arterolane and piperaquine

Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane-piperaquine-mefloquine versus arterolane-piperaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children.. In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2-12 years and had an asexual parasitaemia of 5000-250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane-piperaquine, arterolane-piperaquine-mefloquine, or artemether-lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether-lumefantrine was administered twice daily (target dose 5-24 mg/kg of bodyweight of artemether and 29-144 mg/kg of bodyweight of lumefantrine), and oral arterolane-piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane-piperaquine-mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane-piperaquine-mefloquine versus artemether-lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane-piperaquine-mefloquine versus arterolane-piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was -7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed.. Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane-piperaquine (n=73), arterolane-piperaquine-mefloquine (n=72), or artemether-lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane-piperaquine-mefloquine (100%, 95% CI 95-100; 72/72) was non-inferior to that after treatment with artemether-lumefantrine (96%, 95% CI 88-99; 69/72; risk difference 4%, 95% CI 0-9; p=0·25). The 42-day PCR-corrected efficacy of arterolane-piperaquine-mefloquine was non-inferior to that of arterolane-piperaquine (100%, 95% CI 95-100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane-piperaquine (5%, 95% CI 2-9; ten of 203 drug administrations; p=0·0013) or arterolane-piperaquine-mefloquine (5%, 3-9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether-lumefantrine (1%, 0-2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether-lumefantrine; n=19 for arterolane-piperaquine-mefloquine; n=23 for arterolane-piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths.. This study shows that arterolane-piperaquine-mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance.. UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries.

Topics: Administration, Oral; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Female; Heterocyclic Compounds, 1-Ring; Humans; Kenya; Malaria, Falciparum; Male; Mefloquine; Peroxides; Plasmodium falciparum; Quinolines; Spiro Compounds; Treatment Outcome

Administration of artemisinin-based combination therapy (ACT) to infant and young children can be challenging. A formulation with accurate dose and ease of administration will improve adherence and compliance in children. The fixed-dose combination dispersible tablet of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg can make dosing convenient in children.. This multicenter (India and Africa), comparative, parallel-group trial enrolled 859 patients aged 6 months to 12 years with Plasmodium falciparum malaria. Patients were randomized in a ratio of 2:1 to AM-PQP (571 patients) once daily and artemether-lumefantrine (AL) (288 patients) twice daily for 3 days and followed for 42 days.. The cure rate (ie, polymerase chain reaction-corrected adequate clinical and parasitological response) in the per-protocol population at day 28 was 100.0% and 98.5% (difference, 1.48% [95% confidence interval {CI}, .04%-2.91%]) in the AM-PQP and AL arms, respectively, and 96.0% and 95.8% (difference, 0.14% [95% CI, -2.68% to 2.95%]) in the intention-to-treat (ITT) population. The cure rate was comparable at day 42 in the ITT population (AM-PQP, 94.4% vs AL, 93.1%). The median parasite clearance time was 24 hours in both the arms. The median fever clearance time was 6 hours in AM-PQP and 12 hours in the AL arm. Both the treatments were found to be safe and well tolerated. Overall, safety profile of both the treatments was similar.. The efficacy and safety of fixed-dose combination of AM and PQP was comparable to AL for the treatment of uncomplicated P. falciparum malaria in pediatric patients.. CTRI/2014/07/004764.

Topics: Africa; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Heterocyclic Compounds, 1-Ring; Humans; India; Infant; Malaria, Falciparum; Male; Peroxides; Quinolines; Spiro Compounds; Survival Analysis; Tablets

Chloroquine has been the treatment of choice for acute vivax malaria for more than 60 years. Malaria caused by Plasmodium vivax has recently shown resistance to chloroquine in some places. This study compared the efficacy and safety of fixed dose combination (FDC) of arterolane maleate and piperaquine phosphate (PQP) with chloroquine in the treatment of uncomplicated vivax malaria.. Patients aged 13-65 years with confirmed mono-infection of P. vivax along with fever or fever in the previous 48 h were included. The 317 eligible patients were randomly assigned to receive FDC of arterolane maleate and PQP (n = 159) or chloroquine (n = 158) for 3 days. Primaquine was given as an anti-relapse measure on day 3 and continued for 14 consecutive days. Primary efficacy analysis included assessment of the proportion of aparasitaemic and afebrile patients at 72 h. Safety endpoints were analysis of adverse events, vital signs, laboratory data, and abnormalities on electrocardiograph. Patients participated in the study for at least 42 days.. In per protocol population, the proportion of aparasitaemic and afebrile patients at 72 h was 100% (140/140) in the FDC of arterolane maleate and PQP group, and 99.3% (145/146) in the chloroquine group (Fisher, p > 0.9999). In intent to treat population, the corresponding value was reported to be 96.9% (154/159) in the FDC of arterolane maleate and PQP group and 98.7 % (156/158) in the chloroquine group (Fisher, p = 0.4479). The median parasite clearance time was 24 h in FDC of arterolane maleate and PQP group and 26 h in chloroquine group (Log-rank, p = 0.2264). Similarly, median fever clearance time was 24 h in both the groups (Log-rank, p = 0.7750). In PP population, day 28 cure rates were 100 % in both the groups (95% CI (96.52, 100.0 for FDC of arterolane maleate and PQP and 96.73, 100.0 in chloroquine group)). Incidence of adverse events was 82.4% in the FDC of arterolane maleate and PQP group and 85.4% in the chloroquine group. Most of the adverse events were mild to moderate in intensity. The commonly reported clinical adverse events in the FDC of arterolane maleate and PQP versus chloroquine group were vomiting (5.0 vs 5.1%), headache (1.3 vs 3.2%) and prolonged QT (1.9 vs 3.2%). No deaths were reported. The pharmacokinetic analysis indicates that arterolane maleate is well absorbed and has a relatively short t1/2 of 3.2 h. Piperaquine is also well absorbed after oral administration with a t1/2 of about 228.33 h.. The study showed that FDC of arterolane maleate and PQP effectively cured vivax malaria and attained acceptable level of cure up to day 28. Both the groups showed similar safety profile. Trial Registration Clinical Trial Registry India: CTRI/2011/11/002129.

Topics: Adolescent; Adult; Aged; Antimalarials; Chloroquine; Drug Therapy, Combination; Female; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Malaria, Vivax; Male; Maleates; Middle Aged; Peroxides; Quinolines; Spiro Compounds; Young Adult

Artemisinins, which are derived from plants, are subject to risk of supply interruption due to climatic changes. Consequently, an effort to identify a new synthetic antimalarial was initiated. A fixed-dose combination of arterolane maleate (AM), a new synthetic trioxolane, with piperaquine phosphate (PQP), a long half-life bisquinoline, was evaluated in patients with uncomplicatedPlasmodium falciparummalaria.. In this multicenter, randomized, double-blind, comparative, parallel-group trial, 1072 patients aged 12-65 years withP. falciparummonoinfection received either AM-PQP (714 patients) once daily or artemether-lumefantrine (A-L; 358 patients) twice daily for 3 days. All patients were followed up until day 42.. Of the 714 patients in the AM-PQP group, 638 (89.4%) completed the study; of the 358 patients in the A-L group, 301(84.1%) completed the study. In both groups, the polymerase chain reaction corrected adequate clinical and parasitological response (PCR-corrected ACPR) on day 28 in intent-to-treat (ITT) and per-protocol (PP) populations was 92.86% and 92.46% and 99.25% and 99.07%, respectively. The corresponding figures on day 42 in the ITT and PP populations were 90.48% and 91.34%, respectively. After adjusting for survival ITT, the PCR-corrected ACPR on day 42 was >98% in both groups. The overall incidence of adverse events was comparable.. AM-PQP showed comparable efficacy and safety to A-L in the treatment of uncomplicatedP. falciparummalaria in adolescent and adult patients. AM-PQP demonstrated high clinical and parasitological response rates as well as rapid parasite clearance.. India. CTRI/2009/091/000101.

Topics: Adolescent; Adult; Africa; Aged; Antimalarials; Artemether; Artemisinins; Asia; Child; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Half-Life; Heterocyclic Compounds, 1-Ring; Humans; India; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Peroxides; Plasmodium falciparum; Quinolines; Spiro Compounds; Young Adult

The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria. The present study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate 37.5 mg and piperaquine phosphate (PQP) 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years.. Male and female patients aged 6 months to 12 years who were confirmed cases of P. falciparum mono-infection with fever or documented history of fever in the previous 24 h were included. The patients were administered FDC of arterolane maleate and PQP as single daily doses for three consecutive days based on their age. The primary efficacy outcome was proportion of patients with polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) on day 28. Safety was analysed based on adverse events (AE), laboratory abnormalities and abnormalities on electrocardiograph.. A total of 141 eligible paediatric patients received FDC of arterolane maleate and PQP in a 42-day follow-up study. All the enrolled patients (141) were included in intention to treat (ITT) and safety analyses, and 126 patients were considered in per protocol (PP) population. The PCR-corrected ACPR on day 28 was achieved in all patients (100 %; 95 % CI 97.11-100) included in PP population. The median parasite clearance time (PCT) and fever clearance time (FCT) were 24 h (95 % CI 18.0-24.0) and 10 h (95 % CI 4.0-18.0), respectively. The most frequently reported clinical AE was vomiting. Majority of the AEs were mild to moderate in severity and resolved without sequelae. No patient was discontinued for any QTc (corrected QT interval) prolongation. No deaths or serious AEs were reported during the study.. The findings from this study showed that FDC of arterolane maleate and PQP effectively cures P. falciparum malaria and attains acceptable level of cure by day 28 in paediatric patients. The efficacy and safety results observed in children warrants further studies on FDC of arterolane maleate and PQP dispersible tablets.. Clinical Trial Registry India: CTRI/2009/091/000531.

Topics: Antimalarials; Child; Child, Preschool; Cote d'Ivoire; Drug Combinations; Female; Heterocyclic Compounds, 1-Ring; Humans; India; Infant; Infant, Newborn; Malaria; Malaria, Falciparum; Male; Peroxides; Plasmodium falciparum; Quinolines; Rwanda; Spiro Compounds; Tablets

Artemisinin-based combination therapy is the first-line treatment for uncomplicated falciparum malaria. This study assessed the antimalarial efficacy and safety of a combination of 150 mg of arterolane maleate and 750 mg of piperaquine phosphate (AM-PQP) in comparison to Coartem (artemether and lumefantrine) in patients with acute uncomplicated P. falciparum malaria.. In this open-label, randomized, multicentric, parallel group clinical trial, 240 patients were randomized to receive AM-PQP (160 patients) or Coartem (80 patients). Patients with P. falciparum monoinfection and initial parasite densities ranging from 1000 to 100 000 asexual parasites/µL of blood were followed for 28 days. Polymerase chain reaction-corrected adequate clinical and parasitologic response on day 28, parasite clearance time, and fever clearance time were evaluated.. A total of 151 (94.4%) of 160 patients in the AM-PQP group completed the trial, while 77 (96.3%) of 80 patients in the Coartem group completed the trial. No treatment failure was noted in the AM-PQP group, while one patient receiving Coartem failed treatment on day 28. There was no difference in the median parasite clearance time (30 hours in both groups) or median fever clearance time (24 hours in both groups) after administration of the 2 study treatments.. The available data support the evaluation of a drug combination in a larger population as a fixed-dose combination. Clinical Trials Registration. CTRI/2007/091/000031.

Topics: Adolescent; Adult; Antimalarials; Female; Heterocyclic Compounds, 1-Ring; Humans; Kaplan-Meier Estimate; Malaria, Falciparum; Male; Peroxides; Quinolines; Spiro Compounds; Statistics, Nonparametric

Topics: Antimalarials; Child; Child, Preschool; Drug Resistance; Drug Therapy, Combination; Female; Heterocyclic Compounds, 1-Ring; Humans; Kenya; Malaria, Falciparum; Male; Mefloquine; Peroxides; Plasmodium falciparum; Quinolines; Spiro Compounds

Control of schistosomiasis relies on a single drug, praziquantel (PZQ). Given the rising concerns about the potential emergence of PZQ-resistant strains, it has now become necessary to search for novel therapeutics. However, the current pace for anti-schistosomal drug discovery is slow; hence, repositioning of existing approved drugs can offer a safe, rapid and cost-effective solution. The anti-malarial synthetic artemisinin-derivatives trioxolanes demonstrated anti-schistosomal efficacies against the three major species infecting humans and, unlike PZQ, showed activities against both juvenile and adult worm stages. The 1,2,4-trioxolane/OZ277 (arterolane maleate) in combination with a partner drug: piperaquine phosphate was recently developed as an anti-malarial drug and manufactured by Ranbaxy (India) as Synriam™ (SYN). Herein, the in vivo activities of SYN were investigated in a mouse model of Schistosoma mansoni (S. mansoni), compared to PZQ. We show that a single fixed dose of 240mg/kg SYN (40mg/kg arterolane and 200mg/kg piperaqine) induced significant protective effects in mice, in terms of reduction in worm and tissue egg burdens, which were evident against all schistosome developmental stages. Extensive alterations in the tegument and subtegumental tissues of SYN-exposed worms were revealed by both scanning and transmission electron microscopes. Progressive decrease in worm activity and occurrence of death were noticed in vitro upon exposure to the drug - more pronounced in the presence of haemin. This report provides the first evidence of the efficacy of a combination of 1,2,4-trioxolane and piperaquine against S. mansoni in mice. Being effective against young stages, SYN could be used to prevent early Schistosoma infection.

Topics: Adolescent; Animals; Antimalarials; Cricetinae; Disease Models, Animal; Drug Combinations; Heterocyclic Compounds, 1-Ring; Humans; India; Mice; Microscopy, Electron; Peroxides; Praziquantel; Quinolines; Schistosoma mansoni; Schistosomiasis mansoni; Spiro Compounds

The declining efficacy of artemisinin derivatives against Plasmodium falciparum highlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against both P. falciparum and P. vivax malaria, comparative ex vivo antimalarial activity against Plasmodium isolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP). Ex vivo drug susceptibility was assessed in 46 field isolates (25 P. falciparum and 21 P. vivax). The novel endoperoxide compounds exhibited potent ex vivo activity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC(50)s) in both species (median IC(50)s between 1.9 and 3.6 nM in P. falciparum and 0.7 and 4.6 nM in P. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the two Plasmodium species: whereas their ex vivo activity correlated positively with CQ, PIP, AS, and DHA in P. falciparum, the same was not apparent in P. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistant P. vivax. The high activity against drug-resistant strains of both Plasmodium species confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.

Topics: Adamantane; Amodiaquine; Antimalarials; Artemisinins; Artesunate; Chloroquine; Drug Resistance, Multiple; Heterocyclic Compounds, 1-Ring; Microbial Sensitivity Tests; Peroxides; Plasmodium falciparum; Plasmodium vivax; Quinolines; Spiro Compounds

Using synchronized cultures of Plasmodium falciparum, the time- and concentration-dependent growth changes of erythrocytic parasite stages to DB75, piperaquine, OZ277 and OZ401 were investigated in vitro over a concentration range of approximately 1-100x the IC(50) of piperaquine, OZ277 and OZ401 and approximately 10-1000x the IC(50) of DB75.. The effects of timed in vitro exposure (1, 6, 12 or 24 h) were monitored by the incorporation of [(3)H]hypoxanthine into the parasite nucleic acids.. After 1 h of exposure to the highest concentration of the compound followed by removal of the compound, the growth of all stages of P. falciparum was reduced to < 34% for DB75 and 15% for piperaquine, OZ277 and OZ401 compared with untreated control parasites. At this time point, no stage-specific effects were observed at any of the concentrations. Strong inhibition (< or = 10% growth) of all parasite stages was observed when the parasites were exposed to 10x or 100x the IC(50) of OZ277 and OZ401 for > or = 6 h. At the 6 h incubation time point, DB75 was more active against mature parasite stages, with the IC(50)s of young ring forms elevated up to 7-fold. This trend was observed up to 12 h, but was only statistically significant at the lowest concentration. Interestingly, the stage-specific effect of DB75 on ring forms was not detectable when washing procedures were omitted. This indicates a cytostatic action of DB75 on P. falciparum ring forms.. The current study suggests that P. falciparum ring stages are less susceptible to DB75. A milder and often statistically insignificant stage-specific trend was observed for piperaquine, whereas OZ277 and OZ401 were equally active against the erythrocytic parasite stages.

Topics: Animals; Antimalarials; Benzamidines; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Inhibitory Concentration 50; Peroxides; Plasmodium falciparum; Quinolines; Spiro Compounds; Time Factors

RBx11160 (OZ277) is a promising antimalarial drug candidate that Ranbaxy Laboratories Limited and Medicines for Malaria Venture (MMV) are currently developing as a fixed combination with piperaquine. Here, we describe the in vitro (Plasmodium falciparum) and in vivo (Plasmodium berghei) activities of piperaquine in combination with RBx11160 and artemether. In vitro, both combinations demonstrated a slight tendency towards antagonism with mean sums of fractional inhibitory concentrations (mean Sigma FICs) of 1.5. In vivo, piperaquine and artemether were borderline antagonistic (mean Sigma FIC of 1.4). However, an additive in vivo interaction of piperaquine and RBx11160 (mean Sigma FIC of 1.1) was identified, suggesting that a RBx11160-piperaquine combination therapy in humans should allow each molecule to exert its full antimalarial effect.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Atovaquone; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Erythrocytes; Female; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Mice; Parasitemia; Parasitic Sensitivity Tests; Peroxides; Plasmodium berghei; Plasmodium falciparum; Pyrimethamine; Quinolines; Spiro Compounds