Antimalarial Research Articles

β-Carboline-3-carboxamide Antimalarials: Structure-Activity Relationship, ADME-Tox Studies, and Resistance Profiling.

The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline 1a was orally efficacious in Plasmodium berghei-infected mice and that it showed low cross-resistance between susceptible Plasmodium falciparum and four different drug-resistant strains. In this report, we describe the synthesis and in vitro antimalarial evaluation of 91 new derivatives of 1a. The asexual blood stage growth inhibition data show a clear preference for a 3,4-dihalogenated, 3,5-dihalogenated, 3,4,5-trichloro-, or 4-trifluoromethyphenyl ring at the C1-position. The most potent compound, 3,4,5-trichlorophenyl-substituted 42a, is twice as potent as 1a. Six potent analogues were assessed for their drug-like properties, and four of these were subjected to in vitro barcoded cross-resistance profiling. Compounds 1a, 1m, 42a, and 42m showed no cross-resistance to 32 resistance mutations on the Dd2 genetic background and 10 resistance mutations on the 3D7 genetic background. These data suggest that compounds in this scaffold possess a novel mechanism of antimalarial action.

The Antiviral and Antimalarial Prodrug Artemisinin from the Artemisia Species: A Review

Artemisinin is a truly fascinating drug in many ways. Since the unrestrained procedure of its detection, as an antimalarial drug, artemisinin has received a great deal of consideration. Recently, application of artemisinin-based combination therapy has been broadly applied for treating numerous ailments. Moreover, as an antimalarial compound, artemisinin and its associated compounds have abundant healing efficacy and can be repurposed for additional symptoms, like autoimmune infections, cancer, and viral contaminations. Recently a number of studies have highlighted the significance of the artemisinin-related compounds in SARS-CoV-2 treatment. The current review purposes to present a concise account of the history of the antiviral and antimalarial prodrugs—Artemisinin, from the Artemisia species. It is followed by its antiviral, antimalarial prospective, chemical nature and extraction procedure, photochemistry, mechanism of action, and its clinical trials and patents, and accentuates the significance of the mechanistic studies concerned for therapeutic results, both in viral and malarial circumstances.

The influence of malaria control interventions and climate variability on changes in the geographical distribution of parasite prevalence in Kenya between 2015 and 2020

BackgroundThe burden of malaria in Kenya was showing a declining trend, but appears to have reached a plateau in recent years. This study estimated changes in the geographical distribution of malaria parasite risk in the country between the years 2015 and 2020, and quantified the contribution of malaria control interventions and climatic/ environmental factors to these changes.MethodsBayesian geostatistical models were used to analyse the Kenyan 2015 and 2020 Malaria Indicator Survey (MIS) data. Bivariate models were fitted to identify the most important control intervention indicators and climatic/environmental predictors of parasitaemia risk by age groups (6–59 months and 5–14 years). Parasitaemia risk and the number of infected children were predicted over a 1 × 1 km2 grid. The probability of the decline in parasitaemia risk in 2020 compared to 2015 was also evaluated over the gridded surface and factors associated with changes in parasitaemia risk between the two surveys were evaluated.ResultsThere was a significant decline in the coverage of most malaria indicators related to Insecticide Treated Nets (ITN) and Artemisinin Combination Therapies (ACT) interventions. Overall, there was a 31% and 26% reduction in malaria prevalence among children aged < 5 and 5–14 years, respectively. Among younger children, the highest reduction (50%) and increase (41%) were in the low-risk and semi-arid epi zones, respectively; while among older children there was increased risk in both the low-risk (83%) and semi-arid (100%) epi zones. Increase in nightlights and the proportion of individuals using ITNs in 2020 were associated with reduced parasitaemia risk.ConclusionIncreased nightlights and ITN use could have led to the reduction in parasitaemia risk. However, the reduction is heterogeneous and there was increased risk in northern Kenya. Taken together, these results suggest that constant surveillance and re-evaluation of parasite and vector control measures in areas with increased transmission is necessary. The methods used in this analysis can be employed in other settings.

Optimization of loop mediated isothermal amplification assay (LAMP) for detection of chloroquine resistance in P. vivax malaria

Chloroquine is still used as a first-line treatment for uncomplicated Plasmodium vivax malaria in India and resistance to this therapy can act as a major hurdle for malaria elimination. It is difficult to monitor drug-efficacy and drug resistance through in vivo and in vitro studies in case of Plasmodium vivax so analysis of molecular markers serves as an important tool to track resistance. Molecular methods that are currently in use for detecting single nucleotide polymorphisms in resistant genes including Polymerase chain reaction (PCR), Realtime-Polymerase chain reaction require highly sophisticated labs and are time consuming. So, with this background the study has been designed to optimize Loop Mediated Isothermal Amplification Assay to detect single nucleotide polymorphisms in chloroquine resistance gene of Plasmodium vivax in field settings. Eighty-eight Plasmodium vivax positive samples were collected. Pvmdr1 gene was amplified for all the samples and sequenced. Obtained sequences were analyzed for the presence of single nucleotide polymorphisms in the target gene. Further Loop Mediated Isothermal Amplification Assay primer sets were designed for the target mutants and the assay was optimized. Clinical as well as analytical sensitivity and specificity for the assay was calculated. Double mutants with variations at T958M and F1076L were detected in 100% of the Plasmodium vivax clinical isolates with haplotype M958 Y976 Y1028 L1076. Designed primers for Loop Mediated Isothermal Amplification Assay successfully detected both the mutants (T958M and F1076L) in 100% of the isolates and do not show cross-reactivity with other strains. So, the assay was 100% sensitive and specific for detecting single nucleotide polymorphisms in the target Pvmdr1 gene. Limit of detection was found to be 0.9 copies/µl and lowest DNA template concentration detected by designed assay was 1.5 ng/µL. Observed prevalence of single nucleotide polymorphisms in Pvmdr 1 gene is indicating a beginning of trend towards chloroquine resistance in Plasmodium vivax. The present study optimized LAMP for detecting single nucleotide polymorphisms in Plasmodium vivax cases in field settings, thus would help in finding significant hubs of emerging chloroquine drug resistance and ultimately helping in the management of suitable antimalarial drug policy.

Assessing the role of the for-profit private healthcare sector in malaria elimination efforts in Bangladesh: a cross-sectional study of challenges and opportunities

BackgroundAmong 13 endemic districts, the Chittagong Hill Tracts bear more than 90% of Bangladesh’s malaria burden. Despite the private sector’s prominence in rural healthcare, its role in malaria management remains underutilized. This study aimed to strategize leveraging the for-profit private sector, such as diagnostic and treatment centers, to bolster national malaria surveillance and control, advancing Bangladesh toward malaria elimination by 2030.MethodsThis mixed-method study commenced with a questionnaire-based cross-sectional survey followed by selected focused group discussions (FGDs) among the participants. Three FGDs were held with the for-profit service providers so that further insights and qualitative viewpoints of them can be utilized in situation analysis. Based on the endemicity and strategic priorities, a comprehensive mapping of private for-profit facilities from the regions comprising 15 sub-districts across 8 chosen districts (7 malaria endemic districts and the rest non-endemic districts) was created. For the non-endemic zone, the sub-districts were selected based on their proximity to an area with high malaria transmission.ResultsAmong the 104 representative participants, majority were male (n = 92, 88.5%), had a diploma in their respective fields (n = 53, 51%) and were involved either in laboratory work (n = 49, 47.1%) or as owners/managers of health centers (n = 41, 39.4%). The selected health facilities were close to the corresponding Upazila Health Complexes (mean distance 2.8 km), but were distantly located from the designated district hospitals (mean distance 48.9 km). The main sources of RDT kits (62.3%) and anti-malarial drugs (63.2%) were local wholesale markets. A large share of the corresponding facilities neither provided malaria treatment services (81.7%) nor worked with the NMEP (93.3%).ConclusionsThis study highlights challenges and recommendations for engaging private for-profit health facilities in Bangladesh’s malaria elimination efforts. The identified challenges include low-quality RDTs, staff shortages, and inadequate capacity building. Recommendations emphasize effective training, stakeholder interaction, and enhanced oversight for successful malaria control efforts.

Advances in the study of artemisinin and its derivatives for the treatment of rheumatic skeletal disorders, autoimmune inflammatory diseases, and autoimmune disorders: a comprehensive review

Artemisinin and its derivatives are widely recognized as first-line treatments for malaria worldwide. Recent studies have demonstrated that artemisinin-based antimalarial drugs, such as artesunate, dihydroartemisinin, and artemether, not only possess excellent antimalarial properties but also exhibit antitumor, antifungal, and immunomodulatory effects. Researchers globally have synthesized artemisinin derivatives like SM735, SM905, and SM934, which offer advantages such as low toxicity, high bioavailability, and potential immunosuppressive properties. These compounds induce immunosuppression by inhibiting the activation of pathogenic T cells, suppressing B cell activation and antibody production, and enhancing the differentiation of regulatory T cells. This review summarized the mechanisms by which artemisinin and its analogs modulate excessive inflammation and immune responses in rheumatic and skeletal diseases, autoimmune inflammatory diseases, and autoimmune disorders, through pathways including TNF, Toll-like receptors, IL-6, RANKL, MAPK, PI3K/AKT/mTOR, JAK/STAT, and NRF2/GPX4. Notably, in the context of the NF-κB pathway, artemisinin not only inhibits NF-κB expression by disrupting upstream cascades and/or directly binding to NF-κB but also downregulates multiple downstream genes controlled by NF-κB, including inflammatory chemokines and their receptors. These downstream targets regulate various immune cell functions, apoptosis, proliferation, signal transduction, and antioxidant responses, ultimately intervening in systemic autoimmune diseases and autoimmune responses in organs such as the kidneys, nervous system, skin, liver, and biliary system by modulating immune dysregulation and inflammatory responses. Ongoing multicenter randomized clinical trials are investigating the effects of these compounds on rheumatic, inflammatory, and autoimmune diseases, with the aim of translating promising preclinical data into clinical applications.

Anti-tumor mechanism of artesunate

Artesunate (ART) is a classic antimalarial drug with high efficiency, low toxicity and tolerance. It has been shown to be safe and has good anti-tumor effect. Existing clinical studies have shown that the anti-tumor mechanisms of ART mainly include inducing apoptosis and autophagy of tumor cells, affecting tumor microenvironment, regulating immune response, overcoming drug resistance, as well as inhibiting tumor cell proliferation, migration, invasion, and angiogenesis. ART has been proven to fight against lung cancer, hepatocarcinoma, lymphoma, multiple myeloma, leukemia, colorectal cancer, ovarian cancer, cervical cancer, malignant melanoma, oral squamous cell carcinoma, bladder cancer, prostate cancer and other neoplasms. In this review, we highlight the effects of ART on various tumors with an emphasis on its anti-tumor mechanism, which is helpful to propose the potential research directions of ART and expand its clinical application.

Locally Acquired (Autochthonous) Mosquito-Transmitted Plasmodium vivax Malaria - Saline County, Arkansas, September 2023.

A case of locally acquired (autochthonous) mosquito-transmitted Plasmodium vivax malaria was diagnosed in Arkansas in September 2023. This represents the 10th autochthonous case identified nationally in 2023, after 20 years without recorded local mosquitoborne malaria transmission in the United States. The public health response included case investigation, active case surveillance, mosquito surveillance and control, assessment of medical countermeasures, and clinical and public outreach. Prompt diagnosis and appropriate treatment of malaria can improve clinical outcomes and, in addition to vector control, minimize risk for local transmission. Clinicians should consider malaria among patients who have traveled to countries where malaria is endemic, or with unexplained fever regardless of travel history. Although the risk for autochthonous malaria in the United States remains very low, its reemergence highlights the importance of vectorborne disease preparedness and response. Examples of such efforts include improving awareness among clinicians, access to diagnostics and antimalarial medications, and capacity for mosquito surveillance and control. Collaboration and communication among CDC, health departments, local jurisdictions, clinicians, hospitals, laboratories, and the public can support rapid malaria diagnosis, prevention, and control. Before traveling internationally to areas where malaria is endemic, travelers should consult with their health care provider regarding recommended malaria prevention measures, including chemoprophylaxis and precautions to avoid mosquito bites, to reduce both personal and community risk.

Involvement of Molecular Mechanism and Biological Activities of Pemirolast: A Therapeutic Review

: This review paper aims to investigate the therapeutic benefits of pemirolast across different medical conditions, including asthma, allergic rhinitis, cancer, conjunctivitis, etc. The prevalence of allergic conditions has risen in recent decades, primarily attributed to environmental factors. This paper explores the role of pemirolast in managing and mitigating these diseases, shedding light on its potential applications in the context of evolving environmental influences. : This review paper investigates the diverse biological activities exhibited by pemirolast, encompassing its roles as an antimicrobial, analgesic, antiviral, anti-inflammatory, antioxidant, antihistamine, mast cell stabilizer, anti-tubercular, anticancer, anti-asthmatic, anti-malarial, diuretic, antianxiety, and antifungal agent. The positive outcomes of pemirolast application in various diseases are highlighted, showcasing its potential across a spectrum of medical conditions. : The pharmacological impact of pemirolast extends to diverse inflammatory mediators, enzymes, and hormones associated with various diseases. Pemirolast demonstrates inhibitory effects on key elements such as eosinophil activation, histamine, leukotriene, IgE, mast cells, basophils, prostaglandin, interleukin, T-helper cells, macrophage T-cells, neutrophils, tryptase, T-lymphocytes, interferons I-III, Amyloid β (Aβ) peptide, dsRNA transcription, GABA, dopamine, serotonin, and norepinephrine. This comprehensive exploration underscores pemirolast inhibitory actions across disorders, emphasizing its potential therapeutic relevance in diverse pathological conditions. : This review paper illuminates pemirolast potassium's versatile biological and therapeutic applications across various diseases. The potential synergies of combining pemirolast with buspirone, ritanserin, theophylline, and capreomycin are explored, showcasing its ability to elicit beneficial responses in addressing diverse ailments.

Current trends to design antimalarial drugs targeting N-myristoyltransferase.

Malaria is a disease caused by Plasmodium spp., of which Plasmodium falciparum and Plasmodium vivax are the most prevalent. Unfortunately, traditional and some current treatment regimens face growing protozoan resistance. Thus, searching for and exploring new drugs and targets is necessary. One of these is N-myristoyltransferase (NMT). This enzyme is responsible for the myristoylation of several protein substrates in eukaryotic cells, including Plasmodium spp., thus enabling the assembly of protein complexes and stabilization of protein-membrane interactions. Given the importance of this target in developing new antiparasitic drugs, this review aims to explore the recent advances in the design of antimalarial drugs to target Plasmodium NMT.

A histomorphometric study to evaluate the therapeutic effects of biosynthesized silver nanoparticles on the kidneys infected with Plasmodium chabaudi.

The study aimed to verify the pathogenic malarial kidney infections and histopathological pictures in mice infected with Plasmodium chabaudi using Indigofera oblongifolia leaf extract silver nanoparticles (IOLEAgNPs). Fifty healthy adult female mice C57BL/6 were used. Animals were divided into five groups, with each group of ten mice. The first control non-infected group was given distilled water for 7 days. The second group was orally given 50 mg/kg of IOLEAgNPs. The third, fourth, and fifth groups were injected intraperitoneally with 105 parasitized erythrocytes of P. chabaudi. After 1 h, the fourth group received 50 mg/kg of IOLEAgNPs, while the fifth group orally received 10 mg/kg chloroquine phosphate. The histopathology of the kidney was studied by routine histology method with hematoxylin-eosin staining. The kidney revealed cerebral microvessel congestion, hemorrhages, and necrosis. Cast formation, glomerulonephritis, tubular necrosis, and congestion were observed in the kidney cortex. Consequently, the targeted medical IOLEAgNPs reduced this degeneration impact on renal tissue. Proven that plant-source synthesized IOLEAgNPs play a preventive role as antimalarial agents in female mice infected with P. chabaudi.

Physicochemical Interactions Between Concomitantly Administered Anti-Retroviral and Anti-Malarial Drug

Physicochemical Interactions Between Concomitantly Administered Anti-Retroviral and Anti-Malarial Drug

DISTRIBUTION OF PLASMODIUM FALCIPARUM CHLOROQUINE RESISTANCE TRANSPORTER (PFCRT) AND PLASMODIUM FALCIPARUM MULTIDRUG RESISTANCE 1(PFMDR-1) GENES IN ILORIN NORTH-CENTRAL NIGERIA

Globally, malaria is a peculiar health challenge particularly in continent of Africa. The ease of developing resistance to anti-malaria drugs by Plasmodium falciparum is a serious impediment towards programs aim at control and elimination of malaria. Consequently, drug efficacy surveillance is desirable to institute adequate and effective treatment policies. In this study, distribution of these genes in Plasmodium falciparum isolates in Ilorin metropolis were investigated. One hundred and three samples collected randomly from 5 hospitals in Ilorin metropolis. The samples were amplified at codon 76 and 86 for Pfcrt and Pfmdr-1 respectively using PCR / Restricted Fragment Length Polymorphism (RFLP). The most prevalent alleles were drug susceptible alleles in the study area (K76 and N86) with 31% and 40% respectively, while drug resistance alleles (86Y) have 13% and the least prevalence 2% was the mixed alleles K76T. UITH has the highest number of susceptible alleles followed by CSC 38% and 46% for K76 and N86 respectively. There are significant differences in the distribution of these alleles and the study sites (P&lt; 0.05). The prevalence of resistance alleles in the area is a welcome development that can be employed for possibility of re-introduction of CQ for the treatment of malaria in the study area which will serve as an advantage over expensive ACT due to fact that it is safe cheap and readily affordable.

Ubiquitin-proteasome system in Plasmodium: a potential antimalarial target to overcome resistance – a systematic review

BackgroundMalaria is a devasting parasitic disease that causes over half a million deaths every year. The necessity for prompt and thorough antimalarial drug discovery and development is accelerated by the rise in multidrug resistance and the lack of an effective vaccine. The Plasmodium spp. proteasome represents a prospective target for antimalarial treatment since several chemotherapy types have been shown to potently and selectively limit the growth of parasites. Combined with first-line artemisinin medicines, it creates synergy, even in the artemisinin-resistant parasites.MethodsPRISMA guidelines were used in the development of this systematic review. A literature search was performed in March 2024 in PubMed, Science Direct, and Scopus databases, with the following keywords: ((antimalarial resistance) AND (plasmodium OR malaria) AND (proteasome)) NOT (cancer [Title/Abstract]). Only articles with the susceptibility assessment were included.ResultsHerein, 35 articles were included in the systematic review, which was divided into two subcategories: those that studied the UPS inhibitors, which accounted for 25 articles, and those that studied genetic modifications, including knockouts, knockdowns, and mutations, in the UPS toward antimalarial resistance, accounting for 16 articles. 6 articles included both subcategories. In total, 16 categories of inhibitors were analyzed, together with two knockdowns, one knockout, and 35 mutations.ConclusionIn this study, we reviewed the literature for available inhibitors and their respective susceptibility and ability to develop resistance toward Plasmodium spp. 26 s proteasome. The proteasome was highlighted as a potential antimalarial target and as an artemisinin partner drug. However, host toxicity and susceptibility to resistance appear as the main obstacle in the development of highly potent drugs, indicating a need for additional scrutiny during any further drug development efforts.

Antimalarials in Lupus Nephritis: How Strong is the Evidence?

Systemic lupus erythematosus is a chronic multisystem autoimmune disease that affects the kidneys in approximately 50% of patients, with prevalence rising to as high as 70% in certain populations, such as African Americans and Asians. Antimalarials -and particularly hydroxychloroquine- are currently considered a mainstay of therapy, together with immunosuppressants. Over the last decades, several studies have extensively investigated the mechanisms of action of antimalarial agents, and their potential beneficial properties in patients with SLE in general. However, the evidence for the therapeutic benefit of hydroxychloroquine in patients with lupus nephritis (LN) derives mainly from observational studies, conducted in an era prior to the refinement of induction and maintenance protocols for immunosuppressive therapy. Despite the paucity of high-quality evidence on its efficacy in LN, the nephrology community widely supports the universal use of hydroxychloroquine in LN patients, and recommendations for its use are firmly entrenched in various clinical practice guidelines. Nonetheless, the use of antimalarials may also carry inherent risks, underscoring the importance of personalized approaches in these patients. Herein, we comprehensively review the available literature on antimalarials in LN aiming to update the current evidence, limitations, and future perspectives for the use of antimalarials in adults.

Unraveling Cordia myxa’s anti-malarial potential: integrative insights from network pharmacology, molecular modeling, and machine learning

Malaria is a potentially fatal infective illness caused due to parasites that belong to the Plasmodium genus, which are transferred to humans with the help of the stings of affected female Anopheles mosquitoes, and it persists as a serious public wellness problem worldwide. Cordia myxa is a medicinal plant that possesses various medicinal characteristics like antimicrobial, anti-inflammation, antioxidant, and antidiabetic activities, which makes it an important natural resource for the therapy of different maladies in traditional medicine. In this investigation, a certain network pharmacology method has been utilized to identify the potent active components, possible targets as well as signaling pathways present in C. myxa in relation to malaria therapy. The active compounds were submitted to molecular docking approaches to validate their successful activity against the potential targets. The study concluded that three constituents named cosmosiin, stigmastanol, robinetin, and quercetin were highly active and could regulate the expression of Interleukin 6 (IL6) and Cysteine-aspartic acid protease 3 (CASP3), which may act as a potential therapeutic target for malaria treatment. These analyses are validated by molecular dynamics simulation which reflects on the overall structural stability of the intermolecular conformation and interactions. These results can also be witnessed in simulation-based trajectories binding free energies, which concluded the significant role of electrostatic and van der Waals energies in total intermolecular interactions. Finally, we utilized machine learning to predict the anti-malarial activity of C. myxa compounds, comparing them with approved drugs. Using the Chemprop model and MAIP predictions, we assessed ten compounds, revealing their potential as lead anti-malarial agents. This study establishes a groundwork for comprehending the function of the anti-malaria action of C. myxa.

The economic cost of malaria in Brazil from the perspective of the public health system.

This paper presents an economic evaluation aimed at estimating malaria-related health care expenditures in Brazil from the perspective of the public health system. Comprehensive estimates of the costs of malaria remain scarce, in part because of limited data. Brazil has a universal health system (Sistema Único de Saúde-SUS) in which all cases of malaria are diagnosed and treated. In addition, antimalarial drugs are only available through the SUS. We compiled comprehensive data from multiple administrative sources. Expenditure indicators were calculated for municipalities and states in the Brazilian Amazon, a region where more than 99% of the country's malaria cases are concentrated. We also developed a digital platform that allows interactive visualization of the malaria cost indicators, disaggregated by cost type and geography. Our results show that control and prevention activities are the primary cost in all states, followed by human resources and disease treatment. Expenditures per malaria notification in the Amazon ranged from PPP (purchasing power parity)-US$59.00 (2017) to PPP-US$77.00 (2016), while per capita expenditures remained relatively stable at around PPP-US$3.50. The malaria cost estimates presented here contribute to a better negotiation of the financial resources needed by the NMCP and are one of the critical pieces of information for a strategic plan of activities needed to achieve the elimination goal.

Lyotropic liquid crystal and self-emulsifying drug delivery systems nanoparticles as artesunic acid and praziquantel carriers: An innovative approach for formulation of anti-malaria and schistosomicidal drugs

Praziquantel (PZQ) is the drug of choice for treating cestode and trematode infections, and it is currently the only option against schistosomiasis. Artesunic acid (AcART) is effective against several parasites and has emerged as an alternative for schistosomiasis treatment. However, AcART and PZQ have limited bioavailability due to poor water solubility, low permeability, and rapid cell clearance. To address these challenges, this study aimed to develop self-emulsifying drug delivery systems to develop SEDDS and NPs-LLC to overcome the low water solubility affecting AcART and PZQ bioavailability. The study involved validating the HPLC analytical methodology for AcART, SEDDS, and NPs-LLC formulations, and conducting physicochemical characterization and ex-vivo intestinal permeation assays. The composition of formulations was determined by the solubility balance of AcART and PZQ. The drug content ranged between 83 and 90 %. The anionic zeta potential was attributed to Myverol®, and the particle diameter increased slightly after the drug incorporation, while the polydispersity index indicated the relatively narrow particle size distribution. Additionally, the DSC thermogram confirmed that PZQ and AcART are in solution within SEDDS and NPs-LLC. The FTIR analysis suggests that components of SEDDS and NPs-LLC and drugs do not react to form new chemical species. The selection of specific compound formulations was based on achieving the best solubility balance. The nanostructures were stable and exhibited a surface charge favorable to mucosal permeation, with slightly superior performance for SEDDS. The innovative formulations, SEDDS and NPs-LLC, are suitable and effective carriers for AcART and PZQ.

Artemisinin-resistant malaria.

SUMMARYThe artemisinin antimalarials are the cornerstone of current malaria treatment. The development of artemisinin resistance in Plasmodium falciparum poses a major threat to malaria control and elimination. Recognized first in the Greater Mekong subregion of Southeast Asia nearly 20 years ago, artemisinin resistance has now been documented in Guyana, South America, in Papua New Guinea, and most recently, it has emerged de novo in East Africa (Rwanda, Uganda, South Sudan, Tanzania, Ethiopia, Eritrea, and eastern DRC) where it has now become firmly established. Artemisinin resistance is associated with mutations in the propeller region of the PfKelch gene, which play a causal role, although the parasites' genetic background also makes an important contribution to the phenotype. Clinically, artemisinin resistance manifests as reduced parasiticidal activity and slower parasite clearance and thus an increased risk of treatment failure following artemisinin-based combination therapy (ACT). This results from the loss of artemisinin activity against the younger circulating ring stage parasites. This loss of activity is likely to diminish the life-saving advantage of artesunate in the treatment of severe falciparum malaria. Gametocytocidal and thus transmission blocking activities are also reduced. At current levels of resistance, artemisinin-resistant parasites still remain susceptible at the trophozoite stage of asexual development, and so, artemisinin still contributes to the therapeutic response. As ACTs are the most widely used antimalarial drugs in the world, it is essential from a malaria control perspective that ACT cure rates remain high. Better methods of identifying uncomplicated hyperparasitemia, the main cause of ACT treatment failure, are required so that longer courses of treatment can be given to these high-risk patients. Reducing the use of artemisinin monotherapies will reduce the continued selection pressure which could lead potentially to higher levels of artemisinin resistance. Triple artemisinin combination therapies should be deployed as soon as possible to protect the ACT partner drugs and thereby delay the emergence of higher levels of resistance. As new affordable antimalarial drugs are still several years away, the control of artemisinin resistance must depend on the better use of available tools.

Phytochemicals of Swertia chirayita Roxb. ex Fleming against malarial dihydroorotate dehydrogenase: an in silico study

The global economic burden of malaria is rising and lack of effective drugs against it have imposed an insurmountable challenge in designing it that is both affordable and resistanceless. The plants with ethnobotanical values are relatively safer and its use is a viable option as therapeutics for various demographic locations. In this regard, the chemical components of a plant, Swertia chirayita Roxb. ex Fleming (traditionally used as an antimalarial agent) were explored by multiple computational tools against dihydroorotate dehydrogenase (DHODH) protein of Plasmodium falciparum (PDB ID: 6GJG), a causative agent of the disease. The docking scores were calculated to be − 10.220, − 10.131, − 10.071, − 10.024, and − 9.905 kcal/mol for the top five molecules (decussatin, swerchirin, 1-hydroxy-3,5,8-trimethoxyxanthen-9-one, swertinin, and chiratol), respectively with the native ligand possessing a higher value of − 9.873 kcal/mol. The adducts were geometrically and thermodynamically stable as revealed by several parameters extracted from 200 ns molecular dynamics simulations (MDS) and verified by a single run of 600 ns. The smooth RMSD profiles from a cumulative MDS of 2.0 μs, pointed towards a sturdy nature of the receptor geometry with limited translational or rotational motion of the ligands. The involvement of LEU11, CYS14, LEU15, CYS23, PHE27, ILE102, ARG104, TYR337, LEU340, and VAL341 amino acid residues with mainly hydrophobic interactions at the orthosteric site were observed for most of the adducts. The binding free energy changes (up to − 30.18 ± 4.38 kcal/mol) hinted at the feasibility and sustained thermodynamical spontaneity of the forward reaction of the complex formation. The hit molecules could possibly disrupt or inhibit the normal functioning of the DHODH receptor leading to the likely prevention and cure of the disease and are recommended for experimental trials.