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Background: In 2021, nationwide malaria molecular surveillance revealed a high prevalence of a validated artemisinin resistance marker, the kelch13 (k13) Arg561His mutation, in the Kagera region of northwestern Tanzania. We aimed to investigate the efficacy of artemether-lumefantrine and artesunate-amodiaquine and to confirm the presence of artemisinin partial resistance (ART-R) in the Karagwe district of this region., Methods: This single-arm, therapeutic efficacy study was carried out at the Bukangara dispensary in the Karagwe district of the Kagera region in northwestern Tanzania. Eligible participants were aged between 6 months and 120 months, had confirmed Plasmodium falciparum asexual parasitaemia, and met other inclusion criteria according to WHO's standard protocol. Participants were enrolled, treated sequentially with either artemether-lumefantrine or artesunate-amodiaquine, and assessed clinically and parasitologically for 28 days as per WHO protocol. Parasitaemia was measured every 8 h until day 3, on day 7, and then during weekly follow-up visits until day 28. Mutations in the k13 gene and extended haplotypes with the mutations were analysed, and comparisons were made with previous samples collected in the same region of Kagera and in Rwanda and southeast Asia. The primary endpoint was PCR-corrected cure rate., Findings: Between April 29 and Sept 1, 2022, 343 patients were screened, of whom 176 were enrolled: 88 in each treatment group. The PCR-corrected cure rate was 98% (95% CI 91-100) in the artemether-lumefantrine group and 100% (96-100) in the artesunate-amodiaquine group. Persistent parasitaemia on day 3 occurred in 11 (13%) of 88 patients in the artemether-lumefantrine group and 17 (19%) of 88 patients in the artesunate-amodiaquine group. Arg561His mutations on day 0 and parasitaemia on day 3 were reported in eight (9%) of 87 patients in the artemether-lumefantrine group and ten (12%) of 86 patients in the artesunate-amodiaquine group. The median parasite clearance half-life in patients harbouring parasites with Arg561His mutation was 6·1 h in the artemether-lumefantrine group and 6·0 h in the artesunate-amodiaquine group. Parasites with the Arg561His mutation were not similar to those from southeast Asia and Rwanda but had similar haplotypes to parasites reported in the same Tanzanian region of Kagera in 2021., Interpretation: This study confirms the presence of ART-R in Tanzania, although artemether-lumefantrine and artesunate-amodiaquine showed high efficacy. A context-specific response strategy and vigilance to detect the reduced efficacy of current antimalarial treatments and ART-R in other parts of the country are urgently needed., Funding: The Bill & Melinda Gates Foundation and the US National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Many insect-borne pathogens appear to manipulate the odors of their hosts in ways that influence vector behaviors. In our prior work, we identified characteristic changes in volatile emissions of cultured Plasmodium falciparum parasites in vitro and during natural human falciparum malaria. In the current study, we prospectively evaluate the reproducibility of these findings in an independent cohort of children in Blantyre, Malawi., Methods: We enrolled febrile children under evaluation for malaria and collected breath from children with and without malaria, as well as healthy controls. Using gas chromatography/mass spectrometry, we characterized breath volatiles associated with malaria. By repeated sampling of children with malaria before and after antimalarial use, we determined how breath profiles respond to treatment. In addition, we investigated the stage-specificity of biomarkers through correlation with asexual and sexual-stage parasitemia., Results: Our data provide robust evidence that P. falciparum infection leads to specific, reproducible changes in breath compounds. While no individual compound served as an adequate classifier in isolation, selected volatiles together yielded high sensitivity for diagnosis of malaria. Overall, the results of our predictive models suggest the presence of volatile signatures that reproducibly predict malaria infection status and determine response to therapy, even in cases of low parasitemia., Competing Interests: Potential conflicts of interest. A. R. O. J. reports interest as co-inventor on US Provisional Application Filed 62/550 283. In addition, A. R. O. J. currently serves on the Scientific Advisory Board of Pluton Biosciences, LLC. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In Brazil, where Chagas disease is endemic, the most frequent form of transmission of the parasite is the oral route, associated with greater severity and worse response to benznidazole (BZ), the drug used in its treatment. This study aimed to evaluate the impact of gastrointestinal infection (GI) and BZ treatment on the parasitological and histopathological parameters in mice inoculated with a strain of T. cruzi II. Swiss mice were inoculated by GI and intraperitoneal (IP) routes with 2x10 6 culture-derived metacyclic trypomastigotes of the Y strain (TcII) of T. cruzi and were treated with BZ in the acute phase of the infection. Fresh blood examination, qPCR, histopathological and biochemical evaluations (enzymatic dosages and oxidative stress-OS) were performed. BZ treatment of uninfected animals caused changes in the liver, increased the activity of aspartate aminotransferase and alanine aminotransferase enzymes and OS, showing that the drug alone affects this organ. Inflammation and necrosis in the cardiac tissue were less intense and deaths occurred later in animals inoculated via the GI route than the animals inoculated via the IP route. BZ reduced the intensity of tissue lesions and avoided lethality in animals inoculated via the GI route, and decreased parasitemia and OS in those inoculated via both routes. Although BZ alone caused liver damage, it was less intense than that caused by both routes of inoculation. Infection with the Y strain of T. cruzi II via the GI route proved to be less virulent and pathogenic and responded better to treatment than the infection acquired via the IP route., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Malaria and human immunodeficiency virus (HIV) infection coexist in significant numbers in some geographic areas including sub-Sahara Africa (SSA). HIV-infected patients are a World Health Organization (WHO) recognized high risk group for increased malaria morbidity. Majority of HIV-infected patients undertaking treatment in SSA are on WHO recognized first-line combination antiretroviral therapy (cART). Considering the immunity-enhancing capacity of antiretroviral therapies on people living with HIV, this study aimed to explore the association between first-line combination antiretroviral therapy (cART) with malaria parasitaemia and antigenaemia in adult HIV-infected persons and to determine the predictors of malaria antigenaemia in adult persons living with HIV., Methods: The study was conducted at the AIDS Prevention Initiative in Nigeria (APIN) Centre, Jos University Teaching Hospital, Jos, Plateau State, from August 2018 to February 2019. Epi Info statistical tool was used to determine the sample size and power of the study. The study population consisted of three groups. The first group comprised first-line cART-experienced adult HIV-seropositive subjects, the second group comprised ARV-naïve HIV-seropositive adults and the third group comprised HIV-seronegative adults. For this pilot study, 60 persons were recruited into each group via convenience sampling. Malaria rapid diagnostic test (RDT) was performed according to manufacturer's instruction for all the study participants using SD Bioline Malaria Ag P.f (HRP2/pLDH) (Standard Diagnostics, Hagal-Dong, Korea). All the study participants also had thick and thin blood film malaria microscopy. Data collected was processed and analyzed using the Stata statistical software version 15 (StataCorp, College Station, Texas). Chi square was used to test the association between malaria and first-line cART exposure. Univariate and multivariate analysis were also done to identify factors that were independently associated with malaria antigenaemia., Results: A total of 180 persons participated in the study and involved 60 participants recruited in each of the three study groups. Overall, the predominant study participants were females (56.67%), traders (27.78%), secondary school leavers (43.33%) and urban dwellers (88.89%). Their mean age and standard deviation was 37.07 ± 11.53 years. Using malaria microscopy, the prevalence of malaria parasitaemia in ARV-naïve HIV-infected persons was 5% and 0% in the first-line cART-experienced HIV-infected persons as well as the HIV-negative persons. Malaria RDT result was positive in 7/60 (11.67%) of the first-line cART experienced HIV-infected participants, 6/60 (10%) of the ARV-naïve HIV-infected group and 1/60 (1.67%) of the HIV-negative group. Of the seven positive malaria RDT results in those on first-line cART, five persons were receiving zidovudine/lamivudine/nevirapine (AZT/3TC/NVP) while the remaining two were receiving tenofovir disoproxil fumarate/lamivudine/efavirenz (TDF/3TC/EFV), thus making an antigenaemia proportion of 16.67% and 6.67% respectively. Being an HIV-infected person on first-line cART (OR = 16.20, p = 0.04), having a headache (OR = 6.21, p = 0.03) and non-usage of window nets (OR = 3.74, p = 0.05) were found to be predictors of malaria antigenaemia., Conclusion: Malaria parasite burden in HIV-infected persons on first-line cART is lower than that observed in ARV-naïve HIV-infected persons. Our study suggests that TDF/3TC/EFV may be associated with lower malaria antigenaemia when compared with AZT/3TC/NVP and can be considered an alternative first-line antiretroviral regimen in malaria-endemic regions., (© 2024. The Author(s).)

The rise of multidrug-resistant malaria requires accelerated development of novel antimalarial drugs. Pharmacokinetic-pharmacodynamic (PK-PD) models relate blood antimalarial drug concentrations with the parasite-time profile to inform dosing regimens. We performed a simulation study to assess the utility of a Bayesian hierarchical mechanistic PK-PD model for predicting parasite-time profiles for a Phase 2 study of a new antimalarial drug, cipargamin. We simulated cipargamin concentration- and malaria parasite-profiles based on a Phase 2 study of eight volunteers who received cipargamin 7 days after inoculation with malaria parasites. The cipargamin profiles were generated from a two-compartment PK model and parasite profiles from a previously published biologically informed PD model. One thousand PK-PD data sets of eight patients were simulated, following the sampling intervals of the Phase 2 study. The mechanistic PK-PD model was incorporated in a Bayesian hierarchical framework, and the parameters were estimated. Population PK model parameters describing absorption, distribution, and clearance were estimated with minimal bias (mean relative bias ranged from 1.7% to 8.4%). The PD model was fitted to the parasitaemia profiles in each simulated data set using the estimated PK parameters. Posterior predictive checks demonstrate that our PK-PD model adequately captures the simulated PD profiles. The bias of the estimated population average PD parameters was low-moderate in magnitude. This simulation study demonstrates the viability of our PK-PD model to predict parasitological outcomes in Phase 2 volunteer infection studies. This work will inform the dose-effect relationship of cipargamin, guiding decisions on dosing regimens to be evaluated in Phase 3 trials., Competing Interests: The authors declare no conflict of interest.

Newly arrived refugees offer insights into malaria epidemiology in their countries of origin. We evaluated asymptomatic refugee children within 7 days of arrival in Uganda from South Sudan and the Democratic Republic of Congo (DRC) in 2022 for parasitemia, parasite species, and Plasmodium falciparum drug resistance markers. Asymptomatic P. falciparum infections were common in both populations. Coinfection with P. malariae was more common in DRC refugees. Prevalences of markers of aminoquinoline resistance (PfCRT K76T, PfMDR1 N86Y) were much higher in South Sudan refugees, of antifolate resistance (PfDHFR C59R and I164L, PfDHPS A437G, K540E, and A581G) much higher in DRC refugees, and of artemisinin partial resistance (ART-R; PfK13 C469Y and A675V) moderate in both populations. Prevalences of most mutations differed from those seen in Ugandans attending health centers near the refugee centers. Refugee evaluations yielded insights into varied malaria epidemiology and identified markers of ART-R in 2 previously little-studied countries., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., Competing Interests: The authors declare no conflict of interest in this study.

Malaria remains a major public health issue worldwide, with high rates of morbidity and mortality. The resistance of Plasmodium parasites to commonly used antimalarial drugs has necessitated the development of novel drugs and targets for malaria treatment. Lycopene is a natural compound present in tomatoes and other red fruits and vegetables. This study aimed to evaluate the antimalarial activity of lycopene and its co-administration with chloroquine against chloroquine-resistant malaria, as well as to assess its impact on hematological abnormalities associated with malaria infection. The experimental animals for this study were infected with 10 7 NK65 Plasmodium berghei-infected red blood cells via intraperitoneal injection. The animals were then treated with artemether-lumefantrine, chloroquine, and varying doses of lycopene. The study evaluated percentage parasitemia, mean survival time, and various hematological parameters, including red blood cell count, hematocrit, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, red blood cell distribution width - coefficient of variation, red blood cell distribution width - standard deviation, white blood cell count, granulocyte count, lymphocyte count, monocyte count, and procalcitonin level. The study revealed that lycopene demonstrated significant (p < 0.05) antimalarial activity and the ability to ameliorate hematological abnormalities associated with acute malaria infection. The findings of this study highlight the potential of lycopene as a novel antimalarial agent. The results of this study may contribute to the development of new drugs for malaria treatment, particularly in low- and middle-income countries., Competing Interests: Declaration of competing interest The Authors declare that there is no conflict of interest regarding the research, authorship and publication of this article., (Copyright © 2023. Published by Elsevier B.V.)

Oxidative stress is involved in the pathogenesis of malaria, causing anemia, respiratory complications, and cerebral malaria. To mitigate oxidative stress, we investigated the effect of nutritional supplementation whit lycopene (LYC) on the evolution of parasitemia and survival rate in mice infected with Plasmodium berghei ANKA (Pb), comparing to the effects promoted by N-acetylcysteine (NAC). Therefore, 175 mice were randomly distributed into 4 groups; Sham: untreated and uninfected animals; Pb: animals infected with Pb; LYC+Pb: animals treated with LYC and infected with Pb; NAC+Pb: animals treated with NAC and infected with Pb. The animals were followed for 12 days after infection, and survival and parasitemia rates were evaluated. There was a 40.1% increase in parasitemia in the animals of the Pb group on the 12th day, and a survival rate of 45%. LYC supplementation slowed the development of parasitemia to 19% and promoted a significative increase in the survival rate of 80% on the 12th day after infection, compared to the Pb group, effects superior to those promoted by NAC, providing strong evidence of the beneficial effect of LYC on in vivo malaria and stressing the importance of antioxidant supplementation in the treatment of this disease.

With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1-2 h, the elimination half-life was 8-9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC 90 : 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Malaria-induced alteration of physiological parameters and pharmacokinetic properties of antimalarial drugs may be clinically relevant. Whether and how malaria alters the disposition of piperaquine (PQ) was investigated in this study., Methods: The effect of malaria on drug metabolism-related enzymes and PQ pharmacokinetic profiles was studied in Plasmodium yoelii-infected mice in vitro/in vivo. Whether the malaria effect was clinically relevant for PQ was evaluated using a validated physiologically-based pharmacokinetic model with malaria-specific scalars obtained in mice., Results: The infection led to a higher blood-to-plasma partitioning (R bp ) for PQ, which was concentration-dependent and correlated to parasitemia. No significant change in plasma protein binding was found for PQ. Drug metabolism-related genes (CYPs/UDP-glucuronosyltransferase/nuclear receptor, except for CYP2a5) were downregulated in infected mice, especially at the acute phase. The plasma oral clearances (CL/F) of three probe substrates for CYP enzymes were significantly decreased (by ≥35.9%) in mice even with moderate infection. The validated physiologically-based pharmacokinetic model indicated that the hepatic clearance (CL H ) of PQ was the determinant of its simulated CL/F, which was predicted to slightly decrease (by ≤23.6%) in severely infected mice but not in malaria patients. The result fitted well with the plasma pharmacokinetics of PQ in infected mice and literature data on malaria patients. The blood clearance of PQ was much lower than its plasma clearance due to its high R bp ., Conclusions: The malaria-induced alteration of drug metabolism was substrate-dependent, and its impact on the disposition of PQ and maybe other long-acting aminoquinoline antimalarials was not expected to be clinically relevant., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per μL of blood (p/μL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/μL. However, at follow-up, parasite density increased to 7,630 p/μL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The first-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been local reports of CQ resistance. A clinical study was conducted to determine the efficacy of CQ for the treatment of P. vivax malaria in southern Ethiopia., Methods: In 2021, patients with P. vivax mono-infection and uncomplicated malaria were enrolled and treated with 25 mg/kg CQ for 3 consecutive days. Patients were followed for 28 days according to WHO guidelines. The data were analysed using per-protocol (PP) and Kaplan‒Meier (K‒M) analyses to estimate the risk of recurrent P. vivax parasitaemia on day 28., Results: A total of 88 patients were enrolled, 78 (88.6%) of whom completed the 28 days of follow-up. Overall, 76 (97.4%) patients had adequate clinical and parasitological responses, and two patients had late parasitological failures. The initial therapeutic response was rapid, with 100% clearance of asexual parasitaemia within 48 h., Conclusion: Despite previous reports of declining chloroquine efficacy against P. vivax, CQ retains high therapeutic efficacy in southern Ethiopia, supporting the current national treatment guidelines. Ongoing clinical monitoring of CQ efficacy supported by advanced molecular methods is warranted to inform national surveillance and ensure optimal treatment guidelines., (© 2024. The Author(s).)

Artemisinin resistance threatens malaria control and elimination efforts globally. Recent studies have reported the emergence of Plasmodium falciparum parasites tolerant to artemisinin agents in sub-Saharan Africa, including Uganda. The current study assessed the day 3 parasite clearance and its correlation with P. falciparum K13 propeller gene (pfkelch13) mutations in P. falciparum parasites isolated from patients with uncomplicated malaria under artemether-lumefantrine (AL) treatment. This study enrolled 100 P. falciparum-positive patients to whom AL was prescribed between 09/September/2022 and 06/November/2022. Blood samples were collected in EDTA tubes before treatment initiation (day 0) and on day 3. Parasitemia was assessed by microscopy from blood smears and quantitative polymerase chain reaction (qPCR) from the DNA extracted. The day 0 parasite K13 gene was sequenced using Sanger sequencing. Sequence data were analysed using MEGA version 11 software. The data were analysed using STATA version 15, and the Mann‒Whitney U test was used to compare PCR parasite clearance on day 3 using the comparative CT value method and pfkelch13 mutations. The prevalence of day 3 parasitaemia was 24% (24/100) by microscopy and 63% (63/100) by qPCR from the AL-treated patients. P. falciparum K13-propeller gene polymorphism was detected in 18.8% (15/80) of the day 0 DNA samples. The K13 mutations found were C469Y, 12.5% (10/80); A675V, 2.5% (2/80); A569S, 1.25%, (1/80), A578S, 1.25%, (1/80) and; F491S, 1.25%, (1/80) a new allele not reported anywhere. The C469Y mutation, compared to the wild-type, was associated with delayed parasite clearance p = 0.0278, Hodges-Lehmann estimation 3.2108 on the log scale, (95%CI 1.7076, 4.4730). There was a high prevalence of day 3 P. falciparum among malaria patients treated using artemether-lumefantrine. We conclude the presence of the K13 mutation associated with artemisinin resistance by P. falciparum in Adjumani district, Uganda, necessitates regular surveillance of the effectiveness and efficacy of artemether-lumefantrine in the country., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Angwe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC., Competing Interests: Declaration of Competing Interest All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest, (Copyright © 2024. Published by Elsevier Masson SAS.)

Purpose: Artemisinin combination therapies, the first-line antimalarials in Nigeria, have reportedly suffered multiple failures in malaria treatment, hence the search for novel combination of other compounds. Methyl gallate and palmatine have been reported to exhibit antiplasmodial activities but the antimalarial activity of their combination has not been evaluated. Therefore, the evaluation of the combination of methyl gallate and palmatine for antimalarial activity in vitro and in vivo in the presence of piperine was carried out., Materials and Methods: The inhibitory potential of methyl gallate and palmatine combination on β-hematin (hemozoin) formation was studied in vitro. Also, the antimalarial activity of methyl gallate and palmatine combination with/without a bioenhancer (piperine) was evaluated in Plasmodium berghei NK65-infected mice., Results: Methyl gallate and palmatine in the ratio 3:2 acted synergistically in vitro and had the highest inhibitory effect (IC 50  = 0.73 µg/mL) on β-hematin (hemozoin) formation. The 3:2 combination of methyl gallate and palmatine exhibited no antimalarial activity in vivo in the absence of piperine but caused reduction in parasitemia that exceeded 40% in the presence of piperine at the dose of 25 mg/kg body weight on days 6 and 8 post-inoculation in mice., Conclusion: The 3:2 combination of methyl gallate and palmatine in the presence of piperine exhibited antimalarial activity in vivo, possibly by synergistic inhibition of hemozoin formation which may cause accumulation of haem within the food vacuole of Plasmodium spp. and its death., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Animal African trypanosomosis (AAT) is an important global disease of livestock that causes economic losses of up to 4.5 billion US dollars per year. Thus, eliminating AAT in endemic countries will improve agricultural productivity and economic growth. To prevent AAT, vector control and the development of prophylactic drugs are crucial. Ascofuranone (AF) is a bioactive fungal compound with proven in vitro trypanocidal potency and in vivo treatment efficacy. However, the complex stereoselective synthesis of AF has prevented its cost-effective industrial production. Recently, a genetically modified strain of Acremonium egyptiacum fungus that produces a high yield of AF was developed. Therefore, we hypothesized that the oral administration of the AF-producing fungus itself may be effective against AAT. Hence, this study aimed to evaluate the prophylactic activity of orally administered dry-heat-sterilized A. egyptiacum against Trypanosoma congolense IL3000 infection using a mouse model. The survival rate was significantly prolonged (p = 0.009), and parasitemia was suppressed in all AF-fungus-treated groups (Group 1-9) compared with that in the untreated control group (Group 10). Hence, the trypanocidal activity of AF was retained after dry-heat-sterilization of the AF-producing fungus and that its oral administration effectively prevented AAT. Since AAT is endemic to rural areas with underdeveloped veterinary infrastructure, dry-heat-sterilized A. egyptiacum would be the most cost-effective potential treatment for AAT., Competing Interests: Declaration of competing interest The authors declare no competing interests in association with this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Standard diagnostics used in longitudinal antimalarial studies are unable to characterize the complexity of submicroscopic parasite dynamics, particularly in high transmission settings. We use molecular markers and amplicon sequencing to characterize post-treatment stage-specific malaria parasite dynamics during a 42 day randomized trial of 3- versus 5 day artemether-lumefantrine in 303 children with and without HIV (ClinicalTrials.gov number NCT03453840). The prevalence of parasite-derived 18S rRNA is >70% in children throughout follow-up, and the ring-stage marker SBP1 is detectable in over 15% of children on day 14 despite effective treatment. We find that the extended regimen significantly lowers the risk of recurrent ring-stage parasitemia compared to the standard 3 day regimen, and that higher day 7 lumefantrine concentrations decrease the probability of ring-stage parasites in the early post-treatment period. Longitudinal amplicon sequencing reveals remarkably dynamic patterns of multiclonal infections that include new and persistent clones in both the early post-treatment and later time periods. Our data indicate that post-treatment parasite dynamics are highly complex despite efficacious therapy, findings that will inform strategies to optimize regimens in the face of emerging partial artemisinin resistance in Africa., (© 2024. The Author(s).)

In Indonesia, malaria remains a problem, with 94,610 active cases in 2021 and its current therapy includes chloroquine and artemisinin; however, resistance has been commonly reported. To overcome this problem, studies about potential medicinal plants that can be used as antimalaria, such as moringa ( Moringa oleifera ) started to receive more attention. The aim of this study was to investigate the effects of moringa in parasitemia, monocyte activation, and organomegaly on animal model malaria. This experimental study used male Mus musculus , infected by Plasmodium berghei ANKA, as an animal malaria model. The extract was made by maceration of dry moringa leaves, which were then divided into three concentrations: 25%, 50%, and 75%. Dihydroartemisinin-piperazine was used as a positive control treatment, and distilled water as a negative control treatment. The animals were observed for six days to assess the parasitemia count and the number of monocyte activation. On day 7, the animals were terminated, and the liver, spleen, and kidney were weighed. The results showed that the effective concentrations in reducing parasitemia and inducing monocyte activation were 50% and 25% of moringa leaf extract, respectively. The smallest liver and spleen enlargement was observed among animals within the group treated with a 50% concentration of M. oleifera extract. In contrast, the smallest kidney enlargement was observed in the group treated with 25% of M. oleifera extract. Further analysis is recommended to isolate compounds with antimalarial properties in moringa leaves., Competing Interests: All the authors declare that there are no conflicts of interest., (© 2024 by the authors.)

Trypanosoma evansi is a flagellate protozoan that infects a wide range of hosts, especially horses. Clinically, the infection is characterized by rapid weight loss, anemia and mobility disorders. This study evaluated the efficacy of treatment gallium maltolate (GaM) in rats infected with T. evansi in the acute and chronic phases of the disease and its influence on the enzyme and blood parameters. 48 animals (Rattus norvegicus) were divided into 8 groups (A-H) of 6 animals each, namely: A: (negative control) uninfected; B: acutely infected positive control; C: chronically infected positive control; D: acutely infected, treated with GaM for 7 days post infection (p.i.); E: acutely infected treated with GaM for 3 days before infection (b.i) and 7 days p.i.; F: chronically infected, treated with GaM for 7 days p.i.; G: chronically infected, treated with GaM for 3 days b.i. and 7 days p.i.; and H: uninfected treated with GaM for 10 days. Acute infected animals (B, D and E) had a progressive increase in parasitemia and were died or euthanized before completing treatment days (5th days p.i.) as they had high parasitemia (over 100 field trypanosomes in the blood smear). Thus, it can be concluded that GaM was not effective against an acute infection. In untreated chronically infected animals (C) the parasitemia also increased progressively and they were euthanized on the 7th day p.i.. The chronically infected and treated animals (F and G) showed low parasitemia and after treatment became negative, showing no trypanosomes in the bloodstream until the 50th day of the experiment. Thus, we conclude that GaM was effective against chronic infections. In uninfected and treated animals (H) hematological, biochemical and enzymatic parameters had no significant changes when compared to the negative control group (A) demonstrating the low toxicity of GaM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Owing to evolution of parasite strains that are resistant to existing antimalarial drugs, research for novel antimalarial medicines is progressing on numerous fronts., Purpose: Herein, we evaluated the in vivo anti-Plasmodium berghei activity of β-ionone including its ameliorative potential towards P. berghei-associated anaemia and oxidative organ damage., Methods: Mice were infected with chloroquine-sensitive strain of P. berghei and then treated with β-ionone at doses of 10 and 20 mg/kg body weight (BW) for seven days. The parasitemia, packed cell volume and redox sensitive biomarkers in the liver, brain and spleen were estimated., Results: Our result showed that β-ionone, in a dose-dependent fashion, significantly (p < 0.05) repressed the multiplication of P. berghei. More so, the compound, at doses of 10 and 20 mg/kg BW, significantly (p < 0.05) mitigated anaemia and organ damage induced by P. berghei., Conclusion: Overall, the findings demonstrated that β-ionone has antiplasmodial actions and plays a mitigative role against P. berghei-induced anaemia and oxidative organ damage., (© 2023. The Author(s) under exclusive licence to Witold Stefański Institute of Parasitology, Polish Academy of Sciences.)

Background: Trypanosoma cruzi and HIV coinfection can evolve with depression of cellular immunity and increased parasitemia. We applied quantitative PCR (qPCR) as a marker for preemptive antiparasitic treatment to avoid fatal Chagas disease reactivation and analyzed the outcome of treated cases., Methodology: This mixed cross-sectional and longitudinal study included 171 Chagas disease patients, 60 coinfected with HIV. Of these 60 patients, ten showed Chagas disease reactivation, confirmed by parasites identified in the blood, cerebrospinal fluid, or tissues, 12 exhibited high parasitemia without reactivation, and 38 had low parasitemia and no reactivation., Results: We showed, for the first time, the success of the timely introduction of benznidazole in the non-reactivated group with high levels of parasitemia detected by qPCR and the absence of parasites in reactivated cases with at least 58 days of benznidazole. All HIV+ patients with or without reactivation had a 4.0-5.1 higher chance of having parasitemia than HIV seronegative cases. A positive correlation was found between parasites and viral loads. Remarkably, treated T. cruzi/HIV-coinfected patients had 77.3% conversion from positive to negative parasitemia compared to 19.1% of untreated patients. Additionally, untreated patients showed ~13.6 times higher Odds Ratio of having positive parasitemia in the follow-up period compared with treated patients. Treated and untreated patients showed no differences regarding the evolution of Chagas disease. The main factors associated with all-cause mortality were higher parasitemia, lower CD4 counts/μL, higher viral load, and absence of antiretroviral therapy., Conclusion: We recommend qPCR prospective monitoring of T. cruzi parasitemia in HIV+ coinfected patients and point out the value of pre-emptive therapy for those with high parasitemia. In parallel, early antiretroviral therapy introduction is advisable, aiming at viral load control, immune response restoration, and increasing survival. We also suggest an early antiparasitic treatment for all coinfected patients, followed by effectiveness analysis alongside antiretroviral therapy., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CB is an expert paid consultant on ancestry and diversity for Roche/Genentech. The other authors have no competing interests., (Copyright: © 2024 de Freitas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The adequate management of parasite co-infections represents a challenge that has not yet been overcome, especially considering that the pathological outcomes and responses to treatment are poorly understood. Thus, this study aimed to evaluate the impact of Schistosoma mansoni infection on the efficacy of benznidazole (BZN)-based chemotherapy in Trypanosoma cruzi co-infected mice. BALB/c mice were maintained uninfected or co-infected with S. mansoni and T. cruzi, and were untreated or treated with BZN. Body weight, mortality, parasitemia, cardiac parasitism, circulating cytokines (Th1/Th2/Th17); as well as heart, liver and intestine microstructure were analyzed. The parasitemia peak was five times higher and myocarditis was more severe in co-infected than T. cruzi-infected mice. After reaching peak, parasitemia was effectively controlled in co-infected animals. BZN successfully controlled parasitemia in both co-infected and T. cruzi-infected mice and improved body mass, cardiac parasitism, myocarditis and survival in co-infected mice. Co-infection dampened the typical cytokine response to either parasite, and BZN reduced anti-inflammatory cytokines in co-infected mice. Despite BZN normalizing splenomegaly and liver cellular infiltration, it exacerbated hepatomegaly in co-infected mice. Co-infection or BZN exerted no effect on hepatic granulomas, but increased pulmonary and intestinal granulomas. Marked granulomatous inflammation was identified in the small intestine of all schistosomiasis groups. Taken together, our findings indicate that BZN retains its therapeutic efficacy against T. cruzi infection even in the presence of S. mansoni co-infection, but with organ-specific repercussions, especially in the liver., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Artemisinin-based combination therapy (ACT) has been effective in the supervised treatment of uncomplicated malaria in Ghana. Since ACT usage is primarily unsupervised, this study aimed to determine the effectiveness of artemether-lumefantrine (AL) for treating malaria patients in two transmission settings in Ghana., Methods: Eighty-four individuals with uncomplicated Plasmodium falciparum malaria were recruited from Lekma Hospital (LH) in Accra (low-transmission area; N = 28), southern Ghana, and King's Medical Centre (KMC) in Kumbungu (high-transmission area; N = 56), northern Ghana. Participants were followed up for 28 days after unsupervised treatment with AL. The presence of asexual parasites was determined by microscopic examination of Giemsa-stained blood smears. Plasmodium species identification was confirmed using species-specific primers targeting the 18S rRNA gene. Parasite recrudescence or reinfection was determined by genotyping the Pfmsp 1 and Pfmsp 2 genes., Results: After AL treatment, 3.6% (2/56) of the patients from KMC were parasitaemic on day 3 compared to none from the LH patients. One patient from KMC with delayed parasite clearance on day 3 remained parasite-positive by microscopy on day 7 but was parasite-free by day 14. While none of the patients from LH experienced parasite recurrence during the 28-day follow-up, three and two patients from KMC had recurrent parasitaemia on days 21 and 28, respectively. Percentage reduction in parasite densities from day 1, 2, and 3 for participants from the KMC was 63.2%, 89.5%, and 84.5%. Parasite densities for participants from the LH reduced from 98.2%, 99.8% on day 1, and 2 to 100% on day 3. The 28-day cumulative incidence rate of treatment failure for KMC was 12.8% (95% confidence interval: 1.9-23.7%), while the per-protocol effectiveness of AL in KMC was 89.47%. All recurrent cases were assigned to recrudescence after parasite genotyping by Pfmsp 1 and Pfmsp 2., Conclusion: While AL is efficacious in treating uncomplicated malaria in Ghana, when taken under unsupervised conditions, it showed an 89.4% PCR-corrected cure rate in northern Ghana, which is slightly below the WHO-defined threshold., (© 2024. The Author(s).)

Multiple myeloma (MM) associated with Chagas disease is rarely described. This disease and its therapy suppress T cell and macrophage functions and increase regulatory T cell function, allowing the increase of parasitemia and the risk of Chagas Disease Reactivation (CDR). We aimed to analyze the role of conventional (cPCR) and quantitative Polymerase Chain Reaction (qPCR) for prospective monitoring of T. cruzi parasitemia, searching for markers of preemptive antiparasitic therapy in MM patients with Chagas disease. Moreover, we investigated the incidence and management of hematological diseases and CDR both inside and outside the transplant setting in the MEDLINE database. We found 293 studies and included 31 of them. Around 1.9-2.0% of patients with Chagas disease were reported in patients undergoing Stem Cell Transplantation. One case of CDR was described in eight cases of MM and Chagas disease. We monitored nine MM and Chagas disease patients, seven under Autologous Stem Cell Transplantation (ASCT), during 44.56±32.10 months (mean±SD) using parasitological methods, cPCR, and qPCR. From these patients, three had parasitemia. In the first, up to 256 par Eq/mL were detected, starting from 28 months after ASCT. The second patient dropped out and died soon after the detection of 161.0 par Eq/mL. The third patient had a positive blood culture. Benznidazole induced fast negativity in two cases; followed by notably lower levels in one of them. Increased T. cruzi parasitemia was related to the severity of the underlying disease. We recommend parasitemia monitoring by qPCR for early introduction of preemptive antiparasitic therapy to avoid CDR.

Background: Chagas disease is caused by the parasite Trypanosoma cruzi , and the lack of effective and safe treatments makes identifying new classes of compounds with anti- T. cruzi activity of paramount importance. Methods: Hit-to-lead exploration of a metabolically stable N -imidazoylpiperazine was performed. Results: Compound 2 , a piperazine derivative active against T. cruzi , was selected to perform the hit-to-lead exploration, which involved the design, synthesis and biological evaluation of 39 new derivatives. Conclusion: Compounds 6e and 10a were identified as optimized compounds with low micromolar in vitro activity, low cytotoxicity and suitable preliminary absorption, distribution, metabolism and excretion and physicochemical properties. Both compounds reduced parasitemia in mouse models of Chagas disease, providing a promising opportunity for further exploration of new antichagasic compounds.

Chagas disease is an infection caused by the protozoan Trypanosoma cruzi, affecting 6-8 million people worldwide. Only two drugs are available for its treatment, having a limited efficacy and adverse side-effects. Estafietin is a sesquiterpene lactone isolated from Stevia alpina with in vitro activity against T. cruzi and low cytotoxicity against mammalian cells. The aim of this work was to predict the toxicologic profile of estafietin by in silico methods and assess its in vivo activity on a murine model of Chagas disease. Estafietin showed low toxicity according to pkCSM web tool and passed the PAINS filter from PAINS-remover web server. The treatment of infected mice with 1 mg/Kg/day of estafietin for five consecutive days administrated by intraperitoneal route significatively decreased parasitemia levels and reduced inflammatory infiltrates and myocyte damage on muscle tissue. These results suggest that estafietin had effect both on acute and chronic stages of the infection.

Malaria remains a significant cause of morbidity and mortality, even in low-transmission settings. With the advent of longer acting, more effective, and well-tolerated antimalarials, there is renewed interest in the efficacy of mass drug administration (MDA) to accelerate to elimination. We conducted a systematic review and meta-analysis to assess the efficacy of MDA to reduce the incidence and prevalence of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) infection. From 1,044 articles screened, 14 articles, including 10 randomized controlled trials (RCTs), were identified. Five included data on Pf only; five included Pf and Pv. Two of the Pf studies were conducted in areas of high-moderate transmission, the remainder were in areas of low-very low transmission. In higher transmission areas, MDA reduced incidence of Pf parasitemia (rate ratio = 0.61, 95% CI: 0.40-0.92; moderate certainty) 1 to 3 months after drug administration; no significant effect of MDA on Pf parasitemia prevalence was detected 1 to 3 months post-MDA (risk ratio [RR] = 1.76, 95% CI: 0.58-5.36; low certainty). In lower transmission settings, both incidence and prevalence of Pf parasitemia were reduced 1 to 3 months post-MDA (rate ratio = 0.37, 95% CI: 0.21-0.66; RR = 0.25, 95% CI: 0.15-0.41, respectively). Pv prevalence was reduced 1 to 3 months post-MDA (RR = 0.15, 95% CI: 0.10-0.24); there were no RCTs providing data on incidence of Pv. There was no significant effect of MDA at later time points. MDA may have short-term benefits; however, there was no evidence for longer term impact, although none of the trials assessed prolonged interventions.

Background: In areas co-endemic for Plasmodium vivax and Plasmodium falciparum there is an increased risk of P vivax parasitaemia following P falciparum malaria. Radical cure is currently only recommended for patients presenting with P vivax malaria. Expanding the indication for radical cure to patients presenting with P falciparum malaria could reduce their risk of subsequent P vivax parasitaemia., Methods: We did a multicentre, open-label, superiority randomised controlled trial in five health clinics in Bangladesh, Indonesia, and Ethiopia. In Bangladesh and Indonesia, patients were excluded if they were younger than 1 year, whereas in Ethiopia patients were excluded if they were younger than 18 years. Patients with uncomplicated P falciparum monoinfection who had fever or a history of fever in the 48 h preceding clinic visit were eligible for enrolment and were required to have a glucose-6-dehydrogenase (G6PD) activity of 70% or greater. Patients received blood schizontocidal treatment (artemether-lumefantrine in Ethiopia and Bangladesh and dihydroartemisinin-piperaquine in Indonesia) and were randomly assigned (1:1) to receive either high-dose short-course oral primaquine (intervention arm; total dose 7 mg/kg over 7 days) or standard care (standard care arm; single dose oral primaquine of 0·25 mg/kg). Random assignment was done by an independent statistician in blocks of eight by use of sealed envelopes. All randomly assigned and eligible patients were included in the primary and safety analyses. The per-protocol analysis excluded those who did not complete treatment or had substantial protocol violations. The primary endpoint was the incidence risk of P vivax parasitaemia on day 63. This trial is registered at ClinicalTrials.gov, NCT03916003., Findings: Between Aug 18, 2019, and March 14, 2022, a total of 500 patients were enrolled and randomly assigned, and 495 eligible patients were included in the intention-to-treat analysis (246 intervention and 249 control). The incidence risk of P vivax parasitaemia at day 63 was 11·0% (95% CI 7·5-15·9) in the standard care arm compared with 2·5% (1·0-5·9) in the intervention arm (hazard ratio 0·20, 95% CI 0·08-0·51; p=0·0009). The effect size differed with blood schizontocidal treatment and site. Routine symptom reporting on day 2 and day 7 were similar between groups. In the first 42 days, there were a total of four primaquine-related adverse events reported in the standard care arm and 26 in the intervention arm; 132 (92%) of all 143 adverse events were mild. There were two serious adverse events in the intervention arm, which were considered unrelated to the study drug. None of the patients developed severe anaemia (defined as haemoglobin <5 g/dL)., Interpretation: In patients with a G6PD activity of 70% or greater, high-dose short-course primaquine was safe and relatively well tolerated and reduced the risk of subsequent P vivax parasitaemia within 63 days by five fold. Universal radical cure therefore potentially offers substantial clinical, public health, and operational benefits, but these benefits will vary with endemic setting., Funding: Australian Academy of Science Regional Collaborations Program, Bill & Melinda Gates Foundation, and National Health and Medical Research Council., Competing Interests: Declaration of interests KT is funded by a CSL Century fellowship. JAS and RNP are funded by National Health and Medical Research Council Leadership Investigator Grants (1196068 and 2008501). All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Scope: Malaria remains one of the most important infectious diseases in the world. Allyl isothiocyanate (AITC) is a main ingredient of traditional spice Wasabia japonica, which is reported to have anti-bacterial and antiparasitic activities. However, there is no information on effects of AITC against malaria. The present study investigates the anti-malarial activity of dietary AITC in vivo and that of AITC metabolites in vitro., Methods and Results: The ad libitum administration of 35, 175, or 350 µM AITC-containing drinking water to ICR mice significantly inhibit the parasitemia induced after infection with Plasmodium berghei. On the other hand, after single oral administration of AITC (20 mg kg -1 body weight), N-acetyl-S-(N-allylthiocarbamoyl)-l-cysteine (NAC-AITC) as one of the AITC metabolites displays a serum C max of 11.4 µM at a T max of 0.5 h, but AITC is not detected at any time point. Moreover, NAC-AITC shows anti-malarial activity against Plasmodium falciparum in vitro, and its 50% inhibitory concentration (IC 50 ) against parasitemia is 12.6 µM., Conclusions: These results indicate that orally administered AITC is metabolized to NAC-AITC and exerts anti-malarial activity against malaria parasites in blood, suggesting that the consumption of AITC-containing food stuffs such as cruciferous plants may prevent malaria., (© 2023 Wiley-VCH GmbH.)

Chagas disease (CD) is a neglected tropical disease endemic in 21 countries and affects about 8 million people around the world. The pharmacotherapy for this disease is limited to two drugs (Benznidazole and Nifurtimox) and both are associated with important limitations, as low cure rate in the chronic phase of the disease, high toxicity and increasing resistance by Trypanosoma cruzi. Recently, we reported a bioactive 1,2,3-triazole (compound 35) active in vitro (IC 50 42.8 μM) and in vivo (100 mg/kg) against T. cruzi Y strains and preliminary in silico studies suggested the cysteine protease cruzain as a possible target. Considering these initial findings, we describe here the design and synthesis of new 1,2,3-triazoles derivatives of our hit compound (35). The triazoles were initially evaluated against healthy cells derived from neonatal rat cardiomyoblasts (H9c2 cells) to determine their cytotoxicity and against epimastigotes forms of T. cruzi Y strain. The most active triazoles were compounds 26 (IC 50 19.7 μM) and 27 (IC 50 7.3 μM), while benznidazole was active at 21.6 μM. Derivative 27 showed an interesting selectivity index considering healthy H9c2 cells (>77). Promising activities against trypomastigotes forms of the parasite were also observed for triazoles 26 (IC 50 20.74 μM) and 27 (IC 50 8.41 μM), mainly 27 which showed activity once again higher than that observed for benznidazole (IC 50 12.72 μM). While docking results suggested cruzain as a potential target for these compounds, no significant enzyme inhibition was observed in vitro, indicating that their trypanocidal activity is related to another mode of action. Considering the promising in vitro results of triazoles 26 and 27, the in vivo toxicity was initially verified based on the evaluation of behavioral and physiological parameters, mortality, effect in body weight gain, and through the measurement of AST/ALT enzymes, which are markers of liver toxicity. All these evaluations pointed to a good tolerability of the animals, especially considering triazole 27. A reduction in parasitemia was observed among animals treated with triazole 27, but not among those treated with derivative 26. Regarding the dosage, derivative 27 (100 mg/kg) was the most active sample against T. cruzi infection, showing a 99.4% reduction in parasitemia peak. Triazole 27 at a dosage of 100 mg/kg influenced the humoral immune response and reduced myocarditis in the animals, bringing antibody levels closer to those observed among healthy mice. Altogether, our results indicate compound 27 as a new lead for the development of drug candidates to treat Chagas disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

In this study, it was aimed to investigate the antimalarial activity of cinnamaldehyde (CIN) and cannabidiol (CBD) which have shown various biological activities such as potent antimicrobial activity and eravacycline (ERA), a new generation tetracycline derivative, in an in vivo malaria model. The cytotoxic activities of the active substances were determined by the MTT method against L929 mouse fibroblasts and their antimalarial activity were determined by the four-day test in an in vivo mouse model. In this study, five groups were formed: the CIN group, the CBD group, the ERA group, the chloroquine group (CQ) and the untreated group (TAG). 2.5 x 107 parasites/mL of P.berghei-infected erythrocyte suspension was administered IP to all mice. The determined doses of active substances were given to the mice by oral gavage in accordance with the four-day test and the parasitemia status in the mice was controlled for 21 days with smear preparations made from the blood taken from the tail end of the mice. The IC50 values, which express the cytotoxic activity values of the active substances were determined as 27.55 μg/mL, 16.40 μM and 48.82 μg/mL for CIN, CBD and ERA, respectively. The mean parasitemia rate in untreated mice was 33% on day nine and all mice died on day 11. On the ninth day, when compared with the TAG group, no parasites were observed in the CIN group, while the average parasitemia was 0.08% in the CBD group and 17.8% in the ERA group. Compared to the mice in the TAG group, the life expectancy of the other groups was prolonged by eight days in the CIN group, 12 days in the CBD group and eight days in the ERA group. It has been determined that all three active subtances tested in this study suppressed the development of Plasmodium parasites in an in vivo mouse model and prolonged the life span of the mice. It is thought that the strong antimalarial activity of CIN and CBD shown in the study and the possible positive effect of ERA on the clinical course can be improved by combining them with the existing and potential antimalarial molecules.

Chagas disease is a neglected tropical disease with only two drugs available for treatment and the plant Cecropia pachystachya has several compounds with antimicrobial and anti-inflammatory activities. This study aimed to evaluate a supercritical extract from C. pachystachya leaves in vitro and in vivo against Trypanosoma cruzi. A supercritical CO 2 extraction was used to obtain the extract (CPE). Cytotoxicity and immunostimulation ability were evaluated in macrophages, and the in vitro trypanocidal activity was evaluated against epimastigotes and trypomastigotes forms. In vivo tests were done by infecting BALB/c mice with blood trypomastigotes forms and treating animals orally with CPE for 10 days. The parasitemia, survival rate, weight, cytokines and nitric oxide dosage were evaluated. CPE demonstrated an effect on the epi and trypomastigotes forms of the parasite (IC 50 17.90 ± 1.2 μg/mL; LC 50 26.73 ± 1.2 μg/mL) and no changes in macrophages viability, resulting in a selectivity index similar to the reference drug. CPE-treated animals had a worsening compared to non-treated, demonstrated by higher parasitemia and lower survival rate. This result was attributed to the anti-inflammatory effect of CPE, demonstrated by the higher IL-10 and IL-4 values observed in the treated mice compared to the control ones. CPE demonstrated a trypanocidal effect in vitro and a worsening in the in vivo infection due to its anti-inflammatory activity., (© 2023 John Wiley & Sons Ltd.)

Introduction: Polymorphonuclear neutrophils (PMN) are involved in pathogen clearance by phagocytosis. However, the role of PMNs in the efficacy of artemisinin-based combination therapy (ACT) is poorly understood., Methodology: In a prospective longitudinal in vivo study, neutrophil rates were compared with malaria carriage after treatment with different ACTs: Artemether - lumefantrine (AL), Artesunate - amodiaquine (ASAQ), Dihydroartemisinin - piperaquine (DP) or Pyronaridine artesunate (PA). The study cases were classified as having neutropenia, normal neutrophil levels or neutrophilia depending on the level of neutrophils in the blood. This study included 3148 patients and was analyzed using R., Results: On day 7, only four patients in the neutropenia group and treated with AL had a malaria positive blood smear based on microscopy. On day 28, the rate of recurrent parasitemia in the AL arm was significantly higher in neutropenia patients (50.9%) than in patients with normal rates of neutrophils (43.1%) or in those with neutrophilia (6.0%) (p < 0.001). In ASAQ arm, the rate of recurrent Plasmodium falciparum parasitemia was 58.8% in the neutropenia group versus 29.4% in patients with normal rates of neutrophils and 11.8% in patients with neutrophilia (p < 0.001). No patient treated with DP with normal neutrophil counts or neutrophilia was carrying malaria parasites on day 28. Among the 15 patients with parasitemia on day 28 in the PA arm, 11 (73.33%) had neutropenia while 4 (26.67%) had a normal neutrophil count (p < 0.001)., Conclusions: Patients with neutropenia had higher rates of recurrent P. falciparum parasitemia after ACT., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2023 Moussa Djimde, Kassoum Kayentao, Japhet Kabalu Tshiongo, Bakary Fofana, Charles Arama, Sodiomon B Sirima, Jean Bosco Ouedraogo, Abdoul Habib Beavogui, Issaka Sagara, Alassane Dicko, Petra F Mens, Henk DFH Schallig, Abdoulaye Djimde.)

This study investigated the effects of co-administration of a commercial juice rich in vitamin C (Vit C) on the antimalarial efficacy of artemether-lumefantrine (AL) in Plasmodium berghei-infected mice. Fifty Balb/c mice were infected with Plasmodium berghei NK65 strain from a donor mouse. Parasitemia was established after 72 h. Animals were grouped into 6 (n = 10) and treated daily for 3 days with normal saline, chloroquine, artemether-lumefantrine (AL), AL plus 50% commercial juice (CJ), and AL plus 50% Vit C supplementation in drinks ad libitum, respectively. Body weight, parasitemia levels, and mean survival time were determined. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), nitrite, malondialdehyde, reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were determined in the serum and liver tissues. Spleen histopathological changes were determined by H&E staining. Parasitemia was cleared by administration of AL and was not affected by Vit C and CJ supplementation. Vit C significantly prevented body weight reduction in AL-treated mice. CJ and Vit C supplementation to AL-treated mice significantly improved survival proportion compared with AL alone animals. Vit C and CJ supplementation significantly improved reduction of TNF-α, IL-6, and malondialdehyde, and increased GSH, CAT, and SOD in AL-treated mice. Spleen cell degeneration and presence of malaria pigment were reduced in AL-treated animals. The results suggest that ad libitum co-administration of commercial juice and vitamin C with artemether-lumefantrine does not impair its antimalarial efficacy but rather improved antioxidant and anti-inflammatory effects in mice., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite the recent progress in public health measures, malaria remains a troublesome disease that needs to be eradicated. It is essential to develop new antimalarial medications that are reliable and secure. This report evaluated the pharmacokinetics and antimalarial activity of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the rodent malaria parasite Plasmodium berghei in vivo. After a single oral dose (75 mg /kg) of N-89, its pharmacokinetic parameters were measured, and t1/2 was 0.97 h, Tmax was 0.75 h, and bioavailability was 7.01%. A plasma concentration of 8.1 ng/ml of N-89 was maintained for 8 h but could not be detected at 10 h. The dose inhibiting 50% of parasite growth (ED50) and ED90 values of oral N-89 obtained following a 4-day suppressive test were 20 and 40 mg/kg, respectively. Based on the plasma concentration of N-89, we evaluated the antimalarial activity and cure effects of oral N-89 at a dose of 75 mg/kg 3 times daily for 3 consecutive days in mice harboring more than 0.5% parasitemia. In all the N-89- treated groups, the parasites were eliminated on day 5 post-treatment, and all mice recovered without a parasite recurrence for 30 days. Additionally, administering oral N-89 at a low dose of 50 mg/kg was sufficient to cure mice from day 6 without parasite recurrence. This work was the first to investigate the pharmacokinetic characteristics and antimalarial activity of N-89 as an oral drug. In the future, the following steps should be focused on developing N-89 for malaria treatments; its administration schedule and metabolic pathways should be investigated.

The increasing burden and spread of resistant malaria parasites remains an immense burden to public health. These factors have driven the demand to search for a new therapeutic agent. From our screening, phebestin stood out with nanomolar efficacy against Plasmodium falciparum 3D7. Phebestin was initially identified as an aminopeptidase N inhibitor. Phebestin inhibited the in vitro multiplication of the P. falciparum 3D7 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains at IC 50 values of 157.90 ± 6.26 nM and 268.17 ± 67.59 nM, respectively. Furthermore, phebestin exhibited no cytotoxic against human foreskin fibroblast cells at 2.5 mM. In the stage-specific assay, phebestin inhibited all parasite stages at 100 and 10-fold its IC 50 concentration. Using 72-h in vitro exposure of phebestin at concentrations of 1 μM on P. falciparum 3D7 distorted the parasite morphology, showed dying signs, shrank, and prevented reinvasion of RBCs, even after the compound was washed from the culture. An in silico study found that phebestin binds to P. falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP), as observed for bestatin. In vivo evaluation using P. yoelii 17XNL-infected mice with administrations of 20 mg/kg phebestin, once daily for 7 days, resulted in significantly lower parasitemia peaks in the phebestin-treated group (19.53%) than in the untreated group (29.55%). At the same dose and treatment, P. berghei ANKA-infected mice showed reduced parasitemia levels and improved survival compared to untreated mice. These results indicate that phebestin is a promising candidate for development as a potential therapeutic agent against malaria.

A functional, multi-organ, serum-free system was developed for the culture of P. falciparum in an attempt to establish innovative platforms for therapeutic drug development. It contains 4 human organ constructs including hepatocytes, splenocytes, endothelial cells, as well as recirculating red blood cells which allow for infection with the parasite. Two strains of P. falciparum were used: the 3D7 strain, which is sensitive to chloroquine; and the W2 strain, which is resistant to chloroquine. The maintenance of functional cells was successfully demonstrated both in healthy and diseased conditions for 7 days in the recirculating microfluidic model. To demonstrate an effective platform for therapeutic development, systems infected with the 3D7 strain were treated with chloroquine which significantly decreased parasitemia, with recrudescence observed after 5 days. Conversely, when the W2 systems were dosed with chloroquine, parasitemia levels were moderately decreased when compared to the 3D7 model. The system also allows for the concurrent evaluation of off-target toxicity for the anti-malarial treatment in a dose dependent manner which indicates this model could be utilized for therapeutic index determination. The work described here establishes a new approach to the evaluation of anti-malarial therapeutics in a realistic human model with recirculating blood cells for 7 days., (© 2023. The Author(s).)

Background: The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals., Methods: Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population., Results: Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult., Conclusions: Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976)., Competing Interests: Potential conflicts of interest. B. E. B. and J. S. M. declare receipt of funding from the Bill and Melinda Gates Foundation (BMGF) and Medicines for Malaria Venture (MMV) to perform the study. G. D. S. declares participation on an Expert Scientific Advisory Committee for MMV and participation on Data Safety Monitoring Boards for multiple MMV-sponsored clinical trials. J. J. M. is an employee of MMV. D. W. declares consultation for BMGF under contract. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Chagas Disease (CD) affects around eight million people worldwide. It is considered a neglected disease that presents few treatment options with efficacy only in the acute phase. Nanoparticles have many positive qualities for treating parasite infections and may be effectively and widely employed in clinical medicine. This research aimed to evaluate the nanoencapsulated benznidazole treatment in animals experimentally infected with Trypanosoma cruzi. To analyze the treatment efficacy, we evaluated survival during thirty days, parasitemia, genotoxicity, and heart and liver histopathology. Thirty-five female Swiss mice were organized into seven groups characterizing a dose curve: A - Negative control (uninfected animals), B - Positive control (infected animals), C - Benznidazole (BNZ) 100 mg/kg (infected animals), D - 5 mg/kg Benznidazole nanocapsules (NBNZ) (infected animals), E - 10 mg/kg Benznidazole nanocapsules (infected animals), F - 15 mg/kg Benznidazole nanocapsules (infected animals), G - 20 mg/kg Benznidazole nanocapsules (infected animals). The animals were infected with the Y strain of T. cruzi intraperitoneally. The treatment was administered for eight days by oral gavage. It was possible to observe that the treatment with the highest NBNZ dose presented efficacy similar to the standard benznidazole drug. The 20 mg/kg NBNZ dose was able to reduce parasitemia, increase survival, and drastically reduce heart and liver tissue damage compared to the 100 mg/kg BNZ dose. Moreover, it showed a lower DNA damage index than the BNZ treatment. In conclusion, the nanoencapsulation of BNZ promotes an improvement in parasite proliferation control with a five times smaller dose relative to the standard dose of free BNZ, thus demonstrating to be a potential innovative therapy for CD., Competing Interests: Declaration of competing interest The authors declared no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hyperparasitaemia is an important event in the cascade of Plasmodium falciparum severe malaria (SM), and may also lead to SM associated complications and death, if left untreated. Here, we report two hyperparasitaemic patients with no life-threatening complications. Malaria diagnosis was performed using thick and thin blood smears and immunochromatographic-based rapid diagnostic tests (RDTs) purchased from three different manufacturers. Parasitaemia was calculated following the World Health Organization (WHO) guidelines. Haematological and biochemical investigations were also performed. Weekly follow-up of blood smear examination, blood pressure and temperature were recorded up to day 63. The first patient had 42% parasitaemia (100% asexual parasites). The second patient had 9.5% parasitaemia, comprising 46% asexual and 54% sexual stages, with a 1:1 male to female ratio. On the day of admission, both had presented abnormal haematological and biochemical parameters compared to the reference values. Remarkably, both the patients recovered successfully with oral artemisinin-based combination therapy (ACT) and a single dose of primaquine on day 1. Weekly follow-up did not show any parasite suggesting successful treatment with ACT without any side effects. The presence of hypergametocytaemia may hinder malaria elimination efforts, if not treated immediately., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2023 Benudhar Mukhi, Himanshu Gupta, Kishore Punnath, Anupkumar R Anvikar, Bina Srivastava, Susanta Kumar Ghosh.)

Background: Artemisinin-resistant Plasmodium falciparum is spreading in Southeast Asia and Africa. In vivo susceptibility to artemisinin is studied by looking at the rate of decline of peripheral parasitemia (parasite clearance half-life). However, parasites that are adhered/sequestered to the endothelium and undetectable in the peripheral blood are not considered in the estimation of parasite clearance. Here, we evaluated the influence of sequestration on in vivo artemisinin efficacy in Uganda, where artemisinin resistance is spreading., Methods: We analyzed 133 patients with P. falciparum malaria included in an in vivo study on artemisinin efficacy in northern Uganda in 2018 and 2019. The parasite clearance half-life was estimated from peripheral parasitemia after artemisinin monotherapy. P. falciparum histidine-rich protein 2 (PfHRP2) was measured in pretreatment plasma. The number of sequestered parasites was estimated from PfHRP2 concentration and peripheral parasitemia., Results: The estimated number of sequestered parasites per plasma volume ranged from 0 to 2 564 000/μL. Inflammation, thrombocytopenia, and dyslipidemia were significantly associated with sequestration independent of peripheral parasitemia. The median parasite clearance half-lives were 1.65 hours in patients infected with Pfkelch13 wild-type parasites (n = 104) and 3.95 hours in those with A675V artemisinin-resistant mutant (n = 18). In the multivariable model for the wild-type population, 1 000 000/μL of sequestered parasites were estimated to delay parasite clearance by 16.8% (95% confidence interval, 5.1%-28.5%), although it was not clear in the A675V population., Conclusions: In patients with P. falciparum malaria without artemisinin-resistant mutations, intensive sequestration delays parasite clearance after treatment, which may contribute to reduced artemisinin efficacy., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We aimed to assess safety, tolerability, and Plasmodium vivax relapse rates of ultra-short course (3.5 days) high-dose (1 mg/kg twice daily) primaquine (PQ) for uncomplicated malaria because of any Plasmodium species in children randomized to early- or delayed treatment., Methods: Children aged 0.5 to 12 years with normal glucose-6-phosphate-dehydrogenase (G6PD) activity were enrolled. After artemether-lumefantrine (AL) treatment, children were randomized to receive PQ immediately after (early) or 21 days later (delayed). Primary and secondary endpoints were the appearance of any P. vivax parasitemia within 42 or 84 days, respectively. A non-inferiority margin of 15% was applied (ACTRN12620000855921)., Results: A total of 219 children were recruited, 70% with Plasmodium falciparum and 24% with P. vivax. Abdominal pain (3.7% vs 20.9%, P <0.0001) and vomiting (0.9% vs 9.1%, P = 0.01) were more common in the early group. At day 42, P. vivax parasitemia was observed in 14 (13.2%) and 8 (7.8%) in the early and delayed groups, respectively (difference, -5.4%; 95% confidence interval -13.7 to 2.8). At day 84, P. vivax parasitemia was observed in 36 (34.3%) and 17 (17.5%; difference -16.8%, -28.6 to -6.1)., Conclusion: Ultra-short high-dose PQ was safe and tolerated without severe adverse events. Early treatment was non-inferior to delayed treatment in preventing P. vivax infection at day 42., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Ethiopia rolled out primaquine nationwide in 2018 for radical cure along with chloroquine for the treatment of uncomplicated Plasmodium vivax malaria in its bid for malaria elimination by 2030. The emergence of anti-malarial drug resistance would challenge the elimination goal. There is limited evidence on the emergence of chloroquine drug resistance. The clinical and parasitological outcomes of treatment of P. vivax with chloroquine plus radical cure using low dose 14 days primaquine were assessed in an endemic area of Ethiopia., Methods: A semi-directly observed 42-days follow up in-vivo therapeutic efficacy study was conducted from October 2019 to February 2020. Plasmodium vivax mono-species infected patients (n = 102) treated with a 14 days low dose (0.25 mg/kg body weight per day) primaquine plus chloroquine (a total dose of 25 mg base/kg for 3 days) were followed for 42 days to examine clinical and parasitological outcomes. Samples collected at recruitment and days of recurrence were examined by 18 S based nested polymerase chain reaction (nPCR) and Pvmsp3α nPCR-restriction fragment length polymorphism. Asexual parasitaemia and the presence of gametocytes were assessed on the scheduled days using microscopy. Clinical symptoms, haemoglobin levels, and Hillmen urine test were also assessed., Results: Of the 102 patients followed in this study, no early clinical and parasitological failure was observed. All patients had adequate clinical and parasitological responses within the 28 days of follow up. Late clinical (n = 3) and parasitological (n = 6) failures were observed only after day 28. The cumulative incidence of failure was 10.9% (95% confidence interval, 5.8-19.9%) on day 42. Among the paired recurrent samples, identical clones were detected only in two samples on day 0 and day of recurrences (day 30 and 42) using Pvmsp3α genotyping. No adverse effect was detected related to the low dose 14 days primaquine administrations., Conclusion: Co-administration of CQ with PQ in the study area is well tolerated and there was no recurrence of P. vivax before 28 days of follow up. Interpretation of CQ plus PQ efficacy should be done with caution especially when the recurrent parasitaemia occurs after day 28. Therapeutic efficacy studies with appropriate design might be informative to rule out chloroquine or primaquine drug resistance and/or metabolism in the study area., (© 2023. The Author(s).)

The discovery of new effective and safe antimalarial drugs is mandatory. In this report, we formulate and evaluate transdermal (td) 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the Plasmodium berghei rodent malaria parasite in vivo model. The selected solvent for the ointment type of td N-89 was polyethylene glycol (PEG) [PEG400:PEG 4000 = 8:1 (v/w)]. We tested different application areas of 4, 6, and 8 cm 2 on the shaved backs of mice. Pharmacokinetic (PK) analysis of N-89 parameters after a single 4 cm 2 transdermal application revealed that the T max was 2 h, the T 1/2 was 1.9 h, and the AUC was 1951.1 ng . h/mL. More than 10 ng/mL of plasma concentration was maintained for 12 h. The ED 50 values for the 4, 6, and 8 cm 2 application areas in a 4-day suppressive test were 18.9, 25.1, and 26.8 mg/kg, respectively. We additionally tested the cure effect of td N-89 in mice at a dose of 60 mg/kg, twice daily for 4 days at 0.2% parasitemia. Parasites disappeared following day 7 post-treatment in all td N-89 treated groups. Mice were cured without any parasite recurrence or dermal irritation. In conclusion, this study determined for the first time the PK parameters and effect of a new ointment type of td N-89. This suggests that transdermal treatment with N-89 is an effective and safe alternative route for the treatment of malaria, especially in children., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Malaria continues to be a global public health problem considering the number of cases and death rate worldwide. There were no domestic cases reported from our country in the World Health Organization 2021 malaria report. All the 200-250 annual cases reported from our country have a history of travel to the endemic region. In this report, three malaria cases caused by Plasmodium falciparum and Plasmodium vivax in Kayseri province without a history of travel to the endemic region were presented. The first case was an 18-year-old male patient with no known chronic disease. He admitted to the hospital with the complaint of high fever reaching 40°C, which continued for two days, increased with chills and decreased with sweating. Physical examination revealed hepatosplenomegaly and laboratory results revealed thrombocytopenia. Species identification was made by real-time polymerase chain reaction (Rt-PCR) method in the patient with ring-shaped trophozoites in the peripheral smear. Artemether-lumefantrine and primaquine treatments were given to the patient with mixed parasitemia of P.falciparum and P.vivax. One and two days after the admission, the second and third cases also admitted with similar complaints. Mixed parasitemia was observed in all three patients who did not have a history of traveling abroad. After the antiparasitic treatment, the patients improved clinically and laboratory, and no recurrent parasitemia was observed. With the occurrence of these cases, efforts to combat vectors were initiated throughout the province. In conclusion, the presence of anopheles mosquitoes and imported cases still poses a risk for domestic malaria cases. In patients who do not have a history of traveling abroad, malaria should be considered in the clinical preliminary diagnosis and species identification should be made by methods such as Rt-PCR in order to give appropriate treatments.

Background: Assessing the infectious reservoir is critical in malaria control and elimination strategies. We conducted a longitudinal epidemiological study in a high-malaria-burden region in Kenya to characterize transmission in an asymptomatic population., Methods: 488 study participants encompassing all ages in 120 households within 30 clusters were followed for 1 year with monthly sampling. Malaria was diagnosed by microscopy and molecular methods. Transmission potential in gametocytemic participants was assessed using direct skin and/or membrane mosquito feeding assays, then treated with artemether-lumefantrine. Study variables were assessed using mixed-effects generalized linear models., Results: Asexual and sexual parasite data were collected from 3792 participant visits, with 903 linked with feeding assays. Univariate analysis revealed that the 6-11-year-old age group was at higher risk of harboring asexual and sexual infections than those <6 years old (odds ratio [OR] 1.68, P < .001; and OR 1.81, P < .001), respectively. Participants with submicroscopic parasitemia were at a lower risk of gametocytemia compared with microscopic parasitemia (OR 0.04, P < .001), but they transmitted at a significantly higher rate (OR 2.00, P = .002). A large proportion of the study population who were infected at least once remained infected (despite treatment) with asexual (71.7%, 291/406) or sexual (37.4%, 152/406) parasites. 88.6% (365/412) of feeding assays conducted in individuals who failed treatment the previous month resulted in transmissions., Conclusions: Individuals with asymptomatic infection sustain the transmission cycle, with the 6-11-year age group serving as an important reservoir. The high rates of artemether-lumefantrine treatment failures suggest surveillance programs using molecular methods need to be expanded for accurate monitoring and evaluation of treatment outcomes., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: The incidence of zoonotic Plasmodium knowlesi infections in humans is rising in Southeast Asia, leading to clinical studies to monitor the efficacy of anti-malarial treatments for knowlesi malaria. One of the key outcomes of anti-malarial drug efficacy is parasite clearance. For Plasmodium falciparum, parasite clearance is typically estimated using a two-stage method, that involves estimating parasite clearance for individual patients followed by pooling of individual estimates to derive population estimates. An alternative approach is Bayesian hierarchical modelling which simultaneously analyses all parasite-time patient profiles to determine parasite clearance. This study compared these methods for estimating parasite clearance in P. knowlesi treatment efficacy studies, with typically fewer parasite measurements per patient due to high susceptibility to anti-malarials., Methods: Using parasite clearance data from 714 patients with knowlesi malaria and enrolled in three trials, the Worldwide Antimalarial Resistance Network (WWARN) Parasite Clearance Estimator (PCE) standard two-stage approach and Bayesian hierarchical modelling were compared. Both methods estimate the parasite clearance rate from a model that incorporates a lag phase, slope, and tail phase for the parasitaemia profiles., Results: The standard two-stage approach successfully estimated the parasite clearance rate for 678 patients, with 36 (5%) patients excluded due to an insufficient number of available parasitaemia measurements. The Bayesian hierarchical estimation method was applied to the parasitaemia data of all 714 patients. Overall, the Bayesian method estimated a faster population mean parasite clearance (0.36/h, 95% credible interval [0.18, 0.65]) compared to the standard two-stage method (0.26/h, 95% confidence interval [0.11, 0.46]), with better model fits (compared visually). Artemisinin-based combination therapy (ACT) is more effective in treating P. knowlesi than chloroquine, as confirmed by both methods, with a mean estimated parasite clearance half-life of 2.5 and 3.6 h, respectively using the standard two-stage method, and 1.8 and 2.9 h using the Bayesian method., Conclusion: For clinical studies of P. knowlesi with frequent parasite measurements, the standard two-stage approach (WWARN's PCE) is recommended as this method is straightforward to implement. For studies with fewer parasite measurements per patient, the Bayesian approach should be considered. Regardless of method used, ACT is more efficacious than chloroquine, confirming the findings of the original trials., (© 2023. The Author(s).)

Maternal malaria and infections during pregnancy are risk factors for fetal growth restriction. We assessed the impact of preventive treatment in pregnancy on maternal malaria and fetal growth. Between 2003 and 2006, we enrolled 1,320 pregnant Malawian women, 14-26 gestation weeks, in a randomized trial and treated them with two doses of sulfadoxine-pyrimethamine (SP, control) at enrollment and between 28-34 gestation weeks; with monthly SP from enrollment until 37 gestation weeks; or with monthly SP and azithromycin twice, at enrollment and between 28 and 34 gestation weeks (AZI-SP). Participants were seen at 4-week intervals until 36 completed gestation weeks and weekly thereafter. At each visit, we collected dried blood spots for real-time polymerase chain reaction diagnosing of malaria parasitemia and, in a random subgroup of 341 women, we measured fetal biparietal diameter and femur length with ultrasound. For the monthly SP versus the control group, the odds ratios (OR) (95% CI) of malaria parasitemia during the second, third, and both trimesters combined were 0.79 (0.46-1.37), 0.58 (0.37-0.92), and 0.64 (0.42-0.98), respectively. The corresponding ORs for the AZI-SP versus control group were 0.47 (0.26-0.84), 0.51 (0.32-0.81), and 0.50 (0.32-0.76), respectively. Differences between the AZI-SP and the monthly SP groups were not statistically significant. The interventions did not affect fetal biparietal diameter and femur length growth velocity. The results suggest that preventive maternal treatment with monthly SP reduced malaria parasitemia during pregnancy in Malawi and that the addition of azithromycin did not provide much additional antimalarial effect.