The prevalence of Pfk13 polymorphism in malaria patients treated with artemisinin-based therapy: a systematic review and meta-analysis.

Artemisinin (ART) combination therapy is the main treatment for malaria. Pfk13 mutations (or K13 mutations, Kelch 13) are associated with ART resistance. This study aims to conduct a systematic review and meta-analysis of the prevalence of K13 mutations with ART resistance in malaria-endemic countries. An electronic search of studies in 2018 and a manual search in 2020 were performed to identify relevant studies. The risk of bias was assessed using the National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies. Data analysis was performed using R 4.1.0. Heterogeneity was estimated using the statistic I2 and Cochran Q test. A total of 170 studies were included in our review. Of these, 55 studies investigated the prevalence of K13 mutations in Southeast Asia. The meta-analysis showed that Southeast Asia had the highest prevalence of K13 mutations, whereas Africa, South America, Oceania, and other Asian countries outside Southeast Asia had a low prevalence of K13 mutations. The C580Y mutation was the most common in Southeast Asia with 35.5% (95%CI: 25.4-46.4%), whereas the dominant mutation in Africa was K189T (22.8%, 95%CI: 7.6-43.2%). This study revealed the emergence of ART resistance associated with K13 mutations in Southeast Asia. The diversity of each type of K13 mutation in other regions was also reported.

Quality assessment of oral antimalarial and antiretroviral medicines used by public health systems in Sahel countries.

Malaria and Human Immunodeficiency Virus infections are among the top 10 causes of death in low income countries. Furthermore, many medicines used in these treatment areas are substandard, which contributes to the high death rate. Using a monitoring system to identify substandard and falsified medicines, the study aims to evaluate the quality of antimalarial and antiretroviral medicines in Sahel countries, assessing site conditions, compliance of medicines with pharmacopoeia tests, formulation equivalence with a reference medicine, and the influence of climate on quality attributes. Ultra Performance Liquid Chromatography methods for eight active pharmaceutical ingredients were validated following the International Conference for Harmonization guideline for its detection and quantification. Quality control consists of visual inspections to detect any misinformation or imperfections and pharmacopeial testing to determine the quality of pharmaceutical products. Medicines which complied with uniformity dosage units and dissolution tests were stored under accelerated conditions for 6 months. Artemether/Lumefantrine and Lopinavir/Ritonavir formulations failed uniformity dosage units and disintegration tests respectively, detecting a total of 28.6% substandard medicines. After 6 months stored under accelerated conditions (40 °C // 75% relative humidity) simulating climatic conditions in Sahel countries, some medicines failed pharmacopeia tests. It demonstrated the influence of these two factors in their quality attributes. This study emphasizes the need of certified quality control laboratories as well as the need for regulatory systems to maintain standards in pharmaceutical manufacturing and distribution in these countries, especially when medicines are transported to rural areas where these climatic conditions are harsher.

Cost-effectiveness of village health worker-led integrated community case management (iCCM) versus health facility based management for childhood illnesses in rural southwestern Uganda.

BACKGROUND: In Uganda, village health workers (VHWs) manage childhood illness under the integrated community case management (iCCM) strategy. Care is provided for malaria, pneumonia, and diarrhoea in a community setting. Currently, there is limited evidence on the cost-effectiveness of iCCM in comparison to health facility-based management for childhood illnesses. This study examined the cost-effectiveness of the management of childhood illness using the VHW-led iCCM against health facility-based services in rural south-western Uganda. METHODS: Data on the costs and effectiveness of VHW-led iCCM versus health facility-based services for the management of childhood illness was collected in one sub-county in rural southwestern Uganda. Costing was performed using the ingredients approach. Effectiveness was measured as the number of under-five children appropriately treated. The Incremental Cost-Effectiveness Ratio (ICER) was calculated from the provider perspective. RESULTS: Based on the decision model for this study, the cost for 100 children treated was US$628.27 under the VHW led iCCM and US$87.19 for the health facility based services, while the effectiveness was 77 and 71 children treated for VHW led iCCM and health facility-based services, respectively. An ICER of US$6.67 per under five-year child treated appropriately for malaria, pneumonia and diarrhoea was derived for the provider perspective. CONCLUSION: The health facility based services are less costly when compared to the VHW led iCCM per child treated appropriately. The VHW led iCCM was however more effective with regard to the number of children treated appropriately for malaria, pneumonia and diarrhoea. Considering the public health expenditure per capita for Uganda as the willingness to pay threshold, VHW led iCCM is a cost-effective strategy. VHW led iCCM should, therefore, be enhanced and sustained as an option to complement the health facility-based services for treatment of childhood illness in rural contexts.

Mixed-method evaluation study of a targeted mass drug administration of long-acting anti-malarials among children aged 3 months to 15 years in the Bossangoa sub-prefecture, Ouham, Central African Republic, during the COVID-19 pandemic.

BACKGROUND: In 2020, during the COVID-19 pandemic, Médecins Sans Frontières (MSF) initiated three cycles of dihydroartemisin-piperaquine (DHA-PQ) mass drug administration (MDA) for children aged three months to 15 years within Bossangoa sub-prefecture, Central African Republic. Coverage, clinical impact, and community members perspectives were evaluated to inform the use of MDAs in humanitarian emergencies. METHODS: A household survey was undertaken after the MDA focusing on participation, recent illness among eligible children, and household satisfaction. Using routine surveillance data, the reduction during the MDA period compared to the same period of preceding two years in consultations, malaria diagnoses, malaria rapid diagnostic test (RDT) positivity in three MSF community healthcare facilities (HFs), and the reduction in severe malaria admissions at the regional hospital were estimated. Twenty-seven focus groups discussions (FGDs) with community members were conducted. RESULTS: Overall coverage based on the MDA card or verbal report was 94.3% (95% confidence interval (CI): 86.3-97.8%). Among participants of the household survey, 2.6% (95% CI 1.6-40.3%) of round 3 MDA participants experienced illness in the preceding four weeks compared to 30.6% (95% CI 22.1-40.8%) of MDA non-participants. One community HF experienced a 54.5% (95% CI 50.8-57.9) reduction in consultations, a 73.7% (95% CI 70.5-76.5) reduction in malaria diagnoses, and 42.9% (95% CI 36.0-49.0) reduction in the proportion of positive RDTs among children under five. A second community HF experienced an increase in consultations (+ 15.1% (- 23.3 to 7.5)) and stable malaria diagnoses (4.2% (3.9-11.6)). A third community HF experienced an increase in consultations (+ 41.1% (95% CI 51.2-31.8) and malaria diagnoses (+ 37.3% (95% CI 47.4-27.9)). There were a 25.2% (95% CI 2.0-42.8) reduction in hospital admissions with severe malaria among children under five from the MDA area. FGDs revealed community members perceived less illness among children because of the MDA, as well as fewer hospitalizations. Other indirect benefits such as reduced household expenditure on healthcare were also described. CONCLUSION: The MDA achieved high coverage and community acceptance. While some positive health impact was observed, it was resource intensive, particularly in this rural context. The priority for malaria control in humanitarian contexts should remain diagnosis and treatment. MDA may be additional tool where the context supports its implementation.

Experience of healthcare personnel on Co-payment mechanism and the implications on its use in private drug outlets in Uganda.

BACKGROUND: Malaria treatment is faced with the challenge of access, affordability, availability, and quality of antimalarial medicines. Affordable medicines facility-malaria (AMFm) program and subsequently Co-payment mechanism were developed to help increase access to quality assured Artemisinin-based combination therapies (ACTs) in seven countries in sub-Saharan Africa. We explored through a qualitative study, experience of healthcare personnel on Co-payment mechanism and the implication on its use in private drug outlets in Uganda. METHOD: Private drug outlets that reported stocking antimalarial agents in moderate-to-high and low malaria transmission settings were purposively selected for inclusion in the study. In each drug outlet, data was collected from a pharmacist/dispenser through key informant interview. The interview was done using a key informant interview guide which covered the following areas, (i) sociodemographic characteristics, ii) awareness of healthcare personnel on the co-payment mechanism, (iii) awareness of healthcare personnel on quality assured artemisinin combination therapies (QAACT), (iv) antimalarial stocking in private drug outlets, (v) antimalarial dispensing prices, (vi) considerations made while stocking, and pricing antimalarial agents, vii) challenges in antimalarial dispensing, and (viii) access to antimalarial agents in private drug outlets. Data was managed using Atlas.ti and analyzed using framework methodology. RESULTS: Data was collected from 25 key informants (12 pharmacists and 13 dispensers). Five themes emerged following data analysis, (i) antimalarial stocking influenced by price and client demand, (ii) access and purchasing behavior of drug outlet clients, (iii) basis of dispensing antimalarial agents in private drug outlets, (iv) awareness of QAACT, and (v) awareness of Co-payment mechanism. None of the study participants was aware of the existence of Co-payment mechanism and QAACT in the private sector. Duocotecin brand of ACTs was the most mentioned and dispensed ACT among the study participants in private drug outlets. Nearly all the pharmacists/dispensers said that many clients who request to purchase ACTs don't come with a prescription and prefer buying cheaper antimalarial agents. Study participants reported stocking and selling both ACTs and non-ACT antimalarial agents in the drug outlets. Pharmacists/dispensers in the drug outlets reported that most clients could not afford buying a full dose of an ACT. None of the study participants considered using Co-payment mechanism while stocking ACTs in the drug outlets. CONCLUSION: There is lack of awareness and utilization of Co-payment mechanism in stocking, pricing, and dispensing of ACTs among pharmacists/dispensers in private drug outlets in Uganda. The antimalarial dispensing in drug outlets was mostly based on prescriptions, clients' preferences, and medicine affordability. The Ministry of Health needs to create demand for Co-payment mechanism through public awareness campaigns, training of healthcare personnel and behavior change communication in the private sector.

Rationalizing artemisinin-based combination therapies use for treatment of uncomplicated malaria: A situation analysis in health facilities and private pharmacies of Douala 5e-Cameroon.

Artemisinin-based combination therapies (ACTs) represent one of the mainstays of malaria control. Despite evidence of the risk of ACTs resistant infections in resource-limited countries, studies on the rational use of ACTs to inform interventions and prevent their emergence and/or spread are limited. The aim of this study was designed to analyze practices toward ACTs use for treating the treatment of uncomplicated malaria (UM) in an urban community. Between November 2015 and April 2016, a cross-sectional and prospective study was conducted in the 6 health facilities and all pharmacies in the Douala 5e subdivision, Cameroon. Anonymous interviews including both open- and closed-ended questions were conducted with selected participants among drug prescribers, patients attending the health facilities, and customers visiting the pharmacies. Data analysis was performed using StataSE11 software (version 11 SE). A total of 41 prescribers were included in the study. All were aware of national treatment guidelines, but 37.7% reported not waiting for test results before prescribing an antimalarial drug, and the main reason being stock-outs at health facilities. Likewise, artemether+lumefantrine/AL (81%) and dihydroartemisinin+piperaquine (63.5%) were the most commonly used first- and second-line drugs respectively. Biological tests were requested in 99.2% (128/129) of patients in health facilities, 60.0% (74) were performed and 6.2% were rationally managed. Overall 266 (35%) of 760 customers purchased antimalarial drugs, of these, 261 (98.1%) agreed to participate and of these, 69.4% purchased antimalarial drugs without a prescription. ACTs accounted for 90.0% of antimalarials purchased from pharmacies, of which AL was the most commonly prescribed antimalarial drug (67.1%), and only 19.5% of patients were appropriately dispensed. The current data suggest a gap between the knowledge and practices of prescribers as well as patients and customers misconceptions regarding the use of ACTs in Douala 5e subdivision. Despite government efforts to increase public awareness regarding the use of ACTs as first-line treatment for UM, our findings point out a critical need for the development, implementation and scaling-up of control strategies and continuing health education for better use of ACTs (prescription and dispensing) in Cameroon.

Persistent and multiclonal malaria parasite dynamics despite extended artemether-lumefantrine treatment in children.

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

[Gastrointestinal symptoms may reflect complicated falciparum malaria]. / Gastrointestinale Symptome als Ausdruck einer komplizierten Malaria tropica.

HISTORY: A 42-year-old female presented with a two-day history of vomiting, diarrhea, fever and chills. Two weeks before she had returned to Germany from a Safari in Tanzania. She had disregarded the recommendation to take antimalarial chemoprophylaxis. CLINICAL FINDINGS AND DIAGNOSIS: The thin blood film showed Plasmodium falciparum-parasitized erythrocytes, and Plasmodium falciparum malaria was diagnosed. The full blood count showed thrombocytopenia and ultrasound imaging revealed splenomegaly. Initially the criteria for complicated malaria were not fulfilled. THERAPY AND COURSE: We started oral therapy with atovaquone/proguanil. The patient vomited the tablets twice. Therefore therapy was switched to intravenous artesunate. Subsequently, parasitemia dropped from 2.8 to 1.0 % within 22 hours. After 3 days of artesunate i. v., treatment could then be completed with oral atovaquone/proguanil, and the symptoms resolved. CONCLUSIONS: Patients with malaria and persistent vomiting should be treated intravenously and monitored closely, as severe gastrointestinal symptoms may reflect impending organ failure. We therefore propose including persistent vomiting in the list of criteria for complicated malaria.

Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development.

Identification of new druggable protein targets remains the key challenge in the current antimalarial development efforts. Here we used mass-spectrometry-based cellular thermal shift assay (MS-CETSA) to identify potential targets of several antimalarials and drug candidates. We found that falcilysin (FLN) is a common binding partner for several drug candidates such as MK-4815, MMV000848, and MMV665806 but also interacts with quinoline drugs such as chloroquine and mefloquine. Enzymatic assays showed that these compounds can inhibit FLN proteolytic activity. Their interaction with FLN was explored systematically by isothermal titration calorimetry and X-ray crystallography, revealing a shared hydrophobic pocket in the catalytic chamber of the enzyme. Characterization of transgenic cell lines with lowered FLN expression demonstrated statistically significant increases in susceptibility toward MK-4815, MMV000848, and several quinolines. Importantly, the hydrophobic pocket of FLN appears amenable to inhibition and the structures reported here can guide the development of novel drugs against malaria.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania. METHODS: This was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy. RESULTS: A total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).

Randomized, placebo-controlled, double-blind phase I trial of co-administered pyronaridine and piperaquine in healthy adults of sub-Saharan origin.

Drug resistance to sulfadoxine-pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining pyronaridine (PYR) and piperaquine (PQP), both components of approved antimalarial therapies, has the potential to protect vulnerable populations from severe malaria. This randomized, double-blind, placebo-controlled (double-dummy), parallel-group, single site phase I study in healthy adult males or females of Black sub-Saharan African ancestry investigated the safety, tolerability, and pharmacokinetics of PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8), and double placebo (n = 6) administered orally once daily for 3 days at the registered dose for the treatment of uncomplicated malaria. All participants completed the study. Forty-five adverse events were reported in 26 participants, most (41/45) were mild/moderate in severity, with no serious adverse events, deaths, or study withdrawals. Adverse events were reported in 66.7% (10/15) of participants administered PYR + PQP, 87.5% (7/8) with PYR + placebo, 50.0% (4/8) with PQP + placebo, and 83.3% (5/6) with placebo. For PYR containing regimens, five of 23 participants had asymptomatic transient increases in alanine and/or aspartate aminotransferase. With PQP containing regimens, four of 23 participants had mild Fridericia-corrected QT interval prolongation. Liver enzyme elevations and prolonged QTc interval were consistent with observations for PYR-artesunate and dihydroartemisinin-PQP, respectively, administered to healthy adults and malaria patients. Increases in PYR and PQP exposures were observed following co-administration versus placebo, with substantial interparticipant variability. The findings suggest that PYR + PQP may have potential in chemoprevention strategies. Further studies are needed in the target populations to assess chemoprotective efficacy and define the benefit-risk profile, with special considerations regarding hepatic and cardiac safety.

Next Generation Chemiluminescent Probes for Antimalarial Drug Discovery.

Malaria is caused by parasites of the Plasmodium genus and remains one of the most pressing human health problems. The spread of parasites resistant to or partially resistant to single or multiple drugs, including frontline antimalarial artemisinin and its derivatives, poses a serious threat to current and future malaria control efforts. In vitro drug assays are important for identifying new antimalarial compounds and monitoring drug resistance. Due to its robustness and ease of use, the [3H]-hypoxanthine incorporation assay is still considered a gold standard and is widely applied, despite limited sensitivity and the dependence on radioactive material. Here, we present a first-of-its-kind chemiluminescence-based antimalarial drug screening assay. The effect of compounds on P. falciparum is monitored by using a dioxetane-based substrate (AquaSpark ß-D-galactoside) that emits high-intensity luminescence upon removal of a protective group (ß-D-galactoside) by a transgenic ß-galactosidase reporter enzyme. This biosensor enables highly sensitive, robust, and cost-effective detection of asexual, intraerythrocytic P. falciparum parasites without the need for parasite enrichment, washing, or purification steps. We are convinced that the ultralow detection limit of less than 100 parasites of the presented biosensor system will become instrumental in malaria research, including but not limited to drug screening.

Development of Novel Peptidyl Nitriles Targeting Rhodesain and Falcipain-2 for the Treatment of Sleeping Sickness and Malaria.

In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African trypanosomiasis, and malaria present therapeutic problems due to the onset of resistance, toxicity problems and the limited spectrum of action. In this drug discovery process, rhodesain and falcipain-2, of Trypanosoma brucei rhodesiense and Plasmodium falciparum, are currently considered the most promising targets for the development of novel antitrypanosomal and antiplasmodial agents, respectively. Therefore, in our study we identified a novel lead-like compound, i.e., inhibitor 2b, which we proved to be active against both targets, with a Ki = 5.06 µM towards rhodesain and an IC50 = 40.43 µM against falcipain-2.

Oral acute toxicity study and in vivo antimalarial activity of Strychnos lucida R. Br. tablet.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria eradication has been a major goal of the Indonesian government since 2020. Medicinal plants, such as Strychnos lucida R. Br., are empirically used to treat malaria through traditional preparation methods. However, the safety and efficacy of these plants have not yet been confirmed. Therefore, further investigations are necessary to confirm the safety and efficacy of S. lucida as an antimalarial agent. AIMS OF THE STUDY: To quantify the concentration of brucine in the S. lucida extract, determine the acute oral toxicity of the standardized extract, and evaluate the in vivo antimalarial potency of S. lucida tablet (SLT). MATERIALS AND METHODS: Acute oral toxicity of S.lucida extract was determined using the Organization for Economic Co-operation and Development 420 procedure, and the analytical method for brucine quantification was validated using high-performance liquid chromatography. In addition, antimalarial activity was determined using the Peter's four-day suppressive method. RESULTS: Acute toxicity analysis revealed S. lucida as a low-toxicity compound with a cut-off median lethal dose of 2000-5000 mg/kg body weight [BW], which was supported by the hematological and biochemical profiles of the kidneys, liver, and pancreas (p > 0.05). Extract standardization revealed that S. lucida contained 3.91 ± 0.074% w/w brucine, adhering to the limit specified in the Indonesian Herbal Pharmacopeia. Antimalarial test revealed that SLT inhibited the growth of Plasmodium berghei by 27.74-45.27%. Moreover, SLT improved the hemoglobin and hematocrit levels. White blood cell and lymphocyte counts were lower in the SLT-treated group than in the K (+) group (p < 0.05). CONCLUSION: Histopathological and biochemical evaluations revealed that S. lucida extract was safe at a dose of 2000 mg/kg BW with low toxicity. SLT inhibited Plasmodium growth and improved the hemoglobin, hematocrit, and red blood cell profiles. Additionally, SLT reduced the lymphocyte and WBC counts and increased the monocyte and thrombocyte counts as part of the immune system response against Plasmodium infection.

Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of the antimalarial drug pyronaridine in human whole blood.

Malaria remains a major health concern, aggravated by emerging resistance of the parasite to existing treatments. The World Health Organization recently endorsed the use of artesunate-pyronaridine to treat uncomplicated malaria. However, there is a lack of clinical pharmacokinetic (PK) data of pyronaridine, particularly in special populations such as children and pregnant women. Existing methods for the quantification of pyronaridine in biological matrices to support PK studies exhibit several drawbacks. These include limited sensitivity, a large sample volume required, and extensive analysis time. To overcome these limitations, an ultra-performance reversed-phase liquid chromatography tandem-mass spectrometry method to determine pyronaridine was developed and validated according to international guidelines. The method enabled fast and accurate quantification of pyronaridine in whole blood across a clinically relevant concentration range of 0.500-500 ng/mL (r2 ≥ 0.9963), with a required sample volume of 50 µL. Pyronaridine was extracted from whole blood using liquid-liquid extraction, effectively eliminating the matrix effect and preventing ion enhancement or suppression. The method achieved a satisfactory reproducible sample preparation recovery of 77%, accuracy (as bias) and precision were within ±8.2% and ≤5.3%, respectively. Stability experiments demonstrated that pyronaridine was stable for up to 315 days when stored at -70°C. Adjustments to the chromatographic system substantially reduced carry-over and improved sensitivity compared to prior methods. The method was successfully applied to quantify pyronaridine in whole blood samples from a selection of pregnant malaria patients participating in the PYRAPREG clinical trial (PACTR202011812241529) in the Democratic Republic of the Congo, demonstrating its suitability to support future PK studies. Furthermore, the enhanced sensitivity allows for the determination of pyronaridine up to 42 days post-treatment initiation, enabling assessment of the terminal elimination half-life.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018.

BACKGROUND: The use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania. METHODS: A single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature ≥ 37.5 °C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety. RESULTS: A total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan-Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.

Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure.

Approximately 3.3 billion people live with the threat of Plasmodium vivax malaria. Infection can result in liver-localized hypnozoites, which when reactivated cause relapsing malaria. This work demonstrates that an enzyme-cleavable polymeric prodrug of tafenoquine addresses key requirements for a mass administration, eradication campaign: excellent subcutaneous bioavailability, complete parasite control after a single dose, improved therapeutic window compared to the parent oral drug, and low cost of goods sold (COGS) at less than $1.50 per dose. Liver targeting and subcutaneous dosing resulted in improved liver:plasma exposure profiles, with increased efficacy and reduced glucose 6-phosphate dehydrogenase-dependent hemotoxicity in validated preclinical models. A COGS and manufacturability analysis demonstrated global scalability, affordability, and the ability to redesign this fully synthetic polymeric prodrug specifically to increase global equity and access. Together, this polymer prodrug platform is a candidate for evaluation in human patients and shows potential for P. vivax eradication campaigns.

A case of severe Plasmodium ovale malaria with acute respiratory distress syndrome and splenic infarction in a male traveller presenting in Italy.

BACKGROUND: Plasmodium ovale malaria is usually considered a tropical infectious disease associated with low morbidity and mortality. However, severe disease and death have previously been reported. CASE PRESENTATION: A case of severe P. ovale malaria in a healthy Caucasian man with a triangle splenic infarction and clinical progression towards Acute Respiratory Distress Syndrome was reported despite a rapid response to oral chloroquine treatment with 24-h parasitaemia clearance. CONCLUSION: Plasmodium ovale malaria is generally considered as a benign disease, with low parasitaemia. However, severe disease and death have occasionally been reported. It is important to be aware that occasionally it can progress to serious illness and death even in immunocompetent individuals.

Access to quality-assured artemisinin-based combination therapy and associated factors among clients of selected private drug outlets in Uganda.

BACKGROUND: Malaria treatment in sub-Saharan Africa is faced with challenges including unreliable supply of efficacious agents, substandard medicines coupled with high price of artemisinin-based combinations. This affects access to effective treatment increasing risk of malaria parasite resistance development and adverse drug events. This study investigated access to quality-assured artemisinin-based combination therapy (QAACT) medicines among clients of selected private drug-outlets in Uganda. METHODS: This was a cross sectional study where exit interviews were conducted among clients of private drug outlets in low and high malaria transmission settings in Uganda. This study adapted the World Health Organization/Health Action International (WHO/HAI) standardized criteria. Data was collected using a validated questionnaire. Data entry screen with checks was created in Epi-data ver 4.2 software and data entered in duplicate. Data was transferred to STATA ver 14.0 and cleaned prior to analysis. The analysis was done at 95% level of significance. RESULTS: A total of 1114 exit interviews were conducted among systematically sampled drug outlet clients. Over half, 54.9% (611/1114) of the participants were males. Majority, 97.2% (1083/1114) purchased an artemisinin-based combination anti-malarial. Most, 55.5% (618/1114) of the participants had a laboratory diagnosis of malaria. Majority, 77.9% (868/1114) of the participants obtained anti-malarial agents without a prescription. Less than a third, 27.7% (309/1114) of the participants obtained a QAACT. Of the participants who obtained QAACT, more than half 56.9% (173/309) reported finding the medicine expensive. The predictors of accessing a QAACT anti-malarial among drug outlet clients include type of drug outlet visited (aPR = 0.74; 95%CI 0.6, 0.91), not obtaining full dose (3-day treatment) of ACT (aPR = 0.49; 95%CI 0.33, 0.73), not finding the ACT expensive (aPR = 1.24; 95%CI 1.03, 1.49), post-primary education (aPR = 1.29; 95%CI 1.07,1.56), business occupation (aPR = 1.24; 95%CI 1.02,1.50) and not having a prescription (aPR = 0.76; 95%CI 0.63, 0.92). CONCLUSION: Less than a third of the private drug outlet clients obtained a QAACT for management of malaria symptoms. Individuals who did not find artemisinin-based combinations to be expensive were more likely to obtain a QAACT anti-malarial. The Ministry of Health needs to conduct regular surveillance to monitor accessibility of QAACT anti-malarial agents under the current private sector copayment mechanism.