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Malaria remains a preventable and treatable disease; however, recent efforts to reduce mortality have plateaued. Although artemisinin-based combination therapy demonstrates high efficacy in controlled clinical settings, its real-world effectiveness is often compromised by suboptimal patient adherence. Specifically, the artemether–lumefantrine regimen, administered twice daily over 3 days, has been associated with reduced compliance due to its complexity. Simplified therapeutic regimens that enhance adherence could, therefore, play a critical role in reinvigorating progress toward malaria elimination. Over the past decade, substantial progress has been made in the discovery and development of new chemical entities for malaria treatment, although the most advanced candidate still requires a 3-day dosing regimen. Treatment shortening most likely requires multiple drug combinations. Multi-drug regimens, such as artemether–lumefantrine–amodiaquine appear to be well tolerated, but these are under development to address emerging resistance to lumefantrine and will be unlikely to improve compliance. Sulfadoxine–pyrimethamine was originally developed as a single-dose curative treatment for malaria, and although use was curtailed early due to rapid selection for resistance, it continues to be deployed as a single therapy or in combination with other medicines, in treatment and in prevention. Combining with artemisinin-based combinations would be an option for potential treatment shortening. Of the registered antimalarial treatments, only a few of the artemisinin-based combinations are suitable. Mefloquine is excluded for tolerability concerns, amodiaquine because of its use in seasonal malaria chemoprevention, and lumefantrine and piperaquine due to concerns of emerging resistance. Pyronaridine–artesunate emerges as a promising candidate for association with sulfadoxine–pyrimethamine. A four-drug, single-dose antimalarial regimen would transform compliance, and play a major role in disease elimination. However, to ensure its success it will be important to assess the safety and tolerability of the novel association and understand its efficacy in regions with evolving resistance to sulfadoxine–pyrimethamine. Clinical studies need to assess the risk for selection of strains with novel resistance mechanisms against artesunate or pyronaridine. Importantly, a comprehensive clinical evaluation will generate valuable real-world insights into community acceptance and operational feasibility. This information will be an important foundation for future design of single dose malaria therapies involving new chemical entities.

BackgroundArtemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ) are the first-line treatments against malaria in Mozambique. Dihydroartemisinin-piperaquine (DP) has been used in-country for mass drug administration campaigns, and artesunate-pyronaridine (AS-PY) is considered an alternative drug to delay AL resistance in the country. To assess whether AL and AS-AQ remain efficacious and to confirm that DP and AS-PY are potential alternatives for uncomplicated malaria treatment, an in vivo therapeutic efficacy study was conducted in Mozambique at five sentinel sites. MethodsThis study was conducted in the districts of Montepuez (AL), Dondo (AL and AS-AQ), Mopeia (AL and AS-PY), Moatize (AL and AS-AQ), and Massinga (AL and DP) following the 2009 World Health Organization (WHO)-recommended protocol. Patients aged 6 months to 11 years with uncomplicated Plasmodium falciparum malaria (1000–200,000 parasites/µl) were enrolled, followed, and assessed for 28 days (AL and AS-AQ) or 42 days (DP and AS-PY). Genotyping for msp1/msp2/poly-α markers and match counting via the WHO/Medicines for Malaria Venture (MMV) 3/3 algorithm were used to differentiate recrudescences from new infections. The primary outcome was polymerase chain reaction corrected efficacy for each drug.ResultsIn total, 828 participants were enrolled in the four study arms: AL (462), AS-AQ (183), DP (91), and AS-PY (92). Among the recruited participants, 10.2% (85/828) were lost to follow-up or withdrew, and 60 had recurrent malaria infections, 55 of which were considered new infections and five recrudescences. Day 28 corrected AL efficacy was 100% (95% CI 94.3–100) in Massinga, 100% in Dondo, 100% (95% CI 95.5–100) in Moatize, 97.63% (95% CI 94.4–100) in Mopeia, and 98.68% (95% CI 96.2–100) in Montepuez. Day 28 corrected AS-AQ efficacy was 100% in Dondo and 100% (95% CI 95.4–100) in Moatize. For DP, the corrected efficacy on day 42 was 100% (95% CI 94.1–100) in Massinga, and that on day 42 was 97.75% (95% CI 94.7–100) in Mopeia. All drugs were well tolerated, with adverse events reported in less than 2% of the participants.ConclusionAL and AS-AQ remain effective, as their efficacy remained above the 90% WHO-recommended cut-off. DP and AS-PY also showed therapeutic efficacy above the WHO-acceptable cut-off and could be used as first-line treatments when needed. All four artemisinin-based combinations were well tolerated, with minimal safety concerns.Trial registrationClinicaltrials.gov: NCT05343312.

Background Children are particularly at risk of malaria. This analysis consolidates the clinical data for pyronaridine–artesunate (PA) paediatric granules in children from three randomized clinical trials and a real-world study (CANTAM). Methods An integrated safety analysis of individual patient data from three randomized clinical trials included patients with microscopically-confirmed Plasmodium falciparum , body weight ≥ 5 kg to < 20 kg, who received at least one dose of study drug (paediatric safety population). PA was administered once daily for 3 days; two trials included the comparator artemether–lumefantrine (AL). PCR-adjusted day 28 adequate clinical and parasitological response (ACPR) was evaluated. Real-world PA granules safety and effectiveness was also considered. Results In the integrated safety analysis, 63.9% (95% CI 60.2, 67.4; 426/667) of patients had adverse events following PA and 62.0% (95% CI 56.9, 66.9; 222/358) with AL. Vomiting was more common with PA (7.8% [95% CI 6.0, 10.1; 52/667]) than AL (3.4% [95% CI 1.9, 5.8; 12/358]), relative risk 2.3 (95% CI 1.3, 4.3; P  = 0.004), occurring mainly following the first PA dose (6.7%, 45/667), without affecting re-dosing or adherence. Prolonged QT interval occurred less frequently with PA (3.1% [95% CI 2.1, 4.8; 21/667]) than AL (8.1% [95% CI 5.7, 11.4; 29/358]), relative risk 0.39 (95% CI 0.22, 0.67; P  = 0.0007). In CANTAM, adverse events were reported for 17.7% (95% CI 16.3, 19.2; 460/2599) of patients, most commonly vomiting (5.4% [95% CI 4.6, 6.4; 141/2599]), mainly following the first dose, (4.5% [117/2599]), with all patients successfully re-dosed, and pyrexia (5.4% [95% CI 4.6, 6.3; 140/2599]). In the two comparative clinical trials, Day 28 ACPR in the per-protocol population for PA was 97.1% (95% CI 94.6, 98.6; 329/339) and 100% (95% CI 99.3, 100; 514/514) versus 98.8% (95% CI 95.7, 99.9; 165/167) and 98.4% (95% CI 95.5, 99.7; 188/191) for AL, respectively. In CANTAM, PA clinical effectiveness was 98.0% (95% CI 97.3, 98.5; 2273/2320). Conclusions Anti-malarial treatment with PA paediatric granules administered once daily for 3 days was well tolerated in children and displayed good clinical efficacy in clinical trials, with effectiveness confirmed in a real-world study. Trial registration Clinicaltrials.gov: SP-C-003-05: identifier NCT00331136; SP-C-007-07: identifier NCT0541385; SP-C-021-15: identifier NCT03201770. Pan African Clinical Trials Registry: SP-C-013-11: identifier PACTR201105000286876

Background In Nigeria, declining responsiveness to artemether–lumefantrine (AL), the artemisinin-based combination therapy (ACT) of choice since 2005, has been reported. Pyronaridine–artesunate (PA) is a newer fixed-dose ACT recently prequalified by the WHO for the treatment of uncomplicated falciparum malaria. However, PA data from the Nigerian pediatric population is scarce. Therefore, the efficacy and safety of PA and AL using the WHO 28-day anti-malarial therapeutic efficacy study protocol in Ibadan, southwest Nigeria, were compared. Methods In an open-labelled, randomized, controlled clinical trial, 172 children aged 3–144 months with a history of fever and microscopically confirmed uncomplicated Plasmodium falciparum malaria were enrolled in southwest Nigeria. Enrollees were randomly assigned to receive PA or AL at standard dosages according to body weight for 3 days. Venous blood was obtained for hematology, blood chemistry, and liver function tests on days 0, 3, 7, and 28 as part of the safety evaluation. Results 165 (95.9%) of the enrolled individuals completed the study. About half (52.3%; 90/172) of enrollees were male. Eighty-seven (50.6%) received AL, while 85 (49.4%) received PA. Day 28, adequate clinical and parasitological response for PA was 92.7% [(76/82) 95% CI 83.1, 95.9] and 71.1% [(59/83) 95% CI 60.4, 79.9] for AL (0.001). Fever and parasite clearance were similar in both groups. Two of six and eight of 24 parasite recurrences were observed among PA- and AL-treated children, respectively. PCR-corrected Day-28 cure rates for PA were 97.4% (76/78) and 88.1% (59/67) for AL (= 0.04) in the per-protocol population after new infections were censored. Hematological recovery at day 28 was significantly better among PA-treated patients (34.9% 2.8) compared to those treated with AL (33.1% 3.0) (0.002). Adverse events in both treatment arms were mild and similar to the symptoms of malaria infection. Blood chemistry and liver function tests were mostly within normal limits, with an occasional marginal rise. Conclusion PA and AL were well-tolerated. PA was significantly more efficacious than AL in both the PCR-uncorrected and PCR-corrected per-protocol populations during this study. The results of this study support the inclusion of PA in the anti-malarial treatment guidelines in Nigeria. Retrospective trial registration Clinicaltrials.gov: NCT05192265.

BackgroundThe declining effectiveness of Intermittent Preventive Treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) due to the emergence of Plasmodium falciparum resistance highlights the need for alternative malaria prevention strategies in pregnant women. A novel approach was proposed: screening with an ultra-sensitive rapid diagnostic test and treating positive with pyronaridine-artesunate (ISTp-uRDT-PA). This trial compared the impact of both strategies on maternal malaria and anaemia, abortion, intrauterine death, birth weight, preterm delivery.MethodsThis non-inferiority trial, conducted in Kinshasa, enrolled pregnant women in their second and third trimesters. Participants in the IPTp-SP arm (n = 124) received SP at monthly antenatal visit as per guidelines, while those in the ISTp-uRDT-PA arm (n = 126) were screened monthly with an uRDT and treated with PA if positive. Primary outcomes included asymptomatic parasitaemia (uRDT positive without fever) or symptomatic parasitaemia (uRDT positive with fever or history of fever, and parasite density by microscopy during pregnancy.ResultsAsymptomatic parasitaemia by uRDT during pregnancy was similar in both arms (20.8% in IPTp-SP vs 21.0% in ISTp-uRDT-PA). At delivery, asymptomatic parasitaemia was 51% higher in ISTp-uRDT-PA arm compared to IPTp-SP (cRR = 1.51 [95% CI 0.76–3.00], p = 0.24). Symptomatic parasitaemia by uRDT at delivery showed no significant difference. Malaria by microscopy at enrolment was detected in 34.4% of women. Malaria by microscopy during pregnancy was 9.6% in IPTp-SP and 10.1%. ISTp-uRDT-PA (p = 0.19), decreasing to 3.2% and 0.9%, respectively, at delivery (p = 0.24). Mean haemoglobin concentration at enrolment was 10.1 g/dl in the IPTp-SP and 9.8 g/dl in the ISTp-uRDT-PA with no significant difference in maternal anaemia at delivery (7%; cRR = 1.07 [95% CI 0.87–1.31], p = 0.52). No significant differences were found for spontaneous abortions and in utero death in both arms. The risk of a premature newborn declined by 14% in ISTp-uRDT-PA compared to the IPTp-SP arm (cRR = 0.86 [95% CI 0.29–2.85], p = 0.79) while low-birth-weight was not significantly higher (cRR = 1.74 [95% CI 0.86–3.53], p = 0.12).ConclusionISTp-uRDT-PA was non inferior to IPTp-SP and can be considered as a future alternative for IPTp-SP in case this intervention can no longer be used due to high SP resistance.Clinical trials registration: NCT04783051.

Background Early case detection and prompt treatment are important malaria control and elimination strategies. However, the emergence and rapid spread of drug-resistant strains present a major challenge. This study reports the first therapeutic efficacy profile of pyronaridine-artesunate against uncomplicated Plasmodium falciparum in Northwest Ethiopia. Methods This single-arm prospective study with 42-day follow-up period was conducted from March to May 2021 at Hamusit Health Centre using the World Health Organization (WHO) therapeutic efficacy study protocol. A total of 90 adults ages 18 and older with uncomplicated falciparum malaria consented and were enrolled in the study. A standard single-dose regimen of pyronaridine-artesunate was administered daily for 3 days, and clinical and parasitological outcomes were assessed over 42 days of follow-up. Thick and thin blood films were prepared from capillary blood and examined using light microscopy. Haemoglobin was measured and dried blood spots were collected on day 0 and on the day of failure. Results Out of 90 patients, 86/90 (95.6%) completed the 42-day follow-up study period. The overall PCR-corrected cure rate (adequate clinical and parasitological response) was very high at 86/87 (98.9%) (95% CI: 92.2–99.8%) with no serious adverse events. The parasite clearance rate was high with fast resolution of clinical symptoms; 86/90 (95.6%) and 100% of the study participants cleared parasitaemia and fever on day 3, respectively. Conclusion Pyronaridine-artesunate was highly efficacious and safe against uncomplicated P. falciparum in this study population.

Artemether–lumefantrine and artesunate–amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine–artesunate and dihydroartemisinin–piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment. We did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to <200 000 parasites per μL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine–artesunate or dihydroartemisinin–piperaquine versus either artesunate–amodiaquine or artemether–lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876). Between Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine–artesunate, 967 to artemether–lumefantrine, 1061 to artesunate–amodiaquine, and 1340 to dihydroartemisinin–piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine–artesunate versus artemether–lumefantrine (1·77, 95% CI 1·63–1·93 vs 1·87, 1·72–2·03; rate ratio [RR] 1·05, 95% CI 0·94–1·17); and versus artesunate–amodiaquine (1·39, 95% CI 1·22–1·59 vs 1·35, 1·18–1·54; RR 0·97, 0·87–1·07). Similarly, this endpoint was non-inferior for dihydroartemisinin–piperaquine versus artemether–lumefantrine (1·16, 95% CI 1·01–1·34 vs 1·42 1·25–1·62; RR 1·22, 95% CI 1·06–1·41) and versus artesunate–amodiaquine (1·35, 1·21–1·51 vs 1·68, 1·51–1·88; RR 1·25, 1·02–1·50). For uncomplicated P falciparum malaria, PCR-adjusted ACPR was greater than 99·5% at day 28 and greater than 98·6% at day 42 for all ACTs; unadjusted ACPR was higher for pyronaridine–artesunate versus comparators at day 28 (96·9% vs 82·3% for artemether–lumefantrine and 95·6% vs 89·0% for artesunate–amodiaquine) and for dihydroartemisinin-piperaquine versus comparators (99·5% vs 81·6% for artemether–lumefantrine and 99·0% vs 89·0% for artesunate–amodiaquine). For non-falciparum species, unadjusted ACPR was greater than 98% for all study drugs at day 28 and at day 42 was greater than 83% except for artemether–lumefantrine against Plasmodium ovale (in ten [62·5%] of 16 patients) and against Plasmodium malariae (in nine [75·0%] of 12 patients). Nine deaths occurred during the study, none of which were related to the study treatment. Mostly mild transient elevations in transaminases occurred with pyronaridine–artesunate versus comparators, and mild QTcF prolongation with dihydroartemisinin-piperaquine versus comparators. Pyronaridine–artesunate and dihydroartemisinin–piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified. The European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), the UK Medical Research Council, the Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), University of Science, Techniques and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).

Purpose The in vitro inhibitory effect of two fluroquinolone antibiotics, norfloxacin and ofloxacin, was evaluated in this study on the growth of several Babesia and Theileria parasites with highlighting the bioinformatic analysis for both drugs with the commonly used antibabesial drug, diminazene aceturate (DA), and the recently identified antibabesial drugs, luteolin, and pyronaridine tetraphosphate (PYR). Methods The antipiroplasm efficacy of screened fluroquinolones in vitro and in vivo was assessed using a fluorescence-based SYBR Green I assay. Using atom Pair signatures, we investigated the structural similarity between fluroquinolones and the antibabesial drugs. Results Both fluroquinolones significantly inhibited ( P  < 0.05) the in vitro growths of Babesia bovis (B. bovis), B. bigemina, B. caballi , and Theileria equi (T. equi) in a dose-dependent manner. The best inhibitory effect for both drugs was observed on the growth of T. equi . Atom Pair fingerprints (APfp) results and AP Tanimoto values revealed that both fluroquinolones, norfloxacin with luteolin, and ofloxacin with PYR, showed the maximum structural similarity (MSS). Two drug interactions findings confirmed the synergetic interaction between these combination therapies against the in vitro growth of B. bovis and T. equi . Conclusion This study helped in discovery novel potent antibabesial combination therapies consist of norfloxacin/ofloxacin, norfloxacin/luteolin, and ofloxacin/PYR.

Background The use of pyronaridine-artesunate (PA) has been associated with scarce transaminitis in patients. This analysis aimed to evaluate the hepatic safety profile of repeated treatment with PA versus artemether–lumefantrine (AL) in patients with consecutive uncomplicated malaria episodes in Bobo-Dioulasso, Burkina Faso. Methods This study analysed data from a clinical trial conducted from 2012 to 2015, in which participants with uncomplicated malaria were assigned to either PA or AL arms and followed up to 42 days. Subsequent malaria episodes within a 2-years follow up period were also treated with the same ACT initially allocated. Transaminases (AST/ALT), alkaline phosphatase (ALP), total and direct bilirubin were measured at days 0 (baseline), 3, 7, 28 and on some unscheduled days if required. The proportions of non-clinical hepatic adverse events (AEs) following first and repeated treatments with PA and AL were compared within study arms. The association of these AEs with retreatment in each arm was also determined using a logistic regression model. Results A total of 1379 malaria episodes were included in the intention to treat analysis with 60% of all cases occurring in the AL arm. Overall, 179 non-clinical hepatic AEs were recorded in the AL arm versus 145 in the PA arm. Elevated ALT was noted in 3.05% of treated malaria episodes, elevated AST 3.34%, elevated ALP 1.81%, and elevated total and direct bilirubin in 7.90% and 7.40% respectively. Retreated participants were less likely to experience elevated ALT and AST than first episode treated participants in both arms. One case of Hy’s law condition was recorded in a first treated participant of the PA arm. Participants from the retreatment group were 76% and 84% less likely to have elevated ALT and AST, respectively, in the AL arm and 68% less likely to present elevated ALT in the PA arm. In contrast, they were almost 2 times more likely to experience elevated total bilirubin in both arms. Conclusions Pyronaridine-artesunate and artemether–lumefantrine showed similar hepatic safety when used repeatedly in participants with uncomplicated malaria. Pyronaridine-artesunate represents therefore a suitable alternative to the current first line anti-malarial drugs in use in endemic areas. Trial registration Pan African Clinical Trials Registry. PACTR201105000286876

Human alveolar echinococcosis is a hard-to-treat and largely untreated parasitic disease with high associated health care costs. The current antiparasitic treatment for alveolar echinococcosis relies exclusively on albendazole, which does not act parasiticidally and can induce severe adverse effects. Alternative, and most importantly, improved treatment options are urgently required. A drug repurposing strategy identified the approved antimalarial pyronaridine as a promising candidate against Echinococcus multilocularis infections. Following a 30-day oral regimen (80 mg kg −1 day −1 ), pyronaridine achieved an excellent therapeutic outcome in a clinically relevant hepatic alveolar echinococcosis murine model, showing a significant reduction in both metacestode size (72.0%) and counts (85.2%) compared to unmedicated infected mice, which revealed significantly more potent anti-echinococcal potency than albendazole treatment at an equal dose (metacestode size: 42.3%; counts: 4.1%). The strong parasiticidal activity of pyronaridine was further confirmed by the destructive damage to metacestode tissues observed morphologically. In addition, a screening campaign combined with computational similarity searching against an approved drug library led to the identification of pirenzepine, a gastric acid-inhibiting drug, exhibiting potent parasiticidal activity against protoscoleces and in vitro cultured small cysts, which warranted further in vivo investigation as a promising anti-echinococcal lead compound. Pyronaridine has a known drug profile and a long track record of safety, and its repurposing could translate rapidly to clinical use for human patients with alveolar echinococcosis as an alternative or salvage treatment.