stability at 30 oC/75% RH for a month, and pharmacokinetic study in Sprague Dawley rats. The hardness, and disintegration of the printlets varied from 2.6±1.0 (F4) to 7.7±0.9 (F3) N and 2.0±0.4 (F2) to 7.6±0.6 (F3) sec, respectively. The drug was partially present as an amorphous form in the printlets. The drug was completely (>85%) dissolved in 20 min. No change in drug form or dissolution extent was observed after storage at in use condition. Pharmacokinetic profiles of both formulations (tablets and printlets) were almost superimposable with no statistical difference in pharmacokinetic parameters (Tmax, Cmax, and AUC0-¥)between formulations (p>0.05). Values of EC50 (half maximal effective concentration) and EC90 (maximal concentration inducing 90% maximal response) were 0.50±0.15 and 1.32±0.26 mM, 0.41±0.06 and 1.11±0.21, and 0.42±0.13 and 1.36±0.19 mM for DDS, printlet and tablet formulations, respectively, and differences were statistically insignificant (p>0.05). In conclusion, tablet and printlet formulations are expected to be clinical similar, thus clinically interchangeable.
Assuntos
Antimaláricos , Dapsona , Impressão Tridimensional , Ratos Sprague-Dawley , Antimaláricos/farmacocinética , Antimaláricos/administração & dosagem , Animais , Ratos , Dapsona/farmacocinética , Dapsona/administração & dosagem , Dapsona/química , Química Farmacêutica/métodos , Solubilidade , Masculino , Excipientes/química , Humanos , Comprimidos/farmacocinética , Estabilidade de Medicamentos , Criança , Varredura Diferencial de Calorimetria/métodos , Composição de Medicamentos/métodos , Difração de Raios X/métodosRESUMO
BACKGROUND: Radical cure of Plasmodium vivax infections is key to the control of vivax malaria. However, the standard doses of 8-aminoquinoline drugs used for radical cure can cause severe haemolysis in G6PD-deficient patients. The availability of near-patient G6PD tests could increase use of primaquine (PQ), however direct evidence of the impacts that G6PD testing has on downstream patient outcomes, such as haemolysis and recurrence is lacking. METHODOLOGY/PRINCIPLE FINDINGS: A linked-evidence model was created to investigate changes in the number of severe haemolysis events and P. vivax recurrences within 6 months of treatment when qualitative G6PD testing was used to guide PQ treatment (0.25mg/kg/day for 14 days and 0.5mg/kg/day for 7 days), compared to prescribing 14-day PQ with no G6PD testing. In the model patients identified as G6PD-deficient received 8-week PQ (0.75mg/kg/week). The model was used to simulate scenarios with 1%, 5% and 10% prevalence of G6PD-deficiency (G6PDd) in theoretical populations of 10,000 male and female P. vivax patients and initially assumed 100% adherence to the prescribed PQ regiment. Results illustrate that G6PD testing to guide the 14-day PQ regiment reduced severe haemolysis by 21-80% and increased recurrences by 3-6%, compared to applying the 14-day PQ regiment without G6PD testing. Results for the 7-day PQ regiment informed by G6PD testing were mixed, dependent on G6PDd prevalence and sex. When adherence to the PQ regiments was less than perfect the model predicted reductions in the number of recurrences at all prevalence levels, provided adherence to 7-day PQ was 5-10% higher than adherence to the 14-day regiment. CONCLUSIONS/SIGNIFICANCE: Introduction of G6PD testing to guide PQ treatment reduces severe haemolysis events for the 14-day regiment, and the 7-day regiment in higher G6PDd prevalence settings, compared to use of 14-day PQ without G6PD testing when all patients adhere to the prescribed PQ treatment. At a population level, there were increases in recurrences, but this could be resolved when the 7-day regiment was used and had superior adherence compared to the 14-day regiment.
Assuntos
Antimaláricos , Deficiência de Glucosefosfato Desidrogenase , Hemólise , Malária Vivax , Plasmodium vivax , Primaquina , Humanos , Primaquina/uso terapêutico , Primaquina/administração & dosagem , Primaquina/efeitos adversos , Malária Vivax/tratamento farmacológico , Malária Vivax/parasitologia , Masculino , Feminino , Antimaláricos/uso terapêutico , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Plasmodium vivax/efeitos dos fármacos , Deficiência de Glucosefosfato Desidrogenase/tratamento farmacológico , Adulto , Hemólise/efeitos dos fármacos , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Criança , Recidiva , Glucosefosfato Desidrogenase/metabolismo , Pré-EscolarRESUMO
BACKGROUND: In Senegalese high-burden regions, the existing package of interventions is insufficient to reach the malaria elimination goal. Asymptomatic carriers of Plasmodium contribute significantly to malaria persistence and are not targeted by current interventions. The systematic treatment of all individuals in a community (mass drug administration, MDA) is a relevant intervention to tackle asymptomatic infections. The intervention can only be effective with a high participation of the population and, therefore, depends largely on its acceptability. This study aims to investigate the prospective acceptability of MDA in the Kedougou region to inform its potential use in a future strategy. METHODS: Following a 7-construct theoretical framework, prospective acceptability of MDA implemented in the rainy season was studied. In four villages, a sequential mixed design, from qualitative to quantitative, was used. In November 2021, interviews with healthcare professionals and focus groups with villagers were conducted. Findings from thematic analysis informed the development of a questionnaire administered to individuals aged ≥ 15 years in March 2022. Based on the questionnaire, an acceptability score was constructed and associations with socio-demographic factors were investigated using a linear mixed model. RESULTS: The 7 interviews, the 12 focus groups, and the questionnaire administered to 289 individuals demonstrated a good acceptability of MDA. Two potential barriers were identified: the contradiction of taking a medication without feeling sick and the occurrence of side effects; and four facilitators: the perception of malaria as a burden, a good understanding of MDA, a good perceived effectiveness, and the resulting economic benefits. The average acceptability score was 3.5 (range from -7 to + 7). Young adults aged 15 to 21 had a lower acceptability score compared to the other age groups, indicating an additional barrier to acceptability (ß = -0.78 [-1.67;0.1]). CONCLUSION: MDA is a priori acceptable to communities of Kedougou region in Senegal. Sensitization campaigns co-constructed with the communities, especially targeting young adults, are essential to ensure good acceptability.
Assuntos
Antimaláricos , Malária , Administração Massiva de Medicamentos , Senegal , Administração Massiva de Medicamentos/estatística & dados numéricos , Humanos , Adulto , Feminino , Masculino , Adolescente , Malária/prevenção & controle , Malária/tratamento farmacológico , Adulto Jovem , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Estudos Prospectivos , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Idoso , Infecções AssintomáticasRESUMO
Plasmodium vivax is the most geographically widespread malaria parasite. P. vivax has the ability to remain dormant (as a hypnozoite) in the human liver and subsequently reactivate, which makes control efforts more difficult. Given the majority of P. vivax infections are due to hypnozoite reactivation, targeting the hypnozoite reservoir with a radical cure is crucial for achieving P. vivax elimination. Stochastic effects can strongly influence dynamics when disease prevalence is low or when the population size is small. Hence, it is important to account for this when modelling malaria elimination. We use a stochastic multiscale model of P. vivax transmission to study the impacts of multiple rounds of mass drug administration (MDA) with a radical cure, accounting for superinfection and hypnozoite dynamics. Our results indicate multiple rounds of MDA with a high-efficacy drug are needed to achieve a substantial probability of elimination. This work has the potential to help guide P. vivax elimination strategies by quantifying elimination probabilities for an MDA approach.
Assuntos
Antimaláricos , Erradicação de Doenças , Malária Vivax , Administração Massiva de Medicamentos , Plasmodium vivax , Humanos , Malária Vivax/prevenção & controle , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Administração Massiva de Medicamentos/estatística & dados numéricos , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/fisiologia , Erradicação de Doenças/métodos , Erradicação de Doenças/estatística & dados numéricos , Antimaláricos/uso terapêutico , Antimaláricos/administração & dosagem , Processos Estocásticos , Simulação por ComputadorRESUMO
Several countries of the Guiana Shield are aiming at the control and elimination of malaria in areas where Artisanal and Small-scale Gold Mining (ASGM) activities predominate, raising questions about how to strengthen community engagement to improve the effectiveness of health programs. The Curema project focuses its intervention on the mobile and hard-to-reach ASGM population, complementing the efforts of national programs in the Guiana Shield. The Curema intervention combines targeted drug administration for suspected Plasmodium vivax asymptomatic carriers, the Malakit distribution, and health education activities. The primary goals of this manuscript are to outline a pathway to foster community participation in the Curema project aimed at eliminating malaria. Thus, it presents a vision of the challenges that the AGSM community poses in terms of community participation for an asymptomatic problem; and highlights the community-based model and the Information, Education and Communication (IEC) components as foundations for participation. In addition, it also presents culturally sensitive IEC strategies designed through iterative and collaborative consultative processes and other bottom-up outreach activities. The community engagement approach facilitates adaptability and responsiveness in a complex, evolving context increasing the effectiveness of interventions.
Assuntos
Participação da Comunidade , Humanos , Educação em Saúde/métodos , Guiana , Malária Vivax/prevenção & controle , Erradicação de Doenças , Malária/prevenção & controle , Mineração , Antimaláricos/uso terapêutico , OuroRESUMO
We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.
Assuntos
Antimaláricos , Apicoplastos , Diterpenos , Malária Falciparum , Plasmodium falciparum , Animais , Humanos , Camundongos , Antimaláricos/química , Antimaláricos/farmacologia , Apicoplastos/efeitos dos fármacos , Apicoplastos/metabolismo , Modelos Animais de Doenças , Resistência a Medicamentos/genética , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Diterpenos/química , Diterpenos/farmacologiaRESUMO
BACKGROUND: The World Health Organization 2022 malaria chemoprevention guidelines recommend providing a full course of antimalarial treatment at pre-defined intervals, regardless of malaria status to prevent illness among children resident in moderate to high perennial malaria transmission settings as perennial malaria chemoprevention (PMC) with sulfadoxine-pyrimethamine (SP). The dhps I431V mutation circulating in West Africa has unknown effect on SP protective efficacy. METHODS: This protocol is for a three-arm, parallel, double-blinded, placebo-controlled, randomised trial in Cameroon among children randomly assigned to one of three directly-observed treatment groups: (i) Group 1 (n = 450) receives daily artesunate (AS) placebo on days - 7 to -1, then active SP plus placebo amodiaquine (AQ) on day 0, and placebo AQ on days 1 and 2; (ii) Group 2 (n = 250) receives placebo AS on days - 7 to -1, then active SP and AQ on day 0, and active AQ on days 1 and 2; and (iii) Group 3 (n = 200) receives active AS on days - 7 to -1, then placebo SP on day 0 and placebo AQ on days 0 to 2. On days 0, 2, 5, 7, and thereafter weekly until day 28, children provide blood for thick smear slides. Dried blood spots are collected on the same days and weekly from day 28 to day 63 for quantitative polymerase chain reaction (qPCR) and genotype analyses. DISCUSSION: Our aim is to quantify the chemopreventive efficacy of SP, and SP plus AQ, and measure the effect of the parasite genotypes associated with SP resistance on parasite clearance and protection from infection when exposed to SP chemoprevention. We will report unblinded results including: (i) time-to-parasite clearance among SP and SP plus AQ recipients who were positive on day 0 by qPCR and followed to day 63; (ii) mean duration of SP and SP plus AQ protection against infection, and (iii) mean duration of symptom-free status among SP and SP plus AQ recipients who were parasite free on day 0 by qPCR. Our study is designed to compare the 28-day follow-up of the new WHO malaria chemoprevention efficacy study protocol with extended follow-up to day 63. TRIAL REGISTRATION: ClinicalTrials.gov NCT06173206; 15/12/2023.
Assuntos
Amodiaquina , Antimaláricos , Artesunato , Combinação de Medicamentos , Malária Falciparum , Plasmodium falciparum , Pirimetamina , Sulfadoxina , Humanos , Pirimetamina/uso terapêutico , Pirimetamina/administração & dosagem , Camarões , Sulfadoxina/uso terapêutico , Sulfadoxina/administração & dosagem , Malária Falciparum/prevenção & controle , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Antimaláricos/uso terapêutico , Antimaláricos/administração & dosagem , Pré-Escolar , Amodiaquina/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Método Duplo-Cego , Feminino , Masculino , Artesunato/uso terapêutico , Artemisininas/uso terapêutico , Artemisininas/administração & dosagem , Resultado do Tratamento , Quimioprevenção/métodosRESUMO
BACKGROUND: Malaria and HIV infection overlap geographically in sub-Saharan Africa and share risk factors. HIV infection increases malaria's severity, especially in pregnant women. The World Health Organization (WHO) recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for pregnant women living in areas of stable malaria transmission. However, HIV-positive women on daily cotrimoxazole prophylaxis (recommended for prevention of opportunistic infections in people with HIV) cannot receive SP due to adverse drug interactions, so malaria prevention in this vulnerable population currently relies on daily cotrimoxazole prophylaxis alone. This review is based on a new protocol and provides an update to the 2011 Cochrane Review that evaluated alternative drugs for IPTp to prevent malaria in HIV-positive women. OBJECTIVES: To compare the safety and efficacy of intermittent preventive treatment regimens for malaria prevention in HIV-positive pregnant women. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trial registries to 31 January 2024. To identify relevant additional studies or unpublished work, we checked references and contacted study authors and other researchers working on malaria and HIV. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing any intermittent preventive treatment regimen for preventing malaria in HIV-positive pregnant women against daily cotrimoxazole prophylaxis alone, placebo, current or previous standard of care, or combinations of these options. By 'standard of care' we refer to the country's recommended drug regimen to prevent malaria in pregnancy among HIV-positive women, or the treatment that a trial's research team considered to be the standard of care. DATA COLLECTION AND ANALYSIS: Review authors, in pairs, independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias in included trials, and extracted data. We contacted trial authors when additional information was required. We presented dichotomous outcomes using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes as mean differences (MDs). We presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach for what we considered to be the main comparisons and outcomes. MAIN RESULTS: We included 14 RCTs, with a total of 4976 HIV-positive pregnant women initially randomized. All trials assessed the efficacy and safety of one antimalarial used as IPTp (mefloquine, dihydroartemisinin/piperaquine, SP, or azithromycin) with or without daily cotrimoxazole, compared to daily cotrimoxazole alone, placebo, or a standard of care regimen. We grouped the trials into nine comparisons. Our main comparison evaluated the current standard of care (daily cotrimoxazole) with another drug regimen (mefloquine or dihydroartemisinin/piperaquine) versus daily cotrimoxazole with or without placebo. In this comparison, two trials evaluated mefloquine and three evaluated dihydroartemisinin/piperaquine. We conducted meta-analyses that included trials evaluating dihydroartemisinin/piperaquine plus cotrimoxazole, and trials that evaluated mefloquine plus cotrimoxazole, as we considered there to be no qualitative or quantitative heterogeneity among trials for most outcomes. We considered drug-related adverse events and HIV-related outcomes to be drug-specific. Daily cotrimoxazole prophylaxis plus another drug regimen (mefloquine or dihydroartemisinin/piperaquine) probably results in lower risk of maternal peripheral parasitaemia at delivery (RR 0.62, 95% CI 0.41 to 0.95; 2406 participants, 5 trials; moderate-certainty evidence). It results in little or no difference in maternal anaemia cases at delivery (RR 0.98, 95% CI 0.90 to 1.07; 2417 participants, 3 trials; high-certainty evidence). It probably results in a decrease in placental malaria measured by blood smear (RR 0.54, 95% CI 0.31 to 0.93; 1337 participants, 3 trials; moderate-certainty evidence), and probably results in little or no difference in low birth weight (RR 1.16, 95% CI 0.95 to 1.41; 2915 participants, 5 trials; moderate-certainty evidence). There is insufficient evidence to ascertain whether daily cotrimoxazole prophylaxis plus another drug regimen affects the risk of cord blood parasitaemia (RR 0.27, 95% CI 0.04 to 1.64; 2696 participants, 5 trials; very low-certainty evidence). Daily cotrimoxazole prophylaxis plus another drug regimen probably results in little or no difference in foetal loss (RR 1.03, 95% CI 0.73 to 1.46; 2957 participants, 5 trials; moderate-certainty evidence), and may result in little or no difference in neonatal mortality (RR 1.21, 95% CI 0.68 to 2.14; 2706 participants, 4 trials; low-certainty evidence). Due to the probability of an increased risk of mother-to-child HIV transmission and some adverse drug effects noted with mefloquine, we also looked at the results for dihydroartemisinin/piperaquine specifically. Dihydroartemisinin/piperaquine plus daily contrimoxazole probably results in little to no difference in maternal peripheral parasitaemia (RR 0.59, 95% CI 0.31 to 1.11; 1517 participants, 3 trials; moderate-certainty evidence) or anaemia at delivery (RR 0.95, 95% CI 0.82 to 1.10; 1454 participants, 2 trials; moderate-certainty evidence), but leads to fewer women having placental malaria when measured by histopathologic analysis (RR 0.67, 95% CI 0.50 to 0.90; 1570 participants, 3 trials; high-certainty evidence). The addition of dihydroartemisinin/piperaquine to daily cotrimoxazole probably made little to no difference to rates of low birth weight (RR 1.13, 95% CI 0.87 to 1.48; 1695 participants, 3 trials), foetal loss (RR 1.14, 95% CI 0.68 to 1.90; 1610 participants, 3 trials), or neonatal mortality (RR 1.03, 95% CI 0.39 to 2.72; 1467 participants, 2 trials) (all moderate-certainty evidence). We found low-certainty evidence of no increased risk of gastrointestinal drug-related adverse events (RR 1.42, 95% CI 0.51 to 3.98; 1447 participants, 2 trials) or mother-to-child HIV transmission (RR 1.54, 95% CI 0.26 to 9.19; 1063 participants, 2 trials). AUTHORS' CONCLUSIONS: Dihydroartemisinin/piperaquine and mefloquine added to daily cotrimoxazole seem to be efficacious in preventing malaria infection in HIV-positive pregnant women compared to daily cotrimoxazole alone. However, increased risk of HIV transmission to the foetus and poor drug tolerability may be barriers to implementation of mefloquine in practice. In contrast, the evidence suggests that dihydroartemisinin/piperaquine does not increase the risk of HIV mother-to-child transmission and is well tolerated.