Artemisinin-based Combination Therapy Research Articles

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.

Presence of Plasmodium falciparum strains with artemisinin-resistant K13 mutation C469Y in Busia County, Western Kenya

Malaria remains a key health and economic problem, particularly in sub-Saharan Africa. The emergence of artemisinin drug resistance (ART-R) parasite strains poses a serious threat to the control and elimination of this scourge. This is because artemisinin-based combination therapies (ACTs) remain the first-line treatment in the majority of malaria-endemic regions in Sub-Saharan Africa. Certain single-nucleotide polymorphisms in the propeller domains of Plasmodium falciparum Kelch 13 protein (K13) have been associated with delayed parasite clearance in vivo and in vitro. These mutations serve as vital molecular markers for tracking the emergence and dispersion of resistance. Recently, there have been increasing reports of the emergence and spread of P. falciparum ART-R parasites in the Eastern Africa region. This necessitates continued surveillance to best inform mitigation efforts. This study investigated the presence of all reported mutations of K13 propeller domains in the parasite population in Busia County, Kenya, a known malaria-endemic region. Two hundred twenty-six participants with microscopically confirmed uncomplicated malaria were recruited for this study. They were treated with artemether–lumefantrine under observation for the first dose, and microscopic examination was repeated 1 day later after ensuring the participants had taken the second and third doses. P. falciparum DNA from all samples underwent targeted amplification of the K13 gene using a semi-nested PCR approach, followed by Sanger sequencing. The recently validated ART-R K13 mutation C469Y was identified in three samples. These three samples were among 63 samples with a low reduction in parasitemia on day 1, suggesting day 1 parasitemia reduction rate is a useful parameter to enrich the ART-R parasites for further analysis. Our findings highlight the need for continuous surveillance of ART-R in western Kenya and the region to determine the spread of ART-R and inform containment.

Intermittent Preventive Treatment of Malaria in Pregnancy and the Impact on Neonates in African Countries as Assessed by Entropy Weight and TOPSIS Methods.

Background/Objectives: In regions of Africa with a high prevalence of malaria, pregnant women in their first or second trimester should be administered intermittent preventive treatment in pregnancy (IPTp). However, infants may contract malaria despite the IPTp therapy that their mothers have received. The objective of the present investigation was to assess the symptoms and various treatments for neonatal malaria. Methods: Entropy weight and TOPSIS were used to achieve the study goal. The TOPSIS multi-attribute decision-making system was used to assess newborn malaria symptoms and select the optimal treatment, even for mothers receiving IPTp medication during pregnancy. The entropy weight approach calculated TOPSIS attribute weights. The present research used UNICEF data for 14 African nations in 2023. Results: The results indicated that neonates whose mothers received IPTp therapy ultimately contracted malaria, with diarrhea being the primary symptom. It is important to note that health providers administer a combination of zinc and oral rehydration solution (ORS) to infants as the most effective treatment for malaria symptoms, thereby abandoning the first-line treatment for malaria, artemisinin-based combination therapy (ACT). Conclusions: The most effective treatment for neonatal malaria is a combination of zinc and ORS, although less than half of children in Africa have access to ORS. Therefore, the findings of this study may encourage African countries to prioritize co-pack therapy in their procurement and supply, healthcare provider training, and expenditures. This therapy will also help alleviate the symptoms of malaria in neonates.

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.

ONT sequencing identifies a high prevalence of crt sensitive, triple mutant dhfr and single mutant dhps parasites within an ANC population in Nigeria

BackgroundMalaria in pregnancy is a major public health issue, particularly among vulnerable populations in malaria-endemic sub-Saharan African countries. To mitigate its risks, WHO recommends sulphadoxine-pyrimethamine (SP) for chemoprevention and artemisinin-based combination therapy (ACT) to treat uncomplicated Plasmodium falciparum malaria. These interventions have helped to alleviate the risk associated with malaria in pregnancy; however, in the context of the emergence of SP- and ACT-resistant P. falciparum, maintained efficacy is under threat. Molecular surveillance is a reliable tool to monitor the emergence of resistance where molecular markers are known. Thus, the objective of the study was to use a multiplexed amplicon Oxford Nanopore sequencing approach to assess the molecular markers for antimalarial resistance among pregnant women in Nigeria.MethodsDried blood spots (DBS) were collected from pregnant women who received IPTp-SP at the enrollment and follow-up visits. P. falciparum genomic DNA was extracted by the Chelex® method and Pf18S qPCR was used to detect parasite DNA in each sample. With nested PCR assays, fragments of Pfdhps, Pfdhfr, Pfmdr1, Pfcrt, Pfk13 and Pfama1 genes were amplified and multiplexed amplicon-based sequencing was conducted on the minION Oxford Nanopore Technology.ResultIn total, 251 pregnant women were enrolled in the study and 457 DBS samples were collected. P. falciparum genomic DNA was detected in 12% (56/457) of the samples, 31 at baseline and the remaining during the follow-up visits. Pfama1, pfk13, Pfdhps, Pfdhfr, Pfmdr1 and Pfcrt were successfully sequenced in a single run. Notably, k13 artemisinin resistance mutations were absent, the frequencies of Pfdhfr and Pfdhps SP resistance haplotypes, IRN for pyrimethamine resistance and ISGKA/IAGKA associated with sulphadoxine resistance were 82% (36/44) and 64% (27/42), respectively, and the Pfcrt CVIET resistant haplotype was at approximately 22% (7/32).Conclusion and recommendationsHere a multiplexed amplicon-based ONT assay established that triple mutant Pfdfhr-IRN, double mutant Pfdhps-SG haplotypes and the chloroquine sensitive strain were prevalent among pregnant women in Nigeria.

Towards next-generation treatment options to combat Plasmodium falciparum malaria.

Malaria, which is caused by infection of red blood cells with Plasmodium parasites, can be fatal in non-immune individuals if left untreated. The recent approval of the pre-erythrocytic vaccines RTS, S/AS01 and R21/Matrix-M has ushered in hope of substantial reductions in mortality rates, especially when combined with other existing interventions. However, the efficacy of these vaccines is partial, and chemotherapy remains central to malaria treatment and control. For many antimalarial drugs, clinical efficacy has been compromised by the emergence of drug-resistant Plasmodium falciparum strains. Therefore, there is an urgent need for new antimalarial medicines to complement the existing first-line artemisinin-based combination therapies. In this Review, we discuss various opportunities to expand the present malaria treatment space, appraise the current antimalarial drug development pipeline and highlight examples of promising targets. We also discuss other approaches to circumvent antimalarial resistance and how potency against drug-resistant parasites could be retained.

Ligand-based pharmacophore modeling, virtual screening, and molecular dynamics simulations of Pfhsp90 fingerprints in Plasmodium malaria treatment

The World Health Organization (WHO) documents malaria as one of the leading causes of high morbidity and mortality worldwide. The disease affects millions and kills thousands of people annually. Efforts to reduce the global burden of malaria have prompted the WHO to recommend prevention strategies such as using antimalarial drugs. However, these strategies have been ineffective because of antimalarial drug resistance. The only efficacious malaria treatment is Artemisinin-based Combination Therapy (ACT). However, the extended ACT clearance times, linked to the emergence of artemisinin monotherapy resistance recorded most recently in Africa and the Great Mekong region, pose a danger to its efficacy. Therefore, better efficacious antimalarial drugs are required. Since P. falciparum heat shock protein 90 (PfHsp90) is a well-characterized malaria drug target, this study uses it to discover more efficacious antimalarial drugs. An in silico approach was used to discover PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria using a molecular dynamics simulation (MDS) and hierarchical virtual screening. Geldanamycin (GDM), a well-known anti-PfHsp90 compound, was used to identify PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria by screening it against the ZINC20 database via the ZINCPHARMER web server. This virtual screening process resulted in 17 hits. These ZINCPHARMER hits were subjected to drug-likeness and pharmacokinetics properties analysis in the SwissADME web server, and nine of them satisfied the requirements. The nine ZINC20 compounds were docked with PfHsp90 using the PyRx software version 0.8 to understand their interactions. From the molecular docking results, ZINC09060002 (−8.2 kcal/mol), ZINC72133064 (−7.8 kcal/mol), ZINC72163401 (−7.7 kcal/mol), ZINC72358537 (−8.1 kcal/mol), and ZINC72358557 (−7.6 kcal/mol) had better binding affinities to PfHsp90 than GDM (−7.5 kcal/mol). The stability of these molecularly docked protein–inhibitor complexes was assessed through MDS using GROMACS 2022. ZINC72163401, ZINC72358537, and ZINC72358557 formed stable complexes with PfHsp90. The lead compounds were subjected to in vitro validation for their inhibitory capability. They showed promising inhibition of parasite growth with IC50 values ranging between 200 and 400 ng/mL. In this regard, the three PfHsp90 inhibitors can be further developed as potential antimalarial drugs. However, further structural optimization studies and clinical (in vivo) tests are necessary to ascertain the antimalarial activity of these compounds in humans.

Frequency of chloroquine-resistant haplotype of Plasmodium falciparum (CVIET) in Ibadan, Southwest Nigeria 17 years post-chloroquine withdrawal

The replacement of chloroquine with artemisinin-based combination therapies (ACTs) for over a decade has had varying impacts on the ability of the malaria parasite to sustain its chloroquine resistance prowess in different malaria-endemic regions. We evaluated the frequency of Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutations in Ibadan, Nigeria 17 years after the replacement of chloroquine with ACTs for malaria treatment. Fragments of PfCRT gene from genomic DNA of microscopically confirmed P. falciparum-infected patients were amplified and sequenced. There were 19% CVIET mutant and 81% CVMNK wild-type haplotypes on residues 72–76. A220S change were found in 16.7% of samples occurring concurrently with the CVIET haplotype, while a Q271E mutation occurred in a PfCRT wild-type isolate. The reduced prevalence of the PfCRT mutant alleles in this study compared to previous reports suggests a gradual disappearance of chloroquine-resistant malaria parasites following reduced drug pressure. It may also be a result of fitness demand on the parasites in attempts to evolve resistance against the current first-line regimen. However, evaluating the prevalence of other chloroquine resistance markers such as Plasmodium falciparum multidrug resistance 1 gene mutations in this population, and a more robust sample size will help to consolidate these findings.

Analysis of <em>Pfmdr1</em> and <em>Pfcrt drug</em> resistant markers in <em>Plasmodium falciparum</em> following treatments of patients from Nyando and Mbita, Nyanza region with Artemisinin-based combination therapy

The multidrug resistance of Plasmodium falciparum to antimalarial drugs is a major public health concern in the global management of malaria, especially in developing countries. As of today, malaria treatment is primarily dependent on the sustained efficacy of artemisinin-based combination therapy (ACT). Recent reports indicating decline in efficacy of ACT and artesunate monotherapy in Southeast Asia are a major threat to global malaria control achievements. Initially, mutations in Pfmdr1 were associated with chloroquine and amodiaquine resistance only, but there are now emerging field study reports of Pfmdr1 mutation conferring tolerance to ACT. The current study used Restriction Fragment Length Polymorphism to evaluate the prevalence of genetic polymorphisms of Plasmodium falciparum multidrug resistance (Pfmdr1) and Plasmodium falciparum chloroquine-resistant transporter (Pfcrt) gene mutations in Mbita and Nyando field isolates. The findings report that the prevalence of Pfcrt K76T mutation in Plasmodium falciparum field isolates in Mbita declined significantly from 76.3% (95% CI 21.0-31.0) in 2008 to 51.9% (95% CI 19.0-25.0) in 2014, a reduction of 24.4% (χ2df =1 = 4.709, P = 0.0000). In Nyando, prevalence stood at 66.8% (95% CI 12.0-14.0) in 2014 down from 73.7% (95% CI 27.0-48.0), insignificant reduction of 6.9% (χ2df =1 = 17.699, P = 0.0913). Prevalence for Pfmdr1 in Mbita stood at 14.7% (95% CI 44.0-51.0) in 2014 down from 21.9% (95% CI 31.0-49.0) in 2008, a significant reduction of 4.3% (χ2df =1 = 9.011, P = 0.001). While in Nyando, field isolate samples recorded 16.2% (95% CI 22.0-31.0) in 2014, down from 30.6% (95% CI 12.0-27.0), insignificant reduction of 1.9% (χ2df =1 = 11.777, P = 0.0591). Our findings confirm a common trend reported by previous studies: that there has been a small decline in the prevalence of the Pfcrt mutation over a decade since the withdrawal of Chloroquine as the first line of treatment for uncomplicated cases of malaria in Kenya.

Nanotechnology in Malaria Treatment: Targeted Drug Delivery Systems and Future Applications

Malaria continued to be a major global health challenge, particularly in regions with high disease burden, despite advancements in treatment options such as Artemisinin-based Combination Therapies (ACTs). The emergence of nanotechnology offered a transformative approach to malaria treatment, with its potential to improve drug delivery, bioavailability, and therapeutic outcomes. This review examined the current applications and advancements in nanotechnology for malaria treatment, focusing on the use of nanocarriers like liposomes, polymeric nanoparticles, and solid lipid nanoparticles. These systems enhanced the efficacy of antimalarial drugs by enabling targeted delivery to malaria-infected cells, overcoming drug resistance, and offering controlled release mechanisms. The review also explored emerging strategies such as combination therapies, personalized nanomedicine, responsive nanoparticles, and vaccine delivery systems. While nanotechnology holds great promise, challenges including safety, scalability, regulatory hurdles, and cost were addressed. Future directions suggest innovations such as smart nanocarriers, personalized treatments, and enhanced diagnostic integration. Methodologically, this review synthesized data from recent preclinical and clinical research to provide a comprehensive analysis of nanotechnology’s role in advancing malaria treatment. Global collaboration and interdisciplinary research will be pivotal in realizing the full potential of nanotechnology in combating malaria. Keywords: Nanotechnology, malaria treatment, drug delivery systems, liposomes, nanoparticles, targeted therapy, drug resistance

Advances in Artemisinin Resistance: Mechanisms, Detection, and Novel Therapeutic Approaches

Artemisinin-based combination therapies (ACTs) have been instrumental in reducing global malaria mortality over the past two decades. However, the rise of artemisinin resistance, particularly in Southeast Asia and parts of Africa, threatened these gains. Artemisinin resistance was characterized by delayed parasite clearance and is primarily driven by mutations in the kelch13 (K13) gene, which reduce the drug’s efficacy. This review explored the mechanisms behind artemisinin resistance, including genetic mutations, parasite stress responses, and reduced ring-stage sensitivity. Detection strategies, such as the use of molecular markers like K13 mutations and in vitro phenotypic assays, were discussed in detail. To combat resistance, novel therapeutic approaches were emerging, including the optimization of ACTs, the use of triple-drug regimens, host-directed therapies, and gene-editing technologies. The article highlighted the need for new antimalarial drugs, improved diagnostic tools, and global collaboration to address this growing challenge. We conducted the review by analyzing recent literature and summarizing advances in both resistance mechanisms and therapeutic strategies. Finally, future directions were outlined, emphasizing the importance of research, regulatory frameworks, and investment to mitigate the spread of resistance and ensure effective malaria control. Keywords: Artemisinin resistance, K13 mutations, malaria treatment, combination therapies, gene editing, host-directed therapies.

Hot Melt Extruded High-Dose Amorphous Solid Dispersions Containing Lumefantrine and Soluplus

Over the last 15 years, a small number of paediatric artemisinin-based combination therapy products have been marketed. These included Riamet® and Coartem® dispersible tablets, a combination of artemether and lumefantrine, co-developed by the Medicines for Malaria Venture and Novartis. Disappointingly, patient compliance, requirement for high-fat meal, and sporadic drug dissolution behaviours following administration still result in considerable challenges for these products. The first and foremost barrier that needs addressed for successful delivery of the artemether/lumefantrine combination is the poor solubility of lumefantrine within the gastrointestinal fluids. In this work, amorphous solid dispersions of lumefantrine within Soluplus®-based matrices have been manufactured using hot melt extrusion as a potential formulation strategy to achieve enhanced dissolution and apparent solubility. The drug loading capacity of Soluplus® to accommodate amorphous lumefantrine, whilst ensuring improved in-vitro dissolution performance, was investigated. The extrusion process employed a variety of processing parameters, including various temperature profiles and different production scales. The influence of variation in extrusion conditions upon the physical stability of manufactured amorphous solid dispersions was also examined. This allowed for a greater understanding of the role of extrusion processing conditions on the performance of supersaturated amorphous solid dispersions during dissolution and storage. This may allow for the design and manufacture of drug enabled formulations with lower drug dosing and thus a lower risk of adverse effects.

Comparative clinical study of Mist Amen Fevermix and Edhec Malacure: two polyherbal products used for the treatment of uncomplicated malaria in Ghana against Artemether/Lumefantrine

The use of herbal products for the treatment of malaria, has increased globally. However, inadequate scientific studies about the safety and effectiveness of such herbal products have been raised. Also, the reduced sensitivity of the malaria parasites to artemisinin-based combination therapies is of concern. There is therefore the need for new antimalarial medications including those from alternative sources such as herbal medicinal products. In this study, a prospective, comparative parallel group randomized, clinical study was done to assess the safety and effectiveness of Mist Amen Fevermix and Mist Edhec Malacure with Artemether/Lumefantrine as control at the Tafo Government Hospital, Kumasi between July and November 2019, after Committee on Human Research, Publication and Ethics approval (CHRPE/AP/424/19). The study was conducted in accordance with Good Clinical and Laboratory Practice (GCLP) and registered with the Pan African Clinical Trials Registry with trial number PACTR202109664146698. Participant completed an informed consent form. Randomization was based on a single sequence to allocate participants to a group. SPSS version 19. One-way ANOVA test and exploratory statistics was used for data analysis. Total sample size was 150 participants with 50 on each arm of the group. Male and female patients aged 15–45 years and meet inclusion criteria with clinically established malaria were treated with Mist Amen Fevermix and Mist Edhec Malacure, at the specified doses of 45 mls (0.1063 g) and 30 mls (0.0521 g) three times daily after meals for three days. Artemether/Lumefantrine was administered at a dose of 80/480 mg/kg twice daily after meals for three days. Baseline data was taken on day 0. Patients were then followed up on Day 3, 7 and 28 to establish treatment outcomes and any side effect using a checklist for signs and symptoms and Karnofsky’s scale to assess the quality of life. Mist Amen Fevermix was effective with a cure rate of 95.89%. Mist Edhec Malacure was also effective with a cure rate of 91.87%. The cure rate of Artemether/Lumefantrine was 97.25%. Kidney and liver panels were within normal reference range at the end of the 28-day study. This study supports the use of Mist Amen Fevermix and Mist Edhec Malacure, two multi-component products as safe and effective for the treatment of uncomplicated malaria. Both products achieved a comparable clinical treatment outcome with Artemether/Lumefantrine.

Prevalence and Control of Malaria in Uganda: Epidemiological Trends and Public Health Interventions

Malaria is a critical public health issue in Uganda, a country that bears one of the highest burdens of the disease globally. Despite significant advancements in medical treatments and preventive measures, malaria continues to pose a substantial threat to the health and economic well-being of Ugandans. This review provides a comprehensive analysis of the prevalence and control of malaria in Uganda, examining epidemiological trends and assessing the impact of public health interventions. Recent data indicate that while the overall incidence of malaria has declined due to intensified control efforts, pockets of high transmission persist, particularly in rural and hard-to-reach areas. Seasonal variations and demographic factors further influence malaria transmission, with children under five and pregnant women being particularly vulnerable. Public health interventions such as insecticide-treated nets (ITNs), indoor residual spraying (IRS), rapid diagnostic testing (RDT), and artemisinin-based combination therapies (ACTs) have been instrumental in reducing malaria prevalence, though challenges such as insecticide resistance and health system constraints remain. The methodology used in writing this paper involves a comprehensive review of existing literature on malaria prevalence and control strategies in Uganda. Future directions include integrated vector management, strengthening surveillance systems, and investing in research and innovation to develop new tools and strategies. Addressing these challenges through a multifaceted approach is essential for sustainable malaria control and ultimately eliminating the disease in Uganda. Keywords: Malaria Control, Epidemiological Trends, Public Health Interventions, Insecticide Resistance, Integrated Vector Management (IVM).

Asymptomatic carriage of Plasmodium falciparum in children living in a hyperendemic area occurs independently of IgG responses but is associated with a balanced inflammatory cytokine ratio

BackgroundAsymptomatic carriage of infected red blood cells (iRBCs) can be prevalent in communities regardless of transmission patterns and can occur with infection of different Plasmodium species. Clinical immunity dampens the inflammatory responses leading to disease symptoms in malaria. The aim of this study was to define the immunological correlates of asymptomatic carriage of Plasmodium falciparum in a highly exposed population.Methods142 asymptomatic Plasmodium-infected individuals greater than 2 years of age without fever (body temperature <37.5 ℃) were followed weekly for 10 weeks before being treated with artemisinin-based combination therapy (ACT). Plasma levels of 38 cytokines were measured at baseline by Luminex and the quantity and growth inhibitory activities of circulating parasite-reactive antibodies measured. The Plasmodium antigen tested included P. falciparum merozoite extract (ME) and schizont extract (SE), and the recombinant proteins erythrocyte binding antigen 175 (EBA-175) and merozoite surface protein 1 (MSP-119).ResultsMedian levels of IgG against P. falciparum EBA-175 and MSP-119 at baseline were significantly higher in those older than 20 years of age compared with the younger age group and appeared to correlate with better parasite control. Amongst all participants there were no discernible changes in IgG levels over time. Parasite density was higher in the younger age group and associated with IL-10, TNF and MCP-1 levels. A balanced IL-10:TNF ratio was associated with asymptomatic malaria regardless of age, and balanced ratios of IL-10/TNF and IL-10/IFN-γ were the only significant correlate of maintenance of asymptomatic malaria over the course of the study in individuals 20 years of age and younger.ConclusionThe above findings indicate that asymptomatic carriage of P. falciparum in children living in a hyperendemic area occurs independently of IgG but is associated with a balanced inflammatory cytokine ratio.

Population pharmacokinetics of amodiaquine and piperaquine in African pregnant women with uncomplicated Plasmodium falciparum infections.

Artemisinin-based combination therapy (ACT) is the first-line recommended treatment for uncomplicated malaria. Pharmacokinetic (PK) properties in pregnant women are often based on small studies and need to be confirmed and validated in larger pregnant patient populations. This study aimed to evaluate the PK properties of amodiaquine and its active metabolite, desethylamodiaquine, and piperaquine in women in their second and third trimester of pregnancy with uncomplicated P. falciparum infections. Eligible pregnant women received either artesunate-amodiaquine (200/540 mg daily, n = 771) or dihydroartemisinin-piperaquine (40/960 mg daily, n = 755) for 3 days (NCT00852423). Population PK properties were evaluated using nonlinear mixed-effects modeling, and effect of gestational age and trimester was evaluated as covariates. 1071 amodiaquine and 1087 desethylamodiaquine plasma concentrations, and 976 piperaquine plasma concentrations, were included in the population PK analysis. Amodiaquine concentrations were described accurately with a one-compartment disposition model followed by a two-compartment disposition model of desethylamodiaquine. The relative bioavailability of amodiaquine increased with gestational age (1.25% per week). The predicted exposure to desethylamodiaquine was 2.8%-32.2% higher in pregnant women than that reported in non-pregnant women, while day 7 concentrations were comparable. Piperaquine concentrations were adequately described by a three-compartment disposition model. Neither gestational age nor trimester had significant impact on the PK of piperaquine. The predicted exposure and day 7 concentrations of piperaquine were similar to that reported in non-pregnant women. In conclusion, the exposure to desethylamodiaquine and piperaquine was similar to that in non-pregnant women. Dose adjustment is not warranted for women in their second and their trimester of pregnancy.

Anti-infectivity efficacy and pharmacokinetics of WHO recommended single low-dose primaquine in children with acute Plasmodium falciparum in Burkina Faso: study protocol

BackgroundPrimaquine (PQ) has activity against mature P. falciparum gametocytes and proven transmission blocking efficacy (TBE) between humans and mosquitoes. WHO formerly recommended a single transmission blocking dose of 0.75 mg/kg but this was little used. Then in 2012, faced with the emergence of artemisinin-resistant P. falciparum (ARPf) in SE Asia, the WHO recommended a lower dose of 0.25 mg/kg to be added to artemisinin-based combination therapy in falciparum-infected patients in low transmission areas. This dose was considered safe in glucose-6-phosphate dehydrogenase deficiency (G6PDd) and not requiring G6PD testing. Subsequent single low-dose primaquine (SLDPQ) studies have demonstrated safety in different G6PD variants. Dosing remains challenging in children under the age of 5 because of the paucity of PQ pharmacokinetic (PK) data. We plan to assess the anti-infectivity efficacy of SLDPQ using an allometrically scaled, weight-based regimen, with a target dose of 0.25 mg/kg, in children with acute uncomplicated falciparum malaria.MethodsThis study is an open label, randomised 1:1, phase IIb study to assess TBE, tolerability, pharmacokinetics and acceptability of artesunate pyronaridine (ASPYR) administered alone or combined with SLDPQ in 56 Burkinabe children aged ≥ 6 months– < 5 years, with uncomplicated P. falciparum and a haemoglobin (Hb) concentration of ≥ 5 g/dL. We will assess TBE, using direct membrane feeding assays (DMFA), and further investigate PQ pharmacokinetics, adverse events, Hb dynamics, G6PD, sickle cells, thalassaemia and cytochrome 2D6 (CYP2D6) status, acceptability of flavoured PQ [CAST—ClinSearch Acceptability Score Test®], and the population’s knowledge, attitude and practices on malaria.Expected results and discussionWe expect children to accept tablets, confirm the TBE and gametocytocidal effects of SLDPQ and then construct a PK infectivity model (including age, sex, baseline Hb, G6PD and CYP2D6 status) to define the dose response TBE relationship that may lead to fine tuning our SLDPQ regimen. Our study will complement others that have examined factors associated with Hb dynamics and PQ PK. It will provide much needed, high-quality evidence of SLDPQ in sick African children and provide reassurance that SLDPQ should be used as a strategy against emerging ARPf in Africa.Trial registrationISRCTN16297951. Registered on September 26, 2021

Resistance to Antimalarial Drugs in Uganda: Current Status and Future Directions

Antimalarial drug resistance posed a significant challenge to malaria control in Uganda, where Plasmodium falciparum remains the predominant strain. This review examined the current status of antimalarial drug resistance in Uganda, focusing on the mechanisms underlying resistance, epidemiological trends, and the impact on malaria control programs. Chloroquine and sulfadoxine-pyrimethamine resistance have been well-documented, and recent concerns about reduced efficacy of artemisinin-based combination therapies (ACTs) highlight ongoing challenges. The review identified key mechanisms of resistance, including genetic mutations, drug efflux, metabolic pathway alterations, and potential biofilm formation. The implications of resistance on treatment efficacy, healthcare costs, and policy adjustments are discussed. Future directions included strengthening surveillance systems, optimizing combination therapies, investing in research and development, implementing integrated vector management strategies, and enhancing public education and community engagement. Related published literatures were reviewed and analysis of recent data on drug resistance patterns in Uganda was carried out and utilised in compiling this paper. By exploring these dimensions, the review aims to provide actionable insights for policymakers, healthcare providers, and researchers to effectively address drug resistance and advance malaria control efforts in Uganda. Keywords: Antimalarial Drug Resistance, Plasmodium falciparum, Chloroquine Resistance, Artemisinin-Based Combination Therapies (ACTs), Surveillance and Monitoring.

Effects of long-term repeated treatment with artemisinin-based combination therapy on the reproductive potential of male mice

Effects of long-term repeated treatment with artemisinin-based combination therapy on the reproductive potential of male mice

Therapeutic efficacy and safety of artemether-lumefantrine combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria at Teda Health Centre, Northwest Ethiopia, 2022/23

BackgroundThe emergence of Plasmodium falciparum drug resistance against artemisinin-based combination therapy has threatened malaria control efforts. Since malaria control and elimination plans are dependent on these drugs, they must remain efficacious. However, resistance to these drugs was detected in low-transmission settings and is predicted to emerge in high-transmission settings, including in unspecified areas of Ethiopia. Therefore, this study aimed to assess the therapeutic efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria.MethodsA single-arm prospective observational study was conducted at Teda Health Centre, Northwest Ethiopia, by following the 2009 World Health Organization efficacy study guidelines from September 2022 to February 2023. Patients with uncomplicated falciparum malaria were conveniently selected and treated with a standard dose of artemether-lumefantrine, along with a single low dose of primaquine. Then clinical and parasitological responses and haemoglobin levels were assessed during the 28-day scheduled follow-up. Blood films were examined and asexual parasites were quantified; axillary temperature was measured; and drug adverse events were assessed throughout the follow-up. Finally, the drug efficacy (adequate clinical and parasitological response) was determined by Kaplan–Meier and per-protocol analyses. The data were analysed using the WHO Excel spreadsheet and SPSS version 25 software.ResultsThe success rates of PCR uncorrected and corrected Kaplan–Meier analysis on day 28 were 95.8% (95% CI 87.5–98.6) and 97.3% (95% CI 89.4–99.3), respectively. The per-protocol PCR uncorrected and corrected adequate clinical and parasitological responses were 95.5% (95% CI 87.5–99.1) and 97% (95% CI 89.5–99.6), respectively. On day-3, 97% of study participants were free of asexual parasitaemia, and all of them were fever-free on day-2. All of the gametocyte-positive patients at baseline were found to be negative for gametocytes on day-2. Moreover, the baseline mean hemoglobin of 13.10 g/dl increased slightly on day-14 to 13.27 g/dl but significantly on day-28 to 13.69 g/dl in a paired sample t test. All adverse events reported were mild.ConclusionArtemether-lumefantrine continued to be an efficacious and safe drug for the treatment of uncomplicated Plasmodium falciparum malaria at the Teda Health Centre.Trial registration: unique ID# PACTR202309773069812 at https://pactr.samrc.ac.za on September 1, 2023.