scholarly journals Efficacy and Tolerability Outcomes of a Phase II, Randomized, Open-Label, Multicenter Study of a New Water-Dispersible Pediatric Formulation of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in African Infants

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Nicola Gargano ◽  
Lola Madrid ◽  
Giovanni Valentini ◽  
Umberto D'Alessandro ◽  
Tinto Halidou ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Phase Ii ◽  
Day Treatment ◽  
Plasmodium Falciparum Malaria ◽  
Tablet Formulation ◽  
Tolerability Profile ◽  
Open Label ◽  
Content Type ◽  
Crushed Tablet ◽  
Dispersible Tablet

ABSTRACT Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences (P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.)

scholarly journals Pharmacokinetic and Pharmacodynamic Characteristics of a New Pediatric Formulation of Artemether-Lumefantrine in African Children with Uncomplicated Plasmodium falciparum Malaria

2011 ◽  
Vol 55 (9) ◽  
pp. 3994-3999 ◽  
Author(s):  
Abdoulaye A. Djimdé ◽  
Mamadou Tekete ◽  
Salim Abdulla ◽  
John Lyimo ◽  
Quique Bassat ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Content Type ◽  
African Children ◽  
Crushed Tablet ◽  
Dispersible Tablet ◽  
Pediatric Formulation

ABSTRACTThe pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicatedPlasmodium falciparummalaria. Patients were randomized to 3 different dosing groups (weights of 5 to <15 kg, 15 and <25 kg, and 25 to <35 kg). Treatment was administered twice daily over 3 days. Plasma concentrations of artemether and its active metabolite, dihydroartemisinin (DHA), were determined at 1 and 2 h after the first dose of dispersible (n= 91) and crushed (n= 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (Cmax) for the different body weight groups, with overall means of 175 ± 168 and 190 ± 168 ng/ml, respectively, for artemether and 64.7 ± 58.1 and 63.7 ± 65.0 ng/ml, respectively, for DHA. For lumefantrine, the populationCmaxwere 6.3 μg/ml (dispersible tablet) and 7.7 μg/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 μg · h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHACmaxand parasite clearance time or between the lumefantrineCmaxand the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicatedP. falciparummalaria.

scholarly journals Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment

2015 ◽  
Vol 59 (8) ◽  
pp. 4719-4726 ◽  
Author(s):  
Rithea Leang ◽  
Walter R. J. Taylor ◽  
Denis Mey Bouth ◽  
Lijiang Song ◽  
Joel Tarning ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Falciparum Malaria ◽  
Significant Risk ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Significant Risk Factor ◽  
Open Label ◽  
Content Type

ABSTRACTWestern Cambodia is recognized as the epicenter ofPlasmodium falciparummultidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine (PP), the latest of the artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested forin vitrosusceptibilities to piperaquine and mefloquine, polymorphisms in theK13gene, and the copy number of thePfmdr-1gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (P<10−3). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC50) of PP were independent of treatment outcomes, in contrast to median mefloquine IC50, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM;P= 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying theK13mutant allele (odds ratio [OR], 17.5; 95% confidence interval [CI], 1 to 308;P= 0.04). Our data show evidence ofP. falciparumresistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.)

First long-term results on efficacy and safety of long-acting pasireotide in combination with everolimus in patients with advanced carcinoids (NET) of the lung/thymus: Phase II LUNA trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8574-8574
Author(s):  
Eric Baudin ◽  
Alfredo Berruti ◽  
Mario Giuliano ◽  
Wasat Mansoor ◽  
Catalin Bobirca ◽  
...  
Keyword(s):  
Phase Ii ◽  
Dose Intensity ◽  
Extension Phase ◽  
Long Term Results ◽  
Tolerability Profile ◽  
Efficacy And Safety ◽  
Open Label ◽  
Secondary Endpoints ◽  
Core Phase ◽  
Long Acting

8574 Background: Everolimus (EVE) improves progression-free survival (PFS) in patients (pts) with progressive non-functioning thoracic and digestive advanced neuroendocrine tumors (NET). The LUNA trial aimed to assess the efficacy and safety of long-acting pasireotide (PAS) and EVE alone or in combination in pts with progressive bronchial or thymic carcinoids. Core phase results for primary endpoint (PFS) and secondary endpoints at 9 and 12 months (mo) were previously published. Cumulative data results at the end of the extension phase are presented here. Methods: LUNA was a prospective, multicenter, randomized, open-label, 3-arm, phase II trial. Adult pts with carcinoids of lung/thymus were randomized (1:1:1) to receive either PAS (60 mg/mo i.m.) or EVE (10 mg/day orally) or PAS + EVE. The key secondary endpoints assessed in this extension phase, including all the patients who were still not progressing at 12 months, were PFS, duration of biochemical response (DBR), and biochemical PFS (BPFS). Results: Of the total 124 pts included in the core phase, 41 pts with a median age of 61 years entered the extension phase including PAS (12), EVE (14) and PAS + EVE (15). Lung was the primary site of cancer in 95.1% and 82.9% had non-functioning tumors. Surgery/local or regional therapy was the preferred prior treatment in 63.4% pts. Disease progression was the primary reason for discontinuation among 3 arms with 65.9% in overall extension phase; no pts in PAS arm discontinued due to adverse events (AEs). Mean relative dose intensity (RDI) was higher for PAS (95.6% alone and 90.4% in combination) when compared to EVE (76.6% alone and 72.4% in combination); 38.1% pts in the EVE arm and 43.9% pts in the combination arm with EVE had RDI <70%. PAS +EVE combination showed clinical benefit in terms of PFS and BPFS compared to PAS and EVE alone as shown in Table. At least one dose reduction of PAS or EVE was reported in >50% pts. Most common AEs of any grade regardless of the study drug in PAS +EVE arm were hyperglycemia (87.8%), diarrhea (80.5%), and weight loss (58.5%), while stomatitis was reported in 34.1%. Twelve deaths were reported during the study and up to 56 days from last study treatment dose. Duration of exposure and efficacy. Conclusions: Mature median PFS and BPFS data suggest a benefit of PAS+EVE combination. The safety and tolerability profile of PAS and EVE alone or in combination were consistent with prior experience of these treatments in the oncology setting, with no new safety signals being reported during the study. Post-hoc prognostic studies are ongoing. Clinical trial information: NCT01563354. [Table: see text]

scholarly journals High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children

2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Johan Ursing ◽  
Lars Rombo ◽  
Staffan Eksborg ◽  
Lena Larson ◽  
Anita Bruvoll ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Adverse Events ◽  
Standard Dose ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Chloroquine Resistance ◽  
High Dose ◽  
Qtc Interval ◽  
Content Type ◽  
Qt Interval Prolongation

ABSTRACT Higher chloroquine doses can effectively treat up to 93 to 96% of malaria infections caused by Plasmodium falciparum carrying the resistance-conferring chloroquine resistance transporter (pfcrt) 76T allele. The tolerability of 50 (double the standard dose) and 70 mg/kg total chloroquine doses were assessed in this study. Fifteen 4- to 8-year-old children with uncomplicated malaria were given 10 mg/kg of chloroquine twice daily for 2 days and 5 mg/kg twice daily on the third day. Fifteen additional children were given 5 mg/kg twice daily for 2 more days. Chloroquine concentrations, blood pressure, electrocardiograms (ECGs), parasite density, and adverse events were assessed until day 28. Both dosages were well tolerated, and symptoms resolved by day 3 in parallel with increasing chloroquine concentrations. The median corrected QT (QTc) interval was 12 to 26 ms higher at expected peak concentrations than at day 0 (P < 0.001). Pfcrt 76T was associated with delayed parasite clearance. Day 28 clinical and parasitological responses against P. falciparum with pfcrt 76T were 57% (4/7) and 67% (4/6) after treatment with 50 and 70 mg/kg, respectively. Dosages were well tolerated, and no severe cardiac adverse events occurred. The QTc interval increase was similar to that found in adults taking 25 mg/kg of chloroquine. (This study has been registered at ClinicalTrials.gov under identifier NCT01814423.)

scholarly journals Evaluation of Ebola Virus Inactivation Procedures for Plasmodium falciparum Malaria Diagnostics: TABLE 1

2015 ◽  
Vol 53 (4) ◽  
pp. 1387-1390 ◽  
Author(s):  
Rachel Lau ◽  
Amanda Wang ◽  
Ann Chong-Kit ◽  
Filip Ralevski ◽  
Andrea K. Boggild
Keyword(s):  
Plasmodium Falciparum ◽  
Differential Diagnosis ◽  
Real Time Pcr ◽  
Ebola Virus ◽  
Virus Disease ◽  
Plasmodium Falciparum Malaria ◽  
Virus Inactivation ◽  
Content Type ◽  
Before And After ◽  
Triton X

Plasmodium falciparummalaria is highly endemic in the three most affected countries in the current epidemic of Ebola virus disease (EVD) in West Africa. As EVD and malaria are clinically indistinguishable, both remain part of the differential diagnosis of ill travelers from returning from areas of EVD transmission. We compared the performances of a rapid diagnostic test (BinaxNOW) and real-time PCR withP. falciparum-positive specimens before and after heat and Triton X-100 inactivation, and we documented no loss of sensitivity.

scholarly journals Protein Prenylation and Hsp40 in Thermotolerance of Plasmodium falciparum Malaria Parasites

mBio ◽  
2021 ◽  
Author(s):  
Emily S. Mathews ◽  
Andrew J. Jezewski ◽  
Audrey R. Odom John
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Malaria Parasite ◽  
Plasmodium Falciparum Malaria ◽  
Complex Life Cycle ◽  
Large Temperature ◽  
Protein Prenylation ◽  
Content Type

During its complex life cycle, the malaria parasite survives dramatic environmental stresses, including large temperature shifts. Protein prenylation is required during asexual replication of Plasmodium falciparum , and the canonical heat shock protein 40 protein (HSP40; PF3D7_1437900) is posttranslationally modified with a 15-carbon farnesyl isoprenyl group.

scholarly journals Efficacy and Safety of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for The Treatment of Uncomplicated Plasmodium Falciparum Malaria and Prevalence of Molecular Markers Associated With Artemisinin and Partner Drug Resistance in Uganda

2021 ◽  
Author(s):  
Chris Ebong ◽  
Asadu Sserwanga ◽  
Jane Frances Namuganga ◽  
James Kapisi ◽  
Arthur Mpimbaza ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Falciparum Malaria ◽  
Uncomplicated Malaria ◽  
Plasmodium Falciparum Malaria ◽  
Pharmacokinetic Studies ◽  
Efficacy And Safety ◽  
Open Label ◽  
Serious Adverse Events ◽  
Line Therapy

Abstract Background In Uganda, artemether-lumefantrine (AL) is the first-line therapy and dihydroartemisinin-piperaquine (DP) the second-line therapy for the treatment of uncomplicated malaria. We evaluated the efficacy and safety of AL and DP in the management of uncomplicated Plasmodium falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites from 2018–2019 in Uganda. Methods This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. Results There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2–71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2–94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8–97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9–100%. The uncorrected 42-day efficacy of DP ranged from 73.5–87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1–97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. Conclusions DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration: The trail was also registered with the ISRCTN registry with study Trial no PACTR201811640750761.

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