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 Chloroquine Is Grossly Overdosed and Overused but Well Tolerated in Guinea-Bissau

2008 ◽  
Vol 53 (1) ◽  
pp. 180-185 ◽  
Author(s):  
Johan Ursing ◽  
Poul-Erik Kofoed ◽  
Amabelia Rodrigues ◽  
Yngve Bergqvist ◽  
Lars Rombo
Keyword(s):  
Plasmodium Falciparum ◽  
Adverse Events ◽  
Standard Dose ◽  
High Dose ◽  
Routine Practice ◽  
Double Dose ◽  
Normal Dose ◽  
Guinea Bissau ◽  
High Doses ◽  
Low Prevalence

ABSTRACT High chloroquine doses are commonly prescribed in Guinea-Bissau. Double-dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed, and it was not known if the high doses prescribed in Guinea-Bissau were taken or whether they caused adverse effects. We aimed to determine the dosage of chloroquine commonly prescribed, the doses commonly taken, and whether concentration-dependent adverse events occurred in routine practice. Chloroquine prescriptions by eight physicians and chloroquine intake by 102 children were recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations in whole blood were measured. The median total chloroquine dose prescribed and that reportedly taken were 81 and 77 mg kg−1, respectively. The total dose was usually split into two to three daily doses of 6.6 mg kg−1 each. These were taken unsupervised for a median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50 mg kg−1) of chloroquine was taken. Only 3/102 children had Plasmodium falciparum in the blood at the time of diagnosis and treatment. No severe adverse events were reported. No adverse events were associated with higher chloroquine concentrations. High doses of chloroquine are commonly taken and well tolerated in Guinea-Bissau. Malaria diagnostics are poor, and chloroquine is commonly prescribed to children without parasitemia. Use of high-dose chloroquine is concurrent with an exceptionally low prevalence of chloroquine-resistant P. falciparum.

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 K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Madeline Montenegro ◽  
Aaron T. Neal ◽  
Maritza Posada ◽  
Briegel De las Salas ◽  
Tatiana M. Lopera-Mesa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Content Type ◽  
Drug Effectiveness ◽  
Multiple Copies ◽  
Multidrug Resistance 1 Gene ◽  
Mdr1 Polymorphism ◽  
High Treatment ◽  
Artemisinin Combination Therapies

ABSTRACT High treatment failure rates for Plasmodium falciparum malaria have been reported in Colombia for chloroquine, amodiaquine, and sulfadoxine-pyrimethamine. Artemisinin combination therapies were introduced in 2006 in Colombia, where artemether-lumefantrine (AL) is currently used to treat uncomplicated P. falciparum malaria. Artemisinin (ART) resistance was initially observed in Southeast Asia as an increased parasite clearance time, manifesting as a positive thick-blood smear on day 3 after treatment (D3 positivity). Recently, mutations in the propeller domain of the P. falciparum kelch13 gene (K13 propeller) have been associated with ART resistance. In this study, we surveyed AL effectiveness at D3 and molecular markers of drug resistance among 187 uncomplicated P. falciparum cases in 4 regions of Colombia from June 2014 to July 2015. We found that 3.2% (4/125) of patients showed D3 positivity, 100% (163/163) of isolates carried wild-type K13 propeller alleles, 12.9% (23/178) of isolates had multiple copies of the multidrug resistance 1 gene (mdr1), and 75.8% (113/149) of isolates harbored the double mutant NFSDD mdr1 haplotype (the underlining indicates mutant alleles). These data suggest that ART resistance is not currently suspected in Colombia but that monitoring for lumefantrine resistance and AL failures should continue.

scholarly journals Efficacy and Safety of Pyronaridine-Artesunate for Treatment of Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

2016 ◽  
Vol 60 (7) ◽  
pp. 3884-3890 ◽  
Author(s):  
Rithea Leang ◽  
Sara E. Canavati ◽  
Nimol Khim ◽  
Lasse S. Vestergaard ◽  
Isabelle Borghini Fuhrer ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
World Health ◽  
Rank Test ◽  
Content Type ◽  
Kaplan Meier ◽  
Registration Number ◽  
Health Organization

ABSTRACTPyronaridine-artesunate efficacy for the treatment of uncomplicatedPlasmodium falciparummalaria was assessed in an area of artemisinin resistance in western Cambodia. This nonrandomized, single-arm, observational study was conducted between 2014 and 2015. Eligible patients were adults or children with microscopically confirmedP. falciparuminfection and fever. Patients received pyronaridine-artesunate once daily for 3 days, dosed according to body weight. The primary outcome was an adequate clinical and parasitological response (ACPR) on day 42, estimated by using Kaplan-Meier analysis, PCR adjusted to exclude reinfection. One hundred twenty-three patients were enrolled. Day 42 PCR-crude ACPRs were 87.2% (95% confidence interval [CI], 79.7 to 92.6%) for the overall study, 89.8% (95% CI, 78.8 to 95.3%) for Pursat, and 82.1% (95% CI, 68.4 to 90.2%) for Pailin. Day 42 PCR-adjusted ACPRs were 87.9% (95% CI, 80.6 to 93.2%) for the overall study, 89.8% (95% CI, 78.8 to 95.3%) for Pursat, and 84.0% (95% CI, 70.6 to 91.7%) for Pailin (P= 0.353 by a log rank test). Day 28 PCR-crude and -adjusted ACPRs were 93.2% (95% CI, 82.9 to 97.4%) and 88.1% (95% CI, 75.3 to 94.5%) for Pursat and Pailin, respectively. A significantly lower proportion of patients achieved day 3 parasite clearance in Pailin (56.4% [95% CI, 43.9 to 69.6%]) than in Pursat (86.7% [95% CI, 76.8 to 93.8%];P= 0.0019). Fever clearance was also extended at Pailin versus Pursat (P< 0.0001). Most patients (95.9% [116/121]) harboredP. falciparumkelch13C580Y mutant parasites. Pyronaridine-artesunate was well tolerated; mild increases in hepatic transaminase levels were consistent with data from previous reports. Pyronaridine-artesunate efficacy was below the World Health Organization-recommended threshold at day 42 for medicines with a long half-life (90%) for first-line treatment ofP. falciparummalaria in western Cambodia despite high efficacy elsewhere in Asia and Africa. (This study has been registered at ClinicalTrials.gov under registration number NCT02389439.)

scholarly journals Gastrointestinal Events in High-Dose vs Standard-Dose Influenza Vaccine Recipients

2018 ◽  
Vol 5 (6) ◽  
Author(s):  
H Keipp Talbot ◽  
Andrew J Dunning ◽  
Corwin A Robertson ◽  
Victoria A Landolfi ◽  
David P Greenberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Influenza Vaccine ◽  
Randomized Clinical Trial ◽  
Standard Dose ◽  
High Dose ◽  
Passive Surveillance ◽  
Prospective Randomized Clinical Trial ◽  
Gastrointestinal Events ◽  
Gastrointestinal Adverse Events

Abstract Passive surveillance data had signaled the possibility of gastrointestinal adverse events occurring after the administration of high-dose inactivated influenza vaccine (IIV-HD). However, in a large, prospective randomized clinical trial, rates of serious gastrointestinal events were no greater among IIV-HD recipients than among those who received a standard-dose influenza vaccine.

scholarly journals Emergence and Spread of kelch13 Mutations Associated with Artemisinin Resistance in Plasmodium falciparum Parasites in 12 Thai Provinces from 2007 to 2016

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Theerayot Kobasa ◽  
Eldin Talundzic ◽  
Rungniran Sug-aram ◽  
Patcharida Boondat ◽  
Ira F. Goldman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Mutations ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Resistance Mutations ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
Reduced Ring ◽  
Control And Prevention ◽  
Greater Mekong Subregion

ABSTRACT Artemisinin-based combination therapy (ACT) is the most effective and widely used treatment for uncomplicated Plasmodium falciparum malaria and is a cornerstone for malaria control and prevention globally. Resistance to artemisinin derivatives has been confirmed in the Greater Mekong Subregion (GMS) and manifests as slow parasite clearance in patients and reduced ring stage susceptibility to artemisinins in survival assays. The P. falciparum kelch13 gene mutations associated with artemisinin-resistant parasites are now widespread in the GMS. We genotyped 277 samples collected during an observational study from 2012 to 2016 from eight provinces in Thailand to identify P. falciparum kelch13 mutations. The results were combined with previously reported genotyping results from Thailand to construct a map illustrating the evolution of P. falciparum kelch13 mutations from 2007 to 2016 in that country. Different mutant alleles were found in strains with different geographical origins. The artemisinin resistance-conferring Y493H and R539T mutations were detected mainly in eastern Thailand (bordering Cambodia), while P574L was found only in western Thailand and R561H only in northwestern Thailand. The C580Y mutation was found across the entire country and was nearing fixation along the Thai-Cambodia border. Overall, the prevalence of artemisinin resistance mutations increased over the last 10 years across Thailand, especially along the Thai-Cambodia border. Molecular surveillance and therapeutic efficacy monitoring should be intensified in the region to further assess the extent and spread of artemisinin resistance.

scholarly journals Reduced Polymorphism in the Kelch Propeller Domain in Plasmodium vivax Isolates from Cambodia

2014 ◽  
Vol 59 (1) ◽  
pp. 730-733 ◽  
Author(s):  
Jean Popovici ◽  
Sokheng Kao ◽  
Leanghor Eal ◽  
Sophalai Bin ◽  
Saorin Kim ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Preliminary Data ◽  
Mutant Allele ◽  
Chloroquine Resistance ◽  
Wild Type ◽  
Nonsynonymous Mutation ◽  
Content Type

ABSTRACTPolymorphism in the ortholog gene of thePlasmodium falciparumK13 gene was investigated inPlasmodium vivaxisolates collected in Cambodia. All of them were Sal-1 wild-type alleles except two (2/284, 0.7%), andP. vivaxK12 polymorphism was reduced compared to that of theP. falciparumK13 gene. Both mutant allele isolates had the same nonsynonymous mutation at codon 552 (V552I) and were from Ratanak Kiri province. These preliminary data should encourage additional studies for associating artemisinin or chloroquine resistance and K12 polymorphism.

scholarly journals Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
S. Dian ◽  
V. Yunivita ◽  
A. R. Ganiem ◽  
T. Pramaesya ◽  
L. Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Standard Dose ◽  
Geometric Mean ◽  
Phase Iii ◽  
High Dose ◽  
Treatment Area ◽  
Double Blind ◽  
Time Curve

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)

scholarly journals A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
James S. McCarthy ◽  
Thomas Rückle ◽  
Suzanne L. Elliott ◽  
Emma Ballard ◽  
Katharine A. Collins ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Plasma Concentrations ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Content Type ◽  
Dose Combination ◽  
Combination Study ◽  
Study Support ◽  
New Compounds

ABSTRACT Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.)

scholarly journals Efficacy of dihydroartemisinin/piperaquine and artesunate monotherapy for the treatment of uncomplicated Plasmodium falciparum malaria in Central Vietnam

2020 ◽  
Author(s):  
Eduard Rovira-Vallbona ◽  
Nguyen Van Hong ◽  
Johanna H Kattenberg ◽  
Ro Mah Huan ◽  
Nguyen Thi Thu Hien ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Ex Vivo ◽  
Survival Rates ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Resistance Mutations ◽  
Malaria Burden ◽  
Central Vietnam

Abstract Background Artemisinin-based combination therapies (ACTs) have significantly contributed to reduce Plasmodium falciparum malaria burden in Vietnam, but their efficacy is challenged by treatment failure of dihydroartemisinin/piperaquine ACT in Southern provinces. Objectives To assess the efficacy of dihydroartemisinin/piperaquine for uncomplicated P. falciparum malaria in Gia Lai, Central Vietnam, and determine parasite resistance to artemisinin (ClinicalTrials.gov identifier NCT02604966). Methods Sixty patients received either dihydroartemisinin/piperaquine (4 mg/kg/day, 3 days; n = 33) or artesunate monotherapy (4 mg/kg/day, 3 days; n = 27) followed by dihydroartemisinin/piperaquine (AS + DHA/PPQ). Clinical phenotypes were determined during a 42 day follow-up and analysed together with ex vivo susceptibility to antimalarials and molecular markers of drug resistance. Results Day 3 positivity rate was significantly higher in the AS + DHA/PPQ arm compared with dihydroartemisinin/piperaquine (70.4% versus 39.4%, P = 0.016). Parasite clearance time was 95.2 h (AS + DHA/PPQ) versus 71.9 h (dihydroartemisinin/piperaquine, P = 0.063) and parasite clearance half-life was 7.4 h (AS + DHA/PPQ) versus 7.0 h (dihydroartemisinin/piperaquine, P = 0.140). Adequate clinical and parasitological response at Day 42 was 100% in both arms. By RT–qPCR, 36% (19/53) patients remained positive until Day 7. No recurrences were detected. kelch13 artemisinin resistance mutations were found in 87% (39/45) of isolates and 50% (20/40) were KEL1/C580Y. The piperaquine resistance marker plasmepsin-2 was duplicated in 10.4% (5/48). Isolates from Day 3-positive patients (n = 18) had higher ex vivo survival rates to artemisinin compounds (P &lt; 0.048) and prevalence of kelch13 mutations (P = 0.005) than Day 3-negative patients (n = 5). The WHO definition of artemisinin resistance was fulfilled in 60% (24/40) of cases. Conclusions Although dihydroartemisinin/piperaquine remained effective to treat P. falciparum, the high Day 3 positivity rate and prevalence of KEL1 strains calls for continuous monitoring of dihydroartemisinin/piperaquine efficacy in Central Vietnam.

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