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We report the case of a 51-year-old man with severe malaria, who developed delayed autoimmune haemolytic anaemia following artesunate therapy. Delayed autoimmune haemolytic anaemia following artesunate therapy has been previously described. Its diagnosis can be challenging in the setting of possible dengue coinfection. Clinicians should be vigilant of this potential side effect of artesunate therapy, especially in patients who later develop signs and symptoms of haemolytic anaemia.

Many individuals living with the human immunodeficiency virus (HIV) infection and receiving antiretroviral therapy (ART) reside in areas at high risk for malaria but how malaria affects clinical outcomes is not well described in this population. We evaluated the burden of malaria infection and clinical malaria, and impact on HIV viral load and CD4 + cell count among adults on ART.We recruited Malawian adults on ART who had an undetectable viral load and ≥250 CD4 + cells/μl to participate in this randomized trial to continue daily trimethoprim-sulfamethoxazole (TS), discontinue daily co-trimoxazole, or switch to weekly chloroquine (CQ).We defined clinical malaria as symptoms consistent with malaria and positive blood smear, and malaria infection as Plasmodium falciparum DNA detected from dried blood spots (collected every 4-12 weeks). CD4 + cell count and viral load were measured every 24 weeks. We used Poisson regression and survival analysis to compare the incidence of malaria infection and clinical malaria. Clinicaltrials.gov NCT01650558.Among 1499 participants enrolled, clinical malaria incidence was 21.4/100 person-years of observation (PYO), 2.4/100 PYO and 1.9/100 PYO in the no prophylaxis, TS, and CQ arms, respectively. We identified twelve cases of malaria that led to hospitalization and all individuals recovered. The preventive effect of staying on prophylaxis was approximately 90% compared to no prophylaxis (TS: incidence rate ratio [IRR] 0.11, 95% confidence interval [CI] 0.08, 0.15 and CQ: IRR 0.09, 95% CI 0.06, 0.13). P. falciparum infection prevalence among all visits was 187/1475 (12.7%), 48/1563 (3.1%), and 29/1561 (1.9%) in the no prophylaxis, TS, and CQ arms, respectively. Malaria infection and clinical malaria were not associated with changes in CD4 + cell count or viral load.In clinically stable adults living with HIV on ART, clinical malaria was common after chemoprophylaxis stopped. However, neither malaria infection nor clinical illness appeared to affect HIV disease progression.

Antimalarial drug discovery has until recently been driven by high-throughput phenotypic cellular screening, allowing millions of compounds to be assayed and delivering clinical drug candidates. In this review, we will focus on target-based approaches, describing recent advances in our understanding of druggable targets in the malaria parasite. Targeting multiple stages of the Plasmodium lifecycle, rather than just the clinically symptomatic asexual blood stage, has become a requirement for new antimalarial medicines, and we link pharmacological data clearly to the parasite stages to which it applies. Finally, we highlight the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY, a web resource developed for the malaria research community that provides open and optimized access to published data on malaria pharmacology.

Antimalarial drugs play an important role in the control and treatment of malaria, a deadly disease caused by the protozoan parasite Plasmodium spp. The development of novel antimalarial agents effective against drug-resistant malarial parasites is urgently needed. The novel derivatives, SKM13-MeO and SKM13-F, were designed based on an SKM13 template by replacing the phenyl group with electron-donating (-OMe) or electron-withdrawing groups (-F), respectively, to reverse the electron density. A colorimetric assay was used to quantify cytotoxicity, and in vitro inhibition assays were performed on 3 different blood stages (ring, trophozoite, and schizonts) of P. falciparum 3D7 and the ring/mixed stage of D6 strain after synchronization. The in vitro cytotoxicity analysis showed that 2 new SKM13 derivatives reduced the cytotoxicity of the SKM13 template. SKM13 maintained the IC50 at the ring and trophozoite stages but not at the schizont stage. The IC50 values for both the trophozoite stage of P. falciparum 3D7 and ring/mixed stages of D6 demonstrated that 2 SKM13 derivatives had decreased antimalarial efficacy, particularly for the SKM13-F derivative. SKM13 may be comparably effective in ring and trophozoite, and electron-donating groups (-OMe) may be better maintain the antimalarial activity than electron-withdrawing groups (-F) in SKM13 modification.

Aim & background: Drugs with multiple bioactive moieties have the advantages of multiple modes of action and fewer chances of drug resistance. In continuation of our previous work of developing hybrid antimalarials, we present herein the synthesis and antimalarial activity of two different series of 7-chloroquinoline-sulfonamide hybrids. Materials & methods: The first series of compounds were synthesized by using p-dodecylbenzenesulfonic acid as a Bronsted acid catalyst in ethanol. The second series' compounds were synthesized by 1,3-dipolar cycloaddition of azides and alkynes under click reaction conditions. Results & conclusion: The majority of these compounds demonstrated noncytotoxicity and significant antimalarial activity against Plasmodium falciparum (3D7) with IC50 values in the range of 1.49–13.49 μM. The most promising hybrids (12d, 13a and 13c) may be good starting points for next-generation antimalarials.

Background: Pyrazole is a bioactive heterocyclic congener with numerous biological and pharmacological functionalities. Due to their multiple prospective applications, developing innovative and novel pyrazoles and analogs, revealing revolutionary methods for synthesizing this nucleus, investigating diverse potencies of that heterocycle, and exploring possible pyrazole applications are becoming increasingly relevant. Objectives: Pyrazole scaffolds have been proven successful as antimicrobial, anticancer, and antimalarial therapeutics against multiple targets like DNA gyrase, topoisomerase IV, Hsp90, and several kinase enzymes. For this variability in the biotic zone, their moiety has gained the attention of many scientists interested in researching chemical and pharmacological profiles. Results: The review covers pyrazole scaffolds with a variety of biological functions and attempts to connect the structure-activity relationship. Multiple pyrazole analogs have been produced as lead compounds, and their activities have been evaluated. Conclusion: The combination of pyrazole with other pharmacophores in a molecule might lead to novel potent therapeutic medicines, which could aid in the development of potent lead compounds.

New antimalarial compounds with novel mechanisms of action are urgently needed to combat the recent rise in antimalarial drug resistance. Phenotypic high-throughput screens have proven to be a successful method for identifying new compounds, however, do not provide mechanistic information about the molecular target(s) responsible for antimalarial action. Current and emerging target identification methods such as in vitro resistance generation, metabolomics screening, chemoproteomic approaches and biophysical assays measuring protein stability across the whole proteome have successfully identified novel drug targets. This review provides an overview of these techniques, comparing their strengths and weaknesses and how they can be utilised for antimalarial target identification.

Since their first use in the 1920s, 8-aminoquinolines have been known to have important toxicities such as methemoglobinemia and hemolysis. An empiric pamaquine (plasmochin) combination with quinine was widely used in the British military with relatively little toxicity. Attempts to use pamaquine with a new synthetic antimalarial drug (atabrine, quinacrine) in the 1930–1940s, however, resulted in hemolytic reactions and some deaths from renal failure. An improved 8-aminoquinoline, primaquine, was particularly effective against Plasmodium vivax relapses when combined with either quinine or chloroquine. When used in reduced daily doses (15 mg) over 2 weeks, it was safely given to many thousands of U.S. soldiers returning from Korea. CP tablets (chloroquine 300 mg, primaquine 45 mg weekly) were widely used during the Vietnam War with few hemolytic reactions and no known deaths. Efficacy and toxicity of 8-aminoquinolines is determined in part by the selection of appropriate partner drugs

Abstract: Acridine derivatives have been thoroughly investigated and discovered to have multitarget qualities, inhibiting topoisomerase enzymes that regulate topological changes in DNA and interfering with DNA's vital biological function. This article discusses current progress in the realm of novel 9-substituted acridine heterocyclic compounds, including the structure and structure– activity connection of the most promising molecules. The IC50 values of the new compounds against several human cancer cell lines will also be presented in the publication. The review also looks into the inhibition of topoisomerase by polycyclic aromatic compounds. Background: Acridine rings can be found in molecules used in many different areas, including industry and medicine. Nowadays, acridines with anti-bacterial activity are of research interest due to decreasing bacterial resistance. Some acridine derivatives showed antimalarial or antiviral activity. Acridine derivatives were also investigated for anti-tumor activity due to the interaction with topoisomerase II and DNA base pairs. Considering these possible uses of acridine derivatives, this work overviewed all significant structure performances for the specific action of these compounds. Objective: The objective of this study is to review the activity of acridines as anti-proliferative agents. Design: This review is designed as acridines acting as topoisomerase I and II inhibitors/ poison, Acridines on the G-quadraplux interaction, Acridines with metal complexes, Acridines with quinacrine scaffold, Acridines with sulphur moiety. Conclusion: Although introduced in the 19th century, acridine derivatives are still of scientific interest. In this review, acridine derivatives with various biological activities (antiparasitic, antiviral, anti-bacterial, and antiproliferative) and their structure-activity relationship analyses are presented. Although several mechanisms of their action are known, the only important are discussed here. It can be concluded that the dominant mechanisms are DNA intercalation and interaction with enzymes.

Estimating antimalarial drug efficacy requires differentiating treatment failures from new infections arising during the several-week follow-up period in drug trials. Genetic profiling of malaria infections can guide this decision but is notoriously difficult in practice. Previous World Health Organisation (WHO) guidelines were based on assumptions with an inherently high risk of underestimating failure rates. A recent update to WHO guidelines recognises a wider range of analyses to overcome these limitations. We discuss these new analyses and their underlying logic. Drug failure rate estimates in moderate to high transmissions areas will become more accurate but will likely rise twofold due to better detection of treatment failures, and the malaria community needs to anticipate and prepare for potentially large increases in estimated failure rates.

Contains fulltext : 287660.pdf (Publisher’s version ) (Open Access) BACKGROUND: Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants. METHODS: In this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689. FINDINGS: Between Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 μg/mL (95% CI 1·9-2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136-193) following a single intravenous 10 mg/kg dose. INTERPRETATION: TB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season. FUNDING: PATH's Malaria Vaccine Initiative.

Norcryptotackieine or 6H-indolo[2,3

Intermittent preventive treatment of malaria among schoolchildren (IPTsc) reduces clinical malaria, asymptomatic parasitemia, and anemia. The effects of IPTsc by gender have not been studied longitudinally. We investigated overall IPTsc efficacy and conducted a secondary analysis to explore gender-specific differences. We enrolled schoolchildren aged 6–13 years in an open-label, rolling-cohort randomized controlled trial between September 2007 and February 2013 in Kolle, Mali. Annually, schoolchildren received two full-treatment courses of sulfadoxine-pyrimethamine (SP) plus artesunate, or amodiaquine (AQ) plus artesunate, or no malaria treatment as control. We used mixed-effects generalized linear models to estimate differences in treatment outcomes across groups with interaction terms to explore gender-specific differences associated with Plasmodium falciparum infection, hemoglobin, and grade point averages (GPA) based on standardized testing. Overall, 305 students contributed 4,564 observations. Compared with the control, SP plus artesunate and AQ plus artesunate reduced the odds of P. falciparum infection (odds ratio [OR]: 0.33, 95% CI: 0.26–0.43; OR: 0.46, 95% CI: 0.36–0.59). We found strong evidence of increased mean hemoglobin concentrations (g/dL) in the SP plus artesunate group versus control (difference +0.37, 95% CI: 0.13–0.58). Collectively, schoolchildren given AQ plus artesunate had higher mean GPA (difference +0.36, 95% CI: 0.02–0.69) relative to control. Schoolgirls, compared with schoolboys, given SP plus artesunate had greater improvement in GPA (+0.50, 95% CI: −0.02 to 1.02 versus −0.27, 95% CI: −0.71 to 0.16); interaction P = 0.048, respectively. The IPTsc decreases P. falciparum infections in schoolchildren. Treatment regimens that include longer-acting drugs may be more effective at decreasing malaria-related anemia and improving educational outcomes as observed among girls in this setting.

The malaria landscape in the Greater Mekong Subregion has experienced drastic changes with the ramp-up of the control efforts, revealing formidable challenges that slowed down the progress toward malaria elimination. Problems such as border malaria and cross-border malaria introduction, multidrug resistance in Plasmodium falciparum, the persistence of Plasmodium vivax, the asymptomatic parasite reservoirs, and insecticide resistance in primary vectors require integrated strategies tailored for individual nations in the region. In recognition of these challenges and the need for research, the Southeast Asian International Center of Excellence for Malaria Research has established a network of researchers and stakeholders and conducted basic and translational research to identify existing and emerging problems and develop new countermeasures. The installation of a comprehensive disease and vector surveillance system at sentinel sites in border areas with the implementation of passive/active case detection and cross-sectional surveys allowed timely detection and management of malaria cases, provided updated knowledge for effective vector control measures, and facilitated the efficacy studies of antimalarials. Incorporating sensitive molecular diagnosis to expose the significance of asymptomatic parasite reservoirs for sustaining transmission helped establish the necessary evidence to guide targeted control to eliminate residual transmission. In addition, this program has developed point-of-care diagnostics to monitor the quality of artemisinin combination therapies, delivering the needed information to the drug regulatory authorities to take measures against falsified and substandard antimalarials. To accelerate malaria elimination, this program has actively engaged with stakeholders of all levels, fostered vertical and horizontal collaborations, and enabled the effective dissemination of research findings.

In the course of malaria elimination in the Greater Mekong Subregion (GMS), malaria epidemiology has experienced drastic spatiotemporal changes with residual transmission concentrated along international borders and the rising predominance of Plasmodium vivax. The emergence of Plasmodium falciparum parasites resistant to artemisinin and partner drugs renders artemisinin-based combination therapies less effective while the potential spread of multidrug-resistant parasites elicits concern. Vector behavioral changes and insecticide resistance have reduced the effectiveness of core vector control measures. In recognition of these problems, the Southeast Asian International Center of Excellence for Malaria Research (ICEMR) has been conducting multidisciplinary research to determine how human migration, antimalarial drug resistance, vector behavior, and insecticide resistance sustain malaria transmission at international borders. These efforts allow us to comprehensively understand the ecology of border malaria transmission and develop population genomics tools to identify and track parasite introduction. In addition to employing in vivo, in vitro, and molecular approaches to monitor the emergence and spread of drug-resistant parasites, we also use genomic and genetic methods to reveal novel mechanisms of antimalarial drug resistance of parasites. We also use omics and population genetics approaches to study insecticide resistance in malaria vectors and identify changes in mosquito community structure, vectorial potential, and seasonal dynamics. Collectively, the scientific findings from the ICEMR research activities offer a systematic view of the factors sustaining residual malaria transmission and identify potential solutions to these problems to accelerate malaria elimination in the GMS.

Malaria is the leading cause of disease burden in sub-Saharan Africa. In 2010, the East Africa International Center of Excellence for Malaria Research, also known as the Program for Resistance, Immunology, Surveillance, and Modeling of Malaria (PRISM), was established to provide a comprehensive approach to malaria surveillance in Uganda. We instituted cohort studies and a robust malaria and entomological surveillance network at selected public health facilities that have provided a platform for monitoring trends in malaria morbidity and mortality, tracking the impact of malaria control interventions (indoor residual spraying of insecticide [IRS], use of long-lasting insecticidal nets [LLINs], and case management with artemisinin-based combination therapies [ACTs]), as well as monitoring of antimalarial drug and insecticide resistance. PRISM studies have informed Uganda’s malaria treatment policies, guided selection of LLINs for national distribution campaigns, and revealed widespread pyrethroid resistance, which led to changes in insecticides delivered through IRS. Our continuous engagement and interaction with policy makers at the Ugandan Ministry of Health have enabled PRISM to share evidence, best practices, and lessons learned with key malaria stakeholders, participate in malaria control program reviews, and contribute to malaria policy and national guidelines. Here, we present an overview of interactions between PRISM team members and Ugandan policy makers to demonstrate how PRISM’s research has influenced malaria policy and control in Uganda.

Background Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized. Methods To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age. Results Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes. Conclusions Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way, Introduction: Malaria in infants is common in high-transmission settings, especially in infants >6 months. Infants undergo physiological changes impacting pharmacokinetics and pharmacodynamics of anti-malarial drugs and, consequently, the safety and efficacy of malaria treatment. Yet, treatment guidelines and evidence on pharmacological interventions for malaria often fail to address this vulnerable age group. This review aims to summarize the available data on anti-malarial treatment in infants. Areas covered: The standard recommended treatments for severe and uncomplicated malaria are generally safe and effective in infants. However, infants have an increased risk of drug-related vomiting and have distinct pharmacokinetic parameters of antimalarials compared with older patients. These include larger volumes of distribution, higher clearance rates, and immature enzyme systems. Consequently, infants with malaria may be at increased risk of treatment failure and drug toxicity. Expert opinion: Knowledge expansion to optimize treatment can be achieved by including more infants in antimalarial drug trials and by reporting separately on treatment outcomes in infants. Additional evidence on the efficacy, safety, tolerability, acceptability, and effectiveness of ACTs in infants is needed, as well as population pharmacokinetics studies on antimalarials in the infant population.

Malaria is a parasitic disease that remains a global health issue, responsible for a significant death and morbidity toll. Various factors have impacted the use and delayed the development of antimalarial therapies, such as the associated financial cost and parasitic resistance. In order to discover new drugs and validate parasitic targets, a powerful omics tool, metabolomics, emerged as a reliable approach. However, as a fairly recent method in malaria, new findings are timely and original practices emerge frequently. This review aims to discuss recent research towards the development of new metabolomic methods in the context of uncovering antiplasmodial mechanisms of action in vitro and to point out innovative metabolic pathways that can revitalize the antimalarial pipeline.

The secondary metabolites isolated from soil fungi have received more and more attention, especially new compounds that exhibited good biological activities. In this review, a total of 546 new compounds are included in the relevant literature since 2011. The new compounds are isolated from soil fungi, We divided these compounds into seven categories, including alkaloids, terpenoids, steroids, ketones, phenylpropanoids, quinones, esters, lactones, etc. In addition, the biological activities and structure-activity relationships of these compounds have also been fully discussed. The activities of these compounds are roughly divided into eight categories, including anticancer activity, antimicrobial activity, anti-inflammatory activity, antioxidant activity, antiviral activity, antimalarial activity, immunosuppressive activity and other activities. Since natural products are an important source of new drugs, this review may have a positive guiding effect on drug screening.

Background: As COVID-19 pandemic continues to affect people’s lives, the government of India gave emergency use approval to the ayurvedic antimalarial drug Ayush-64 in April 2021 to treat asymptomatic COVID-19 positive and mild COVID-19 positive patients. Objective: This study aims to explore the therapeutic potential of Ayush-64 to treat COVID-19 and provide a new approach for repurposing Ayurvedic drugs. Methods: The bioactives present in Ayush-64 were found along with their targets, and a plantbioactive- target network was created. A protein-protein interaction network of the common targets of Ayush-64 and COVID-19 was constructed and analyzed to find the key targets of Ayush-64 associated with the disease. Gene ontology and pathway enrichment analysis were performed to find COVID-19 related biological processes and pathways involved by the key targets. The key bioactives were docked with SARS-CoV-2 main protease 3CL, native Human Angiotensin-converting Enzyme ACE2, Spike protein S1, and RNA-dependent RNA polymerase RdRp. Results: From the 336 targets for Ayush-64, we found 38 key targets. Functional enrichment analysis of the key targets resulted in 121 gene ontology terms and 38 pathways. When molecular docking was performed with four receptors, thirteen bioactives showed good binding affinity comparable to that of the eight drugs presently used to treat COVID-19. Conclusion: Network pharmacological analysis and molecular docking study of Ayush-64 revealed that it can be recommended to treat COVID-19. Further in vitro and in vivo studies are needed to confirm the results. The study demonstrated a new approach for repurposing Ayurvedic drugs.

Many of the therapeutic effects of plant extracts and bioactive compounds appear related to their immunomodulatory effects and impact on the host immune system. The immune response is desirable to mitigate established infections and, in the case of severe malaria, is a feasible approach to dealing with the overwhelming cytokine response. Glycogen synthase kinase-3 (GSK3), a Ser/Thr kinase that is a central regulator of the cytokine response, is a promising antimalarial drug target. In this review, we discussed our ongoing research projects, which include assessing the antimalarial activities of medicinal plants and their bioactive compounds, immunomodulatory activities mediated by GSK3, and the potential inflammatory pathway involved in malarial infection.

Malaria caused by Plasmodium vivax is comparatively less virulent than Plasmodium falciparum, which can also lead to severe disease and death. It shows a wide geographical distribution. Chloroquine serves as a drug of choice, with primaquine as a radical cure. However, with the appearance of resistance to chloroquine and treatment has been shifted to artemisinin combination therapy followed by primaquine as a radical cure. Sulphadoxine-pyrimethamine, mefloquine, and atovaquone-proguanil are other drugs of choice in chloroquine-resistant areas, and later resistance was soon reported for these drugs also. The emergence of drug resistance serves as a major hurdle to controlling and eliminating malaria. The discovery of robust molecular markers and regular surveillance for the presence of mutations in malaria-endemic areas would serve as a helpful tool to combat drug resistance. Here, in this review, we will discuss the endemicity of P. vivax, a historical overview of antimalarial drugs, the appearance of drug resistance and molecular markers with their global distribution along with different measures taken to reduce malaria burden due to P. vivax infection and their resistance.

Drugs are often removed from clinical trials or market progression owing to their unforeseen effects on cardiac action potential and calcium handling. Induced pluripotent stem cell-derived cardiomyocytes and tissues fabricated from these cells are promising as screening tools for early identification of these potential cardiac liabilities. In this study, we describe an automated, open-source MATLAB-based analysis software for calculating cardiac action potentials and calcium transients from fluorescent reporters. We first identified the most robust manner in which to automatically identify the initiation point for action potentials and calcium transients in a user-independent manner, and used this approach to quantify the duration and morphology of these signals. We then demonstrate the software by assessing changes to action potentials and calcium transients in our micro-heart muscles after exposure to hydroxychloroquine, an antimalarial drug with known cardiac liability. Consistent with clinical observations, our system predicted mild action potential prolongation. However, we also observed marked calcium transient suppression, highlighting the advantage of testing multiple physiologic readouts in cardiomyocytes rather than relying on heterologous overexpression of single channels such as the human

A central challenge of antimalarial therapy is the emergence of resistance to the components of artemisinin-based combination therapies (ACTs) and the urgent need for new drugs acting through novel mechanism of action. Over the last decade, compounds identified in phenotypic high throughput screens (HTS) have provided the starting point for six candidate drugs currently in the Medicines for Malaria Venture (MMV) clinical development portfolio. However, the published screening data which provided much of the new chemical matter for malaria drug discovery projects have been extensively mined. Here we present a new screening and selection cascade for generation of hit compounds active against the blood stage of Plasmodium falciparum. In addition, we validate our approach by testing a library of 141,786 compounds not reported earlier as being tested against malaria. The Hit Generation Library 1 (HGL1) was designed to maximise the chemical diversity and novelty of compounds with physicochemical properties associated with potential for further development. A robust HTS cascade containing orthogonal efficacy and cytotoxicity assays, including a newly developed and validated nanoluciferase-based assay was used to profile the compounds. 75 compounds (Screening Active hit rate of 0.05%) were identified meeting our stringent selection criteria of potency in drug sensitive (NF54) and drug resistant (Dd2) parasite strains (IC50 ≤ 2 µM), rapid speed of action and cell viability in HepG2 cells (IC50 ≥ 10 µM). Following further profiling, 33 compounds were identified that meet the MMV Confirmed Active profile and are high quality starting points for new antimalarial drug discovery projects.

This is a review of Plasmodium vivax epidemiology, pathogenesis, disease presentation, treatment and innovations in control and elimination. Here, we examine the recent literature and summarize new advances and ongoing challenges in the management of P. vivax .P. vivax has a complex life cycle in the human host which impacts disease severity and treatment regimens. There is increasing data for the presence of cryptic reservoirs in the spleen and bone marrow which may contribute to chronic vivax infections and possibly disease severity. Methods to map the geospatial epidemiology of P. vivax chloroquine resistance are advancing, and they will inform local treatment guidelines. P. vivax treatment requires an 8-aminoquinoline to eradicate the dormant liver stage. Evidence suggests that higher doses of 8-aminoquinolines may be needed for radical cure of tropical frequent-relapsing strains.P. vivax is a significant global health problem. There have been recent developments in understanding the complexity of P. vivax biology and optimization of antimalarial therapy. Studies toward the development of best practices for P. vivax control and elimination programs are ongoing.

Malaria continues to be one of the most crucial infectious burdens in endemic areas worldwide, as well as for travelers visiting malaria transmission regions. It has been reported that 8-aminoquinolines are effective against the Plasmodium species, particularly primaquine, for anti-hypnozoite therapy in P. vivax malaria. However, primaquine causes acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Therefore, G6PD deficiency testing should precede hypnozoite elimination with 8-aminoquinoline. Several point-of-care devices have been developed to detect G6PD deficiency. The aim of the present study was to evaluate the performance of a novel, quantitative G6PD diagnostics based on a metagenomic blue fluorescent protein (mBFP). We comparatively evaluated the sensitivity and specificity of the G6PD diagnostic modality with standard methods using 120 human whole blood samples. The G6PD deficiency was spectrophotometrically confirmed. The performance of the G6PD quantitative test kit was compared with that of a licensed control medical device, the G6PD strip. The G6PD quantitative test kit had a sensitivity of 95% (95% confidence interval (CI): 89.3-100%) and a specificity of 100% (95% CI: 94.3-100%). This study shows that the novel diagnostic G6PD quantitative test kit could be a cost-effective and time-efficient, and universally mandated screening tool for G6PD deficiency.

Evidence for the utility of medications in settings lacking randomized trial data can come from studies of treatment persistence. The present study was undertaken to examine patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicenter longitudinal cohort.Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) and medication details, captured at every visit from 2013-2018, were used. Medications were categorized as glucocorticoids (GCs), antimalarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity.Data from 19,804 visits of 2,860 patients were analyzed. Eight medication categories were observed: no treatment; GC, AM, or IS only; GC plus AM; GC plus IS; AM plus IS; and GC plus AM plus IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits, and biologics in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with a time-adjusted mean SLEDAI-2K score of ≥10 had lower discontinuation of GCs and higher discontinuation of IS.Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments.

Malaria is one of the most important parasitic infectious diseases worldwide. Despite the scale-up of effective antimalarials, mortality rates from severe malaria (SM) remain significantly high; thus, numerous trials are investigating both antimalarials and adjunctive therapy. This review aimed to summarise all the outcome measures used in trials in the last 10 years to see the need for a core outcome set.A systematic review was undertaken to summarise outcomes of individually randomised trials assessing treatments for SM in adults and children. We searched key databases and trial registries between 1 January 2010 and 30 July 2020. Non-randomised trials were excluded to allow comparison of similar trials. Trial characteristics including phase, region, population, interventions, were summarised. All primary and secondary outcomes were extracted and categorised using a taxonomy table.Twenty-seven of 282 screened trials met our inclusion criteria, including 10,342 patients from 19 countries: 19 (70%) trials from Africa and 8 (30%) from Asia. A large amount of heterogeneity was observed in the selection of outcomes and instruments, with 101 different outcomes measures recorded, 78/101 reported only in a single trial. Parasitological outcomes (17 studies), neurological status (14 studies), death (14 studies) and temperature (10 studies), were the most reported outcomes. Where an outcome was reported in1 study it was often measured differently: temperature (4 different measures), renal function (7 measures), nervous system (13 measures) and parasitology (10 measures).Outcomes used in SM trials are inconsistent and heterogeneous. Absence of consensus for outcome measures used impedes research synthesis and comparability of different interventions. This systematic review demonstrates the need to develop a standardised collection of core outcomes for clinical trials of treatments for SM and next steps to include the development of a panel of experts in the field, a Delphi process, and a consensus meeting.

Plasmodium falciparum parasites which cause malaria, traffic hundreds of proteins into the red blood cells (RBCs) they infect. These exported proteins remodel their RBCs enabling host immune evasion through processes such as cytoadherence that greatly assist parasite survival. As resistance to all current anti-malarial compounds is rising new compounds need to be identified and those that could inhibit parasite protein secretion and export would both rapidly reduce parasite virulence and ultimately lead to parasite death. To identify compounds that inhibit protein export we used transgenic parasites expressing an exported nanoluciferase reporter to screen the Medicines for Malaria Venture Malaria box of 400 anti-malarial compounds with mostly unknown targets. The most potent inhibitor identified in this screen was MMV396797 whose application led to export inhibition of both the reporter and endogenous exported proteins. MMV396797 mediated blockage of protein export and slowed the rigidification and cytoadherence of infected RBCs - modifications which are both mediated by parasite-derived exported proteins. Overall, we have identified a new protein export inhibitor in P. falciparum whose target though unknown, could be developed into a future anti-malarial that rapidly inhibits parasite virulence before eliminating parasites from the host.SynopsisPlasmodium falciparum exports proteins into its host cell to perform a myriad of functions required for survival. We adapted an assay to screen for small molecules that inhibit protein secretion and export. Screening the 400-compound Medicines for Malaria Venture (MMV) Malaria Box uncovered several potential export inhibitors. The most promising of these compounds, MMV396797, blocked protein export at the parasite and reduced host rigidification and cytoadherence, two functions which are mediated by exported proteins.

Aims: Development of resistance by the malaria parasite, a systemic inflammatory and infectious pathogen, has raised the need for novel efficacious antimalarials. Plant-derived natural compounds are known to modulate the immune response and eradicate the infectious pathogens. Therefore we carried out experiments with swertiamarin to dissect its anti-inflammatory and immunomodulatory potential. Materials & methods: We carried out studies in Swiss albino mice that received infectious challenge with Plasmodium berghei and swertiamarin treatment in a prophylactic manner. Results & conclusion: Oral administration of swertiamarin prior to infectious challenge with P. berghei in experimental mice showed delayed parasite development as compared with untreated control. IFN-γ and IL-10 appeared to be adapted/modulated by regular swertiamarin treatment. Further, withdrawal of swertiamarin pressure did not affect parasite replication. However, the short half-life of swertiamarin limited its long-lasting therapeutic effect, requiring higher and frequent dosing schedules.

There have been recent calls for the use of artemisinin-based combination therapies (ACTs) for uncomplicated malaria in the first trimester of pregnancy. Nevertheless, the 2021 WHO Guidelines for Malaria reaffirmed their position that there is not adequate clinical safety data on artemisinins to support that usage. The WHO's position is consistent with several issues with the existing clinical data. First, first trimester safety results from multiple ACTs were lumped in a meta-analysis which does not demonstrate that each of the included ACTs is equally safe. Second, safety results from all periods of the first trimester were lumped in the meta-analysis which does not demonstrate the same level of safety for all subperiods, particularly gestational Weeks 6-8 which is likely to be the most sensitive period. Third, even if there is evidence of a lack of an effect on miscarriage rate for a particular ACT, it does not follow then there are no developmental effects for any ACT. In monkeys, artesunate caused marked embryonal anemia leading to embryo death but the long-term consequences of lower levels of embryonal anemia are not known. Fourth, there have been advances in the sensitivity and usage of rapid diagnostic tests that will lead to diagnoses of malaria earlier in gestation which is less well studied and more likely sensitive to artemisinins. Any clinical studies of the safety of ACTs in the first trimester need to evaluate the results of treatment with individual ACTs during different 1- to 2-week periods of the first trimester.

Currently recommended methods of assessing the efficacy of uncomplicated falciparum malaria treatment work less well in high-transmission than in low-transmission settings. There is also uncertainty how to assess intermittent preventive therapies and seasonal malaria chemoprevention (SMC), and Plasmodium vivax radical cure. A pharmacometric antimalarial resistance monitoring (PARM) approach is proposed specifically for evaluating slowly eliminated antimalarial drugs in areas of high transmission. In PARM antimalarial drug concentrations at recurrent parasitaemia are measured to identify outliers (i.e., recurrent parasitaemias in the presence of normally suppressive drug concentrations) and to evaluate changes over time. PARM requires characterization of pharmacometric profiles but should be simpler and more sensitive than current molecular genotyping-based methodologies. PARM does not require parasite genotyping and can be applied to the assessment of both prevention and treatment.

Plasmodium falciparum causes malaria, and its resistance to artemisinin (ART) - a drug used for managing malaria - threatens to interfere with the effective control of malaria. ART resistance (ARTr) is driven by increased tolerance to oxidative stress and reduced haemoglobin trafficking to the food vacuole. We discuss how extracellular vesicles (EVs) may play a role in developing ARTr.

African children are at risk of malaria and malnutrition. We quantified relationships between malaria and malnutrition among young Ugandan children in a high malaria transmission region. Data were used from a randomized controlled trial where Ugandan HIV-unexposed (n=393) and HIV-exposed (n=186) children were randomized to receive no malaria chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole, or monthly dihydroartemisinin-piperaquine (DP) from age 6-24 months, and then were followed off chemoprevention until age 36 months. Monthly height and weight, and time of incident malaria episodes were obtained; 89 children who received DP contributed piperaquine (PQ) concentrations. Malaria hazard was modeled using parametric survival analysis adjusted for repeated events, and height and weight were modeled using a Brody growth model. Among 579 children, stunting (height-for-age z-score [ZHA]

Background Because of the efficacy and good safety profile of antimalarials in systemic lupus erythematosus (SLE), hydroxychloroquine (HCQ) is currently recommended in all SLE patients. However, patients’ compliance was reported as suboptimal. This study aims to elucidate the reasons for discontinuing antimalarials in a large series of SLE patients followed in a single centre during the last 50 years. Material and methods Among all patients diagnosed between 1968 and 2017 at our reference centre, retrospective data were obtained from electronic medical records of SLE patients consecutively visited during 2015–2017 and controlled for at least 1 year. Demographic, clinical, laboratory and therapeutic data at disease onset and during the follow-up in the whole cohort and differences between SLE patients discontinuing and continuing on antimalarials were analysed. Results Five-hundred thirty-nine patients followed during a median of 19 years were analysed. Median age at disease diagnosis was 29 years and 91.8% were women. Antimalarials were initiated by 521 (96.7%) patients and 18 (3.3%) cases did not start them mainly because of a quiescent or life-threatening SLE disease. In the 129 (24.7%) patients starting antimalarials with subsequent discontinuation, median treatment duration was 8.4 years. The main reason leading to treatment cessation was drug toxicity in 97 (18.6%) patients, of which macular toxicity was the most frequent adverse effect (n = 80; 15.3%). Treatment was stopped because of patient’s preference in 13 (2.5%) cases. The factors independently associated with antimalarial discontinuation were age at the end of follow-up (OR 1.130, 95% CI 1.005–1.269, p = 0.040), duration on antimalarials (OR 0.872, 95% CI 0.841–0.903, p < 0.001), presence of hepatitis C virus infection (HCV) (OR 13.948, 95% CI 1.321–147.324, p = 0.028) and anti-β2-glycoprotein 1 antibodies (OR 2.275, 95% CI 1.146–4.517, p = 0.019). Conclusions In our 50 years-experience, almost all SLE patients underwent antimalarials. These drugs are usually stopped because of adverse effects, particularly macular toxicity. After a long-term follow-up, patients’ compliance to antimalarials was considerably high in our SLE patients.

Substandard and falsified medicines are harmful to patients, causing prolonged illness, side effects, and preventable deaths. Moreover, they have an impact on the health system and society more broadly by leading to additional care, higher disease burden, productivity losses and loss of trust in health care. Models that estimate the health and economic impacts of substandard and falsified medicines can be useful for regulators to contextualize the problem and to make an economic case for solutions. Yet these models have not been systematically catalogued to date. We reviewed existing models that estimate the health and economic impact of substandard and falsified medicines to describe the varying modeling approaches and gaps in knowledge. We compared model characteristics, data sources, assumptions, and limitations. Seven models were identified. The models assessed the impact of antimalarial (n = 5) or antibiotic (n = 2) quality at a national (n = 4), regional (n = 2), or global (n = 1) level. Most models conducted uncertainty analysis and provided ranges around potential outcomes. We found that models are lacking for other medicines, few countries’ data have been analyzed, and capturing population heterogeneity remains a challenge. Providing the best estimates of the impact of substandard and falsified medicines on a level that is actionable for decision-makers is important. To enable this, research on the impact of substandard and falsified medicines should be expanded to more medicine types and classes and tailored to more countries that are affected, with greater specificity.

Among all the parasitic diseases in humans, malaria is the most significant and malicious one. The widespread species are Plasmodium falciparum and Plasmodium vivax, but the infection caused by the former is the deadliest. According to the November 2018 report of the World Health Organization (WHO), a total of 219 million cases of malaria were reported globally in 2017, which led to an estimated 435,000 deaths. Mortality due to malaria is estimated at 1.5 - 2.7 million deaths each year. Among all the complications associated with Plasmodium falciparum infection, cerebral malaria (CM) is the most fretful, accounting for almost 13% of all malaria-related deaths. CM is a medical emergency that requires immediate clinical testing and treatment. A compromised microcirculation, with sequestration of parasitized erythrocytes, is central in the disease pathology. No effective therapeutic agents are available yet for the treatment of CM, and therefore, potential interventions are needed to be developed urgently. The currently available anti-malarial drugs lack lipophilicity and are thus not able to reach the brain tissues. Therefore, safe, cost-effective agents with improved lipophilicity possessing the potential to target brain tissues are needed to be searched in order to fight CM worldwide. The aim of present review is to systematically revise the published research work available concerning the development and evaluation of some potential drug targets in the management of CM.

During intraerythrocytic growth, the human malaria parasite Plasmodium falciparum degrades up to 80% of the host cell's hemoglobin inside an acidified organelle called the digestive vacuole (DV). Here, the globin chains are broken down by a number of proteases, while heme is detoxified through biomineralization, a process that is targeted by several potent antimalarial drugs. This review explores our current understanding of the DV, including the digestion of hemoglobin, the sequestration of heme, and the functions of lipids and transporters of the DV membrane. Furthermore, the mechanisms of drug action inside the DV and the molecular adaptations that mediate resistance are discussed.

Recognising systemic lupus erythematosus (SLE) patients at higher risk for hospitalization, aiming at developing tailored management strategies, may help minimize admissions and improve long-term health outcomes. Our study aimed to identify predictors for hospitalization in patients with SLE.Cohort study of SLE patients followed in a referral centre. All hospitalizations from study baseline up to 120 months were identified, and the primary indication for admission was categorized as follows: (1) SLE disease activity; (2); infection; and (3) other conditions. Demographic, clinical, and laboratory parameters at baseline were sought as predictors of hospitalization for (i) any cause, (ii) disease activity, and (iii) infection using survival analysis with Kaplan-Meier curves and log-rank tests. Potential predictors were further tested using multivariate Cox proportional hazards regression models.We included 398 patients (median follow-up: 120 months). The incidence rate of hospitalization was 17.7 per 100 patient-years. The most frequent indications for hospitalization were SLE disease activity (29.4%) and infection (23.4%). In multivariate analysis, male gender, age 50 years, antiphospholipid antibodies positivity (aPL), SLEDAI-2 K 5, organ damage, and prednisone daily dose (PDN) predicted hospitalization for any cause. SLEDAI-2 K 5, aPL, PDN, and IS medication predicted hospitalization for active SLE. Male gender, prior biopsy-proven lupus nephritis, aPL, organ damage, and ongoing treatment with high-risk IS predicted hospitalization for infection. Treatment with antimalarials was associated with a lower risk of hospitalization for any cause and for infection.Positive aPL identifies SLE patients presenting a higher risk of hospitalization, while medication with antimalarials was associated with a lower risk. Key Points • Positive aPL is predictive of hospitalization for any medical condition, disease activity, and infection • Organ damage is predictive of hospitalization for any condition and infection • Antimalarials are predictive of a lower risk of hospitalization for any condition and infection.

Chloroquine and azithromycin were developed in combination for the preventive treatment of malaria in pregnancy, and more recently were proposed as coronavirus disease 2019 (COVID-19) treatment options. Billions of doses of chloroquine have been administered worldwide over the past 70 years but concerns regarding cardiotoxicity, notably the risk of torsades de pointes (TdP), remain. This investigation aimed to characterize the pharmacokinetics and electrocardiographic effects of chloroquine and azithromycin observed in a large previously conducted healthy volunteer study. Healthy adult volunteers (n = 119) were randomized into 5 arms: placebo, chloroquine alone (600 mg base), or chloroquine with either 500 mg, 1,000 mg, or 1,500 mg of azithromycin all given daily for 3 days. Chloroquine and azithromycin levels, measured using liquid-chromatography tandem mass spectrometry, and electrocardiograph intervals were recorded at frequent intervals. Time-matched changes in the PR, QRS, and heart rate-corrected JT, and QT intervals were calculated and the relationship with plasma concentrations was evaluated using linear and nonlinear mixed-effects modeling. Chloroquine and azithromycin pharmacokinetics were described satisfactorily by two- and three-compartment distribution models, respectively. No drug–drug interaction between chloroquine and azithromycin was observed. Chloroquine resulted in concentration-dependent prolongation of the PR, QRS, JTc and QTc intervals with a minimal additional effect of azithromycin. QRS widening contributed ~ 28% of the observed QT prolongation. Chloroquine causes significant concentration-dependent delays in both ventricular depolarization and repolarization. Co-administration of azithromycin did not significantly increase these effects. The arrhythmogenic risk of TdP associated with chloroquine may have been substantially overestimated in studies which did not separate electrocardiograph QRS and JT prolongation.

With over 200 million cases and close to half a million deaths each year, malaria is a threat to global health, particularly in developing countries.

Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5′-monophosphate–mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid–sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5′-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum , namely tyrosine RS ( Pf YRS). ML901 exerts whole-life-cycle–killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.

Malaria is a major cause of suffering, disease, and death worldwide and is considered the most important of all human parasitic diseases. Malaria is still endemic in most tropical and sub-tropical areas and globalization has contributed to an increase of imported cases around the world. We report a Plasmodium ovale infection in a traveler with recent return from a long land trip across West Africa. He declared adherence to mefloquine chemoprophylaxis only at the start of the trip. Initially, he was seen at two different hospitals and in both he was screened for malaria by microscopy and rapid diagnostic test, but his diagnosis was not confirmed. The traveler was then diagnosed at our hospital with a malaria infection by Plasmodium ovale. Complete blood count showed mild anemia, but leukocytes and platelets were already normal. Symptoms resolved in 24 hours after treatment started. Microscopy of stained blood films remains the gold standard for malaria diagnosis, which is critically dependent on trained eyes. In non-endemic regions with few cases during the year, training programs in malaria microscopy are crucial. The aim is to prevent the reintroduction of malaria in Europe, reduce individual morbidity and suffering, and thus contribute towards reduction in deaths caused by this disease.A malária é uma das principais causas de sofrimento, doença e morte no mundo e é considerada a mais importante doença parasitária em humanos. A malária ainda é endémica na maioria das áreas tropicais e sub-tropicais e a globalização tem contribuído para o aumento de casos em todo o mundo. Relatamos um caso de infeção por Plasmodium ovale num viajante com regresso recente de uma viagem por terra por vários países de África Ocidental. O viajante aderiu à profilaxia com mefloquina apenas no início da viagem. Já em Portugal, sentindo-se doente, febril, dirigiu-se a dois hospitais, onde realizou despiste para malária por microscopia e teste rápido, que foram descritos como negativos. Posteriormente, o viajante dirigiu-se ao nosso serviço onde foi diagnosticada uma infeção de malária por Plasmodium ovale. Os achados analíticos revelaram uma contagem de leucócitos normal, anemia moderada e, uma contagem de plaquetas já normal. Os sintomas terminaram com apenas 24 horas de tratamento. O método de referência do diagnóstico de malária continua a ser a microscopia, que é altamente dependente da experiência do pessoal do laboratório. Em regiões não endémicas com poucos casos durante o ano, é essencial promover e manter programas de capacitação em microscopia para prevenir a reintrodução da malária na Europa, diminuir a morbilidade e o sofrimento, e contribuir assim, para a redução do número de mortes pela doença.

Background\ud \ud New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers.\ud Methods\ud \ud A three-part clinical trial was conducted in healthy adults (aged 18–55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25, 75, 150, 450, 900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic–pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112).\ud Findings\ud \ud 48 participants were enrolled in part one (eight per cohort for 25–1500 mg cohorts), eight in part two (four in each group, all dosed with 300 mg), and 15 in part three (five dosed with 200 mg, eight with 300 mg, and two with 900 mg). In part one, the incidence of drug-related adverse events was higher in the 1500 mg dose group (occurring in all six participants) than in lower-dose groups and the placebo group (occurring in one of six in the 25 mg group, two of six in the 75 mg group, three of six in the 150 mg group, two of six in the 450 mg group, four of six in the 900 mg group, and four of 12 in the placebo group), due to the occurrence of mild gastrointestinal symptoms. Maximum plasma concentrations occurred 5–9 h post-dosing, and the elimination half-life was 50–97 h across the dose range. In part two, three of seven participants had a treatment-related adverse event in the fed state and four of eight in the fasted state. Dosing in the fed state delayed absorption (maximum plasma concentration occurred a median of 12·0 h [range 7·5–16·0] after dosing in the fed state vs 6·0 h [4·5–9·1] in the fasted state) but had no effect on overall exposure (difference in area under the concentration–time curve from time 0 [dosing] extrapolated to infinity between fed and fasted states was −0·013 [90% CI −0·11 to 0·08]). In part three, drug-related adverse events occurred in four of five participants in the 200 mg group, seven of eight in the 300 mg group, and both participants in the 900 mg group. Rapid initial parasite clearance occurred in all participants following dosing (clearance half-life 6·6 h [95% CI 6·2–6·9] for 200 mg, 6·8 h [95% CI 6·5–7·1] for 300 mg, and 7·1 h [95% CI 6·6–7·6] for 900 mg). Recrudescence occurred in four of five participants in the 200 mg group, five of eight in the 300 mg group, and neither of the two participants in the 900 mg group. Simulations done using a pharmacokinetic–pharmacodynamic model predicted that a single dose of 1100 mg would clear baseline parasitaemia by a factor of 10 9 .\ud Interpretation\ud \ud The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy.

The response to antenatal care (ANC) for maternal and offspring outcomes, especially in pregnant women has been thoroughly studied. However, despite the number of interventional studies on the treatment of sulfadoxine-pyrimethamine combination (IPTp-SP) uptake, the point in point cases of the positive responses of ANC in improving health conditions of pregnant women are not found in the literature.This review collected ANC responses to the positive health outcomes for pregnant women with malaria, the challenges faced regarding IPTp-SP uptake during ANC visits and the role of ANC in preventing and controlling malaria in sub-Saharan Africa. It elucidated ANC and uptake of optimal intermittent preventive IPTp-SP and further described ANC as a tool for heterogeneity for malaria prevention.ANC is seen as a microscope to malaria in pregnacy, maternal iron deficiency and anemia checkpoints, ANC and malaria treatment strategies, and ANC and the use of insecticide treated nets (ITN). The review further discussed ANC attendance influencing factors, limitations to ANC implications and the prospects in ANC visits on preventing malaria in pregnancy.A declining trend of malaria transmission in Africa has been observed in recent years. However, the burden of malaria in pregnancy remains a health concern. The rate of SP resistance, low uptake of IPTp-SP, low LLINs distribution, late gestational ANC visits and low turnaround for optimal ANC visits for first time mothers' aggrevated the malaria-endemic settings among pregnant women in sub-Saharan Africa.

Dihydroartemisinin-Piperaquine (DHP) combination is the first-line treatment for uncomplicated malaria in Indonesia and has been used since 2010. This study was conducted to determine the efficacy of DHP combination for uncomplicated malaria treatment in a community-based evaluation.Recruitment was done by active or passive case detection. All uncomplicated malaria patients were treated with DHP once a day, for 3 days, administered orally (as is done in primary health care). Patients were followed up until day 28 post-treatment. The primary end point was a 28-day cure rate.In this study, 484 subjects were screened through active and passive cases detection. A total of 45 subjects infected byDHP was effective, safe, and well tolerated in the treatment of uncomplicated malaria at primary health care.Dihidroartemisinin-Piperaquine (DHP) kombinasyonu, Endonezya’da komplike olmayan sıtma için birinci basamak tedavidir ve 2010 yılından beri kullanılmaktadır. Bu çalışma, toplum temelli bir değerlendirmede komplike olmayan sıtma tedavisi için DHP kombinasyonunun etkinliğini belirlemek için yapılmıştır.Çalışmaya katılım, aktif veya pasif olgu tespiti ile yapıldı. Komplike olmayan tüm sıtma hastaları günde bir kez üç gün boyunca ağızdan DHP ile tedavi edildi (birinci basamak sağlık hizmetinde yapıldığı gibi). Hastalar tedavi sonrası 28. güne kadar takip edildi. Birincil son nokta 28 günlük bir iyileşme oranıydı.Bu çalışmada 484 denek aktif ve pasif olgu tespiti ile tarandı.DHP, birinci basamak sağlık hizmetlerinde komplike olmayan sıtmanın tedavisinde etkili, güvenlidir ve iyi tolere edilmektedir.

In the Qinghai-Tibet Plateau, both the large daily temperature difference and soil salinization make plants susceptible to abiotic stresses such as freeze-thaw and salinity. Meanwhile, crops in this area can be affected by artemisinin, an antimalarial secondary metabolite produced in Artemisia. Under freeze-thaw and salinity stresses, artemisinin was induced as an allelopathy stress factor to explore the physiological response of highland barley, including the relative electrical conductivity (RC), soluble protein (SP) content, malondialdehyde (MDA) content, antioxidant enzyme activity, and water use efficiency (WUE). Compared with the control group, the contents of RC and MDA in seedling leaves under stress were significantly increased by 24.74-402.37% and 20.18-77.95%, indicating that cell membrane permeability was greatly damaged, and WUE was significantly decreased by 15.77-238.59%. The activity of enzymes increased under single stress and decreased under combined stress. Salinity, artemisinin, and freeze-thaw stress show a synergistic relationship; that is, compound stresses were more serious than single stress. In summary, the results of this study revealed the physiological and ecological responses of barley seedlings under different habitat stresses and the interactions among different stress factors.

Ripe figs, barks, and wood of Ficus vallis-choudae are used in traditional medicine against several conditions including nausea and malaria. However, its use is still to be scientifically documented and validated. Hence, the aim of the present work was to evaluate the antiplasmodial activity of the dichloromethane-methanol (DCM-MeOH (1:1)) crude extract, their hexane, dichloromethane, ethyl acetate, and methanoli fractions, as well as the isolated chemical constituents. The chemical study of the DCM-MeOH (1:1) crude extract of F. vallis-choudae figs led to the isolation of fifteen (15) known compounds identified based on their spectroscopic data [one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR), mass spectrometry] and by comparison of these data with those reported in the literature. Some of the isolated compounds were assessed in vitro for their antiplasmodial activity against Plasmodium falciparum chloroquine-sensitive 3D7 (Pf3D7) and multidrug-resistant Dd2 strains. The dichloromethane fraction exhibited very good antiplasmodial activity against both strains with IC50 values of 13.86mug/mL and 8.18mug/mL, respectively. Among the tested compounds, wighteone (2) was the most active against P. falciparum 3D7 (IC50=24.6±1.5muM) and Dd2 (IC50=11.9±2.4muM) strains. The obtained results could justify the traditional uses of F. vallis-choudae against malaria. Wighteone appears to be the most active ingredient. However, further consideration of this compound as starting point for antimalarial drug discovery will depend upon its selectivity of action towards Plasmodium parasites. HIGHLIGHTS: 15 (fifteen) compounds were isolated from the dichloromethane-methanol extract of Ficus vallis-choudae. Their structures were determined on the basis of their spectroscopic data. The dichloromethane fraction showed promising activities on the Pf3D7 and PfDd2 strains with IC50 values of 13.86 and 8.18g/mL, respectively. Wighteone was the most active compound against PfDd2 (IC50=11.9±2.4muM). © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Two routes to the antimalarial drug Pyronaridine are described. The first is a linear sequence that includes a two-step, one-pot transformation in an aqueous surfactant medium, leading to an overall yield of 87%. Alternatively, a convergent route utilizes a telescoped three-step sequence involving an initial neat reaction, followed by two steps performed under aqueous micellar catalysis conditions affording Pyronaridine in 95% overall yield. Comparisons to existing literature performed exclusively in organic solvents reveal a 5-fold decrease in environmental impact as measured by E Factors.