Safety and pharmacokinetic properties of a new formulation of parenteral artesunate in healthy Thai volunteers.

BACKGROUND: Parenteral artesunate is the first-line therapy for severe malaria. Artesunate, in its current formulation, must be prepared immediately before administration by first dissolving in sodium bicarbonate solution and then diluting in saline. A novel solvent for rapid and stable single step reconstitution of artesunate was recently developed showing improved solubility and stability. This study aimed to compare the safety and pharmacokinetic properties of the currently available and newly developed parenteral formulation of artesunate in healthy Thai volunteers. METHODS: This was an open-label, randomized, 4 periods, 4-treatments, 24-sequence, single-dose, cross-over study in 72 male and female healthy Thai volunteers. Frequent pharmacokinetic samples were collected in all volunteers at each dose occasion. Observed concentration-time profiles were analysed with a non-compartmental approach followed by a bioequivalence evaluation. RESULTS: Both intramuscular and intravenous administrations of the new parenteral formulation of artesunate were safe and well-tolerated, with no additional safety signals compared to the currently used formulation. The pharmacokinetic properties of artesunate and its active metabolite, dihydroartemisinin, were well-characterized, and showed rapid conversion of artesunate into dihydroartemisinin. Intramuscular administration of the newly formulated artesunate resulted in almost complete bioavailability of dihydroartemisinin. The pharmacokinetic properties were similar between the old and new formulation. CONCLUSIONS: The new and more easily prepared formulation of artesunate was safe and well-tolerated, with similar pharmacokinetic properties compared to the currently used formulation. Dihydroartemisinin, the active metabolite responsible for the majority of the anti-malarial effect, showed equivalent exposure after both intravenous and intramuscular administration of artesunate, suggesting that both routes of administration should generate comparable therapeutic effects. TRIAL REGISTRATION: The study was registered to clinicaltrials.gov (#TCTR20170907002).

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

BACKGROUND: Primaquine (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. METHODS: This 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 DISCUSSION: We 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 REGISTRATION: ISRCTN16297951. Registered on September 26, 2021.

Brugada syndrome precipitated by uncomplicated malaria treated with dihydroartemisinin piperaquine: a case report.

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

Efficacy and safety of single-dose artesunate plus sulfalene/pyrimethamine combined with praziquantel for the treatment of children with Schistosoma mansoni or Schistosoma haematobium in western Kenya: a randomised, open-label controlled trial.

BACKGROUND: Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult and juvenile schistosome worms is urgently needed to improve praziquantel efficacy and delay the potential development of drug resistance. We assessed the efficacy and safety of single-dose praziquantel combined with single-dose artesunate plus sulfalene-pyrimethamine in the treatment of Kenyan children with schistosomiasis. METHODS: This was an open-label, randomised clinical trial involving 426 school-aged children (7-15 years old) diagnosed with Schistosoma mansoni (by Kato-Katz) or S. haematobium (by urine filtration). They were randomly assigned (1:1:1) to receive a single dose of praziquantel (40 mg/kg), a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate) or combination therapy using a single dose of praziquantel (40 mg/kg) combined with a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate). The primary outcome was cure and egg reduction rates at 6 weeks post-treatment in the available case population. Adverse events were assessed within 3 h after treatment. RESULTS: Of the 426 children enrolled, 135 received praziquantel, 150 received artesunate plus sulfalene-pyrimethamine, and 141 received combination therapy. Outcome data were available for 348 (81.7%) children. For S. mansoni-infected children (n = 335), the cure rates were 75.6%, 60.7%, and 77.8%, and the egg reduction rates were 80.1%, 85.0%, and 88.4% for praziquantel, artesunate plus sulfalene-pyrimethamine, and combination therapy, respectively. For S. haematobium-infected children (n = 145), the corresponding cure rates were 81.4%, 71.1%, and 82.2%, and the egg reduction rates were 95.6%, 97.1%, and 97.7%, respectively. Seventy-one (16.7%) children reported mild-intensity adverse events. The drugs were well tolerated and no serious adverse events were reported. CONCLUSIONS: A single oral dose of praziquantel combined with artesunate plus sulfalene-pyrimethamine cured a high proportion of children with S. haematobium but did not significantly improve the treatment efficacy for either urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may enhance the efficacy and safety outcomes.

Therapeutic efficacy and safety of artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria treatment in Metehara, Central-east Ethiopia.

BACKGROUND: Malaria remains a major global health problem although there was a remarkable achievement between 2000 and 2015. Malaria drug resistance, along with several other factors, presents a significant challenge to malaria control and elimination efforts. Numerous countries in sub-Saharan Africa have documented the presence of confirmed or potential markers of partial resistance against artemisinin, the drug of choice for the treatment of uncomplicated Plasmodium falciparum malaria. The World Health Organization (WHO) recommends regular surveillance of artemisinin therapeutic efficacy to inform policy decisions. METHODS: This study aimed to evaluate the therapeutic efficacy of artemether-lumefantrine (AL), which is the first-line treatment for uncomplicated P. falciparum malaria in Ethiopia since 2004. Using a single-arm prospective evaluation design, the study assessed the clinical and parasitological responses of patients with uncomplicated P. falciparum malaria in Metehara Health Centre, central-east Ethiopia. Out of 2332 malaria suspects (1187 males, 1145 females) screened, 80 (50 males, 30 females) were enrolled, followed up for 28 days, and 73 (44 males, 29 females) completed the follow up. The study was conducted and data was analysed by employing the per-protocol and Kaplan-Meier analyses following the WHO Malaria Therapeutic Efficacy Evaluation Guidelines 2009. RESULTS: The results indicated rapid parasite clearance and resolution of clinical symptoms, with all patients achieving complete recovery from asexual parasitaemia and fever by day (D) 3. The prevalence of gametocytes decreased from 6.3% on D0 to 2.5% on D2, D3, D7, and ultimately achieving complete clearance afterward. CONCLUSION: The overall cure rate for AL treatment was 100%, demonstrating its high efficacy in effectively eliminating malaria parasites in patients. No serious adverse events related to AL treatment were reported during the study, suggesting its safety and tolerability among the participants. These findings confirm that AL remains a highly efficacious treatment for uncomplicated P. falciparum malaria in the study site after 20 years of its introduction in Ethiopia.

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).

Efficacy and safety of Artemisinin Combination Therapy for the treatment of uncomplicated Plasmodium falciparum malaria across international borders of India.

BACKGROUND OBJECTIVES: Malaria due to Plasmodium falciparum (Pf) remains a major public threat in India. Artemisinin-based combination therapy (ACT) has been the country's first-line drug for uncomplicated Pf malaria. In 2013-2014, Artesunate plus sulfadoxine (AS+SP) was replaced by Artemether Lumefantrine (AL) as the first- line antimalarial in North East (NE) states of the country which are endemic for Pf malaria. Regular monitoring of antimalarial drugs is of utmost importance to achieve the goal of elimination. This study aimed to assess the efficacy and safety of ACT for treating uncomplicated Pf malaria in the NE states of India. METHODS: A prospective study of 28-day follow-up was conducted to monitor the efficacy and safety of AL from 2018-2019 in four districts, Udalgiri, Meghalaya, Lawngtlai, and Dhalai of NE, India. The clinical and parasitological response and the polymorphism analysis of the Pfdhps, P/dhfr, and Pfkelch 13 gene were evaluated. RESULTS: A total of 234 patients were enrolled in the study out of 216 patients who completed the follow-up to 28 days. One-hundred percent adequate clinical and parasitological responses (ACPR) were observed with polymerase chain reaction (PCR) correction. The genotype results suggest no recrudescence in the treatment-failure patients. The classical single nucleotide polymorphisms (SNP) in the Pfdhfr gene was S108N (94.9%), followed by C59R (91.5%), whereas, in the Pfdhps gene, the common SNP was A437G (79.6%), followed by S3436A. No associated or validated mutations were found in the propeller region of the PfKelch13 gene. INTERPRETATION CONCLUSION: AL was efficacious and safe in uncomplicated P. falciparum malaria in North East India. In contrast, mutations in the genes responsible for sulfadoxine and pyrimethamine resistance have been fixed in northeast India's population.

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.

Efficacy of a Single Oral Dose of Artesunate plus Sulfalene-Pyrimethamineversus Praziquantel in the Treatment of Schistosoma mansoni in Kenyan Children: An Open-Label, Randomized, Exploratory Trial.

Unlike praziquantel, artemisinin derivatives are effective against juvenile schistosome worms. We assessed the efficacy and safety of a single oral dose of artesunate plus sulfalene-pyrimethamine versus praziquantel in the treatment of Schistosoma mansoni. Seventy-three schoolchildren (aged 9-15 years) with confirmed S. mansoni infection in Rarieda, western Kenya, were randomly assigned to receive either a single oral dose of artesunate plus sulfalene-pyrimethamine (n = 39) or a single dose of praziquantel (n = 34). The cure and egg reduction rates at 4 weeks posttreatment were 69.4% (25/36) versus 80.6% (25/31) (P = 0.297) and 99.1% versus 97.5% (P = 0.607) in the artesunate plus sulfalene-pyrimethamine group versus praziquantel group, respectively. Fourteen children developed adverse events, and there were no serious adverse events. A single oral dose of artesunate plus sulfalene-pyrimethamine has efficacy comparable to that of praziquantel in the treatment of S. mansoni, but these results should be confirmed in larger randomized controlled trials.

Population-specific variations in KCNH2 predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy.

Dihydroartemisinin-piperaquine is efficacious for the treatment of uncomplicated malaria and its use is increasing globally. Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the KCNH2 gene) by piperaquine has raised concerns about cardiac safety. Whether genetic factors could modulate the risk of piperaquine-mediated QT prolongations remained unclear. Here, we first profiled the genetic landscape of KCNH2 variability using data from 141,614 individuals. Overall, we found 1,007 exonic variants distributed over the entire gene body, 555 of which were missense. By optimizing the gene-specific parametrization of 16 partly orthogonal computational algorithms, we developed a KCNH2-specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of KCNH2 variability, we then sequenced 293 Malian patients with uncomplicated malaria and identified 13 variations within the voltage sensing and pore domains of Kv11.1 that directly interact with channel blockers. Cross-referencing of genetic and electrocardiographic data before and after piperaquine exposure revealed that carriers of two common variants, rs1805121 and rs41314375, experienced significantly higher QT prolongations (ΔQTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc >30 ms. Furthermore, we identified three carriers of rare population-specific variations who experienced clinically relevant delayed ventricular repolarization. Combined, our results map population-scale genetic variability of KCNH2 and identify genetic biomarkers for piperaquine-induced QT prolongation that could help to flag at-risk patients and optimize efficacy and adherence to antimalarial therapy.

Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study.

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.

Artemisinin-naphthoquine plus lower-dose primaquine to treat and prevent recurrence of Plasmodium vivax malaria: an open-label randomized and non-inferiority trial.

BACKGROUND: Plasmodium vivax malaria, with the widest geographic distribution, can cause severe disease and death. Primaquine is the main licensed antimalarial drug that can kill hypnozoites. The dose-dependent acute haemolysis in individuals with glucose-6-phospate dehydrogenase (G6PD) deficiency is the main safety concern when using primaquine. The recommended treatment regimen for P. vivax malaria is chloroquine plus primaquine for 14 days (CQPQ14) in Myanmar. The study aimed to evaluate the therapeutic efficacy, safety and adherence for the regimen of artemisinin-naphthoquine plus primaquine for 3 days (ANPQ3) in patients with P. vivax infections compared to those with CQPQ14. METHODS: The patients in the ANPQ3 group were given fixed-dose artemisinin-naphthoquine (a total 24.5 mg/kg bodyweight) plus a lower total primaquine dose (0.9 mg/kg bodyweight) for 3 days. The patients in the CQPQ14 group were given a total chloroquine dose of 30 mg/kg body weight for 3 days plus a total primaquine dose of 4.2 mg/kg bodyweight for 14 days. All patients were followed up for 365 days. RESULTS: A total of 288 patients completed follow-up, 172 in the ANPQ3 group and 116 in the CQPQ14 group. The first recurrence patients were detected by day 58 in both groups. By day 182, 16 recurrences had been recorded: 12 (7.0%) patients in the ANPQ3 group and 4 (3.4%) in the CQPQ14 group. The difference in recurrence-free patients was 3.5 (-8.6 to 1.5) percentage points between ANPQ3 and CQPQ14 group (P = 0.2946). By day 365, the percentage of recurrence-free patients was not significant between the two groups (P = 0.2257). Mean fever and parasite clearance time of ANPQ3 group were shorter than those in CQPQ14 group (P ≤ 0.001). No severe adverse effect was observed in ANPQ3 group, but five (3.9%) patients had acute haemolysis in CQPQ14 group (P = 0.013). Medication percentage of ANPQ3 group was significantly higher than that of CQPQ14 group (P < 0.0001). CONCLUSIONS: Both ANPQ3 and CQPQ14 promised clinical cure efficacy, and the radical cure efficacy was similar between the ANPQ3 and CQPQ14 group. ANPQ3 clears fever and parasites faster than CQPQ14. ANPQ3 is safer and shows better patient adherence to the regimen for treatment of P. vivax malaria along the China-Myanmar border. TRIAL REGISTRATION: ChiCTR-INR-17012523. Registered 31 August 2017, https://www.chictr.org.cn/showproj.html?proj=21352.

Safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnant women with HIV from Gabon and Mozambique: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The cornerstone of malaria prevention in pregnancy, intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. We assessed whether IPTp with dihydroartemisinin-piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs. METHODS: For this randomised, double-blind, placebo-controlled clinical trial, women with HIV attending the first antenatal care clinic visit, resident in the study area, and with a gestational age up to 28 weeks were enrolled at five sites in Gabon and Mozambique. Participants were randomly assigned (1:1) to receive either IPTp with dihydroartemisinin-piperaquine at each scheduled antenatal care visit plus daily co-trimoxazole (intervention group) or placebo at each scheduled antenatal care visit plus daily co-trimoxazole (control group). Randomisation was done centrally via block randomisation (block sizes of eight), stratified by country. IPTp was given over 3 days under direct observation by masked study personnel. The number of daily IPTp tablets was based on bodyweight and according to the treatment guidelines set by WHO (target dose of 4 mg/kg per day [range 2-10 mg/kg per day] of dihydroartemisinin and 18 mg/kg per day [range 16-27 mg/kg per day] of piperaquine given once a day for 3 days). At enrolment, all participants received co-trimoxazole (fixed combination drug containing 800 mg trimethoprim and 160 mg sulfamethoxazole) for daily intake. The primary study outcome was prevalence of peripheral parasitaemia detected by microscopy at delivery. The modified intention-to-treat population included all randomly assigned women who had data for the primary outcome. Secondary outcomes included frequency of adverse events, incidence of clinical malaria during pregnancy, and frequency of poor pregnancy outcomes. All study personnel, investigators, outcome assessors, data analysts, and participants were masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT03671109. FINDINGS: From Sept 18, 2019, to Nov 26, 2021, 666 women (mean age 28·5 years [SD 6·4]) were enrolled and randomly assigned to the intervention (n=332) and control (n=334) groups. 294 women in the intervention group and 308 women in the control group had peripheral blood samples taken at delivery and were included in the primary analysis. Peripheral parasitaemia at delivery was detected in one (<1%) of 294 women in the intervention group and none of 308 women in the control group. The incidence of clinical malaria during pregnancy was lower in the intervention group than in the control group (one episode in the intervention group vs six in the control group; relative risk [RR] 0·12, 95% CI 0·03-0·52, p=0·045). In a post-hoc analysis, the composite outcome of overall malaria infection (detected by any diagnostic test during pregnancy or delivery) was lower in the intervention group than in the control group (14 [5%] of 311 women vs 31 [10%] of 320 women; RR 0·48, 95% CI 0·27-0·84, p=0·010). The frequency of serious adverse events and poor pregnancy outcomes (such as miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups. The most frequently reported drug-related adverse events were gastrointestinal disorder (reported in less than 4% of participants) and headache (reported in less than 2% of participants), with no differences between study groups. INTERPRETATION: In the context of low malaria transmission, the addition of IPTp with dihydroartemisinin-piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection, so it should be considered as a strategy to protect pregnant women with HIV from malaria. FUNDING: European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) and Medicines for Malaria Venture. TRANSLATIONS: For the Portuguese and French translations of the abstract see Supplementary Materials section.

New clinical application prospects of artemisinin and its derivatives: a scoping review.

BACKGROUND: Recent research has suggested that artemisinin and its derivatives may have therapeutic effects on parasites, viruses, tumors, inflammation and skin diseases. This study aimed to review clinical research on artemisinin and its derivatives except anti-malaria and explore possible priority areas for future development. METHODS: Relevant articles in English and Chinese published before 28 October 2021 were reviewed. All articles were retrieved and obtained from databases including WanFang, PubMed/MEDLINE, the Cochrane Library, China National Knowledge International, Embase, OpenGrey, the Grey Literature Report, Grey Horizon, and ClinicalTrials.gov. Studies were selected for final inclusion based on predefined criteria. Information was then extracted and analyzed by region, disease, outcome, and time to identify relevant knowledge gaps. RESULTS: Seventy-seven studies on anti-parasitic (35), anti-tumor (16), anti-inflammatory (12), anti-viral (8), and dermatological treatments (7) focused on the safety and efficacy of artemisinin and its derivatives. The anti-parasitic clinical research developed rapidly, with a large number of trials, rapid clinical progress, and multiple research topics. In contrast, anti-viral research was limited and mainly stayed in phase I clinical trials (37.50%). Most of the studies were conducted in Asia (60%), followed by Africa (27%), Europe (8%), and the Americas (5%). Anti-parasite and anti-inflammatory research were mainly distributed in less developed continents such as Asia and Africa, while cutting-edge research such as anti-tumor has attracted more attention in Europe and the United States. At the safety level, 58 articles mentioned the adverse reactions of artemisinin and its derivatives, with only one study showing a Grade 3 adverse event, while the other studies did not show any related adverse reactions or required discontinuation. Most studies have discovered therapeutic effects of artemisinin or its derivatives on anti-parasitic (27), anti-tumor (9), anti-inflammatory (9) and dermatological treatment (6). However, the efficacy of artemisinin-based combination therapies (ACTs) for parasitic diseases (non-malaria) is still controversial. CONCLUSIONS: Recent clinical studies suggest that artemisinin and its derivatives may be safe and effective candidates for anti-tumor, anti-parasitic, anti-inflammatory and dermatological drugs. More phase II/III clinical trials of artemisinin and its derivatives on antiviral effects are needed.

The compound artemisinin-hydroxychloroquine ameliorates bleomycin-induced pulmonary fibrosis in rats by inhibiting TGF-ß1/Smad2/3 signaling pathway.

Pulmonary fibrosis (PF) is a lethal disease characterized by a progressive decline in lung function. Currently, lung transplantation remains the only available treatment for PF. However, both artemisinin (ART) and hydroxychloroquine (HCQ) possess potential antifibrotic properties. This study aimed to investigate the effects and mechanisms of a compound known as Artemisinin-Hydroxychloroquine (AH) in treating PF, specifically by targeting the TGF-ß1/Smad2/3 pathway. To do this, we utilized an animal model of PF induced by a single tracheal drip of bleomycin (BLM) in Sprague-Dawley (SD) rats. The PF animal models were administered various doses of AH, and the efficacy and safety of AH were evaluated through pulmonary function testing, blood routine tests, serum biochemistry tests, organ index measurements, and pathological examinations. Additionally, Elisa, western blotting, and qPCR techniques were employed to explore the potential molecular mechanisms of AH in treating PF. Our findings reveal that AH effectively and safely alleviate PF by inhibiting BLM-induced specific inflammation, reducing extracellular matrix (ECM) deposition, and interfering with the TGF-ß1/Smad2/3 signaling pathway. Notably, the windfall for this study is that the inhibition of ECM may initiate self-healing in the BLM-induced PF animal model. In conclusion, AH shows promise as a potential therapeutic drug for PF, as it inhibits disease progression through the TGF-ß1/Smad2/3 signaling pathway.

SCHISTOACT: a protocol for an open-label, five-arm, non-inferiority, individually randomized controlled trial of the efficacy and safety of praziquantel plus artemisinin-based combinations in the treatment of Schistosoma mansoni infection.

BACKGROUND: Schistosomiasis control relies on praziquantel for preventive chemotherapy. Alternative drugs are needed for the treatment and control of schistosomiasis. Praziquantel is effective against adult schistosome worms but ineffective against larval stages of the parasite and cannot prevent re-infection or interrupt the transmission of infection. Continued reliance on praziquantel for wide-scale schistosomiasis control will likely accelerate the emergence of drug resistance. Artemisinin derivatives are effective against the juvenile stages but ineffective against adult worms. The SCHISTOACT study aimed to evaluate the efficacy and safety of praziquantel plus one of four artemisinin-based combinations in treating Schistosoma mansoni infection in Kenya. METHODS: The SCHISTOACT study is an open-label, head-to-head, five-arm, proof-of-concept, non-inferiority, individually randomized controlled trial with a follow-up of 12 weeks. A total of 540 primary school-aged children from the Mwea area, Kirinyaga County in central Kenya, diagnosed with S. mansoni infection (by Kato-Katz method) are randomly allocated (1:1:1:1:1) to a single dose of praziquantel plus a 3-day course of artesunate-sulfalene/pyrimethamine, or artesunate-amodiaquine, or artesunate plus mefloquine, or dihydroartemisinin-piperaquine, or praziquantel control arm. The primary endpoints are efficacy (cure rate, assessed by microscopy) and safety (adverse events) of each study arm 6 weeks after treatment. Secondary endpoints include cumulative cure rate, egg reduction rate, and re-infection 12 weeks after treatment. The non-inferiority margin is set at - 10 for the risk difference in cure rates between praziquantel and the combined treatment. DISCUSSION: This study assesses a strategy for repurposing artemisinin-based combination therapies (ACTs) for treating schistosomiasis. It adopts a head-to-head comparison of four different ACTs to test a non-inferiority hypothesis and to strengthen local capacity to conduct clinical trials for interventions against neglected tropical diseases. TRIAL REGISTRATION: Pan-African Clinical Trials Registry PACTR202001919442161 . Retrospectively registered on 6 January 2020.

Efficacy and safety of pyronaridine-artesunate (PYRAMAX) for the treatment of P. falciparum uncomplicated malaria in African pregnant women (PYRAPREG): study protocol for a phase 3, non-inferiority, randomised open-label clinical trial.

INTRODUCTION: Malaria infection during pregnancy increases the risk of low birth weight and infant mortality and should be prevented and treated. Artemisinin-based combination treatments are generally well tolerated, safe and effective; the most used being artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Pyronaridine-artesunate (PA) is a new artemisinin-based combination. The main objective of this study is to determine the efficacy and safety of PA versus AL or DP when administered to pregnant women with confirmed Plasmodium falciparum infection in the second or third trimester. The primary hypothesis is the pairwise non-inferiority of PA as compared with either AL or DP. METHODS AND ANALYSIS: A phase 3, non-inferiority, randomised, open-label clinical trial to determine the safety and efficacy of AL, DP and PA in pregnant women with malaria in five sub-Saharan, malaria-endemic countries (Burkina Faso, Democratic Republic of the Congo, Mali, Mozambique and the Gambia). A total of 1875 pregnant women will be randomised to one of the treatment arms. Women will be actively monitored until Day 63 post-treatment, at delivery and 4-6 weeks after delivery, and infants' health will be checked on their first birthday. The primary endpoint is the PCR-adjusted rate of adequate clinical and parasitological response at Day 42 in the per-protocol population. ETHICS AND DISSEMINATION: This protocol has been approved by the Ethics Committee for Health Research in Burkina Faso, the National Health Ethics Committee in the Democratic Republic of Congo, the Ethics Committee of the Faculty of Medicine and Odontostomatology/Faculty of Pharmacy in Mali, the Gambia Government/MRCG Joint Ethics Committee and the National Bioethics Committee for Health in Mozambique. Written informed consent will be obtained from each individual prior to her participation in the study. The results will be published in peer-reviewed open access journals and presented at (inter)national conferences and meetings. TRIAL REGISTRATION NUMBER: PACTR202011812241529.

Tafenoquine co-administered with dihydroartemisinin-piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study.

BACKGROUND: Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin-piperaquine for the radical cure of P vivax malaria. METHODS: In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin-piperaquine alone, dihydroartemisinin-piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin-piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin-piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov, NCT02802501 and is completed. FINDINGS: Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4-22) in patients treated with dihydroartemisinin-piperaquine alone versus 21% (11-34) in patients treated with tafenoquine plus dihydroartemisinin-piperaquine (hazard ratio 0·44; 95% CI [0·29-0·69]) and 52% (37-65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin-piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin-piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin-piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively. INTERPRETATION: Although tafenoquine plus dihydroartemisinin-piperaquine was statistically superior to dihydroartemisinin-piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria. FUNDING: ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK. TRANSLATION: For the Indonesian translation of the abstract see Supplementary Materials section.

Use of artesunate in the treatment of severe imported malaria in France: review of the effectiveness and real-life safety in two French university hospitals.

BACKGROUND: Intravenous artesunate (AS) is the first-line treatment for patients with severe imported malaria (SIM) worldwide. However, after 10 years of use in France, AS hasn't yet received marketing authorization.The purpose of this study was to assess the real-life effectiveness and safety of AS in the treatment of SIM in two Hospitals in France. METHODS: We performed a bicenter retrospective and observational study. All patients treated with AS for SIM between 2014 and 2018 and 2016-2020 were included. The effectiveness of AS was evaluated by parasite clearance, number of deaths, and the length of hospital stay. The real-life safety was assessed by related adverse events (AE) and monitoring of biological blood parameters during the hospital stay and follow-up period. RESULTS: 110 patients were included during the six-year study period. 71.8% of patients were parasite-negative of their day 3 thick and thin blood smears after AS treatment. No patients discontinued AS due to an AE and no serious AE were declared. Two cases of delayed post-artesunate hemolysis occurred and required blood transfusions. CONCLUSION: This study highlights effectiveness and safety of AS in non-endemic areas. Administrative procedures must be accelerated in order to obtain full registration and facilitate access to AS in France.

Immune-mediated herb-induced liver injury: a potential association with herbal artemisinin use as supported by the updated RUCAM.

Immune-mediated herb-induced liver injury (HILI) is an acute or chronic inflammatory liver disease precipitated by a hepatotoxic agent with a presentation similar to acute autoimmune hepatitis. It is distinguished in clinical course from true autoimmune hepatitis by remission on drug discontinuation and immunosuppressive treatment. We report a potential case of immune-mediated HILI associated with artemisinin use, an herb underlying first-line malarial treatments, in a woman undergoing radiotherapy for right-sided pelvic sarcoma. A probable association in this case is supported by causality assessment using the updated Roussel Uclaf Causality Assessment Method (score of 6). She achieved clinical improvement with a course of oral corticosteroids and remained stable without relapse following discontinuation. Increased awareness of this complication is imperative, as literature to date only documents direct hepatocellular and cholestatic liver injury from artemisinin use, and should augment clinician counsel regarding complementary medicine administration, especially in high-risk individuals like those with cancer.