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Background: Cardiovascular events following anti-malarial treatment are reported infrequently; only a few studies have reported adverse outcomes. This case presentation emphasizes cardiological assessment of Brugada syndrome, presenting as life-threatening arrhythmia during anti-malarial treatment. Without screening and untreated, this disease may lead to sudden cardiac death. Case presentation: This is a case of 23-year-old male who initially presented with palpitations followed by syncope and shortness of breath with a history of malaria. He had switched treatment from quinine to dihydroartemisinin-piperaquine (DHP). Further investigations revealed the ST elevation electrocardiogram pattern typical of Brugada syndrome, confirmed with flecainide challenge test. Subsequently, anti-malarial treatment was stopped and an Implantable Cardioverter Defibrillator (ICD) was inserted. Conclusions: Another possible cause of arrhythmic events happened following anti-malarial consumption. This case highlights the possibility of proarrhytmogenic mechanism of malaria infection and anti-malarial drug resulting in typical manifestations of Brugada syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiovascular events following anti-malarial treatment are reported infrequently; only a few studies have reported adverse outcomes. This case presentation emphasizes cardiological assessment of Brugada syndrome, presenting as life-threatening arrhythmia during anti-malarial treatment. Without screening and untreated, this disease may lead to sudden cardiac death. Case presentation This is a case of 23-year-old male who initially presented with palpitations followed by syncope and shortness of breath with a history of malaria. He had switched treatment from quinine to dihydroartemisinin-piperaquine (DHP). Further investigations revealed the ST elevation electrocardiogram pattern typical of Brugada syndrome, confirmed with flecainide challenge test. Subsequently, anti-malarial treatment was stopped and an Implantable Cardioverter Defibrillator (ICD) was inserted. Conclusions Another possible cause of arrhythmic events happened following anti-malarial consumption. This case highlights the possibility of proarrhytmogenic mechanism of malaria infection and anti-malarial drug resulting in typical manifestations of Brugada syndrome.

The influence of micellar systems based on cationic surfactants—gadolinium(III) and copper(II) complexes with alkylated 1,4-diazabicyclo[2.2.2]octane, 1-hexadecyl-4-aza-1-azoniabicyclo[2.2.2]octane bromide (ligand) and the conventional surfactant cetyltrimethylammonium bromide – on the solubility of the antimalarial drug artemisinin in water was studied by spectrophotometric method. A quantitative assessment of the solubilizing ability of surfactant aggregates was carried out. The value of the solubilization capacity of the systems was determined. The ligand has the greatest influence on the solubility of artemisinin, and, consequently, its bioavailability. The concentration of the drug increases up to 36 times in the presence of a relatively low surfactant content in the aqueous solution. The period of chemical stability of artemisinin in cationic surfactants solutions was determined. Aggregates formed in surfactant-artemisinin systems were characterized by dynamic and electrophoretic light scattering. [ABSTRACT FROM AUTHOR]

The public health care system is currently facing a major problem with malaria. Globally, malarial deaths have decreased by an estimated 40% in the past two decades because of the clinically effective drugs (artemisinin-based combination therapies) against Plasmodium falciparum. In recent years, P falciparum develop resistance against all antimalarial drugs and then becomes developed multidrug resistance that a major challenge. Even though drug discovery programs have made substantial progress in the past decade, the potential for new drugs/combinations to improve the effectiveness of current malaria control strategies. Beyond, we have compiled a comprehensive review of clinically approved anti-malarial drugs with resistance mechanisms and a novel drug-resistance reversal approach in one place to meet this demand. The review aimed to provide detailed information on drug resistance, its regulatory molecular mechanisms responsible for resistance, and the novel available treatment of malaria. In this review, the article will help in developing effective interventions, potential approaches, and strategies to handle antimalarial resistance. This will prevent life-threatening infections. [ABSTRACT FROM AUTHOR]

Simple Summary: This study is focused on exploring the anticancer properties of proguanil, an old antimalarial drug. Proguanil demonstrated a significant ability to induce cell death through the increased production of reactive oxygen species (ROS) and subsequent disruption in mitochondrial function in breast cancer cells. In several breast cancer cell lines and mouse tumor models, proguanil showed promising results by inhibiting tumor growth and altering key proteins associated with cancer progression. These findings suggest that proguanil could be a promising candidate for further clinical investigation as a potential treatment option for breast cancer. Breast cancer, ranking as the second leading cause of female cancer-related deaths in the U.S., demands the exploration of innovative treatments. Repurposing FDA-approved drugs emerges as an expedited and cost-effective strategy. Our study centered on proguanil, an antimalarial drug, reveals notable anti-proliferative effects on diverse breast cancer cell lines, including those derived from patients. Proguanil-induced apoptosis was associated with a substantial increase in reactive oxygen species (ROS) production, leading to reduced mitochondrial membrane potential, respiration, and ATP production. Proguanil treatment upregulated apoptotic markers (Bax, p-H2AX, cleaved-caspase 3, 9, cleaved PARP) and downregulated anti-apoptotic proteins (bcl-2, survivin) in breast cancer cell lines. In female Balb/c mice implanted with 4T1 breast tumors, daily oral administration of 20 mg/kg proguanil suppressed tumor enlargement by 55%. Western blot analyses of proguanil-treated tumors supported the in vitro findings, demonstrating increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 as compared to controls. Our results collectively highlight proguanil's anticancer efficacy in vitro and in vivo in breast cancer, prompting further consideration for clinical investigations. [ABSTRACT FROM AUTHOR]

Mefloquine (MQ) is a quinoline-based anti-malarial drug used for chemoprophylaxis or as a treatment in combination with artesunate. Although MQ has clear anti-Plasmodium falciparum properties, it can induce neurotoxicity and undesired neuropsychiatric side effects in humans. Hence, this study aimed to characterize the neurotoxicity of MQ using human neuroblastoma SH-SY5Y cells. The effects of MQ on neuronal toxicity and cell viability were investigated over a concentration range of 1–100 µM using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The influence of MQ on cellular bioenergetics was examined by measuring cellular ATP levels and from the induction of reactive oxygen species (ROS). An in silico approach was used to assess the potential neurotoxicity of MQ mediated via binding to the active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and then experimentally validated via in vitro enzymatic assays. MQ was cytotoxic to neuronal cells in a concentration and exposure duration dependent manner and induced a significant reduction in viability at concentrations of ≥25 µM after a 24 h exposure. MQ adversely impacted cellular bioenergetics and significantly depleted ATP production at concentrations of ≥1 µM after 24 h. MQ-induced cellular ROS production, which was correlated with the induction of apoptosis, as revealed by flow cytometry. In silico studies suggested that MQ was a dual cholinesterase inhibitor and one with remarkably potent binding to BuChE. Modelling data were supported by in vitro studies which showed that MQ inhibited both human AChE and BuChE enzymes. In summary, MQ is an antimalarial drug that may induce neurotoxicity by impacting cellular bioenergetics and perturbing the activity of cholinesterases at exposure concentrations relevant to human dosage. [ABSTRACT FROM AUTHOR]

Background: Malaria has always been a serious infectious disease prevalent in the world. Antimalarial drugs such as chloroquine and artemisinin have been the main compounds used to treat malaria. However, the massive use of this type of drugs accelerates the evolution and spread of malaria parasites, leading to the development of resistance. A large number of related data have been published by researchers in recent years. CiteSpace software has gained popularity among us researchers in recent years, because of its ability to help us obtain the core information we want in a mass of articles. In order to analyze the hotspots and develop trends in this field through visual analysis, this study used CiteSpace software to summarize the available data in the literature to provide insights. Method: Relevant literature was collected from the Web of Science Core Collection (WOSCC) from 1 January 2015 to 29 March 2023. CiteSpace software and Microsoft Excel were used to analyze and present the data, respectively. Results: A total of 2,561 literatures were retrieved and 2,559 literatures were included in the analysis after the removal of duplicates. An irrefutable witness of the ever-growing interest in the topic of antimalarial drug resistance could be expressed by the exponentially increased number of publications and related citations from 2015 to 2022, and its sustained growth trend by 2023. During the past 7 years, USA, Oxford University, and David A Fidock are the country, institution, and author with the most publications in this field of research, respectively. We focused on the references and keywords from literature and found that the research and development of new drugs is the newest hotspot in this field. A growing number of scientists are devoted to finding new antimalarial drugs. Conclusion: This study is the first visual metrological analysis of antimalarial drug resistance, using bibliometric methods. As a baseline information, it is important to analyze research output published globally on antimalarial drug resistance. In order to better understand the current research situation and future research plan agenda, such baseline data are needed accordingly. [ABSTRACT FROM AUTHOR]

Aims: Calmodulin (CaM) is vital for the survival of Plasmodium knowlesi, a simian malaria parasite that infects both macaques and humans in Southeast Asia. To advance antimalarial drugs development targeting this protein, it is imperative to produce ample quantities of pure CaM for further research. Hence, this study aims to establish a robust strategy for the heterologous expression and purification of CaM from Plasmodium knowlesi (Pk-CaM). Methodology and results: First, we optimised the gene sequence of Pk-CaM for Escherichia coli expression, chemically synthesised it and integrated it into the pET28a plasmid. The optimised gene displayed a 45.15% GC content and a 0.81 codon-adaptation index, making it highly compatible with E. coli. Pk-CaM expression was assessed under various conditions, with the best results achieved at a post-induction temperature of 20 °C for 16 h, yielding a fully soluble protein. Subsequently, we purified the protein using Ni2+ -NTA affinity chromatography and size-exclusion chromatography (SEC), obtaining 15 mg from 1 L of culture. The folding properties of purified Pk-CaM were analysed using far-UV circular dichroism (CD) spectroscopy, revealing a predominance of helical structures, both with and without Ca2+ ions. Binding to Ca2+ ions induced structural changes, increasing the helical content compared to when Ca2+ ions were absent. Conclusion, significance and impact of study: The optimal conditions for the recombinant expression and purification of Pk-CaM in a correctly folded and functional form were successfully established in this study. This achievement provides a solid foundation for conducting further comprehensive research in the pursuit of novel antimalarial drugs. [ABSTRACT FROM AUTHOR]

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.

BackgroundMalaria has always been a serious infectious disease prevalent in the world. Antimalarial drugs such as chloroquine and artemisinin have been the main compounds used to treat malaria. However, the massive use of this type of drugs accelerates the evolution and spread of malaria parasites, leading to the development of resistance. A large number of related data have been published by researchers in recent years. CiteSpace software has gained popularity among us researchers in recent years, because of its ability to help us obtain the core information we want in a mass of articles. In order to analyze the hotspots and develop trends in this field through visual analysis, this study used CiteSpace software to summarize the available data in the literature to provide insights.MethodRelevant literature was collected from the Web of Science Core Collection (WOSCC) from 1 January 2015 to 29 March 2023. CiteSpace software and Microsoft Excel were used to analyze and present the data, respectively.ResultsA total of 2,561 literatures were retrieved and 2,559 literatures were included in the analysis after the removal of duplicates. An irrefutable witness of the ever-growing interest in the topic of antimalarial drug resistance could be expressed by the exponentially increased number of publications and related citations from 2015 to 2022, and its sustained growth trend by 2023. During the past 7 years, USA, Oxford University, and David A Fidock are the country, institution, and author with the most publications in this field of research, respectively. We focused on the references and keywords from literature and found that the research and development of new drugs is the newest hotspot in this field. A growing number of scientists are devoted to finding new antimalarial drugs.ConclusionThis study is the first visual metrological analysis of antimalarial drug resistance, using bibliometric methods. As a baseline information, it is important to analyze research output published globally on antimalarial drug resistance. In order to better understand the current research situation and future research plan agenda, such baseline data are needed accordingly.

The relevance of the subject matter is conditioned by the constantly growing need to meet human needs in the field of medicine, in particular, the search, study, and further introduction of new types of medicines into practical use. The purpose of this study is to investigate the synthesis of modified quinine alkaloid derivatives, and their structure, to identify the properties and biological activity of antimalarial drugs based on quinine molecules, and to structure the general data of these substances. The leading approach is the analysis of the synthesis of quinine derivatives, their chemical and physical properties, and their ability to exert a medicinal effect. The abstracting method allows structuring alkaloid derivatives and establishing a general relationship between the structural configuration of molecules and their impact on human health in a number of related derivatives. The study identifies the main antimalarial drugs based on quinine molecules, including a comparative analysis of their effectiveness and overall biological activity.

Malaria is a significant cause of death in numerous countries, and the discovery of effective drugs is crucial. In this research, a new method was employed to synthesize a derivative of aryl amino alcohol using eugenol. Initially, an epoxide compound called 2-methoxy-4-(oxiran-2-ylmethyl) phenol was synthesized from eugenol by reacting it with peroxyacetic acid in dichloromethane. Subsequently, the epoxide compound was subjected to a reaction with various amine compounds, including aniline, naphthylamine, and diphenylamine for 10 minutes under 100 W microwave conditions, resulting in the production of three derivative compounds of aryl amino alcohol. The antimalarial activity of these synthesized compounds was assessed in-vitro through an assay called heme polymerization inhibition activity (HPIA). Additionally, an in-silico analysis was conducted to evaluate the bioactivity of the three aryl amino alcohol derivatives by performing molecular docking with the Plasmepsin II enzyme. The identification of the products were determined using Fourier Transform Infrared (FTIR) spectrophotometry, proton nuclear magnetic resonance (1HNMR) spectrometry, and Electrospray ionization-Mass Spectrometry (ESI-MS). The research successfully obtained three aryl amino alcohol derivatives: 2-hydroxy-3-(phenylamino) propyl)-2-methoxyphenol, 4-(2-hydroxy-3-(naphthalene-1-ylamino) propyl)-2-methoxyphenol, and 4-(2-hydroxy-3-(diphenylamine)-2-methoxy phenol. All the synthesized compounds demonstrated lower IC50 values compared to chloroquine, indicating their potential as antimalarial drugs. Molecular docking studies revealed that these aryl amino alcohol derivatives effectively inhibited the activity of the Plasmepsin II enzyme. [ABSTRACT FROM AUTHOR]

Malaria is a potentially fatal disease caused by protozoan parasites of the genus Plasmodium. It is responsible for significant morbidity and mortality in endemic countries of the tropical and subtropical world, particularly in Africa, Southeast Asia, and South America. It is estimated that 247 million malaria cases and 619,000 deaths occurred in 2021 alone. The World Health Organization's (WHO) global initiative aims to reduce the burden of disease but has been massively challenged by the emergence of parasitic strains resistant to traditional and emerging antimalarial therapy. Therefore, development of new antimalarial drugs with novel mechanisms of action that overcome resistance in a safe and efficacious manner is urgently needed. Based on the evolving understanding of the physiology of Plasmodium, identification of potential targets for drug intervention has been made in recent years, resulting in more than 10 unique potential anti-malaria drugs added to the pipeline for clinical development. This review article will focus on current therapies as well as novel targets and therapeutics against malaria. [ABSTRACT FROM AUTHOR]

Methylene blue (MB) is an alternative for combating drug-resistant malaria parasites. Its transmission-blocking potential has been demonstrated in vivo in murine models, in vitro, and in clinical trials. MB shows high efficacy against Plasmodium vivax asexual stages; however, its efficacy in sexual stages is unknown. In this study, we evaluated the potential of MB against asexual and sexual forms of P. vivax isolated from the blood of patients residing in the Brazilian Amazon. An ex vivo schizont maturation assay, zygote to ookinete transformation assay, direct membrane feed assay (DMFA), and standard membrane feed assay (SMFA) using P. vivax gametocytes with MB exposure were performed. A cytotoxicity assay was also performed on freshly collected peripheral blood mononuclear cells (PBMCs) and the hepatocyte carcinoma cell line HepG2. MB inhibited the P. vivax schizont maturation and demonstrated an IC50 lower than that of chloroquine (control drug). In the sexual forms, the MB demonstrated a high level of inhibition in the transformation of the zygotes into ookinetes. In the DMFA, MB did not considerably affect the infection rate and showed low inhibition, but it demonstrated a slight decrease in the infection intensity in all tested concentrations. In contrast, in the SMFA, MB was able to completely block the transmission at the highest concentration (20 μM). MB demonstrated low cytotoxicity to fresh PBMCs but demonstrated higher cytotoxicity to the hepatocyte carcinoma cell line HepG2. These results show that MB may be a potential drug for vivax malaria treatment. [ABSTRACT FROM AUTHOR]

This study describes the use of copper nanoparticles (CuNPs) and reduced graphene oxide (rGO) as an electrode modifier for the determination of chloroquine phosphate (CQP). The synthetized rGO-CuNPs composite was morphologically characterized using scanning electron microscopy and electrochemically characterized using cyclic voltammetry. The parameters were optimized and the developed electrochemical sensor was applied in the determination of CQP using square-wave voltammetry (SWV). The analytical range for the determination of CQP was 0.5 to 110 μmol L−1 (one of the highest linear ranges for CQP considering electrochemical sensors), with limits of detection and quantification of 0.23 and 0.78 μmol L−1, respectively. Finally, the glassy carbon (GC) electrode modified with rGO-CuNPs was used for quantification of CQP in tap water; a study was carried out with interferents using SWV and obtained great results. The use of rGO-CuNP material as an electrode modifier was thus shown to be a good alternative for the development of low-cost devices for CQP analysis. [ABSTRACT FROM AUTHOR]

Mefloquine (MQ) is a quinoline-based anti-malarial drug used for chemoprophylaxis or as a treatment in combination with artesunate. Although MQ has clear anti-Plasmodium falciparum properties, it can induce neurotoxicity and undesired neuropsychiatric side effects in humans. Hence, this study aimed to characterize the neurotoxicity of MQ using human neuroblastoma SH-SY5Y cells. The effects of MQ on neuronal toxicity and cell viability were investigated over a concentration range of 1–100 µM using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The influence of MQ on cellular bioenergetics was examined by measuring cellular ATP levels and from the induction of reactive oxygen species (ROS). An in silico approach was used to assess the potential neurotoxicity of MQ mediated via binding to the active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and then experimentally validated via in vitro enzymatic assays. MQ was cytotoxic to neuronal cells in a concentration and exposure duration dependent manner and induced a significant reduction in viability at concentrations of ≥25 µM after a 24 h exposure. MQ adversely impacted cellular bioenergetics and significantly depleted ATP production at concentrations of ≥1 µM after 24 h. MQ-induced cellular ROS production, which was correlated with the induction of apoptosis, as revealed by flow cytometry. In silico studies suggested that MQ was a dual cholinesterase inhibitor and one with remarkably potent binding to BuChE. Modelling data were supported by in vitro studies which showed that MQ inhibited both human AChE and BuChE enzymes. In summary, MQ is an antimalarial drug that may induce neurotoxicity by impacting cellular bioenergetics and perturbing the activity of cholinesterases at exposure concentrations relevant to human dosage.

Methylene blue (MB) is an alternative for combating drug-resistant malaria parasites. Its transmission-blocking potential has been demonstrated in vivo in murine models, in vitro, and in clinical trials. MB shows high efficacy against Plasmodium vivax asexual stages; however, its efficacy in sexual stages is unknown. In this study, we evaluated the potential of MB against asexual and sexual forms of P. vivax isolated from the blood of patients residing in the Brazilian Amazon. An ex vivo schizont maturation assay, zygote to ookinete transformation assay, direct membrane feed assay (DMFA), and standard membrane feed assay (SMFA) using P. vivax gametocytes with MB exposure were performed. A cytotoxicity assay was also performed on freshly collected peripheral blood mononuclear cells (PBMCs) and the hepatocyte carcinoma cell line HepG2. MB inhibited the P. vivax schizont maturation and demonstrated an IC50 lower than that of chloroquine (control drug). In the sexual forms, the MB demonstrated a high level of inhibition in the transformation of the zygotes into ookinetes. In the DMFA, MB did not considerably affect the infection rate and showed low inhibition, but it demonstrated a slight decrease in the infection intensity in all tested concentrations. In contrast, in the SMFA, MB was able to completely block the transmission at the highest concentration (20 µM). MB demonstrated low cytotoxicity to fresh PBMCs but demonstrated higher cytotoxicity to the hepatocyte carcinoma cell line HepG2. These results show that MB may be a potential drug for vivax malaria treatment.

The pharmacological treatment of systemic lupus erythematosus (SLE) aims to decrease disease activity, progression, systemic compromise, and mortality. Among the pharmacological alternatives, there are chemically synthesized drugs whose efficacy has been evaluated, but which have the potential to generate adverse events that may compromise adherence and response to treatment. Therapy selection and monitoring will depend on patient characteristics and the safety profile of each drug. The aim of this review is to provide a comprehensive understanding of the most important synthetic drugs used in the treatment of SLE, including the current treatment options (mycophenolate mofetil, azathioprine, and cyclophosphamide), review their mechanism of action, efficacy, safety, and, most importantly, provide monitoring parameters that should be considered while the patient is receiving the pharmacotherapy. [ABSTRACT FROM AUTHOR]

In this study, an electrochemical sensor towards the determination of an antimalarial drug, amodiaquine (Adqn), was performed. The proposed sensor was fabricated by electro-polymerisation of calcein (CCN) onto pencil graphite electrode (PGE). The electrochemical behaviour of 0.40 mM Adqn at both poly(calcein)-modified pencil graphite electrode (poly(CCN)/PGE) and bare PGE was evaluated in pH 3.0 Britton–Robinson buffer solution by cyclic voltammetry (CV) method. The voltammograms indicated that poly(CCN)/PGE presents a remarkable response towards oxidation and reduction of Adqn compared with PGE. The characterisation studies at poly(CCN)/PGE were performed by recording the electrochemical impedance curves, scanning electron microscopy images and energy-dispersive X-ray spectra. To determine the analytical performance of the poly(CCN)/PGE, the parameters such as linear range, limit of detection and sensitivity were determined based on the oxidation of Adqn by differential pulse voltammetry (DPV) method and were calculated to be 0.50–25 µM, 0.16 µM and 20.566 µA µM−1, respectively. The recovery studies at poly(CCN)/PGE were carried out with various matrixes (tap water, artificial blood and maternal milk) by DPV-spike methods, and the high recovery values (99.2–100.6%) confirmed that poly(CCN)/PGE can be used towards sensitive and accurate determination of Adqn in different sample matrixes containing Adqn. [ABSTRACT FROM AUTHOR]

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

Abstract Background Plasmodium vivax remains the predominant species at the China–Myanmar border, imposing a major challenge to the recent gains in regional malaria elimination. To closely supervise the emerging of drug resistance in this area, we surveyed the variations in genes potentially correlated with drug resistance in P. vivax parasite and the possible drug selection with time. Methods A total of 235 P. vivax samples were collected from patients suffering uncomplicated malaria at Yingjiang, Tengchong, and Longling counties, and Nabang port in China, Yunnan province, and Laiza sub-township in Myanmar, from 2008 to 2017. Five potential drug resistance genes were amplified utilizing nested-PCR and analyzed, including pvdhfr, pvdhps, pvmdr1, pvcrt-o, and pvk12. The Pearson’s Chi-squared test or Fisher’s exact test were applied to determine the statistical frequency differences of mutations between categorical data. Results The pvdhfr F57I/L, S58R, T61M and S117T/N presented in 40.6%, 56.7%, 40.1%, and 56.0% of the sequenced P. vivax isolates, and these mutations significantly decreased with years. The haplotype formed by these quadruple mutations predominated in Yingjiang, Tengchong, Longling and Nabang. While a mutation H99S/R (56.6%) dominated in Laiza and increased with time. In pvdhps, the A383G prevailed in 69.2% of the samples, which remained the most prevalent haplotype. However, a significant decrease of its occurrence was also noticed over the time. The S382A/C and A553G existed in 8.4% and 30.8% of the isolates, respectively. In pvmdr1, the mutation Y976F occurred at a low frequency in 5/232 (2.2%), while T958M was fixed and F1076L was approaching fixed (72.4%). The K10 insertion was detected at an occurrence of 33.2% in pvcrt-o, whereas there was no significant difference among the sites or over the time. No mutation was identified in pvk12. Conclusions Mutations related with resistance to antifolate drugs are prevalent in this area, while their frequencies decrease significantly with time, suggestive of increased susceptibility of P. vivax parasite to antifolate drugs. Resistance to chloroquine (CQ) is possibly emerging. However, since the molecular mechanisms underneath CQ resistance is yet to be better understood, close supervision of clinical drug efficiency and continuous function investigation is urgently needed to alarm drug resistance. Graphical abstract

Abstract Background The development of novel malaria vaccines and antimalarial drugs is limited partly by emerging challenges to conduct field trials in malaria endemic areas, including unknown effects of existing immunity and a reported fall in malaria incidence. As a result, Controlled Human Malaria Infection (CHMI) has become an important approach for accelerated development of malarial vaccines and drugs. We conducted a systematic review of the literature to establish aggregate evidence on the reproducibility of a malaria sporozoite challenge model. Methods A systematic review of research articles published between 1990 and 2018 on efficacy testing of malaria vaccines and drugs using sporozoite challenge and sporozoite infectivity studies was conducted using Pubmed, Scopus, Embase and Cochrane Library, ClinicalTrials.gov and Trialtrove. The inclusion criteria were randomized and non-randomized, controlled or open-label trials using P. falciparum or P. vivax sporozoite challenges. The data were extracted from articles using standardized data extraction forms and descriptive analysis was performed for evidence synthesis. The endpoints considered were infectivity, prepatent period, parasitemia and safety of sporozoite challenge. Results Seventy CHMI trials conducted with a total of 2329 adult healthy volunteers were used for analysis. CHMI was induced by bites of mosquitoes infected with P. falciparum or P. vivax in 52 trials and by direct venous inoculation of P. falciparum sporozoites (PfSPZ challenge) in 18 trials. Inoculation with P. falciparum-infected mosquitoes produced 100% infectivity in 40 studies and the mean/median prepatent period assessed by thick blood smear (TBS) microscopy was ≤ 12 days in 24 studies. On the other hand, out of 12 infectivity studies conducted using PfSPZ challenge, 100% infection rate was reproduced in 9 studies with a mean or median prepatent period of 11 to 15.3 days as assessed by TBS and 6.8 to 12.6 days by PCR. The safety profile of P. falciparum and P.vivax CHMI was characterized by consistent features of malaria infection. Conclusion There is ample evidence on consistency of P. falciparum CHMI models in terms of infectivity and safety endpoints, which supports applicability of CHMI in vaccine and drug development. PfSPZ challenge appears more feasible for African trials based on current evidence of safety and efficacy.

In this study, the electrochemical determination of the amodiaquine (ADQ) drug was evaluated using an electrochemically pretreated boron-doped diamond (BDD) electrode due to the enhanced surface activity. The cyclic voltammogram results of ADQ were given as single reversible and diffusion-controlled peaks at +0.48 V for the oxidation peak and +0.05 V for the reduction peak (vs. Ag/AgCl) in Britton-Robinson (BR) buffer at pH 8.0. The peak potential and current signals of ADQ were evaluated at the surface of the BDD electrode using instrumental parameters to develop a simple method for ADQ detection. Also, the effect of an anionic surfactant, sodium dodecyl sulfate (SDS), on the adsorption applicability of the BDD electrode significantly increased the stripping voltammetric determination of ADQ. Under the optimal conditions chosen and employing square-wave adsorptive stripping voltammetry at the BDD electrode, ADQ was determined at + 0.34 V (vs. Ag/AgCl) at the open-circuit condition in BR buffer at pH 8.0 in the presence of 2·10–4 mol l–1 SDS. Furthermore, analytical parameters showed the linear relationship for ADQ determination in the concentration range of 0.1–20.0 μg ml–1 (2.2·10–7 – 4.3·10–5 mol l–1), with a detection limit of 0.03 μg ml–1 (6.5·10–8 mol l–1). The proposed approach can be applied to determine ADQ in water samples.

With the emergence of chloroquine resistance, Artemisinin Combination Therapy use was advocated for by the WHO and this has been fully adopted by Nigeria for treating malaria due to P. falciparum infection. The present study focused on assessing the clinico-parasitological efficacy of Artemether-Lumefantrine, following the need to monitor the efficacy of ACTs as a tool for early detection of resistance. The WHO 2009 protocols for studying the efficacy of antimalarial agents were adopted. The study enrolled 75 adult patients living within Anambra state, diagnosed with falciparum malaria and met the inclusion criteria of the study. Patients were administered 6 doses of Artemether-Lumefantrine and monitored for 28days for any therapy failure or adverse events. Early treatment failure of 15.95% was recorded. Although ACPR, cure rate and parasite clearance were above 70% (76.8%, 97.10% and 80.4% respectively). The study also showed clearance of asexual stage (gametocytes) by day 3 of treatment. There was a satisfactory efficacy and safety of AL thus supporting the continued use of AL as the drug of choice for non-complicated malaria in the studied population. [ABSTRACT FROM AUTHOR]

Untreated malaria can progress rapidly to severe forms (<24 h). Moreover, resistance to antimalarial drugs is a threat to global efforts to protect people from malaria. Given this, it is clear that new chemotherapy must be developed. We contribute new data about using methylene blue (MB) to cure malaria and cerebral malaria in a combined therapy with common antimalarial drugs, including mefloquine (MQ) and amodiaquine (AQ). A C57BL6/J mouse model was used in an experimental cerebral malaria model. Mice were infected with Plasmodium berghei ANKA on Day 0 (D0) and the treatment started on D3 (nearly 1% parasitaemia) with AQ, MQ or MB alone or in combination with AQ or MQ. AQ, MQ and MB alone were unable to prevent cerebral malaria as part of a late chemotherapy. MB-based combination therapies were efficient even if treatment began at a late stage. We found a significant difference in survival rate (p < 0.0001) between MBAQ and the untreated group, but also with the AQ (p = 0.0024) and MB groups (p < 0.0001). All the infected mice treated with MB in combination with AQ were protected from cerebral malaria. Partial protection was demonstrated with MB associated with MQ. In this group, a significant difference was found between MBMQ and the untreated group (p < 0.0001), MQ (p = 0.0079) and MB (p = 0.0039). MB associated with AQ would be a good candidate for preventing cerebral malaria. [ABSTRACT FROM AUTHOR]

Malaria is a potentially fatal disease caused by protozoan parasites of the genus Plasmodium. It is responsible for significant morbidity and mortality in endemic countries of the tropical and subtropical world, particularly in Africa, Southeast Asia, and South America. It is estimated that 247 million malaria cases and 619,000 deaths occurred in 2021 alone. The World Health Organization’s (WHO) global initiative aims to reduce the burden of disease but has been massively challenged by the emergence of parasitic strains resistant to traditional and emerging antimalarial therapy. Therefore, development of new antimalarial drugs with novel mechanisms of action that overcome resistance in a safe and efficacious manner is urgently needed. Based on the evolving understanding of the physiology of Plasmodium, identification of potential targets for drug intervention has been made in recent years, resulting in more than 10 unique potential anti-malaria drugs added to the pipeline for clinical development. This review article will focus on current therapies as well as novel targets and therapeutics against malaria.

In this study, the electrochemical determination of the amodiaquine (ADQ) drug was evaluated using an electrochemically pretreated boron-doped diamond (BDD) electrode due to the enhanced surface activity. The cyclic voltammogram results of ADQ were given as single reversible and diffusioncontrolled peaks at +0.48 V for the oxidation peak and +0.05 V for the reduction peak (vs. Ag/AgCl) in Britton-Robinson (BR) buffer at pH 8.0. The peak potential and current signals of ADQ were evaluated at the surface of the BDD electrode using instrumental parameters to develop a simple method for ADQ detection. Also, the effect of an anionic surfactant, sodium dodecyl sulfate (SDS), on the adsorption applicability of the BDD electrode significantly increased the stripping voltammetric determination of ADQ. Under the optimal conditions chosen and employing square-wave adsorptive stripping voltammetry at the BDD electrode, ADQ was determined at + 0.34 V (vs. Ag/AgCl) at the open-circuit condition in BR buffer at pH 8.0 in the presence of 2·10–4 mol l–1 SDS. Furthermore, analytical parameters showed the linear relationship for ADQ determination in the concentration range of 0.1–20.0 μg ml–1 (2.2·10–7 – 4.3·10–5 mol l–1 ), with a detection limit of 0.03 μg ml–1 (6.5·10–8 mol l–1 ). The proposed approach can be applied to determine ADQ in water samples. [ABSTRACT FROM AUTHOR]

The caseinolytic protease (Clp) system plays an essential role in the protein homeostasis of the malaria parasite, particularly at the stage of apicoplast development. The inhibition of this protein is known to have a lethal effect on the parasite and is therefore considered an interesting avenue for antimalaria drugs discovery. The catalytic activity of the Clp system is modulated by its proteolytic subunit (ClpP), which belongs to the serine protease family member and is therefore extensively studied for further inhibitors development. Among many inhibitors, the group of β-lactone is known to be a specific inhibitor for ClpP. Nevertheless, other groups of lactones have never been studied. This study aims to characterize the catalytic properties of ClpP of Plasmodium knowlesi (Pk-ClpP) and the inhibition properties of a δ-lactone hyptolide against this protein. Accordingly, a codon-optimized synthetic gene encoding Pk-ClpP was expressed in Escherichia coli BL21(DE3) and purified under a single step of Ni2+-affinity chromatography, yielding a 2.20 mg from 1 L culture. Meanwhile, size-exclusion chromatography indicated that Pk-ClpP migrated primarily as homoheptameric with a size of 205 kDa. The specific activity of pure Pk-ClpP was 0.73 U µg−1, with a catalytic efficiency kcat/KM of 0.05 µM−1 s−1, with optimum temperature and pH of 50 °C and 7.0–7.5, respectively. Interestingly, hyptolide, a member of δ-lactone, was shown to inhibit Pk-ClpP with an IC50 value of 17.36 ± 1.44 nM. Structural homology modelling, secondary structure prediction, and far-UV CD spectra revealed that helical structures dominate this protein. In addition, the structural homology modeling showed that this protein forms a barrel-shaped homoheptamer. Docking simulation revealed that the inhibition was found to be a competitive inhibition in which hyptolide was able to dock into the catalytic site and block the substrate. The competitiveness of hyptolide is due to the higher binding affinity of this molecule than the substrate. [ABSTRACT FROM AUTHOR]

Anopheles stephensi mosquitoes share urban breeding sites with Aedes aegypti and Culex quinquefasciatus mosquitoes in the Republic of Djibouti. We present evidence that A. stephensi mosquitoes might be responsible for an increase in malaria incidence in this country. We also document resistance of Plasmodium falciparum to dihydroartemisinin/piperaquine.

Provision of the bed net in Sub-Saharan Africa has substantially resulted in the decrease in malaria incidences in the region. However, malaria still ravages these regions causing significant deaths. This situation has been attributed to socio-economic inequalities that reduce access to the net, failure to seek treatment, and poor antimalarial drug use. Information about these factors in malaria control in Western Kenya highlands is not clearly documented. This study sought to find out bed net availability and use, treatment-seeking, and antimalarial drug use behavior in two rural communities. The study was a qualitative-quantitative baseline cross-sectional survey carried out in two rural villages in Western Kenya highlands in November – December 2018. Focus group discussion, a semi-structured questionnaire, and in-depth interviews were conducted in 736 households to determine: socio-demographic characteristics; bed net availability and use; action taken when sick with malaria, and antimalarial drug usage. Socio-demographic characteristics and the responses of the participants were expressed as percentages. Dependent and independent variables were cross-tabulated for calculation of OR and association was tested using Pearson Chi-square at 95% CI and a p ≤ 0.05 was considered significant. Ninety-three percent of the respondents had used the net the previous night, females (56.50%) constituted the majority of respondents, going to health facility (84.26%) was the preferred action taken when a person had malaria, Artemether Lumefantrine (90.19%), and a pain killer was the most cited drug, 22.96% of the responders reported to have failed to complete antimalarial dose saying that they had recovered from the malaria bout and 9.80% reported to re-use the remaining part of the dosage. This was the first study in mining and sugarcane growing communities in Western Kenya Highlands that has shown that there was no association between socio-demographic parameters and bed net use, action taken when having malaria, and adherence to drug use. The two rural communities have the bed net and know its use. They have good knowledge of malaria and seek treatment whenever they saw malaria signs. The study also reported that the action the sick person took when they had a malaria bout, the drug they got from the health facility, or failure to complete an AL dosage regimen was not associated with socio-demographic characteristics of the responder. These findings raise the need for further qualitative studies in other settings to accept or deny that there was no association between socio-demographics and action taken when hit with malaria bout, the drug used, and failure to complete drug dosage.

[Display omitted] • Novel Dy-MOF@MWCNT composite was prepared by ultrasonication method. • Dy-MOF@MWCNT composites exhibits 60 % increment in oxidation peak current than other unmodified GC electrodes of ADD. • Result shows detection limits and sensitivity of 0.377 μM and 1.817 μA.μM−1 respectively. • The prepared sensor exhibited practical usefulness by determining the drug ADD in human urine samples. Herein, we report on fabrication of dysprosium-based metal–organic framework (Dy-MOF)@multiwalled carbon nanotubes (MWCNT) composites modified with glassy carbon electrode (Dy-MOF@MWCNT/GC) as a working electrode for Antimalarial drug detection. Dy-MOF@MWCNT composites was prepared by sonochemical process along with ultrasonication. The composite structure, phase purity, morphology and composition of the composites were confirmed by X-ray diffraction, Scanning electron microscope, and X-ray photoelectron spectroscopy. Further, Dy@MWCNT composites were deposited on a glassy carbon electrode by drop casting method, and used as an electrode material to efficiently detect Amodiaquine (ADD) by electrochemical techniques such as CV and DPV. The as-prepared Dy@MWCNT composite material showed the oxidation peak current of ADD to be ∼ 60 % higher than other unmodified GC electrodes and showed a low charge transfer resistance (R ct) of 24 Ω. The Dy@MWCNT provided a broad linear range of 0.4 to 20 µM with a limit of detection of 0.377 μM and sensitivity of 1.817 μA.μM−1 for the detection of ADD. According to the pH study, the amount of electrons and protons involved in the electrochemical processes of ADD was calculated and a plausible mechanism for ADD electro-oxidation was proposed. Thus, the prepared sensor exhibited practical usefulness by determining the ADD drug in human urine samples. Hence, the results shows that the Dy@MWCNT- modified sensor has good electrocatalytic activity for the redox of ADD. [ABSTRACT FROM AUTHOR]

This study describes the use of copper nanoparticles (CuNPs) and reduced graphene oxide (rGO) as an electrode modifier for the determination of chloroquine phosphate (CQP). The synthetized rGO-CuNPs composite was morphologically characterized using scanning electron microscopy and electrochemically characterized using cyclic voltammetry. The parameters were optimized and the developed electrochemical sensor was applied in the determination of CQP using square-wave voltammetry (SWV). The analytical range for the determination of CQP was 0.5 to 110 μmol L−1 (one of the highest linear ranges for CQP considering electrochemical sensors), with limits of detection and quantification of 0.23 and 0.78 μmol L−1, respectively. Finally, the glassy carbon (GC) electrode modified with rGO-CuNPs was used for quantification of CQP in tap water; a study was carried out with interferents using SWV and obtained great results. The use of rGO-CuNP material as an electrode modifier was thus shown to be a good alternative for the development of low-cost devices for CQP analysis.

Background: Plasmodium vivax remains the predominant species at the China–Myanmar border, imposing a major challenge to the recent gains in regional malaria elimination. To closely supervise the emerging of drug resistance in this area, we surveyed the variations in genes potentially correlated with drug resistance in P. vivax parasite and the possible drug selection with time. Methods: A total of 235 P. vivax samples were collected from patients suffering uncomplicated malaria at Yingjiang, Tengchong, and Longling counties, and Nabang port in China, Yunnan province, and Laiza sub-township in Myanmar, from 2008 to 2017. Five potential drug resistance genes were amplified utilizing nested-PCR and analyzed, including pvdhfr, pvdhps, pvmdr1, pvcrt-o, and pvk12. The Pearson's Chi-squared test or Fisher's exact test were applied to determine the statistical frequency differences of mutations between categorical data. Results: The pvdhfr F57I/L, S58R, T61M and S117T/N presented in 40.6%, 56.7%, 40.1%, and 56.0% of the sequenced P. vivax isolates, and these mutations significantly decreased with years. The haplotype formed by these quadruple mutations predominated in Yingjiang, Tengchong, Longling and Nabang. While a mutation H99S/R (56.6%) dominated in Laiza and increased with time. In pvdhps, the A383G prevailed in 69.2% of the samples, which remained the most prevalent haplotype. However, a significant decrease of its occurrence was also noticed over the time. The S382A/C and A553G existed in 8.4% and 30.8% of the isolates, respectively. In pvmdr1, the mutation Y976F occurred at a low frequency in 5/232 (2.2%), while T958M was fixed and F1076L was approaching fixed (72.4%). The K10 insertion was detected at an occurrence of 33.2% in pvcrt-o, whereas there was no significant difference among the sites or over the time. No mutation was identified in pvk12. Conclusions: Mutations related with resistance to antifolate drugs are prevalent in this area, while their frequencies decrease significantly with time, suggestive of increased susceptibility of P. vivax parasite to antifolate drugs. Resistance to chloroquine (CQ) is possibly emerging. However, since the molecular mechanisms underneath CQ resistance is yet to be better understood, close supervision of clinical drug efficiency and continuous function investigation is urgently needed to alarm drug resistance. [ABSTRACT FROM AUTHOR]

This article summarizes the background, specific conditions, main measures, steps and effects of the implementation of Mass Drug Administration (MDA) to control the local P. vivax malaria epidemic in Anhui Province in central China. Distributing medicines to the designated population quickly controlled the local epidemic of P. vivax. Implementing MDA to control P. vivax ensured the correct selection of medicines, clarification of the targeted population for receipt of medicines, and assurance of a high rate of compliance through government support and health education. These results provide a reference for countries and regions experiencing similar events and planning to implement MDA in malaria control. [ABSTRACT FROM AUTHOR]

Amodiaquine (AQ) is a commonly used antimalarial drug, and N-desethyl-AQ (N-DEAQ) is an active metabolite of AQ. Given the significance of drug quality in the management of malaria cases, this study aims to develop antibody-based assays for the detection and quantitation of AQ without the need for sophisticated equipment. Two monoclonal antibodies (mAbs) against AQ, designated as JUN7 and TE7, were selected, which showed 72.7% and 9.5% cross-reactivity to N-DEAQ, respectively. These mAbs showed <0.1% cross-reactivity to other commonly used antimalarial drugs. An indirect competitive enzyme-linked immunosorbent assay (icELISA) based on JUN7 showed a 50% inhibitory concentration (IC50) of 0.16 ng/mL and a working range of 0.06–0.46 ng/mL. A lateral flow immunoassay (LFIA) based on JUN7 was also developed with a working range of 2.58–30.86 ng/mL. The icELISA and LFIA were applied for the quantification of AQ in commercial drugs, and the results were comparable to those determined using high-performance liquid chromatography. In addition, a combination dipstick for simultaneous, qualitative analysis of AQ and artesunate was developed. All immunoassays based on JUN7 can be applied for quality control of AQ-containing artemisinin-based combination therapies. As TE7 showed low cross-reactivity to N-DEAQ, an icELISA based on TE7 was developed with an IC50 of 0.38 ng/mL and a working range of 0.14–1.67 ng/mL. The TE7 icELISA was applied for the study of pharmacokinetics of AQ in rat serum after intragastric administration, and the results were consistent with those of previous studies. [ABSTRACT FROM AUTHOR]

Background: The development of novel malaria vaccines and antimalarial drugs is limited partly by emerging challenges to conduct field trials in malaria endemic areas, including unknown effects of existing immunity and a reported fall in malaria incidence. As a result, Controlled Human Malaria Infection (CHMI) has become an important approach for accelerated development of malarial vaccines and drugs. We conducted a systematic review of the literature to establish aggregate evidence on the reproducibility of a malaria sporozoite challenge model.Methods: A systematic review of research articles published between 1990 and 2018 on efficacy testing of malaria vaccines and drugs using sporozoite challenge and sporozoite infectivity studies was conducted using Pubmed, Scopus, Embase and Cochrane Library, ClinicalTrials.gov and Trialtrove. The inclusion criteria were randomized and non-randomized, controlled or open-label trials using P. falciparum or P. vivax sporozoite challenges. The data were extracted from articles using standardized data extraction forms and descriptive analysis was performed for evidence synthesis. The endpoints considered were infectivity, prepatent period, parasitemia and safety of sporozoite challenge.Results: Seventy CHMI trials conducted with a total of 2329 adult healthy volunteers were used for analysis. CHMI was induced by bites of mosquitoes infected with P. falciparum or P. vivax in 52 trials and by direct venous inoculation of P. falciparum sporozoites (PfSPZ challenge) in 18 trials. Inoculation with P. falciparum-infected mosquitoes produced 100% infectivity in 40 studies and the mean/median prepatent period assessed by thick blood smear (TBS) microscopy was ≤ 12 days in 24 studies. On the other hand, out of 12 infectivity studies conducted using PfSPZ challenge, 100% infection rate was reproduced in 9 studies with a mean or median prepatent period of 11 to 15.3 days as assessed by TBS and 6.8 to 12.6 days by PCR. The safety profile of P. falciparum and P.vivax CHMI was characterized by consistent features of malaria infection.Conclusion: There is ample evidence on consistency of P. falciparum CHMI models in terms of infectivity and safety endpoints, which supports applicability of CHMI in vaccine and drug development. PfSPZ challenge appears more feasible for African trials based on current evidence of safety and efficacy. [ABSTRACT FROM AUTHOR]

ABSTRACT: Objectives: At the end of November 2019, a novel coronavirus responsible for respiratory tract infections (COVID-19) emerged in China. Despite drastic containment measures, this virus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread in Asia and Europe. The pandemic is ongoing with a particular hotspot in Southern Europe and America; many studies predicted a similar epidemic in Africa, as is currently seen in Europe and the United States of America. However, reported data have not confirmed these predictions. One of the hypotheses that could explain the later emergence and spread of COVID-19 pandemic in African countries is the use of antimalarial drugs to treat malaria, and specifically, artemisinin-based combination therapy (ACT). Methods: The antiviral activity of fixed concentrations of ACT at concentrations consistent with those observed in human plasma when ACT is administered at oral doses for uncomplicated malaria treatment was evaluatedin vitro against a clinically isolated SARS-CoV-2 strain (IHUMI-3) in Vero E6 cells. Results: Mefloquine-artesunate exerted the highest antiviral activity with % inhibition of 72.1 ± 18.3 % at expected maximum blood concentration (Cmax) for each ACT drug at doses commonly administered in malaria treatment. All the other combinations, artesunate-amodiaquine, artemether-lumefantrine, artesunate-pyronaridine, or dihydroartemisinin-piperaquine, showed antiviral inhibition in the same ranges (27.1 to 34.1 %). Conclusions: Antimalarial drugs for which concentration data in the lungs are available are concentrated from 10 to 160 fold more in the lungs than in blood. Thesein vitro results reinforce the hypothesis that antimalarial drugs could be effective as an anti-COVID-19 treatment.

Background and Aim Standard treatment for autoimmune hepatitis (AIH) consists of predniso(lo)ne and azathioprine. However, alternative therapy is required for non‐ or partial responders and in cases of side effects. The aim of this study was to evaluate the treatment outcomes associated with chloroquine plus prednisone in AIH patients. Methods Fifty‐seven patients were recruited to receive either azathioprine or chloroquine, both with prednisone, in a randomized trial. The primary end‐point was complete remission, based on normalization of aminotransferase levels in the first 6 months of treatment plus maintenance for at least 18 months, with minimal or no inflammatory activity in the liver biopsy. Secondary end‐points were partial and nonresponse, severe side effects, and treatment withdrawal. Results There were no differences between groups regarding clinical, serological, histological, and treatment characteristics at baseline. There were no significant differences in the biochemical response rate (67.7 vs 53.8%, P = 0.41) or the complete remission rate (32.26 vs 15.38%, P = 0.217). However, despite the long study period, the sample size was smaller than that required for a noninferiority study. The mean prednisone dose was similar in both groups. There was a nonsignificantly higher rate of adverse effects and a tendency toward improvement in glycemic and cholesterol profiles in the chloroquine group (P = 0.09 and P = 0.07, respectively). Conclusions The combination of chloroquine and prednisone exhibited potentially beneficial effects in AIH patients (ClinicalTrials.gov: NCT02463331).

Abstract Background The Plasmodium falciparum chloroquine transporter gene (pfcrt) is known to be involved in chloroquine and amodiaquine resistance, and more particularly the mutations on the loci 72 to 76 localized within the second exon. Additionally, new mutations (T93S, H97Y, C101F, F145I, M343L, C350R and G353V) were recently shown to be associated with in vitro reduced susceptibility to piperaquine in Asian or South American P. falciparum strains. However, very few data are available on the prevalence of these mutations and their effect on parasite susceptibility to anti-malarial drugs, and more particularly piperaquine in Africa. Methods A molecular investigation of these mutations was performed in 602 African P. falciparum parasites collected between 2017 and 2018 on malaria patients hospitalized in France after a travel in African countries. Associations between genotypes and in vitro susceptibilities to piperaquine and standard antimalarial drugs were assessed. Results None of the mutations, previously described as associated with piperaquine resistance, was found in the 602 P. falciparum African isolates. The K76T mutation is associated with resistance to chloroquine (p < 0.0002) and desethylamodiaquine (p < 0.002) in Africa. The K76T mutation is not associated with in vitro reduced susceptibility to piperaquine. The mutation I356T, identified in 54.7% (n = 326) of the African isolates, was significantly associated with reduced susceptibility to quinine (p < 0.02) and increased susceptibility to mefloquine (p < 0.04). The K76T and I356T mutations were significantly associated in West African isolates (p = 0.008). Conclusion None of the mutations in pfcrt found to be associated with piperaquine reduced susceptibility in Asia or South America (T93S, H97Y, C101F, F145I, M343L C350R and G353V) were found in the 602 African isolates including the three isolates with reduced susceptibility to piperaquine. The K76T mutation, involved in resistance to chloroquine and amodiaquine, and the I356T mutation were not associated with in vitro reduced susceptibility to piperaquine. Differences in mefloquine susceptibility between I356 and 356T isolates were, while statistically different, minimal. Further analyses are needed with a more important sample size from the same geographic area to confirm the role of the I356T mutation on quinine susceptibility.

Abstract Background Reports on the antischistosomal effect of several antimalarial drugs such as artesunate, mefloquine, and amodiaquine suggest that febrifugine, which exerts an antimalarial effect, can also be expected to possess antischistosomal potential. The present study investigates the antischistosomal effects of febrifugine. Methods In experiment 1, Schistosoma mansoni adult worm pairs were incubated in a medium alone as a control or supplemented with febrifugine at 0.05, 0.1, 0.2, and 0.5 μg/ml for 14 days. The morphology of the worms and the egg production of the female worms were observed simultaneously. In experiment 2, the incubation was conducted as in experiment 1, except that the febrifugine concentrations were reduced to 0.005, 0.01, and 0.02 μg/ml. In addition, S. mansoni adult worms were incubated with either 0.5 μg/ml febrifugine or none as a control for 5 days and stained with neutral red dye. Results Febrifugine significantly reduced the survival of S. mansoni male and female worms at concentrations of 0.02–0.5 μg/ml following incubation for 14 days and remarkably inhibited the daily egg output of the female worms. The non-treated male and female worms remained morphologically normal within the period of 14 days, whereas male and female worms treated with febrifugine at different concentrations gradually twisted and subsequently died. In addition, S. mansoni adult worms were incubated with either 0.5 μg/ml febrifugine or none as a control for 5 days and stained with neutral red dye. Non-treated male worms were morphologically normal and stained dark red with neutral red, while febrifugine-treated male worms appeared similar to those in the control group and were stained at a slightly lower level of dark red than the non-treated male worms. Non-treated female worms were morphologically normal, and their intestinal tract and vitellaria were stained deep red and dark red, respectively. In contrast, febrifugine-treated female worms were morphologically damaged, and their intestinal tract and vitellaria remained mostly unstained and stained dark red, respectively. Conclusion Febrifugine exerts potent antischistosomal effects and can be expected to contribute to the development of a novel antischistosomal drug.

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331 , exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596 , a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598 , a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.

The pharmacological treatment of systemic lupus erythematosus (SLE) aims to decrease disease activity, progression, systemic compromise, and mortality. Among the pharmacological alternatives, there are chemically synthesized drugs whose efficacy has been evaluated, but which have the potential to generate adverse events that may compromise adherence and response to treatment. Therapy selection and monitoring will depend on patient characteristics and the safety profile of each drug. The aim of this review is to provide a comprehensive understanding of the most important synthetic drugs used in the treatment of SLE, including the current treatment options (mycophenolate mofetil, azathioprine, and cyclophosphamide), review their mechanism of action, efficacy, safety, and, most importantly, provide monitoring parameters that should be considered while the patient is receiving the pharmacotherapy.

Deep learning significantly accelerates the drug discovery process, and contributes to global efforts to stop the spread of infectious diseases. Besides enhancing the efficiency of screening of antimicrobial compounds against a broad spectrum of pathogens, deep learning has also the potential to efficiently and reliably identify drug candidates against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Consequently, deep learning has been successfully used for the identification of a number of potential drugs against SARS-CoV-2, including Atazanavir, Remdesivir, Kaletra, Enalaprilat, Venetoclax, Posaconazole, Daclatasvir, Ombitasvir, Toremifene, Niclosamide, Dexamethasone, Indomethacin, Pralatrexate, Azithromycin, Palmatine, and Sauchinone. This mini-review discusses recent advances and future perspectives of deep learning-based SARS-CoV-2 drug discovery. [ABSTRACT FROM AUTHOR]

Background: The spread of drug resistance has seriously impacted the effective treatment of infection with the malaria parasite, Plasmodium falciparum. Continuous monitoring of molecular marker polymorphisms associated with drug resistance in parasites is essential for malaria control and elimination efforts. Our study describes mutations observed in the resistance genes Pfkelch13, Pfcrt , and Pfmdr1 in imported malaria and identifies additional potential drug resistance-associated molecular markers. Methods: Chinese patients infected in Africa with P. falciparum were treated with intravenous (IV) injections of artesunate 240–360 mg for 3–5 days while hospitalized and treated with oral dihydroartemisinin-piperaquine (DHP) for 3 days after hospital discharge. Blood samples were collected and PCR sequencing performed on genes Pfkelch13, Pfcrt , and Pfmdr1 from all isolates. Results: We analyzed a total of 225 patients from Guangxi, China with P. falciparum malaria acquired in Africa between 2016 and 2018. All patients were cured completely after treatment. The F446I mutation of the Pfkelch13 gene was detected for the first time from samples of West African P. falciparum , with a frequency of 1.0%. Five haplotypes of Pfcrt that encode residues 72–76 were found, with the wild-type CVMNK sequence predominating (80.8% of samples), suggesting that the parasites might be chloroquine sensitive. For Pfmdr1 , N86 Y (13.1%) and Y184 F (58.8%) were the most prevalent, suggesting that artemether-lumefantrine may not, in general, be a suitable treatment for the group. Conclusions: For the first time, this study detected the F446I mutation of the Pfkelch13 gene from Africa parasites that lacked clinical evidence of resistance. This study provides the latest data for molecular marker surveillance related to antimalarial drug resistance genes Pfkelch13, Pfcrt , and Pfmdr1 imported from Africa, in Guangxi, China from Chinese migrate workers. Clinical Trial Registration: ChiCTROPC17013106. [ABSTRACT FROM AUTHOR]

Molecularly imprinted polymers (MIP) have been used primarily to improve selectivity in solid-phase extraction. Synthetic MIPs composed by 2-vinyl pyridine as the monomer, ethylene glycol dimethacrylate as a cross-linker, toluene as the porogen solvent, and azobisisobutyronitrile as initiator were obtained by the precipitation polymerization and were investigated to describe the interaction between the template and the MIP. The non-isothermal interactions between MIP and the antimalarial drug lumefantrine as a template were investigated by differential scanning calorimetry. The data were recorded at the heating rates of 5, 7.5, 10, and 15 °C min−1. During the experiments, the obtained compound lumefantrine–MIP and the kinetics of this process were investigated using Vyazovkin isoconversional method and multilayer perceptron network (MLP). Thermal analysis and powder X-ray diffraction indicate a specific thermal and crystalline event (fingerprint) for this compound. According to the Vyazovkin method, the determined activation energy to initiate the compound formation is about 80 kJ mol−1 and about 166 kJ mol−1 to achieve 60% of conversion. MLP determined activation energy of 159–196 kJ mol−1 for the whole process and attested a significant contribution of the Avrami–Erofeev kinetic model to describe the event. [ABSTRACT FROM AUTHOR]

Background: The spread of drug resistance has seriously impacted the effective treatment of infection with the malaria parasite, Plasmodium falciparum. Continuous monitoring of molecular marker polymorphisms associated with drug resistance in parasites is essential for malaria control and elimination efforts. Our study describes mutations observed in the resistance genes Pfkelch13, Pfcrt, and Pfmdr1 in imported malaria and identifies additional potential drug resistance-associated molecular markers.Methods: Chinese patients infected in Africa with P. falciparum were treated with intravenous (IV) injections of artesunate 240–360 mg for 3–5 days while hospitalized and treated with oral dihydroartemisinin-piperaquine (DHP) for 3 days after hospital discharge. Blood samples were collected and PCR sequencing performed on genes Pfkelch13, Pfcrt, and Pfmdr1 from all isolates.Results: We analyzed a total of 225 patients from Guangxi, China with P. falciparum malaria acquired in Africa between 2016 and 2018. All patients were cured completely after treatment. The F446I mutation of the Pfkelch13 gene was detected for the first time from samples of West African P. falciparum, with a frequency of 1.0%. Five haplotypes of Pfcrt that encode residues 72–76 were found, with the wild-type CVMNK sequence predominating (80.8% of samples), suggesting that the parasites might be chloroquine sensitive. For Pfmdr1, N86Y (13.1%) and Y184F (58.8%) were the most prevalent, suggesting that artemether-lumefantrine may not, in general, be a suitable treatment for the group.Conclusions: For the first time, this study detected the F446I mutation of the Pfkelch13 gene from Africa parasites that lacked clinical evidence of resistance. This study provides the latest data for molecular marker surveillance related to antimalarial drug resistance genes Pfkelch13, Pfcrt, and Pfmdr1 imported from Africa, in Guangxi, China from Chinese migrate workers.Clinical Trial Registration: ChiCTROPC17013106.

Deep learning significantly accelerates the drug discovery process, and contributes to global efforts to stop the spread of infectious diseases. Besides enhancing the efficiency of screening of antimicrobial compounds against a broad spectrum of pathogens, deep learning has also the potential to efficiently and reliably identify drug candidates against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Consequently, deep learning has been successfully used for the identification of a number of potential drugs against SARS-CoV-2, including Atazanavir, Remdesivir, Kaletra, Enalaprilat, Venetoclax, Posaconazole, Daclatasvir, Ombitasvir, Toremifene, Niclosamide, Dexamethasone, Indomethacin, Pralatrexate, Azithromycin, Palmatine, and Sauchinone. This mini-review discusses recent advances and future perspectives of deep learning-based SARS-CoV-2 drug discovery.

Untreated malaria can progress rapidly to severe forms (Plasmodium berghei ANKA on Day 0 (D0) and the treatment started on D3 (nearly 1% parasitaemia) with AQ, MQ or MB alone or in combination with AQ or MQ. AQ, MQ and MB alone were unable to prevent cerebral malaria as part of a late chemotherapy. MB-based combination therapies were efficient even if treatment began at a late stage. We found a significant difference in survival rate (p < 0.0001) between MBAQ and the untreated group, but also with the AQ (p = 0.0024) and MB groups (p < 0.0001). All the infected mice treated with MB in combination with AQ were protected from cerebral malaria. Partial protection was demonstrated with MB associated with MQ. In this group, a significant difference was found between MBMQ and the untreated group (p < 0.0001), MQ (p = 0.0079) and MB (p = 0.0039). MB associated with AQ would be a good candidate for preventing cerebral malaria.